Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. - Longstreth, W T; Arnold, Alice M; Beauchamp, Norman J; Manolio, Teri A; Lefkowitz, David; Jungreis, Charles; Hirsch, Calvin H; O'Leary, Daniel H; Furberg, Curt D (Stroke, 2005)
BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) scans in the elderly commonly show white matter findings that may raise concerns. We sought to document incidence, manifestations, and predictors of worsening white matter grade on serial imaging. METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people aged 65 years and older, of whom 1919 have had extensive initial and follow-up evaluations, including 2 MRI scans separated by 5 years. Scans were read without clinical information in standard side-by-side fashion to determine worsening white matter grade. RESULTS: Worsening was evident in 538 participants (28%), mostly (85%) by 1 grade. Although similar at initial scan, participants with worsening white matter grade, compared with those without, experienced greater decline on modified Mini-Mental State examination and Digit-Symbol Substitution test (both P< or =0.001) after controlling for potential confounding factors, including occurrence of transient ischemic attack or stroke between scans. Independent predictors of worsening white matter grade included cigarette smoking before initial scan and infarct on initial scan. Otherwise, predictors differed according to white matter grade on initial scan. For low initial grade, increased age, increased diastolic blood pressure, increased high-density lipoprotein cholesterol, and decreased low-density lipoprotein cholesterol were associated with increased risk of worsening. For high initial grade, any cardiovascular disease and low ankle-arm index were associated with decreased risk of worsening, whereas use of diuretics and statins were associated with increased risk. CONCLUSIONS: Worsening white matter grade on serial MRI scans in elderly is common, is associated with cognitive decline, and has complex relations with cardiovascular risk factors.
Keywords: Aged; Brain; Cardiovascular Diseases; Cognition Disorders; Female; Humans; Incidence; Leukoaraiosis; Longitudinal Studies; Magnetic Resonance Imaging; Male; Risk Factors; Stroke

Incidence of cardiovascular disease in older Americans: the cardiovascular health study. - Arnold, Alice M; Psaty, Bruce M; Kuller, Lewis H; Burke, Gregory L; Manolio, Teri A; Fried, Linda P; Robbins, John A; Kronmal, Richard A (J Am Geriatr Soc, 2005)
OBJECTIVES: To estimate incidence rates of major cardiovascular disease (CVD) in older Americans. DESIGN: Longitudinal cohort study using prospectively collected data on cardiovascular events. SETTING: Four U.S. communities in the Cardiovascular Health Study (CHS). PARTICIPANTS: Five thousand eight hundred eighty-eight participants in CHS, aged 65 or older at enrollment, including 3,393 women (581 African American) and 2,495 men (343 African American). MEASUREMENTS: At semiannual contacts, participants reported any occurrence of clinical CVD. Medical records were obtained and adjudicated to confirm diagnosis of CVD. RESULTS: During 10 years of follow-up, incidence of coronary heart disease (CHD) per 1,000 person-years was 39.6 (95% confidence interval (CI)=36.4-43.1) in men and 22.3 (95% CI=20.4-24.2) in women. Cumulative event rates for CHD and myocardial infarction for women aged 75 and older at baseline were similar to those for men aged 65 to 74. The overall incidence of stroke was similar for men and women (14.7 (95% CI=13.0-16.6) and 13.7 (95% CI=12.4-15.1) per 1,000 person-years, respectively), but the risk of stroke increased with age more rapidly in women, resulting in a greater cumulative event rate for stroke in women than in men aged 75 and older. The incidence of congestive heart failure increased 9% with each year of age over 65 and was greater than 6% per year in Caucasian men and women aged 85 and older at baseline. Rates were similar in African Americans and Caucasians. CONCLUSION: The occurrence of new CVD in older Americans is high, indicating that preventive efforts need to be maintained into older ages.
Keywords: African Americans; Age Distribution; Aged; Aged, 80 and over; Cardiovascular Diseases; European Continental Ancestry Group; Female; Geriatric Assessment; Humans; Incidence; Longitudinal Studies; Male; Sex Distribution; Survival Rate; United States

Kidney function as a predictor of noncardiovascular mortality. - Fried, Linda F; Katz, Ronit; Sarnak, Mark J; Shlipak, Michael G; Chaves, Paulo H M; Jenny, Nancy Swords; Stehman-Breen, Catherine; Gillen, Dan; Bleyer, Anthony J; Hirsch, Calvin; Siscovick, David; Newman, Anne B (J Am Soc Nephrol, 2005)
Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.
Keywords: Age Factors; Aged; Aged, 80 and over; Cardiovascular Diseases; Cause of Death; Cohort Studies; Confidence Intervals; Creatinine; Cystatin C; Cystatins; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Kidney Function Tests; Longitudinal Studies; Male; Probability; Proportional Hazards Models; Risk Assessment; Severity of Illness Index; Survival Analysis; United States

Morphometric analysis of gray matter volume in demented older adults: exploratory analysis of the cardiovascular health study brain MRI database. - Rosano, C; Becker, J; Lopez, O; Lopez-Garcia, P; Carter, C S; Newman, A; Kuller, L; Aizenstein, H (Neuroepidemiology, 2005)
We tested the feasibility of a fully automated brain MRI voxel count technique--automated labeling pathway (ALP)--in a sample of 15 demented and 13 cognitively normal women (age 75-85 years) participating to the Cardiovascular Health Study (CHS). We hypothesized that ALP would replicate well-established findings of the anatomical correlates of dementia. In particular, we hypothesized that ALP volumetric measures would: (1) significantly differ between cognitively normal and demented women in those brain areas that are established markers for diagnosis of dementia (temporal and medial temporal lobes, hippocampus, amygdala and parahippocampus) but not in other brain areas (e.g., occipital lobe, visual cortex, motor cortex) and (2) correlate with visual ratings of brain disease which have been previously collected as part of the CHS. ALP required minimal operator intervention (input of brain images and verification of misalignments) and employed computer time of about 1 h per brain. ALP detected significant focal volumetric differences in the limbic system (p values between groups for hippocampus and parahippocampus: 0.002 and 0.005, respectively), temporal lobe (p < 0.0001) and caudate (p = 0.009), but not in other brain areas (e.g. occipital lobe, visual or motor cortex). Furthermore, ALP measures of medial temporal lobe atrophy strongly correlated with CHS visual ratings of ventricular enlargement (r(2) = 0.6, p = 0.002 for medial temporal lobe). In conclusion, ALP-detected focal brain atrophy was strongly associated with dementia. Because of its fully automated design, ALP technique is an ideal candidate to assess whether volumetric measures of specific areas can discriminate dementia better than currently available measures of global brain atrophy in large epidemiological studies.
Keywords: Aged; Aged, 80 and over; Brain; Dementia; Educational Status; Feasibility Studies; Female; Health Status; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Organ Size; Reproducibility of Results

Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study. - Reiner, Alexander P; Ziv, Elad; Lind, Denise L; Nievergelt, Caroline M; Schork, Nicholas J; Cummings, Steven R; Phong, Angie; Burchard, Esteban González; Harris, Tamara B; Psaty, Bruce M; Kwok, Pui-Yan (Am J Hum Genet, 2005)
U.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide-polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing-based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.
Keywords: African Americans; Aged; Aging; Algorithms; Cardiovascular Diseases; Cohort Studies; Female; Genetics, Population; Genotype; Humans; Male; Models, Genetic; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Risk Factors; Socioeconomic Factors

Renovascular disease and the risk of adverse coronary events in the elderly: a prospective, population-based study. - Edwards, Matthew S; Craven, Timothy E; Burke, Gregory L; Dean, Richard H; Hansen, Kimberley J (Arch Intern Med, 2005)
BACKGROUND: Renovascular disease is a cause of secondary hypertension and renal insufficiency and is suspected to contribute to morbidity and mortality of coronary heart disease. This investigation prospectively examined associations between renovascular disease and adverse coronary events among a population-based sample of elderly Americans. METHODS: The Cardiovascular Health Study is a prospective, multicenter cohort study of cardiovascular disease risk factors, morbidity, and mortality among Americans older than 65 years. Renal duplex sonography was performed on 870 individuals between January 1995 and February 1997. Renovascular disease was defined as any focal peak systolic velocity of 1.8 m/s or greater (renal artery stenosis) or the absence of a Doppler-shifted signal from an imaged artery (renal artery occlusion). Adverse coronary events were defined as hospitalized angina, fatal or nonfatal myocardial infarction, and coronary revascularization. RESULTS: During a mean follow-up of 14 months, 68 participants experienced incident or recurrent adverse coronary events. The presence of renovascular disease demonstrated a significant relationship with adverse coronary events (hazard ratio, 1.96; 95% confidence interval, 1.00-3.83; P = .05) that remained after controlling for the effects of coexisting atherosclerotic risk factors and prevalent cardiovascular disease. The relationship between renovascular disease and adverse coronary events was not dependent on the effects of increased blood pressure. CONCLUSIONS: The presence of renovascular disease was associated with an increase in the risk of adverse coronary events in this sample. The increment in risk was not dependent on the effects of associated atherosclerotic risk factors, other prevalent cardiovascular disease, or increased blood pressure.
Keywords: Age Distribution; Aged; Aged, 80 and over; Analysis of Variance; Cohort Studies; Comorbidity; Coronary Disease; Female; Geriatric Assessment; Heart Function Tests; Humans; Hypertension, Renovascular; Incidence; Kidney Function Tests; Male; Multivariate Analysis; Probability; Prognosis; Prospective Studies; Risk Assessment; Severity of Illness Index; Sex Distribution; Survival Rate; Ultrasonography, Doppler; United States

Risk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study. - Kennedy, Margaret; Solomon, Cam; Manolio, Teri A; Criqui, Michael H; Newman, Anne B; Polak, Joseph F; Burke, Gregory L; Enright, Paul; Cushman, Mary (Arch Intern Med, 2005)
BACKGROUND: An ankle-brachial index (ABI) of less than 0.9 is a noninvasive measure of lower extremity arterial disease and a predictor of cardiovascular events. Little information is available on longitudinal change in ABI or on risk factors for declining ABI in a community-based population. METHODS: To assess risk factors for ABI decline, we studied 5888 participants in the Cardiovascular Health Study cohort (men and women 65 years or older). We measured ABI in 1992-1993 and again in 1998-1999. At baseline, we excluded individuals with an ABI less than 0.9, ABI greater than 1.4, or confirmed symptomatic lower extremity arterial disease (n = 823). The group with ABI decline included 218 participants with decline greater than 0.15 and to 0.9 or less. The comparison group comprised the remaining 2071 participants with follow-up ABI. RESULTS: The percentage of participants with ABI decline was 9.5% over 6 years of follow-up. The mean +/- SD decline was 0.33 +/- 0.12 in cases of ABI decline and 0.02 +/- 0.13 in non-cases. Independent predictors of ABI decline, reported as odds ratios, were age, 1.96 (95% confidence interval [CI], 1.42-2.71) for 75 to 84 years and 3.79 (95% CI, 1.36-10.5) for those older than 85 years compared with those younger than 75 years; current cigarette use, 1.74 (95% CI, 1.02-2.96); hypertension, 1.64 (95% CI, 1.18-2.28); diabetes, 1.77 (95% CI, 1.14-2.76); higher low-density lipoprotein cholesterol level, 1.60 (95% CI, 1.03-2.51), and lipid-lowering drug use 1.74 (95% CI, 1.05-2.89). CONCLUSION: Worsening lower extremity arterial disease, assessed as ABI decline, occurred in 9.5% of this elderly cohort over 6 years and was associated with modifiable vascular disease risk factors.
Keywords: Aged; Aged, 80 and over; Ankle; Brachial Artery; Cardiovascular Diseases; Female; Humans; Male; Peripheral Vascular Diseases; Risk Assessment; Risk Factors

Sleepiness in patients with moderate to severe sleep-disordered breathing. - Kapur, Vishesh K; Baldwin, Carol M; Resnick, Helaine E; Gottlieb, Daniel J; Nieto, F Javier (Sleep, 2005)
BACKGROUND: Population-based studies suggest that complaints of sleepiness are absent in many individuals with sleep-disordered breathing. We investigated the prevalence of sleepiness as well as factors associated with sleepiness in individuals with moderate to severe sleep-disordered breathing (apnea-hypopnea index > or = 15). DESIGN: Cross-sectional study. SETTING: The Sleep Heart Health Study. PARTICIPANTS: Sleep Heart Health Study participants (N = 6440). MEASUREMENTS AND RESULTS: Sleepiness was defined as an Epworth Sleepiness Scale score >10 or a report of at least frequently feeling unrested or sleepy. Forty-six percent of participants with moderate to severe sleep-disordered breathing (n = 1149) reported sleepiness. Characteristics associated with sleepiness after adjustment for confounders included presence of respiratory disease, shorter self-reported weekday and weekend sleep, sleep durations, complaints of insufficient sleep, complaints of sleep maintenance insomnia, early morning awakening, habitual snoring, and complaints of awakening with leg cramps or leg jerks. Some respiratory polysomnography measures were associated with sleepiness, but sleep-stage percentages and measures of sleep disruption were not. CONCLUSIONS: In this community-based cohort, subjective sleepiness is absent in many individuals with significant sleep-disordered breathing. Comorbid conditions, including respiratory disease, sleep restriction, insomnia, and nocturnal leg complaints, are important risk factors for sleepiness in individuals with moderate to severe sleep-disordered breathing.
Keywords: Aged; Body Mass Index; Cohort Studies; Cross-Sectional Studies; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Oxygen; Polysomnography; Prevalence; Risk Factors; Severity of Illness Index; Sleep Apnea Syndromes; Sleep Arousal Disorders; Sleep Stages; Surveys and Questionnaires

Statin use and the risk of incident dementia: the Cardiovascular Health Study. - Rea, Thomas D; Breitner, John C; Psaty, Bruce M; Fitzpatrick, Annette L; Lopez, Oscar L; Newman, Anne B; Hazzard, William R; Zandi, Peter P; Burke, Gregory L; Lyketsos, Constantine G; Bernick, Charles; Kuller, Lewis H (Arch Neurol, 2005)
BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce cardiovascular risk through mechanisms that might affect the development of dementia. OBJECTIVE: To evaluate whether statin use is associated with a lower risk of dementia compared with never use of lipid-lowering agents (LLAs). DESIGN: Cohort study of community-dwelling adults 65 years and older. The analysis included 2798 participants free of dementia at baseline. MAIN OUTCOME MEASURES: Using Cox proportional hazards regression analysis, we estimated the risk of incident all-cause and type-specific dementia associated with time-dependent statin therapy compared with never use of LLAs. The primary analyses incorporated a 1-year lag between exposure and outcome. Secondary analyses included the final year of exposure and modeled statin use as current use vs nonuse to simulate a case-control approach. RESULTS: Compared with never use of LLAs, ever use of statins was not associated with the risk of all-cause dementia (multivariable-adjusted hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.77-1.52), Alzheimer disease alone (HR, 1.21; 95% CI, 0.76-1.91), mixed Alzheimer disease and vascular dementia (HR, 0.87; 95% CI, 0.44-1.72), or vascular dementia alone (HR, 1.36; 95% CI, 0.61-3.06). In contrast, in secondary analyses, current use of statins compared with nonuse of LLAs was associated with HRs of 0.69 (95% CI, 0.46-1.02) for all-cause dementia and 0.56 (95% CI, 0.35-0.92) for any Alzheimer disease. CONCLUSIONS: In this cohort study, statin therapy was not associated with a decreased risk of dementia. Methodological differences may explain why results of this cohort investigation differ from those of prior case-control studies. Additional investigation is needed to determine whether and for whom statin use may affect dementia risk.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; Dementia; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male

Statins and cognitive function in the elderly: the Cardiovascular Health Study. - Bernick, C; Katz, R; Smith, N L; Rapp, S; Bhadelia, R; Carlson, M; Kuller, L (Neurology, 2005)
OBJECTIVE: To examine the association of statin drug use on cognitive and MRI change in older adults. METHODS: Participants in the Cardiovascular Health Study, a longitudinal study of people age 65 or older, were classified into three groups determined by whether they were taking statin drugs on a continuous basis, intermittently, or not at all. The untreated group was further divided into categories based on National Cholesterol Education Program recommendations for lipid-lowering treatment. Participants with prevalent or incident clinical TIA or stroke or with baseline Modified Mini-Mental State Examination (3MS) scores at or below 80 were excluded. Outcomes examined included rate of change on the 3MS over an average observational period of 7 years, along with changes in MRI white matter grade and measures of atrophy. RESULTS: Three thousand three hundred thirty-four participants had adequate data for analysis. At baseline, the untreated group in which lipid-lowering drug treatment was recommended were slightly older, less likely to be on estrogen replacement, and had higher serum cholesterol and lower 3MS scores than the statin-treated group. The rate of decline on the 3MS was 0.48 point/year less in those taking statins compared with the untreated group for which treatment was recommended (p = 0.069) and 0.49 point/year less in statin users compared with the group in which lipid-lowering treatment was not recommended (p = 0.009). This effect remained after controlling for serum cholesterol levels. One thousand seven hundred thirty participants with baseline 3MS scores of > 80 underwent cranial MRI scans on two occasions separated by 5 years. There was no significant difference in white matter grade change or atrophy measures between groups. CONCLUSION: Statin drug use was associated with a slight reduction in cognitive decline in an elderly population. This relationship could not be completely explained by the effect of statins on lowering of serum cholesterol.
Keywords: Aged; Aged, 80 and over; Aging; Anticholesteremic Agents; Atrophy; Brain; Cholesterol; Cognition Disorders; Cohort Studies; Dementia; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Longitudinal Studies; Male; Memory Disorders; Nootropic Agents; Treatment Outcome

Too much or too little step width variability is associated with a fall history in older persons who walk at or near normal gait speed. - Brach, Jennifer S; Berlin, Jaime E; VanSwearingen, Jessie M; Newman, Anne B; Studenski, Stephanie A (J Neuroeng Rehabil, 2005)
BACKGROUND: Decreased gait speed and increased stride time, stride length, double support time, and stance time variability have consistently been associated with falling whereas step width variability has not been strongly related to falls. The purpose was to examine the linear and nonlinear associations between gait variability and fall history in older persons and to examine the influence of gait speed. METHODS: Gait characteristics and fall history were obtained in 503 older adults (mean age = 79; 61% female) participating in the Cardiovascular Health Study who could ambulate independently. Gait characteristics were recorded from two trials on a 4 meter computerized walkway at the subject's self-selected walking speed. Gait variability was calculated as the coefficient of variation. The presence of a fall in the past 12 months was determined by interview. The nonlinear association between gait variability and fall history was examined using a simple three level classification derived from the distribution of the data and from literature based cut-points. Multivariate logistic regression was used to examine the association between step width variability (extreme or moderate) and fall history stratifying by gait speed (1.0 m/s) and controlling for age and gender. RESULTS: Step length, stance time, and step time variability did not differ with respect to fall history (p > .33). Individuals with extreme step width variability (either low or high step width variability) were more likely to report a fall in the past year than individuals with moderate step width variability. In individuals who walked > or = 1.0 m/s (n = 281), after controlling for age, gender, and gait speed, compared to individuals with moderate step width variability individuals with either low or high step width variability were more likely to have fallen in the past year (OR and 95% CI 4.38 [1.79-10.72]). The association between step width variability and fall history was not significant in individuals who walked < 1.0 m/s (n = 224). CONCLUSION: Extreme (either too little or too much) step width variability is associated with falls in the past year in older persons who walk at or near normal gait speed and not in older persons who walk slowly (< 1.0 m/s).

Utility of 2-Hour Postchallenge Glucose in Predicting Incident Diabetes in Older Adults with Normal Fastng Glucose: 9-Year Follow-up of the Cardiovascular Health Study. - Shaffer, DN; Smith, NL; Barzilay, JI; Savage, PJ; Kuller, LK; Burke, GL (JCOM, 2005)
S.80 (PUBLISHED) Utility of 2-Hour Postchallenge Glucose in Predicting Incident Diabetes in Older Adults with Normal Fastng Glucose: 9-Year Follow-up of the Cardiovascular Health Study. Doug Shaffer Writing Chair CHS Collaborator Proposal Status PUB: (Diab.Med) 2-05; vol 12 no. 2 83-87 Writing Group Doug Shaffer, Nicholas Smith, Joshua Barzilay,Peter Savage, Lewis Kuller, Gregory Burke Keywords Description ABSTRACT Objective We calculated rates of diabetes mellitus (DM, defined as having a fasting glucose (FG) > 126 mg/dl or starting diabetic medication) in older adults > 65 years of age (mean 72.9 years, SD=5.6) with normal FG and evaluated the added value of baseline 2-hour glucose (2HG) level as a predictor of subsequent DM. Methods We evaluated 3563 participants in the Cardiovascular Health Study with normal FG (< 110 mg/dl) and calculated DM incidence rates overall and stratified by baseline 2HG using 3 World Health Organization categories (< 140 [normal], 140-199 [impaired glucose tolerance], and > 200 mg/dl [DM]). Results Ninety-five participants (2.7%) developed DM during a mean follow-up of 8.5 years (median follow-up 9.9 years) corresponding to an overall incidence rate of 3.1 cases per 1000 person-years. The DM incidence rates given baseline 2HG category were 1.7 (< 140 mg/dl), 4.4 (140-199 mg/dl), and 13.1 (> 200 mg/dl) per 1000 person-years, respectively. Individuals with baseline 2HG concentrations of 140-199 mg/dl and > 200 mg/dl were 2.7 times (HR=2.7, 95% CI 1.7, 4.2) and 7.8 times (HR=7.8, 95% CI 4.2, 13.3) more likely to develop DM compared to those with baseline 2HG measure < 140 mg/dl, respectively. These risks changed little after adjusting for baseline FG, age, sex, race, and BMI: HR=2.3 (1.4, 3.8) and HR=7.5 (4.3, 13.1), respectively. Conclusions While 2HG is predictive of DM, the overall DM rate in older adults with normal FG is low. FG without 2HG may be adequate for DM screening in this population.
Keywords: Adult; Diabetes; Glucose; Health

10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study. - Kuller, Lewis H; Arnold, Alice M; Psaty, Bruce M; Robbins, John A; O'Leary, Daniel H; Tracy, Russell P; Burke, Gregory L; Manolio, Teri A; Chaves, Paolo H M (Arch Intern Med, 2006)
BACKGROUND: The incidence of coronary heart disease (CHD) is very high among individuals 65 years or older. METHODS: We evaluated the relationships between measurements of subclinical disease at baseline (1989-1990) and at the third-year follow-up examination (1992-1993) and subsequent incidence of cardiovascular disease and total mortality as of June 2001. Approximately 61% of the participants without clinical cardiovascular disease at baseline had subclinical disease based on our previously described criteria from the Cardiovascular Health Study. RESULTS: The incidence of CHD was substantially increased for participants with subclinical disease compared with those who had no subclinical disease: 30.5 per 1000 person-years with and 16.3 per 1000 person-years without for white individuals, and 31.2 per 1000 person-years with and 12.5 per 1000 person-years without for black individuals. The risk persisted over the entire follow-up period. Incidence rates were higher for men than for women with or without subclinical disease, but there was little difference in rates for black individuals and white individuals. CONCLUSIONS: In multivariable models, subclinical disease at baseline remained a significant predictor of CHD in both men and women; the hazard ratios (95% confidence intervals) of their relative risks were 1.64 (1.30-2.06) and 1.49 (1.21-1.84), respectively. The presence of subclinical disease substantially increased the risk of subsequent CHD for participants with hypertension, diabetes mellitus, or elevated C-reactive protein. In summary, subclinical disease is very prevalent among older individuals, is independently associated with risk of CHD even over a 10-year follow-up period, and substantially increases the risk of CHD among participants with hypertension or diabetes mellitus.
Keywords: African Continental Ancestry Group; Aged; Blood Chemical Analysis; Cardiovascular Diseases; Comorbidity; Coronary Disease; Echocardiography; European Continental Ancestry Group; Female; Follow-Up Studies; Humans; Incidence; Male; Multivariate Analysis; Prevalence; Proportional Hazards Models; Regression Analysis; Risk Factors; Sex Distribution; United States

Adjusted mortality after hip fracture: From the cardiovascular health study. - Robbins, John A; Biggs, Mary L; Cauley, Jane (J Am Geriatr Soc, 2006)
OBJECTIVES: To estimate the risk of death associated with hip fracture (HFx), stratifying by sex and time since fracture. DESIGN: Prospective cohort study compared participants with and without hip fracture, matched on sex, age, race, recruitment period, and time since enrollment. SETTING: The Cardiovascular Health Study, a more-than-15-year longitudinal study of 5,888 older individuals from four U.S. sites. PARTICIPANTS: Three hundred seventy-nine individuals with HFx were compared with 1,134 without HFx. MEASUREMENTS: Extended Cox models were used to estimate mortality hazard ratios (HRs) for different periods after fracture, adjusting for prefracture health. RESULTS: Age- and race-adjusted excess mortality was 9% in women and 24% in men 1 year after fracture, and 24% in women and 26% men 5 years postfracture. Multivariable-adjusted HRs of mortality associated with HFx in women were 7.1 (95% confidence interval (CI) = 2.3-21.5), 2.1 (95% CI = 1.0-4.1), 1.4 (95% CI = 1.1-2.0), and 1.0 (95% CI = 0.6-1.5) for 0 to 1 months, 2 to 6 months, 7 months to 4 years, and 5 to 8 years, respectively, after index date. In men, respective HRs for the same time periods were 39.9 (95% CI = 5.2-308.7), 3.8 (95% CI = 1.4-10.3), 1.1 (95% CI = 0.7-1.8), and 1.0 (95% CI = 0.3-2.7). HRs adjusted for age and race were 20% to 40% higher. CONCLUSION: The risk of mortality was highest in the first 6 months after HFx. In men, the risk of death approximated that of men without HFx after 6 months; in women, a moderately greater risk persisted through the fourth year. Although the mortality pattern was different in women and men, excess mortality 5 years postfracture was similar for both sexes.
Keywords: Aged; Cohort Studies; Female; Health Status; Health Surveys; Hip Fractures; Humans; Male; Mortality; Multicenter Studies as Topic; Proportional Hazards Models; Sex Distribution; Time Factors; United States

African ancestry, socioeconomic status, and kidney function in elderly African Americans: a genetic admixture analysis. - Peralta, Carmen A; Ziv, Elad; Katz, Ronit; Reiner, Alex; Burchard, Esteban González; Fried, Linda; Kwok, Pui-Yan; Psaty, Bruce; Shlipak, Michael (J Am Soc Nephrol, 2006)
Kidney disease is a major public health problem in the United States that affects African Americans disproportionately. The relative contribution of environmental and genetic factors to the increased burden of kidney disease among African Americans is unknown. The associations of genetic African ancestry and socioeconomic status with kidney function were studied cross-sectionally and longitudinally among 736 community-dwelling African Americans who were aged >65 yr and participating in the Cardiovascular Health Study. Genetic African ancestry was determined by genotyping 24 biallelic ancestry-informative markers and combining this information statistically to generate an estimate of ancestry for each individual. Kidney function was evaluated by cystatin C and estimated GFR (eGFR) using the Modification of Diet in Renal Disease equation. Longitudinal changes in serum creatinine and eGFR were estimated using baseline and follow-up values. In cross-sectional analyses, there was no association between genetic African ancestry and either measure of kidney function (P = 0.36 for cystatin C and 0.68 for eGFR). African ancestry was not associated with change in serum creatinine > or =0.05 mg/dl per yr (odds ratio [OR] 0.94; 95% confidence interval [CI] 0.83 to 1.06) or with change in eGFR > or =3 ml/min per 1.73 m(2) per yr (OR 1.02; 95% CI 0.92 to 1.13). In contrast, self reported African-American race was strongly associated with increased risk for kidney disease progression compared with white individuals for change in creatinine (OR 1.77; 95% CI 1.33 to 2.36) and for change in eGFR (OR 3.21; 95% CI 2.54 to 4.06). Among self-identified African Americans, low income (< US dollars 8000/yr) was strongly associated with prevalent kidney dysfunction by cystatin C >1.29 g/dl (adjusted OR 2.7; 95% CI 1.0 to 7.5) or by eGFR <60 ml/min per 1.73 m(2) (adjusted OR 3.2; 95% CI 1.1 to 9.4) compared with those with incomes >US dollars 35,000/yr. Alleles that are known to be present more frequently in the African ancestral group were not associated with kidney dysfunction or kidney disease progression. Rather, kidney dysfunction in elderly African Americans seems more attributable to differences in environmental and social factors.
Keywords: African Americans; Aged; Creatinine; Cross-Sectional Studies; Cystatin C; Cystatins; Disease Progression; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Linear Models; Longitudinal Studies; Male; Social Class

Alcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study. - Mukamal, Kenneth J; Chung, Hyoju; Jenny, Nancy S; Kuller, Lewis H; Longstreth, W T; Mittleman, Murray A; Burke, Gregory L; Cushman, Mary; Psaty, Bruce M; Siscovick, David S (J Am Geriatr Soc, 2006)
OBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome. DESIGN: Prospective cohort study. SETTING: Four U.S. communities. PARTICIPANTS: Four thousand four hundred ten adults aged 65 and older free of cardiovascular disease at baseline. MEASUREMENTS: Risk of incident myocardial infarction or coronary death according to self-reported consumption of beer, wine, and spirits ascertained yearly. RESULTS: During an average follow-up period of 9.2 years, 675 cases of incident myocardial infarction or coronary death occurred. Compared with long-term abstainers, multivariate relative risks of 0.90 (95% confidence interval (CI)=0.71-1.14), 0.93 (95% CI=0.73-1.20), 0.76 (95% CI=0.53-1.10), and 0.58 (95% CI=0.39-0.86) were found in consumers of less than one, one to six, seven to 13, and 14 or more drinks per week, respectively (P for trend=.007). Associations were similar for secondary coronary outcomes, including nonfatal and fatal events. No strong mediators of the association were identified, although fibrinogen appeared to account for 9% to 10% of the relationship. The associations were statistically similar for intake of wine, beer, and liquor and generally similar in subgroups, including those with and without an apolipoprotein E4 allele. CONCLUSION: In this population, consumption of 14 or more drinks per week was associated with the lowest risk of coronary heart disease, although clinicians should not recommend moderate drinking to prevent coronary heart disease based on this evidence alone, because current National Institute on Alcohol Abuse and Alcoholism guidelines suggest that older adults limit alcohol intake to one drink per day.
Keywords: Aged; Alcohol Drinking; Apolipoproteins E; Beer; Cohort Studies; Coronary Disease; Female; Genotype; Health Behavior; Humans; Incidence; Male; Residence Characteristics; Risk Assessment; Socioeconomic Factors; United States; Wine

The association of alcohol consumption and incident heart failure: the Cardiovascular Health Study. - Bryson, Chris L; Mukamal, Kenneth J; Mittleman, Murray A; Fried, Linda P; Hirsch, Calvin H; Kitzman, Dalane W; Siscovick, David S (J Am Coll Cardiol, 2006)
OBJECTIVES: We investigated the association between alcohol consumption and incident congestive heart failure (CHF) both overall and after adjusting for incident myocardial infarction (MI). BACKGROUND: Moderate alcohol consumption has been associated with lower risk of CHF and MI. METHODS: The Cardiovascular Health study, a prospective cohort study of cardiovascular disease risk factors and outcomes, followed 5,888 subjects > or =65 years old for 7 to 10 years. Cox models were used to estimate the adjusted risk of CHF by reported alcohol consumption. RESULTS: There were 5,595 subjects at baseline at risk for incident CHF with alcohol data and 1,056 events during follow-up. Compared with abstainers, the adjusted risk of CHF was lower among subjects who reported consuming 1 to 6 drinks per week (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.67 to 1.00, p = 0.05) and 7 to 13 drinks per week (HR 0.66, 95% CI 0.47 to 0.91, p = 0.01). Time-dependent adjustment for incident MI altered only slightly the association between moderate alcohol consumption and CHF (for 1 to 6 drinks per week, HR 0.84, 95% CI 0.65 to 1.04; for 7 to 13 drinks per week, HR 0.69, 95% CI 0.49 to 0.99). Baseline former drinkers had a higher risk of CHF than abstainers (HR 1.51, p < 0.01), but those who quit during the study did not have a higher risk (HR 0.83, 95% CI 0.66 to 1.03). CONCLUSIONS: Moderate alcohol use is associated with a lower risk of incident CHF among older adults, even after accounting for incident MI and other factors.
Keywords: Aged; Alcohol Drinking; Chi-Square Distribution; Comorbidity; Female; Heart Failure; Humans; Life Style; Male; Multicenter Studies as Topic; Myocardial Infarction; Proportional Hazards Models; Risk Factors; Smoking

The association of markers of inflammation with weight change in older adults: the Cardiovascular Health Study. - Barzilay, J I; Forsberg, C; Heckbert, S R; Cushman, M; Newman, A B (Int J Obes (Lond), 2006)
OBJECTIVE: Elevated levels of inflammation factors often precede weight loss and may be causally related to it. Newer studies suggest that elevated levels of inflammation factors also precede weight gain. In this study, we examined whether inflammation factors are elevated in individuals, age >or=65 years, who lost or gained >5% weight over a 3 year follow-up period compared to those with stable weight. SUBJECTS: In total, 3254 participants in the Cardiovascular Health Study whose weight was stable; 661 who gained >5% weight; and 842 who lost >5% weight. MEASUREMENTS: C-reactive protein (CRP), fibrinogen, factor VIIIc, white blood cell (WBC) and platelet counts, and interleukin-6 (IL-6) levels. RESULTS: As compared to participants whose weight was stable, those who lost >5% weight had higher baseline CRP concentration (1.05 (95% CI, 1.02, 1.08) per interquartile increase) and WBC count (1.10 (1.01, 1.19) per interquartile increase) on adjusted analyses. Those who gained >5% weight had higher baseline CRP (1.05 (1.01, 1.08)), fibrinogen (1.13 (1.01, 1.27)), and factor VIIIc (1.15 (1.03, 1.30)). CONCLUSIONS: Inflammation factors are associated with weight gain and weight loss in older individuals. These findings suggest that subclinical inflammation, or unknown factors associated with subclinical inflammation, contribute to weight change.
Keywords: Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Factor VIII; Female; Fibrinogen; Humans; Inflammation; Interleukin-6; Leukocyte Count; Male; Platelet Count; Weight Gain; Weight Loss

The association of microalbuminuria with clinical cardiovascular disease and subclinical atherosclerosis in the elderly: the Cardiovascular Health Study. - Cao, Jie J; Barzilay, Joshua I; Peterson, Do; Manolio, Teri A; Psaty, Bruce M; Kuller, Lewis; Wexler, Jason; Bleyer, Anthony J; Cushman, Mary (Atherosclerosis, 2006)
PURPOSE: Microalbuminuria (MA) is a risk factor for cardiovascular disease (CVD). It is not known whether this association is due to the effect of MA on the development of subclinical atherosclerosis or whether MA destabilizes subclinical atherosclerosis, leading to clinical events. METHODS: In a cross-sectional analysis we evaluated 3312 Cardiovascular Health Study participants, age >or=65 years, who had MA testing. Participants were divided into three groups: those without diabetes or hypertension (33%), those with hypertension (52%) and those with diabetes, with or without hypertension (15%). Clinical CVD was defined as presence of coronary heart disease (angina, MI, CABG, PTCA), cerebrovascular disease (stroke, TIA) and peripheral arterial disease (requiring intervention). Among those without clinical disease, subclinical atherosclerosis was defined as increased carotid artery intima-media thickness, decreased ankle arm index or increased left ventricular mass. RESULTS: In each of the three groups of participants, the adjusted odds of prevalent clinical CVD in the presence of MA was 1.70-1.80-fold increased, independent of other risk factors. MA was not associated with risk of subclinical atherosclerosis in those without hypertension or diabetes (OR 1.14 [95% CI 0.59, 2.23]), whereas it was associated with subclinical atherosclerosis in those with hypertension (OR 1.58 [95% CI 1.08, 2.30]) or diabetes (OR 2.51 [95% CI 1.27, 4.94]). CONCLUSION: In the absence of hypertension or diabetes, MA was associated with clinical CVD but not with subclinical atherosclerosis. Thus, a hypothesis may be made that the mechanism of association of MA with clinical vascular disease involves destabilization of the vasculature, leading to clinical disease.
Keywords: Aged; Aged, 80 and over; Albuminuria; Atherosclerosis; Cardiovascular Diseases; Coronary Disease; Diabetes Mellitus; Female; Humans; Hypertension; Male; Peripheral Vascular Diseases; Prevalence; Risk Factors; Stroke; United States

Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. - Mehra, Reena; Benjamin, Emelia J; Shahar, Eyal; Gottlieb, Daniel J; Nawabit, Rawan; Kirchner, H Lester; Sahadevan, Jayakumar; Redline, Susan (Am J Respir Crit Care Med, 2006)
RATIONALE: Sleep-disordered breathing recurrent intermittent hypoxia and sympathetic nervous system activity surges provide the milieu for cardiac arrhythmia development. OBJECTIVE: We postulate that the prevalence of nocturnal cardiac arrhythmias is higher among subjects with than without sleep-disordered breathing. METHODS: The prevalence of arrhythmias was compared in two samples of participants from the Sleep Heart Health Study frequency-matched on age, sex, race/ethnicity, and body mass index: (1) 228 subjects with sleep-disordered breathing (respiratory disturbance index>or=30) and (2) 338 subjects without sleep-disordered breathing (respiratory disturbance index<5). RESULTS: Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy (nonsustained ventricular tachycardia or bigeminy or trigeminy or quadrigeminy) were more common in subjects with sleep-disordered breathing compared with those without sleep-disordered breathing: 4.8 versus 0.9% (p=0.003) for atrial fibrillation; 5.3 versus 1.2% (p=0.004) for nonsustained ventricular tachycardia; 25.0 versus 14.5% (p=0.002) for complex ventricular ectopy. Compared with those without sleep-disordered breathing and adjusting for age, sex, body mass index, and prevalent coronary heart disease, individuals with sleep-disordered breathing had four times the odds of atrial fibrillation (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.03-15.74), three times the odds of nonsustained ventricular tachycardia (OR, 3.40; 95% CI, 1.03-11.20), and almost twice the odds of complex ventricular ectopy (OR, 1.74; 95% CI, 1.11-2.74). A significant relation was also observed between sleep-disordered breathing and ventricular ectopic beats/h (p<0.0003) considered as a continuous outcome. CONCLUSIONS: Individuals with severe sleep-disordered breathing have two- to fourfold higher odds of complex arrhythmias than those without sleep-disordered breathing even after adjustment for potential confounders.
Keywords: Aged; Aged, 80 and over; Arrhythmias, Cardiac; Circadian Rhythm; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Odds Ratio; Polysomnography; Prevalence; Retrospective Studies; Risk Factors; Severity of Illness Index; Sleep; Sleep Apnea, Obstructive

Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. - Lange, Leslie A; Carlson, Christopher S; Hindorff, Lucia A; Lange, Ethan M; Walston, Jeremy; Durda, J Peter; Cushman, Mary; Bis, Joshua C; Zeng, Donglin; Lin, Danyu; Kuller, Lewis H; Nickerson, Deborah A; et al. (JAMA, 2006)
CONTEXT: C-reactive protein (CRP) is an inflammation protein that may play a role in the pathogenesis of cardiovascular disease (CVD). OBJECTIVE: To assess whether polymorphisms in the CRP gene are associated with plasma CRP, carotid intima-media thickness (CIMT), and CVD events. DESIGN, SETTING, AND PARTICIPANTS: In the prospective, population-based Cardiovascular Health Study, 4 tag single-nucleotide polymorphisms (SNPs) (1919A/T, 2667G/C, 3872G/A, 5237A/G) were genotyped in 3941 white (European American) participants and 5 tag SNPs (addition of 790A/T) were genotyped in 700 black (African American) participants, aged 65 years or older, all of whom were without myocardial infarction (MI) or stroke before study entry. Median follow-up was 13 years (1989-2003). MAIN OUTCOME MEASURES: Baseline CIMT; occurrence of MI, stroke, and CVD mortality during follow-up. RESULTS: In white participants, 461 incident MIs, 491 incident strokes, and 490 CVD-related deaths occurred; in black participants, 67 incident MIs, 78 incident strokes, and 75 CVD-related deaths occurred. The 1919T and 790T alleles were associated with higher CRP levels in white and black participants, respectively. The 3872A allele was associated with lower CRP levels in both populations, and the 2667C allele was associated with lower CRP levels in white participants only. There was no association between CIMT and any CRP gene polymorphism in either population. In white participants, the 1919T allele was associated with increased risk of stroke for TT vs AA (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.06-1.87) and for CVD mortality (HR, 1.40; 95% CI, 1.10-1.90). In black participants, homozygosity for the 790T allele was associated with a 4-fold increased risk of MI compared with homozygosity for the 790A allele (95% CI, 1.58-10.53). The minor alleles of the 2 SNPs associated with lower plasma CRP concentration in white participants (2667C and 3872A) were associated with decreased risk of CVD mortality. CONCLUSIONS: Genetic variation in the CRP gene is associated with plasma CRP levels and CVD risk in older adults.
Keywords: African Continental Ancestry Group; Aged; C-Reactive Protein; Cardiovascular Diseases; Carotid Arteries; European Continental Ancestry Group; Female; Genotype; Humans; Male; Myocardial Infarction; Polymorphism, Single Nucleotide; Proportional Hazards Models; Risk; Stroke; Tunica Intima

Association of usual sleep duration with hypertension: the Sleep Heart Health Study. - Gottlieb, Daniel J; Redline, Susan; Nieto, F Javier; Baldwin, Carol M; Newman, Anne B; Resnick, Helaine E; Punjabi, Naresh M (Sleep, 2006)
STUDY OBJECTIVES: Limited experimental data suggest that sleep restriction acutely elevates blood pressure; however, little is known about the relationship between usual sleep duration and hypertension. This study assesses the relationship between usual sleep duration and hypertension in a community-based cohort. DESIGN: Cross-sectional observational study. SETTING: The Sleep Heart Health Study, a community-based prospective study of the cardiovascular consequences of sleep-disordered breathing. PARTICIPANTS: Two thousand eight hundred thirteen men and 3097 women, aged 40 to 100 years. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Usual weekday and weekend sleep durations were obtained by questionnaire, and their weighted average were categorized as less than 6, 6 to less than 7, 7 to less than 8, 8 to less than 9, and 9 or more hours per night. Hypertension was defined as a systolic blood pressure of 140 mm Hg or greater, a diastolic blood pressure of 90 mm Hg or greater, or use of medication to treat hypertension. The relationship between sleep duration and hypertension was examined using categorical logistic regression with adjustment for age, sex, race, apnea-hypopnea index, and body mass index. Compared to subjects sleeping 7 to less than 8 hours per night, those sleeping less than 6 and between 6 and 7 hours per night had adjusted odds ratios for hypertension of 1.66 (95% confidence interval 1.35-2.04) and 1.19 (1.02-1.39), respectively, whereas those sleeping between 8 and 9 and 9 or more hours per night had adjusted odds ratios for hypertension of 1.19 (1.04-1.37) and 1.30 (1.04-1.62), respectively (p < .0001 for association of sleep duration with hypertension). These associations persisted when analyses were further adjusted for caffeine and alcohol consumption, current smoking, insomnia symptoms, depression symptoms, sleep efficiency, and prevalent diabetes mellitus or cardiovascular disease. CONCLUSIONS: Usual sleep duration above or below the median of 7 to less than 8 hours per night is associated with an increased prevalence of hypertension, particularly at the extreme of less than 6 hours per night.
Keywords: Adult; Aged; Aged, 80 and over; Body Mass Index; Cohort Studies; Comorbidity; Cross-Sectional Studies; Female; Health Surveys; Humans; Hypertension; Male; Middle Aged; Odds Ratio; Prospective Studies; Sleep; Sleep Apnea, Obstructive; Sleep Deprivation; Statistics as Topic

Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death. - Sotoodehnia, Nona; Siscovick, David S; Vatta, Matteo; Psaty, Bruce M; Tracy, Russell P; Towbin, Jeffrey A; Lemaitre, Rozenn N; Rea, Thomas D; Durda, J Peter; Chang, Joel M; Lumley, Thomas S; Kuller, Lewis H; et al. (Circulation, 2006)
BACKGROUND: Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk. METHODS AND RESULTS: In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study. CONCLUSIONS: Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.
Keywords: African Continental Ancestry Group; Aged; Case-Control Studies; Death, Sudden, Cardiac; European Continental Ancestry Group; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Glutamine; Haplotypes; Homozygote; Humans; Male; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-2; Reproducibility of Results

Cardiovascular morbidity and mortality in community-dwelling elderly individuals with calcification of the fibrous skeleton of the base of the heart and aortosclerosis (The Cardiovascular Health Study). - Barasch, Eddy; Gottdiener, John S; Marino Larsen, Emily K; Chaves, Paulo H M; Newman, Anne B (Am J Cardiol, 2006)
In the elderly, mitral annular calcification (MAC) and aortic valve sclerosis (AVS) are associated with increased cardiovascular morbidity and mortality. Aortic annular calcification (AAC) commonly occurs with MAC. However, the prognostic value of AAC, singly or in combination with MAC and AVS, for incident cardiovascular disease and mortality is unknown. From the Cardiovascular Health Study, we analyzed 3,782 participants (76 +/- 5 years of age, 60% women) who had an echocardiogram at the 1994 to 1995 examination and who were prospectively followed for an average of 6.6 years (range 0.01 to 8.5). All 3 calcification categories were associated with incident congestive heart failure (MAC: hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.35 to 2.18, AAC: HR 1.62, 95% CI 1.28 to 2.06, and AVS: HR 1.50, 95% CI 1.19 to 1.89) and death. A stronger association with incident cardiovascular disease and mortality was observed with a larger number of calcification categories and with increased MAC severity. Moreover, in the participants with prevalent cardiovascular disease at echocardiographic examination (n = 1,054), MAC and AAC were still associated with cardiovascular mortality (MAC: HR 1.91, 95% CI 1.04 to 3.50; AAC: HR 2.11, 95% CI 1.16 to 3.85) even in fully adjusted models. In conclusion, MAC, AAC, and AVS are associated with a significant risk of incident congestive heart failure, cardiovascular and all-cause mortalities, and worse outcome in older patients with preexisting cardiovascular disease. Elderly patients with these findings represent a high-risk group and may require close medical attention.
Keywords: Aged; Aortic Valve; Calcinosis; Echocardiography; Female; Follow-Up Studies; Heart Failure; Heart Valve Diseases; Humans; Male; Mitral Valve; Prospective Studies; Risk Factors; Sclerosis; Severity of Illness Index; United States

Clinical significance of calcification of the fibrous skeleton of the heart and aortosclerosis in community dwelling elderly. The Cardiovascular Health Study (CHS). - Barasch, Eddy; Gottdiener, John S; Larsen, Emily K Marino; Chaves, Paulo H M; Newman, Anne B; Manolio, Teri A (Am Heart J, 2006)
BACKGROUND: Mitral annular calcification (MAC), aortic annular calcification (AAC), and aortic valve sclerosis (AVS) are associated with aging, and MAC and AVS are markers of advanced atherosclerosis. No studies have examined the prevalence and the clinical relevance of all 3 forms of calcification in a single free-living elderly population. METHODS: We used 2-dimensional echocardiography to evaluate MAC, AAC, AVS and all 3 combined in 3929 participants, mean age 76 +/- 5 years, 60% women, in the Cardiovascular Health Study, a prospective community-based observational study designed to assess cardiovascular disease (CVD) risk factors and outcomes in elderly persons. RESULTS: Mitral annular calcification was found in 1640 (42 %) subjects, AAC in 1710 (44 %), AVS in 2114 (54 %), and all 3 combined in 662 (17 %). The participants with these findings were older than those without them, and those with MAC had worse cardiovascular, renal, metabolic, and functional profile than those with AAC and AVS. Age-, sex-, and race-adjusted logistic regression analysis found a significant association between the 3 calcification categories and CVD, the strongest being between the combined group with congestive heart failure (odds ratio 2.04, 95% CI 1.34-3.09). In highly adjusted models, only MAC was associated with CVD, and the strength of association was related to the severity of MAC. CONCLUSIONS: In free-living elderly, MAC, AAC, and AVS are highly prevalent and are associated with CVD. Mitral annular calcification in particular has strong association with CVD, and with an adverse biomedical profile.
Keywords: Aged; Aortic Valve; Calcinosis; Female; Heart Valve Diseases; Humans; Male; Mitral Valve; Prevalence; Prospective Studies; Risk Factors; Sclerosis; Ultrasonography

Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study. - Barnes, Deborah E; Alexopoulos, George S; Lopez, Oscar L; Williamson, Jeff D; Yaffe, Kristine (Arch Gen Psychiatry, 2006)
CONTEXT: Depressive symptoms are common in patients with dementia and may be associated with increased risk of developing dementia. It has been hypothesized that depressive symptoms and dementia may be attributable to underlying vascular disease in some older persons. OBJECTIVES: To test the hypotheses (1) that depressive symptoms are associated with increased risk of developing mild cognitive impairment (MCI), a preclinical state that often precedes dementia, and (2) that the association between depressive symptoms and MCI is attributable to underlying vascular disease. DESIGN: Prospective, population-based, longitudinal study. SETTING: Random sample of adults 65 years or older recruited from 4 US communities. PARTICIPANTS: Subjects were 2220 participants in the Cardiovascular Health Study Cognition Study with high cognitive function at baseline. Depressive symptoms were measured at baseline using the 10-item Center for Epidemiological Studies Depression Scale and were classified as none (0-2 points), low (3-7 points), and moderate or high (>/=8 points). Vascular disease measures at baseline included confirmed history of stroke, transient ischemic attack, diabetes mellitus, or hypertension; carotid artery stenosis; ankle-arm blood pressure index; and small or large infarcts or white matter disease on cerebral magnetic resonance imaging. Mild cognitive impairment was diagnosed after 6 years of follow-up based on the consensus of a team of dementia experts using standard clinical criteria. MAIN OUTCOME MEASURE: Diagnosis of MCI. RESULTS: Depressive symptoms at baseline were associated with increased risk of MCI (10.0%, 13.3%, and 19.7% for those with no, low, and moderate or high depressive symptoms, respectively). This association was diminished only slightly by adjustment for vascular disease measures and demographics. Vascular disease measures also were associated with increased risk of MCI, and these associations were not diminished by adjustment for depressive symptoms or demographics. CONCLUSION: Depressive symptoms were associated with increased risk of MCI, and this association was independent of underlying vascular disease.
Keywords: Aged; Cerebrovascular Disorders; Cognition Disorders; Comorbidity; Dementia; Dementia, Vascular; Depressive Disorder; Female; Follow-Up Studies; Geriatric Assessment; Humans; Longitudinal Studies; Male; Prospective Studies; Psychiatric Status Rating Scales; Risk Factors; Sampling Studies; Vascular Diseases

Education and the cognitive decline associated with MRI-defined brain infarct. - Elkins, J S; Longstreth, W T; Manolio, T A; Newman, A B; Bhadelia, R A; Johnston, S C (Neurology, 2006)
OBJECTIVE: To assess whether educational attainment, a correlate of cognitive reserve, predicts the amount of cognitive decline associated with a new brain infarct. METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of people aged 65 years and older. Cognitive function was measured annually using the Modified Mini-Mental State Examination (3MS) and the Digit-Symbol Substitution Test (DSST). The authors tested whether education level modified 1) the cross-sectional association between cognitive performance and MRI-defined infarct and 2) the change in cognitive function associated with an incident infarct at a follow-up MRI. RESULTS: In cross-sectional analysis (n = 3,660), MRI-defined infarct was associated with a greater impact on 3MS performance in the lowest education quartile when compared with others (p for heterogeneity = 0.012). Among those with a follow-up MRI who had no infarct on initial MRI (n = 1,433), education level was not associated with the incidence, size, or location of new brain infarct. However, a new MRI-defined infarct predicted substantially greater decline in 3MS scores in the lowest education group compared with the others (6.3, 95% CI 4.4- to 8.2-point decline vs 1.7, 95% CI 0.7- to 2.7-point decline; p for heterogeneity < 0.001). Higher education was not associated with smaller declines in DSST performance in the setting of MRI-defined infarct. CONCLUSIONS: Education seems to modify an individual's decline on a test of general cognitive function when there is incident brain infarct. These findings are consistent with the hypothesis that cognitive reserve influences the impact of vascular injury in the brain.
Keywords: Cerebral Infarction; Cognition Disorders; Cross-Sectional Studies; Educational Status; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Neuropsychological Tests

Lipoprotein subclass and particle size differences in Afro-Caribbeans, African Americans, and white Americans: associations with hepatic lipase gene variation. - Miljkovic-Gacic, Iva; Bunker, Clareann H; Ferrell, Robert E; Kammerer, Candace M; Evans, Rhobert W; Patrick, Alan L; Kuller, Lewis H (Metabolism, 2006)
Despite a higher prevalence of coronary heart disease risk factors, men of African origin have less coronary atherosclerosis, as measured by coronary calcification, than whites. In part, this is thought to be because of the less atherogenic lipoprotein profile observed in men of African origin, characterized by lower triglycerides and higher high-density lipoprotein (HDL) cholesterol. We hypothesized that the -514C>T polymorphism in the hepatic lipase gene (LIPC) plays a significant role in determining a less atherogenic lipoprotein profile observed in men of African origin. Previously conducted studies of the LIPC -514C>T polymorphism in African Americans may have been confounded by a higher level of European admixture; in addition, the results from these studies do not necessarily apply to other African populations because gene-environment interactions may differ. Thus, we compared nuclear magnetic resonance spectroscopy-measured lipoprotein subclass patterns and LIPC -514C>T genotypes in population-based samples of older white American (n = 532) and African American (n = 97) men from the Cardiovascular Health Study to those among older, less admixed, Afro-Caribbean men (n = 205) from the Tobago Health Study. Men of African origin had a more favorable lipoprotein profile than whites. In addition, levels of low-density lipoprotein cholesterol, total cholesterol, and triglyceride, and large and small very low-density lipoprotein, small low-density lipoprotein, as well as very low-density lipoprotein particle size, were remarkably lower in Afro-Caribbean men than in either African American or white men. The frequency of the LIPC -514T allele was much higher in Afro-Caribbeans (0.57) and in African Americans (0.49) than in whites (0.20). The -514T allele in both populations of African origin, but not in whites, was associated with elevated large HDL and greater HDL size. Our findings indicate that the higher frequency of the LIPC -514T allele found in men of African origin living in different environments significantly contributes to the more favorable distribution of HDL subclasses compared with whites.
Keywords: Adult; African Americans; Age Factors; Aged; Alleles; Body Mass Index; Cardiovascular Diseases; Caribbean Region; Cohort Studies; DNA; European Continental Ancestry Group; Gene Frequency; Genetic Variation; Humans; Lipase; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Longitudinal Studies; Male; Middle Aged; Particle Size; Trinidad and Tobago; United States

Metabolic syndrome and cardiovascular disease in older people: The cardiovascular health study. - McNeill, Ann Marie; Katz, Ronit; Girman, Cynthia J; Rosamond, Wayne D; Wagenknecht, Lynne E; Barzilay, Joshua I; Tracy, Russell P; Savage, Peter J; Jackson, Sharon A (J Am Geriatr Soc, 2006)
OBJECTIVES: To assess the prospective association between metabolic syndrome (MetS) and cardiovascular disease (CVD) in older people and to evaluate the effect of lowering the threshold for impaired fasting glucose (IFG) on the prevalence of IFG and MetS and the risk of CVD. DESIGN: Prospective cohort study. SETTING: Four field centers in U.S. communities. PARTICIPANTS: Three thousand five hundred eighty-five subjects in the Cardiovascular Health Study free of diabetes mellitus and CVD at baseline (mean age 72, 62% female, 14% black). MEASUREMENTS: Baseline measures of MetS components and adjudicated incident CVD events. MetS (2001) was defined first using the original criteria from the Third Adult Treatment Panel Report of the National Cholesterol Education Program (> or =3 of the following: large waist circumference (women >88 cm, men >102 cm), elevated triglycerides (> or =1.70 mmol/L), low high-density lipoprotein cholesterol (men <1.04 mmol/L, women <1.30 mmol/L), elevated fasting glucose (6.1-6.9 mmol/L), and high blood pressure (> or =130/85 mmHg or self-reported use of medications for hypertension). Subjects were also classified according to the revised definition of the MetS (2005) that applies the lower threshold for fasting glucose (5.6-6.9 mmol/L). RESULTS: During follow-up (median 11 years), 818 coronary heart disease (CHD), 401 stroke, and 554 congestive heart failure (CHF) events occurred. Age- and race-adjusted hazard ratios (HRs) for CHD, stroke, and CHF were 1.30 (95% confidence interval (CI) = 1.07-1.57), 0.94 (95% CI = 0.73-1.21), and 1.40 (95% CI = 1.12-1.76) for women and 1.35 (95% CI = 1.10-1.66), 1.51 (95% CI = 1.08-2.12), and 1.47 (95% CI = 1.14-1.90) for men, respectively. Overall, women and men with MetS (2005) were 20% to 30% more likely to experience any CVD event than subjects without MetS (2005). Using the lower cut-point for IFG resulted in a near tripling in IFG prevalence (16% to 46%) and an additional 9% classified with MetS (2005) but HRs similar to those estimated from the original MetS (2001) criteria. High blood pressure was the component most strongly associated with incident CHD. CONCLUSION: Results from this study of an elderly, population-based cohort provide support for earlier investigations in primarily middle-aged populations that link the presence of MetS with the development of CVD and further underscore the importance of recognizing and treating its individual components, particularly high blood pressure.
Keywords: African Americans; Age Factors; Aged; Aged, 80 and over; Blood Glucose; Cardiovascular Diseases; Cohort Studies; European Continental Ancestry Group; Fasting; Female; Humans; Incidence; Male; Metabolic Syndrome; Risk Factors; Sex Factors

Mortality in pharmacologically treated older adults with diabetes: the Cardiovascular Health Study, 1989-2001. - Kronmal, Richard A; Barzilay, Joshua I; Smith, Nicholas L; Psaty, Bruce M; Kuller, Lewis H; Burke, Gregory L; Furberg, Curt (PLoS Med, 2006)
BACKGROUND: Diabetes mellitus (DM) confers an increased risk of mortality in young and middle-aged individuals and in women. It is uncertain, however, whether excess DM mortality continues beyond age 75 years, is related to type of hypoglycemic therapy, and whether women continue to be disproportionately affected by DM into older age. METHODS AND FINDINGS: From the Cardiovascular Health Study, a prospective study of 5,888 adults, we examined 5,372 participants aged 65 y or above without DM (91.2%), 322 with DM treated with oral hypoglycemic agents (OHGAs) (5.5%), and 194 with DM treated with insulin (3.3%). Participants were followed (1989-2001) for total, cardiovascular disease (CVD), coronary heart disease (CHD), and non-CVD/noncancer mortality. Compared with non-DM participants, those treated with OHGAs or insulin had adjusted hazard ratios (HRs) for total mortality of 1.33 (95% confidence interval [CI], 1.10 to 1.62) and 2.04 (95% CI, 1.62 to 2.57); CVD mortality, 1.99 (95% CI, 1.54 to 2.57) and 2.16 (95% CI, 1.54 to 3.03); CHD mortality, 2.47 (95% CI, 1.89 to 3.24) and 2.75 (95% CI, 1.95 to 3.87); and infectious and renal mortality, 1.35 (95% CI, 0.70 to 2.59) and 6.55 (95% CI, 4.18 to 10.26), respectively. The interaction of age (65-74 y versus > or =75 y) with DM was not significant. Women treated with OHGAs had a similar HR for total mortality to men, but a higher HR when treated with insulin. CONCLUSIONS: DM mortality risk remains high among older adults in the current era of medical care. Mortality risk and type of mortality differ between OHGA and insulin treatment. Women treated with insulin therapy have an especially high mortality risk. Given the high absolute CVD mortality in older people, those with DM warrant aggressive CVD risk factor reduction.
Keywords: Administration, Oral; Aged; Cardiovascular Diseases; Coronary Disease; Diabetes Mellitus; Female; Humans; Hypoglycemic Agents; Insulin; Male; Proportional Hazards Models; Prospective Studies; Risk Assessment; Sex Distribution

Neuropsychological characteristics of mild cognitive impairment subgroups. - Lopez, O L; Becker, J T; Jagust, W J; Fitzpatrick, A; Carlson, M C; DeKosky, S T; Breitner, J; Lyketsos, C G; Jones, B; Kawas, C; Kuller, L H (J Neurol Neurosurg Psychiatry, 2006)
OBJECTIVE: To describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study. METHODS: MCI was classified as MCI-amnestic type (MCI-AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI-multiple cognitive deficits type (MCI-MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition. RESULTS: MCI-AT (n = 10) had worse verbal and non-verbal memory performance than MCI-MCDT (n = 28) or normal controls (n = 374). By contrast, MCI-MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI-AT or normal controls. MCI-MCDT subjects had memory deficits, though they were less pronounced than in MCI-AT. Of the MCI-MCDT cases, 22 (78.5%) had memory deficits, and 6 (21.5%) did not. MCI-MCDT with memory disorders had more language deficits than MCI-MCDT without memory disorders. By contrast, MCI-MCDT without memory deficits had more fine motor control deficits than MCI-MCDT with memory deficits. CONCLUSIONS: The most frequent form of MCI was the MCI-MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16% of all MCI cases and 21.5% of the MCI-MCDT cases did not have memory impairment. Study of idiopathic amnestic and non-amnestic forms of MCI is essential for an understanding of the aetiology of MCI.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Cognition Disorders; Female; Humans; Male; Neuropsychological Tests; Psychometrics; Reference Values

New-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study. - Smith, Nicholas L; Barzilay, Joshua I; Kronmal, Richard; Lumley, Thomas; Enquobahrie, Daniel; Psaty, Bruce M (Diabetes Care, 2006)
OBJECTIVE: Cardiovascular risk associated with new-onset diabetes is not well characterized. We hypothesized that risk of all-cause and cardiovascular mortality would be similar among participants with and without new-onset diabetes in the first years of follow-up and rise over time for new-onset diabetes. RESEARCH DESIGN AND METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of cardiovascular risk factors in adults aged > or =65 years. We used CHS participants to define a cohort (n = 282) with new-onset diabetes during 11 years of follow-up. New-onset diabetes was defined by initiation of antidiabetes medication or by fasting plasma glucose >125 mg/dl among CHS participants without diabetes at study entry. Three CHS participants without diabetes were matched for age, sex, and race to each participant with new-onset diabetes at the time of diabetes identification (n = 837). Survival analysis provided adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality. RESULTS: During a median of 5.9 years of follow-up, there were 352 deaths, of which 41% were cardiovascular. In adjusted analyses, new-onset diabetes was associated with an HR of 1.9 (95% CI 1.4-2.5) for all-cause and 2.2 (1.4-3.4) for cardiovascular mortality compared with no diabetes. Mortality risks were elevated within 2 years of onset, especially cardiovascular risk (4.3 [95% CI 1.7-10.8]), and did not increase over time. CONCLUSIONS: Our findings indicate that there may be a mortality differential soon after diabetes onset in older adults and suggest that long-term macrovascular damage from atherosclerosis may not be primarily responsible for increased risk.
Keywords: Aged; Aged, 80 and over; Atherosclerosis; Blood Glucose; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Risk Factors; Survival Rate; Time Factors

Obstructive sleep apnea and plasma natriuretic peptide levels in a community-based sample. - Patwardhan, Anjali A; Larson, Martin G; Levy, Daniel; Benjamin, Emelia J; Leip, Eric P; Keyes, Michelle J; Wang, Thomas J; Gottlieb, Daniel J; Vasan, Ramachandran S (Sleep, 2006)
STUDY OBJECTIVES: We hypothesized that alterations in cardiac hemodynamics associated with obstructive sleep apnea-hypopnea (OSAH) would be reflected in higher natriuretic peptide levels. We examined the association of OSAH with natriuretic peptides in a community-based sample. DESIGN: Cross-sectional, retrospective, observational study. SETTING: Framingham Heart Study Offspring Cohort and Sleep Heart Health Study. PARTICIPANTS: Community-based sample of 623 individuals. MEASUREMENTS: Full-montage home polysomnography was used to determine apnea-hypopnea index (AHI) and percentage of time with an oxyhemoglobin saturation < 90% (PctLt90). Sensitive immunoradiometric assays were used to measure plasma B-type (BNP) and N-terminal pro-atrial natriuretic peptide (NT-ANP). Multivariable regression was used to examine the relations between natriuretic peptides and indicators of OSAH, adjusting for age, sex, body mass index, and clinical covariates. RESULTS: No statistically significant relations between OSAH indices and BNP were observed in the multivariable model. Compared with an AHI < 5, relative levels of 1.20, 0.88, and 0.91 were observed forAHI categories 5-15, 15-30, >30 events per hour, respectively. For NT-ANP, no significant relations were seen with AHI in the multivariable model (relative levels of 0.98, 0.91, and 0.90). An inverse association was observed between NT-ANP and PctLt90 in age- and sex-adjusted models (relative levels of 0.93, 0.87, and 0.80), although this association became statistically nonsignificant after adjusting for body mass index. CONCLUSION: Lack of association of natriuretic peptides with OSAH indices suggests that undiagnosed OSAH may not be associated with major alterations in left ventricular function, as reflected in morning natriuretic peptide levels.
Keywords: Atrial Fibrillation; Body Mass Index; Cohort Studies; Female; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptides; Obesity; Polysomnography; Prevalence; Residence Characteristics; Severity of Illness Index; Sleep Apnea, Obstructive

Obstructive sleep apnea-hypopnea and neurocognitive functioning in the Sleep Heart Health Study. - Quan, Stuart F; Wright, Ron; Baldwin, Carol M; Kaemingk, Kristine L; Goodwin, James L; Kuo, Tracy F; Kaszniak, Alfred; Boland, Lori L; Caccappolo, Elise; Bootzin, Richard R (Sleep Med, 2006)
BACKGROUND AND PURPOSE: Obstructive sleep apnea-hypopnea (OSAH) is associated with sleep fragmentation and nocturnal hypoxemia. In clinical samples, patients with OSAH frequently are found to have deficits in neuropsychological function. However, the nature and severity of these abnormalities in non-clinical populations is less well defined. PATIENTS AND METHODS: One hundred and forty-one participants from the Tucson, AZ and New York, NY field centers of the Sleep Heart Health Study completed a battery of neuropsychological tests for 9-40 months (mean=24 months, SD=7 months) after an unattended home polysomnogram. Sixty-seven participants had OSAH (AHI>10) and 74 did not have OSAH (control (CTL), apnea-hypopnea index (AHI)<5). In addition to the individual tests, composite variables representing attention, executive function, MotorSpeed and processing speed were constructed from the neuropsychological test battery. RESULTS: There were no significant differences in any individual neuropsychological test or composite variable between the OSAH and CTL groups. However, when time spent with O(2) saturations less than 85% was dichotomized into those participants in the top quartile of the distribution and those in the lower three quartiles, motor speed was significantly impaired in those who were more hypoxemic. In addition, poorer motor speed (model adjusted R(2)=0.242, P<0.001) and processing speed performance (model adjusted R(2)=0.122, P<0.001) were associated with more severe oxygen desaturation even after controlling for degree of daytime sleepiness, age, gender and educational level. CONCLUSIONS: Mild to moderate OSAH has little impact on the selected measures of attention, executive function, motor speed and processing speed. However, hypoxemia adversely affects both motor and processing speed. These results suggest that in middle-aged to elderly adults the neuropsychological effects of clinically unrecognized mild to moderate OSAH are neither global nor large.
Keywords: Brain; Cognition Disorders; Continuous Positive Airway Pressure; Demography; Disorders of Excessive Somnolence; Electromyography; Electrooculography; Female; Health Status; Humans; Hypoxia; Male; Middle Aged; Neuropsychological Tests; Oxygen; Polysomnography; Severity of Illness Index; Sleep Apnea, Obstructive; Surveys and Questionnaires

The prevalence of the 65-kilodalton isoform of glutamic acid decarboxylase autoantibodies by glucose tolerance status in elderly patients from the cardiovascular health study. - Barinas-Mitchell, Emma; Kuller, Lewis H; Pietropaolo, Susan; Zhang, Ying-Jian; Henderson, Tyona; Pietropaolo, Massimo (J Clin Endocrinol Metab, 2006)
CONTEXT: Autoantibodies (AA) to glutamic acid decarboxylase (GAD65), a determinant of risk for autoimmune diabetes, have been found in up to 10% of patients with type 2 diabetes. In older adults, this marker may also serve as a determinant of risk for autoimmune diabetes and enhance diabetes classification. OBJECTIVE: The objective of this study was to evaluate the relationship between GAD65AA and glucose tolerance status, current diabetes treatment, and clinical measures in older adults. DESIGN: GAD65AA were measured at baseline in 3318 participants from the Cardiovascular Health Study, a cohort study of 5888 individuals 65 or older. SETTING: The population-based cohort was recruited from four U.S. sites. PATIENTS: Patients included all Cardiovascular Health Study participants with known diabetes, newly diagnosed diabetes, impaired fasting glucose, impaired glucose tolerance, and a sample of normal glucose-tolerant participants. MAIN OUTCOME MEASURES: GAD65AA, body mass index, fasting glucose and insulin levels, blood pressure, lipid levels, and diabetes treatment at baseline were measured. RESULTS: The prevalence of GAD65AA increased with decreasing glucose tolerance in both Blacks (n = 560) and Whites (n = 2730), being more pronounced in known diabetic individuals. GAD65AA were found in 2.3, 5.8, 7.8, and 8.3% of diabetic participants, reporting use of no diabetes medication, oral hypoglycemic agents, insulin only, and both oral hypoglycemic agents and insulin, respectively (P = 0.02, linear trend). Among diabetic participants, GAD65AA positivity was associated with diabetes treatment, higher fasting glucose, and lower body mass index. CONCLUSIONS: Even among older individuals with diabetes, GAD65AA may be a useful marker in identifying a subgroup of autoimmune diabetes, serve as a marker of insulin requirement, and remain stable over years.
Keywords: Aged; Aging; Autoantibodies; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Glutamate Decarboxylase; Humans; Insulin; Isoenzymes; Lipids; Logistic Models; Male; Nutrition Surveys

Quantitative measures of gait characteristics indicate prevalence of underlying subclinical structural brain abnormalities in high-functioning older adults. - Rosano, Caterina; Brach, Jennifer; Longstreth, William T; Newman, Anne B (Neuroepidemiology, 2006)
Abnormal gait in high-functioning older adults may indicate underlying subtle structural brain abnormalities. We tested the hypothesis that temporal and spatial parameters of gait, including speed, stride length and double support time, are cross-sectionally associated with white matter hyperintensity, subcortical infarcts or brain atrophy on brain MRI. We examined 321 men and women (mean age = 78.3) participating to the Cardiovascular Health Study who were free of dementia or stroke at the time of the gait assessment. Analyses were set with gait as independent variable and brain MRIs as dependent variables. Gait measures were determined from the footfalls recorded on a 4-meter-long instrumented walking surface, the GaitMat II. Brain MRIs were examined for the presence of white matter hyperintensity (WMG, graded from 0 to 9), brain infarcts (predominantly subcortical) and ventricular enlargement (graded from 0 to 9). Slower gait, shorter stride length and longer double support times were associated with greater prevalence of white matter grade > or =3 (p = 0.02), and at least 1 brain infarct (p = 0.04) independent of age. In multivariate logistic regression models adjusted for demographics and clinical cardiovascular diseases, those with gait speed <1.02 m/s were more likely to have WMG > or =3 and at least 1 brain infarct, compared with those with faster gait - odds ratio (OR): 2.85, 95% confidence interval (95% CI): 1.35, 6.02, and OR: 2.09, 95% CI: 1.04, 4.19. Shorter stride length was also associated with greater probability of having at least 1 brain infarct (gait stride <0.88 vs. >1.10 m: OR: 3.20, 95% CI: 1.49, 6.88), while longer double support times were associated with a greater probability of having WMG > or =3 (double support time >0.19 vs. <0.14 s: OR: 2.3, 95% CI: 1.1, 4.7) independent of demographics and clinical cardiovascular diseases. Gait parameters were not significantly associated with ventricular grade. In summary, in this group of high-functioning older adults, poorer gait speed, shorter stride and longer double support time are associated with high white matter disease and subclinical strokes.
Keywords: Aged; Brain; Cerebral Infarction; Cerebral Ventricles; Cerebrovascular Disorders; Cohort Studies; Dementia; Female; Gait; Gait Disorders, Neurologic; Humans; Hypertension; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Stroke; United States

Thyroid status, cardiovascular risk, and mortality in older adults. - Cappola, Anne R; Fried, Linda P; Arnold, Alice M; Danese, Mark D; Kuller, Lewis H; Burke, Gregory L; Tracy, Russell P; Ladenson, Paul W (JAMA, 2006)
CONTEXT: Previous studies have suggested that subclinical abnormalities in thyroid-stimulating hormone levels are associated with detrimental effects on the cardiovascular system. OBJECTIVE: To determine the relationship between baseline thyroid status and incident atrial fibrillation, incident cardiovascular disease, and mortality in older men and women not taking thyroid medication. DESIGN, SETTING, AND PARTICIPANTS: A total of 3233 US community-dwelling individuals aged 65 years or older with baseline serum thyroid-stimulating hormone levels were enrolled in 1989-1990 in the Cardiovascular Health Study, a large, prospective cohort study. MAIN OUTCOME MEASURES: Incident atrial fibrillation, coronary heart disease, cerebrovascular disease, cardiovascular death, and all-cause death assessed through June 2002. Analyses are reported for 4 groups defined according to thyroid function test results: subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism. RESULTS: Individuals with overt thyrotoxicosis (n = 4) were excluded because of small numbers. Eighty-two percent of participants (n = 2639) had normal thyroid function, 15% (n = 496) had subclinical hypothyroidism, 1.6% (n = 51) had overt hypothyroidism, and 1.5% (n = 47) had subclinical hyperthyroidism. After exclusion of those with prevalent atrial fibrillation, individuals with subclinical hyperthyroidism had a greater incidence of atrial fibrillation compared with those with normal thyroid function (67 events vs 31 events per 1000 person-years; adjusted hazard ratio, 1.98; 95% confidence interval, 1.29-3.03). No differences were seen between the subclinical hyperthyroidism group and euthyroidism group for incident coronary heart disease, cerebrovascular disease, cardiovascular death, or all-cause death. Likewise, there were no differences between the subclinical hypothyroidism or overt hypothyroidism groups and the euthyroidism group for cardiovascular outcomes or mortality. Specifically, individuals with subclinical hypothyroidism had an adjusted hazard ratio of 1.07 (95% confidence interval, 0.90-1.28) for incident coronary heart disease. CONCLUSION: Our data show an association between subclinical hyperthyroidism and development of atrial fibrillation but do not support the hypothesis that unrecognized subclinical hyperthyroidism or subclinical hypothyroidism is associated with other cardiovascular disorders or mortality.
Keywords: Aged; Atrial Fibrillation; Cardiovascular Diseases; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Proportional Hazards Models; Risk Factors; Thyroid Gland; Thyrotropin

Transthyretin V122I in African Americans with congestive heart failure. - Buxbaum, Joel; Jacobson, Daniel R; Tagoe, Clement; Alexander, Alice; Kitzman, Dalane W; Greenberg, Barry; Thaneemit-Chen, Surai; Lavori, Philip (J Am Coll Cardiol, 2006)
Keywords: African Americans; Gene Frequency; Heart Failure; Heterozygote; Humans; Isoleucine; Mutation; Prealbumin; Valine

Acceleration of cerebral ventricular expansion in the Cardiovascular Health Study. - Carmichael, Owen T; Kuller, L H; Lopez, O L; Thompson, P M; Dutton, R A; Lu, A; Lee, S E; Lee, J Y; Aizenstein, H J; Meltzer, C C; Liu, Y; Toga, A W; et al. (Neurobiol Aging, 2007)
Interactions between prevalent late-life medical conditions and expansion of the cerebral ventricles are not well understood. Thirty elderly subjects received three magnetic resonance (MR) scans each, in 1997-1999, 2002-2004, and 2003-2005. A linear expansion model of MR-measured lateral ventricle volume was estimated for each subject by fitting a line to a plot of their 1997-1999 and 2002-2004 volumes as a function of time. Acceleration in ventricular expansion was defined as the deviation between the 2003-2005 volumes measured from MR and the 2003-2005 volumes predicted by the linear expansion model. Ventricular acceleration was analyzed in a multivariate model with age, race, history of heart disease, diabetes, and hypertension as fixed effects. Ventricular acceleration was significantly higher in non-whites, diabetics, and those without heart disease (p<0.05). Ventricular acceleration was higher in subjects with a history of hypertension, but the difference was not statistically significant (p=0.08). Acceleration of ventricular expansion in the elderly may be related to demographic and cardiovascular factors.
Keywords: Aged; Analysis of Variance; Cardiovascular Diseases; Cerebral Ventricles; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Reference Values; Retrospective Studies; Sex Factors; Time Factors

Alcohol consumption and type 2 diabetes among older adults: the Cardiovascular Health Study. - Djoussé, Luc; Biggs, Mary L; Mukamal, Kenneth J; Siscovick, David S (Obesity (Silver Spring), 2007)
OBJECTIVE: The objective was to examine the role of total and beverage-specific alcohol consumption on the incidence of type 2 diabetes mellitus (DM) among elderly men and women. RESEARCH METHODS AND PROCEDURES: We studied prospectively 4655 participants of the Cardiovascular Health Study who were free of DM at baseline. Alcohol consumption was obtained at baseline and during follow-up examinations. DM was defined using fasting glucose and/or use of hypoglycemic medications. We used Cox proportional hazard models to estimate adjusted relative risks of diabetes across alcohol categories. RESULTS: During a mean follow-up of 6.3 years, 234 incident cases of DM were documented. Compared with never drinkers, hazard ratios [95% confidence interval (CI)] for DM were 0.7 (0.3 to 1.4), 0.5 (0.3 to 0.9), 0.6 (0.4 to 1.1), and 0.8 (0.4 to 1.3) for former drinkers and current drinkers of <1, 1 to 6, and 7+ drinks per week, respectively, for men after adjustment for age, BMI, education, and smoking. Corresponding values for women were 1.2 (0.6 to 2.3), 0.7 (0.4 to 1.1), 0.6 (0.3 to 1.1), and 0.4 (0.2 to 1.0), respectively. A reduced risk of DM was observed with all types of beverage consumed. Similar findings were observed when we repeated the above analyses using simple or weighted cumulative alcohol update and covariates over time. DISCUSSION: Light to moderate alcohol consumption was associated with a lower incidence of DM among elderly people, irrespective of the type of beverage consumed.
Keywords: Aged; Aged, 80 and over; Alcohol Drinking; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Male; Medicare; Middle Aged; Risk; Smoking; Temperance; United States

Association of kidney function with incident hip fracture in older adults. - Fried, Linda F; Biggs, Mary Louise; Shlipak, Michael G; Seliger, Stephen; Kestenbaum, Bryan; Stehman-Breen, Catherine; Sarnak, Mark; Siscovick, David; Harris, Tamara; Cauley, Jane; Newman, Anne B; Robbins, John (J Am Soc Nephrol, 2007)
Kidney dysfunction is associated with bone loss, and patients with ESRD have an increased risk for hip fracture. However, the association of mild to moderate kidney disease with hip fracture has not been studied previously. The association of kidney function with incident hip fracture was examined among participants in the Cardiovascular Health Study, a community-based cohort of older individuals. The primary measure of kidney function was serum cystatin C, a measure that does not depend on lean mass. Hip fractures were identified using International Classification of Diseases, Ninth Revision codes for hospitalizations. A total of 4699 individuals had cystatin C measured in 1992 to 1993 and did not have a hip fracture before cystatin C measurement. The association of kidney function with hip fracture was analyzed with Cox proportional hazards models. Analyses were conducted separately for men and women. After a mean follow-up of 7.1 yr, 195 incident hip fractures occurred in women and 79 occurred in men. Higher cystatin C levels were associated with a higher risk for fracture in women (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.14 to 1.38 per SD) and in men (HR 1.27; 95% CI 1.11 to 1.46). After multivariable adjustment, higher cystatin C levels were significantly associated with hip fracture in women (HR 1.16; 95% CI 1.01, 1.33) but not in men (HR 1.14; 95% CI 0.86 to 1.52), although the magnitude of the association was similar. Kidney dysfunction, as assessed by cystatin C, is associated with an increased risk for hip fracture. Further studies are needed to evaluate potential mediators of this relationship and to assess whether interventions can decrease this risk.
Keywords: Aged; Aged, 80 and over; Cystatin C; Cystatins; Female; Hip Fractures; Humans; Kidney; Kidney Failure, Chronic; Longitudinal Studies; Male; Osteoporosis; Prospective Studies; Risk Factors; Sex Factors

Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. - Yeboah, Joseph; Crouse, John R; Hsu, Fang-Chi; Burke, Gregory L; Herrington, David M (Circulation, 2007)
BACKGROUND: The relationship between impaired brachial flow-mediated dilation (FMD) and subsequent clinical cardiovascular events is not well established, especially in older adults whose FMD is often diminished. We assessed the hypothesis that FMD predicts incident cardiovascular events in a population-based cohort of older adults. METHODS AND RESULTS: FMD was measured at the 1997 to 1998 Cardiovascular Health Study clinic visit in 2792 adults aged 72 to 98 years (82.7% white, 58.6% women) recruited at 4 clinic sites in the United States. Log-rank test and Cox proportional hazard models were used to examine the association between FMD and adjudicated cardiovascular events. A total of 674 subjects (24.1%) had an adjudicated event over the 5-year follow-up period. Event-free survival rates for cardiovascular events were significantly higher in subjects with FMD greater than the sex-specific medians than in subjects with FMD less than or equal to the sex-specific medians (78.3% versus 73.6%, log-rank P=0.006). FMD remained a significant predictor of cardiovascular events after adjustment for age, gender, diabetes mellitus, cigarette smoking, systolic and diastolic blood pressure, baseline cardiovascular disease status, and total cholesterol (hazard ratio, 0.91 [95% CI, 0.83 to 0.99], P=0.02 per unit SD of FMD) but added only approximately 1% to the prognostic accuracy of the best Cox model. Brachial artery diameter was also predictive of CV events in the adjusted Cox proportional hazard model (hazard ratio, 1.12 [95% CI, 1.02 to 1.28], P=0.025) and also added approximately 1% to the accuracy of our best Cox model. CONCLUSIONS: FMD is a predictor of future cardiovascular events but adds very little to the prognostic accuracy of traditional cardiovascular risk scores/factors in older adults. FMD and brachial artery diameter may have similar predictive values for cardiovascular events in older adults.
Keywords: Aged; Aged, 80 and over; Atherosclerosis; Biomarkers; Brachial Artery; Cardiovascular Diseases; Cohort Studies; Disease-Free Survival; Endothelium, Vascular; Female; Hemorheology; Humans; Hyperemia; Male; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Reproducibility of Results; Risk Factors; Stress, Mechanical; Tourniquets; Ultrasonography; United States; Vasodilation

Cerebral ventricular changes associated with transitions between normal cognitive function, mild cognitive impairment, and dementia. - Carmichael, Owen T; Kuller, Lewis H; Lopez, Oscar L; Thompson, Paul M; Dutton, Rebecca A; Lu, Allen; Lee, Sharon E; Lee, Jessica Y; Aizenstein, Howard J; Meltzer, Carolyn C; Liu, Yanxi; Toga, Arthur W; et al. (Alzheimer Dis Assoc Disord, 2007)
Expansion of the cerebral ventricles may occur at an accelerated rate in subjects with dementia, but the time course of expansion during transitions between normal cognitive function, mild cognitive impairment (MCI), and dementia is not well understood. Furthermore, the effects of cardiovascular risk factors on rate of ventricular expansion are unclear. We used a fully automated segmentation technique to measure change rate in lateral ventricle-to-brain ratio (VBR) on 145 longitudinal pairs of magnetic resonance images of subjects in the Cardiovascular Health Study Cognition Study from the Pittsburgh Center. A multivariate model analyzed VBR change rate, accounting for dementia statuses at both imaging times (normal, MCI, or dementia), age, sex, education, race, magnetic resonance-defined infarcts, Center for Epidemiology Studies Depression Scale, baseline ventricular volume, and cardiovascular risk factors. VBR change was faster in subjects who were demented or transitioned from MCI to dementia, compared with subjects normal at both images and subjects who transitioned from normal to MCI or dementia. Patients with diabetes had faster VBR change. Ventricular expansion may accelerate late in the progression from normal cognitive function to dementia, and may be modulated by diabetes.
Keywords: Aged; Aged, 80 and over; Case-Control Studies; Cerebral Ventricles; Cognition Disorders; Dementia; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Risk Factors; Severity of Illness Index; Time Factors

Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases. - Ballantyne, C; Cushman, M; Psaty, B; Furberg, C; Khaw, K T; Sandhu, M; Oldgren, J; Rossi, G P; Maiolino, G; Cesari, M; Lenzini, L; James, S K; et al. (Eur J Cardiovasc Prev Rehabil, 2007)
BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors. OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes. METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.
Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Cardiovascular Diseases; Humans; Phospholipases A2

Costs of the metabolic syndrome in elderly individuals: findings from the Cardiovascular Health Study. - Curtis, Lesley H; Hammill, Bradley G; Bethel, M Angelyn; Anstrom, Kevin J; Gottdiener, John S; Schulman, Kevin A (Diabetes Care, 2007)
OBJECTIVE: The cardiovascular consequences of the metabolic syndrome and its component risk factors have been documented in elderly individuals. Little is known about how the metabolic syndrome and its individual components translate into long-term medical costs. RESEARCH DESIGN AND METHODS: We used log-linear regression models to assess the independent contributions of the metabolic syndrome and its individual components to 10-year medical costs among 3,789 individuals aged > or = 65 years in the Cardiovascular Health Study. RESULTS: As defined by the National Cholesterol Education Program Third Adult Treatment Panel report, the metabolic syndrome was present in 47% of the sample. Total costs to Medicare were 20% higher among participants with the metabolic syndrome ($40,873 vs. $33,010; P < 0.001). Controlling for age, sex, race/ethnicity, and other covariates, we found that abdominal obesity, low HDL cholesterol, and elevated blood pressure were associated with 15% (95% CI 4.3-26.7), 16% (1.7-31.8), and 20% (10.1-31.7) higher costs, respectively. When added to the model, the metabolic syndrome composite variable did not contribute significantly (P = 0.32). CONCLUSIONS: Abdominal obesity, low HDL cholesterol, and hypertension but not the metabolic syndrome per se are important predictors of long-term costs in the Medicare population.
Keywords: Aged; Aged, 80 and over; Cholesterol, HDL; Continental Population Groups; Cost of Illness; Diabetic Angiopathies; Female; Humans; Hypertension; Interviews as Topic; Male; Medicare; Metabolic Syndrome; Multivariate Analysis; Obesity; Patient Education as Topic; Prospective Studies; Regression Analysis; United States

Determinants of serum total and free testosterone levels in women over the age of 65 years. - Cappola, Anne R; Ratcliffe, Sarah J; Bhasin, Shalender; Blackman, Marc R; Cauley, Jane; Robbins, John; Zmuda, Joseph M; Harris, Tamara; Fried, Linda P (J Clin Endocrinol Metab, 2007)
CONTEXT: Little is known about testosterone (T) levels and their determinants in women of late postmenopausal age. OBJECTIVE: We describe levels of total and free T and selected factors that influence these levels in a random sample of older women. DESIGN: Levels of serum total T and free T by microdialysis were measured using ultrasensitive assays in 347 community-dwelling women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to define factors associated with total and free T levels. RESULTS: In adjusted models: 1) total T levels declined with age until 80, whereas free T levels did not vary by age; 2) women with bilateral oophorectomy had 23% lower total T and 16% lower free T levels than those with at least one intact ovary; 3) oral estrogen users had total and free T levels that were 47% lower than never users; 4) obese women had 47% higher total T and 20% higher free T levels, and overweight women had 24% higher total T and 14% higher free T levels, than normal weight women; and 5) free T levels were 51% higher in black women. Corticosteroid users had 75% lower total T and 43% lower free T levels than nonusers. CONCLUSIONS: Bilateral oophorectomy, estrogen use, corticosteroid use, and low body mass index are independent risk factors for lower T levels in women aged 65 yr and over. Although highly prevalent in women of this age, the physiological significance of low T levels in late postmenopausal women requires further investigation.
Keywords: Age Distribution; Aged; Aged, 80 and over; Aging; Body Mass Index; Cross-Sectional Studies; Estrogen Replacement Therapy; Female; Humans; Hypogonadism; Multivariate Analysis; Nonlinear Dynamics; Obesity; Ovariectomy; Ovary; Postmenopause; Predictive Value of Tests; Prevalence; Risk Factors; Testosterone

The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases. - Danesh, J; Erqou, S; Walker, M; Thompson, S G; Tipping, R; Ford, C; Pressel, S; Walldius, G; Jungner, I; Folsom, A R; Chambless, L E; Knuiman, M; et al. (Eur J Epidemiol, 2007)
Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.
Keywords: Albumins; Biomarkers; Cardiovascular Diseases; Databases, Factual; Far East; Humans; Inflammation; Leukocyte Count; Lipids; Lipoproteins, HDL; Prospective Studies; Risk Factors; Triglycerides

Focal atrophy and cerebrovascular disease increase dementia risk among cognitively normal older adults. - Rosano, Caterina; Aizenstein, Howard J; Wu, Minjie; Newman, Anne B; Becker, James T; Lopez, Oscar L; Kuller, Lewis H (J Neuroimaging, 2007)
BACKGROUND AND PURPOSE: This study investigated the association of medial temporal lobe (MTL) atrophy and cerebrovascular disease (white matter hyperintensities [WMH], subclinical infarcts) with the risk of developing Alzheimer's disease (AD) among cognitively normal older adults. METHODS: Risk of developing AD was examined for 155 cognitively normal older adults (77.4 years, 60% women, 81% white). The MTL volumes and the presence of WMH and of subclinical infarcts were determined from brain magnetic resonance imaging (MRI) at the beginning of the study. Follow-up cognitive evaluations (average 4.3 years) identified those who developed AD. RESULTS: The presence of either MTL atrophy or subclinical infarcts was independently and significantly associated with a greater risk to develop AD (OR [95% CI]: 4.4 [1.5, 12.3] and 2.7 [1.0, 7.1], respectively). In addition, those participants with both MTL atrophy and at least one brain infarct had a 7-fold increase in the risk of developing AD (OR [95% CI]: 7.0 [1.5, 33.1]), compared to those who had neither of these conditions. CONCLUSIONS: In cognitively normal older adults, markers of neurodegeneration (as reflected by MTL atrophy) and of cerebrovascular disease (as reflected by infarcts on MRI) independently contribute to the risk to develop AD.
Keywords: Aged; Alzheimer Disease; Analysis of Variance; Atrophy; Cerebrovascular Disorders; Cognition; Female; Humans; Logistic Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Risk Factors; Temporal Lobe; United States

Frailty and risk of venous thromboembolism in older adults. - Folsom, Aaron R; Boland, Lori L; Cushman, Mary; Heckbert, Susan R; Rosamond, Wayne D; Walston, Jeremy D (J Gerontol A Biol Sci Med Sci, 2007)
BACKGROUND: Frailty is a common risk factor for morbidity and mortality in elderly persons. Recent evidence links frailty to activation of coagulation and inflammatory pathways. We aimed to determine whether frailty in community-dwelling older adults is a risk factor for venous thromboembolism (VTE). METHODS: We conducted a prospective cohort study in four U.S. communities involving 4859 participants 65 years old and older. At baseline, in 1989-1993, we assessed frailty based on weight loss, grip strength, feelings of exhaustion, walk time, and physical activity. Incident VTE (deep vein thrombosis or pulmonary embolus) through 2002 was identified by review of hospital records. RESULTS: Fifty-two percent of the sample was classified as having intermediate or definite frailty. After adjustment for age, race, sex, body mass index, and diabetes, the relative risk of total VTE (n = 150) for people who were frail compared with no frailty was 1.31 (95% confidence interval [CI], 0.93-1.84). The comparably adjusted relative risk for idiopathic VTE (n = 58) was 1.79 (95% CI, 1.02-3.13). CONCLUSIONS: The incidence rates of idiopathic VTE was higher in community-dwelling older adults with baseline frailty compared with no frailty. Further studies of the clotting process in frailty may allow the development of an improved strategy to determine VTE risk in this vulnerable subset of older adults.
Keywords: Age Factors; Aged; Aged, 80 and over; Female; Follow-Up Studies; Frail Elderly; Humans; Male; Morbidity; Motor Activity; Prospective Studies; Risk Factors; Thromboembolism; United States; Venous Thrombosis

Gait variability and the risk of incident mobility disability in community-dwelling older adults. - Brach, Jennifer S; Studenski, Stephanie A; Perera, Subashan; VanSwearingen, Jessie M; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2007)
BACKGROUND: Gait speed is a strong predictor of incident walking disability. The objective was to determine if gait variability adds to the prediction of incident mobility disability independent of gait speed. METHODS: Participants included 379 older adults (mean age = 79 years; 78% Caucasian, and 40% men) in the Cardiovascular Health Study at the Pittsburgh site. All could ambulate independently and reported no difficulty walking a half mile. Gait characteristics were determined from a 4-meter computerized walkway. For each gait parameter, variability was defined as the standard deviation from the individual steps from two passes. Incident walking disability was obtained by phone interview every 6 months for 54 months and was defined as new difficulty walking a half mile or inability to walk a half mile. RESULTS: Of the 379 participants, 222 (58.6%) developed incident mobility disability. In unadjusted Cox proportional hazards models gait speed, mean step length, mean stance time, and stance time variability were associated with incident mobility disability. After adjusting for gait speed, demographics, chronic conditions, prescription medications, health status, and physical activity level, only stance time variability remained an important indicator of disability. In the adjusted model, an increase in stance time variability of 0.01 seconds was associated with a 13% higher incidence of mobility disability (hazard ratio 1.13, 95% confidence interval, 1.01-1.27). CONCLUSIONS: Stance time variability is an independent predictor of future mobility disability. Future efforts are needed to determine whether interventions that decrease stance time variability will also delay mobility disability.
Keywords: Aged; Aged, 80 and over; Aging; Cohort Studies; Female; Gait; Gait Disorders, Neurologic; Humans; Male; Mobility Limitation; Prospective Studies; Risk Factors; Walking

Gait variability is associated with subclinical brain vascular abnormalities in high-functioning older adults. - Rosano, Caterina; Brach, Jennifer; Studenski, Stephanie; Longstreth, W T; Newman, Anne B (Neuroepidemiology, 2007)
BACKGROUND: Gait variability is an index of how much gait parameters, such as step length, change from one step to the next. Gait variability increases with age and in individuals affected by cortical and subcortical neurodegenerative conditions, and it is associated with falls and incident mobility disability. The brain anatomical correlates of gait variability have not been studied in high-functioning community-dwelling older adults. METHODS: Gait variability and brain MRIs were assessed in a cohort of 331 men and women (mean age = 78.3 years) free from stroke, dementia or Parkinson's disease. Gait variability was computed for spatial parameters (step length and step width) and for temporal parameters (stance time). Subclinical brain vascular abnormalities were measured on brain MRIs as infarcts and white matter hyperintensities. RESULTS: Greater variability of step length was associated with greater prevalence of infarcts, including infarcts in the basal ganglia, and with greater white matter hyperintensities severity, independent of age, gender, cognitive function and cardiovascular disease. Weaker associations were found between the other variability measures and the MRI measures. CONCLUSION: In this group of older adults free from neurodegenerative diseases, a greater variability of step length was associated with greater burden of subclinical brain vascular abnormalities as defined by MRI.
Keywords: Accidental Falls; Activities of Daily Living; Aged; Aged, 80 and over; Basal Ganglia Cerebrovascular Disease; Brain; Cerebral Infarction; Comorbidity; Female; Gait Disorders, Neurologic; Geriatric Assessment; Health Surveys; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mobility Limitation; Neurodegenerative Diseases; Neurologic Examination; Risk Factors; United States

IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. - Walston, Jeremy D; Fallin, M Daniele; Cushman, Mary; Lange, Leslie; Psaty, Bruce; Jenny, Nancy; Browner, Warren; Tracy, Russell; Durda, Peter; Reiner, Alex (Hum Genet, 2007)
Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.
Keywords: African Americans; Aged; Alleles; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; European Continental Ancestry Group; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Humans; Interleukin-6; Introns; Longitudinal Studies; Male; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

Incidence of dementia in mild cognitive impairment in the cardiovascular health study cognition study. - Lopez, Oscar L; Kuller, Lewis H; Becker, James T; Dulberg, Corinne; Sweet, Robert A; Gach, H Michael; DeKosky, Steven T (Arch Neurol, 2007)
OBJECTIVES: To examine the incidence of dementia in subjects with mild cognitive impairment (MCI) in the Cardiovascular Health Study Cognition Study. DESIGN: Prospective epidemiological study. SETTING: The Cardiovascular Health Study Cognition Study of Pittsburgh, Pa, was conducted from 2002 through 2003 to determine the incidence of dementia in participants classified as having MCI in 1998 and 1999. Subjects There were 136 subjects with MCI. Mild cognitive impairment was subclassified as MCI amnestic type and MCI multiple cognitive deficits type (MCI-MCDT); subjects with MCI-MCDT were also grouped based on the presence of a memory impairment. Subjects with MCI were classified as possible when there were comorbidities that could explain the subjects' cognitive deficits and as probable when there were none. Main Outcome Measure Dementia. RESULTS: The incidence of all dementias in the subjects with MCI was 147 per 1000 person-years (mean follow-up overall, 4.3 years). Of the 136 subjects with MCI, 69 (51%) in 1998 through 1999 progressed to dementia (57 [83%] to Alzheimer disease [AD]), but 25 (18%) returned to normal. Of the 10 subjects with probable MCI amnestic type, 7 (70%) progressed to dementia (all of them to AD) and none returned to normal, whereas 7 (41%) of the 17 subjects with possible MCI amnestic type became demented (6 [86%] to AD) and 3 (18%) returned to normal. Of the 40 subjects with probable MCI-MCDT, 21 (52%) progressed to dementia (17 [81%] to AD) and 2 (5%) returned to normal. Of the 69 subjects with possible MCI-MCDT, 34 (49%) progressed to dementia (28 [82%] to AD) and 20 (29%) returned to normal. Among the subjects with probable MCI-MCDT, 15 (54%) of 28 with and 6 (50%) of 12 without memory deficits progressed to dementia. CONCLUSIONS: Subjects with MCI are at high risk for dementia. The probable MCI diagnosis identified individuals in the earliest stages of dementia, usually AD, whereas the possible MCI diagnosis identified a more heterogeneous group. However, this latter group had only a slightly lower rate of conversion to dementia than the group with probable MCI, suggesting that even with comorbid conditions, there is a high likelihood of the presence of a progressive dementing disorder.
Keywords: Aged; Aged, 80 and over; Cardiovascular System; Cognition Disorders; Dementia; Disease Progression; Female; Humans; Incidence; Male; Retrospective Studies

Insulin resistance and inflammation as precursors of frailty: the Cardiovascular Health Study. - Barzilay, Joshua I; Blaum, Caroline; Moore, Tisha; Xue, Qian Li; Hirsch, Calvin H; Walston, Jeremy D; Fried, Linda P (Arch Intern Med, 2007)
BACKGROUND: Our research group has previously shown that the geriatric syndrome of frailty is associated with features of the metabolic syndrome (MetS) on cross-sectional analysis. METHODS: To test whether MetS and its physiologic determinants-insulin resistance as measured by homeostasis model assessment score (IR-HOMA), increased inflammation and coagulation factor levels, and elevated blood pressure-are associated with incident frailty, we studied a subcohort of participants from the Cardiovascular Health Study observed from 1989/1990 through 1998/1999: 3141 community-dwelling adults, aged 69 to 74 years, without frailty and illnesses that increase inflammation markers or mimic frailty. The association of baseline MetS, IR-HOMA, levels of inflammation and coagulation factors, and systolic blood pressure (SBP) with time to onset of frailty was adjusted for demographic and psychosocial factors and incident events. Our main outcome measure was incident frailty. RESULTS: Metabolic syndrome was not significantly associated with incident frailty (hazard ratio, 1.16 (95% confidence interval [CI], 0.85-1.57). On the other hand, IR-HOMA and C-reactive protein levels were associated with incident frailty: for every standard deviation increment the hazard ratio for frailty was 1.15 (95% CI, 1.02-1.31) and 1.16 (95% CI, 1.02-1.32), respectively. The white blood cell count and factor VIIIc levels had a borderline association. Elevated systolic blood pressure had no association. Similar trends were found for incident prefrailty, a condition that precedes frailty. CONCLUSIONS: Two physiologic components of MetS- IR-HOMA and inflammation-are associated with incident frailty. Based on these results, IR-HOMA can be considered part of a larger process that leads to generalized decline.
Keywords: Aged; Aged, 80 and over; Female; Frail Elderly; Geriatrics; Humans; Inflammation; Insulin Resistance; Male; Metabolic Syndrome; Prospective Studies

Longitudinal association between depressive symptoms and incident type 2 diabetes mellitus in older adults: the cardiovascular health study. - Carnethon, Mercedes R; Biggs, Mary L; Barzilay, Joshua I; Smith, Nicholas L; Vaccarino, Viola; Bertoni, Alain G; Arnold, Alice; Siscovick, David (Arch Intern Med, 2007)
BACKGROUND: Prospective studies indicate that a single self-report of high depressive symptoms is associated with an increased risk of developing type 2 diabetes mellitus. METHODS: We tested whether a single report of high depressive symptoms, an increase in depressive symptoms, or persistently high depressive symptoms over time were associated with the development of diabetes in adults 65 years and older. Participants from the Cardiovascular Health Study completed the 10-item Center for Epidemiological Studies-Depression Scale (CES-D) annually from 1989 to 1999. A single report of high depressive symptoms (CES-D score, >/=8), an increase in symptoms during follow-up (>/=5 from baseline), and persistently high symptoms (2 consecutive scores >/=8) were each studied in relation to incident diabetes, defined by initiation of diabetes control medications among participants who were free from diabetes at baseline (n = 4681). RESULTS: The mean CES-D score at baseline was 4.5 (SD, 4.5). The incidence rate of diabetes was 4.4 per 1000 person-years. Following adjustment for baseline demographic characteristics and measures of physical activity, smoking, alcohol intake, body mass index, and C-reactive protein during follow-up, each measure of depressive symptoms was significantly associated with incident diabetes (high baseline CES-D score: hazard ratio, 1.6 [95% confidence interval, 1.1-2.3]; CES-D score increase: hazard ratio, 1.5 [95% confidence interval, 1.1-2.2]; and persistently high symptoms: hazard ratio, 1.5 [95% confidence interval, 1.1-2.3]). CONCLUSION: Older adults who reported higher depressive symptoms were more likely to develop diabetes than their counterparts; this association was not fully explained by risk factors for diabetes.
Keywords: Aged; Body Mass Index; C-Reactive Protein; Depression; Diabetes Mellitus, Type 2; Drinking; Female; Humans; Longitudinal Studies; Male; Smoking

Physical activity and white matter lesion progression: assessment using MRI. - Podewils, L J; Guallar, E; Beauchamp, N; Lyketsos, C G; Kuller, L H; Scheltens, P (Neurology, 2007)
We evaluated the association between physical activity and changes in white matter lesions (WMLs) on MRI in a sample of 179 older adults comprising 59 incident cases of Alzheimer disease, 60 persons with mild cognitive impairment, and 60 persons who remained cognitively stable over a median 5-year follow-up. Physical activity was not significantly associated with a decreased rate of periventricular or deep WML progression.
Keywords: Activities of Daily Living; Aged; Alzheimer Disease; Cognition Disorders; Cohort Studies; Demyelinating Diseases; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Motor Activity; United States

Relationship between reported and measured sleep times: the sleep heart health study (SHHS). - Silva, Graciela E; Goodwin, James L; Sherrill, Duane L; Arnold, Jean L; Bootzin, Richard R; Smith, Terry; Walsleben, Joyce A; Baldwin, Carol M; Quan, Stuart F (J Clin Sleep Med, 2007)
STUDY OBJECTIVE: Subjective and objective assessments of sleep may be discrepant due to sleep misperception and measurement effects, the latter of which may change the quality and quantity of a person's usual sleep. This study compared sleep times from polysomnography (PSG) with self-reports of habitual sleep and sleep estimated on the morning after a PSG in adults. DESIGN: Total sleep time and sleep onset latency obtained from unattended home PSGs were compared to sleep times obtained from a questionnaire completed before the PSG and a Morning Survey completed the morning after the PSG. PARTICIPANTS: A total of 2,113 subjects who were > or = 40 years of age were included in this analysis. MEASURES AND RESULTS: Subjects were 53% female, 75% Caucasian, and 38% obese. The mean habitual sleep time (HABTST), morning estimated sleep time (AMTST), and PSG total sleep times (PSGTST) were 422 min, 379 min, and 363 min, respectively. The mean habitual sleep onset latency, morning estimated sleep onset latency, and PSG sleep onset latency were 17.0 min, 21.8 min, and 16.9 min, respectively. Models adjusting for related demographic factors showed that HABTST and AMTST differ significantly from PSGTST by 61 and 18 minutes, respectively. Obese and higher educated people reported less sleep time than their counterparts. Similarly, small but significant differences were seen for sleep latency. CONCLUSIONS: In a community population, self-reported total sleep times and sleep latencies are overestimated even on the morning following overnight PSG.
Keywords: Adult; Attitude to Health; Female; Health Status; Humans; Male; Middle Aged; Polysomnography; Psychometrics; Sleep Initiation and Maintenance Disorders; Sleep Stages; Surveys and Questionnaires; Time Factors; Wakefulness

The relationship of heart rate and heart rate variability to non-diabetic fasting glucose levels and the metabolic syndrome: the Cardiovascular Health Study. - Stein, P K; Barzilay, J I; Domitrovich, P P; Chaves, P M; Gottdiener, J S; Heckbert, S R; Kronmal, R A (Diabet Med, 2007)
BACKGROUND: Increased heart rate (HR) and diminished heart rate variability (HRV) are signs of early cardiovascular autonomic neuropathy. We tested the hypotheses that increased HR and diminished HRV are present in people: (i) with increased fasting glucose (FG) levels not in the range of diabetes mellitus (DM), and (ii) in people with the metabolic syndrome (MetS) independent of elevated FG levels. METHODS: HR and HRV were determined in 1267 adults (mean age 72 years) who had Holter monitoring and FG measures: 536 had normal FG levels (NORM, FG 4.5-5.5 mmol/l), 363 had mildly impaired FG (IFG-1, FG 5.6-6.0 mmol/l), 182 had significantly impaired FG (IFG-2, FG 6.1-6.9 mmol/l) and 178 had DM (FG > 6.9 mmol/l or use of glucose-lowering agents/insulin). HR and HRV in NORM/IFG-1 was further compared by the number of components of the MetS and compared by the presence or absence of MetS in IFG-2/DM. RESULTS: HRV indices were more impaired in IFG-2 and DM than in NORM or IFG-1. There were few differences in HRV indices between NORM and IFG-1 or between IFG-2 and DM. In NORM/IFG-1 participants, having > or = 2 components of the MetS was associated with a greater decrease in HRV compared with having no or one components. In IFG-2/DM participants, MetS was associated with decreased HRV compared with no MetS. CONCLUSIONS: Increased HR and diminished HRV occur in the non-diabetic FG range. Diminished HRV is associated with the MetS, independent of FG levels. Both these results suggest that factors associated with increasing non-diabetic FG levels and the MetS play a role in the onset of cardiac autonomic impairment.
Keywords: Aged; Aged, 80 and over; Arrhythmias, Cardiac; Blood Glucose; Fasting; Female; Glucose Intolerance; Heart Rate; Humans; Male; Metabolic Syndrome; Risk Factors

Retinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study. - Baker, Michelle L; Marino Larsen, Emily K; Kuller, Lewis H; Klein, Ronald; Klein, Barbara E K; Siscovick, David S; Bernick, Charles; Manolio, Teri A; Wong, Tien Yin (Stroke, 2007)
BACKGROUND AND PURPOSE: Cerebral microvascular disease may be a risk factor for the development of dementia in elderly persons. We describe the association of retinal microvascular signs with cognitive function and dementia among older individuals. METHODS: In the population-based Cardiovascular Health Study, 2211 persons aged 69 to 97 years at recruitment had retinal photography. Photographs were evaluated for retinopathy (eg, microaneurysms, retinal hemorrhages), focal arteriolar narrowing, arteriovenous nicking, and retinal arteriolar and venular caliber. Cognitive status was determined from the Digit-Symbol Substitution Test and Modified Mini-Mental State Examination. Participants were also further evaluated for the presence of dementia with detailed neuropsychological testing. Persons with a prior stroke or taking antipsychotic or antidepressant medications were excluded. RESULTS: After adjusting for age, gender, race, field center, education level, internal carotid intima-media thickness, body mass index, hypertension, diabetes, and cigarette smoking status, persons with retinopathy had lower mean Digit-Symbol Substitution Test scores but not Modified Mini-Mental State Examination than those without retinopathy (39 versus 41, P=0.002). In hypertensive persons, retinopathy (multivariable-adjusted OR, 2.10; 95% CI, 1.04 to 4.24) and focal arteriolar narrowing (OR, 3.02; 95% CI, 1.51 to 6.02) were associated with dementia. These associations were not present in individuals without hypertension. CONCLUSIONS: In older persons, our study shows a modest cross-sectional association between retinopathy signs with poorer cognitive function and, in persons with hypertension, with dementia. These data support a possible role of cerebral microvascular disease in the pathogenesis of impaired cognitive function and dementia in older hypertensive persons.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Cognition; Cross-Sectional Studies; Dementia; Female; Humans; Longitudinal Studies; Male; Microcirculation; Neuropsychological Tests; Retinal Vessels; Risk Factors

Socioeconomic position and incident mobility impairment in the Cardiovascular Health Study. - Nordstrom, Cheryl K; Diez Roux, Ana V; Schulz, Richard; Haan, Mary N; Jackson, Sharon A; Balfour, Jennifer L (BMC Geriatr, 2007)
BACKGROUND: We investigated if personal socioeconomic position (SEP) factors and neighborhood characteristics were associated with incident mobility impairment in the elderly. METHODS: We used data from the Cardiovascular Health Study, a longitudinal, population-based examination of coronary heart disease and stroke among persons aged 65 and older in the United States. RESULTS: Among 3,684 persons without baseline mobility impairment, lower baseline SEP was associated with increased risk of incident mobility disability during the 10-year follow-up period, although the strengths of these associations varied by socioeconomic indicator and race/sex group. CONCLUSION: Among independent-living elderly, SEP affected development of mobility impairment into later life. Particular effort should be made to prevent or delay its onset among the elderly with low income, education, and/or who live in economically disadvantaged neighborhoods.
Keywords: Aged; Aged, 80 and over; Coronary Disease; Disabled Persons; Education; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Male; Mobility Limitation; Residence Characteristics; Social Class; Stroke; United States

Ventricular structure and function in hypertensive participants with heart failure and a normal ejection fraction: the Cardiovascular Health Study. - Maurer, Mathew S; Burkhoff, Daniel; Fried, Linda P; Gottdiener, John; King, Donald L; Kitzman, Dalane W (J Am Coll Cardiol, 2007)
OBJECTIVES: The purpose of this study was to evaluate left ventricular (LV) size and structure in elderly subjects with hypertension (HTN) and heart failure who have a normal ejection fraction (HFNEF) in a large population-based sample. BACKGROUND: The pathophysiology of HFNEF is incompletely understood but is generally attributed to LV diastolic dysfunction with normal or reduced LV diastolic chamber size despite greater than normal filling pressures. METHODS: In the Cardiovascular Health Study (n = 5,888), demographic and clinical characteristics and ventricular structure and function were compared in healthy normal subjects (healthy; n = 499), subjects with HTN but not heart failure (HTN; n = 2,184), and subjects with HTN and HFNEF (HFNEF; n = 167). RESULTS: Subjects with HFNEF were older, more obese, and more often African American than healthy and HTN subjects and had a higher prevalence of diabetes, coronary heart disease, and anemia than HTN subjects. Serum creatinine and cystatin-C were increased in HFNEF subjects. Average LV diastolic dimension was significantly increased in HFNEF subjects (5.2 +/- 0.8 cm) compared with healthy (4.8 +/- 0.6 cm) and HTN (4.9 +/- 0.6 cm) subjects. As a result, average calculated stroke volume (89 +/- 25 ml vs. 78 +/- 20 ml and 80 +/- 20 ml) and cardiac output (6.0 +/- 2.0 l/min vs. 4.8 +/- 1.3 l/min and 5.1 +/- 1.4 l/min) were increased in HFNEF compared with healthy and HTN subjects, respectively. CONCLUSIONS: As a group, HFNEF subjects have increased LV diastolic diameter and increased calculated stroke volume. They also have increased prevalence of multiple comorbidities, including anemia, renal dysfunction, and obesity, that can cause volume overload. These data suggest that extracardiac factors, via volume overload, may contribute to the pathophysiology of HFNEF in the elderly.
Keywords: Age Distribution; Aged; Body Size; Case-Control Studies; Cohort Studies; Comorbidity; Continental Population Groups; Echocardiography; Female; Heart Failure; Heart Ventricles; Humans; Hypertension; Longitudinal Studies; Male; Multivariate Analysis; Prevalence; Regression Analysis; Risk Factors; Sex Distribution; Stroke Volume; United States

Ventricular volume and dementia progression in the Cardiovascular Health Study. - Carmichael, Owen T; Kuller, Lewis H; Lopez, Oscar L; Thompson, Paul M; Dutton, Rebecca A; Lu, Allen; Lee, Sharon E; Lee, Jessica Y; Aizenstein, Howard J; Meltzer, Carolyn Cidis; Liu, Yanxi; Toga, Arthur W; et al. (Neurobiol Aging, 2007)
Elevated cerebral ventricular volume may be associated with dementia risk and progression. A fully-automated technique that agreed highly with radiological readings was used to estimate lateral ventricle volume on MR scans done at baseline in 1997-99 of 377 subjects in the Cardiovascular Health Study (CHS) from the Pittsburgh Center. 327 subjects were normal or diagnosed with mild cognitive impairment (MCI) at baseline and were evaluated 4 years later. Baseline ventricular volume was analyzed in multivariate models with age, gender, education level, presence and incidence of cerebral infarcts, and dementia category (normal, MCI, or dementia) at baseline and follow-up as fixed effects. Ventricular volume at baseline was significantly higher among subjects normal at baseline and demented 4 years later. Age, gender, education level, and dementia progression were significant factors affecting ventricular volume. Ventricular volume was higher in dementia compared to MCI, higher in MCI compared to controls, and higher in Possible-Alzheimer's-disease (AD) dementia compared to Probable-AD. Larger ventricles in healthy subjects may indicate susceptibility to, or progression of, dementia-related pathology.
Keywords: Aged; Aged, 80 and over; Aging; Cognition Disorders; Cross-Sectional Studies; Dementia; Disease Progression; Female; Follow-Up Studies; Humans; Lateral Ventricles; Linear Models; Magnetic Resonance Imaging; Male; Predictive Value of Tests; Prospective Studies; Retrospective Studies; Time Factors

White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study. - Kuller, Lewis H; Arnold, Alice M; Longstreth, W T; Manolio, Teri A; O'Leary, Daniel H; Burke, Gregory L; Fried, Linda P; Newman, Anne B (Neurobiol Aging, 2007)
High white matter grade (WMG) on magnetic resonance imaging (MRI) is a risk factor for dementia, stroke and disability. Higher ventricular size is a marker of brain "atrophy." In the Cardiovascular Health Study (CHS) (n=3245) mean age 75 years, 50% black and 40% men, we evaluated WM and ventricular grade (VG), total, cardiovascular and noncardiovascular mortality and longevity before and after adjusting for numerous determinants of longevity over an approximate 10-12 years of follow-up. A low WMG and VG was a marker for low total, cardiovascular and noncardiovascular mortality and for increased longevity over 10+ years of follow-up. We estimated that a 75-year-old with WMG below median would have about a 5-6 years greater longevity and for VG about 3 years, than above the median even after adjustment for numerous risk factors. Low WMG and VG on MRI is a powerful determinant of long-term survival among older individuals.
Keywords: African Continental Ancestry Group; Aged; Aged, 80 and over; Biomarkers; Brain; Cardiovascular Diseases; Cerebral Ventricles; European Continental Ancestry Group; Female; Geriatric Assessment; Health Status; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Retrospective Studies; Risk Factors; Sex Factors

Abnormal regional cerebral blood flow in cognitively normal elderly subjects with hypertension. - Dai, Weiying; Lopez, Oscar L; Carmichael, Owen T; Becker, James T; Kuller, Lewis H; Gach, H Michael (Stroke, 2008)
BACKGROUND AND PURPOSE: The purpose of this study was to examine regional cerebral blood flow (rCBF) in normal cognitive-performing subjects with hypertension (HTN) using continuous arterial spin-labeled MRI. The most common explanation for the effect of blood pressure on cognition is that HTN increases the risk of cerebrovascular disease, and it may increase the risk for Alzheimer disease possibly through small vessel disease, ischemia, oxidative stress, and inflammation. However, few studies to date have examined the rCBF of cognitively normal subjects with HTN in population-based cohorts, and none have used continuous arterial spin-labeled MRI. This is a noninvasive technique that does not require either injections or ionizing radiation and can measure absolute rCBF rates over the entire brain. METHODS: rCBF was measured at 1.5 T using continuous arterial spin-labeled MRI in 41 cognitively normal subjects who were participating in the Cardiovascular Health Study Cognition Study. A deformable atrophy-corrected registration method was used to warp the rCBF maps to the standard colin27 brain space. Image and cluster-based statistical analyses were performed between subject groups. RESULTS: Cognitively normal subjects with HTN (n=19) had decreased rCBF in the putamen, globus pallidus, bilaterally, and in the left hippocampus compared with normotensives (n=22). In addition, decreased rCBF was observed in the right and left anterior cingulate gyrus with extension to the subcallosal region, left posterior cingulate gyrus and medial precuneus, left lateral inferior and superior frontal, and inferior parietal, left orbitofrontal, and left superior temporal cortices. CONCLUSIONS: rCBF is affected in normal subjects with HTN, not only in the subcortical regions, but also in limbic and paralimbic structures. We hypothesize that the HTN creates a vulnerability state for the development of neurodegenerative disorders, especially Alzheimer disease.
Keywords: Aged; Aged, 80 and over; Cerebral Cortex; Cerebrovascular Circulation; Cognition; Cognition Disorders; Female; Globus Pallidus; Gyrus Cinguli; Humans; Hypertension; Magnetic Resonance Imaging; Male; Putamen; Spin Labels

Adiponectin and risk of coronary heart disease in older men and women. - Kizer, Jorge R; Barzilay, Joshua I; Kuller, Lewis H; Gottdiener, John S (J Clin Endocrinol Metab, 2008)
CONTEXT: Despite established insulin-sensitizing and antiatherogenic preclinical effects, epidemiological investigations of adiponectin have yielded conflicting findings, and its relationship with coronary heart disease (CHD) remains uncertain. OBJECTIVE: Our objective was to investigate the relationship between adiponectin and CHD in older adults. DESIGN, SETTING, AND PARTICIPANTS: This was a case-control study (n = 1386) nested within the population-based Cardiovascular Health Study from 1992--2001. Controls were frequency-matched to cases by age, sex, race, subclinical cardiovascular disease, and center. MAIN OUTCOME MEASURES: Incident CHD was defined as angina pectoris, percutaneous or surgical revascularization, nonfatal myocardial infarction (MI), or CHD death. A more restrictive CHD endpoint was limited to nonfatal MI and CHD death. RESULTS: Adiponectin exhibited significant negative correlations with baseline adiposity, insulin resistance, dyslipidemia, inflammatory markers, and leptin. After controlling for matching factors, adjustment for waist to hip ratio, hypertension, smoking, alcohol, low-density lipoprotein cholesterol, creatinine, and leptin revealed a modestly increased risk of incident CHD with adiponectin concentrations at the upper end [odds ratio = 1.37 (quintile 5 vs. 1-4), 95% confidence interval 1.02-1.84]. This association was stronger when the outcome was limited to nonfatal MI and fatal CHD (odds ratio = 1.69, 95% confidence interval 1.23-2.32). The findings were not influenced by additional adjustment for weight change, health status, or cystatin C, nor were they abolished by adjustment for potential mediators. CONCLUSIONS: This study shows an association between adiponectin and increased risk of first-ever CHD in older adults. Further research is needed to elucidate the basis for the concurrent beneficial and detrimental aspects of this relationship, and under what circumstances one or the other may predominate.
Keywords: Adiponectin; Age Factors; Aged; Aged, 80 and over; Body Weight; Case-Control Studies; Cohort Studies; Coronary Disease; Female; Humans; Longitudinal Studies; Male; Odds Ratio; Risk Factors

Albuminuria and dementia in the elderly: a community study. - Barzilay, Joshua I; Fitzpatrick, Annette L; Luchsinger, Jose; Yasar, Sevil; Bernick, Charles; Jenny, Nancy S; Kuller, Lewis H (Am J Kidney Dis, 2008)
BACKGROUND: Dementia is associated with microvascular disease of the retina. In this study, we examine whether cognitive status (normal cognition, mild cognitive impairment, and dementia) is associated with albuminuria, a microvascular disorder of the kidney. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: 2,316 participants from the Cardiovascular Health Cognition Study who underwent brain magnetic resonance imaging and testing for albuminuria. PREDICTOR: Doubling of albuminuria. OUTCOME: Dementia defined according to neuropsychological and clinical evaluation. MEASUREMENTS: Multinomial logistic modeling was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of dementia and mild cognitive impairment with doubling of albuminuria compared with the odds with normal cognition. RESULTS: 283 participants (12.2%) had dementia, 344 (14.9%) had mild cognitive impairment, and 1,689 (72.9%) had normal cognition. Compared with participants with normal cognition, doubling of albuminuria was associated with increased odds of dementia (OR, 1.22; 95% CI, 1.15 to 1.29). Adjustment for prevalent cardiovascular disease and cardiovascular risk factors, lipid levels, C-reactive protein level, estimated glomerular filtration rate, and apolipoprotein E-4 genotype attenuated this association, but it remained statistically significant (OR, 1.12; 95% CI, 1.03 to 1.22). Mild cognitive impairment was associated with albuminuria on unadjusted analysis, but not with adjustment for other factors. LIMITATIONS: Results are cross-sectional; causality cannot be imputed. CONCLUSIONS: The odds of dementia increased in the presence of albuminuria. These findings suggest a role of shared susceptibility for microvascular disease in the brain and kidney in older adults.
Keywords: Age Factors; Aged; Aged, 80 and over; Albuminuria; Brain; Cognition; Cross-Sectional Studies; Dementia; Female; Humans; Incidence; Magnetic Resonance Imaging; Male; Odds Ratio; Population Surveillance; Prognosis; Retrospective Studies; Risk Factors

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. - Fowkes, F G R; Murray, G D; Butcher, I; Heald, C L; Lee, R J; Chambless, L E; Folsom, A R; Hirsch, A T; Dramaix, M; deBacker, G; Wautrecht, J-C; Kornitzer, M; et al. (JAMA, 2008)
CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Ankle; Atherosclerosis; Blood Pressure; Brachial Artery; Cardiovascular Diseases; Cohort Studies; Confidence Intervals; Female; Global Health; Humans; Male; Middle Aged; Odds Ratio; Predictive Value of Tests; Risk Assessment; Risk Factors; Severity of Illness Index

Antidepressant treatment and worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. - Steffens, David C; Chung, Hyoju; Krishnan, K Ranga R; Longstreth, W T; Carlson, Michelle; Burke, Gregory L (Stroke, 2008)
BACKGROUND AND PURPOSE: In some studies, late life depression is associated with white matter lesions on MRI. The effect of different classes of antidepressants on progression of white matter lesions is unknown. Selective serotonergic reuptake inhibitors (SSRIs) may decrease platelet aggregation. We hypothesized that Cardiovascular Health Study participants taking SSRIs would less often have worsening white matter on serial MRI than participants not on antidepressants. METHODS: Among 1826 participants who were not using an antidepressant at initial MRI scan, we examined the association of worsening in white matter grade from initial to follow-up MRI scans, 5 years apart on average, and antidepressant use between the scans. Logistic regression models were used, controlling for a variety of potential confounding variables. RESULTS: Use of any antidepressant during the period of study was associated with worsening white matter. In a multivariable model, risk was slightly increased, not reduced, with use of serotonergic agents (OR 1.36, 95% CI 0.87 to 2.12) and was significantly increased with the use of tricyclic antidepressants (OR 1.77, 95% CI 1.07 to 2.94). CONCLUSIONS: The association between worsening white matter and use of tricyclic antidepressants was an unexpected finding that may relate to indications for use other than depression or to side effects such as hypotension. Protection against worsening was not seen with use of serotonergic agents.
Keywords: Aged; Antidepressive Agents; Antidepressive Agents, Tricyclic; Cohort Studies; Disease Progression; Female; Follow-Up Studies; Humans; Leukoaraiosis; Magnetic Resonance Imaging; Male; Multivariate Analysis; Risk Assessment; Serotonin Uptake Inhibitors

Association between brachial artery reactivity and cardiovascular disease status in an elderly cohort: the cardiovascular health study. - Yeboah, Joseph; Sutton-Tyrrell, Kim; McBurnie, Mary Ann; Burke, Gregory L; Herrington, David M; Crouse, John R (Atherosclerosis, 2008)
BACKGROUND AND OBJECTIVES: The association of brachial flow-mediated dilation (FMD) and cardiovascular disease (CVD) status is unclear especially in older adults whose FMD is greatly diminished. We assessed the association of FMD and the presence or absence of subclinical and clinical CVD in a population based cohort of older adults. METHODS AND RESULTS: FMD was measured in 2971 adults aged 72-98 years (mean age 78.6 years) who participated in the Cardiovascular Health Study. Multiple linear regression analysis was used to examine the association between FMD and CVD status (clinical, subclinical and free of CVD). Out of 2791 with complete data, 82.7% were Caucasians and 59% females. Seven hundred and forty-three were classified as having clinical CVD, 607 as subclinical CVD and 1441 as neither clinical CVD nor subclinical CVD (CVD free). FMD was higher in the CVD free group compared with either the clinical (3.13+/-0.05% vs 2.93+/-0.07%, p=0.025) or the subclinical CVD group (3.13+/-0.05% vs 2.95+/-0.08%, p=0.05) after adjusting for covariates. There was no significant difference between the FMD of subjects with clinical and subclinical CVD (2.93+/-0.07% vs 2.95+/-0.08%, p=0.84). Similar but inverted associations were observed between height adjusted brachial artery diameter (BAD) and CVD status. However, FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD. CONCLUSION: Among older adults, those with either clinical or subclinical CVD have lower FMD than CVD free subjects. BAD showed similar but inverted associations with CVD status in this cohort. FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.
Keywords: Aged; Aged, 80 and over; Biomarkers; Brachial Artery; Cardiovascular Diseases; Cohort Studies; Female; Hemorheology; Humans; Male; Peripheral Vascular Diseases; ROC Curve; Ultrasonography; Vasodilation

Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. - Shiffman, Dov; O'Meara, Ellen S; Bare, Lance A; Rowland, Charles M; Louie, Judy Z; Arellano, Andre R; Lumley, Thomas; Rice, Kenneth; Iakoubova, Olga; Luke, May M; Young, Bradford A; Malloy, Mary J; et al. (Arterioscler Thromb Vasc Biol, 2008)
OBJECTIVE: We asked whether single nucleotide polymorphisms (SNPs) that had been nominally associated with cardiovascular disease in antecedent studies were also associated with cardiovascular disease in a population-based prospective study of 4522 individuals aged 65 or older. METHODS AND RESULTS: Based on antecedent studies, we prespecified a risk allele and an inheritance model for each of 74 SNPs. We then tested the association of these SNPs with myocardial infarction (MI) in the Cardiovascular Health Study (CHS). The prespecified risk alleles of 8 SNPs were nominally associated (1-sided P<0.05) with increased risk of MI in White CHS participants. The false discovery rate for these 8 was 0.43, suggesting that about 4 of these 8 are likely to be true positives. The 4 of these 8 SNPs that had the strongest evidence for association with cardiovascular disease before testing in CHS (association in 3 antecedent studies) were in KIF6 (CHS HR=1.29; 90%CI 1.1 to 1.52), VAMP8 (HR=1.2; 90%CI 1.02 to 1.41), TAS2R50 (HR=1.13; 90%CI 1 to 1.27), and LPA (HR=1.62; 90%CI 1.09 to 2.42). CONCLUSIONS: Although most of the SNPs investigated were not associated with MI in CHS, evidence from this investigation combined with previous studies suggests that 4 of these SNPs are likely associated with MI.
Keywords: African Americans; Aged; Aged, 80 and over; Coronary Disease; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Humans; Longitudinal Studies; Male; Myocardial Infarction; National Heart, Lung, and Blood Institute (U.S.); Polymorphism, Single Nucleotide; Proportional Hazards Models; United States

Cardiovascular and mortality risk prediction and stratification using urinary albumin excretion in older adults ages 68-102: the Cardiovascular Health Study. - Cao, Jie J; Biggs, Mary L; Barzilay, Joshua; Konen, Joseph; Psaty, Bruce M; Kuller, Lewis; Bleyer, Anthony J; Olson, Jean; Wexler, Jason; Summerson, John; Cushman, Mary (Atherosclerosis, 2008)
BACKGROUND: Elevated urinary albumin excretion (UAE) is associated with the risk of cardiovascular disease (CVD) and all-cause mortality. We tested the hypothesis that elevated UAE improves cardiovascular risk stratification in an elderly cohort aged 68-102 years. METHODS: We evaluated UAE in 3112 participants of the Cardiovascular Health Study who attended the 1996-1997 examination and had median follow up of 5.4 years. Elevated UAE was defined as urinary albumin to creatinine ratio > or =30 microg/mg. Microalbuminuria and macroalbuminuria were defined as urinary albumin to creatinine ratio 30-300 microg/mg and >300 microg/mg, respectively. Outcomes included CVD (myocardial infarction, stroke, cardiovascular death) and all-cause mortality. Cox proportional hazards models were used to assess the risk of outcomes associated with elevated UAE. RESULTS: The prevalence of elevated UAE was 14.3%, 17.1% and 26.9% in those aged 68-74, 75-84 and 85-102 years, respectively. CVD incidence and all-cause mortality were doubled (7.2% and 8.1% per year) in those with microalbuminuria and tripled (11.1% and 12.3% per year) in those with macroalbuminuria compared to those with normal UAE (3.3% and 3.8% per year). The increased CVD and mortality risks were observed in all age groups after adjustment for conventional risk factors. The adjusted population attributable risk percent of CVD and all-cause mortality for elevated UAE was 11% and 12%, respectively. When participants were cross-classified by UAE and Framingham Risk Score categories, the 5-year cumulative incidence of coronary heart disease among participants with elevated UAE and a 5-year predicted risk of 5-10% was 20%, substantially higher than 6.3% in those with UAE <30m microg/mg. CONCLUSION: Elevated UAE was associated with an increased risk of CVD and all-cause mortality in all age groups from 68 to 102 years. Combining elevated UAE with the Framingham risk scores may improve risk stratification for CVD in the elderly.
Keywords: Aged; Aged, 80 and over; Albuminuria; Biomarkers; Cohort Studies; Coronary Disease; Cross-Sectional Studies; Female; Health Surveys; Humans; Male; Predictive Value of Tests; Risk

Coronary artery calcium, carotid artery wall thickness, and cardiovascular disease outcomes in adults 70 to 99 years old. - Newman, Anne B; Naydeck, Barbara L; Ives, Diane G; Boudreau, Robert M; Sutton-Tyrrell, Kim; O'Leary, Daniel H; Kuller, Lewis H (Am J Cardiol, 2008)
Few population studies have evaluated the associations of both coronary artery calcium (CAC) and carotid ultrasound with cardiovascular events, especially in adults >70 years of age. At the Pittsburgh Field Center of the Cardiovascular Health Study, 559 men and women, mean age 80.2 (SD 4.1) years had CAC score assessed by electron beam computerized tomographic scan and common and internal carotid artery intimal medial wall thickness (CCA-IMT and ICA-IMT) by carotid ultrasound between 1998 and 2000 and were followed for total and incident cardiovascular disease events through June 2003. Crude rates and hazard ratios for total and incident events were examined with and without adjustment for cardiovascular risk factors. After 5 years, there were 127 cardiovascular disease events, 48 myocardial infarctions or cardiovascular disease deaths, and 28 strokes or stroke deaths. Total and incident cardiovascular disease event rates were higher in each quartile of CAC and CCA-IMT, but not of ICA-IMT. For total cardiovascular disease, the adjusted hazard ratio for the fourth versus first quartile of CAC was 2.1 (95% confidence interval 1.2 to 3.9) and for CCA-IMT was 2.3 (95% confidence interval 1.3 to 4.1). The CCA-IMT was more strongly related to stroke risk than was CAC, although CAC was also an important predictor of stroke. No significant gender differences were found, although relative risks appeared to be stronger in women, especially for stroke. In conclusion, in adults >70 years of age, CAC and CCA-IMT had similar hazard ratios for total cardiovascular disease and coronary heart disease. The CCA-IMT was more strongly related to stroke than CAC, but CAC was also a predictor of stroke.
Keywords: Aged; Aged, 80 and over; Carotid Artery Diseases; Carotid Artery, Common; Carotid Artery, Internal; Coronary Artery Disease; Coronary Vessels; Female; Humans; Male; ROC Curve; Severity of Illness Index; Survival Analysis; Ultrasonography; United States

Diabetes mellitus and gait dysfunction: possible explanatory factors. - Brach, Jennifer S; Talkowski, Jaime B; Strotmeyer, Elsa S; Newman, Anne B (Phys Ther, 2008)
BACKGROUND AND OBJECTIVE: Gait characteristics differ in individuals with diabetes compared with those without diabetes. Limited information regarding potential explanatory factors for this association exists. This study examined the association between diabetes and gait characteristics in older adults and explored potential explanatory factors. DESIGN: A cross-sectional, observational study design was used. METHODS: At the 1998-1999 clinic visit, 558 ambulatory older adults (mean age=79 years) from the Pittsburgh site of the Cardiovascular Health Study had an assessment of their gait characteristics, diabetes, health status, cognition, mood, lower-extremity circulation and sensation, vision, lower-extremity strength (force-producing capacity), physical activity, and body mass index (BMI). A series of linear regression models were developed to examine the association between diabetes and gait characteristics and to examine potential explanatory factors for the associations. RESULTS: Diabetes was related to gait speed (beta=-.06 m/s); however, the association was partially explained by health status variables, cognition, mood, lower-extremity circulation and sensation, visual impairment, lower-extremity strength, physical activity, and BMI. Health status and lower-extremity strength each explained the greatest proportion of the association (beta reduced 66% by each). Diabetes was related to step width (beta=.02 m), and the association could not be explained by the examined factors. CONCLUSIONS: Diabetes was associated with gait alterations in older adults. Slowed gait speed appears to be secondary to the peripheral effect of the disease on other body systems. The effect of diabetes on step width was not explained in the analyses and may be related to peripheral motor nerve function or central influences of the disease, which could not be assessed in this study.
Keywords: Aged; Body Mass Index; Cognition; Cross-Sectional Studies; Diabetes Mellitus; Female; Gait; Geriatric Assessment; Health Status; Humans; Linear Models; Longitudinal Studies; Male; Multicenter Studies as Topic; Muscle Strength

Higher levels of inflammation factors and greater insulin resistance are independently associated with higher heart rate and lower heart rate variability in normoglycemic older individuals: the Cardiovascular Health Study. - Stein, Phyllis K; Barzilay, Joshua I; Chaves, Paulo H M; Traber, Jennifer; Domitrovich, Peter P; Heckbert, Susan R; Gottdiener, John S (J Am Geriatr Soc, 2008)
OBJECTIVES: To explore the relationship between (1) insulin resistance and inflammation factors with (2) higher heart rate (HR) and lower heart rate variability (HRV) in normoglycemic older adults. DESIGN: Cross-sectional population-based study. PARTICIPANTS: Five hundred forty-five adults aged 65 and older with normoglycemia (fasting glucose <100 mg/dL) who participated in the Cardiovascular Health Study. MEASUREMENTS: Serum levels of three inflammation proteins (C-reactive protein (CRP), interleukin 6 (IL-6), and fibrinogen); insulin resistance, quantified according to the homeostasis assessment model (HOMA-IR); HR; and four representative measures of HRV (the standard deviation of normal beat to beat intervals (SDNN), the root mean square of successive differences (rMSSD), very low frequency power (VLF), and the low- to high-frequency power ratio (LF/HF)) derived from 24-hour Holter recordings. RESULTS: High CRP and IL-6 levels were associated with higher HR and lower SDNN and VLF after adjustment for multiple covariates, including HOMA-IR and clinical cardiovascular disease. High IL-6 was also associated with lower LF/HF. Significant univariate inverse relationships between HOMA-IR and HR and HRV were also found, but the strengths of these relationships were attenuated after adjustment for inflammation factors. CONCLUSION: Increased levels of inflammation markers and HOMA-IR are associated with higher HR and lower HRV. These findings suggest that inflammation may contribute to the pathogenesis of cardiovascular autonomic decline in older adults.
Keywords: Aged; C-Reactive Protein; Cardiovascular Diseases; Cross-Sectional Studies; Electrocardiography, Ambulatory; Female; Fibrinogen; Heart Rate; Humans; Inflammation Mediators; Insulin Resistance; Interleukin-6; Male; Risk Factors

Impact of health perception, balance perception, fall history, balance performance, and gait speed on walking activity in older adults. - Talkowski, Jaime B; Brach, Jennifer S; Studenski, Stephanie; Newman, Anne B (Phys Ther, 2008)
BACKGROUND AND PURPOSE: Disagreement currently exists regarding the contributions of various factors to physical activity in older adults. The purpose of this cross-sectional study was to investigate the simultaneous impact of psychological (health perception and balance perception) and physiological (gait speed, fall history, and balance performance) factors on walking activity in older adults. SUBJECTS AND METHODS: This cross-sectional secondary data analysis included 2,269 community-dwelling older adults from the Cardiovascular Health Study. A series of simultaneous linear regression models were constructed to examine the association of walking activity with health and balance perception, gait speed, fall history, and balance performance after controlling for potential confounding factors. RESULTS: Health and balance perception and gait speed were significantly related to walking activity after controlling for potential confounding factors. Participants who perceived both their health and their balance to be good walked more blocks per week than those who reported a discordant perception, who walked more than those who perceived both their health and their balance to be poor. Participants who walked at a normal speed walked more blocks per week than those who walked at a slow speed. DISCUSSION AND CONCLUSION: The measure of physical activity used in this study included only walking, not other low- to moderate-intensity activities that are common in older adults. Health and balance perception and gait speed were associated with walking activity more so than fall history or balance performance after controlling for potential confounding factors.
Keywords: Accidental Falls; Aged; Aged, 80 and over; Attitude to Health; Cross-Sectional Studies; Female; Gait; Geriatric Assessment; Health Status; Humans; Male; Motor Activity; Multivariate Analysis; Perception; Postural Balance; Risk Assessment; Walking

Incident physical disability in people with lower extremity peripheral arterial disease: the role of cardiovascular disease. - Brach, Jennifer S; Solomon, Cam; Naydeck, Barbara L; Sutton-Tyrrell, Kim; Enright, Paul L; Jenny, Nancy Swords; Chaves, Paulo M; Newman, Anne B (J Am Geriatr Soc, 2008)
OBJECTIVES: To evaluate the risk of incident physical disability and the decline in gait speed over a 6-year follow-up associated with a low ankle-arm index (AAI) in older adults. DESIGN: Observational cohort study. SETTING: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania. PARTICIPANTS: Four thousand seven hundred five older adults, 58% women and 17.6% black, participating in the Cardiovascular Health Study. MEASUREMENTS: AAI was measured in 1992/93 (baseline). Self-reported mobility, activity of daily living (ADL), and instrumental activity of daily living (IADL) disability and gait speed were recorded at baseline and at 1-year intervals over 6 years of follow-up. Mobility disability was defined as any difficulty walking half a mile and ADL and IADL disability was defined as any difficulty with 11 specific ADL and IADL tasks. Individuals with mobility, ADL, or IADL disability at baseline were excluded from the respective incident disability analyses. RESULTS: Lower baseline AAI values were associated with increased risk of mobility disability and ADL/IADL disability. Clinical cardiovascular disease (CVD), diabetes mellitus, and interim CVD events partially explained these associations for mobility disability and clinical CVD and diabetes mellitus partially explained these associations for ADL and IADL disability. Individuals with an AAI less than 0.9 had on average a mean decrease in gait speed of 0.02 m/s per year, or a decline of 0.12 m/s over the 6-year follow-up. Prevalent CVD partly explained this decrease but interim CVD events did not further attenuate it. CONCLUSION: Low AAI serves as marker of future disability risk. Reduction of disability risk in patients with a low AAI should consider cardiovascular comorbidity and the prevention of additional disabling CVD events.
Keywords: Activities of Daily Living; Aged; Cardiovascular Diseases; Cohort Studies; Comorbidity; Disability Evaluation; Female; Gait; Geriatric Assessment; Humans; Lower Extremity; Male; Mobility Limitation; Peripheral Vascular Diseases; Proportional Hazards Models; Risk Assessment; Risk Factors; United States

Inflammatory markers and longitudinal lung function decline in the elderly. - Jiang, Rui; Burke, Gregory L; Enright, Paul L; Newman, Anne B; Margolis, Helene G; Cushman, Mary; Tracy, Russell P; Wang, Yuanjia; Kronmal, Richard A; Barr, R Graham (Am J Epidemiol, 2008)
Longitudinal studies examining associations of the inflammatory markers fibrinogen and C-reactive protein (CRP) with lung function decline are sparse. The authors examined whether elevated fibrinogen and CRP levels were associated with greater longitudinal lung function decline in the elderly. The Cardiovascular Health Study measured fibrinogen and CRP in 5,790 Whites and African Americans from four US communities aged 65 years or older in 1989-1990 or 1992-1993. Spirometry was performed in 1989-1990 and 4, 7, and 16 years later. Fibrinogen and CRP were inversely associated with lung function at baseline after adjustment for multiple potential confounders. In mixed models, the rate of decline in forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) ratio with increasing age was faster among those with higher baseline fibrinogen (-0.032%/year per standard deviation higher fibrinogen (95% confidence interval: -0.057, -0.0074)) but not among those with higher CRP (-0.0037%/year per standard deviation higher CRP (95% confidence interval: -0.013, 0.0056)). Longitudinal analyses for FEV(1) and FVC yielded results in the direction opposite of that hypothesized, possibly because of the high mortality rate and strong inverse association of FEV(1) and FVC but not FEV(1)/FVC with mortality. An alternative approach to missing data yielded similar results. In conclusion, higher levels of fibrinogen, but not CRP, independently predicted greater FEV(1)/FVC decline in the elderly.
Keywords: Aged; C-Reactive Protein; Cross-Sectional Studies; Female; Fibrinogen; Forced Expiratory Volume; Geriatric Assessment; Humans; Logistic Models; Longitudinal Studies; Lung Volume Measurements; Male; Multicenter Studies as Topic; Pulmonary Disease, Chronic Obstructive; Spirometry

Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. - Roddam, Andrew W; Allen, Naomi E; Appleby, Paul; Key, Timothy J; Ferrucci, Luigi; Carter, H Ballentine; Metter, E Jeffrey; Chen, Chu; Weiss, Noel S; Fitzpatrick, Annette; Hsing, Ann W; Lacey, James V; et al. (Ann Intern Med, 2008)
BACKGROUND: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer. PURPOSE: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer. DATA SOURCES: Studies identified in PubMed, Web of Science, and CancerLit. STUDY SELECTION: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate. DATA EXTRACTION: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom. DATA SYNTHESIS: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake. LIMITATIONS: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies. CONCLUSION: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.
Keywords: Aged; Humans; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Risk Factors; Somatomedins

Left ventricular morphology and systolic function in sleep-disordered breathing: the Sleep Heart Health Study. - Chami, Hassan A; Devereux, Richard B; Gottdiener, John S; Mehra, Reena; Roman, Mary J; Benjamin, Emelia J; Gottlieb, Daniel J (Circulation, 2008)
BACKGROUND: Whether sleep-disordered breathing (SDB) is a risk factor for left ventricular (LV) hypertrophy and dysfunction is controversial. We assessed the relation of SDB to LV morphology and systolic function in a community-based sample of middle-aged and older adults. METHODS AND RESULTS: The present study was a cross-sectional observational study of 2058 Sleep Heart Health Study participants (mean age 65+/-12 years; 58% women; 44% ethnic minorities) who had technically adequate echocardiograms. A polysomnographically derived apnea-hypopnea index (AHI) and hypoxemia index (percent of sleep time with oxyhemoglobin saturation < 90%) were used to quantify SDB severity. LV mass index was significantly associated with both AHI and hypoxemia index after adjustment for age, sex, ethnicity, study site, body mass index, current and prior smoking, alcohol consumption, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and prevalent myocardial infarction. Adjusted LV mass index was 41.3 (SD 9.90) g/m(2.7) in participants with AHI < 5 (n=957) and 44.1 (SD 9.90) g/m(2.7) in participants with AHI > or = 30 (n=84) events per hour. Compared with participants with AHI < 5, those with AHI > or = 30 had an adjusted odds ratio of 1.78 (95% confidence interval 1.14 to 2.79) for LV hypertrophy. A higher AHI and higher hypoxemia index were also associated with larger LV diastolic dimension and lower LV ejection fraction, with a trend toward lower LV fractional shortening. LV wall thickness was significantly associated with the hypoxemia index but not with AHI. Left atrial diameter was not associated with either SDB measure. CONCLUSIONS: In a community-based cohort, SDB is associated with echocardiographic evidence of increased LV mass and reduced LV systolic function.
Keywords: Aged; Echocardiography; Female; Humans; Hypertrophy, Left Ventricular; Hypoxia; Male; Middle Aged; Odds Ratio; Sleep Apnea Syndromes; Systole; Ventricular Dysfunction, Left

Lipoprotein-associated phospholipase A2 and risk of venous thrombosis in older adults. - Olson, Nels; O'Meara, Ellen S; Jenny, Nancy S; Folsom, Aaron R; Bovill, Edwin G; Furberg, Curt D; Heckbert, Susan R; Psaty, Bruce M; Cushman, Mary (Am J Hematol, 2008)
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme involved in inflammation and platelet function. Inherited deficiency and elevated levels are associated with atherosclerosis. Given potential common etiologies of atherosclerosis and venous thrombosis (VT), we hypothesized that low and high Lp-PLA2 would be associated with VT risk. Lp-PLA(2) mass and activity were measured in baseline samples of Cardiovascular Health Study participants (5,888 men and women age > or =65), excluding 354 reporting pre-baseline VT. The study endpoint was VT unrelated to cancer after 11.6 years follow-up. Hazard ratios were estimated using Cox proportional hazard models, adjusting for age, race, sex, and body-mass index. With 129 cases of VT, there was no association of Lp-PLA2 activity with risk. Adjusted hazard ratios were 1.19 (CI 0.62, 2.29) and 0.87 (CI 0.43, 1.76) for the lowest and highest decile, respectively, compared to the 10-25th percentile. Corresponding hazard ratios for Lp-PLA2 mass were 1.63 (CI 0.79, 3.34) and 1.33 (CI 0.61, 2.87). Results were robust to several definitions of low or high Lp-PLA2. While the association of Lp-PLA(2) levels with arterial disease events implies a role for this enzyme in atherogenesis, our findings suggest that it is not prothrombotic.
Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Female; Humans; Male; Risk Factors; Venous Thrombosis

Metabolic syndrome, endothelial dysfunction, and risk of cardiovascular events: the Northern Manhattan Study (NOMAS). - Suzuki, Takeki; Hirata, Kumiko; Elkind, Mitchell S V; Jin, Zhezhen; Rundek, Tanja; Miyake, Yumiko; Boden-Albala, Bernadette; Di Tullio, Marco R; Sacco, Ralph; Homma, Shunichi (Am Heart J, 2008)
BACKGROUND: Metabolic syndrome (MetS) predisposes to cardiovascular disease. Endothelial dysfunction is thought to be an important factor in the pathogenesis of atherosclerosis. We tested the hypothesis that both MetS and endothelial dysfunction are vascular risk factors and provide additive prognostic values in predicting cardiovascular events in a multiethnic community sample. METHODS: The study population consisted of 819 subjects (467 female, mean age 66.5 +/- 8.8 years, 66% Hispanic) enrolled in the NOMAS. Metabolic syndrome was defined using the revised Adult Treatment Panel III criteria. Brachial artery flow-mediated dilation (FMD) was measured using high-resolution ultrasound. Endothelial dysfunction was defined as FMD <8.44% (lower 3 quartiles). Cox proportional hazards models were used to assess the effect of MetS and endothelial dysfunction on risk of cardiovascular events. RESULTS: During 81 +/- 21 months of follow-up, events occurred in 84 subjects. Metabolic syndrome was independently associated with cardiovascular events in a multivariate model, including cardiovascular risk factors (adjusted hazard ratio 2.08, 95% CI 1.27-3.40). Subjects with both MetS and endothelial dysfunction were at higher risk for cardiovascular events than those with either one of them alone (adjusted hazard ratio 2.60, 95% CI 1.14-5.92). CONCLUSIONS: Metabolic syndrome is associated with incident cardiovascular events. Combined use of MetS and FMD identifies those who are at higher risk of cardiovascular events. Metabolic syndrome and noninvasive FMD testing can be used concurrently for cardiovascular risk prediction.
Keywords: Adult; Aged; Brachial Artery; Endothelium, Vascular; Female; Humans; Kaplan-Meier Estimate; Male; Metabolic Syndrome; Middle Aged; Prognosis; Prospective Studies; Risk Factors; Stroke; Vascular Diseases

No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies. - Szekely, C A; Green, R C; Breitner, J C S; Østbye, T; Beiser, A S; Corrada, M M; Dodge, H H; Ganguli, M; Kawas, C H; Kuller, L H; Psaty, B M; Resnick, S M; et al. (Neurology, 2008)
INTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk. METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs. RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13). CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.
Keywords: Acetaminophen; Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cohort Studies; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Peptide Fragments; Proportional Hazards Models; Prospective Studies; Risk Factors

Novel measures of heart rate variability predict cardiovascular mortality in older adults independent of traditional cardiovascular risk factors: the Cardiovascular Health Study (CHS). - Stein, Phyllis K; Barzilay, Joshua I; Chaves, Paulo H M; Mistretta, Stephanie Q; Domitrovich, Peter P; Gottdiener, John S; Rich, Michael W; Kleiger, Robert E (J Cardiovasc Electrophysiol, 2008)
UNLABELLED: Novel HRV Predicts CV Mortality in the Elderly. BACKGROUND: It is unknown whether abnormal heart rate turbulence (HRT) and abnormal fractal properties of heart rate variability identify older adults at increased risk of cardiovascular death (CVdth). METHODS: Data from 1,172 community-dwelling adults, ages 72 +/- 5 (65-93) years, who participated in the Cardiovascular Health Study (CHS), a study of risk factors for CV disease in people >or=65 years. HRT and the short-term fractal scaling exponent (DFA1) derived from 24-hour Holter recordings. HRT categorized as: normal (turbulence slope [TS] and turbulence onset [TO] normal) or abnormal (TS and/or TO abnormal). DFA1 categorized as low (<or=1) or high (>1). Cox regression analyses stratified by Framingham Risk Score (FRS) strata (low = <10, mid = 10-20, and high >20) and adjusted for prevalent clinical cardiovascular disease (CVD), diabetes, and quartiles of ventricular premature beat counts (VPCs). RESULTS: CVdths (N = 172) occurred over a median follow-up of 12.3 years. Within each FRS stratum, low DFA1 + abnormal HRT predicted risk of CVdth (RR = 7.7 for low FRS; 3.6, mid FRS; 2.8, high FRS). Among high FRS stratum participants, low DFA1 alone also predicted CVdth (RR = 2.0). VPCs in the highest quartile predicted CVdth, but only in the high FRS group. Clinical CV disease predicted CVdth at each FRS stratum (RR = 2.9, low; 2.6, mid; and 1.9, high). Diabetes predicted CVdth in the highest FRS group only (RR = 2.2). CONCLUSIONS: The combination of low DFA1 + abnormal HRT is a strong risk factor for CVdth among older adults even after adjustment for conventional CVD risk measures and the presence of CVD.
Keywords: Aged; Aged, 80 and over; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Electrocardiography, Ambulatory; Female; Heart Rate; Humans; Male; Maryland; Reproducibility of Results; Risk Assessment; Risk Factors; Sensitivity and Specificity; Survival Analysis; Survival Rate

NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. - Szekely, C A; Breitner, J C S; Fitzpatrick, A L; Rea, T D; Psaty, B M; Kuller, L H; Zandi, P P (Neurology, 2008)
BACKGROUND: Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD. METHODS: Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one epsilon 4 allele at APOE, race, and individual NSAIDs' reported ability to reduce production of the amyloid-beta peptide variant A beta(42). RESULTS: Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95% CI or CI 0.60-0.96) and, in particular, AD (aHR 0.63, CI 0.45-0.88), but not VaD (aHR 0.92, CI 0.65-1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79-1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE epsilon 4 allele (aHR 0.34, CI 0.18-0.65; aHR for others 0.88, CI 0.59-1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce A beta(42). CONCLUSIONS: Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE epsilon 4 allele, and there was no advantage for A beta(42)-lowering NSAIDs.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Apolipoproteins E; Cardiovascular System; Dementia; Female; Humans; Incidence; Male; Proportional Hazards Models; Prospective Studies; Risk Factors

Pancreatic beta-cell function as a predictor of cardiovascular outcomes and costs: findings from the Cardiovascular Health Study. - Curtis, Lesley H; Hammill, Bradley G; Bethel, M Angelyn; Anstrom, Kevin J; Liao, Lawrence; Gottdiener, John S; Schulman, Kevin A (Curr Med Res Opin, 2008)
OBJECTIVE: To explore relationships between beta-cell function and incident cardiovascular events, death, and medical costs among elderly individuals. RESEARCH DESIGN AND METHODS: In a prospective, population-based cohort of 4555 elderly individuals, we examined the effect of beta-cell function on incident cardiovascular events and mortality. We also examined costs for 3715 of these individuals. We used the computer-based homeostasis model assessment (HOMA) to calculate indices of beta-cell function (HOMA-%B) and insulin sensitivity (HOMA-%S) using baseline fasting glucose and insulin levels. All subjects were followed from 1992/1993 for 6 years or until death. MAIN OUTCOME MEASURES: Discrete-time survival model of the effects of beta-cell function on incident cardiovascular events and all-cause mortality; and semiparametric estimators for calculations of mean 6-year costs. RESULTS: Controlling for HOMA-%S, a 20% decrease in HOMA-%B was associated with increased odds of incident cardiovascular events (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.05-1.14) and death (OR, 1.10; 95% CI, 1.07-1.14). The relationships persisted after controlling for clinical and sociodemographic confounders. A 20% decrease in HOMA-%B was also associated with increased costs (cost ratio, 1.03; 95% CI, 1.01-1.05). The significant association did not persist after controlling for confounders. LIMITATIONS: The sample comprises relatively healthy elderly individuals and is based on data from 1992 through 1999, which may not reflect current experience. The measure of beta-cell function is an estimate generated from single measures of glucose and insulin. CONCLUSIONS: Beta-cell function as measured by HOMA-%B is a significant predictor of incident cardiovascular events and mortality but not of costs, controlling for HOMA-%S and sociodemographic and clinical confounders.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; Coronary Disease; Female; Follow-Up Studies; Health Care Costs; Heart Failure; Humans; Insulin-Secreting Cells; Male; Myocardial Infarction; Outcome Assessment, Health Care; Prognosis; Prospective Studies; Stroke

A physiologic index of comorbidity: relationship to mortality and disability. - Newman, Anne B; Boudreau, Robert M; Naydeck, Barbara L; Fried, Linda F; Harris, Tamara B (J Gerontol A Biol Sci Med Sci, 2008)
BACKGROUND: In older adults, there is often substantial undiagnosed chronic disease detectable on noninvasive testing, not accounted for by most comorbidity indices. We developed a simple physiologic index of comorbidity by scoring five noninvasive tests across the full range of values. We examined the predictive validity of this index for mortality and disability. METHODS: There were 2928 (mean age 74.5 years, 60% women, 85% white, and 15% black) participants in the Cardiovascular Health Study (1992-1993) who had carotid ultrasound, pulmonary function testing, brain magnetic resonance scan, serum cystatin-C, and fasting glucose. These were combined into a single physiologic index of comorbid chronic disease on a scale of 0-10. Cox proportional hazard models were used to predict mortality, mobility limitation, and activities of daily living (ADL) difficulty after a maximum of 9 years. RESULTS: The range of the physiologic index was quite broad, with very few individuals having total scores of either 0 or 10. Those with an index of 7-10 had a hazard ratio of 3.80 (95% confidence interval, 2.82-5.13) for mortality compared to those with scores of 0-2, after adjustment for demographics, behavioral risk factors, and clinically diagnosed conditions. Associations with mobility limitation and ADL difficulty were also significant. The index explained about 40% of the age effect on mortality risk. CONCLUSION: Older adults with low levels of markers of chronic disease are rather rare but have remarkably good health outcomes. The ability of such an index to distinguish usual from low risk might provide an opportunity to better understand optimal health in old age.
Keywords: Activities of Daily Living; Aged; Comorbidity; Disabled Persons; Female; Health Status; Humans; Male; Mobility Limitation; Mortality; Predictive Value of Tests; Proportional Hazards Models

Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study. - Lopez, O L; Kuller, L H; Mehta, P D; Becker, J T; Gach, H M; Sweet, R A; Chang, Y F; Tracy, R; DeKosky, S T (Neurology, 2008)
OBJECTIVES: To examine the association between incident Alzheimer disease (AD), and plasma A beta 1-40 and A beta 1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study. METHODS: We determined the plasma A beta 1-40 and A beta 1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998-1999 and repeated the measurements in 2002-2003. The mean age of the subjects at baseline was 79.3 +/- 3.6 years. We examined the association between A beta levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts. RESULTS: In an unadjusted prospective model in normal subjects, both A beta 1-40 and A beta 1-42 levels in 1998-1999 were associated with incident AD (n = 55) in 2002-2003 (longitudinal analysis). In the fully adjusted multivariate model, neither A beta 1-42 nor A beta 1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for A beta 1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002-2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD. CONCLUSIONS: Plasma A beta levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, A beta-40 and A beta 1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of A beta do not seem to be useful biomarkers for AD.
Keywords: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Brain; Cerebrovascular Disorders; Comorbidity; Cross-Sectional Studies; Cystatin C; Cystatins; Female; Humans; Incidence; Longitudinal Studies; Magnetic Resonance Imaging; Male; Models, Statistical; Neuropsychological Tests; Peptide Fragments; Predictive Value of Tests; Prospective Studies; Reference Values; Risk Factors

Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. - Reiner, Alexander P; Barber, Mathew J; Guan, Yongtao; Ridker, Paul M; Lange, Leslie A; Chasman, Daniel I; Walston, Jeremy D; Cooper, Gregory M; Jenny, Nancy S; Rieder, Mark J; Durda, J Peter; Smith, Joshua D; et al. (Am J Hum Genet, 2008)
Data from the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) study and the Cardiovascular Health Study (CHS) provide independent and confirmatory evidence for association between common polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha and plasma C-reactive protein (CRP) concentration. Analyses with the use of imputation-based methods to combine genotype data from both studies and to test untyped SNPs from the HapMap database identified several SNPs within a 5 kb region of HNF1A intron 1 with the strongest evidence of association with CRP phenotype.
Keywords: Aged; Bayes Theorem; C-Reactive Protein; Female; Hepatocyte Nuclear Factor 1-alpha; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Polymorphism, Single Nucleotide; Pravastatin; Simvastatin

Power spectral analysis of EEG activity during sleep in cigarette smokers. - Zhang, Lin; Samet, Jonathan; Caffo, Brian; Bankman, Isaac; Punjabi, Naresh M (Chest, 2008)
BACKGROUND: Research on the effects of cigarette smoking on sleep architecture is limited. The objective of this investigation was to examine differences in sleep EEG between smokers and nonsmokers. METHODS: Smokers and nonsmokers who were free of all medical comorbidities were matched on different factors, including age, gender, race, body mass index, and anthropometric measures. Home polysomnography was conducted using a standard recording montage. Sleep architecture was assessed using visual sleep-stage scoring. The discrete fast Fourier transform was used to calculate the EEG power spectrum for the entire night within contiguous 30-s epochs of sleep for the following frequency bandwidths: delta (0.8 to 4.0 Hz); theta (4.1 to 8.0 Hz); alpha (8.1 to 13.0 Hz); and beta (13.1 to 20.0 Hz). RESULTS: Conventional sleep stages were similar between the two groups. However, spectral analysis of the sleep EEG showed that, compared to nonsmokers, smokers had a lower percentage of EEG power in the delta-bandwidth (59.7% vs 62.6%, respectively; p < 0.04) and higher percentage of EEG power in alpha-bandwidth (15.6% vs 12.5%, respectively; p < 0.001). Differences in the EEG power spectrum between smokers and nonsmokers were greatest in the early part of the sleep period and decreased toward the end. Subjective complaints of lack of restful sleep were also more prevalent in smokers than in nonsmokers (22.5% vs 5.0%, respectively; p < 0.02) and were explained, in part, by the differences in EEG spectral power. CONCLUSIONS: Cigarette smokers manifest disturbances in the sleep EEG that are not evident in conventional measures of sleep architecture. Nicotine in cigarette smoke and withdrawal from it during sleep may contribute to these changes and the subjective experience of nonrestorative sleep.
Keywords: Electroencephalography; Female; Humans; Logistic Models; Male; Middle Aged; Polysomnography; Sleep; Smoking; Spectroscopy, Fourier Transform Infrared

Relation of sleep-disordered breathing to carotid plaque and intima-media thickness. - Wattanakit, Keattiyoat; Boland, Lori; Punjabi, Naresh M; Shahar, Eyal (Atherosclerosis, 2008)
BACKGROUND: Sleep-disordered breathing (SDB) is associated with clinical cardiovascular disease (CVD), but its relation to subclinical atherosclerosis remains to be determined. METHODS: We analyzed the cross-sectional associations of SDB, measured by the respiratory disturbance index (RDI), a hypoxemia index, and an arousal index, with carotid plaque and carotid intima-media thickness (IMT), measured by ultrasound. The sample included 985 participants in the Sleep Heart Health Study (mean age-62, median RDI-8.7) with no history of coronary heart disease and stroke, of whom 396 had evidence of a carotid plaque. RESULTS: As compared with the first quartile of the RDI (0-1.2), the crude odds ratio for carotid plaque was 1.14, 1.27, and 1.48 for the second (1.3-4.1), third (4.2-10.7), and fourth (>10.7) quartile, respectively. After adjustment for CVD risk factors, the corresponding odds ratios were reduced (1.00, 1.04, 1.07, and 1.25). Similarly, the unadjusted mean carotid IMT increased with RDI, but adjusted means (mm) were similar (0.84, 0.85, 0.84, 0.85). Spline regression models did not show monotonicity of the dose-response functions at the right end of the RDI distribution. Neither the hypoxemia index nor the arousal index was associated with carotid plaque or carotid IMT. CONCLUSION: The results of this study suggest that crude, positive associations between SDB and subclinical atherosclerosis can be attributed to confounding by CVD risk factors.
Keywords: Aged; Carotid Arteries; Carotid Artery Diseases; Female; Humans; Male; Middle Aged; Odds Ratio; Risk Factors; Sleep Apnea Syndromes; Tunica Intima; Tunica Media; Ultrasonography

Relationship between brachial flow-mediated dilation and carotid intima-media thickness in an elderly cohort: the Cardiovascular Health Study. - Yeboah, Joseph; Burke, Gregory L; Crouse, John R; Herrington, David M (Atherosclerosis, 2008)
OBJECTIVE: The aim of this study was to determine the relationship between brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) in a large multi-ethnic elderly cohort. BACKGROUND: Brachial flow-mediated dilation (FMD) is a physiologic measure and carotid IMT is an anatomic structural measure of subclinical atherosclerosis. Both brachial FMD and carotid IMT have been associated with cardiovascular risk factors and cardiovascular events. The relationship between brachial FMD and carotid IMT is less clear especially in older adults. METHODS: Brachial FMD, carotid IMT and traditional cardiovascular risk factors were measured in 2338 adults, age 72-98 years who were participants in the Cardiovascular Health Study. The relationship between FMD and IMT was assessed both unadjusted and also after adjusting for age, gender and race/ethnicity, BMI, HDL, LDL, systolic and diastolic blood pressure, serum creatinine, current smoking, diabetes mellitus, hormone therapy and prior CVD. RESULTS: Both brachial FMD and carotid IMT correlated significantly with age, HDL levels, waist/hip ratio, serum cholesterol and number of CV risk factors. Brachial FMD was not associated with CCA IMT in this elderly cohort (Pearson partial correlation coefficient=-0.0252, p=0.222). In the adjusted linear regression model with CCA IMT as the dependent variable, brachial FMD was also not associated with CCA IMT (beta coefficient=-0.006, p=0.470). CONCLUSION: Brachial FMD and CCA IMT are not related in population-based older adults. Brachial FMD and CCA IMT may be distinct and independent stages in the complex atherosclerotic process.
Keywords: Age Factors; Aged; Aged, 80 and over; Brachial Artery; Carotid Arteries; Carotid Artery Diseases; Cohort Studies; Female; Hemorheology; Humans; Male; Tunica Intima; Tunica Media; Ultrasonography; Vasodilation

The reliability and validity of measures of gait variability in community-dwelling older adults. - Brach, Jennifer S; Perera, Subashan; Studenski, Stephanie; Newman, Anne B (Arch Phys Med Rehabil, 2008)
OBJECTIVE: To examine the test-retest reliability and concurrent validity of variability of gait characteristics. DESIGN: Cross-sectional study. SETTING: Research laboratory. PARTICIPANTS: Older adults (N=558) from the Cardiovascular Health Study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Gait characteristics were measured using a 4-m computerized walkway. SD determined from the steps recorded were used as the measures of variability. Intraclass correlation coefficients (ICC) were calculated to examine test-retest reliability of a 4-m walk and two 4-m walks. To establish concurrent validity, the measures of gait variability were compared across levels of health, functional status, and physical activity using independent t tests and analysis of variances. RESULTS: Gait variability measures from the two 4-m walks demonstrated greater test-retest reliability than those from the single 4-m walk (ICC=.22-.48 and ICC=.40-.63, respectively). Greater step length and stance time variability were associated with poorer health, functional status and physical activity (P<.05). CONCLUSIONS: Gait variability calculated from a limited number of steps has fair to good test-retest reliability and concurrent validity. Reliability of gait variability calculated from a greater number of steps should be assessed to determine if the consistency can be improved.
Keywords: Activities of Daily Living; Aged; Cross-Sectional Studies; Disability Evaluation; Exercise; Female; Gait; Health Status; Humans; Male; Pennsylvania; Rehabilitation; Reproducibility of Results

Sleep-disordered breathing and impaired glucose metabolism in normal-weight and overweight/obese individuals: the Sleep Heart Health Study. - Seicean, Sinziana; Kirchner, H Lester; Gottlieb, Daniel J; Punjabi, Naresh M; Resnick, Helaine; Sanders, Mark; Budhiraja, Rohit; Singer, Mendel; Redline, Susan (Diabetes Care, 2008)
OBJECTIVE: To characterize the association between sleep-disordered breathing (SDB) and impaired fasting glucose (IFG), impaired glucose tolerance (IGT), combined IFG and IGT, and occult diabetes in individuals of different body habitus. RESEARCH DESIGN AND METHODS: Cross-sectional analysis of 2,588 participants (aged 52-96 years; 46% men) without known diabetes. SDB was defined as respiratory disturbance index >or=10 events/h. IFG, IGT, occult diabetes, and body weight were classified according to recent accepted guidelines. Participants with and without SDB were compared on prevalence and odds ratios for measures of impaired glucose metabolism (IGM), adjusting for age, sex, race, BMI, and waist circumference. RESULTS: SDB was observed in 209 nonoverweight and 1,036 overweight/obese participants. SDB groups had significantly higher adjusted prevalence and adjusted odds of IFG, IFG plus IGT, and occult diabetes. The adjusted odds ratio for all subjects was 1.3 (95% CI 1.1-1.6) for IFG, 1.2 (1.0-1.4) for IGT, 1.4 (1.1-2.7) for IFG plus IGT, and 1.7 (1.1-2.7) for occult diabetes. CONCLUSIONS: SDB was associated with occult diabetes, IFG, and IFG plus IGT, after adjusting for age, sex, race, BMI, and waist circumference. The magnitude of these associations was similar in nonoverweight and overweight participants. The consistency of associations across all measures of IGM and body habitus groups and the significant association between SDB and IFG plus IGT, a risk factor for rapid progression to diabetes, cardiovascular disease, and mortality, suggests the importance of SDB as a risk factor for clinically important levels of metabolic dysfunction.
Keywords: Aged; Aged, 80 and over; Body Weight; Cardiovascular Diseases; Cross-Sectional Studies; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Male; Middle Aged; Obesity; Overweight; Polysomnography; Reference Values; Sleep Wake Disorders

Stance time and step width variability have unique contributing impairments in older persons. - Brach, Jennifer S; Studenski, Stephanie; Perera, Subashan; VanSwearingen, Jessie M; Newman, Anne B (Gait Posture, 2008)
Gait variability may have multiple causes. We hypothesized that central nervous system (CNS) impairments would affect motor control and be manifested as increased stance time and step length variability, while sensory impairments would affect balance and be manifested as increased step width variability. Older adults (mean+/-standard deviation (S.D.) age=79.4+/-4.1, n=558) from the Pittsburgh site of the Cardiovascular Health Study participated. The S.D. across steps was the indicator of gait variability, determined for three gait measures, step length, stance time and step width, using a computerized walkway. Impairment measures included CNS function (modified mini-mental state examination, Trails A and B, Digit Symbol Substitution, finger tapping), sensory function (lower extremity (LE) vibration, vision), strength (grip strength, repeated chair stands), mood, and LE pain. Linear regression models were fit for the three gait variability characteristics using impairment measures as independent variables, adjusted for age, race, gender, and height. Analyses were repeated stratified by gait speed. All measures of CNS impairment were directly related to stance time variability (p<0.01), with increased CNS impairment associated with increased stance time variability. CNS impairments were not related to step length or width variability. Both sensory impairments were inversely related to step width (p<0.01) but not step length or stance time variability. CNS impairments affected stance time variability especially in slow walkers while sensory impairments affected step width variability in fast walkers. Specific patterns of gait variability may imply different underlying causes. Types of gait variability should be specified. Interventions may be targeted at specific types of gait variability.
Keywords: Aged; Aged, 80 and over; Biomechanical Phenomena; Female; Gait Disorders, Neurologic; Humans; Linear Models; Longitudinal Studies; Male; Neuropsychological Tests; Postural Balance; Range of Motion, Articular; Risk Factors; Signal Processing, Computer-Assisted

Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study. - Rodondi, Nicolas; Bauer, Douglas C; Cappola, Anne R; Cornuz, Jacques; Robbins, John; Fried, Linda P; Ladenson, Paul W; Vittinghoff, Eric; Gottdiener, John S; Newman, Anne B (J Am Coll Cardiol, 2008)
OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities. BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited. METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism. RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF. CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.
Keywords: Aged; Aged, 80 and over; Cohort Studies; Echocardiography; Female; Heart; Heart Failure; Heart Function Tests; Humans; Hyperthyroidism; Hypertrophy, Left Ventricular; Hypothyroidism; Male; Risk Factors; Time Factors

Subjective and objective sleep quality in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the sleep heart health study. - Unruh, Mark L; Sanders, Mark H; Redline, Susan; Piraino, Beth M; Umans, Jason G; Chami, Hassan; Budhiraja, Rohit; Punjabi, Naresh M; Buysse, Daniel; Newman, Anne B (Am J Kidney Dis, 2008)
BACKGROUND: Studies examining sleep in the hemodialysis (HD) population have largely lacked an adequate comparison group. It therefore is uncertain whether poor sleep quality in the HD population reflects age, chronic health conditions, or effects of conventional HD therapy. STUDY DESIGN: Cross-sectional matched-group study. SETTING & PARTICIPANTS: Forty-six in-center HD patients were compared with 137 community participants participating in the Sleep Heart Health Study matched for age, sex, body mass index, and race. PREDICTOR: HD patients compared with community-dwelling non-HD participants. OUTCOMES & MEASUREMENTS: Home unattended polysomnography was performed and scored by using similar protocols. Sleep habits and sleepiness were assessed by using the Sleep Habits Questionnaire and Epworth Sleepiness Scale. RESULTS: Average age of study samples was 63 years, 72% were white, and average body mass index was 28 +/- 5 kg/m(2). HD patients were significantly more likely than community participants to have short sleep (odds ratio, 3.27; 95% confidence interval, 1.16 to 9.25) and decreased sleep efficiency (odds ratio, 5.5; 95% confidence interval, 1.5 to 19.6). HD patients reported more difficulty getting back to sleep (odds ratio, 2.25; 95% confidence interval, 1.11 to 4.60) and waking up too early (odds ratio, 2.39; 95% confidence interval, 1.01 to 5.66). There was no association between polysomnography sleep time and self-reported sleep time (r = 0.09; P = 0.6) or between the Epworth Sleepiness Scale and severity of sleep apnea (r = 0.10; P = 0.5) in the HD population. LIMITATIONS: The study was limited to participants older than 45 years. CONCLUSIONS: Kidney failure treated with thrice-weekly HD is significantly associated with poor subjective and objective sleep quality.
Keywords: Aged; Aged, 80 and over; Body Mass Index; Cross-Sectional Studies; Disease Progression; Female; Follow-Up Studies; Heart Rate; Humans; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Odds Ratio; Pennsylvania; Polysomnography; Prognosis; Renal Dialysis; Retrospective Studies; Risk Factors; Severity of Illness Index; Sleep; Sleep Apnea Syndromes; Surveys and Questionnaires

Weight, mortality, years of healthy life, and active life expectancy in older adults. - Diehr, Paula; O'Meara, Ellen S; Fitzpatrick, Annette; Newman, Anne B; Kuller, Lewis; Burke, Gregory (J Am Geriatr Soc, 2008)
OBJECTIVES: To determine whether weight categories predict subsequent mortality and morbidity in older adults. DESIGN: Multistate life tables, using data from the Cardiovascular Health Study, a longitudinal population-based cohort of older adults. SETTING: Data were provided by community-dwelling seniors in four U.S. counties: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania. PARTICIPANTS: Five thousand eight hundred eighty-eight adults aged 65 and older at baseline. MEASUREMENTS: The age- and sex-specific probabilities of transition from one health state to another and from one weight category to another were estimated. From these probabilities, future life expectancy, years of healthy life, active life expectancy, and the number of years spent in each weight and health category after age 65 were estimated. RESULTS: Women who are healthy and of normal weight at age 65 have a life expectancy of 22.1 years. Of that, they spend, on average, 9.6 years as overweight or obese and 5.3 years in fair or poor health. For both men and women, being underweight at age 65 was associated with worse outcomes than being normal weight, whereas being overweight or obese was rarely associated with worse outcomes than being normal weight and was sometimes associated with significantly better outcomes. CONCLUSION: Similar to middle-aged populations, older adults are likely to be or to become overweight or obese, but higher weight is not associated with worse health in this age group. Thus, the number of older adults at a "healthy" weight may be much higher than currently believed.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Body Mass Index; Body Weight; Female; Health Status Indicators; Humans; Life Expectancy; Life Style; Male; Prognosis; Risk Factors; Sex Factors; Survival Rate; United States

Age, Alzheimer disease, and brain structure. - Raji, C A; Lopez, O L; Kuller, L H; Carmichael, O T; Becker, J T (Neurology, 2009)
BACKGROUND: Lack of clear understanding remains on the overlapping atrophy patterns of aging and early Alzheimer disease (AD) pathology in gray matter (GM) of the brain in vivo. OBJECTIVE: To evaluate the independent and overlapping patterns of GM atrophy in normal aging and AD. METHODS: A total of 169 cognitively normal subjects and 33 persons with probable AD enrolled in the longitudinal Cardiovascular Health Study-Cognition Study underwent 3-dimensional volumetric MRI scans. Controls remained cognitively normal for at least 5 years after their MRI scans and the probable AD subjects were relatively early in their clinical course with an average modified Mini-Mental State Examination score of 76/100. The scans were analyzed using voxel-based morphometry adjusting for total intracranial volume, gender, education, and race. RESULTS: With older age, GM volume was lower in the sensorimotor and heteromodal association areas in frontal, temporal, occipital, and parietal lobes, as well as in the cerebellum (false discovery rate p = 0.05). Additional atrophy was observed in the posterior hippocampus, thalamus, and middle cingulate gyrus. By contrast, atrophy was seen in subjects with AD in the anterior hippocampal/parahippocampal regions and the precuneus. Normal aging and AD overlapped in the hippocampal body and the entorhinal cortex. CONCLUSION: Brain atrophy with aging was observed in supratentorial and infratentorial areas, as well in primary motor, sensory, and heteromodal association regions. Age and Alzheimer disease exert independent gray matter atrophy patterns but these effects overlapped substantially in the hippocampus and entorhinal cortex.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Brain; Brain Mapping; Cognition Disorders; Female; Humans; Image Processing, Computer-Assisted; Linear Models; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Retrospective Studies

Association between elevated fibrosis markers and heart failure in the elderly: the cardiovascular health study. - Barasch, Eddy; Gottdiener, John S; Aurigemma, Gerard; Kitzman, Dalane W; Han, Jing; Kop, Willem J; Tracy, Russell P (Circ Heart Fail, 2009)
BACKGROUND: Myocardial fibrosis reflects excess collagen deposition in the extracellular left ventricular matrix, which has been associated with heart failure (HF). No studies have addressed the relation between fibrosis biomarkers and HF in the elderly. METHODS AND RESULTS: Serum fibrosis markers were measured in 880 participants of the Cardiovascular Health Study (mean age 77+/-6 years, 48% women). Participants with systolic HF (n=131, left ventricular ejection fraction <55%) and those with diastolic HF (n=179, left ventricular ejection fraction > or =55%) were compared with controls (280 with cardiovascular risk factors, and 279 healthy individuals) using a nested case-control design. Fibrosis markers included carboxyl-terminal peptide of procollagen type I, carboxyl-terminal telopeptide of collagen type I, and amino-terminal peptide of procollagen type III. Echocardiography was used to document systolic and diastolic function parameters. Analysis of variance and logistic regression analysis (per tertile odds ratios [OR]), adjusted by age, gender, race, hypertension, atrial fibrillation, coronary heart disease, baseline serum glucose, serum cystatin C, serum creatinine, C-reactive protein, any angiotensin-converting enzyme inhibitor, spironolactone or any diuretic, NT-proBNP, and total bone mineral density were performed. Systolic HF was associated with significantly elevated carboxyl-terminal telopeptide of collagen type I (OR=2.6; 95% CI=1.2 to 5.7) and amino-terminal peptide of procollagen type III (OR=3.3; 95% CI=1.6 to 5.8), when adjusting for covariates. Associations of diastolic HF were significant for carboxyl-terminal telopeptide of collagen type I (OR=3.9; 95% CI=1.9 to 8.3) and amino-terminal peptide of procollagen type III (OR=2.7; 95% CI=1.4 to 5.4). HF was not associated with elevated carboxyl-terminal peptide of procollagen type I (P>0.10), and fibrosis markers did not significantly differ between HF with diastolic versus those with systolic dysfunction (P>0.10) whereas NT-proBNP mean values were higher in systolic heart failure than in diastolic heart failure (P<0.0001). CONCLUSIONS: Fibrosis markers are significantly elevated in elderly individuals with diastolic or systolic HF. These associations remained significant when adjusting for covariates relevant to the aging process.
Keywords: Aged; Aged, 80 and over; Female; Fibrosis; Heart Failure; Humans; Male; Myocardium; Ultrasonography

Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. - Pawlikowska, Ludmila; Hu, Donglei; Huntsman, Scott; Sung, Andrew; Chu, Catherine; Chen, Justin; Joyner, Alexander H; Schork, Nicholas J; Hsueh, Wen-Chi; Reiner, Alexander P; Psaty, Bruce M; Atzmon, Gil; et al. (Aging Cell, 2009)
The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.
Keywords: Aged; Aged, 80 and over; Female; Follow-Up Studies; Forkhead Box Protein O3; Forkhead Transcription Factors; Genome, Human; Genotype; Humans; Insulin; Insulin-Like Growth Factor I; Longevity; Male; Osteoporosis; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-akt; Signal Transduction

Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. - Dehghan, Abbas; Yang, Qiong; Peters, Annette; Basu, Saonli; Bis, Joshua C; Rudnicka, Alicja R; Kavousi, Maryam; Chen, Ming-Huei; Baumert, Jens; Lowe, Gordon D O; McKnight, Barbara; Tang, Weihong; et al. (Circ Cardiovasc Genet, 2009)
BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels. METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)). CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.
Keywords: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; European Continental Ancestry Group; Female; Fibrinogen; Genetic Loci; Genome-Wide Association Study; Humans; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Young Adult

Brachial artery diameter, blood flow and flow-mediated dilation in sleep-disordered breathing. - Chami, Hassan A; Keyes, Michelle J; Vita, Joseph A; Mitchell, Gary F; Larson, Martin G; Fan, Shuxia; Vasan, Ramachandran S; O'Connor, George T; Benjamin, Emelia J; Gottlieb, Daniel J (Vasc Med, 2009)
Clinic-based, case-control studies linked sleep-disordered breathing (SDB) to markers of endothelial dysfunction. We attempted to validate this association in a large community-based sample, and evaluate the relation of SDB to arterial diameter and peripheral blood flow. This community-based, cross-sectional observational study included 327 men and 355 women, aged 42-83 years, from the Framingham Heart Study site of the Sleep Heart Health Study. The polysomnographically derived apnea-hypopnea index and the hypoxemia index (percent sleep time with oxyhemoglobin saturation below 90%) were used to quantify the severity of SDB. Brachial artery ultrasound measurements included baseline diameter, percent flow-mediated dilation, and baseline and hyperemic flow velocity and volume. The baseline brachial artery diameter was significantly associated with both the apnea-hypopnea index and the hypoxemia index. The association was diminished by adjustment for body mass index, but remained significant for the apnea-hypopnea index. Age-, sex-, race- and body mass index-adjusted mean diameters were 4.32, 4.33, 4.33, 4.56, 4.53 mm for those with apnea-hypopnea index < 1.5, 1.5-4.9, 5-14.9, 15-29.9, >/= 30, respectively; p = 0.03. Baseline flow measures were associated with the apnea-hypopnea index but this association was non-significant after adjusting for body mass index. No significant association was observed between measures of SDB and percent flow-mediated dilation or hyperemic flow in any model. In conclusion, this study supports a moderate association of SDB and larger baseline brachial artery diameter, which may reflect SDB-induced vascular remodeling. This study does not support a link between SDB and endothelial dysfunction as measured by brachial artery flow-mediated dilation.
Keywords: Adult; Aged; Aged, 80 and over; Blood Flow Velocity; Brachial Artery; Cross-Sectional Studies; Female; Humans; Hyperemia; Hypoxia; Laser-Doppler Flowmetry; Male; Middle Aged; Polysomnography; Regional Blood Flow; Severity of Illness Index; Sleep Apnea Syndromes; Ultrasonography; Vasodilation

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. - Psaty, Bruce M; O'Donnell, Christopher J; Gudnason, Vilmundur; Lunetta, Kathryn L; Folsom, Aaron R; Rotter, Jerome I; Uitterlinden, André G; Harris, Tamara B; Witteman, Jacqueline C M; Boerwinkle, Eric (Circ Cardiovasc Genet, 2009)
BACKGROUND: The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci. CONCLUSIONS: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.
Keywords: Adult; Aged; Aging; Cohort Studies; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Heart Diseases; Humans; Male; Meta-Analysis as Topic; Middle Aged; Phenotype; Research Design; Risk Factors

Common coding variants of the HNF1A gene are associated with multiple cardiovascular risk phenotypes in community-based samples of younger and older European-American adults: the Coronary Artery Risk Development in Young Adults Study and The Cardiovascula - Reiner, Alexander P; Gross, Myron D; Carlson, Christopher S; Bielinski, Suzette J; Lange, Leslie A; Fornage, Myriam; Jenny, Nancy S; Walston, Jeremy; Tracy, Russell P; Williams, O Dale; Jacobs, David R; Nickerson, Deborah A (Circ Cardiovasc Genet, 2009)
BACKGROUND: The transcription factor hepatocyte nuclear factor (HNF)-1 alpha regulates the activity of a number of genes involved in innate immunity, blood coagulation, lipid and glucose transport and metabolism, and cellular detoxification. Common polymorphisms of the HNF-1 alpha gene (HNF1A) were recently associated with plasma C-reactive protein and gamma-glutamyl transferase concentration in middle-aged to older European Americans (EA). METHODS AND RESULTS: We assessed whether common variants of HNF1A are associated with C-reactive protein, gamma-glutamyl transferase, and other atherosclerotic and metabolic risk factors, in the large, population-based Coronary Artery Risk Development in Young Adults Study of healthy young EA (n=2154) and African American (AA; n=2083) adults. The minor alleles of Ile27Leu (rs1169288) and Ser486Asn (rs2464196) were associated with 0.10 to 0.15 standard deviation units lower C-reactive protein and gamma-glutamyl transferase levels in EA. The same HNF1A coding variants were associated with higher low-density lipoprotein cholesterol, apolipoprotein B, creatinine, and fibrinogen in EA. We replicated the associations between HNF1A coding variants and C-reactive protein, fibrinogen, low-density lipoprotein cholesterol, and renal function in a second population-based sample of EA adults 65 years and older from the Cardiovascular Health Study. The HNF1A Ser486Asn and/or Ile27Leu variants were also associated with increased risk of subclinical coronary atherosclerosis in Coronary Artery Risk Development in Young Adults and with incident coronary heart disease in Cardiovascular Health Study. The Ile27Leu and Ser486Asn variants were 3-fold less common in AA than in EA. There was little evidence of association between HNF1A genotype and atherosclerosis-related phenotypes in AA. CONCLUSIONS: Common polymorphisms of HNF1A seem to influence multiple phenotypes related to cardiovascular risk in the general population of younger and older EA adults.
Keywords: Adolescent; Adult; African Americans; Aged; Aged, 80 and over; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, LDL; Cohort Studies; European Continental Ancestry Group; Female; Fibrinogen; gamma-Glutamyltransferase; Genetic Predisposition to Disease; Genotype; Hepatocyte Nuclear Factor 1-alpha; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Risk Factors

Common variants at ten loci influence QT interval duration in the QTGEN Study. - Newton-Cheh, Christopher; Eijgelsheim, Mark; Rice, Kenneth M; de Bakker, Paul I W; Yin, Xiaoyan; Estrada, Karol; Bis, Joshua C; Marciante, Kristin; Rivadeneira, Fernando; Noseworthy, Peter A; Sotoodehnia, Nona; Smith, Nicholas L; et al. (Nat Genet, 2009)
QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.
Keywords: Adaptor Proteins, Signal Transducing; Adult; Aged; Arrhythmias, Cardiac; Chromosome Mapping; Death, Sudden, Cardiac; Electroencephalography; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; European Continental Ancestry Group; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; Humans; KCNQ1 Potassium Channel; Meta-Analysis as Topic; Muscle Proteins; NAV1.5 Voltage-Gated Sodium Channel; Polymorphism, Single Nucleotide; Potassium Channels, Voltage-Gated; Risk Factors; Sodium Channels

C-reactive protein, interleukin-6, and prostate cancer risk in men aged 65 years and older. - Pierce, Brandon L; Biggs, Mary L; DeCambre, Marvalyn; Reiner, Alexander P; Li, Christopher; Fitzpatrick, Annette; Carlson, Christopher S; Stanford, Janet L; Austin, Melissa A (Cancer Causes Control, 2009)
Inflammation is believed to play a role in prostate cancer (PCa) etiology, but it is unclear whether inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) associate with PCa risk in older men. Using Cox regression, we assessed the relationship between baseline concentrations of CRP and IL-6 and the subsequent PCa risk in the Cardiovascular Health Study, a population-based cohort study of mostly European American men of ages >64 years (n = 2,234; mean follow-up = 8.7 years; 215 incident PCa cases). We also tested associations between CRP and IL-6 tagSNPs and PCa risk, focusing on SNPs that are known to associate with circulating CRP and/or IL-6. Neither CRP nor IL-6 blood concentrations was associated with PCa risk. The C allele of IL-6 SNP rs1800795 (-174), a known functional variant, was associated with increased risk in a dominant model (HR = 1.44; 95% CI = 1.03-2.01; p = 0.03), but was not statistically significant after accounting for multiple tests (permutation p = 0.21). Our results suggest that circulating CRP and IL-6 do not influence PCa risk. SNPs at the CRP locus are not associated with PCa risk in this cohort, while the association between rs1800795 and PCa risk warrants further investigation.
Keywords: African Americans; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; European Continental Ancestry Group; Humans; Inflammation; Interleukin-6; Male; Polymorphism, Single Nucleotide; Prospective Studies; Prostatic Neoplasms; Risk Factors

Depressed mood is not a risk factor for incident dementia in a community-based cohort. - Becker, James T; Chang, Yue-Fang; Lopez, Oscar L; Dew, Mary Amanda; Sweet, Robert A; Barnes, Deborah; Yaffe, Kristine; Young, Jeffrey; Kuller, Lewis; Reynolds, Charles F (Am J Geriatr Psychiatry, 2009)
OBJECTIVES: To determine the relationship between depressed mood and the development of Alzheimer disease in cognitively normal individuals. DESIGN: Longitudinal and observational. SETTING: Community-based cohort study. PARTICIPANTS: A total of 288 participants in the Cardiovascular Health Study-Cognition Study (mean age: 77.52, SD =3.65, range: 70-89). All of the participants were adjudicated as cognitively normal in 1998/1999, and all had at least three visits before 1998/1999 with measures of cognition and mood state. The mean length of follow-up from 1998-1999 to 2007 was 7.1 years (range: 1-9 years, median =9 years). MEASUREMENTS: The Center for Epidemiological Studies-Depression Scale (CESD) was used to index mood state, and the Modified Mini-Mental State Examination (3MSE) was the index of cognitive function among participants before 1998/1999. These measures were considered in two ways: participants were classified according to: 1) whether they showed a high-negative correlation between their CESD and 3MSE scores (i.e., indicating that greater depression was linked to poorer cognition) and 2) whether they showed persistently elevated CESD scores. The study outcome, development of dementia (N = 48), was based on consensus classifications, which was based on detailed neuropsychological and neurological exams. RESULTS: The authors could find no consistent relationship between mood state, either alone or in relation to cognitive status, and the subsequent development of dementia. Those individuals whose cognitive functions were highly correlated with their mood state were no more likely to develop dementia than other participants. Those who had persistently depressed mood were also no more likely to develop dementia than those without persistently depressed mood. CONCLUSION: Within the confines of this prospective, community-based study of elderly adults, the authors could not find strong evidence to support the hypothesis that mood disturbance was linked with the development of dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Dementia; Depression; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Prospective Studies; Psychiatric Status Rating Scales; Residence Characteristics; Risk Factors

Early age-related macular degeneration, cognitive function, and dementia: the Cardiovascular Health Study. - Baker, Michelle L; Wang, Jie Jin; Rogers, Sophie; Klein, Ronald; Kuller, Lewis H; Larsen, Emily K; Wong, Tien Yin (Arch Ophthalmol, 2009)
OBJECTIVE: To describe the association of cognitive function and dementia with early age-related macular degeneration (AMD) in older individuals. METHODS: This population-based study included 2,088 persons aged 69 to 97 years who participated in the Cardiovascular Health Study. The AMD was assessed from retinal photographs based on a modified Wisconsin AMD grading system. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination. Participants were also evaluated for dementia using detailed neuropsychological testing. RESULTS: After controlling for age, sex, race, and study center, persons with low DSST scores (lowest quartile of scores, < or =30) were more likely to have early AMD (odds ratio, 1.38; 95% confidence interval, 1.03-1.85) than were persons with higher DSST scores. In analyses further controlling for education, systolic blood pressure, total cholesterol level, diabetes mellitus, smoking status, and apolipoprotein E genotype, this association was stronger (odds ratio, 2.00; 95% confidence interval, 1.29-3.10). There was no association of low Modified Mini-Mental State Examination scores, dementia, or Alzheimer disease with early AMD. CONCLUSIONS: In this older population, cognitive impairment may share common age-related pathogenesis and risk factors with early AMD.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Cognition Disorders; Dementia; Female; Humans; Intelligence Tests; Macular Degeneration; Male; Neuropsychological Tests; Odds Ratio; Prospective Studies; Risk Factors; United States

Gene variants associated with ischemic stroke: the cardiovascular health study. - Luke, May M; O'Meara, Ellen S; Rowland, Charles M; Shiffman, Dov; Bare, Lance A; Arellano, Andre R; Longstreth, W T; Lumley, Thomas; Rice, Kenneth; Tracy, Russell P; Devlin, James J; Psaty, Bruce M (Stroke, 2009)
BACKGROUND AND PURPOSE: The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke. METHODS: Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS). RESULTS: In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10% versus 6%) and black (12% versus 3%) participants of CHS. CONCLUSIONS: The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.
Keywords: African Continental Ancestry Group; Aged; Alleles; Brain Ischemia; Cardiovascular Diseases; Coronary Disease; Ethnic Groups; European Continental Ancestry Group; Female; Gene Frequency; Genetic Variation; Humans; Kaplan-Meier Estimate; Male; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Stroke; United States

Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. - Vasan, Ramachandran S; Glazer, Nicole L; Felix, Janine F; Lieb, Wolfgang; Wild, Philipp S; Felix, Stephan B; Watzinger, Norbert; Larson, Martin G; Smith, Nicholas L; Dehghan, Abbas; Grosshennig, Anika; Schillert, Arne; et al. (JAMA, 2009)
CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
Keywords: Adult; Aged; Aged, 80 and over; Aorta; Cardiovascular Diseases; Echocardiography; European Continental Ancestry Group; Female; Genome-Wide Association Study; Genotype; Heart Atria; Heart Ventricles; Humans; Male; Middle Aged; Organ Size; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations. - Kao, W H Linda; Arking, Dan E; Post, Wendy; Rea, Thomas D; Sotoodehnia, Nona; Prineas, Ronald J; Bishe, Bryan; Doan, Betty Q; Boerwinkle, Eric; Psaty, Bruce M; Tomaselli, Gordon F; Coresh, Josef; et al. (Circulation, 2009)
BACKGROUND: The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOS1AP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOS1AP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study. METHODS AND RESULTS: We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs10494366 and rs4657139 in NOS1AP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOS1AP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs12567209, which was not correlated with rs16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs16847548 and SCD, and such adjustment had no effect on the association between rs12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOS1AP and either QT interval or SCD were observed in blacks. CONCLUSIONS: In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOS1AP were associated with baseline QT interval and the risk of SCD in white US adults.
Keywords: Adaptor Proteins, Signal Transducing; Aged; Death, Sudden, Cardiac; Electrocardiography; European Continental Ancestry Group; Genotype; Humans; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Genome-wide association studies of cardiovascular risk factors: design, conduct and interpretation. - Bis, J C; Glazer, N L; Psaty, B M (J Thromb Haemost, 2009)
Relying on known biology, candidate-gene studies have been only modestly successful in identifying genetic variants associated with cardiovascular risk factors. Genome-wide association (GWA) studies, in contrast, allow broad scans across millions of loci in search of unsuspected genetic associations with phenotypes. The large numbers of statistical tests in GWA studies and the large sample sizes required to detect modest-sized associations have served as a powerful incentive for the development of large collaborative efforts such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. This article uses published data on three phenotypes, fibrinogen, uric acid, and electrocardiographic QT interval duration, from the CHARGE Consortium to describe several methodologic issues in the design, conduct, and interpretation of GWA studies, including the use of imputation and the need for additional genotyping. Even with large studies, novel genetic loci explain only a small proportion of the variance of cardiovascular phenotypes.
Keywords: Cardiovascular Diseases; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Quantitative Trait Loci; Risk Factors

Genomewide association studies of stroke. - Ikram, M Arfan; Seshadri, Sudha; Bis, Joshua C; Fornage, Myriam; DeStefano, Anita L; Aulchenko, Yurii S; Debette, Stephanie; Lumley, Thomas; Folsom, Aaron R; van den Herik, Evita G; Bos, Michiel J; Beiser, Alexa; et al. (N Engl J Med, 2009)
BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
Keywords: African Continental Ancestry Group; Aged; Chromosomes, Human, Pair 12; Cohort Studies; European Continental Ancestry Group; Female; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Proportional Hazards Models; Risk Factors; Stroke

Genome-wide association study of blood pressure and hypertension. - Levy, Daniel; Ehret, Georg B; Rice, Kenneth; Verwoert, Germaine C; Launer, Lenore J; Dehghan, Abbas; Glazer, Nicole L; Morrison, Alanna C; Johnson, Andrew D; Aspelund, Thor; Aulchenko, Yurii; Lumley, Thomas; et al. (Nat Genet, 2009)
Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.
Keywords: Blood Pressure; Cell Line; Chromosome Mapping; Chromosomes, Human; Diastole; Gene Expression Regulation; Genetic Association Studies; Genome-Wide Association Study; Humans; Hypertension; Liver; Lymphocytes; Meta-Analysis as Topic; Odds Ratio; Phenotype; Prevalence; Risk Assessment; Systole

Heart rate variability and its changes over 5 years in older adults. - Stein, Phyllis K; Barzilay, Joshua I; Chaves, Paulo H M; Domitrovich, Peter P; Gottdiener, John S (Age Ageing, 2009)
PURPOSE: to characterise the association between age, ageing and heart rate variability (HRV) in older individuals, 585 adults age >65 years with two 24-h Holter recordings in the Cardiovascular Health Study were studied. METHODS: heart rate (HR), ventricular premature contractions (VPCs), atrial premature contractions (APCs), frequency-domain, ratio-based and non-linear HRV and heart rate turbulence (HRT) were examined cross-sectionally by 5-year age groups and prospectively over 5 years. Analyses adjusted for gender, lower versus elevated cardiovascular (CV) risk and for the change in CV risk. RESULTS: HR declined, and VPCs and APCs increased per 5-year increase in age. Frequency-domain HRV decreased more at 65-69, less at 70-74 and minimally at > or =75 years, independent of CVD risk or change in CVD risk. Ratio and non-linear HRV continued to decline to > or =75 years old. Ratio HRV and HRT slope were more strongly related to CVD risk than frequency-domain HRV. CONCLUSIONS: cardiac autonomic function, assessed by frequency-domain HRV, declines most at 65-70 and levels off at age >75. The decline is independent of CVD risk or change in CVD risk. Ratio-based and non-linear HRV and HRT slope continued to change with increasing age and were more closely related to CVD risk than frequency-domain HRV.
Keywords: Age Distribution; Aged; Aging; Atrial Premature Complexes; Autonomic Nervous System; Cardiovascular Diseases; Cross-Sectional Studies; Electrocardiography, Ambulatory; Female; Heart Rate; Humans; Hypertension; Male; Nonlinear Dynamics; Prevalence; Prospective Studies; Risk Factors; Ventricular Premature Complexes

Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease. - Patel, Shrita M; Ratcliffe, Sarah J; Reilly, Muredach P; Weinstein, Rachel; Bhasin, Shalender; Blackman, Marc R; Cauley, Jane A; Sutton-Tyrrell, Kim; Robbins, John; Fried, Linda P; Cappola, Anne R (J Clin Endocrinol Metab, 2009)
CONTEXT: Early postmenopausal women with higher testosterone (T) levels have increased insulin resistance (IR) and cardiovascular risk factors, but whether this translates into increased cardiovascular disease later in life is unknown. OBJECTIVE: The objective of the study was to determine whether higher T levels are associated with IR, the metabolic syndrome (MetSyn), and coronary heart disease (CHD) in elderly women. DESIGN: Total T and free T by equilibrium dialysis were measured using ultrasensitive assays in 344 women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to examine the associations between total and free T and IR, MetSyn, and CHD. RESULTS: There was a stepwise increase in the homeostasis model assessment of insulin resistance with increasing total (P = 0.0.003) and free T (P = 0.02) level and a corresponding decrease in Quantitative Insulin Sensitivity Check Index (P < 0.001 and P = 0.002, respectively). In adjusted models, higher levels of both total and free T were strongly associated with abdominal obesity and high fasting glucose, the two MetSyn components most strongly linked to IR. After adjustment, women in the top quartile of total T levels had a 3-fold greater odds of MetSyn (odds ratio 3.15, 95% confidence interval 1.57-6.35) than those in the bottom quartile and a 3-fold greater odds of CHD (odds ratio 2.95, 95% confidence interval 1.2-7.3) than those in second quartile, whereas free T was not significantly associated with MetSyn or CHD. CONCLUSIONS: Higher levels of T are associated with IR, MetSyn, and CHD in elderly women. Whether T is a marker or mediator of cardiovascular disease in this population merits further investigation.
Keywords: Aged; Aged, 80 and over; Blood Glucose; Cardiovascular Diseases; Coronary Disease; Female; Humans; Insulin; Insulin Resistance; Metabolic Syndrome; Odds Ratio; Radioimmunoassay; Socioeconomic Factors; Testosterone; Treatment Outcome

Imaging cerebral blood flow in the cognitively normal aging brain with arterial spin labeling: implications for imaging of neurodegenerative disease. - Lee, Charles; Lopez, Oscar L; Becker, James T; Raji, Cyrus; Dai, Weiying; Kuller, Lewis H; Gach, H Michael (J Neuroimaging, 2009)
INTRODUCTION: Arterial spin labeling (ASL) is a safe, noninvasive imaging method for evaluating cerebral blood flow (rCBF). The purpose of this article is to present ASL imaging features of 38 elderly cognitively normals (CN) with their rCBF values and an averaged profile of targeted anatomic regions rCBF values. METHODS: Thirty-eight CN underwent MR imaging especially ASL with voxel morphometric techniques fusing the MR anatomical and ASL images to a standard reference brain (colin27). The ASL images were fused to echo planar images, which were then coregistered to high-resolution anatomical SPGR images. rCBF was calculated per region of interest using a modified continuous arterial spin labeling (CASL) convolutional method. Anatomical regions were selected and identified by the Talairach atlas in SPM2. RESULTS: We identified areas of decreased and increased perfusion (compared to the averaged rCBF of all 38 CN) corresponding to decreased and increased quantified rCBF. The most common sites for decreased perfusion were precuneus (53%), superior temporal (48%), and orbitofrontal (37%), and for increased perfusion the caudate (39%), posterior cingulate (34%), anterior cingulate (32%), and amygdala (32%). CONCLUSION: There are regional variations in rCBF both increased and decreased with the posterior cingulate and precuneus cortex showing the highest averaged values and signal intensity (bright spots). These variations represent the normal profile of a CN elderly brain, with higher perfusion in areas associated with cognition, memory, and behavior. It is necessary to understand these normal variations in order to determine if there are perfusion changes in ASL detected in neurodegenerative disorders such as Alzheimer's disease.
Keywords: Aged, 80 and over; Aging; Brain; Brain Mapping; Cerebrovascular Circulation; Female; Humans; Magnetic Resonance Imaging; Male; Neurodegenerative Diseases; Signal Processing, Computer-Assisted; Spin Labels

Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults. - Walston, Jeremy D; Matteini, Amy M; Nievergelt, Caroline; Lange, Leslie A; Fallin, Dani M; Barzilai, Nir; Ziv, Elad; Pawlikowska, Ludmila; Kwok, Pui; Cummings, Steve R; Kooperberg, Charles; LaCroix, Andrea; et al. (Exp Gerontol, 2009)
Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%-20% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p<10(-4)). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415--longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the "risk" of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62-1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.
Keywords: Aged; Aged, 80 and over; Aging; Cardiovascular Diseases; Case-Control Studies; Female; Genetic Variation; Genotype; Humans; Inflammation; Interleukin-6; Longevity; Male; Phenotype; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Risk Factors

Insomnia did not predict incident hypertension in older adults in the cardiovascular health study. - Phillips, Barbara; Bůzková, Petra; Enright, Paul (Sleep, 2009)
STUDY OBJECTIVE: We hypothesized that the sleep complaints of insomnia predict incident hypertension, particularly in African Americans. The purpose of this study was to analyze insomnia complaints as predictors of incident hypertension in the Cardiovascular Health Study (CHS), stratifying by gender and allowing for race and sleep variable interaction. DESIGN: This is a prospective cohort study over a 6-year period of follow-up. SETTING: This is a community-based study of participants in Forsyth County, North Carolina; Pittsburgh, Pennsylvania; Sacramento County, California; and Washington County, Maryland. PARTICIPANTS: The study analyzed data from 1419 older individuals (baseline mean age 73.4 +/- 4.4 years) from the Cardiovascular Health Study who were not hypertensive at baseline. INTERVENTIONS: none. MEASUREMENTS: We constructed relative risks of incident hypertension over a 6-year period for insomnia complaints singly and in combination. RESULTS: Difficulty falling asleep, singly or in combination with other sleep complaints, predicted a statistically significant reduction of risk for incident hypertension for non-African American men in 6 years of follow-up. Insomnia complaints did not predict incident hypertension in 6 years of follow-up in women or in African Americans, although there may not have been enough power to show a significant association for African Americans. CONCLUSIONS: Insomnia did not predict hypertension in this older cohort which was free of hypertension at baseline. Difficulty falling asleep was associated with reduced risk of hypertension in non-African American men.
Keywords: African Americans; Aged; Cohort Studies; Comorbidity; European Continental Ancestry Group; Female; Follow-Up Studies; Health Surveys; Humans; Hypertension; Male; Prospective Studies; Risk Factors; Sleep Initiation and Maintenance Disorders; United States

Longitudinal evaluation of sleep-disordered breathing and sleep symptoms with change in quality of life: the Sleep Heart Health Study (SHHS). - Silva, Graciela E; An, Ming-Wen; Goodwin, James L; Shahar, Eyal; Redline, Susan; Resnick, Helaine; Baldwin, Carol M; Quan, Stuart F (Sleep, 2009)
STUDY OBJECTIVES: Findings from population studies evaluating the progression and incidence of sleep disordered breathing have shown evidence of a longitudinal increase in the severity of sleep disordered breathing. The present study evaluates the association among changes in sleep disordered breathing, sleep symptoms, and quality of life over time. DESIGN: Prospective cohort study. Data were from the Sleep Heart Health Study. SETTING: Multicenter study. PARTICIPANTS: Three thousand seventy-eight subjects aged 40 years and older from the baseline and follow-up examination cycles were included. MEASUREMENTS: The primary outcomes were changes in the Physical Component Summary and Mental Component Summary scales obtained from the Medical Outcomes Study Short-Form Health Survey. The primary exposure was change in the respiratory disturbance index obtained from unattended overnight polysomnograms performed approximately 5 years apart. Other covariates included measures of excessive daytime sleepiness and difficulty initiating and maintaining sleep. RESULTS: Mean respiratory disturbance index increased from 8.1 +/- 11 SD at baseline to 10.9 +/- 14 (P < 0.0001) at follow-up. The mean Physical Component Summary and Mental Component Summary scores were 48.5 and 54.1 at baseline and 46.3 and 54.8 at follow-up. No associations between change in respiratory disturbance index and changes in Physical Component Summary or Mental Component Summary scores were seen. However, worsening of difficulty initiating and maintaining sleep and excessive daytime sleepiness were significantly associated with lower quality of life. CONCLUSIONS: A slight increase in severity of sleep disordered breathing was seen over 5 years; this was not associated with worsening of quality of life. However, subjective symptoms of quality of sleep and daytime sleepiness were associated with declining quality of life.
Keywords: Aged; Attitude to Health; Cohort Studies; Comorbidity; Disease Progression; Disorders of Excessive Somnolence; Female; Humans; Longitudinal Studies; Male; Middle Aged; Polysomnography; Quality of Life; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders

Meta-analysis: retinal vessel caliber and risk for coronary heart disease. - McGeechan, Kevin; Liew, Gerald; Macaskill, Petra; Irwig, Les; Klein, Ronald; Klein, Barbara E K; Wang, Jie Jin; Mitchell, Paul; Vingerling, Johannes R; Dejong, Paulus T V M; Witteman, Jacqueline C M; Breteler, Monique M B; et al. (Ann Intern Med, 2009)
BACKGROUND: Retinal vessel caliber may be a novel marker of coronary heart disease (CHD) risk. However, the sex-specific effect, magnitude of association, and effect independent of traditional CHD disease risk factors remain unclear. PURPOSE: To determine the association between retinal vessel caliber and risk for CHD. DATA SOURCES: Relevant studies in any language identified through MEDLINE (1950 to June 2009) and EMBASE (1950 to June 2009) databases. STUDY SELECTION: Studies were included if they examined a general population, measured retinal vessel caliber from retinal photographs, and documented CHD risk factors and incident CHD events. DATA EXTRACTION: 6 population-based prospective cohort studies provided data for individual participant meta-analysis. DATA SYNTHESIS: Proportional hazards models, adjusted for traditional CHD risk factors, were constructed for retinal vessel caliber and incident CHD in women and men. Among 22,159 participants who were free of CHD and followed for 5 to 14 years, 2219 (10.0%) incident CHD events occurred. Retinal vessel caliber changes (wider venules and narrower arterioles) were each associated with an increased risk for CHD in women (pooled multivariable-adjusted hazard ratios, 1.16 [95% CI, 1.06 to 1.26] per 20-microm increase in venular caliber and 1.17 [CI, 1.07 to 1.28] per 20-microm decrease in arteriolar caliber) but not in men (1.02 [CI, 0.94 to 1.10] per 20-microm increase in venular caliber and 1.02 [CI, 0.95 to 1.10] per 20-microm decrease in arteriolar caliber). Women without hypertension or diabetes had higher hazard ratios. LIMITATION: Error in the measurement of retinal vessel caliber and Framingham variables was not taken into account. CONCLUSION: Retinal vessel caliber changes were independently associated with an increased risk for CHD events in women.
Keywords: Adult; Aged; Arterioles; Biomarkers; Coronary Disease; Female; Humans; Male; Middle Aged; Proportional Hazards Models; Retinal Vessels; Risk Factors; Sex Factors; Venules

Mild cognitive impairment and alzheimer disease: patterns of altered cerebral blood flow at MR imaging. - Dai, Weiying; Lopez, Oscar L; Carmichael, Owen T; Becker, James T; Kuller, Lewis H; Gach, H Michael (Radiology, 2009)
PURPOSE: To examine regional cerebral blood flow (rCBF) in incident mild cognitive impairment (MCI) and Alzheimer disease (AD) by using continuous arterial spin-labeling (CASL) magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the local institutional review board and was compliant with HIPAA regulations. Informed consent was obtained. rCBF was measured in 38 control subjects, 29 MCI patients, and 37 AD patients who were participating in a longitudinal epidemiologic study. Multisection CASL MR imaging with alternating single and double adiabatic inversion pulses and ramp-sampled echo-planar imaging were performed to acquire 19 contiguous axial sections. Voxel-level rCBF was compared among groups by using an analysis of variance design; clusters of voxels with significant group differences were identified. Multiple regression models controlled for age, sex, and presence of hypertension and related the mean rCBF in those clusters to the presence of MCI and AD. RESULTS: MCI and AD patients had decreased rCBF in the posterior cingulate gyrus (P = .01) with extension to the medial precuneus compared with that in control subjects. MCI patients had increased rCBF in the left hippocampus (P < .001), right amygdala (P = .007), and rostral head of the right caudate nucleus and ventral putamen and globus pallidus (P = .003) compared with that in control subjects. AD patients had decreased rCBF relative to that in control subjects and MCI patients in the left inferior parietal (P = .005), left lateral frontal (P < .001), left superior temporal (P = .001), and left orbitofrontal (P = .003) cortices. AD patients had increased rCBF in the right anterior cingulate gyrus (P = .02) compared with that in control subjects. CONCLUSION: The transition from normal cognition to AD is associated with dynamic pathologic processes in the brain, and this is reflected by both decreases and increases in rCBF. Increases in rCBF suggest a cellular and vascular compensatory process associated with incipient AD. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/2503080751/DC1.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebrovascular Circulation; Cognition Disorders; Female; Humans; Magnetic Resonance Imaging; Male

Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population. - Arking, Dan E; Khera, Amit; Xing, Chao; Kao, W H Linda; Post, Wendy; Boerwinkle, Eric; Chakravarti, Aravinda (PLoS One, 2009)
Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.
Keywords: Adaptor Proteins, Signal Transducing; Adolescent; Adult; African Americans; Aged; Death, Sudden, Cardiac; Electrocardiography; Ethnic Groups; European Continental Ancestry Group; Female; Genome-Wide Association Study; Heart Diseases; Heart Rate; Hispanic Americans; Humans; Linear Models; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Sex Factors; Young Adult

Multiple loci associated with indices of renal function and chronic kidney disease. - Köttgen, Anna; Glazer, Nicole L; Dehghan, Abbas; Hwang, Shih-Jen; Katz, Ronit; Li, Man; Yang, Qiong; Gudnason, Vilmundur; Launer, Lenore J; Harris, Tamara B; Smith, Albert V; Arking, Dan E; et al. (Nat Genet, 2009)
Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.
Keywords: Chromosome Mapping; Cohort Studies; Genetic Variation; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Meta-Analysis as Topic; Mucoproteins; Netherlands; Polymorphism, Single Nucleotide; Prevalence; Uromodulin

Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. - Ganesh, Santhi K; Zakai, Neil A; van Rooij, Frank J A; Soranzo, Nicole; Smith, Albert V; Nalls, Michael A; Chen, Ming-Huei; Köttgen, Anna; Glazer, Nicole L; Dehghan, Abbas; Kuhnel, Brigitte; Aspelund, Thor; et al. (Nat Genet, 2009)
Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
Keywords: Blood Pressure; Cell Line; Cohort Studies; Endothelial Cells; Erythrocytes; Gene Expression; Genome, Human; Genome-Wide Association Study; Humans; Hypertension; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci

NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. - Heard-Costa, Nancy L; Zillikens, M Carola; Monda, Keri L; Johansson, Asa; Harris, Tamara B; Fu, Mao; Haritunians, Talin; Feitosa, Mary F; Aspelund, Thor; Eiriksdottir, Gudny; Garcia, Melissa; Launer, Lenore J; et al. (PLoS Genet, 2009)
Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
Keywords: Aged; Body Mass Index; Cohort Studies; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Nerve Tissue Proteins; Obesity; Polymorphism, Single Nucleotide; Waist Circumference

Polysomnographic and health-related quality of life correlates of restless legs syndrome in the Sleep Heart Health Study. - Winkelman, John W; Redline, Susan; Baldwin, Carol M; Resnick, Helaine E; Newman, Anne B; Gottlieb, Daniel J (Sleep, 2009)
STUDY OBJECTIVES: Sleep disturbance is the primary clinical morbidity of restless legs syndrome (RLS). To date, sleep disturbance in RLS has been measured in (1) clinical samples with polysomnography (PSG) or (2) population-based samples by self-report. The objective of this study was to analyze sleep by PSG in a population-based sample with symptoms of RLS. DESIGN: Cross-sectional observational study. SETTING: Community-based. PARTICIPANTS: 3433 older men and women. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: RLS was evaluated using an 8-item self-administered questionnaire based on NIH diagnostic criteria and required symptoms occurring > or = five times per month and associated with at least moderate distress. Health-related quality of life (HRQOL) was determined using the SF-36. Unattended, in-home PSG was performed. Data were assessed using general linear models with adjustment for demographic, health-related variables, and apnea-hypopnea index (AHI). Subjects with RLS had longer adjusted mean sleep latency (39.8 vs 26.4 min, P < 0.0001) and higher arousal index (20.1 vs 18.0, P = 0.0145) than those without RLS. Sleep latency increased progressively as the frequency of RLS symptoms increased from 5-15 days per month to 6-7 days per week. No differences in sleep stage percentages were observed between participants with and without RLS. Subjects with RLS also reported poorer HRQOL in all physical domains as well as in the Mental Health and Vitality domains. CONCLUSIONS: These novel PSG data from a nonclinical, community-based sample of individuals with RLS document sleep disturbance in the home even in individuals with intermittent symptoms.
Keywords: Adult; Aged; Cohort Studies; Comorbidity; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Polysomnography; Prospective Studies; Quality of Life; Restless Legs Syndrome; Sleep Initiation and Maintenance Disorders; Statistics as Topic

Predicting risk of dementia in older adults: The late-life dementia risk index. - Barnes, D E; Covinsky, K E; Whitmer, R A; Kuller, L H; Lopez, O L; Yaffe, K (Neurology, 2009)
OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years. METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients. RESULTS: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores. CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.
Keywords: Age Factors; Aged; Aged, 80 and over; Alcohol Drinking; Apolipoprotein E4; Body Mass Index; Carotid Stenosis; Cerebrum; Cognition Disorders; Cohort Studies; Coronary Artery Bypass; Dementia; Female; Genetic Markers; Health Status Indicators; Humans; Logistic Models; Male; Predictive Value of Tests; Risk Assessment; Risk Factors; Risk Reduction Behavior

Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis. - McGeechan, Kevin; Liew, Gerald; Macaskill, Petra; Irwig, Les; Klein, Ronald; Klein, Barbara E K; Wang, Jie Jin; Mitchell, Paul; Vingerling, Johannes R; de Jong, Paulus T V M; Witteman, Jacqueline C M; Breteler, Monique M B; et al. (Am J Epidemiol, 2009)
The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5-12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95% confidence interval: 1.05, 1.25 per 20-micron increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.
Keywords: Aged; Fluorescein Angiography; Humans; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; Retinal Artery; Retinal Vein; Retinal Vessels; Risk Factors; Stroke

Prevalence of hearing loss in Black and White elders: results of the Cardiovascular Health Study. - Pratt, Sheila R; Kuller, Lewis; Talbott, Evelyn O; McHugh-Pemu, Kathleen; Buhari, Alhaji M; Xu, Xiaohui (J Speech Lang Hear Res, 2009)
PURPOSE: The goal of this study was to determine the impact of age, gender, and race on the prevalence and severity of hearing loss in elder adults, aged 72-96 years, after accounting for income, education, smoking, and clinical and subclinical cardiovascular disease. Methods Air-conduction thresholds for standard and extended high-frequency pure-tones were obtained from a cohort of 548 (out of 717) elderly adults (ages 72-96 years) who were recruited during the Year 11 clinical visit (1999-2000) of the Cardiovascular Health Study (CHS) at the Pittsburgh, Pennsylvania site. Participant smoking, income, education, and cardiovascular disease histories were obtained from the CHS database and were included as factors. RESULTS: Hearing loss was more common and more severe for the participants in their 80s than for those in their 70s-the men more than the women and the White participants more than the Black participants. The inclusion of education, income, smoking, and cardiovascular disease (clinical and subclinical) histories as factors did not substantively impact the overall results. CONCLUSION: Although the data reported in this article were cross-sectional and a cohort phenomenon might have been operational, they suggested that hearing loss is more substantive in the 8th than the 7th decade of life and that race and gender influence this decline in audition. Given the high prevalence in the aging population and the differences across groups, there is a clear need to understand the nature and causes of hearing loss across various groups in order to improve prevention and develop appropriate interventions.
Keywords: African Americans; Aged; Aged, 80 and over; Aging; Auditory Threshold; Cardiovascular Diseases; Cohort Studies; Cross-Sectional Studies; European Continental Ancestry Group; Female; Hearing Loss; Hearing Tests; Humans; Male; Occupations; Prevalence; Sex Characteristics; Smoking; Socioeconomic Factors; United States

Sibling history of myocardial infarction or stroke and risk of cardiovascular disease in the elderly: the Cardiovascular Health Study. - Yanez, N David; Burke, Gregory L; Manolio, Teri; Gardin, Julius M; Polak, Joseph (Ann Epidemiol, 2009)
PURPOSE: To assess the relationship between sibling history of myocardial infarction (MI) or stroke with cardiovascular disease (CVD) and risk factors in older adults. METHODS: Prospective cohort study of 5,888 older adults participating in the Cardiovascular Health Study (CHS). History of MI and stroke in siblings was obtained by self-report. Participants with positive sibling histories were compared to those with negative histories to determine if prevalent or incident disease (coronary heart disease [CHD], MI, stroke, angina), subclinical CVD (carotid wall thickness, left ventricular mass, hypertension, diabetes, ankle-brachial index), CVD risk factors differed between groups. RESULTS: More than 91% (n = 5,383) of CHS participants reported at least one sibling. Sibling history of MI was associated with increased disease prevalence (CHD, MI, angina) and incidence (CHD, angina). Sibling history of stroke was associated with increased disease prevalence (CHD, angina). Sibling history of either MI or stroke was associated with increased disease prevalence and incidence for CHD, MI and angina, more subclinical disease, and a higher CVD risk profile. CONCLUSIONS: Sibling history of MI and stroke were markers of higher CVD risk status even in older adults. Of clinical importance, participants with positive sibling history have numerous risk factors amenable to intervention.
Keywords: Aged; Atherosclerosis; Female; Genetic Predisposition to Disease; Humans; Incidence; Male; Myocardial Infarction; Odds Ratio; Prevalence; Prospective Studies; Risk Factors; Siblings; Stroke; United States

Sleep-disordered breathing and frailty in the Cardiovascular Health Study Cohort. - Endeshaw, Yohannes W; Unruh, Mark L; Kutner, Michael; Newman, Anne B; Bliwise, Donald L (Am J Epidemiol, 2009)
Sleep-disordered breathing (SDB) is associated with pathophysiology that may influence the development and progression of frailty. Using data collected in 1995-1996, the authors explored the relation between SDB and components of frailty among 1,042 participants of the Cardiovascular Health Study. Diagnosis of SDB was based on the results of overnight polysomnography, and severe SDB was defined as an apnea-hypopnea index of >30 per hour of sleep. Slow walking speed, low grip strength, exhaustion, low physical activity, and unexplained weight loss were referred to as frailty indicator variables. There were 584 (56%) female and 458 (44%) male participants, and the mean age was 77 (standard deviation, 4) years. There was independent association between severe SDB and 1 or more frailty indicator variables (adjusted odds ratio = 4.85, 95% confidence interval: 1.40, 16.78), slow walking speed (adjusted odds ratio = 2.67, 95% confidence interval: 1.04, 6.84), and low grip strength (adjusted odds ratio = 3.29, 95% confidence interval: 1.36, 7.96) among female study participants. The finding of an independent association between SDB and frailty indicator variables among older women could have important implications in interventions aimed at preventing or delaying the progression of frailty.
Keywords: Activities of Daily Living; Aged; Cardiovascular Diseases; Cardiovascular System; Cohort Studies; Confidence Intervals; Exercise Tolerance; Female; Frail Elderly; Hand Strength; Humans; Logistic Models; Male; Mobility Limitation; Models, Statistical; Motor Activity; Muscle Strength; Odds Ratio; Polysomnography; Psychometrics; Risk Factors; Sleep Apnea, Obstructive; Weight Loss

Spousal suffering and partner's depression and cardiovascular disease: the Cardiovascular Health Study. - Schulz, Richard; Beach, Scott R; Hebert, Randy S; Martire, Lynn M; Monin, Joan K; Tompkins, Connie A; Albert, Steven M (Am J Geriatr Psychiatry, 2009)
OBJECTIVES: To assess the effects of suffering in a spouse on prevalent and incident psychiatric (depression) and physical morbidity (cardiovascular disease [CVD]) in their partner, controlling for known risk factors for depression and CVD. DESIGN: Descriptive longitudinal study. PARTICIPANTS: A total of 1,330 older married couples enrolled in the Cardiovascular Health Study, a large epidemiologic study of the elderly. MEASUREMENTS: Predictor variables were physical, psychological, and existential/spiritual indicators of suffering. Primary outcomes were prevalent and incident depression and CVD. RESULTS: Controlling for known risk factors for depression, the authors found a dose-response relationship between suffering in a spouse and concurrent depression in their partner as well as a relationship between suffering and the partner's future risk for depression. With respect to CVD, and controlling for subclinical CVD at baseline, husbands whose wives reported high levels of suffering also had higher rates of prevalent CVD, but there were no significant associations between wives suffering and husbands incident CVD. There were no associations between husbands' suffering and wives' prevalent or incident CVD. CONCLUSION: Exposure to spousal suffering is an independent and unique source of distress in married couples that contributes to psychiatric and physical morbidity. More attention should be paid to the interpersonal effects of suffering in married couples and to its role in contributing to morbidity.
Keywords: Activities of Daily Living; Aged; Cardiovascular Diseases; Caregivers; Depression; Female; Follow-Up Studies; Humans; Incidence; Logistic Models; Longitudinal Studies; Male; Prevalence; Risk Factors; Socioeconomic Factors; Spouses; Stress, Psychological; Surveys and Questionnaires

Systematically missing confounders in individual participant data meta-analysis of observational cohort studies. - Jackson, Dan; White, Ian; Kostis, J B; Wilson, A C; Folsom, A R; Wu, K; Chambless, L; Benderly, M; Goldbourt, U; Willeit, J; Kiechl, S; Yarnell, J W G; et al. (Stat Med, 2009)
One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts
Keywords: Cohort Studies; Computer Simulation; Coronary Disease; Data Interpretation, Statistical; Female; Fibrinogen; Humans; Male; Meta-Analysis as Topic; Models, Statistical

Total and cause-specific mortality in the cardiovascular health study. - Newman, Anne B; Sachs, Michael C; Arnold, Alice M; Fried, Linda P; Kronmal, Richard; Cushman, Mary; Psaty, Bruce M; Harris, Tamara B; Robbins, John A; Burke, Gregory L; Kuller, Lewis H; Lumley, Thomas (J Gerontol A Biol Sci Med Sci, 2009)
BACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity. METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models. RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death. CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.
Keywords: Age Factors; Aged; Aged, 80 and over; Aging; Cardiovascular Diseases; Cause of Death; Chronic Disease; Cohort Studies; Female; Geriatric Assessment; Health Surveys; Humans; Kaplan-Meier Estimate; Male; Probability; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Analysis; United States

Trajectories of dehydroepiandrosterone sulfate predict mortality in older adults: the cardiovascular health study. - Cappola, Anne R; O'Meara, Ellen S; Guo, Wensheng; Bartz, Traci M; Fried, Linda P; Newman, Anne B (J Gerontol A Biol Sci Med Sci, 2009)
BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual's ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging. METHODS: Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged >or=65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points. RESULTS: Overall, there was a slight decline in DHEAS levels over time (-0.013 microg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32-2.33) and extreme variability (HR 1.89, CI 1.47-2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88-1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001). CONCLUSIONS: Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.
Keywords: Age Factors; Aged; Aged, 80 and over; Aging; Biomarkers; Cardiovascular Diseases; Cause of Death; Cohort Studies; Dehydroepiandrosterone Sulfate; Female; Geriatric Assessment; Humans; Longitudinal Studies; Male; Predictive Value of Tests; Proportional Hazards Models; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Analysis; United States

Usefulness of myeloperoxidase levels in healthy elderly subjects to predict risk of developing heart failure. - Tang, W H Wilson; Katz, Ronit; Brennan, Marie-Luise; Aviles, Ronnier J; Tracy, Russell P; Psaty, Bruce M; Hazen, Stanley L (Am J Cardiol, 2009)
Increased systemic myeloperoxidase (MPO) has been associated with both the presence and severity of heart failure (HF). This study tested the hypothesis that increased systemic MPO in apparently healthy elderly subjects may predict increased risk of developing HF. Systemic MPO was measured in all available samples from the 1992 to 1993 visit of the Cardiovascular Health Study (CHS). After excluding subjects without available blood samples or with a history of prevalent HF, myocardial infarction (MI), or stroke, 3,733 subjects were included. A total of 569 subjects developed incident HF during 7.2 +/- 2.3 years of follow-up. Patients in the highest MPO quartile (>432 pmol/L) showed higher risk of developing incident HF after adjusting for MI, age, gender, systolic blood pressure, smoking, low-density lipoprotein cholesterol, diabetes mellitus, and any subclinical cardiovascular disease (hazard ratio 1.34, 95% confidence interval 1.06 to 1.72, p = 0.013). However, the relation was more apparent after censoring subjects with incident MI before incident HF, even when adjusted for C-reactive protein and cystatin C (hazard ratio 1.46, 95% confidence interval 1.08 to 1.97, p = 0.02). Interestingly, stratified analyses showed that the relation between increased MPO and HF risk was stronger in subjects without traditional cardiovascular risk factors (<or=75 years old, systolic blood pressure <or=136 mm Hg, no subclinical cardiovascular disease, and no diabetes mellitus). In conclusion, an independent association between increased MPO and the development of HF in apparently healthy elderly subjects was observed, particularly beyond MI and traditional cardiac risk factors.
Keywords: Age Factors; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Female; Geriatric Assessment; Heart Failure; Humans; Longitudinal Studies; Male; Peroxidase; Predictive Value of Tests; Probability; Prognosis; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Sex Factors

Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. - Benjamin, Emelia J; Rice, Kenneth M; Arking, Dan E; Pfeufer, Arne; van Noord, Charlotte; Smith, Albert V; Schnabel, Renate B; Bis, Joshua C; Boerwinkle, Eric; Sinner, Moritz F; Dehghan, Abbas; Lubitz, Steven A; et al. (Nat Genet, 2009)
We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).
Keywords: Atrial Fibrillation; Chromosomes, Human, Pair 16; European Continental Ancestry Group; Genetic Predisposition to Disease; Genome-Wide Association Study; Homeodomain Proteins; Humans; Meta-Analysis as Topic; Mutation; Polymorphism, Single Nucleotide; Reproducibility of Results

Age and cystatin C in healthy adults: a collaborative study. - Odden, Michelle C; Tager, Ira B; Gansevoort, Ron T; Bakker, Stephan J L; Katz, Ronit; Fried, Linda F; Newman, Anne B; Canada, Robert B; Harris, Tamara; Sarnak, Mark J; Siscovick, David; Shlipak, Michael G (Nephrol Dial Transplant, 2010)
BACKGROUND: Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum. METHODS: The authors pooled individual-level cross-sectional data from 18 253 persons aged 28-100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure. RESULTS: Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction). CONCLUSIONS: There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.
Keywords: Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Cystatin C; Humans; Kidney; Middle Aged; Reference Values

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. - Speliotes, Elizabeth K; Willer, Cristen J; Berndt, Sonja I; Monda, Keri L; Thorleifsson, Gudmar; Jackson, Anne U; Lango Allen, Hana; Lindgren, Cecilia M; Luan, Jian'an; Mägi, Reedik; Randall, Joshua C; Vedantam, Sailaja; et al. (Nat Genet, 2010)
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Keywords: Body Height; Body Mass Index; Body Size; Body Weight; Chromosome Mapping; European Continental Ancestry Group; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Obesity; Polymorphism, Single Nucleotide

Association between adiposity in midlife and older age and risk of diabetes in older adults. - Biggs, Mary L; Mukamal, Kenneth J; Luchsinger, José A; Ix, Joachim H; Carnethon, Mercedes R; Newman, Anne B; de Boer, Ian H; Strotmeyer, Elsa S; Mozaffarian, Dariush; Siscovick, David S (JAMA, 2010)
CONTEXT: Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults. OBJECTIVE: To examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years of age and older. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study (1989-2007) of 4193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later. MAIN OUTCOME MEASURE: Incident diabetes was ascertained based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater. RESULTS: Over median follow-up of 12.4 years (range, 0.9-17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person-years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9-6.5) for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), 3.0 (95% CI, 2.0-4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8-6.4) for weight, 4.0 (95% CI, 2.6-6.0) for fat mass, 4.2 (95% CI, 2.8-6.2) for waist circumference, 2.4 (95% CI, 1.6-3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6-5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (+/-2 kg), those who gained the most weight from 50 years of age to baseline (> or = 9 kg), and from baseline to the third follow-up visit (> or = 6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9-4.3) and 2.0 (95% CI, 1.1-3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less. CONCLUSION: Among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.
Keywords: Adiposity; Age Factors; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Incidence; Male; Prospective Studies; Risk Factors; United States; Weight Gain

Association between depressive symptoms and fibrosis markers: the Cardiovascular Health Study. - Kop, Willem J; Kuhl, Emily A; Barasch, Eddy; Jenny, Nancy S; Gottlieb, Stephen S; Gottdiener, John S (Brain Behav Immun, 2010)
OBJECTIVE: Fibrosis plays an important role in heart failure (HF) and other diseases that occur more frequently with increasing age. Depression is associated with an increased risk of heart failure and other age-related diseases. This study examined the association between depressive symptoms and fibrosis markers in adults aged 65 years and above. METHODS: Fibrosis markers and depressive symptoms were assessed in 870 participants (age=80.9+/-5.9 yrs, 49% women) using a case-control design based on heart failure status (307 HF patients and 563 age- and sex-matched controls, of whom 284 with CVD risk factors (hypertension, diabetes mellitus, or hypercholesterolemia) and 279 controls without these CVD risk factors). Fibrosis markers were procollagen type I (PIP), type I collagen (CITP), and procollagen type III (PIIINP). Inflammation markers included C-reactive protein, white blood cell counts and fibrinogen. Depression was assessed using the Center for Epidemiological Studies-Depression (CES-D) scale using a previously validated cut-off point for depression (CES-D > or = 8). Covariates included demographic and clinical variables. RESULTS: Depression was associated with higher levels of PIP (median=411.0, inter-quartile range (IQR)=324.4-472.7 ng/mL vs. 387.6, IQR=342.0-512.5 ng/mL, p=0.006) and CITP (4.99, IQR=3.53-6.85 vs. 4.53, IQR=3.26-6.22 microg/L, p=0.024), but not PIIIINP (4.07, IQR=2.75-5.54 microg/L vs. 3.58, IQR=2.71-5.01 microg/L, p=0.29) compared to individuals without depression. Inflammation markers were also elevated in depressed participants (CRP, p=0.014; WBC, p=0.075; fibrinogen, p=0.074), but these inflammation markers did not account for the relationship between depression and fibrosis markers. CONCLUSIONS: Depression is associated with elevated fibrosis markers and may therefore adversely affect heart failure and other age-related diseases in which extra-cellular matrix formation plays a pathophysiological role.
Keywords: Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Collagen Type I; Depression; Electrocardiography; Endomyocardial Fibrosis; Fatigue; Female; Fibrosis; Health Surveys; Heart Failure; Humans; Inflammation Mediators; Male; Multivariate Analysis; Peptide Fragments; Procollagen; Psychiatric Status Rating Scales; Risk Factors; Socioeconomic Factors

Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. - Smith, Nicholas L; Felix, Janine F; Morrison, Alanna C; Demissie, Serkalem; Glazer, Nicole L; Loehr, Laura R; Cupples, L Adrienne; Dehghan, Abbas; Lumley, Thomas; Rosamond, Wayne D; Lieb, Wolfgang; Rivadeneira, Fernando; et al. (Circ Cardiovasc Genet, 2010)
BACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3. CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.
Keywords: African Americans; Aged; Aged, 80 and over; Cohort Studies; Endopeptidases; European Continental Ancestry Group; Female; Genome-Wide Association Study; Heart Failure; Humans; Incidence; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk; Ubiquitin-Specific Proteases

Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression. - Kop, Willem J; Stein, Phyllis K; Tracy, Russell P; Barzilay, Joshua I; Schulz, Richard; Gottdiener, John S (Psychosom Med, 2010)
OBJECTIVE: To investigate prospectively whether autonomic nervous system (ANS) dysfunction and inflammation play a role in the increased cardiovascular disease (CVD)-related mortality risk associated with depression. METHODS: Participants in the Cardiovascular Health Study (n = 907; mean age, 71.3 ± 4.6 years; 59.1% women) were evaluated for ANS indices derived from heart rate variability (HRV) analysis (frequency and time domain HRV, and nonlinear indices, including detrended fluctuation analysis (DFA(1)) and heart rate turbulence). Inflammation markers included C-reactive protein, interleukin-6, fibrinogen, and white blood cell count). Depressive symptoms were assessed, using the 10-item Centers for Epidemiological Studies Depression scale. Cox proportional hazards models were used to investigate the mortality risk associated with depression, ANS, and inflammation markers, adjusting for demographic and clinical covariates. RESULTS: Depression was associated with ANS dysfunction (DFA(1), p = .018), and increased inflammation markers (white blood cell count, p = .012, fibrinogen p = .043) adjusting for covariates. CVD-related mortality occurred in 121 participants during a median follow-up of 13.3 years. Depression was associated with an increased CVD mortality risk (hazard ratio, 1.88; 95% confidence interval, 1.23-2.86). Multivariable analyses showed that depression was an independent predictor of CVD mortality (hazard ratio, 1.72; 95% confidence interval, 1.05-2.83) when adjusting for independent HRV and inflammation predictors (DFA(1), heart rate turbulence, interleukin-6), attenuating the depression-CVD mortality association by 12.7% (p < .001). CONCLUSION: Autonomic dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression, but a large portion of the predictive value of depression remains unexplained by these neuroimmunological measures.
Keywords: Aged; Autonomic Nervous System Diseases; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cause of Death; Cohort Studies; Comorbidity; Depressive Disorder; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Inflammation; Interleukin-6; Leukocyte Count; Male; Risk Factors

Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables. - Burgess, Stephen; Thompson, Simon G; Burgess, S; Thompson, S G; Andrews, G; Samani, N J; Hall, A; Whincup, P; Morris, R; Lawlor, D A; Davey Smith, G; Timpson, N; et al. (Stat Med, 2010)
Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.
Keywords: Bayes Theorem; Biostatistics; C-Reactive Protein; Fibrinogen; Genetic Markers; Humans; Meta-Analysis as Topic; Models, Statistical; Phenotype; Polymorphism, Single Nucleotide

Biological, clinical and population relevance of 95 loci for blood lipids. - Teslovich, Tanya M; Musunuru, Kiran; Smith, Albert V; Edmondson, Andrew C; Stylianou, Ioannis M; Koseki, Masahiro; Pirruccello, James P; Ripatti, Samuli; Chasman, Daniel I; Willer, Cristen J; Johansen, Christopher T; Fouchier, Sigrid W; et al. (Nature, 2010)
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Keywords: African Americans; Animals; Asian Continental Ancestry Group; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Europe; European Continental Ancestry Group; Female; Genetic Loci; Genome-Wide Association Study; Genotype; Humans; Lipid Metabolism; Lipids; Liver; Male; Mice; N-Acetylgalactosaminyltransferases; Phenotype; Polymorphism, Single Nucleotide; Protein Phosphatase 1; Reproducibility of Results; Triglycerides

Brain structure and obesity. - Raji, Cyrus A; Ho, April J; Parikshak, Neelroop N; Becker, James T; Lopez, Oscar L; Kuller, Lewis H; Hua, Xue; Leow, Alex D; Toga, Arthur W; Thompson, Paul M (Hum Brain Mapp, 2010)
Obesity is associated with increased risk for cardiovascular health problems including diabetes, hypertension, and stroke. These cardiovascular afflictions increase risk for cognitive decline and dementia, but it is unknown whether these factors, specifically obesity and Type II diabetes, are associated with specific patterns of brain atrophy. We used tensor-based morphometry (TBM) to examine gray matter (GM) and white matter (WM) volume differences in 94 elderly subjects who remained cognitively normal for at least 5 years after their scan. Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions. A multiple regression model, also correcting for multiple comparisons, revealed that BMI was still negatively correlated with brain atrophy (FDR <5%), while DM2 and FPI were no longer associated with any volume differences. In an Analysis of Covariance (ANCOVA) model controlling for age, gender, and race, obese subjects with a high BMI (BMI > 30) showed atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus compared with individuals with a normal BMI (18.5-25). Overweight subjects (BMI: 25-30) had atrophy in the basal ganglia and corona radiata of the WM. Overall brain volume did not differ between overweight and obese persons. Higher BMI was associated with lower brain volumes in overweight and obese elderly subjects. Obesity is therefore associated with detectable brain volume deficits in cognitively normal elderly subjects.
Keywords: Age Factors; Aged; Analysis of Variance; Body Mass Index; Brain; Continental Population Groups; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Insulin; Magnetic Resonance Imaging; Male; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Obesity; Organ Size; Regression Analysis; Sex Factors

Cancer linked to Alzheimer disease but not vascular dementia. - Roe, C M; Fitzpatrick, A L; Xiong, C; Sieh, W; Kuller, L; Miller, J P; Williams, M M; Kopan, R; Behrens, M I; Morris, J C (Neurology, 2010)
OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cohort Studies; Dementia, Vascular; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Hospitalization; Humans; Male; Neoplasms; Nerve Degeneration; Parkinson Disease; Prevalence; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors

Candidate gene association resource (CARe): design, methods, and proof of concept. - Musunuru, Kiran; Lettre, Guillaume; Young, Taylor; Farlow, Deborah N; Pirruccello, James P; Ejebe, Kenechi G; Keating, Brendan J; Yang, Qiong; Chen, Ming-Huei; Lapchyk, Nina; Crenshaw, Andrew; Ziaugra, Liuda; et al. (Circ Cardiovasc Genet, 2010)
BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans. METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups. CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.
Keywords: African Americans; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Databases, Genetic; European Continental Ancestry Group; Genetic Association Studies; Genotype; Humans; Phenotype; Pilot Projects; Polymorphism, Single Nucleotide; Research Design; Triglycerides

Cardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the cardiovascular health study all stars study. - Sanders, Jason L; Boudreau, Robert M; Cappola, Anne R; Arnold, Alice M; Robbins, John; Cushman, Mary; Newman, Anne B (J Am Geriatr Soc, 2010)
OBJECTIVES: To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age. DESIGN: Longitudinal cohort study. SETTING: Pittsburgh, Pennsylvania. PARTICIPANTS: Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N=989, mean age 85.2, 63.5% women, 16.5% African American). MEASUREMENTS: Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change. RESULTS: Mean +/- standard deviation DHEAS was 0.555 +/- 0.414 microg/mL in 1996/97 and 0.482 +/- 0.449 microg/mL in 2005/06 for women and 0.845 +/- 0.520 microg/mL in 1996/97 and 0.658 +/- 0.516 microg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (-0.200 microg/mL) than in women (-0.078 microg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 microg/mL (P=.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (beta=-0.04 microg/mL, P=.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio=1.46, 95% confidence interval=1.03-2.05). CONCLUSION: DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.
Keywords: Age Distribution; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Dehydroepiandrosterone Sulfate; Female; Humans; Longitudinal Studies; Male; Multivariate Analysis; Regression Analysis; Sex Distribution; United States

Combined association of lipids and blood pressure in relation to incident cardiovascular disease in the elderly: the cardiovascular health study. - Wong, Nathan D; Lopez, Victor A; Roberts, Craig S; Solomon, Henry A; Burke, Gregory L; Kuller, Lewis; Tracy, Russell; Yanez, David; Psaty, Bruce M (Am J Hypertens, 2010)
BACKGROUND: Hypertension and dyslipidemia are highly prevalent in the elderly. We studied the combined impact of both conditions on cardiovascular disease (CVD) events. METHODS: We studied 4,311 participants aged 65-98 (61.2% female) from the Cardiovascular Health Study (CHS), a longitudinal epidemiologic study, with no prior CVD. We evaluated the relation of low-density lipoprotein (LDL), high-density lipoprotein (HDL), or non-HDL-cholesterol combined with blood pressure (BP) categories to incident CVD-including coronary heart disease (CHD) (angina, myocardial infarction (MI), angioplasty, coronary bypass surgery, or CHD death), stroke, claudication, and CVD death over 15 years. RESULTS: CVD incidence (per 1,000 person years) ranged from 38.4 when BP <120/80 mm Hg and LDL-C <100 mg/dl to 94.8 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl, and from 28.9 when BP <120/80 mm Hg and HDL >60 mg/dl to 87.1 for a BP >or=160/100 and HDL-C <40 mg/dl. Compared with those with BP <120/80 mm Hg with either LDL-C <100 mg/dl or HDL-C >60 mg/dl, hazard ratios (HRs) for CVD events were 2.1 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl and 2.1 when BP >or=160/100 and HDL-C <40 mg/dl (all P < 0.01), with similar results for non-HDL-C. Elevated BP was associated with increased risk across all lipid levels. Increased LDL-C added risk mainly when BP <140/90 mm Hg, but lower HDL-C also predicted CVD in those with higher BP. CONCLUSION: Increased BP confers increased risks for CVD in elderly persons across all lipid levels. Although increased LDL-C added risk mainly when BP <140/90 mm Hg, low HDL-C added risk also in those with hypertension. These results document the importance of combined hypertension and dyslipidemia.
Keywords: Age Factors; Aged; Aged, 80 and over; Blood Pressure; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Female; Health Surveys; Humans; Likelihood Functions; Lipids; Male; Proportional Hazards Models; Sex Factors; Smoking; Socioeconomic Factors; United States

Commentary on "Developing a national strategy to prevent dementia: Leon Thal Symposium 2009." Dementia risk indices: A framework for identifying individuals with a high dementia risk. - Barnes, Deborah E; Covinsky, Kenneth E; Whitmer, Rachel A; Kuller, Lewis H; Lopez, Oscar L; Yaffe, Kristine (Alzheimers Dement, 2010)
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Dementia; Diagnosis, Differential; Disability Evaluation; Early Diagnosis; Humans; National Health Programs; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors; United States

Common genetic determinants of vitamin D insufficiency: a genome-wide association study. - Wang, Thomas J; Zhang, Feng; Richards, J Brent; Kestenbaum, Bryan; van Meurs, Joyce B; Berry, Diane; Kiel, Douglas P; Streeten, Elizabeth A; Ohlsson, Claes; Koller, Daniel L; Peltonen, Leena; Cooper, Jason D; et al. (Lancet, 2010)
BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
Keywords: Canada; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 4; Cohort Studies; Dietary Supplements; Europe; European Continental Ancestry Group; Genetic Predisposition to Disease; Genome-Wide Association Study; Heterozygote; Homozygote; Humans; Immunoassay; International Cooperation; Linkage Disequilibrium; Polymorphism, Single Nucleotide; Seasons; United States; Vitamin D; Vitamin D Deficiency

Common genetic variants associate with serum phosphorus concentration. - Kestenbaum, Bryan; Glazer, Nicole L; Köttgen, Anna; Felix, Janine F; Hwang, Shih-Jen; Liu, Yongmei; Lohman, Kurt; Kritchevsky, Stephen B; Hausman, Dorothy B; Petersen, Ann-Kristin; Gieger, Christian; Ried, Janina S; et al. (J Am Soc Nephrol, 2010)
Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.
Keywords: Adult; Aged; European Continental Ancestry Group; Female; Fibroblast Growth Factors; Gene Frequency; Genetic Loci; Genetic Variation; Genome-Wide Association Study; Humans; Kidney; Male; Middle Aged; Phosphorus; Polymorphism, Single Nucleotide; Receptors, Calcium-Sensing; Sex Factors; Sodium-Phosphate Cotransporter Proteins, Type IIa

Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. - Sotoodehnia, Nona; Isaacs, Aaron; de Bakker, Paul I W; Dörr, Marcus; Newton-Cheh, Christopher; Nolte, Ilja M; van der Harst, Pim; Müller, Martina; Eijgelsheim, Mark; Alonso, Alvaro; Hicks, Andrew A; Padmanabhan, Sandosh; et al. (Nat Genet, 2010)
The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
Keywords: Animals; Animals, Newborn; Chromosomes, Human; Computational Biology; Electrocardiography; Genetic Loci; Genome-Wide Association Study; Heart Conduction System; Humans; Mice; Mice, Transgenic; Models, Animal; Myocytes, Cardiac; NAV1.8 Voltage-Gated Sodium Channel; Polymorphism, Single Nucleotide; Sodium Channels

Common variants in KCNN3 are associated with lone atrial fibrillation. - Ellinor, Patrick T; Lunetta, Kathryn L; Glazer, Nicole L; Pfeufer, Arne; Alonso, Alvaro; Chung, Mina K; Sinner, Moritz F; de Bakker, Paul I W; Mueller, Martina; Lubitz, Steven A; Fox, Ervin; Darbar, Dawood; et al. (Nat Genet, 2010)
Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.
Keywords: Adolescent; Adult; Aged; Atrial Fibrillation; Case-Control Studies; Cohort Studies; Female; Genome-Wide Association Study; Humans; Introns; Male; Meta-Analysis as Topic; Middle Aged; Polymorphism, Single Nucleotide; Small-Conductance Calcium-Activated Potassium Channels; Young Adult

Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. - O'Seaghdha, Conall M; Yang, Qiong; Glazer, Nicole L; Leak, Tennille S; Dehghan, Abbas; Smith, Albert V; Kao, W H Linda; Lohman, Kurt; Hwang, Shih-Jen; Johnson, Andrew D; Hofman, Albert; Uitterlinden, André G; et al. (Hum Mol Genet, 2010)
Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.
Keywords: Adult; Calcium; Female; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Calcium-Sensing

Concurrent change in dehydroepiandrosterone sulfate and functional performance in the oldest old: results from the Cardiovascular Health Study All Stars study. - Sanders, J L; Cappola, A R; Arnold, A M; Boudreau, R M; Chaves, P H; Robbins, J; Cushman, M; Newman, A B (J Gerontol A Biol Sci Med Sci, 2010)
INTRODUCTION: The correlation between dehydroepiandrosterone sulfate (DHEAS) decline and age led to the hypothesis that DHEAS might be a marker of primary aging, though conflicting data from observational studies of mortality do not support this. We evaluated concurrent DHEAS and functional decline in a very old cohort to test if DHEAS change tracks with functional change during aging. METHODS: DHEAS and functional performance (gait speed, grip strength, Modified Mini-Mental State Examination [3MSE] score, and digit symbol substitution test [DSST] score) were measured in 1996-1997 and 2005-2006 in 989 participants in the Cardiovascular Health Study All Stars study (mean age 85.2 years in 2005-2006, 63.5% women and 16.5% African American). We used multivariable linear regression to test the association of DHEAS decline with functional decline. RESULTS: After adjustment, each standard deviation decrease in DHEAS was associated with greater declines in gait speed (0.12 m/s, p = .01), grip strength (0.09 kg, p = .03), 3MSE score (0.13 points, p < .001), and DSST score (0.14 points, p = .001) in women only. Additional adjustment for baseline DHEAS attenuated the association with grip strength but did not alter other estimates appreciably, and baseline DHEAS was unassociated with functional decline. CONCLUSIONS: In this cohort of very old individuals, DHEAS decline tracked with declines in gait speed, 3MSE score, and DSST score, but not grip strength, in women independent of baseline DHEAS level. DHEAS decline might be a marker for age-associated performance decline, but its relevance is specific to women.
Keywords: Aged, 80 and over; Biomarkers; Cognition; Cohort Studies; Dehydroepiandrosterone Sulfate; Female; Gait; Geriatric Assessment; Hand Strength; Health Surveys; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Sex Factors; United States

Diabetes and coronary heart disease as risk factors for mortality in older adults. - Carnethon, Mercedes R; Biggs, Mary L; Barzilay, Joshua; Kuller, Lewis H; Mozaffarian, Dariush; Mukamal, Kenneth; Smith, Nicholas L; Siscovick, David (Am J Med, 2010)
BACKGROUND: Type 2 diabetes has been described as a coronary heart disease (CHD) "risk equivalent." We tested whether cardiovascular and all-cause mortality rates were similar between participants with prevalent CHD vs diabetes in an older adult population in whom both glucose disorders and preexisting atherosclerosis are common. METHODS: The Cardiovascular Health Study is a longitudinal study of men and women (n=5784) aged > or =65 years at baseline who were followed from baseline (1989/1992-1993) through 2005 for mortality. Diabetes was defined by fasting plasma glucose > or =7.0 mmol/L or use of diabetes control medications. Prevalent CHD was determined by confirmed history of myocardial infarction, angina, or coronary revascularization. RESULTS: Following multivariable adjustment for other cardiovascular disease risk factors and subclinical atherosclerosis, CHD mortality risk was similar between participants with CHD alone vs diabetes alone (hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.83-1.30). The proportion of mortality attributable to prevalent diabetes (population-attributable risk percent=8.4%) and prevalent CHD (6.7%) was similar in women, but the proportion of mortality attributable to CHD (16.5%) as compared with diabetes (6.4%) was markedly higher in men. Patterns were similar for cardiovascular disease mortality. By contrast, the adjusted relative hazard of total mortality was lower among participants with CHD alone (HR 0.85, 95% CI, 0.75-0.96) as compared with those who had diabetes alone. CONCLUSIONS: Among older adults, diabetes alone confers a risk for cardiovascular mortality similar to that from established clinical CHD. The public health burden of both diabetes and CHD is substantial, particularly among women.
Keywords: Aged; Coronary Disease; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Male; Prevalence; Risk Factors; Sex Distribution; Survival Rate; Time Factors; United States

Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies. - Gkrania-Klotsas, Effrossyni; Ye, Zheng; Cooper, Andrew J; Sharp, Stephen J; Luben, Robert; Biggs, Mary L; Chen, Liang-Kung; Gokulakrishnan, Kuppan; Hanefeld, Markolf; Ingelsson, Erik; Lai, Wen-An; Lin, Shih-Yi; et al. (PLoS One, 2010)
OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated. RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored. RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference. CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.
Keywords: Adult; Aged; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Leukocyte Count; Male; Middle Aged; Prospective Studies

European ancestry as a risk factor for atrial fibrillation in African Americans. - Marcus, Gregory M; Alonso, Alvaro; Peralta, Carmen A; Lettre, Guillaume; Vittinghoff, Eric; Lubitz, Steven A; Fox, Ervin R; Levitzky, Yamini S; Mehra, Reena; Kerr, Kathleen F; Deo, Rajat; Sotoodehnia, Nona; et al. (Circulation, 2010)
BACKGROUND: Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF. METHODS AND RESULTS: We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results. CONCLUSIONS: European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.
Keywords: African Americans; Aged; Atrial Fibrillation; European Continental Ancestry Group; Female; Genome-Wide Association Study; Humans; Male; Middle Aged; Risk Factors

Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. - Ikram, M Kamran; Sim, Xueling; Xueling, Sim; Jensen, Richard A; Cotch, Mary Frances; Hewitt, Alex W; Ikram, M Arfan; Wang, Jie Jin; Klein, Ronald; Klein, Barbara E K; Breteler, Monique M B; Cheung, Ning; et al. (PLoS Genet, 2010)
There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Child; Child, Preschool; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 6; Cohort Studies; European Continental Ancestry Group; Female; Genetic Loci; Genome-Wide Association Study; Humans; Male; Meta-Analysis as Topic; Microcirculation; Middle Aged; Polymorphism, Single Nucleotide; Retinal Vessels; Young Adult

Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. - McGovern, Dermot P B; Jones, Michelle R; Taylor, Kent D; Marciante, Kristin; Yan, Xiaofei; Dubinsky, Marla; Ippoliti, Andy; Vasiliauskas, Eric; Berel, Dror; Derkowski, Carrie; Dutridge, Deb; Fleshner, Phil; et al. (Hum Mol Genet, 2010)
Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.
Keywords: Adolescent; Adult; Aged; Child; Child, Preschool; Cohort Studies; Crohn Disease; Female; Fucosyltransferases; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Young Adult

Genetic ancestry in lung-function predictions. - Kumar, Rajesh; Seibold, Max A; Aldrich, Melinda C; Williams, L Keoki; Reiner, Alex P; Colangelo, Laura; Galanter, Joshua; Gignoux, Christopher; Hu, Donglei; Sen, Saunak; Choudhry, Shweta; Peterson, Edward L; et al. (N Engl J Med, 2010)
BACKGROUND: Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American. METHODS: We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations. RESULTS: African ancestry was inversely related to forced expiratory volume in 1 second (FEV(1)) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV(1)) in 4 to 5% of participants. CONCLUSIONS: Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)
Keywords: Adolescent; Adult; African Americans; Aged; Aged, 80 and over; Female; Forced Expiratory Volume; Genetic Markers; Genotype; Humans; Linear Models; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Reference Values; Respiratory Function Tests; Vital Capacity; Young Adult

Genetic predictors of medically refractory ulcerative colitis. - Haritunians, Talin; Taylor, Kent D; Targan, Stephan R; Dubinsky, Marla; Ippoliti, Andrew; Kwon, Soonil; Guo, Xiuqing; Melmed, Gil Y; Berel, Dror; Mengesha, Emebet; Psaty, Bruce M; Glazer, Nicole L; et al. (Inflamm Bowel Dis, 2010)
BACKGROUND: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC. METHODS: A GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls. RESULTS: MR-UC was associated with more extensive disease (P = 2.7 × 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10(-6)). CONCLUSIONS: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.
Keywords: Acute Disease; Adolescent; Adult; Cohort Studies; Colectomy; Colitis, Ulcerative; Female; Genetic Loci; Genome-Wide Association Study; Humans; Major Histocompatibility Complex; Male; Polymorphism, Single Nucleotide; Risk Factors; Severity of Illness Index; Tumor Necrosis Factor Ligand Superfamily Member 15; Young Adult

Genome-wide analysis of genetic loci associated with Alzheimer disease. - Seshadri, Sudha; Fitzpatrick, Annette L; Ikram, M Arfan; DeStefano, Anita L; Gudnason, Vilmundur; Boada, Merce; Bis, Joshua C; Smith, Albert V; Carassquillo, Minerva M; Lambert, Jean Charles; Harold, Denise; Schrijvers, Elisabeth M C; et al. (JAMA, 2010)
CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases). DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. MAIN OUTCOME MEASURE: Presence of Alzheimer disease. RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.
Keywords: Age of Onset; Aged; Alzheimer Disease; Case-Control Studies; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Odds Ratio; Polymorphism, Single Nucleotide

Genome-wide association analysis identifies multiple loci related to resting heart rate. - Eijgelsheim, Mark; Newton-Cheh, Christopher; Sotoodehnia, Nona; de Bakker, Paul I W; Müller, Martina; Morrison, Alanna C; Smith, Albert V; Isaacs, Aaron; Sanna, Serena; Dörr, Marcus; Navarro, Pau; Fuchsberger, Christian; et al. (Hum Mol Genet, 2010)
Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
Keywords: Adult; Aged; Base Pairing; Cohort Studies; Female; Genetic Loci; Genome, Human; Genome-Wide Association Study; Heart Rate; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Rest

Genome-wide association identifies multiple ulcerative colitis susceptibility loci. - McGovern, Dermot P B; Gardet, Agnès; Törkvist, Leif; Goyette, Philippe; Essers, Jonah; Taylor, Kent D; Neale, Benjamin M; Ong, Rick T H; Lagacé, Caroline; Li, Chun; Green, Todd; Stevens, Christine R; et al. (Nat Genet, 2010)
Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.
Keywords: Colitis, Ulcerative; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Membrane Proteins; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Receptors, IgG

Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. - Levy, Daniel; Neuhausen, Susan L; Hunt, Steven C; Kimura, Masayuki; Hwang, Shih-Jen; Chen, Wei; Bis, Joshua C; Fitzpatrick, Annette L; Smith, Erin; Johnson, Andrew D; Gardner, Jeffrey P; Srinivasan, Sathanur R; et al. (Proc Natl Acad Sci U S A, 2010)
Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.
Keywords: Cohort Studies; Genome-Wide Association Study; Genotype; Humans; Leukocytes; Polymorphism, Single Nucleotide; Receptors, CXCR4; Telomere; Telomere-Binding Proteins

Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. - Debette, Stephanie; Bis, Joshua C; Fornage, Myriam; Schmidt, Helena; Ikram, M Arfan; Sigurdsson, Sigurdur; Heiss, Gerardo; Struchalin, Maksim; Smith, Albert V; van der Lugt, Aad; DeCarli, Charles; Lumley, Thomas; et al. (Stroke, 2010)
BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct). RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
Keywords: African Americans; Aged; Brain; Brain Infarction; Cohort Studies; DNA Mutational Analysis; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Magnetic Resonance Imaging; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies

Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. - Meyer, Tamra E; Verwoert, Germaine C; Hwang, Shih-Jen; Glazer, Nicole L; Smith, Albert V; van Rooij, Frank J A; Ehret, Georg B; Boerwinkle, Eric; Felix, Janine F; Leak, Tennille S; Harris, Tamara B; Yang, Qiong; et al. (PLoS Genet, 2010)
Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.
Keywords: Adult; Aged; European Continental Ancestry Group; Female; Genome-Wide Association Study; Humans; Magnesium; Male; Middle Aged; Polymorphism, Single Nucleotide; Potassium; Sodium

Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. - Arking, Dan E; Reinier, Kyndaron; Post, Wendy; Jui, Jonathan; Hilton, Gina; O'Connor, Ashley; Prineas, Ronald J; Boerwinkle, Eric; Psaty, Bruce M; Tomaselli, Gordon F; Rea, Thomas; Sotoodehnia, Nona; et al. (PLoS One, 2010)
BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA. METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01). CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.
Keywords: Aged; Alleles; Case-Control Studies; Cohort Studies; Death, Sudden, Cardiac; Ethnic Groups; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Glypicans; Heart Diseases; Humans; Male; Middle Aged; Models, Genetic; Oligonucleotide Array Sequence Analysis; Oregon; Polymorphism, Single Nucleotide

Genome-wide association study of PR interval. - Pfeufer, Arne; van Noord, Charlotte; Marciante, Kristin D; Arking, Dan E; Larson, Martin G; Smith, Albert Vernon; Tarasov, Kirill V; Müller, Martina; Sotoodehnia, Nona; Sinner, Moritz F; Verwoert, Germaine C; Li, Man; et al. (Nat Genet, 2010)
The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.
Keywords: Aged; Atrial Fibrillation; Cohort Studies; Electrocardiography; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Heart Conduction System; Humans; Male; Meta-Analysis as Topic

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. - Franke, Andre; McGovern, Dermot P B; Barrett, Jeffrey C; Wang, Kai; Radford-Smith, Graham L; Ahmad, Tariq; Lees, Charlie W; Balschun, Tobias; Lee, James; Roberts, Rebecca; Anderson, Carl A; Bis, Joshua C; et al. (Nat Genet, 2010)
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
Keywords: Computational Biology; Crohn Disease; Genetic Linkage; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; Genome-Wide Association Study; Humans; Reproducibility of Results

Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium. - Morrison, Alanna C; Felix, Janine F; Cupples, L Adrienne; Glazer, Nicole L; Loehr, Laura R; Dehghan, Abbas; Demissie, Serkalem; Bis, Joshua C; Rosamond, Wayne D; Aulchenko, Yurii S; Wang, Ying A; Haritunians, Talin; et al. (Circ Cardiovasc Genet, 2010)
BACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance. CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.
Keywords: African Americans; Aged; Aged, 80 and over; Chemokines; Cohort Studies; European Continental Ancestry Group; Female; Genome-Wide Association Study; Genotype; Heart Failure; Humans; Introns; Male; MARVEL Domain-Containing Proteins; Membrane Proteins; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Glycosylated hemoglobin and the risk of death and cardiovascular mortality in the elderly. - Chonchol, M; Katz, R; Fried, L F; Sarnak, M J; Siscovick, D S; Newman, A B; Strotmeyer, E S; Bertoni, A; Shlipak, M G (Nutr Metab Cardiovasc Dis, 2010)
BACKGROUND AND AIMS: Glycosylated hemoglobin (HbA(1c)) has been associated with incident cardiovascular disease (CVD), but the findings are inconsistent. We tested the hypothesis that HbA(1c) may be associated with an increased risk of death and cardiovascular mortality in older adults. METHODS AND RESULTS: We evaluated the association between HbA(1c) with all-cause and cardiovascular mortality in 810 participants without a history of diabetes in a sub-study of the Cardiovascular Health Study (CHS), a community cohort study of individuals > or =65 years of age. Glycosylated hemoglobin was measured at baseline and all-cause and cardiovascular mortality was assessed during the follow-up period. The relation between baseline HbA(1c) and death was evaluated with multivariate Cox proportional hazards regression models. After a median follow-up of 14.2 years, 416 deaths were observed. The crude incidence rates of all-cause mortality across HbA(1c) groups were: 4.4% per year, 4.3% per year and 4.6% per year for tertile 1 (< or =5.6%), tertile 2 (5.61-6.20%) and tertile 3 (> or =6.21%), respectively. In unadjusted and fully adjusted analyses, baseline HbA(1c) was not associated with all-cause mortality and cardiovascular mortality (hazard ratio: 1.16 [95% confidence interval 0.91-1.47] and hazard ratio: 1.31 [95% confidence interval 0.90-1.93], respectively for the highest HbA(1c) tertile compared with the lowest). CONCLUSION: These results suggest that HbA(1c) does not significantly predict all-cause and cardiovascular mortality in non-diabetic community-dwelling older adults.
Keywords: Aged; Aged, 80 and over; Body Mass Index; Cardiovascular Diseases; Cohort Studies; Disease Progression; Female; Glycated Hemoglobin A; Health Surveys; Heart Failure; Humans; Incidence; Male; Myocardial Infarction; Risk Factors; Statistics as Topic; Stroke; United States

Hip fractures and heart failure: findings from the Cardiovascular Health Study. - Carbone, Laura; Bůzková, Petra; Fink, Howard A; Lee, Jennifer S; Chen, Zhao; Ahmed, Ali; Parashar, Susmita; Robbins, John R (Eur Heart J, 2010)
AIMS: The aim of the study was to find the epidemiology of hip fractures in heart failure. The increasing survival rate for patients with heart failure places them at risk for other diseases of ageing, including osteoporosis. METHODS AND RESULTS: We included 5613 persons from the Cardiovascular Health Study (CHS) with an average of 11.5 year follow-up. We determined incidence rates and hazard ratios (HRs) in persons with heart failure compared with persons without heart failure and mortality hazards following these fractures. Annualized incidence rates for hip fractures were 14 per 1000 person-years in heart failure and 6.8 per 1000 person-years without heart failure. Unadjusted and multivariable adjusted HRs for hip fracture associated with heart failure in men were 1.87 (95% CI 1.2-2.93) and 1.59 (95% CI 0.93-2.72), respectively. Respective HRs for women were 1.75 (95% CI 1.27-2.4) and 1.41 (95% CI 0.98-2.03). Mortality hazard was approximately 2-fold greater in patients with heart failure and hip fracture compared with those having heart failure alone. CONCLUSION: Persons with heart failure are at high risk for hip fractures. However, much of the association between hip fractures and heart failure is explained by shared risk factors. Hip fractures are a substantial contributor to mortality in men and women with heart failure.
Keywords: Aged; Female; Heart Failure; Hip Fractures; Humans; Incidence; Male; Risk Factors; United States

Hundreds of variants clustered in genomic loci and biological pathways affect human height. - Lango Allen, Hana; Estrada, Karol; Lettre, Guillaume; Berndt, Sonja I; Weedon, Michael N; Rivadeneira, Fernando; Willer, Cristen J; Jackson, Anne U; Vedantam, Sailaja; Raychaudhuri, Soumya; Ferreira, Teresa; Wood, Andrew R; et al. (Nature, 2010)
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Keywords: Body Height; Chromosomes, Human, Pair 3; Genetic Loci; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Metabolic Networks and Pathways; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide

Independent susceptibility markers for atrial fibrillation on chromosome 4q25. - Lubitz, Steven A; Sinner, Moritz F; Lunetta, Kathryn L; Makino, Seiko; Pfeufer, Arne; Rahman, Rosanna; Veltman, Caroline E; Barnard, John; Bis, Joshua C; Danik, Stephan P; Sonni, Akshata; Shea, Marisa A; et al. (Circulation, 2010)
BACKGROUND: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. METHODS AND RESULTS: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. CONCLUSIONS: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.
Keywords: Aged; Aged, 80 and over; Atrial Fibrillation; Chromosome Mapping; Chromosomes, Human, Pair 4; European Continental Ancestry Group; Female; Genetic Markers; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies. - Nettleton, Jennifer A; McKeown, Nicola M; Kanoni, Stavroula; Lemaitre, Rozenn N; Hivert, Marie-France; Ngwa, Julius; van Rooij, Frank J A; Sonestedt, Emily; Wojczynski, Mary K; Ye, Zheng; Tanaka, Tosh; Garcia, Melissa; et al. (Diabetes Care, 2010)
OBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant. RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
Keywords: Adult; Aged; Blood Glucose; Edible Grain; European Continental Ancestry Group; Fasting; Female; Genetic Loci; Genome-Wide Association Study; Genotype; Humans; Insulin; Male; Middle Aged; Polymorphism, Single Nucleotide

Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. - Barbalic, Maja; Dupuis, Josée; Dehghan, Abbas; Bis, Joshua C; Hoogeveen, Ron C; Schnabel, Renate B; Nambi, Vijay; Bretler, Monique; Smith, Nicholas L; Peters, Annette; Lu, Chen; Tracy, Russell P; et al. (Hum Mol Genet, 2010)
P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.
Keywords: ABO Blood-Group System; Blood Platelets; Enzyme-Linked Immunosorbent Assay; European Continental Ancestry Group; Fluorescence; Genome-Wide Association Study; Humans; Intercellular Adhesion Molecule-1; P-Selectin

Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. - Thompson, Alexander; Gao, Pei; Orfei, Lia; Watson, Sarah; Di Angelantonio, Emanuele; Kaptoge, Stephen; Ballantyne, Christie; Cannon, Christopher P; Criqui, Michael; Cushman, Mary; Hofman, Albert; Packard, Chris; et al. (Lancet, 2010)
BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. METHODS: With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease. FINDINGS: Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure. INTERPRETATION: Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. FUNDING: UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.
Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Blood Pressure; Coronary Disease; Female; Humans; Linear Models; Lipids; Male; Middle Aged; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Systole

Long-term retention of older adults in the Cardiovascular Health Study: implications for studies of the oldest old. - Strotmeyer, Elsa S; Arnold, Alice M; Boudreau, Robert M; Ives, Diane G; Cushman, Mary; Robbins, John A; Harris, Tamara B; Newman, Anne B (J Am Geriatr Soc, 2010)
OBJECTIVES: To describe retention according to age and visit type (clinic, home, telephone) and to determine characteristics associated with visit types for a longitudinal epidemiological study in older adults. DESIGN: Longitudinal cohort study. SETTING: Four U.S. clinical sites. PARTICIPANTS: Five thousand eight hundred eighty-eight Cardiovascular Health Study (CHS) participants aged 65 to 100 at 1989/90 or 1992/93 enrollment (58.6% female; 15.7% black). CHS participants were contacted every 6 months, with annual assessments through 1999 and in 2005/06 for the All Stars Study visit of the CHS cohort (aged 77-102; 66.5% female; 16.6% black). MEASUREMENTS: All annual contacts through 1999 (n=43,772) and for the 2005/06 visit (n=1,942). RESULTS: CHS had 43,772 total participant contacts from 1989 to 1999: 34,582 clinic visits (79.0%), 2,238 refusals (5.1%), 4,401 telephone visits (10.1%), 1,811 home visits (4.1%), and 740 other types (1.7%). In 2005/06, the All Stars participants of the CHS cohort had 36.6% clinic, 22.3% home, and 41.1% telephone visits. Compared with participants aged 65 to 69, odds ratios of not attending a CHS clinic visit were 1.82 (95% confidence interval (CI)=1.54-2.13), 2.94 (95% CI=2.45-3.57), 4.55 (95% CI=3.70-5.56), and 9.09 (95% CI=7.69-11.11) for those aged 70 to 74, 75 to 79, 80 to 84, and 85 and older, respectively, in sex-adjusted regression. In multivariable regression, participants with a 2005/06 clinic visit were younger, more likely to be male and in good health, and had had better cognitive and physical function 7 years earlier than participants with other visit types. Participants with home, telephone, and missing visits were similar on characteristics measured 7 years earlier. CONCLUSION: Offering home, telephone, and proxy visits are essential to optimizing follow-up of aging cohorts. Home visits increased in-person retention from 36.5% to 58.8% and diversified the cohort with respect to age, health, and physical functioning.
Keywords: Age Factors; Aged; Aged, 80 and over; Ambulatory Care Facilities; Analysis of Variance; Cardiovascular Diseases; Chi-Square Distribution; Epidemiologic Studies; Female; Geriatric Assessment; House Calls; Humans; Logistic Models; Longitudinal Studies; Male; Multivariate Analysis; Patient Dropouts; Patient Selection; Research Subjects; Telephone; United States

Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. - Hancock, Dana B; Eijgelsheim, Mark; Wilk, Jemma B; Gharib, Sina A; Loehr, Laura R; Marciante, Kristin D; Franceschini, Nora; van Durme, Yannick M T A; Chen, Ting-Hsu; Barr, R Graham; Schabath, Matthew B; Couper, David J; et al. (Nat Genet, 2010)
Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.
Keywords: Databases, Genetic; Female; Forced Expiratory Volume; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Lung; Lung Diseases; Male; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Spirometry; Vital Capacity

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. - Heid, Iris M; Jackson, Anne U; Randall, Joshua C; Winkler, Thomas W; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M Carola; Speliotes, Elizabeth K; Mägi, Reedik; Workalemahu, Tsegaselassie; White, Charles C; et al. (Nat Genet, 2010)
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
Keywords: Adipose Tissue; Age Factors; Chromosome Mapping; Female; Genome, Human; Genome-Wide Association Study; Humans; Male; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Sex Characteristics; Waist-Hip Ratio

A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. - Newman, Anne B; Walter, Stefan; Lunetta, Kathryn L; Garcia, Melissa E; Slagboom, P Eline; Christensen, Kaare; Arnold, Alice M; Aspelund, Thor; Aulchenko, Yurii S; Benjamin, Emelia J; Christiansen, Lene; D'Agostino, Ralph B; et al. (J Gerontol A Biol Sci Med Sci, 2010)
BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity. METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort. RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage. CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Alleles; Cohort Studies; Confidence Intervals; Female; Genome-Wide Association Study; Genotype; Humans; Longevity; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide

Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. - Yang, Qiong; Köttgen, Anna; Dehghan, Abbas; Smith, Albert V; Glazer, Nicole L; Chen, Ming-Huei; Chasman, Daniel I; Aspelund, Thor; Eiriksdottir, Gudny; Harris, Tamara B; Launer, Lenore; Nalls, Michael; et al. (Circ Cardiovasc Genet, 2010)
BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD). METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study. CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
Keywords: Cardiovascular Diseases; Coronary Disease; Female; Genetic Loci; Genome-Wide Association Study; Gout; Humans; Male; Risk Factors; Uric Acid

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. - Dupuis, Josée; Langenberg, Claudia; Prokopenko, Inga; Saxena, Richa; Soranzo, Nicole; Jackson, Anne U; Wheeler, Eleanor; Glazer, Nicole L; Bouatia-Naji, Nabila; Gloyn, Anna L; Lindgren, Cecilia M; Mägi, Reedik; et al. (Nat Genet, 2010)
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Keywords: Adolescent; Adult; Alleles; Blood Glucose; Child; Databases, Genetic; Diabetes Mellitus, Type 2; DNA Copy Number Variations; Fasting; Gene Expression Regulation; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Homeostasis; Humans; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Quantitative Trait, Heritable; Reproducibility of Results

New loci associated with kidney function and chronic kidney disease. - Köttgen, Anna; Pattaro, Cristian; Böger, Carsten A; Fuchsberger, Christian; Olden, Matthias; Glazer, Nicole L; Parsa, Afshin; Gao, Xiaoyi; Yang, Qiong; Smith, Albert V; O'Connell, Jeffrey R; Li, Man; et al. (Nat Genet, 2010)
Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
Keywords: Cohort Studies; Creatinine; Cystatin C; Diet; Europe; Genetic Markers; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Models, Genetic; Risk Factors

Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. - Smith, Nicholas L; Chen, Ming-Huei; Dehghan, Abbas; Strachan, David P; Basu, Saonli; Soranzo, Nicole; Hayward, Caroline; Rudan, Igor; Sabater-Lleal, Maria; Bis, Joshua C; de Maat, Moniek P M; Rumley, Ann; et al. (Circulation, 2010)
BACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated. CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.
Keywords: Adult; Factor VII; Factor VIII; Female; Genome-Wide Association Study; Hemostasis; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Thrombosis; von Willebrand Factor

Obesity is linked with lower brain volume in 700 AD and MCI patients. - Ho, April J; Raji, Cyrus A; Becker, James T; Lopez, Oscar L; Kuller, Lewis H; Hua, Xue; Lee, Suh; Hibar, Derrek; Dinov, Ivo D; Stein, Jason L; Jack, Clifford R; Weiner, Michael W; et al. (Neurobiol Aging, 2010)
Obesity is associated with lower brain volumes in cognitively normal elderly subjects, but no study has yet investigated the effects of obesity on brain structure in patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD). To determine if higher body mass index (BMI) is associated with brain volume deficits in cognitively impaired elderly subjects, we analyzed brain magnetic resonance imaging (MRI) scans of 700 MCI or AD patients from 2 different cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Cardiovascular Health Study-Cognition Study (CHS-CS). Tensor-based morphometry (TBM) was used to create 3-dimensional maps of regional tissue excess or deficits in subjects with MCI (ADNI, n = 399; CHS-CS, n = 77) and AD (ADNI, n = 188; CHS, n = 36). In both AD and MCI groups, higher body mass index was associated with brain volume deficits in frontal, temporal, parietal, and occipital lobes; the atrophic pattern was consistent in both ADNI and CHS populations. Cardiovascular risk factors, especially obesity, should be considered as influencing brain structure in those already afflicted by cognitive impairment and dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Body Mass Index; Brain; Cognition Disorders; Cohort Studies; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Obesity; Organ Size; Prospective Studies; Risk Factors

Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study. - Erickson, K I; Raji, C A; Lopez, O L; Becker, J T; Rosano, C; Newman, A B; Gach, H M; Thompson, P M; Ho, A J; Kuller, L H (Neurology, 2010)
OBJECTIVES: Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation. METHODS: In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline. RESULTS: Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold. CONCLUSION: Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.
Keywords: Aged; Aged, 80 and over; Brain; Brain Mapping; Cardiovascular Diseases; Cognition Disorders; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Motor Activity; Neuropsychological Tests; Odds Ratio; Predictive Value of Tests; Surveys and Questionnaires

Polymorphisms in the mitochondrial DNA control region and frailty in older adults. - Moore, Ann Z; Biggs, Mary L; Matteini, Amy; O'Connor, Ashley; McGuire, Sarah; Beamer, Brock A; Fallin, M Danielle; Fried, Linda P; Walston, Jeremy; Chakravarti, Aravinda; Arking, Dan E (PLoS One, 2010)
BACKGROUND: Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults. METHODOLOGY/PRINCIPAL FINDINGS: To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989-1990, 1992-1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07-3.60, p = 0.020) and lower grip strength (adjusted coefficient = -2.04, 95% CI = -3.33- -0.74, p = 0.002). CONCLUSIONS: This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.
Keywords: Aged; Aged, 80 and over; DNA, Mitochondrial; Female; Frail Elderly; Genotype; Humans; Male; Polymorphism, Genetic

Post hoc Parkinson's disease: identifying an uncommon disease in the Cardiovascular Health Study. - Ton, T G; Jain, S; Boudreau, R; Thacker, E L; Strotmeyer, E S; Newman, A B; Longstreth, W T; Checkoway, H (Neuroepidemiology, 2010)
BACKGROUND: Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson's disease (PD), they typically have limited information for clinical diagnosis. METHODS: We used combinations of self-report, International Classification of Diseases - 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD. RESULTS: We identified 60 cases with prevalent PD (1.0%; 95% confidence interval, CI = 0.8-1.3%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95% CI = 0.26-0.95) and for those who smoked ≥50 pack-years (OR = 0.53; 95% CI = 0.29-0.96). Estimates for smoking were similar when ≥2 data sources were required. Estimates for self-report alone were attenuated towards null. CONCLUSIONS: Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.
Keywords: Aged; Aged, 80 and over; Cardiovascular System; Cohort Studies; Female; Health Status; Humans; Incidence; Male; Odds Ratio; Parkinson Disease; Prevalence; Prospective Studies; Risk Factors; Smoking; Surveys and Questionnaires; United States

Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis. - de Weerd, Marjolein; Greving, Jacoba P; Hedblad, Bo; Lorenz, Matthias W; Mathiesen, Ellisiv B; O'Leary, Daniel H; Rosvall, Maria; Sitzer, Matthias; Buskens, Erik; Bots, Michiel L (Stroke, 2010)
BACKGROUND AND PURPOSE: In the discussion on the cost-effectiveness of screening, precise estimates of severe asymptomatic carotid stenosis are vital. Accordingly, we assessed the prevalence of moderate and severe asymptomatic carotid stenosis by age and sex using pooled cohort data. METHODS: We performed an individual participant data meta-analysis (23 706 participants) of 4 population-based studies (Malmö Diet and Cancer Study, Tromsø, Carotid Atherosclerosis Progression Study, and Cardiovascular Health Study). Outcomes of interest were asymptomatic moderate (> or =50%) and severe carotid stenosis (> or =70%). RESULTS: Prevalence of moderate asymptomatic carotid stenosis ranged from 0.2% (95% CI, 0.0% to 0.4%) in men aged <50 years to 7.5% (5.2% to 10.5%) in men aged > or =80 years. For women, this prevalence increased from 0% (0% to 0.2%) to 5.0% (3.1% to 7.5%). Prevalence of severe asymptomatic carotid stenosis ranged from 0.1% (0.0% to 0.3%) in men aged <50 years to 3.1% (1.7% to 5.3%) in men aged > or =80. For women, this prevalence increased from 0% (0.0% to 0.2%) to 0.9% (0.3% to 2.4%). CONCLUSIONS: The prevalence of severe asymptomatic carotid stenosis in the general population ranges from 0% to 3.1%, which is useful information in the discussion on the cost-effectiveness of screening.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Carotid Stenosis; Female; Humans; Male; Mass Screening; Middle Aged; Prevalence; Severity of Illness Index; Sex Factors

Secondhand smoke, vascular disease, and dementia incidence: findings from the cardiovascular health cognition study. - Barnes, Deborah E; Haight, Thaddeus J; Mehta, Kala M; Carlson, Michelle C; Kuller, Lewis H; Tager, Ira B (Am J Epidemiol, 2010)
Recent studies have found that smoking is associated with an increased risk of dementia, but the effects of secondhand smoke (SHS) on dementia risk are not known to have previously been studied. The authors used Cox proportional hazards marginal structural models to examine the association between self-reported lifetime household SHS exposure and risk of incident dementia over 6 years among 970 US participants in the Cardiovascular Health Cognition Study (performed from 1991 to 1999) who were never smokers and were free of clinical cardiovascular disease (CVD), dementia, and mild cognitive impairment at baseline. In addition, because prior studies have found that SHS is associated with increased risk of CVD and that CVD is associated with increased risk of dementia, the authors tested for interactions between SHS and measures of clinical and subclinical CVD on dementia risk. Moderate (16-25 years) and high (>25 years) SHS exposure levels were not independently associated with dementia risk; however, subjects with >25 years of SHS exposure and >25% carotid artery stenosis had a 3-fold increase (hazard ratio = 3.00, 95% confidence interval: 1.03, 9.72) in dementia risk compared with subjects with no/low (0-15 years) SHS exposure and < or =25% carotid artery stenosis. High lifetime SHS exposure may increase the risk of dementia in elderly with undiagnosed CVD.
Keywords: Aged; Dementia; Female; Humans; Incidence; Male; Risk Factors; Tobacco Smoke Pollution; Vascular Diseases

Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. - Buxbaum, Joel; Alexander, Alice; Koziol, James; Tagoe, Clement; Fox, Ervin; Kitzman, Dalane (Am Heart J, 2010)
BACKGROUND: Many African Americans carry an amyloidogenic transthyretin mutation (TTR V122I), with a high risk for cardiac TTR amyloid deposition after the age of 65 years. We wished to determine the allele frequency and its clinical penetrance in community-dwelling African Americans. METHODS: Five thousand consenting African Americans, aged 41 to 93 years, in 2 community studies of cardiovascular risk (CHS and ARIC) were included in the study. The following were performed: genotyping of banked DNA for TTR V122I allele status and review of cardiovascular and demographic parameters in CHS and ARIC databases, with statistical comparisons of the frequency of congestive heart failure, survival, and occurrence of features of cardiac amyloidosis in carriers of the amyloidogenic allele and controls. RESULTS: One hundred nineteen (3.23%) of 3,712 ARIC and 17 (2.12%) of 805 CHS African Americans carried TTR V122I. After the age of 65 years (CHS), the frequencies of congestive heart failure (38% vs 15%, relative risk 2.62, P = .04) and mortality (76% vs 53%, relative risk 1.46, P = .08) were higher in V122I allele carriers than in age-, gender- and ethnically matched controls. In ARIC (all subjects <65 years old), there were no differences between carriers and noncarriers in mortality, frequency of congestive heart failure, or findings consistent with cardiac amyloidosis. CONCLUSIONS: Heterozygosity for the amyloidogenic TTR V122I mutation is relatively common in community-dwelling African Americans. Before the age of 65 years, the allele has no discernible impact on cardiac function or mortality. After the age of 70 years, carriers show a higher frequency of congestive failure and greater mortality with more echocardiographic evidence suggestive of cardiac amyloidosis, findings consistent with age-dependent clinical penetrance of this autosomal dominant gene.
Keywords: Adult; African Americans; Aged; Aged, 80 and over; Amyloidosis; Female; Gene Frequency; Heart Diseases; Humans; Isoleucine; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Prealbumin; Ultrasonography; Valine

Sleep disturbances, quality of life, and ethnicity: the Sleep Heart Health Study. - Baldwin, Carol M; Ervin, Ann-Margret; Mays, Mary Z; Robbins, John; Shafazand, Shirin; Walsleben, Joyce; Weaver, Terri (J Clin Sleep Med, 2010)
STUDY OBJECTIVES: To compare health-related quality of life (HR-QOL) across subgroups defined by sleep disturbances and ethnicity. METHODS: Men (47%) and women (53%) Sleep Heart Health Study participants age 40 and older (N = 5237) underwent overnight polysomnography and completed self-report questionnaires on symptoms of sleep disturbances. The physical and mental composite scales (PCS and MCS) of the Medical Outcomes Study 36-item short form survey assessed HR-QOL and were compared to sleep data. RESULTS: Participants self-identified as Caucasian/White (n = 4482, 86%), African American/Black (n = 490, 9%), or Hispanic/Mexican American (n = 265, 5%). The prevalence of obstructive sleep apnea (OSA) was 17%, frequent snoring was 34%, difficulty initiating or maintaining sleep (DIMS; insomnia symptoms) was 30%, and excessive daytime sleepiness (EDS) was 25%. African American participants with frequent snoring, insomnia symptoms, or EDS had significantly poorer physical health compared to Caucasians (p < 0.001). Hispanics with frequent snoring, insomnia symptoms, or EDS had significantly poorer mental health than Caucasian participants (p <0.001). Neither PCS nor MCS scores differed significantly across ethnic subgroups for participants with moderate to severe OSA (respiratory disturbance index > 15, 4% desaturation). CONCLUSIONS: Across ethnic/racial subgroups, sleep disturbances are associated with worse physical and better mental HR-QOL than the U.S. norm, but this relationship may be moderated by comorbid health conditions. This study replicates and extends prior research indicating differences among minority and non-minority participants and highlights the need for future studies of sleep disturbances with larger samples of minorities that control for comorbid health conditions.
Keywords: African Americans; Cohort Studies; Ethnic Groups; European Continental Ancestry Group; Female; Health Status; Heart Diseases; Hispanic Americans; Humans; Longitudinal Studies; Male; Mental Health; Middle Aged; Polysomnography; Prevalence; Quality of Life; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders; Snoring; Surveys and Questionnaires; United States

Sleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing. - Chami, Hassan A; Baldwin, Carol M; Silverman, Angela; Zhang, Ying; Rapoport, David; Punjabi, Naresh M; Gottlieb, Daniel J (Am J Respir Crit Care Med, 2010)
RATIONALE: The impact of REM-predominant sleep-disordered breathing (SDB) on sleepiness, quality of life (QOL), and sleep maintenance is uncertain. OBJECTIVE: To evaluate the association of SDB during REM sleep with daytime sleepiness, health-related QOL, and difficulty maintaining sleep, in comparison to their association with SDB during non-REM sleep in a community-based cohort. METHODS: Cross-sectional analysis of 5,649 Sleep Heart Health Study participants (mean age 62.5 [SD = 10.9], 52.6% women, 22.6% ethnic minorities). SDB during REM and non-REM sleep was quantified using polysomnographically derived apnea-hypopnea index in REM (AHI(REM)) and non-REM (AHI(NREM)) sleep. Sleepiness, sleep maintenance, and QOL were respectively quantified using the Epworth Sleepiness Scale (ESS), the Sleep Heart Health Study Sleep Habit Questionnaire, and the physical and mental composites scales of the Medical Outcomes Study Short Form (SF)-36. MEASUREMENTS AND MAIN RESULTS: AHI(REM) was not associated with the ESS scores or the physical and mental components scales scores of the SF-36 after adjusting for demographics, body mass index, and AHI(NREM) x AHI(REM) was not associated with frequent difficulty maintaining sleep or early awakening from sleep. AHI(NREM) was associated with the ESS score (beta = 0.25; 95% confidence interval [CI], 0.16 to 0.34) and the physical (beta = -0.12; 95% CI, -0.42 to -0.01) and mental (beta = -0.20; 95% CI, -0.20 to -0.01) components scores of the SF-36 adjusting for demographics, body mass index, and AHI(REM). CONCLUSIONS: In a community-based sample of middle-aged and older adults, REM-predominant SDB is not independently associated with daytime sleepiness, impaired health-related QOL, or self-reported sleep disruption.
Keywords: Aged; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Polysomnography; Quality of Life; Sleep; Sleep Apnea Syndromes; Sleep, REM

Subclinical hypothyroidism and the risk of coronary heart disease and mortality. - Rodondi, Nicolas; den Elzen, Wendy P J; Bauer, Douglas C; Cappola, Anne R; Razvi, Salman; Walsh, John P; Asvold, Bjørn O; Iervasi, Giorgio; Imaizumi, Misa; Collet, Tinh-Hai; Bremner, Alexandra; Maisonneuve, Patrick; et al. (JAMA, 2010)
CONTEXT: Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants' age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease. OBJECTIVE: To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched. DATA EXTRACTION: Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations. RESULTS: Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease. CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Coronary Disease; Female; Humans; Hypothyroidism; Male; Middle Aged; Mortality; Prospective Studies; Risk; Thyrotropin; Young Adult