@article {748, title = {Isolated systolic hypertension and subclinical cardiovascular disease in the elderly. Initial findings from the Cardiovascular Health Study.}, journal = {JAMA}, volume = {268}, year = {1992}, month = {1992 Sep 09}, pages = {1287-91}, abstract = {

OBJECTIVE: To assess the association between isolated systolic hypertension (ISH) and subclinical disease in adults aged 65 years and above.

DESIGN: Medicare eligibility lists were used to obtain a representative sample of 5201 community-dwelling elderly persons for the Cardiovascular Health Study, a National Heart, Lung, and Blood Institute--sponsored cohort study of risk factors for coronary heart disease and stroke. In this cross-sectional analysis of baseline data, we excluded 3012 participants who were receiving antihypertensive medications, had clinical cardiovascular disease, or had a diastolic blood pressure of at least 90 mm Hg.

MAIN OUTCOME MEASURES: For electrocardiogram: myocardial infarction, left ventricular hypertrophy, and left ventricular mass as measures of myocardial damage and strain; for echocardiography: left ventricular mass, fractional shortening, and Doppler flow velocities as measures of cardiac systolic and diastolic function; and for carotid sonography: carotid arterial intima-media thickness as a measure of atherosclerosis.

RESULTS: Among the 2189 men and women in this analysis, 195 (9\%) had ISH (systolic blood pressure, greater than or equal to 160 mm Hg) and 596 (23\%) had borderline ISH (systolic blood pressure, 140 to 159 mm Hg). Systolic blood pressure was associated with myocardial infarction by electrocardiogram (P = .02). Borderline and definite ISH were strongly associated with left ventricular mass (P less than .001). While there was little association with cardiac systolic function, borderline and definite ISH were associated with cardiac diastolic function (P less than .001). Isolated systolic hypertension was also strongly associated with increased intima-media thickness of the carotid artery (P less than .001).

CONCLUSIONS: While cohort analyses of future repeated measures will provide a better assessment of risk, both borderline and definite ISH were strongly related to a variety of measures of subclinical disease in elderly men and women.

}, keywords = {Aged, Aged, 80 and over, Cardiomegaly, Cardiovascular Diseases, Carotid Artery Diseases, Cerebrovascular Disorders, Coronary Disease, Cross-Sectional Studies, Echocardiography, Electrocardiography, Female, Humans, Hypertension, Male, Myocardial Infarction, Prospective Studies, Risk Factors, Systole}, issn = {0098-7484}, author = {Psaty, B M and Furberg, C D and Kuller, L H and Borhani, N O and Rautaharju, P M and O{\textquoteright}Leary, D H and Bild, D E and Robbins, J and Fried, L P and Reid, C} } @article {1451, title = {Ischemic episodes in 24-h ambulatory electrocardiograms of elderly persons: the Cardiovascular Health Study.}, journal = {Int J Cardiol}, volume = {51}, year = {1995}, month = {1995 Sep}, pages = {165-75}, abstract = {

We examined correlates of ischemic episodes in 24-h ambulatory electrocardiograms (ECG) in a sample of 1511 men and women 65 years old and older. Ischemic episodes had a high prevalence period during early afternoon and also during morning hours after awakening, and the overall prevalence was 13\% in men and 9\% in women (P < 0.001 for gender difference). The prevalence was 9.6\% in participants with no history of myocardial infarction and no major or minor resting ECG abnormalities. In multivariate analysis by logistic regression, being on digitalis medication was associated with over a three-fold risk of ischemic episodes, with an odds ratio (95\% confidence limits) of 3.21 (1.80 to 5.74). Left ventricular hypertrophy by ECG and atrial fibrillation had almost a three-fold excess risk of ischemic episodes, with odds ratios 2.81 (1.37 to 5.74) and 2.63 (1.17 to 5.91), respectively. Isolated ST-T abnormalities had almost a two-fold excess of ischemic episodes, with an odds ratio of 1.89 (1.01 to 3.54). Being overweight was associated with a 33\% reduced likelihood of ischemic episodes after adjustment for other factors, with an odds ratio of 0.67 (0.46 to 0.98). It is concluded that the prevalence of silent ischemic episodes is high in older men and women.

}, keywords = {Age Factors, Aged, Arrhythmias, Cardiac, Atrial Fibrillation, California, Circadian Rhythm, Digitalis Glycosides, Electrocardiography, Electrocardiography, Ambulatory, Female, Health Surveys, Humans, Hypertrophy, Left Ventricular, Logistic Models, Male, Maryland, Multivariate Analysis, Myocardial Infarction, Myocardial Ischemia, North Carolina, Obesity, Odds Ratio, Pennsylvania, Prevalence, Risk Factors, Sex Characteristics}, issn = {0167-5273}, author = {Rautaharju, P M and Manolio, T A and Furberg, C D and Siscovick, D and Newman, A B and Borhani, N O and Gardin, J M} } @article {1488, title = {Incidence of and risk factors for atrial fibrillation in older adults.}, journal = {Circulation}, volume = {96}, year = {1997}, month = {1997 Oct 07}, pages = {2455-61}, abstract = {

BACKGROUND: This study aimed to describe the incidence of atrial fibrillation (AF) among older adults during 3 years of follow-up.

METHODS AND RESULTS: In this cohort study, 5201 adults > or = 65 years old were examined annually on four occasions between June 1989 and May 1993. At baseline, participants answered questionnaires and underwent a detailed examination that included carotid ultrasound, pulmonary function tests, ECG, and echocardiography. Subjects with a pacemaker or AF at baseline (n=357) were excluded. New cases of AF were identified from three sources: (1) annual self-reports, (2) annual ECGs, and (3) hospital discharge diagnoses. Cox proportional-hazards models were used to assess baseline risk factors as predictors of incident AF. Among 4844 participants, 304 developed a first episode of AF during an average follow-up of 3.28 years, for an incidence of 19.2 per 1000 person-years. The onset was strongly associated with age, male sex, and the presence of clinical cardiovascular disease. For men 65 to 74 and 75 to 84 years old, the incidences were 17.6 and 42.7, respectively, and for women, 10.1 and 21.6 events per 1000 person-years. In stepwise models, the use of diuretics, a history of valvular heart disease, coronary disease, advancing age, higher levels of systolic blood pressure, height, glucose, and left atrial size were all associated with an increased risk of AF. The use of beta-blockers and high levels of alcohol use, cholesterol, and forced expiratory volume in 1 second were associated with a reduced risk of AF.

CONCLUSIONS: The incidence of AF in older adults may be higher than estimated by previous population studies. Left atrial size appears to be an important risk factor, and the control of blood pressure and glucose may be important in preventing the development of AF.

}, keywords = {Adult, Aged, Atrial Fibrillation, Blood Glucose, Blood Pressure, Cerebrovascular Disorders, Cohort Studies, Coronary Disease, Electrocardiography, Female, Follow-Up Studies, Hospital Records, Humans, Incidence, Male, Prospective Studies, Risk Factors, United States}, issn = {0009-7322}, author = {Psaty, B M and Manolio, T A and Kuller, L H and Kronmal, R A and Cushman, M and Fried, L P and White, R and Furberg, C D and Rautaharju, P M} } @article {1471, title = {Infarctlike lesions in the brain: prevalence and anatomic characteristics at MR imaging of the elderly--data from the Cardiovascular Health Study.}, journal = {Radiology}, volume = {202}, year = {1997}, month = {1997 Jan}, pages = {47-54}, abstract = {

PURPOSE: To determine the prevalence and anatomic characteristics of infarctlike lesions seen on cranial magnetic resonance (MR) images.

MATERIALS AND METHODS: The study cohort consisted of 5,888 community-living individuals aged 65 years and older enrolled in a longitudinal, population-based study of cardiovascular disease. MR images were obtained from 3,658 participants and evaluated by trained readers. Lesion size, anatomic location, and signal intensity were recorded. Infarctlike lesion was defined as a nonmass, hyperintense region on spin-density- and T2-weighted images and, in cerebral white matter and brain stem, a hypointense region on T1-weighted images.

RESULTS: Infarctlike lesions were depicted on MR images of 1,323 (36\%) participants. Eighty-five percent (1,128 participants) had lesions 3 mm or larger in maximum dimension, although 70.9\% (1,320 of 1,861) of these lesions were 10 mm or less. Lesion prevalence increased with age, especially with lesions 3 mm or larger, which increased from 22.1\% (86 of 389) in the 65-69-year age group to 42.9\% (88 of 205) in the over-85-year age group (P < .0001). Lesion prevalence was slightly greater in men (497 of 1,527 [32.5\%]) than in women (631 of 2,131 [29.6\%]), but did not differ between blacks and non-blacks. The deep nuclei were the most commonly affected anatomic sites, with 78.2\% (1,451 of 1,856) of lesions. Lesions that involved the cerebrum and posterior fossa accounted for 11.7\% (218 of 1,856) and 10.1\% (187 of 1,856) of lesions, respectively.

CONCLUSION: If the lesions reported in this study indicate cerebrovascular disease, subclinical disease may be more prevalent than clinical disease, and the prevalence of disease may rise with age. Also, infarctlike lesions have a distinctive anatomic profile.

}, keywords = {Aged, Brain, Cardiovascular Diseases, Cerebral Infarction, Cohort Studies, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Prevalence}, issn = {0033-8419}, doi = {10.1148/radiology.202.1.8988191}, author = {Bryan, R N and Wells, S W and Miller, T J and Elster, A D and Jungreis, C A and Poirier, V C and Lind, B K and Manolio, T A} } @article {594, title = {Increased blood glucose and insulin, body size, and incident colorectal cancer.}, journal = {J Natl Cancer Inst}, volume = {91}, year = {1999}, month = {1999 Jul 07}, pages = {1147-54}, abstract = {

BACKGROUND: Abdominal obesity--an elevated level of visceral adipose tissue--has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer.

METHODS: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided.

RESULTS: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95\% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95\% CI = 1.0-1.5) for fasting glucose level was statistically significant (P =. 02). Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95\% CI = 1.2-4. 7]/LT RR = 1.3 [95\% CI = 1.0-1.6; P =.02]; 2-hour insulin levels: RR = 2.0 [95\% CI = 1.0-3.8]/LT RR = 1.2 [95\% CI = 1.0-1.5; P =.04]). Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95\% CI = 1.1-2.4; P =.02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95\% CI = 1.1-3.3; P =.02).

CONCLUSIONS: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer.

}, keywords = {Adipose Tissue, Aged, Blood Glucose, Body Constitution, Cholesterol, HDL, Colorectal Neoplasms, Female, Humans, Incidence, Insulin, Male, Prospective Studies, Risk, Triglycerides, Viscera}, issn = {0027-8874}, doi = {10.1093/jnci/91.13.1147}, author = {Schoen, R E and Tangen, C M and Kuller, L H and Burke, G L and Cushman, M and Tracy, R P and Dobs, A and Savage, P J} } @article {632, title = {Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS Research Group. Cardiovascular Health Study.}, journal = {Am J Cardiol}, volume = {87}, year = {2001}, month = {2001 Feb 15}, pages = {413-9}, abstract = {

Although congestive heart failure (CHF) is a common syndrome among the elderly, there is a relative paucity of population-based data, particularly regarding CHF with normal systolic left ventricular function. A total of 4,842 independent living, community-dwelling subjects aged 66 to 103 years received questionnaires on medical history, family history, personal habits, physical activity, and socioeconomic status, confirmation of pre-existing cardiovascular and cerebrovascular disease, anthropometric measurements, casual seated random-zero blood pressure, forced vital capacity and expiratory volume in 1 second, 12-lead supine electrocardiogram, fasting glucose, creatinine, plasma lipids, carotid artery wall thickness by ultrasonography, and echocardiography-Doppler examinations. Participants with at least 1 confirmed episode of CHF by Cardiovascular Health Study criteria were considered prevalent for CHF. The prevalence of CHF was 8.8\% and was associated with increased age, particularly for women, in whom it increased more than twofold from age 65 to 69 years (6.6\%) to age > or = 85 years (14\%). In multivariate analysis, subjects with CHF were more likely to be older (odds ratio [OR] 1.2 for 5-year difference, men OR 1.1), and more often had a history of myocardial infarction (OR 7.3), atrial fibrillation (OR 3.0), diabetes mellitus (OR 2.1), renal dysfunction (OR 2.0 for creatinine < or = 1.5 mg/ dl), and chronic pulmonary disease (OR 1.8; women only). The echocardiographic correlates of CHF were increased left atrial and ventricular dimensions. Importantly, 55\% of subjects with CHF had normal left ventricular systolic function and 80\% had either normal or only mildly reduced systolic function. Among subjects with CHF, women had normal systolic function more frequently than men (67\% vs 42\%; p < 0.001). Thus, CHF is common among community-dwelling elderly. It increases with age and is usually associated with normal systolic LV function, particularly among women. The finding that a large proportion of elderly with CHF have preserved LV systolic function is important because there is a paucity of data to guide management in this dominant subset.

}, keywords = {Aged, Aged, 80 and over, Analysis of Variance, Chi-Square Distribution, Echocardiography, Doppler, Female, Health Status, Heart Failure, Humans, Logistic Models, Longitudinal Studies, Male, Prevalence, Risk Factors, Surveys and Questionnaires, United States, Ventricular Function, Left}, issn = {0002-9149}, doi = {10.1016/s0002-9149(00)01393-x}, author = {Kitzman, D W and Gardin, J M and Gottdiener, J S and Arnold, A and Boineau, R and Aurigemma, G and Marino, E K and Lyles, M and Cushman, M and Enright, P L} } @article {668, title = {Incidence and predictors of coronary heart disease among older African Americans--the Cardiovascular Health Study.}, journal = {J Natl Med Assoc}, volume = {93}, year = {2001}, month = {2001 Nov}, pages = {423-9}, abstract = {

Although coronary heart disease (CHD) is the leading cause of death and morbidity in older African Americans, relatively little is known about the incidence and predictors of CHD in this population. This study was undertaken to determine the incidence and predictors of CHD in African-American men and women aged 65 years and older. The participants in this study included a total of 924 African-American men and women aged 65 years of age and older who participated in the Cardiovascular Health Study (CHS). The overall CHD incidence was 26.6 per 1,000 person-years of risk. Rates were higher in men than women (35.3 vs. 21.6) and in those 75 years or older than in those less than 75 years (31.3 vs. 24.5). In multivariate analysis, factors associated with higher risk of incident disease were male gender [relative risk (RR) = 1.8, 95\% confidence interval (CI) = 1.1, 2.7], diabetes mellitus (RR = 1.9, 95\% CI = 1.2, 2.9), total cholesterol (RR for 40 mg/dL increment = 1.3, 95\% CI = 1.0, 1.5), and low (i.e., <0.9) ankle-arm index (RR = 2.1, 95\% CI = 1.3, 3.4) after adjusting for age. Within this cohort of older African Americans, male gender, diabetes mellitus, total cholesterol, and low ankle-arm index and were independently predictive of incident events. These results suggest that the ankle-arm index, a measure of advanced atherosclerosis, should be further evaluated for its efficacy in identifying older African Americans at risk for incident clinical events.

}, keywords = {Age Distribution, Aged, Black or African American, Coronary Disease, Female, Health Status, Humans, Incidence, Male, Predictive Value of Tests}, issn = {0027-9684}, author = {Jackson, S A and Burke, G L and Thach, C and Cushman, M and Ives, D and Powe, N and Manolio, T A} } @article {653, title = {Involvement in caregiving and adjustment to death of a spouse: findings from the caregiver health effects study.}, journal = {JAMA}, volume = {285}, year = {2001}, month = {2001 Jun 27}, pages = {3123-9}, abstract = {

CONTEXT: Most deaths in the United States occur among older persons who have 1 or more disabling conditions. As a result, many deaths are preceded by an extended period during which family members provide care to their disabled relative.

OBJECTIVE: To better understand the effect of bereavement on family caregivers by examining predeath vs postdeath changes in self-reported and objective health outcomes among elderly persons providing varying levels of care prior to their spouse{\textquoteright}s death.

DESIGN AND SETTING: Prospective, population-based cohort study conducted in 4 US communities between 1993 and 1998.

PARTICIPANTS: One hundred twenty-nine individuals aged 66 to 96 years whose spouse died during an average 4-year follow-up. Individuals were classified as noncaregivers (n = 40), caregivers who reported no strain (n = 37), or strained caregivers (n = 52).

MAIN OUTCOME MEASURES: Changes in depression symptoms (assessed by the 10-item Center for Epidemiological Studies-Depression [CES-D] scale), antidepressant medication use, 6 health risk behaviors, and weight among the 3 groups of participants.

RESULTS: Controlling for age, sex, race, education, prevalent cardiovascular disease at baseline, and interval between predeath and postdeath assessments, CES-D scores remained high but did not change among strained caregivers (9.44 vs 9.19; P =.76), while these scores increased for both noncaregivers (4.74 vs 8.25; F(1,116) = 14.33; P<.001) and nonstrained caregivers (4.94 vs 7.13; F(1,116) = 4.35; P =.04). Noncaregivers were significantly more likely to be using nontricyclic antidepressant medications following the death than the nonstrained caregiver group (odds ratio [OR], 12.85; 95\% confidence interval [CI], 1.02-162.13; P =.05). The strained caregiver group experienced significant improvement in health risk behaviors following the death of their spouse (1.47 vs 0.66 behaviors; F(1,118) = 20.23; P<.001), while the noncaregiver and nonstrained caregiver groups showed little change (0.27 vs 0.27 [P =.99] and 0.46 vs 0.27 [P =.39] behaviors, respectively). Noncaregivers experienced significant weight loss following the death (149.1 vs 145.3 lb [67.1 vs 65.4 kg]; F(1,101) = 8.12; P =.005), while the strained and nonstrained caregiving groups did not show significant weight change (156.2 vs 155.2 lb [70.3 vs 69.8 kg] [P =.41] and 156.2 vs 154.0 lb [70.3 vs 69.3 kg] [P =.12], respectively).

CONCLUSIONS: These data indicate that the impact of losing one{\textquoteright}s spouse among older persons varies as a function of the caregiving experiences that precede the death. Among individuals who are already strained prior to the death of their spouse, the death itself does not increase their level of distress. Instead, they show reductions in health risk behaviors. Among noncaregivers, losing one{\textquoteright}s spouse results in increased depression and weight loss.

}, keywords = {Aged, Aged, 80 and over, Antidepressive Agents, Bereavement, Caregivers, Death, Depression, Female, Follow-Up Studies, Health Behavior, Humans, Male, Socioeconomic Factors, Spouses, Weight Loss}, issn = {0098-7484}, doi = {10.1001/jama.285.24.3123}, author = {Schulz, R and Beach, S R and Lind, B and Martire, L M and Zdaniuk, B and Hirsch, C and Jackson, S and Burton, L} } @article {713, title = {In the elderly, interleukin-6 plasma levels and the -174G>C polymorphism are associated with the development of cardiovascular disease.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {22}, year = {2002}, month = {2002 Dec 01}, pages = {2066-71}, abstract = {

OBJECTIVE: Interleukin (IL)-6-mediated inflammation is involved in cardiovascular disease (CVD). We assessed IL-6 levels and the -174G>C genotype in a case-control study of men and women (average age 73 years) within the Cardiovascular Health Study.

METHODS AND RESULTS: Cases included incident angina, myocardial infarction (MI), and stroke (5-year follow-up), prevalent MI, and MRI-detectable infarcts. A control group and a group free of subclinical CVD were used for comparison. The -174C allele was associated with higher C-reactive protein (11\% higher, P=0.02), fibrinogen (3\% higher, P=0.02), and IL-6 (5\% higher; P=0.16). IL-6 was associated with increased atherosclerosis when the control group was compared with the group free of subclinical CVD. No further association with CVD events was found when case groups were compared with the control group. Compared with its absence, presence of the -174C allele was associated with risk of MRI infarcts (odds ratio 1.5).

CONCLUSIONS: IL-6 levels differentiated those with subclinical CVD from those without. Although the -174C allele was not associated with incident events, associations of the genotype with inflammation and MRI infarcts, combined with the plasma IL-6 results, suggest that IL-6 may chronically predispose an individual to develop atherosclerosis.

}, keywords = {Age Factors, Aged, Biomarkers, Cardiovascular Diseases, Case-Control Studies, Cytosine, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genotype, Guanine, Health Surveys, Humans, Inflammation, Interleukin-6, Linear Models, Male, Polymorphism, Genetic, Predictive Value of Tests, Promoter Regions, Genetic}, issn = {1524-4636}, doi = {10.1161/01.atv.0000040224.49362.60}, author = {Jenny, Nancy S and Tracy, Russell P and Ogg, Malcolm S and Luong, Le Ahn and Kuller, Lewis H and Arnold, Alice M and Sharrett, A Richey and Humphries, Steve E} } @article {703, title = {Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {33}, year = {2002}, month = {2002 Oct}, pages = {2376-82}, abstract = {

BACKGROUND AND PURPOSE: MRI-defined infarcts are common in the elderly. We sought to explore incidence, manifestations, and predictors of such infarcts.

METHODS: The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of 5888 people aged > or =65 years. Participants have had extensive baseline and follow-up evaluations; 1433 participants underwent 2 MRI scans separated by 5 years and had no infarcts on initial MRI.

RESULTS: On follow-up MRI, 254 participants (17.7\%) had 1 or more infarcts. Most were single (75.6\%), subcortical (79.9\%), and small (3 to 20 mm in 87.0\%). Only 11.4\% of those with infarcts experienced a documented transient ischemic attack or stroke between the scans. Although participants were similar at initial MRI, those with MRI-defined infarcts on follow-up experienced greater decline than those without infarcts on the Modified Mini-Mental State Examination and Digit-Symbol Substitution test (both P<0.01). Severity of white matter changes on initial MRI was the strongest predictor of incident infarcts. When it was excluded from stepwise multivariable models, predictors were serum creatinine, age, and ankle-arm index.

CONCLUSIONS: Incident MRI-defined infarcts commonly affect the elderly. Most are small, subcortical, and not associated with acute symptoms recognized as a transient ischemic attack or stroke. Nonetheless, they cannot be considered silent because of their association with subtle cognitive deficits. These covert infarcts are associated with white matter changes, which may share a common pathophysiology. Whether control of vascular risk factors, such as blood pressure, would reduce the risk of developing these infarcts and associated cognitive decline deserves further investigation.

}, keywords = {Aged, Brain Infarction, California, Cohort Studies, Creatinine, Follow-Up Studies, Humans, Incidence, Longitudinal Studies, Magnetic Resonance Imaging, Maryland, Multivariate Analysis, Neuropsychological Tests, North Carolina, Odds Ratio, Pennsylvania, Predictive Value of Tests, Risk Factors}, issn = {1524-4628}, doi = {10.1161/01.str.0000032241.58727.49}, author = {Longstreth, W T and Dulberg, Corinne and Manolio, Teri A and Lewis, Michael R and Beauchamp, Norman J and O{\textquoteright}Leary, Daniel and Carr, Jeff and Furberg, Curt D} } @article {678, title = {Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia.}, journal = {Am J Cardiol}, volume = {89}, year = {2002}, month = {2002 Feb 15}, pages = {419-24}, abstract = {

Depression is associated with increased cardiovascular disease, but the underlying mechanisms are not well understood. This study examines associations of depressive symptoms with inflammation and coagulation factors in persons aged > 65 years. Blood samples were obtained from 4,268 subjects free of cardiovascular disease (age 72.4 +/- 5.5 years, 2,623 women). Inflammation markers were C-reactive protein (CRP), white blood cell (WBC) count, total platelet count, and albumin; coagulation factors included factors VIIc and VIIIc and fibrinogen. Depression was assessed with the Center for Epidemiologic Studies Depression scale, and states of energy depletion with a validated exhaustion index. Statistical adjustments were made for risk factors (age, sex, race, systolic blood pressure, smoking status, diabetes mellitus) and physical measures of frailty (isometric handgrip, timed 15-feet walk test, activity level). Depression was associated with elevated CRP (3.31 +/- 0.10 vs 3.51 +/- 0.21 mg/L), WBC (6.14 +/- 0.03 vs 6.43 +/- 0.11 10(6)/L), fibrinogen (319 +/- 1 vs 326 +/- 3 mg/dl), and factor VIIc (124.6 +/- 0.6\% vs 127.2 +/- 1.3\%; all p <0.05). Exhaustion also was related to elevated inflammation and coagulation markers (p < 0.05). Exhausted men had markedly elevated CRP levels (6.82 +/- 2.10 mg/L) versus nonexhausted men (3.05 +/- 0.16: p = 0.007). After adjustment for control variables, exhaustion remained associated with albumin (p = 0.033), fibrinogen (p = 0.017), CRP (p = 0.066), and WBC (p = 0.060), whereas associations of depressive symptoms with biochemistry measures lost statistical significance. Thus, depression and exhaustion are associated with low-grade inflammation and elevated coagulation factors in persons aged > 65 years.

}, keywords = {Aged, Blood Chemical Analysis, Blood Coagulation Factors, Cardiovascular Diseases, Depression, Female, Humans, Inflammation, Male, Risk Factors}, issn = {0002-9149}, doi = {10.1016/s0002-9149(01)02264-0}, author = {Kop, Willem J and Gottdiener, John S and Tangen, Catherine M and Fried, Linda P and McBurnie, Mary Ann and Walston, Jeremy and Newman, Anne and Hirsch, Calvin and Tracy, Russell P} } @article {754, title = {Imputation of missing longitudinal data: a comparison of methods.}, journal = {J Clin Epidemiol}, volume = {56}, year = {2003}, month = {2003 Oct}, pages = {968-76}, abstract = {

BACKGROUND AND OBJECTIVES: Missing information is inevitable in longitudinal studies, and can result in biased estimates and a loss of power. One approach to this problem is to impute the missing data to yield a more complete data set. Our goal was to compare the performance of 14 methods of imputing missing data on depression, weight, cognitive functioning, and self-rated health in a longitudinal cohort of older adults.

METHODS: We identified situations where a person had a known value following one or more missing values, and treated the known value as a "missing value." This "missing value" was imputed using each method and compared to the observed value. Methods were compared on the root mean square error, mean absolute deviation, bias, and relative variance of the estimates.

RESULTS: Most imputation methods were biased toward estimating the "missing value" as too healthy, and most estimates had a variance that was too low. Imputed values based on a person{\textquoteright}s values before and after the "missing value" were superior to other methods, followed by imputations based on a person{\textquoteright}s values before the "missing value." Imputations that used no information specific to the person, such as using the sample mean, had the worst performance.

CONCLUSIONS: We conclude that, in longitudinal studies where the overall trend is for worse health over time and where missing data can be assumed to be primarily related to worse health, missing data in a longitudinal sequence should be imputed from the available longitudinal data for that person.

}, keywords = {Aged, Analysis of Variance, Bias, Coronary Disease, Data Interpretation, Statistical, Depression, Female, Health Status, Humans, Longitudinal Studies, Male, Research Design, Risk Factors, Stroke, United States}, issn = {0895-4356}, doi = {10.1016/s0895-4356(03)00170-7}, author = {Engels, Jean Mundahl and Diehr, Paula} } @article {758, title = {Inflammation as a risk factor for atrial fibrillation.}, journal = {Circulation}, volume = {108}, year = {2003}, month = {2003 Dec 16}, pages = {3006-10}, abstract = {

BACKGROUND: The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and prediction of AF has not been studied in a large population-based cohort.

METHODS AND RESULTS: CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9+/-1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5\%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4\% versus 3.7\%, adjusted OR 1.8, 95\% CI 1.2 to 2.5; P=0.002). Of 5491 subjects without AF at baseline, 897 (16\%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95\% CI 1.08 to 1.58; P=0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95\% CI 1.11 to 1.40; P<0.001).

CONCLUSIONS: CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.

}, keywords = {Aged, Atrial Fibrillation, C-Reactive Protein, Cross-Sectional Studies, Female, Humans, Inflammation, Longitudinal Studies, Male, Risk Factors}, issn = {1524-4539}, doi = {10.1161/01.CIR.0000103131.70301.4F}, author = {Aviles, Ronnier J and Martin, David O and Apperson-Hansen, Carolyn and Houghtaling, Penny L and Rautaharju, Pentti and Kronmal, Richard A and Tracy, Russell P and Van Wagoner, David R and Psaty, Bruce M and Lauer, Michael S and Chung, Mina K} } @article {762, title = {Incidence and prevalence of dementia in the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {52}, year = {2004}, month = {2004 Feb}, pages = {195-204}, abstract = {

OBJECTIVES: To estimate the incidence and prevalence of dementia, Alzheimer{\textquoteright}s disease (AD), and vascular dementia (VaD) in the Cardiovascular Health Study (CHS) cohort.

DESIGN: Longitudinal cohort study using prospectively and retrospectively collected data to evaluate dementia.

SETTING: Four U.S. communities.

PARTICIPANTS: There were 3,602 CHS participants, including 2,865 white and 492 African-American participants free of dementia, who completed a cranial magnetic resonance image between 1992 and 1994 and were followed for an average of 5.4 years.

MEASUREMENTS: Dementia was classified by neurologist/psychiatrist committee review using neuropsychological tests, neurological examinations, medical records, physician questionnaires, and proxy/informant interviews. Demographics and apolipoprotein E (APOE) genotype were collected at baseline. Incidence by type of dementia was determined using National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer{\textquoteright}s Disease and Related Disorders Association criteria for AD and Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Center{\textquoteright}s State of California criteria for VaD.

RESULTS: Classification resulted in 227 persons with prevalent dementia at entry into the study and 480 incident cases during follow-up. Incidence rates of dementia scaled to age 80 were 34.7 per 1,000 person-years for white women, 35.3 for white men, 58.8 for African-American women, and 53.0 for African-American men. Sex differences were not significant within race. Adjusted for age and education, racial differences were only of borderline significance and may have been influenced by ascertainment methodology. Rates differed substantially by educational attainment but were only significant for whites. Those with the APOE epsilon4 allele had an incidence rate at age 80 of 56.4, compared with 29.6 for those without this allele (P<.001). In whites, type-specific incidence at age 80 was 19.2 for AD versus 14.6 for VaD. These rates were 34.7 and 27.2 for African Americans. At termination of observation, women had only a slightly higher prevalence of dementia (16.0\%) than men (14.7\%).

CONCLUSION: Sex and racial differences were not found, and VaD was higher than reported in other studies. These data provide new estimates of dementia incidence in a community sample for projection of future burden.

}, keywords = {African Americans, Age Distribution, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Dementia, Dementia, Vascular, Education, European Continental Ancestry Group, Female, Humans, Incidence, Longitudinal Studies, Male, Prevalence, Proportional Hazards Models, Risk Factors, Sex Distribution, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2004.52058.x}, author = {Fitzpatrick, Annette L and Kuller, Lewis H and Ives, Diane G and Lopez, Oscar L and Jagust, William and Breitner, John C S and Jones, Beverly and Lyketsos, Constantine and Dulberg, Corinne} } @article {790, title = {Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study.}, journal = {J Am Coll Cardiol}, volume = {43}, year = {2004}, month = {2004 Jun 16}, pages = {2207-15}, abstract = {

OBJECTIVES: Our aim in this study was to determine whether increased left ventricular mass (LVM) is a risk factor for the development of a reduced left ventricular ejection fraction (LVEF).

BACKGROUND: Prior studies have shown that increased LVM is a risk factor for heart failure but not whether it is a risk factor for a low LVEF.

METHODS: As part of the Cardiovascular Health Study, a prospective population-based longitudinal study, we performed echocardiograms upon participant enrollment and again at follow-up of 4.9 +/- 0.14 years. In the present analysis, we identified 3,042 participants who had at baseline a normal LVEF and an assessment of LVM (either by electrocardiogram or echocardiogram), and at follow-up a measurable LVEF. The frequency of the development of a qualitatively depressed LVEF on two-dimensional echocardiography, corresponding approximately to an LVEF <55\%, was analyzed by quartiles of baseline LVM. Multivariable regression determined whether LVM was independently associated with the development of depressed LVEF.

RESULTS: Baseline quartile of echocardiographic LVM indexed to body surface area was associated with development of a depressed LVEF (4.8\% in quartile 1, 4.4\% in quartile 2, 7.5\% in quartile 3, and 14.1\% in quartile 4 [p < 0.001]). A similar relationship was seen in the subgroup of participants without myocardial infarction (p < 0.001). In multivariable regression that adjusted for confounders, both baseline echocardiographic (p < 0.001) and electrocardiographic (p < 0.001) LVM remained associated with development of depressed LVEF.

CONCLUSIONS: Increased LVM as assessed by electrocardiography or echocardiography is an independent risk factor for the development of depressed LVEF.

}, keywords = {Aged, Body Surface Area, Coronary Artery Disease, Diastole, Echocardiography, Electrocardiography, Female, Follow-Up Studies, Heart Ventricles, Humans, Hypertrophy, Left Ventricular, Longitudinal Studies, Male, Multivariate Analysis, Prospective Studies, Risk Factors, Sensitivity and Specificity, Statistics as Topic, Stroke Volume, Ventricular Dysfunction, Left}, issn = {0735-1097}, doi = {10.1016/j.jacc.2003.11.064}, author = {Drazner, Mark H and Rame, J Eduardo and Marino, Emily K and Gottdiener, John S and Kitzman, Dalane W and Gardin, Julius M and Manolio, Teri A and Dries, Daniel L and Siscovick, David S} } @article {813, title = {Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals.}, journal = {J Am Soc Nephrol}, volume = {15}, year = {2004}, month = {2004 Dec}, pages = {3184-91}, abstract = {

Inflammatory and prothrombotic markers are elevated in individuals with mild to moderate renal disease. It was hypothesized that these markers may also be determinants of the progression of renal disease. The association of six markers-serum C-reactive protein (CRP), white blood cell (WBC) count, fibrinogen, factor VII, albumin, and hemoglobin-with subsequent elevations of creatinine and decline in estimated GFR in the Cardiovascular Health Study, a community-based cohort of elderly individuals, was analyzed. Linear regression was used to determine predictors of an annualized change in serum creatinine as the main outcome. Duration of follow-up was 7 yr for the original cohort and 4 yr for the more recently recruited black cohort. A total of 588 (12.7\%) individuals had a decline in estimated GFR of at least 3 ml/min per yr per 1.73 m(2). Higher CRP (P < 0.001), WBC count (P < 0.001), fibrinogen (P < 0.001), and factor VII (P < 0.001) levels and lower albumin (P < 0.001) and hemoglobin levels (P < 0.001) were associated with a rise in creatinine, after adjusting for age. With additional adjustments for race, gender, baseline creatinine, systolic and diastolic BP, lipid levels, weight, and pack-years smoking, higher CRP, factor VII, fibrinogen, WBC count, and lower albumin and hemoglobin levels remained associated with a rise in creatinine. Similar results were found for decline in estimated GFR. The decline in GFR was greater with increasing number of inflammatory or prothrombotic markers that were above the median (below for hemoglobin and albumin). Inflammatory and prothrombotic markers are predictors for a change in kidney function in elderly individuals. Interventions that reduce inflammation might confer significant cardiovascular and renal benefits.

}, keywords = {Aged, Biomarkers, C-Reactive Protein, Creatinine, Factor VII, Female, Fibrinogen, Follow-Up Studies, Glomerular Filtration Rate, Hemoglobins, Humans, Leukocyte Count, Linear Models, Longitudinal Studies, Male, Predictive Value of Tests, Prospective Studies, Renal Insufficiency, Serum Albumin, Thrombosis}, issn = {1046-6673}, doi = {10.1097/01.ASN.0000146422.45434.35}, author = {Fried, Linda and Solomon, Cam and Shlipak, Michael and Seliger, Stephen and Stehman-Breen, Catherine and Bleyer, Anthony J and Chaves, Paolo and Furberg, Curt and Kuller, Lewis and Newman, Anne} } @article {812, title = {Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {36}, year = {2005}, month = {2005 Jan}, pages = {56-61}, abstract = {

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}, issn = {1524-4628}, doi = {10.1161/01.STR.0000149625.99732.69}, author = {Longstreth, W T and Arnold, Alice M and Beauchamp, Norman J and Manolio, Teri A and Lefkowitz, David and Jungreis, Charles and Hirsch, Calvin H and O{\textquoteright}Leary, Daniel H and Furberg, Curt D} } @article {820, title = {Incidence of cardiovascular disease in older Americans: the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Feb}, pages = {211-8}, abstract = {

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}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53105.x}, author = {Arnold, Alice M and Psaty, Bruce M and Kuller, Lewis H and Burke, Gregory L and Manolio, Teri A and Fried, Linda P and Robbins, John A and Kronmal, Richard A} } @article {885, title = {Intake of tuna or other broiled or baked fish versus fried fish and cardiac structure, function, and hemodynamics.}, journal = {Am J Cardiol}, volume = {97}, year = {2006}, month = {2006 Jan 15}, pages = {216-22}, abstract = {

Fish intake is associated with improved cardiovascular health, including a lower risk of arrhythmic death, atrial fibrillation, and heart failure. However, the physiologic effects that may produce these cardiovascular benefits are not well-established. We investigated the cross-sectional associations between a usual dietary intake of fish during the previous year and cardiac structure, function, and hemodynamics as determined by physical examination and 2-dimensional, Doppler, and M-mode transthoracic echocardiography among 5,073 older adults enrolled in the Cardiovascular Health Study. On multivariate-adjusted analyses, consumption of tuna or other broiled or baked fish was associated with a lower heart rate (p < 0.001), lower systemic vascular resistance (p = 0.002), and greater stroke volume (p < 0.001). Tuna/other fish intake was also associated with a higher E/A ratio (p = 0.004), a measure of more normal diastolic function. In contrast, fried fish or fish sandwich (fish burger) intake was associated with left ventricular wall motion abnormalities (p = 0.02), a reduced ejection fraction (p < 0.001), lower cardiac output (p = 0.04), a trend toward a larger left ventricular diastolic dimension (p = 0.07), and higher systemic vascular resistance (p = 0.003). In conclusion, in this large population-based study, the intake of tuna or other broiled or baked fish was associated with improved cardiac hemodynamics, but fried fish intake was associated with structural abnormalities indicative of systolic dysfunction and potential coronary atherosclerosis. These findings suggest potential specific physiologic mechanisms that may, in part, account for the effects of fish intake on cardiovascular health.

}, keywords = {Animals, Blood Pressure, Cardiac Output, Confounding Factors, Epidemiologic, Cooking, Heart Rate, Hemodynamics, Humans, Seafood, Tuna, Vascular Resistance}, issn = {0002-9149}, doi = {10.1016/j.amjcard.2005.08.025}, author = {Mozaffarian, Dariush and Gottdiener, John S and Siscovick, David S} } @article {982, title = {IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study.}, journal = {Hum Genet}, volume = {122}, year = {2007}, month = {2007 Dec}, pages = {485-94}, abstract = {

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}, issn = {1432-1203}, doi = {10.1007/s00439-007-0428-x}, author = {Walston, Jeremy D and Fallin, M Daniele and Cushman, Mary and Lange, Leslie and Psaty, Bruce and Jenny, Nancy and Browner, Warren and Tracy, Russell and Durda, Peter and Reiner, Alex} } @article {947, title = {Incidence of dementia in mild cognitive impairment in the cardiovascular health study cognition study.}, journal = {Arch Neurol}, volume = {64}, year = {2007}, month = {2007 Mar}, pages = {416-20}, abstract = {

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{\textquoteright} 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}, issn = {0003-9942}, doi = {10.1001/archneur.64.3.416}, author = {Lopez, Oscar L and Kuller, Lewis H and Becker, James T and Dulberg, Corinne and Sweet, Robert A and Gach, H Michael and DeKosky, Steven T} } @article {964, title = {Individual and neighborhood socioeconomic status and progressive chronic kidney disease in an elderly population: The Cardiovascular Health Study.}, journal = {Soc Sci Med}, volume = {65}, year = {2007}, month = {2007 Aug}, pages = {809-21}, abstract = {

Few studies have focused on the association between socioeconomic status (SES) and progressive chronic kidney disease (pCKD) in an elderly population. We conducted a cohort study of 4735 Cardiovascular Health Study participants, ages 65 and older and living in 4 US communities, to examine the independent risk of pCKD associated with income, education and living in a low SES area. pCKD was defined as creatinine elevation 0.4 mg/dL (35 micromol/L) over a 4-7 year follow-up or CKD hospitalization. Area SES was characterized using measures of income, wealth, education and occupation for 1990 (corresponding to time of enrollment) US Census block groups of residence. Age and study site-adjusted incidence rates (per 1000 person years) of pCKD by quartiles of area-level SES score, income and education showed decreasing rates with increasing SES. Cox proportional hazards models showed that living in the lowest SES area quartile, as opposed to the highest, was associated with 50\% greater risk of pCKD, after adjusting for age, gender, study site, baseline creatinine, and individual-level SES. This increased risk and trend persisted after adjusting for lifestyle risk factors, diabetes and hypertension. We found no significant independent associations between pCKD and individual-level income or education (after adjusting for all other SES factors). As such, living in a low SES area is associated with greater risk of pCKD in an elderly US population.

}, keywords = {Age Factors, Aged, Cohort Studies, Female, Humans, Incidence, Kidney Failure, Chronic, Male, Proportional Hazards Models, Residence Characteristics, Risk Factors, Sex Factors, Social Class, United States}, issn = {0277-9536}, doi = {10.1016/j.socscimed.2007.04.011}, author = {Merkin, Sharon Stein and Diez Roux, Ana V and Coresh, Josef and Fried, Linda F and Jackson, Sharon A and Powe, Neil R} } @article {950, title = {Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {5}, year = {2007}, month = {2007 Jun}, pages = {1128-35}, abstract = {

BACKGROUND: There are few studies of inflammation and hemostasis biomarkers and cardiovascular disease risk (CVD) in older adults.

OBJECTIVES: To assess multiple biomarkers simultaneously and in combinations for CVD risk assessment in older individuals.

PATIENTS/METHODS: Thirteen biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, fibrinogen, factor VII, factor VIII, leukocyte count (WBC), platelet count, lipoprotein(a), soluble intercellular adhesion molecule-1 (sICAM-1), albumin, homocysteine and uric acid, were correlated with incident CVD in 4510 individuals in the Cardiovascular Health Study. Baseline biomarkers were analyzed as gender-specific SD increments and quintiles in proportional hazards models adjusted for demographics, CVD risk factors and medications.

RESULTS: Over 9 years with 1700 CVD events, seven biomarkers were associated with CVD. Adjusted hazard ratios (HRs, 95\% CI) per SD increment were 1.16 (1.09, 1.23) for IL-6, 1.16 (1.09, 1.23) for CRP, 1.13 (1.05, 1.21) for D-dimer, 1.17 (1.09, 1.25) for homocysteine, 1.06 (1.00, 1.12) for WBC, 1.06 (1.00, 1.12) for factor VIII, and 1.07 (1.00, 1.13) for lipoprotein(a). Fibrinogen was associated with CVD in men only (HR 1.12, 95\% CI 1.04, 1.22) and sICAM-1 in women only (HR 1.16, 95\% CI 1.05, 1.27). IL-6 and CRP remained associated with CVD when modeled with WBC. Participants were classified by all combinations of two biomarkers being high or low (IL-6, CRP, WBC, factor VIII, cholesterol/HDL). All were associated with CVD when cholesterol/HDL was low and none when CRP was low.

CONCLUSIONS: Seven biomarkers were associated with CVD in older adults, with CRP having some advantages compared with others. Even larger studies are needed to better characterize these associations.

}, keywords = {Aged, Aging, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, Cohort Studies, Factor VIII, Female, Fibrinogen, Hemostasis, Homocysteine, Humans, Inflammation Mediators, Interleukin-6, Leukocyte Count, Lipoprotein(a), Male, Prospective Studies, Risk Factors}, issn = {1538-7933}, doi = {10.1111/j.1538-7836.2007.02528.x}, author = {Zakai, N A and Katz, R and Jenny, N S and Psaty, B M and Reiner, A P and Schwartz, S M and Cushman, M} } @article {936, title = {Inflammation biomarkers and near-term death in older men.}, journal = {Am J Epidemiol}, volume = {165}, year = {2007}, month = {2007 Mar 15}, pages = {684-95}, abstract = {

Associations of C-reactive protein (CRP) and fibrinogen with death may weaken over time. Combining both markers may improve prediction of death in older adults. In 5,828 Cardiovascular Health Study participants (United States, 1989-2000), 383 deaths (183 cardiovascular disease (CVD)) in years 1-3 (early) and 914 deaths (396 CVD) in years 4-8 (late) occurred. For men, when comparing highest to lowest quartiles, hazard ratios for early death were 4.1 (95\% confidence interval (CI): 2.7, 6.3) for CRP and 4.1 (95\% CI: 2.7, 6.4) for fibrinogen in models adjusted for CVD risk. For early CVD death, hazard ratios were 4.3 (95\% CI: 2.2, 8.4) and 3.4 (95\% CI: 1.8, 6.3), respectively. When comparing men in the highest quartiles of both biomarkers with those in the lowest, hazard ratios were 9.6 (95\% CI: 4.3, 21.1) for early death and 13.5 (95\% CI: 3.2, 56.5) for early CVD death. Associations were weaker for late deaths. For women, CRP (hazard ratio = 2.3, 95\% CI: 1.4, 3.9), but not fibrinogen (hazard ratio = 1.3, 95\% CI: 0.8, 2.2), was associated with early death. Results were similar for CVD death. Neither was associated with late deaths. CRP and fibrinogen were more strongly associated with death in older men than women and more strongly associated with early than late death. Combining both markers may identify older men at greatest risk of near-term death.

}, keywords = {Age Distribution, Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Diabetes Complications, Epidemiologic Studies, Female, Fibrinogen, Follow-Up Studies, Humans, Hypercholesterolemia, Hypertension, Inflammation, Male, Middle Aged, Obesity, Population Surveillance, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Risk Factors, Sex Distribution, Smoking, Time Factors, United States}, issn = {0002-9262}, doi = {10.1093/aje/kwk057}, author = {Jenny, Nancy Swords and Yanez, N David and Psaty, Bruce M and Kuller, Lewis H and Hirsch, Calvin H and Tracy, Russell P} } @article {955, title = {Insulin resistance and inflammation as precursors of frailty: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {167}, year = {2007}, month = {2007 Apr 09}, pages = {635-41}, abstract = {

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}, issn = {0003-9926}, doi = {10.1001/archinte.167.7.635}, author = {Barzilay, Joshua I and Blaum, Caroline and Moore, Tisha and Xue, Qian Li and Hirsch, Calvin H and Walston, Jeremy D and Fried, Linda P} } @article {1058, title = {Impact of health perception, balance perception, fall history, balance performance, and gait speed on walking activity in older adults.}, journal = {Phys Ther}, volume = {88}, year = {2008}, month = {2008 Dec}, pages = {1474-81}, abstract = {

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}, issn = {1538-6724}, doi = {10.2522/ptj.20080036}, author = {Talkowski, Jaime B and Brach, Jennifer S and Studenski, Stephanie and Newman, Anne B} } @article {1024, title = {Incident physical disability in people with lower extremity peripheral arterial disease: the role of cardiovascular disease.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 Jun}, pages = {1037-44}, abstract = {

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}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2008.01719.x}, author = {Brach, Jennifer S and Solomon, Cam and Naydeck, Barbara L and Sutton-Tyrrell, Kim and Enright, Paul L and Jenny, Nancy Swords and Chaves, Paulo M and Newman, Anne B} } @article {1048, title = {Inflammatory markers and longitudinal lung function decline in the elderly.}, journal = {Am J Epidemiol}, volume = {168}, year = {2008}, month = {2008 Sep 15}, pages = {602-10}, abstract = {

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}, issn = {1476-6256}, doi = {10.1093/aje/kwn174}, author = {Jiang, Rui and Burke, Gregory L and Enright, Paul L and Newman, Anne B and Margolis, Helene G and Cushman, Mary and Tracy, Russell P and Wang, Yuanjia and Kronmal, Richard A and Barr, R Graham} } @article {991, title = {Insulin-like growth factor-(IGF)-axis, inflammation, and glucose intolerance among older adults.}, journal = {Growth Horm IGF Res}, volume = {18}, year = {2008}, month = {2008 Apr}, pages = {166-73}, abstract = {

Increasing evidence suggests that the insulin-like growth factor (IGF)-axis may play a role in glucose metabolism and may also be associated with systemic inflammation. The aim of this study was to evaluate the association of insulin-like growth factor-1 (IGF-I) and its binding proteins, IGFBP-1 and IGFBP-3, with glucose intolerance and inflammation among older adults. We conducted a cross-sectional analysis in a in a random subsample (n=922) of the Cardiovascular Health Study (CHS), a prospective cohort of men and women > or = 65 years. Mean IGFBP-1 levels were significantly lower in older adults with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and diabetes compared to those with normal fasting and post-load glucose. High IGFBP-1 was associated with a reduced prevalence of IGT and IFG; the multivariable OR between extreme quartiles of IGFBP-1 was 0.60 (95\% CI: 0.37, 0.95; p-trend: 0.03) for IGT and 0.41 (95\% CI: 0.26, 0.64; p-trend: <0.01) for IFG. We did not find any significant association between IGF-I and glucose intolerance in this study and the association for IGFBP-3 was less clear. However, low levels of IGF-I and IGFBP-3 were associated with increased levels of markers of inflammation including C-reactive protein and interleukin-6 levels. We conclude that among adults > or = 65 years, low IGFBP-1 levels are associated with increased prevalence of glucose intolerance. We did not confirm prior associations of low IGF-I with glucose intolerance in this cohort of older individuals.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Cross-Sectional Studies, Female, Glucose Intolerance, Humans, Inflammation, Insulin-Like Growth Factor Binding Proteins, Male, Signal Transduction, Somatomedins}, issn = {1096-6374}, doi = {10.1016/j.ghir.2007.08.004}, author = {Rajpathak, Swapnil N and McGinn, Aileen P and Strickler, Howard D and Rohan, Thomas E and Pollak, Michael and Cappola, Anne R and Kuller, Lewis and Xue, XiaoNan and Newman, Anne B and Strotmeyer, Elsa S and Psaty, Bruce M and Kaplan, Robert C} } @article {1055, title = {Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies.}, journal = {Ann Intern Med}, volume = {149}, year = {2008}, month = {2008 Oct 07}, pages = {461-71, W83-8}, abstract = {

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}, issn = {1539-3704}, doi = {10.7326/0003-4819-149-7-200810070-00006}, author = {Roddam, Andrew W and Allen, Naomi E and Appleby, Paul and Key, Timothy J and Ferrucci, Luigi and Carter, H Ballentine and Metter, E Jeffrey and Chen, Chu and Weiss, Noel S and Fitzpatrick, Annette and Hsing, Ann W and Lacey, James V and Helzlsouer, Kathy and Rinaldi, Sabina and Riboli, Elio and Kaaks, Rudolf and Janssen, Joop A M J L and Wildhagen, Mark F and Schr{\"o}der, Fritz H and Platz, Elizabeth A and Pollak, Michael and Giovannucci, Edward and Schaefer, Catherine and Quesenberry, Charles P and Vogelman, Joseph H and Severi, Gianluca and English, Dallas R and Giles, Graham G and Stattin, P{\"a}r and Hallmans, G{\"o}ran and Johansson, Mattias and Chan, June M and Gann, Peter and Oliver, Steven E and Holly, Jeff M and Donovan, Jenny and Meyer, Fran{\c c}ois and Bairati, Isabelle and Galan, Pilar} } @article {1029, title = {Item response theory facilitated cocalibrating cognitive tests and reduced bias in estimated rates of decline.}, journal = {J Clin Epidemiol}, volume = {61}, year = {2008}, month = {2008 Oct}, pages = {1018-27.e9}, abstract = {

OBJECTIVE: To cocalibrate the Mini-Mental State Examination, the Modified Mini-Mental State, the Cognitive Abilities Screening Instrument, and the Community Screening Instrument for Dementia using item response theory (IRT) to compare screening cut points used to identify cases of dementia from different studies, to compare measurement properties of the tests, and to explore the implications of these measurement properties on longitudinal studies of cognitive functioning over time.

STUDY DESIGN AND SETTING: We used cross-sectional data from three large (n>1000) community-based studies of cognitive functioning in the elderly. We used IRT to cocalibrate the scales and performed simulations of longitudinal studies.

RESULTS: Screening cut points varied quite widely across studies. The four tests have curvilinear scaling and varied levels of measurement precision, with more measurement error at higher levels of cognitive functioning. In longitudinal simulations, IRT scores always performed better than standard scoring, whereas a strategy to account for varying measurement precision had mixed results.

CONCLUSION: Cocalibration allows direct comparison of cognitive functioning in studies using any of these four tests. Standard scoring appears to be a poor choice for analysis of longitudinal cognitive testing data. More research is needed into the implications of varying levels of measurement precision.

}, keywords = {Aged, Aged, 80 and over, Cognition Disorders, Dementia, Disease Progression, Epidemiologic Methods, Female, Humans, Male, Neuropsychological Tests, Psychometrics}, issn = {1878-5921}, doi = {10.1016/j.jclinepi.2007.11.011}, author = {Crane, Paul K and Narasimhalu, Kaavya and Gibbons, Laura E and Mungas, Dan M and Haneuse, Sebastien and Larson, Eric B and Kuller, Lewis and Hall, Kathleen and van Belle, Gerald} } @article {1086, title = {Imaging cerebral blood flow in the cognitively normal aging brain with arterial spin labeling: implications for imaging of neurodegenerative disease.}, journal = {J Neuroimaging}, volume = {19}, year = {2009}, month = {2009 Oct}, pages = {344-52}, abstract = {

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{\textquoteright}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}, issn = {1552-6569}, doi = {10.1111/j.1552-6569.2008.00277.x}, author = {Lee, Charles and Lopez, Oscar L and Becker, James T and Raji, Cyrus and Dai, Weiying and Kuller, Lewis H and Gach, H Michael} } @article {1081, title = {Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults.}, journal = {Exp Gerontol}, volume = {44}, year = {2009}, month = {2009 May}, pages = {350-5}, abstract = {

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}, issn = {1873-6815}, doi = {10.1016/j.exger.2009.02.004}, author = {Walston, Jeremy D and Matteini, Amy M and Nievergelt, Caroline and Lange, Leslie A and Fallin, Dani M and Barzilai, Nir and Ziv, Elad and Pawlikowska, Ludmila and Kwok, Pui and Cummings, Steve R and Kooperberg, Charles and LaCroix, Andrea and Tracy, Russell P and Atzmon, Gil and Lange, Ethan M and Reiner, Alex P} } @article {1076, title = {Insomnia did not predict incident hypertension in older adults in the cardiovascular health study.}, journal = {Sleep}, volume = {32}, year = {2009}, month = {2009 Jan}, pages = {65-72}, abstract = {

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}, issn = {0161-8105}, author = {Phillips, Barbara and B{\r u}zkov{\'a}, Petra and Enright, Paul} } @article {1088, title = {Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Nov}, pages = {1103-6}, abstract = {

The insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.

}, keywords = {Aged, Aging, Cross-Sectional Studies, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Leukocytes, Linear Models, Male, Sex Characteristics, Telomere}, issn = {1758-535X}, doi = {10.1093/gerona/glp036}, author = {Kaplan, Robert C and Fitzpatrick, Annette L and Pollak, Michael N and Gardner, Jeffrey P and Jenny, Nancy S and McGinn, Aileen P and Kuller, Lewis H and Strickler, Howard D and Kimura, Masayuki and Psaty, Bruce M and Aviv, Abraham} } @article {1166, title = {Impaired kidney function and atrial fibrillation in elderly subjects.}, journal = {J Card Fail}, volume = {16}, year = {2010}, month = {2010 Jan}, pages = {55-60}, abstract = {

BACKGROUND: Impaired kidney function is associated with increased risk for cardiovascular events. We evaluated whether kidney function is associated with atrial fibrillation (AF) risk in elderly persons.

METHODS AND RESULTS: Subjects were participants in the Cardiovascular Health Study (CHS), a population-based cohort of ambulatory elderly. Measures of kidney function were cystatin C and creatinine-based estimated glomerular filtration rate (eGFR). Among the 4663 participants, 342 (7\%) had AF at baseline and 579 (13\%) developed incident AF during follow-up (mean 7.4 years). In unadjusted analyses, cystatin C quartiles were strongly associated with prevalent AF with a nearly 3-fold odds in the highest quartile compared with the lowest (HR=1.19, 95\% CI [0.80-1.76] in quartile 2; HR=2.00, 95\% CI [1.38-2.88] in quartile 3; and HR=2.87, 95\% CI [2.03-4.07] in quartile 4). This increased risk for prevalent AF remained significant after multivariate adjustment. The risk for incident AF increased across cystatin C quartiles in the unadjusted analysis (HR=1.37, 95\% CI [1.07-1.75] in quartile 2; HR=1.43, 95\% CI [1.11-1.84] in quartile 3; and HR=1.88, 95\% CI [1.47-2.41] in quartile 4); however, after multivariate adjustment, these findings were no longer significant. An estimated GFR <60 mL.min.1.73m(2) was associated with prevalent and incident AF in unadjusted, but not multivariate analyses.

CONCLUSIONS: Impaired kidney function, as measured by cystatin C, is an independent marker of prevalent AF; however, neither cystatin C nor eGFR are predictors of incident AF.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Atrial Fibrillation, Cohort Studies, Cross-Sectional Studies, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney Diseases, Kidney Function Tests, Male}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2009.07.002}, author = {Deo, Rajat and Katz, Ronit and Kestenbaum, Bryan and Fried, Linda and Sarnak, Mark J and Psaty, Bruce M and Siscovick, David S and Shlipak, Michael G} } @article {1226, title = {Independent susceptibility markers for atrial fibrillation on chromosome 4q25.}, journal = {Circulation}, volume = {122}, year = {2010}, month = {2010 Sep 07}, pages = {976-84}, abstract = {

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}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.109.886440}, author = {Lubitz, Steven A and Sinner, Moritz F and Lunetta, Kathryn L and Makino, Seiko and Pfeufer, Arne and Rahman, Rosanna and Veltman, Caroline E and Barnard, John and Bis, Joshua C and Danik, Stephan P and Sonni, Akshata and Shea, Marisa A and Del Monte, Federica and Perz, Siegfried and M{\"u}ller, Martina and Peters, Annette and Greenberg, Steven M and Furie, Karen L and van Noord, Charlotte and Boerwinkle, Eric and Stricker, Bruno H C and Witteman, Jacqueline and Smith, Jonathan D and Chung, Mina K and Heckbert, Susan R and Benjamin, Emelia J and Rosand, Jonathan and Arking, Dan E and Alonso, Alvaro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T} } @article {1127, title = {Inflammatory biomarkers and decline in kidney function in the elderly: the Cardiovascular Health Study.}, journal = {Nephrol Dial Transplant}, volume = {25}, year = {2010}, month = {2010 Jan}, pages = {119-24}, abstract = {

BACKGROUND: Cross-sectional studies have demonstrated a consistent and linear association between circulating inflammatory markers and kidney function. The objective of this study was to determine whether elevated markers of inflammation are independently associated with longitudinal kidney function decline.

METHODS: This study included 4128 subjects from the Cardiovascular Health Study. Cystatin C was measured at baseline, 3 years later and 7 years later; eligible subjects had at least two measures. Cystatin C-based estimated glomerular filtration rate (eGFR(cysC)) was estimated, and rapid kidney function decline was defined as an annual loss of eGFR(cysC) >3 mL/min/1.73 m(2). Predictors included ten inflammatory and procoagulant biomarkers: C-reactive protein, interleukin-6, intercellular adhesion molecule-1, white blood cell count, fibrinogen, factor VII, factor VIII, D-dimer, plasmin-antiplasmin complex and serum albumin.

RESULTS: During the study, 1059 subjects (26\%) had a rapid decline in kidney function. In contrast to the other nine inflammatory or procoagulant biomarkers, serum albumin had a consistent and inverse association with rapid kidney function decline [final adjusted logistic regression model: 1.14-fold increased odds (95\% CI 1.06-1.23) of rapid decline per standard deviation lower albumin]. The lowest quartile of albumin had an odds ratio of 1.55 (95\% CI 1.23-1.96) for rapid decline compared with the highest quartile. These associations persisted after adjusting the albumin models for CRP, IL-6 and fibrinogen.

CONCLUSIONS: In contrast to nine other inflammatory and procoagulant markers, only lower baseline levels of serum albumin were consistently associated with a rapid decline in kidney function, as measured by cystatin C-based eGFR.

}, keywords = {Aged, Biomarkers, C-Reactive Protein, Cohort Studies, Cystatin C, Female, Glomerular Filtration Rate, Humans, Inflammation, Intercellular Adhesion Molecule-1, Interleukin-6, Kidney, Logistic Models, Longitudinal Studies, Male, Prospective Studies, Serum Albumin}, issn = {1460-2385}, doi = {10.1093/ndt/gfp429}, author = {Keller, Christopher and Katz, Ronit and Sarnak, Mark J and Fried, Linda F and Kestenbaum, Bryan and Cushman, Mary and Shlipak, Michael G} } @article {1158, title = {Interaction between fibrinogen and IL-6 genetic variants and associations with cardiovascular disease risk in the Cardiovascular Health Study.}, journal = {Ann Hum Genet}, volume = {74}, year = {2010}, month = {2010 Jan}, pages = {1-10}, abstract = {

The inflammatory cytokine interleukin-6 (IL-6) is a main regulator of fibrinogen synthesis, though its interaction with fibrinogen genes (FGA, FGB, FGG) and subsequent impact on cardiovascular disease (CVD) risk is not well-studied. We investigated joint associations of fibrinogen and IL6 tagSNPs with fibrinogen concentrations, carotid intima-media thickness, and myocardial infarction or ischemic stroke in 3900 European-American Cardiovascular Health Study participants. To identify combinations of genetic main effects and interactions associated with outcomes, we used logic regression. We also evaluated whether the relationship between fibrinogen SNPs and fibrinogen level varied by IL-6 level using linear regression models with multiplicative interaction terms. Combinations of fibrinogen and IL6 SNPs were significantly associated with fibrinogen level (p < 0.005), but not with other outcomes. Fibrinogen levels were higher in individuals having FGB1437 (rs1800790) and lacking FGA6534 (rs6050) minor alleles; these SNPs interacted with IL6 rs1800796 to influence fibrinogen level. Marginally significant (p= 0.03) interactions between IL-6 level and FGA and FGG promoter SNPs associated with fibrinogen levels were detected. We identified potential gene-gene interactions influencing fibrinogen levels. Although IL-6 responsive binding sites are present in fibrinogen gene promoter regions, we did not find strong evidence of interaction between fibrinogen SNPs and IL6 SNPs or levels influencing CVD.

}, keywords = {Aged, Cardiovascular Diseases, Carotid Arteries, Female, Fibrinogen, Genetic Predisposition to Disease, Genetic Variation, Humans, Interleukin-6, Male, Models, Biological, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk, Stroke}, issn = {1469-1809}, doi = {10.1111/j.1469-1809.2009.00551.x}, author = {Carty, Cara L and Heagerty, Patrick and Heckbert, Susan R and Jarvik, Gail P and Lange, Leslie A and Cushman, Mary and Tracy, Russell P and Reiner, Alexander P} } @article {1222, title = {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.}, journal = {Diabetes Care}, volume = {33}, year = {2010}, month = {2010 Dec}, pages = {2684-91}, abstract = {

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}, issn = {1935-5548}, doi = {10.2337/dc10-1150}, author = {Nettleton, Jennifer A and McKeown, Nicola M and Kanoni, Stavroula and Lemaitre, Rozenn N and Hivert, Marie-France and Ngwa, Julius and van Rooij, Frank J A and Sonestedt, Emily and Wojczynski, Mary K and Ye, Zheng and Tanaka, Tosh and Garcia, Melissa and Anderson, Jennifer S and Follis, Jack L and Djouss{\'e}, Luc and Mukamal, Kenneth and Papoutsakis, Constantina and Mozaffarian, Dariush and Zillikens, M Carola and Bandinelli, Stefania and Bennett, Amanda J and Borecki, Ingrid B and Feitosa, Mary F and Ferrucci, Luigi and Forouhi, Nita G and Groves, Christopher J and Hallmans, G{\"o}ran and Harris, Tamara and Hofman, Albert and Houston, Denise K and Hu, Frank B and Johansson, Ingegerd and Kritchevsky, Stephen B and Langenberg, Claudia and Launer, Lenore and Liu, Yongmei and Loos, Ruth J and Nalls, Michael and Orho-Melander, Marju and Renstrom, Frida and Rice, Kenneth and Riserus, Ulf and Rolandsson, Olov and Rotter, Jerome I and Saylor, Georgia and Sijbrands, Eric J G and Sjogren, Per and Smith, Albert and Steingr{\'\i}msd{\'o}ttir, Laufey and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Prokopenko, Inga and Pankow, James S and van Duijn, Cornelia M and Florez, Jose C and Witteman, Jacqueline C M and Dupuis, Jos{\'e}e and Dedoussis, George V and Ordovas, Jose M and Ingelsson, Erik and Cupples, L Adrienne and Siscovick, David S and Franks, Paul W and Meigs, James B} } @article {1173, title = {Intravenous tissue plasminogen activator and stroke in the elderly.}, journal = {Am J Emerg Med}, volume = {28}, year = {2010}, month = {2010 Mar}, pages = {359-63}, abstract = {

OBJECTIVE: Since publication in 1995 of the National Institute of Neurological Disorders and Stroke (NINDS) trial of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke, the benefit and frequency of use of IV tPA in the elderly have remained uncertain.

METHODS: We obtained data from the NINDS trial to summarize outcomes for randomized subjects older than 80 years. We used data from the Cardiovascular Health Study, a cohort study of 5888 elderly participants from 4 US communities followed longitudinally for stroke since 1989 to estimate the use of and hospital outcome after IV tPA in older adults following publication of the trial in 1995.

RESULTS: In the NINDS trial, 44 subjects older than 80 years were randomized, and their 3-month functional outcomes were not significantly improved with IV tPA. Of 25 randomized to IV tPA, 4 experienced symptomatic intracranial hemorrhages within 36 hours of treatment. Compared with younger patients, older patients were 2.87 times more likely to experience a symptomatic intracranial hemorrhage within 36 hours of IV tPA (95\% confidence interval, 1.04-7.93). Of 227 Cardiovascular Health Study participants hospitalized for ischemic stroke between 1995 and 2002, seven, whose mean age was 84 years, were treated with IV tPA (3.1\%; 95\% confidence interval 1.2-6.2). Two had symptomatic intracranial hemorrhages, 3 failed to improve, and 2 of the 7 had good outcomes.

CONCLUSIONS: These data highlight the need to clarify the risk-benefit profile of IV tPA in ischemic stroke victims who are older than 80 years.

}, keywords = {Aged, 80 and over, Female, Fibrinolytic Agents, Humans, Longitudinal Studies, Male, Placebos, Randomized Controlled Trials as Topic, Stroke, Tissue Plasminogen Activator, Treatment Outcome, United States}, issn = {1532-8171}, doi = {10.1016/j.ajem.2009.01.025}, author = {Longstreth, W T and Katz, Ronit and Tirschwell, David L and Cushman, Mary and Psaty, Bruce M} } @article {1304, title = {Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jun}, pages = {e1002158}, abstract = {

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8{\texttimes}10(-10)). The risk allele, while ancestral, has a frequency of ~1.4\%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95\% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

}, keywords = {Adult, Aged, Alleles, Chromosomes, Human, Pair 2, Death, Sudden, Cardiac, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Contraction, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002158}, author = {Arking, Dan E and Junttila, M Juhani and Goyette, Philippe and Huertas-Vazquez, Adriana and Eijgelsheim, Mark and Blom, Marieke T and Newton-Cheh, Christopher and Reinier, Kyndaron and Teodorescu, Carmen and Uy-Evanado, Audrey and Carter-Monroe, Naima and Kaikkonen, Kari S and Kortelainen, Marja-Leena and Boucher, Gabrielle and Lagac{\'e}, Caroline and Moes, Anna and Zhao, XiaoQing and Kolodgie, Frank and Rivadeneira, Fernando and Hofman, Albert and Witteman, Jacqueline C M and Uitterlinden, Andr{\'e} G and Marsman, Roos F and Pazoki, Raha and Bardai, Abdennasser and Koster, Rudolph W and Dehghan, Abbas and Hwang, Shih-Jen and Bhatnagar, Pallav and Post, Wendy and Hilton, Gina and Prineas, Ronald J and Li, Man and K{\"o}ttgen, Anna and Ehret, Georg and Boerwinkle, Eric and Coresh, Josef and Kao, W H Linda and Psaty, Bruce M and Tomaselli, Gordon F and Sotoodehnia, Nona and Siscovick, David S and Burke, Greg L and Marb{\'a}n, Eduardo and Spooner, Peter M and Cupples, L Adrienne and Jui, Jonathan and Gunson, Karen and Kesaniemi, Y Antero and Wilde, Arthur A M and Tardif, Jean-Claude and O{\textquoteright}Donnell, Christopher J and Bezzina, Connie R and Virmani, Renu and Stricker, Bruno H C H and Tan, Hanno L and Albert, Christine M and Chakravarti, Aravinda and Rioux, John D and Huikuri, Heikki V and Chugh, Sumeet S} } @article {1342, title = {Identification of patients with sleep disordered breathing: comparing the four-variable screening tool, STOP, STOP-Bang, and Epworth Sleepiness Scales.}, journal = {J Clin Sleep Med}, volume = {7}, year = {2011}, month = {2011 Oct 15}, pages = {467-72}, abstract = {

STUDY OBJECTIVE: The Epworth Sleepiness Scale (ESS) has been used to detect patients with potential sleep disordered breathing (SDB). Recently, a 4-Variable screening tool was proposed to identify patients with SDB, in addition to the STOP and STOP-Bang questionnaires. This study evaluated the abilities of the 4-Variable screening tool, STOP, STOP-Bang, and ESS questionnaires in identifying subjects at risk for SDB.

METHODS: A total of 4,770 participants who completed polysomnograms in the baseline evaluation of the Sleep Heart Health Study (SHHS) were included. Subjects with RDIs >= 15 and >= 30 were considered to have moderate-to-severe or severe SDB, respectively. Variables were constructed to approximate those in the questionnaires. The risk of SDB was calculated by the 4-Variable screening tool according to Takegami et al. The STOP and STOP-Bang questionnaires were evaluated including variables for snoring, tiredness/sleepiness, observed apnea, blood pressure, body mass index, age, neck circumference, and gender. Sleepiness was evaluated using the ESS questionnaire and scores were dichotomized into < 11 and >= 11.

RESULTS: The STOP-Bang questionnaire had higher sensitivity to predict moderate-to-severe (87.0\%) and severe (70.4\%) SDB, while the 4-Variable screening tool had higher specificity to predict moderate-to-severe and severe SDB (93.2\% for both).

CONCLUSIONS: In community populations such as the SHHS, high specificities may be more useful in excluding low-risk patients, while avoiding false positives. However, sleep clinicians may prefer to use screening tools with high sensitivities, like the STOP-Bang, in order to avoid missing cases that may lead to adverse health consequences and increased healthcare costs.

}, keywords = {Blood Pressure, Body Mass Index, Cohort Studies, Female, Humans, Male, Mass Screening, Middle Aged, Polysomnography, Predictive Value of Tests, Prospective Studies, Risk, ROC Curve, Sensitivity and Specificity, Severity of Illness Index, Sleep Apnea Syndromes, Snoring, Surveys and Questionnaires}, issn = {1550-9397}, doi = {10.5664/JCSM.1308}, author = {Silva, Graciela E and Vana, Kimberly D and Goodwin, James L and Sherrill, Duane L and Quan, Stuart F} } @article {1566, title = {The Impact of Sleep-Disordered Breathing on Body Mass Index (BMI): The Sleep Heart Health Study (SHHS).}, journal = {Southwest J Pulm Crit Care}, volume = {3}, year = {2011}, month = {2011 Dec 08}, pages = {159-168}, abstract = {

INTRODUCTION: It is well known that obesity is a risk factor for sleep-disordered breathing (SDB). However, whether SDB predicts increase in BMI is not well defined. Data from the Sleep Heart Health Study (SHHS) were analyzed to determine whether SDB predicts longitudinal increase in BMI, adjusted for confounding factors. METHODS: A full-montage unattended home polysomnogram (PSG) and body anthropometric measurements were obtained approximately five years apart in 3001 participants. Apnea-hypopnea index (AHI) was categorized using clinical thresholds: < 5 (normal), >= 5 to <15 (mild sleep apnea), and >= 15 (moderate to severe sleep apnea). Linear regression was used to examine the association between the three AHI groups and increased BMI. The model included age, gender, race, baseline BMI, and change in AHI as covariates. RESULTS: Mean (SD) age was 62.2 years (10.14), 55.2\% were female and 76.1\% were Caucasian. Five-year increase in BMI was modest with a mean (SD) change of 0.53 (2.62) kg/m(2) (p=0.071). A multivariate regression model showed that subjects with a baseline AHI between 5-15 had a mean increase in BMI of 0.22 kg/m(2) (p=0.055) and those with baseline AHI >= 15 had a BMI increase of 0.51 kg/m(2) (p<0.001) compared to those with baseline AHI of <5. CONCLUSION: Our findings suggest that there is a positive association between severity of SDB and subsequent increased BMI over approximately 5 years. This observation may help explain why persons with SDB have difficulty losing weight.

}, issn = {2160-6773}, author = {Brown, Mark A and Goodwin, James L and Silva, Graciela E and Behari, Ajay and Newman, Anne B and Punjabi, Naresh M and Resnick, Helaine E and Robbins, John A and Quan, Stuart F} } @article {6179, title = {Impact of ancestry and common genetic variants on QT interval in African Americans.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Dec}, pages = {647-55}, abstract = {

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.

METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 {\texttimes} 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 {\texttimes} 10(-15)) and ATP1B1 (rs1320976, P=2 {\texttimes} 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.

CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

}, keywords = {Adult, African Americans, Aged, Electrocardiography, European Continental Ancestry Group, Female, Genealogy and Heraldry, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.112.962787}, author = {Smith, J Gustav and Avery, Christy L and Evans, Daniel S and Nalls, Michael A and Meng, Yan A and Smith, Erin N and Palmer, Cameron and Tanaka, Toshiko and Mehra, Reena and Butler, Anne M and Young, Taylor and Buxbaum, Sarah G and Kerr, Kathleen F and Berenson, Gerald S and Schnabel, Renate B and Li, Guo and Ellinor, Patrick T and Magnani, Jared W and Chen, Wei and Bis, Joshua C and Curb, J David and Hsueh, Wen-Chi and Rotter, Jerome I and Liu, Yongmei and Newman, Anne B and Limacher, Marian C and North, Kari E and Reiner, Alexander P and Quibrera, P Miguel and Schork, Nicholas J and Singleton, Andrew B and Psaty, Bruce M and Soliman, Elsayed Z and Solomon, Allen J and Srinivasan, Sathanur R and Alonso, Alvaro and Wallace, Robert and Redline, Susan and Zhang, Zhu-Ming and Post, Wendy S and Zonderman, Alan B and Taylor, Herman A and Murray, Sarah S and Ferrucci, Luigi and Arking, Dan E and Evans, Michele K and Fox, Ervin R and Sotoodehnia, Nona and Heckbert, Susan R and Whitsel, Eric A and Newton-Cheh, Christopher} } @article {6085, title = {Impact of blood pressure and blood pressure change during middle age on the remaining lifetime risk for cardiovascular disease: the cardiovascular lifetime risk pooling project.}, journal = {Circulation}, volume = {125}, year = {2012}, month = {2012 Jan 03}, pages = {37-44}, abstract = {

BACKGROUND: Prior estimates of lifetime risk (LTR) for cardiovascular disease (CVD) examined the impact of blood pressure (BP) at the index age and did not account for changes in BP over time. We examined how changes in BP during middle age affect LTR for CVD, coronary heart disease, and stroke.

METHODS AND RESULTS: Data from 7 diverse US cohort studies were pooled. Remaining LTRs for CVD, coronary heart disease, and stroke were estimated for white and black men and women with death free of CVD as a competing event. LTRs for CVD by BP strata and by changes in BP over an average of 14 years were estimated. Starting at 55 years of age, we followed up 61 585 men and women for 700 000 person-years. LTR for CVD was 52.5\% (95\% confidence interval, 51.3-53.7) for men and 39.9\% (95\% confidence interval, 38.7-41.0) for women. LTR for CVD was higher for blacks and increased with increasing BP at index age. Individuals who maintained or decreased their BP to normal levels had the lowest remaining LTR for CVD, 22\% to 41\%, compared with individuals who had or developed hypertension by 55 years of age, 42\% to 69\%, suggesting a dose-response effect for the length of time at high BP levels.

CONCLUSIONS: Individuals who experience increases or decreases in BP in middle age have associated higher and lower remaining LTR for CVD. Prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension to reduce the LTR for CVD.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, Cardiovascular Diseases, Cohort Studies, Female, Follow-Up Studies, Humans, Hypertension, Life Tables, Longitudinal Studies, Male, Middle Aged, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.002774}, author = {Allen, Norrina and Berry, Jarett D and Ning, Hongyan and Van Horn, Linda and Dyer, Alan and Lloyd-Jones, Donald M} } @article {1407, title = {The impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study.}, journal = {Eur Heart J}, volume = {33}, year = {2012}, month = {2012 Nov}, pages = {2709-17}, abstract = {

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia. Increased body size has been associated with AF, but the relationship is not well understood. In this study, we examined the effect of increased height on the risk of AF and explore potential mediators and implications for clinical practice.

METHODS AND RESULTS: We examined data from 5860 individuals taking part in the Cardiovascular Health Study, a cohort study of older US adults followed for a median of 13.6 (women) and 10.3 years (men). Multivariate linear models and age-stratified Cox proportional hazards and risk models were used, with focus on the effect of height on both prevalent and incident AF. Among 684 (22.6\%) and 568 (27.1\%) incident cases in women and men, respectively, greater height was significantly associated with AF risk [hazard ratio (HR)(women) per 10 cm 1.32, confidence interval (CI) 1.16-1.50, P < 0.0001; HR(men) per 10 cm 1.26, CI 1.11-1.44, P < 0.0001]. The association was such that the incremental risk from sex was completely attenuated by the inclusion of height (for men, HR 1.48, CI 1.32-1.65, without height, and HR 0.94, CI 0.85-1.20, with height included). Inclusion of height in the Framingham model for incident AF improved discrimination. In sequential models, however, we found minimal attenuation of the risk estimates for AF with adjustment for left ventricular (LV) mass and left atrial (LA) dimension. The associations of LA and LV size measurements with AF risk were weakened when indexed to height.

CONCLUSION: Independent from sex, increased height is significantly associated with the risk of AF.

}, keywords = {Aged, Atrial Fibrillation, Body Height, Epidemiologic Methods, Female, Humans, Male, Sex Factors, United States}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehs301}, author = {Rosenberg, Michael A and Patton, Kristen K and Sotoodehnia, Nona and Karas, Maria G and Kizer, Jorge R and Zimetbaum, Peter J and Chang, James D and Siscovick, David and Gottdiener, John S and Kronmal, Richard A and Heckbert, Susan R and Mukamal, Kenneth J} } @article {1557, title = {Incidence of mild cognitive impairment in the Pittsburgh Cardiovascular Health Study-Cognition Study.}, journal = {Neurology}, volume = {79}, year = {2012}, month = {2012 Oct 09}, pages = {1599-606}, abstract = {

OBJECTIVES AND METHODS: The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 years) in the Cardiovascular Health Study-Cognition Study from 1998-1999 to 2010-2011.

RESULTS: Two hundred (70\%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95\% confidence interval, 88.13-142.95) per 1,000 person-years. A total of 107 (53.5\%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 {\textpm} 1.8 years. Forty (20\%) of the incident MCI cases had an "unstable" course: 19 (9.5\%) converted to MCI and later returned to normal; 10 (5\%) converted to MCI, to normal, and later back to MCI; 7 (3.5\%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2\%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years).

CONCLUSIONS: The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts.

}, keywords = {Aged, Aged, 80 and over, Cognitive Dysfunction, Dementia, Disease Progression, Female, Health Surveys, Humans, Incidence, Male, Risk Factors, Severity of Illness Index}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e31826e25f0}, author = {Lopez, Oscar L and Becker, James T and Chang, Yue-Fang and Sweet, Robert A and DeKosky, Steven T and Gach, Michael H and Carmichael, Owen T and McDade, Eric and Kuller, Lewis H} } @article {1370, title = {Insulin resistance and incident peripheral artery disease in the Cardiovascular Health Study.}, journal = {Vasc Med}, volume = {17}, year = {2012}, month = {2012 Apr}, pages = {85-93}, abstract = {

Type 2 diabetes is a risk factor for peripheral artery disease (PAD), and insulin resistance is a key feature of diabetes and pre-diabetes. No longitudinal epidemiological study has examined the relation between insulin resistance and PAD. Our study analyzed the association of quartiles of the homeostatic model of insulin resistance (HOMA-IR) and the development of PAD defined by two methods. PAD was first defined as the development of an abnormal ankle-brachial index (ABI) (dichotomous outcome) after 6 years of follow-up. PAD was alternatively defined as the development of clinical PAD (time-to-event analysis). The study samples included adults over the age of 65 years who were enrolled in the Cardiovascular Health Study, had fasting measurements of insulin and glucose, had ABI measurements, and were not receiving treatment for diabetes. Multivariable models were adjusted for potential confounders, including age, sex, field center and cohort, body mass index (BMI), smoking status, alcohol use, and exercise intensity. Additional models adjusted for potential mediators, including blood pressure, lipids, kidney function, and prevalent vascular disease. In the ABI analysis (n = 2108), multivariable adjusted models demonstrated a positive relation between HOMA-IR and incident PAD (odds ratio = 1.80 comparing the 4th versus 1st quartile of HOMA-IR, 95\% confidence interval [CI] 1.20-2.71). In the clinical PAD analysis (n = 4208), we found a similar relation (hazard ratio = 2.30 comparing the 4th versus 1st quartile of HOMA-IR, 95\% CI 1.15-4.58). As expected, further adjustment for potential mediators led to some attenuation of effect estimates. In conclusion, insulin resistance is associated with a higher risk of PAD in older adults.

}, keywords = {Aged, Ankle Brachial Index, Biomarkers, Blood Glucose, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Fasting, Female, Health Surveys, Humans, Incidence, Insulin, Insulin Resistance, Logistic Models, Longitudinal Studies, Male, Odds Ratio, Peripheral Arterial Disease, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, United States}, issn = {1477-0377}, doi = {10.1177/1358863X11436195}, author = {Britton, Kathryn A and Mukamal, Kenneth J and Ix, Joachim H and Siscovick, David S and Newman, Anne B and de Boer, Ian H and Thacker, Evan L and Biggs, Mary L and Gaziano, J Michael and Djouss{\'e}, Luc} } @article {1372, title = {Insulin resistance, cystatin C, and mortality among older adults.}, journal = {Diabetes Care}, volume = {35}, year = {2012}, month = {2012 Jun}, pages = {1355-60}, abstract = {

OBJECTIVE: Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.

RESEARCH DESIGN AND METHODS: We performed a cohort study of 3,138 Cardiovascular Health Study participants (age >= 65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).

RESULTS: A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21\% (95\% CI 6-41) and 11\% (-3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22\% (4-43) and 4\% (-12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.

CONCLUSIONS: Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, Blood Pressure, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Cystatin C, Fasting, Female, Glomerular Filtration Rate, Humans, Insulin Resistance, Life Style, Male, Mortality, Predictive Value of Tests, Proportional Hazards Models, Renal Insufficiency, Risk Factors, Triglycerides, Waist Circumference}, issn = {1935-5548}, doi = {10.2337/dc11-1657}, author = {de Boer, Ian H and Katz, Ronit and Chonchol, Michel B and Fried, Linda F and Ix, Joachim H and Kestenbaum, Bryan and Mukamal, Kenneth J and Peralta, Carmen A and Siscovick, David S} } @article {8015, title = {Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Jun}, pages = {621-31}, abstract = {

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

}, keywords = {Animals, Arrhythmias, Cardiac, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Heart Rate, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1546-1718}, doi = {10.1038/ng.2610}, author = {den Hoed, Marcel and Eijgelsheim, Mark and Esko, T{\~o}nu and Brundel, Bianca J J M and Peal, David S and Evans, David M and Nolte, Ilja M and Segr{\`e}, Ayellet V and Holm, Hilma and Handsaker, Robert E and Westra, Harm-Jan and Johnson, Toby and Isaacs, Aaron and Yang, Jian and Lundby, Alicia and Zhao, Jing Hua and Kim, Young Jin and Go, Min Jin and Almgren, Peter and Bochud, Murielle and Boucher, Gabrielle and Cornelis, Marilyn C and Gudbjartsson, Daniel and Hadley, David and van der Harst, Pim and Hayward, Caroline and den Heijer, Martin and Igl, Wilmar and Jackson, Anne U and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Kemp, John P and Kristiansson, Kati and Ladenvall, Claes and Lorentzon, Mattias and Montasser, May E and Njajou, Omer T and O{\textquoteright}Reilly, Paul F and Padmanabhan, Sandosh and St Pourcain, Beate and Rankinen, Tuomo and Salo, Perttu and Tanaka, Toshiko and Timpson, Nicholas J and Vitart, Veronique and Waite, Lindsay and Wheeler, William and Zhang, Weihua and Draisma, Harmen H M and Feitosa, Mary F and Kerr, Kathleen F and Lind, Penelope A and Mihailov, Evelin and Onland-Moret, N Charlotte and Song, Ci and Weedon, Michael N and Xie, Weijia and Yengo, Loic and Absher, Devin and Albert, Christine M and Alonso, Alvaro and Arking, Dan E and de Bakker, Paul I W and Balkau, Beverley and Barlassina, Cristina and Benaglio, Paola and Bis, Joshua C and Bouatia-Naji, Nabila and Brage, S{\o}ren and Chanock, Stephen J and Chines, Peter S and Chung, Mina and Darbar, Dawood and Dina, Christian and D{\"o}rr, Marcus and Elliott, Paul and Felix, Stephan B and Fischer, Krista and Fuchsberger, Christian and de Geus, Eco J C and Goyette, Philippe and Gudnason, Vilmundur and Harris, Tamara B and Hartikainen, Anna-Liisa and Havulinna, Aki S and Heckbert, Susan R and Hicks, Andrew A and Hofman, Albert and Holewijn, Suzanne and Hoogstra-Berends, Femke and Hottenga, Jouke-Jan and Jensen, Majken K and Johansson, Asa and Junttila, Juhani and K{\"a}{\"a}b, Stefan and Kanon, Bart and Ketkar, Shamika and Khaw, Kay-Tee and Knowles, Joshua W and Kooner, Angrad S and Kors, Jan A and Kumari, Meena and Milani, Lili and Laiho, P{\"a}ivi and Lakatta, Edward G and Langenberg, Claudia and Leusink, Maarten and Liu, Yongmei and Luben, Robert N and Lunetta, Kathryn L and Lynch, Stacey N and Markus, Marcello R P and Marques-Vidal, Pedro and Mateo Leach, Irene and McArdle, Wendy L and McCarroll, Steven A and Medland, Sarah E and Miller, Kathryn A and Montgomery, Grant W and Morrison, Alanna C and M{\"u}ller-Nurasyid, Martina and Navarro, Pau and Nelis, Mari and O{\textquoteright}Connell, Jeffrey R and O{\textquoteright}Donnell, Christopher J and Ong, Ken K and Newman, Anne B and Peters, Annette and Polasek, Ozren and Pouta, Anneli and Pramstaller, Peter P and Psaty, Bruce M and Rao, Dabeeru C and Ring, Susan M and Rossin, Elizabeth J and Rudan, Diana and Sanna, Serena and Scott, Robert A and Sehmi, Jaban S and Sharp, Stephen and Shin, Jordan T and Singleton, Andrew B and Smith, Albert V and Soranzo, Nicole and Spector, Tim D and Stewart, Chip and Stringham, Heather M and Tarasov, Kirill V and Uitterlinden, Andr{\'e} G and Vandenput, Liesbeth and Hwang, Shih-Jen and Whitfield, John B and Wijmenga, Cisca and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Witteman, Jacqueline C M and Wong, Andrew and Wong, Quenna and Jamshidi, Yalda and Zitting, Paavo and Boer, Jolanda M A and Boomsma, Dorret I and Borecki, Ingrid B and van Duijn, Cornelia M and Ekelund, Ulf and Forouhi, Nita G and Froguel, Philippe and Hingorani, Aroon and Ingelsson, Erik and Kivimaki, Mika and Kronmal, Richard A and Kuh, Diana and Lind, Lars and Martin, Nicholas G and Oostra, Ben A and Pedersen, Nancy L and Quertermous, Thomas and Rotter, Jerome I and van der Schouw, Yvonne T and Verschuren, W M Monique and Walker, Mark and Albanes, Demetrius and Arnar, David O and Assimes, Themistocles L and Bandinelli, Stefania and Boehnke, Michael and de Boer, Rudolf A and Bouchard, Claude and Caulfield, W L Mark and Chambers, John C and Curhan, Gary and Cusi, Daniele and Eriksson, Johan and Ferrucci, Luigi and van Gilst, Wiek H and Glorioso, Nicola and de Graaf, Jacqueline and Groop, Leif and Gyllensten, Ulf and Hsueh, Wen-Chi and Hu, Frank B and Huikuri, Heikki V and Hunter, David J and Iribarren, Carlos and Isomaa, Bo and Jarvelin, Marjo-Riitta and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kiemeney, Lambertus A and van der Klauw, Melanie M and Kooner, Jaspal S and Kraft, Peter and Iacoviello, Licia and Lehtim{\"a}ki, Terho and Lokki, Marja-Liisa L and Mitchell, Braxton D and Navis, Gerjan and Nieminen, Markku S and Ohlsson, Claes and Poulter, Neil R and Qi, Lu and Raitakari, Olli T and Rimm, Eric B and Rioux, John D and Rizzi, Federica and Rudan, Igor and Salomaa, Veikko and Sever, Peter S and Shields, Denis C and Shuldiner, Alan R and Sinisalo, Juha and Stanton, Alice V and Stolk, Ronald P and Strachan, David P and Tardif, Jean-Claude and Thorsteinsdottir, Unnur and Tuomilehto, Jaako and van Veldhuisen, Dirk J and Virtamo, Jarmo and Viikari, Jorma and Vollenweider, Peter and Waeber, G{\'e}rard and Widen, Elisabeth and Cho, Yoon Shin and Olsen, Jesper V and Visscher, Peter M and Willer, Cristen and Franke, Lude and Erdmann, Jeanette and Thompson, John R and Pfeufer, Arne and Sotoodehnia, Nona and Newton-Cheh, Christopher and Ellinor, Patrick T and Stricker, Bruno H Ch and Metspalu, Andres and Perola, Markus and Beckmann, Jacques S and Smith, George Davey and Stefansson, Kari and Wareham, Nicholas J and Munroe, Patricia B and Sibon, Ody C M and Milan, David J and Snieder, Harold and Samani, Nilesh J and Loos, Ruth J F} } @article {6167, title = {Impact of inflammatory biomarkers on relation of high density lipoprotein-cholesterol with incident coronary heart disease: cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {231}, year = {2013}, month = {2013 Dec}, pages = {246-51}, abstract = {

BACKGROUND: Inflammatory factors and low HDL-C relate to CHD risk, but whether inflammation attenuates any protective association of high HDL-C is unknown.

OBJECTIVE: Investigate inflammatory markers{\textquoteright} individual and collective impact on the association of HDL-C with incident coronary heart disease (CHD).

METHODS: In 3888 older adults without known cardiovascular disease (CVD), we examined if the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A2 (Lp-PLA$_{2}$) modify the relation of HDL-C with CHD. HDL-C, CRP, IL-6, and Lp-PLA$_{2}$ values were grouped as using gender-specific tertiles. Also, an inflammation index of z-score sums for CRP, IL-6, and Lp-PLA$_{2}$ was categorized into tertiles. We calculated CHD incidence for each HDL-C/inflammation group and performed Cox regression, adjusted for standard CVD risk factors and triglycerides to examine the relationship of combined HDL-C-inflammation groups with incident events.

RESULTS: CHD incidence (per 1000 person years) was higher for higher levels of CRP, IL-6, and the index, and lower for higher levels of HDL-C. Compared to high HDL-C/low-inflammation categories (referent), adjusted HRs for incident CHD were increased for those with high HDL-C and high CRP (HR = 1.50, p < 0.01) or highest IL-6 tertile (HR = 1.40, p < 0.05), but not with highest Lp-PLA$_{2}$ tertile. Higher CHD incidence was similarly seen for those with intermediate or low HDL-C accompanied by high CRP, high IL-6, or a high inflammatory index.

CONCLUSION: The protective relation of high HDL-C for incident CHD appears to be attenuated by greater inflammation.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, African Americans, Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, HDL, Coronary Disease, European Continental Ancestry Group, Female, Humans, Incidence, Inflammation, Interleukin-6, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2013.08.036}, author = {Tehrani, David M and Gardin, Julius M and Yanez, David and Hirsch, Calvin H and Lloyd-Jones, Donald M and Stein, Phyllis K and Wong, Nathan D} } @article {5993, title = {Inflammation and sudden cardiac death in a community-based population of older adults: the Cardiovascular Health Study.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Oct}, pages = {1425-32}, abstract = {

BACKGROUND: Inflammation is linked to adverse cardiovascular events, but its association with sudden cardiac death (SCD) has been controversial. Older subjects, who are at particular risk for SCD, were underrepresented in previous studies addressing this issue.

OBJECTIVE: The purpose of this study was to study the association between inflammation and SCD in a community-based population of older adults.

METHODS: In the Cardiovascular Health Study, 5806 and 5382 participants had measurements of C-reactive protein (CRP) and interleukin-6 (IL6), respectively, and were followed for up to 17 years. SCD risk as a function of baseline IL-6 and CRP was assessed in the overall population and in a group of participants without known prevalent cardiac disease.

RESULTS: In univariate analyses, both IL-6 (hazard ratio [HR] 1.79 for 1+ log IL-6, 95\% confidence interval [CI] 1.50-2.13; 5th vs 1st quintile HR 3.36, 95\% CI 2.24-5.05) and CRP (HR 1.31 for 1+ log CRP, 95\% CI 1.18-1.45; 5th vs 1st quintile HR 2.00, 95\% CI 1.40-2.87) were associated with SCD risk. In covariate-adjusted analyses, accounting for baseline risk factors, incident myocardial infarction, and heart failure, the association with SCD risk persisted for IL-6 (HR 1.26 for 1+ log IL-6, 95\% CI 1.02-1.56; 5th vs 1st quintile HR 1.63, 95\% CI 1.03-2.56) but was significantly attenuated for CRP (HR 1.13 for 1+ log CRP, 95\% CI 1.00-1.28; 5th vs 1st quintile HR 1.34, 95\% CI 0.88-2.05). Similar findings were observed in participants without prevalent cardiac disease.

CONCLUSION: Greater burden of inflammation, assessed by IL-6 levels, is associated with SCD risk beyond traditional risk factors, incident myocardial infarction, and heart failure.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, C-Reactive Protein, Case-Control Studies, Cohort Studies, Death, Sudden, Cardiac, Female, Humans, Inflammation, Interleukin-6, Male, Risk Factors}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2013.07.004}, author = {Hussein, Ayman A and Gottdiener, John S and Bartz, Traci M and Sotoodehnia, Nona and DeFilippi, Christopher and See, Vincent and Deo, Rajat and Siscovick, David and Stein, Phyllis K and Lloyd-Jones, Donald} } @article {6630, title = {The influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study.}, journal = {Diabetes}, volume = {62}, year = {2013}, month = {2013 May}, pages = {1763-7}, abstract = {

Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages >=70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m{\texttwosuperior}, respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Aging, Body Mass Index, Cohort Studies, Cross-Sectional Studies, European Continental Ancestry Group, Female, Genetic Association Studies, Health Surveys, Humans, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Proteins, United States, Young Adult}, issn = {1939-327X}, doi = {10.2337/db12-0863}, author = {Graff, Mariaelisa and Gordon-Larsen, Penny and Lim, Unhee and Fowke, Jay H and Love, Shelly-Ann and Fesinmeyer, Megan and Wilkens, Lynne R and Vertilus, Shawyntee and Ritchie, Marilyn D and Prentice, Ross L and Pankow, Jim and Monroe, Kristine and Manson, JoAnn E and Le Marchand, Lo{\"\i}c and Kuller, Lewis H and Kolonel, Laurence N and Hong, Ching P and Henderson, Brian E and Haessler, Jeff and Gross, Myron D and Goodloe, Robert and Franceschini, Nora and Carlson, Christopher S and Buyske, Steven and B{\r u}zkov{\'a}, Petra and Hindorff, Lucia A and Matise, Tara C and Crawford, Dana C and Haiman, Christopher A and Peters, Ulrike and North, Kari E} } @article {5875, title = {Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e53830}, abstract = {

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5{\texttimes}10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3{\texttimes}10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1{\texttimes}10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9{\texttimes}10(-6)) and upstream of GLI2 (rs6721654; P = 6.5{\texttimes}10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5{\texttimes}10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

}, keywords = {Apolipoproteins E, Complement Factor H, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Kruppel-Like Transcription Factors, Macular Degeneration, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Proteins, Risk Factors, Zinc Finger Protein Gli3}, issn = {1932-6203}, doi = {10.1371/journal.pone.0053830}, author = {Holliday, Elizabeth G and Smith, Albert V and Cornes, Belinda K and Buitendijk, Gabri{\"e}lle H S and Jensen, Richard A and Sim, Xueling and Aspelund, Thor and Aung, Tin and Baird, Paul N and Boerwinkle, Eric and Cheng, Ching Yu and van Duijn, Cornelia M and Eiriksdottir, Gudny and Gudnason, Vilmundur and Harris, Tamara and Hewitt, Alex W and Inouye, Michael and Jonasson, Fridbert and Klein, Barbara E K and Launer, Lenore and Li, Xiaohui and Liew, Gerald and Lumley, Thomas and McElduff, Patrick and McKnight, Barbara and Mitchell, Paul and Psaty, Bruce M and Rochtchina, Elena and Rotter, Jerome I and Scott, Rodney J and Tay, Wanting and Taylor, Kent and Teo, Yik Ying and Uitterlinden, Andr{\'e} G and Viswanathan, Ananth and Xie, Sophia and Vingerling, Johannes R and Klaver, Caroline C W and Tai, E Shyong and Siscovick, David and Klein, Ronald and Cotch, Mary Frances and Wong, Tien Y and Attia, John and Wang, Jie Jin} } @article {5845, title = {Insulin resistance and risk of incident heart failure: Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {6}, year = {2013}, month = {2013 May}, pages = {364-70}, abstract = {

BACKGROUND: Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance as compared with matched controls. Insulin resistance leads to structural abnormalities in the heart, such as increased left atrial size, left ventricular mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether insulin resistance precedes the development of HF or whether the relationship between insulin resistance and HF is present among adults with HF caused by nonischemic heart disease.

METHODS AND RESULTS: We examined 4425 participants (60\% women) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes mellitus at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry. There were 1216 cases of incident HF (1103 without antecedent myocardial infarction) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (hazard ratio, 1.10; 95\% confidence interval, 1.05-1.15, per SD change) when adjusted for age, sex, race, field center, physical activity, smoking, alcohol intake, high-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent myocardial infarction (hazard ratio, 1.10; 95\% confidence interval, 1.05-1.15). Measures of left atrial size, left ventricular mass, and peak A velocity at baseline were associated both with fasting insulin levels and with HF; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (hazard ratio, 1.08; 95\% confidence interval, 1.03-1.14 per 1-SD increase in fasting insulin).

CONCLUSIONS: Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in Cardiovascular Health Study participants, including those without an antecedent myocardial infarction.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, keywords = {Aged, Female, Heart Atria, Heart Failure, Heart Ventricles, Humans, Incidence, Insulin, Insulin Resistance, Male, Middle Aged, Myocardial Infarction, Organ Size, Proportional Hazards Models, Prospective Studies}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.112.000022}, author = {Banerjee, Dipanjan and Biggs, Mary L and Mercer, Laina and Mukamal, Kenneth and Kaplan, Robert and Barzilay, Joshua and Kuller, Lewis and Kizer, Jorge R and Djouss{\'e}, Luc and Tracy, Russell and Zieman, Susan and Lloyd-Jones, Donald and Siscovick, David and Carnethon, Mercedes} } @article {6627, title = {Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study.}, journal = {BMC Genet}, volume = {14}, year = {2013}, month = {2013}, pages = {33}, abstract = {

BACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study.

RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses.

CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.

}, keywords = {Female, Genetic Heterogeneity, Genome, Human, Genome-Wide Association Study, Humans, Lipids, Male, Polymorphism, Single Nucleotide, Population Groups}, issn = {1471-2156}, doi = {10.1186/1471-2156-14-33}, author = {Taylor, Kira C and Carty, Cara L and Dumitrescu, Logan and B{\r u}zkov{\'a}, Petra and Cole, Shelley A and Hindorff, Lucia and Schumacher, Fred R and Wilkens, Lynne R and Shohet, Ralph V and Quibrera, P Miguel and Johnson, Karen C and Henderson, Brian E and Haessler, Jeff and Franceschini, Nora and Eaton, Charles B and Duggan, David J and Cochran, Barbara and Cheng, Iona and Carlson, Chris S and Brown-Gentry, Kristin and Anderson, Garnet and Ambite, Jose Luis and Haiman, Christopher and Le Marchand, Lo{\"\i}c and Kooperberg, Charles and Crawford, Dana C and Buyske, Steven and North, Kari E and Fornage, Myriam} } @article {6108, title = {Ischemic stroke is associated with the ABO locus: the EuroCLOT study.}, journal = {Ann Neurol}, volume = {73}, year = {2013}, month = {2013 Jan}, pages = {16-31}, abstract = {

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 {\texttimes} 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 {\texttimes} 10(-186)), rs10665 with FVII (p = 2.4 {\texttimes} 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 {\texttimes} 10(-57)) and factor VIII (p = 1.2 {\texttimes} 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95\% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

}, keywords = {ABO Blood-Group System, Adolescent, Adult, Aged, Aged, 80 and over, Blood Coagulation, Brain Ischemia, Cohort Studies, Europe, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Stroke, Young Adult}, issn = {1531-8249}, doi = {10.1002/ana.23838}, author = {Williams, Frances M K and Carter, Angela M and Hysi, Pirro G and Surdulescu, Gabriela and Hodgkiss, Dylan and Soranzo, Nicole and Traylor, Matthew and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M W and Sudlow, Cathie and Farrall, Martin and Silander, Kaisa and Kaunisto, Mari and Wagner, Peter and Saarela, Olli and Kuulasmaa, Kari and Virtamo, Jarmo and Salomaa, Veikko and Amouyel, Philippe and Arveiler, Dominique and Ferrieres, Jean and Wiklund, Per-Gunnar and Ikram, M Arfan and Hofman, Albert and Boncoraglio, Giorgio B and Parati, Eugenio A and Helgadottir, Anna and Gretarsdottir, Solveig and Thorsteinsdottir, Unnur and Thorleifsson, Gudmar and Stefansson, Kari and Seshadri, Sudha and DeStefano, Anita and Gschwendtner, Andreas and Psaty, Bruce and Longstreth, Will and Mitchell, Braxton D and Cheng, Yu-Ching and Clarke, Robert and Ferrario, Marco and Bis, Joshua C and Levi, Christopher and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Fornage, Myriam and Sharma, Pankaj and Furie, Karen L and Rosand, Jonathan and Nalls, Mike and Meschia, James and Mosely, Thomas H and Evans, Alun and Palotie, Aarno and Markus, Hugh S and Grant, Peter J and Spector, Tim D} } @article {6294, title = {Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Feb}, pages = {e1004123}, abstract = {

Autoimmune thyroid diseases (AITD) are common, affecting 2-5\% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto{\textquoteright}s thyroiditis), as well as autoimmune hyperthyroidism (Graves{\textquoteright} disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5{\texttimes}10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95\% CI 1.68-2.81, P = 8.1{\texttimes}10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95\% CI 1.26-1.82, P = 2.9{\texttimes}10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95\% CI 0.66-0.89, P = 6.5{\texttimes}10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves{\textquoteright} disease (OR: 1.37, 95\% CI 1.22-1.54, P = 1.2{\texttimes}10(-7) and OR: 1.25, 95\% CI 1.12-1.39, P = 6.2{\texttimes}10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95\% CI 1.18-2.10, P = 1.9{\texttimes}10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

}, keywords = {Autoantibodies, Genetic Loci, Genome-Wide Association Study, Graves Disease, Hashimoto Disease, Humans, Iodide Peroxidase, Risk Factors, Thyroiditis, Autoimmune, Thyrotropin}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004123}, author = {Medici, Marco and Porcu, Eleonora and Pistis, Giorgio and Teumer, Alexander and Brown, Suzanne J and Jensen, Richard A and Rawal, Rajesh and Roef, Greet L and Plantinga, Theo S and Vermeulen, Sita H and Lahti, Jari and Simmonds, Matthew J and Husemoen, Lise Lotte N and Freathy, Rachel M and Shields, Beverley M and Pietzner, Diana and Nagy, Rebecca and Broer, Linda and Chaker, Layal and Korevaar, Tim I M and Plia, Maria Grazia and Sala, Cinzia and V{\"o}lker, Uwe and Richards, J Brent and Sweep, Fred C and Gieger, Christian and Corre, Tanguy and Kajantie, Eero and Thuesen, Betina and Taes, Youri E and Visser, W Edward and Hattersley, Andrew T and Kratzsch, J{\"u}rgen and Hamilton, Alexander and Li, Wei and Homuth, Georg and Lobina, Monia and Mariotti, Stefano and Soranzo, Nicole and Cocca, Massimiliano and Nauck, Matthias and Spielhagen, Christin and Ross, Alec and Arnold, Alice and van de Bunt, Martijn and Liyanarachchi, Sandya and Heier, Margit and Grabe, Hans J{\"o}rgen and Masciullo, Corrado and Galesloot, Tessel E and Lim, Ee M and Reischl, Eva and Leedman, Peter J and Lai, Sandra and Delitala, Alessandro and Bremner, Alexandra P and Philips, David I W and Beilby, John P and Mulas, Antonella and Vocale, Matteo and Abecasis, Goncalo and Forsen, Tom and James, Alan and Widen, Elisabeth and Hui, Jennie and Prokisch, Holger and Rietzschel, Ernst E and Palotie, Aarno and Feddema, Peter and Fletcher, Stephen J and Schramm, Katharina and Rotter, Jerome I and Kluttig, Alexander and Radke, D{\"o}rte and Traglia, Michela and Surdulescu, Gabriela L and He, Huiling and Franklyn, Jayne A and Tiller, Daniel and Vaidya, Bijay and De Meyer, Tim and J{\o}rgensen, Torben and Eriksson, Johan G and O{\textquoteright}Leary, Peter C and Wichmann, Eric and Hermus, Ad R and Psaty, Bruce M and Ittermann, Till and Hofman, Albert and Bosi, Emanuele and Schlessinger, David and Wallaschofski, Henri and Pirastu, Nicola and Aulchenko, Yurii S and de la Chapelle, Albert and Netea-Maier, Romana T and Gough, Stephen C L and Meyer Zu Schwabedissen, Henriette and Frayling, Timothy M and Kaufman, Jean-Marc and Linneberg, Allan and R{\"a}ikk{\"o}nen, Katri and Smit, Johannes W A and Kiemeney, Lambertus A and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Walsh, John P and Meisinger, Christa and den Heijer, Martin and Visser, Theo J and Spector, Timothy D and Wilson, Scott G and V{\"o}lzke, Henry and Cappola, Anne and Toniolo, Daniela and Sanna, Serena and Naitza, Silvia and Peeters, Robin P} } @article {6572, title = {Incidence of and risk factors for sick sinus~syndrome in the general population.}, journal = {J Am Coll Cardiol}, volume = {64}, year = {2014}, month = {2014 Aug 12}, pages = {531-8}, abstract = {

BACKGROUND: Little is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation.

OBJECTIVES: This study sought to describe the epidemiology of SSS.

METHODS: This analysis included 20,572 participants (mean baseline age 59 years, 43\% male) in the ARIC (Atherosclerosis Risk In Communities) study and the CHS (Cardiovascular Health Study), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of >= 50 beats/min unless using beta blockers, and were identified as of white or black race. Incident SSS cases were identified by hospital discharge International Classification of Disease-revision 9-Clinical Modification code 427.81 and validated by medical record review.

RESULTS: During an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (hazard ratio [HR]: 1.73; 95\% confidence interval [CI]: 1.47 to 2.05 per 5-year increment), and blacks had a 41\% lower risk of SSS than whites (HR: 0.59; 95\% CI: 0.37 to 0.98). Incident SSS was associated with greater baseline body mass index, height, N-terminal pro-B-type natriuretic peptide, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060.

CONCLUSIONS: Blacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Cohort Studies, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Population Surveillance, Prospective Studies, Risk Factors, Sick Sinus Syndrome}, issn = {1558-3597}, doi = {10.1016/j.jacc.2014.03.056}, author = {Jensen, Paul N and Gronroos, Noelle N and Chen, Lin Y and Folsom, Aaron R and deFilippi, Chris and Heckbert, Susan R and Alonso, Alvaro} } @article {6210, title = {The influence of sex on cardiovascular outcomes associated with diabetes among older black and white adults.}, journal = {J Diabetes Complications}, volume = {28}, year = {2014}, month = {2014 May-Jun}, pages = {316-22}, abstract = {

AIMS: It is unknown whether sex differences in the association of diabetes with cardiovascular outcomes vary by race. We examined sex differences in the associations of diabetes with incident congestive heart failure (CHF) and coronary heart disease (CHD) between older black and white adults.

METHODS: We analyzed data from the Cardiovascular Health Study (CHS), a prospective cohort study of community-dwelling individuals aged >=65 from four US counties. We included 4817 participants (476 black women, 279 black men, 2447 white women and 1625 white men). We estimated event rates and multivariate-adjusted hazard ratios for incident CHF, CHD, and all-cause mortality by Cox regression and competing risk analyses.

RESULTS: Over a median follow-up of 12.5years, diabetes was more strongly associated with CHF among black women (HR, 2.42 [95\% CI, 1.70-3.40]) than black men (1.39 [0.83-2.34]); this finding did not reach statistical significance (P for interaction=0.08). Female sex conferred a higher risk for a composite outcome of CHF and CHD among black participants (2.44 [1.82-3.26]) vs. (1.44 [0.97-2.12]), P for interaction=0.03). There were no significant sex differences in the HRs associated with diabetes for CHF among whites, or for CHD or all-cause mortality among blacks or whites. The three-way interaction between sex, race, and diabetes on risk of cardiovascular outcomes was not significant (P=0.07).

CONCLUSIONS: Overall, sex did not modify the cardiovascular risk associated with diabetes among older black or white adults. However, our results suggest that a possible sex interaction among older blacks merits further study.

}, keywords = {African Continental Ancestry Group, Age Factors, Aged, Aged, 80 and over, Cohort Studies, Coronary Disease, Diabetes Complications, European Continental Ancestry Group, Female, Heart Failure, Humans, Incidence, Longitudinal Studies, Male, Prospective Studies, Regression Analysis, Retrospective Studies, Risk Factors, Sex Factors, Survival Rate}, issn = {1873-460X}, doi = {10.1016/j.jdiacomp.2013.12.004}, author = {Vimalananda, Varsha G and Biggs, Mary L and Rosenzweig, James L and Carnethon, Mercedes R and Meigs, James B and Thacker, Evan L and Siscovick, David S and Mukamal, Kenneth J} } @article {6600, title = {Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.}, journal = {Circulation}, volume = {130}, year = {2014}, month = {2014 Oct 7}, pages = {1225-35}, abstract = {

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.

METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95\% confidence interval [CI], 1.13-1.23; P=6.5{\texttimes}10(-16)), GJA1 (rs13216675; RR=1.10; 95\% CI, 1.06-1.14; P=2.2{\texttimes}10(-8)), TBX5 (rs10507248; RR=1.12; 95\% CI, 1.08-1.16; P=5.7{\texttimes}10(-11)), and CAND2 (rs4642101; RR=1.10; 95\% CI, 1.06-1.14; P=9.8{\texttimes}10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95\% CI, 1.26-1.39; P=2.0{\texttimes}10(-25)) and CUX2 (rs6490029; RR=1.12; 95\% CI, 1.08-1.16; P=3.9{\texttimes}10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6{\texttimes}10(-19)), GJA1 (P=2.66{\texttimes}10(-6)), and TBX5 (P=1.36{\texttimes}10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17\% and 45\%, respectively).

CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

}, keywords = {Aged, Animals, Atrial Fibrillation, Chromosome Mapping, Connexin 43, Europe, Female, Gene Knockdown Techniques, Genetic Loci, Genetic Predisposition to Disease, Genotype, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Muscle Proteins, Nuclear Proteins, Quantitative Trait Loci, Repressor Proteins, T-Box Domain Proteins, Transcription Factors, Ubiquitin-Protein Ligases, Zebrafish, Zebrafish Proteins}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.114.009892}, author = {Sinner, Moritz F and Tucker, Nathan R and Lunetta, Kathryn L and Ozaki, Kouichi and Smith, J Gustav and Trompet, Stella and Bis, Joshua C and Lin, Honghuang and Chung, Mina K and Nielsen, Jonas B and Lubitz, Steven A and Krijthe, Bouwe P and Magnani, Jared W and Ye, Jiangchuan and Gollob, Michael H and Tsunoda, Tatsuhiko and M{\"u}ller-Nurasyid, Martina and Lichtner, Peter and Peters, Annette and Dolmatova, Elena and Kubo, Michiaki and Smith, Jonathan D and Psaty, Bruce M and Smith, Nicholas L and Jukema, J Wouter and Chasman, Daniel I and Albert, Christine M and Ebana, Yusuke and Furukawa, Tetsushi and Macfarlane, Peter W and Harris, Tamara B and Darbar, Dawood and D{\"o}rr, Marcus and Holst, Anders G and Svendsen, Jesper H and Hofman, Albert and Uitterlinden, Andr{\'e} G and Gudnason, Vilmundur and Isobe, Mitsuaki and Malik, Rainer and Dichgans, Martin and Rosand, Jonathan and Van Wagoner, David R and Benjamin, Emelia J and Milan, David J and Melander, Olle and Heckbert, Susan R and Ford, Ian and Liu, Yongmei and Barnard, John and Olesen, Morten S and Stricker, Bruno H C and Tanaka, Toshihiro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T} } @article {6772, title = {Impact of gait speed and instrumental activities of daily living on all-cause mortality in adults >=65~years with heart failure.}, journal = {Am J Cardiol}, volume = {115}, year = {2015}, month = {2015 Mar 15}, pages = {797-801}, abstract = {

Mobility and function are important predictors of survival. However, their combined impact on mortality in adults >=65 years with heart failure (HF) is not well understood. This study examined the role of gait speed and instrumental activities of daily living (IADL) in all-cause mortality in a cohort of 1,119 community-dwelling Cardiovascular Health Study participants >=65 years with incident HF. Data on HF and mortality were collected through annual examinations or contact during the 10-year follow-up period. Slower gait speed (<0.8 m/s vs >=0.8 m/s) and IADL impairment (>=1 vs 0 areas of dependence) were determined from baseline and follow-up assessments. A total of 740 (66\%) of the 1,119 participants died during the follow-up period. Multivariate Cox proportional hazards models showed that impairments in either gait speed (hazard ratio 1.37, 95\% confidence interval 1.10 to 1.70; p = 0.004) or IADL (hazard ratio 1.56, 95\% confidence interval 1.29-1.89; p <0.001), measured within 1 year before the diagnosis of incident HF, were independently associated with mortality, adjusting for sociodemographic and clinical characteristics. The combined presence of slower gait speed and IADL impairment was associated with a greater risk of mortality and suggested an additive relation between gait speed and IADL. In conclusion, gait speed and IADL are important risk factors for mortality in adults >=65 years with HF, but the combined impairments of both gait speed and IADL can have an especially important impact on mortality.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Early Diagnosis, Female, Follow-Up Studies, Gait, Geriatric Assessment, Heart Failure, Humans, Male, Odds Ratio, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Sensitivity and Specificity, Survival Analysis, United States, Walking}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2014.12.044}, author = {Lo, Alexander X and Donnelly, John P and McGwin, Gerald and Bittner, Vera and Ahmed, Ali and Brown, Cynthia J} } @article {6860, title = {Integrative pathway genomics of lung function and airflow obstruction.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Dec 1}, pages = {6836-48}, abstract = {

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10{\textquoteright}s role in influencing lung{\textquoteright}s susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

}, keywords = {Airway Obstruction, Animals, Cell Proliferation, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Immune System, Lung, Male, Metabolic Networks and Pathways, Mice, Phenotype, Polymorphism, Single Nucleotide, Signal Transduction}, issn = {1460-2083}, doi = {10.1093/hmg/ddv378}, author = {Gharib, Sina A and Loth, Daan W and Soler Artigas, Maria and Birkland, Timothy P and Wilk, Jemma B and Wain, Louise V and Brody, Jennifer A and Obeidat, Ma{\textquoteright}en and Hancock, Dana B and Tang, Wenbo and Rawal, Rajesh and Boezen, H Marike and Imboden, Medea and Huffman, Jennifer E and Lahousse, Lies and Alves, Alexessander C and Manichaikul, Ani and Hui, Jennie and Morrison, Alanna C and Ramasamy, Adaikalavan and Smith, Albert Vernon and Gudnason, Vilmundur and Surakka, Ida and Vitart, Veronique and Evans, David M and Strachan, David P and Deary, Ian J and Hofman, Albert and Gl{\"a}ser, Sven and Wilson, James F and North, Kari E and Zhao, Jing Hua and Heckbert, Susan R and Jarvis, Deborah L and Probst-Hensch, Nicole and Schulz, Holger and Barr, R Graham and Jarvelin, Marjo-Riitta and O{\textquoteright}Connor, George T and K{\"a}h{\"o}nen, Mika and Cassano, Patricia A and Hysi, Pirro G and Dupuis, Jos{\'e}e and Hayward, Caroline and Psaty, Bruce M and Hall, Ian P and Parks, William C and Tobin, Martin D and London, Stephanie J} } @article {6808, title = {Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults.}, journal = {Am Heart J}, volume = {170}, year = {2015}, month = {2015 Aug}, pages = {306-12}, abstract = {

BACKGROUND: Pneumonia is associated with high risk of heart failure (HF) in the short term (30 days) postinfection. Whether this association persists beyond this period is unknown.

METHODS: We studied 5,613 elderly (>=65 years) adults enrolled in the Cardiovascular Health Study between 1989 and 1994 at 4 US communities. Participants had no clinical diagnosis of HF at enrollment, and they were followed up through December 2010. Hospitalizations for pneumonia were identified using validated International Classification of Disease Ninth Revision codes. A centralized committee adjudicated new-onset HF events. Using Cox regression, we estimated adjusted hazard ratios (HRs) of new-onset HF at different time intervals after hospitalization for pneumonia.

RESULTS: A total of 652 participants hospitalized for pneumonia during follow-up were still alive and free of clinical diagnosis of HF by day 30 posthospitalization. Relative to the time of their hospitalization, new-onset HF occurred in 22 cases between 31 and 90 days (HR 6.9, 95\% CI 4.46-10.63, P < .001), 14 cases between 91 days and 6 months (HR 3.2, 95\% CI 1.88-5.50, P < .001), 20 cases between 6 months and 1 year (HR 2.6, 95\% CI 1.64-4.04, P < .001), 76 cases between 1 and 5 years (HR 1.7, 95\% CI 1.30-2.12, P < .001), and 71 cases after 5 years (HR 2.0, 95\% CI 1.56-2.58, P < .001). Results were robust to sensitivity analyses using stringent definitions of pneumonia and extreme assumptions for potential informative censoring.

CONCLUSION: Hospitalization for pneumonia is associated with increased risk of new-onset HF in the intermediate and long term. Studies should characterize the mechanisms of this association in order to prevent HF in elderly pneumonia survivors.

}, keywords = {Aged, Disease Progression, Female, Follow-Up Studies, Forecasting, Heart Failure, Hospitalization, Humans, Incidence, Inpatients, Male, Patient Readmission, Pneumonia, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors}, issn = {1097-6744}, doi = {10.1016/j.ahj.2015.04.028}, author = {Corrales-Medina, Vicente F and Taljaard, Monica and Yende, Sachin and Kronmal, Richard and Dwivedi, Girish and Newman, Anne B and Elkind, Mitchell S V and Lyles, Mary F and Chirinos, Julio A} } @article {7166, title = {Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.}, journal = {Am Heart J}, volume = {175}, year = {2016}, month = {2016 May}, pages = {9-17}, abstract = {

BACKGROUND: Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier status of 9 AF-associated SNPs on the efficacy of RAS inhibition for the primary prevention of AF.

METHODS: We performed SNP-RAS inhibitor interaction testing with unadjusted and adjusted Cox proportional hazards models using a discovery (Cardiovascular Health Study) and a replication (Atherosclerosis Risk in Communities) cohort. Additive genetic models were used for the SNP analyses, and 2-tailed P values <.05 were considered statistically significant.

RESULTS: Among 2,796 Cardiovascular Health Study participants, none of the 9 a priori identified candidate SNPs exhibited a significant SNP-drug interaction. Two of the 9 SNPs, rs2106261 (16q22) and rs6666258 (1q21), revealed interaction relationships that neared statistical significance (with point estimates in the same direction for angiotensin-converting enzyme inhibitor only and angiotensin II receptor blocker only analyses), but neither association could be replicated among 8,604 participants in Atherosclerosis Risk in Communities.

CONCLUSIONS: Our study failed to identify AF-associated SNP genetic subtypes of AF that derive increased benefit from upstream RAS inhibition for AF prevention. Future studies should continue to investigate the impact of genotype on the response to AF treatment strategies in an effort to develop personalized approaches to therapy and prevention.

}, issn = {1097-6744}, doi = {10.1016/j.ahj.2016.02.002}, author = {Roberts, Jason D and Dewland, Thomas A and Glidden, David V and Hoffmann, Thomas J and Arking, Dan E and Chen, Lin Y and Psaty, Bruce M and Olgin, Jeffrey E and Alonso, Alvaro and Heckbert, Susan R and Marcus, Gregory M} } @article {7002, title = {Incident Atrial Fibrillation and Disability-Free Survival in the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Apr}, pages = {838-43}, abstract = {

OBJECTIVES: To assess the associations between incident atrial fibrillation (AF) and disability-free survival and risk of disability.

DESIGN: Prospective cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older and enrolled in fee-for-service Medicare followed between 1991 and 2009 (MN = 4,046). Individuals with prevalent AF, activity of daily living (ADL) disability, or a history of stroke or heart failure at baseline were excluded.

MEASUREMENTS: Incident AF was identified according to annual study electrocardiogram, hospital discharge diagnosis, or Medicare claims. Disability-free survival was defined as survival free of ADL disability (any difficulty or inability in bathing, dressing, eating, using the toilet, walking around the home, or getting out of a bed or chair). ADLs were assessed at annual study visits or in a telephone interview. Association between incident AF and disability-free survival or risk of disability was estimated using Cox proportional hazards models.

RESULTS: Over an average of 7.0 years of follow-up, 660 individuals (16.3\%) developed incident AF, and 3,112 (77\%) became disabled or died. Incident AF was associated with shorter disability-free survival (hazard ratio (HR) for death or ADL disability = 1.71, 95\% confidence interval (CI) = 1.55-1.90) and a higher risk of ADL disability (HR = 1.36, 95\% CI = 1.18-1.58) than in individuals with no history of AF. This association persisted after adjustment for interim stroke and heart failure.

CONCLUSION: These results suggest that AF is a risk factor for shorter functional longevity in older adults, independent of other risk factors and comorbid conditions.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Atrial Fibrillation, Disability Evaluation, Electrocardiography, Female, Geriatric Assessment, Humans, Incidence, Longevity, Longitudinal Studies, Male, Medicare, Prevalence, Prospective Studies, Survival Rate, United States}, issn = {1532-5415}, doi = {10.1111/jgs.14037}, author = {Wallace, Erin R and Siscovick, David S and Sitlani, Colleen M and Dublin, Sascha and Mitchell, Pamela H and Odden, Michelle C and Hirsch, Calvin H and Thielke, Stephen and Heckbert, Susan R} } @article {6612, title = {Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration.}, journal = {Eur J Prev Cardiol}, volume = {23}, year = {2016}, month = {2016 Jan}, pages = {194-205}, abstract = {

BACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.

METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.

RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). {\textquoteright}Inflammatory load{\textquoteright}, defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest {\textquoteright}inflammatory load{\textquoteright} had a greater CCA-IMT progression (p = 0.015).

CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for {\textquoteright}inflammatory load{\textquoteright} suggest important combined effects of the three inflammatory markers on early atherosclerosis.

}, issn = {2047-4881}, doi = {10.1177/2047487314560664}, author = {Willeit, Peter and Thompson, Simon G and Agewall, Stefan and Bergstr{\"o}m, G{\"o}ran and Bickel, Horst and Catapano, Alberico L and Chien, Kuo-Liong and de Groot, Eric and Empana, Jean-Philippe and Etgen, Thorleif and Franco, Oscar H and Iglseder, Bernhard and Johnsen, Stein H and Kavousi, Maryam and Lind, Lars and Liu, Jing and Mathiesen, Ellisiv B and Norata, Giuseppe D and Olsen, Michael H and Papagianni, Aikaterini and Poppert, Holger and Price, Jackie F and Sacco, Ralph L and Yanez, David N and Zhao, Dong and Schminke, Ulf and B{\"u}lb{\"u}l, Alpaslan and Polak, Joseph F and Sitzer, Matthias and Hofman, Albert and Grigore, Liliana and D{\"o}rr, Marcus and Su, Ta-Chen and Ducimetiere, Pierre and Xie, Wuxiang and Ronkainen, Kimmo and Kiechl, Stefan and Rundek, Tatjana and Robertson, Christine and Fagerberg, Bj{\"o}rn and Bokemark, Lena and Steinmetz, Helmuth and Ikram, M Arfan and V{\"o}lzke, Henry and Lin, Hung-Ju and Plichart, Matthieu and Tuomainen, Tomi-Pekka and Desvarieux, Mo{\"\i}se and McLachlan, Stela and Schmidt, Caroline and Kauhanen, Jussi and Willeit, Johann and Lorenz, Matthias W and Sander, Dirk} } @article {7258, title = {Insulinlike growth factor binding protein-1 and ghrelin predict health outcomes among older adults: CHS cohort.}, journal = {J Clin Endocrinol Metab}, year = {2016}, month = {2016 Nov 07}, pages = {jc20162779}, abstract = {

CONTEXT: Multiple diseases may explain the association of the growth hormone / insulinlike growth factor-I (GH/IGF-I) axis with longevity.

OBJECTIVE: To relate circulating GH/IGF-I system protein levels with major health events.

DESIGN: Cohort study Setting: Four US communities Participants: Adults (n=2268) 65 years and older free of diabetes and cardiovascular disease.

MEASUREMENTS: We assessed insulinlike growth factor binding protein-1 (IGFBP-1) and ghrelin in fasting and 2-hour oral glucose tolerance test (OGTT) blood samples, as well as fasting IGF-I and IGFBP-3. Hazard ratios for mortality and a composite outcome for first incident myocardial infarction, stroke, heart failure, hip fracture, or death were adjusted for sociodemographic, behavioral, and physiologic covariates.

RESULTS: During 13,930 person-years of follow-up, 48.1\% individuals sustained one or more components of the composite outcome and 31.8\% died. Versus the lowest quartiles, the highest quartiles of fasting and 2-h ghrelin were associated with a 27\% higher (95\% CI: 6\%, 53\%) and 39\% higher (95\% CI: 14\%, 71\%) risks of the composite outcome, respectively. The highest quartile of 2-h IGFBP-1 was associated with 35\% higher (95\% CI: 1\%, 52\%) risk of the composite endpoint. Similarly, higher mortality was significantly associated with higher fasting and 2-h ghrelin level, and with 2-h IGFBP-1 level. When examined together, 2-h post-OGTT levels of IGFBP-1 and ghrelin tended to predict outcomes better than fasting levels.

CONCLUSIONS: Circulating IGFBP-1 and ghrelin measured during an OGTT predict major health events and death in older adults, which may explain the influence of the GH-IGF-axis on lifespan and health.

}, issn = {1945-7197}, doi = {10.1210/jc.2016-2779}, author = {Kaplan, Robert C and Strizich, Garrett and Aneke-Nash, Chino and Dominguez-Islas, Clara and B{\r u}zkov{\'a}, Petra and Strickler, Howard and Rohan, Thomas and Pollak, Michael and Kuller, Lewis and Kizer, Jorge R and Cappola, Anne and Li, Christopher I and Psaty, Bruce M and Newman, Anne} } @article {6951, title = {Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Am J Clin Nutr}, volume = {103}, year = {2016}, month = {2016 Feb}, pages = {567-78}, abstract = {

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 {\texttimes} 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84\%, P = 3.51 {\texttimes} 10(18)) and lower circulating EPA (β = -1.46\%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83\%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

}, keywords = {Apolipoproteins E, ATP Binding Cassette Transporter 1, Cholesterol, HDL, Cohort Studies, Diet, DNA Methylation, Eicosapentaenoic Acid, Epigenesis, Genetic, Fatty Acids, Gene Expression Regulation, Humans, Lipids, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.115.112987}, author = {Ma, Yiyi and Follis, Jack L and Smith, Caren E and Tanaka, Toshiko and Manichaikul, Ani W and Chu, Audrey Y and Samieri, Cecilia and Zhou, Xia and Guan, Weihua and Wang, Lu and Biggs, Mary L and Chen, Yii-der I and Hernandez, Dena G and Borecki, Ingrid and Chasman, Daniel I and Rich, Stephen S and Ferrucci, Luigi and Irvin, Marguerite Ryan and Aslibekyan, Stella and Zhi, Degui and Tiwari, Hemant K and Claas, Steven A and Sha, Jin and Kabagambe, Edmond K and Lai, Chao-Qiang and Parnell, Laurence D and Lee, Yu-Chi and Amouyel, Philippe and Lambert, Jean-Charles and Psaty, Bruce M and King, Irena B and Mozaffarian, Dariush and McKnight, Barbara and Bandinelli, Stefania and Tsai, Michael Y and Ridker, Paul M and Ding, Jingzhong and Mstat, Kurt Lohmant and Liu, Yongmei and Sotoodehnia, Nona and Barberger-Gateau, Pascale and Steffen, Lyn M and Siscovick, David S and Absher, Devin and Arnett, Donna K and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {7546, title = {Identifying risk for type 2 diabetes in different age cohorts: does one size fit all?}, journal = {BMJ Open Diabetes Res Care}, volume = {5}, year = {2017}, month = {2017}, pages = {e000447}, abstract = {

Objective: To estimate age-specific risk equations for type 2 diabetes onset in young, middle-aged, and older US adults, and to compare the performance of simple equations based on readily available demographic information alone, against enhanced equations that require both demographic and clinical information (fasting plasma glucose, high-density lipoprotein, and triglyceride levels).

Research design and methods: We estimated the probability of developing diabetes by age group using data from the Coronary Artery Risk Development in Young Adults (for ages 18-40 years), Atherosclerosis Risk in Communities (for ages 45-64 years), and the Cardiovascular Health Study (for ages 65 years and older). Simple and enhanced equations were estimated using logistic regression models, and performance was compared by age group. Thresholds based on these risk equations were evaluated using split-sample bootstraps and calibrating the constant of one age cohort to others.

Results: Simple risk equations had an area under the receiver-operating curve (AUROC) of 0.72, 0.79, 0.75, and 0.69 for age groups 18-30, 28-40, 45-64, and 65 and older, respectively. The corresponding AUROCs for enhanced equations were 0.75, 0.85, 0.85, and 0.81. Risk equations based on younger populations, when applied to older cohorts, underpredict diabetes incidence and risk. Conversely, risk equations based on older populations overpredict the likelihood of diabetes in younger cohorts.

Conclusions: In general, risk equations are more successful in middle-aged adults than in young and old populations. The results demonstrate the importance of applying age-specific risk equations to identify target populations for intervention. While the predictive capacity of equations that include biomarkers is better than of those based solely on self-reported variables, biomarkers are more important in older populations than in younger ones.

}, issn = {2052-4897}, doi = {10.1136/bmjdrc-2017-000447}, author = {Alva, Maria L and Hoerger, Thomas J and Zhang, Ping and Gregg, Edward W} } @article {7596, title = {Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.}, journal = {PLoS Med}, volume = {14}, year = {2017}, month = {2017 Sep}, pages = {e1002383}, abstract = {

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS \& FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95\% CI 1.04-1.06, per HbA1c-raising allele, p = 3 {\texttimes} 10-29); whereas GS-E was not (OR = 1.00, 95\% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11\%) was associated with an absolute decrease in HbA1c of 0.81\%-units (95\% CI 0.66-0.96) per allele in hemizygous men, and 0.68\%-units (95\% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2\% (N = 0.65 million, 95\% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

}, keywords = {Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Phenotype, Risk}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002383}, author = {Wheeler, Eleanor and Leong, Aaron and Liu, Ching-Ti and Hivert, Marie-France and Strawbridge, Rona J and Podmore, Clara and Li, Man and Yao, Jie and Sim, Xueling and Hong, Jaeyoung and Chu, Audrey Y and Zhang, Weihua and Wang, Xu and Chen, Peng and Maruthur, Nisa M and Porneala, Bianca C and Sharp, Stephen J and Jia, Yucheng and Kabagambe, Edmond K and Chang, Li-Ching and Chen, Wei-Min and Elks, Cathy E and Evans, Daniel S and Fan, Qiao and Giulianini, Franco and Go, Min Jin and Hottenga, Jouke-Jan and Hu, Yao and Jackson, Anne U and Kanoni, Stavroula and Kim, Young Jin and Kleber, Marcus E and Ladenvall, Claes and Lecoeur, C{\'e}cile and Lim, Sing-Hui and Lu, Yingchang and Mahajan, Anubha and Marzi, Carola and Nalls, Mike A and Navarro, Pau and Nolte, Ilja M and Rose, Lynda M and Rybin, Denis V and Sanna, Serena and Shi, Yuan and Stram, Daniel O and Takeuchi, Fumihiko and Tan, Shu Pei and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Wong, Andrew and Yengo, Loic and Zhao, Wanting and Goel, Anuj and Martinez Larrad, Maria Teresa and Radke, D{\"o}rte and Salo, Perttu and Tanaka, Toshiko and van Iperen, Erik P A and Abecasis, Goncalo and Afaq, Saima and Alizadeh, Behrooz Z and Bertoni, Alain G and Bonnefond, Am{\'e}lie and B{\"o}ttcher, Yvonne and Bottinger, Erwin P and Campbell, Harry and Carlson, Olga D and Chen, Chien-Hsiun and Cho, Yoon Shin and Garvey, W Timothy and Gieger, Christian and Goodarzi, Mark O and Grallert, Harald and Hamsten, Anders and Hartman, Catharina A and Herder, Christian and Hsiung, Chao Agnes and Huang, Jie and Igase, Michiya and Isono, Masato and Katsuya, Tomohiro and Khor, Chiea-Chuen and Kiess, Wieland and Kohara, Katsuhiko and Kovacs, Peter and Lee, Juyoung and Lee, Wen-Jane and Lehne, Benjamin and Li, Huaixing and Liu, Jianjun and Lobbens, Stephane and Luan, Jian{\textquoteright}an and Lyssenko, Valeriya and Meitinger, Thomas and Miki, Tetsuro and Miljkovic, Iva and Moon, Sanghoon and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nauck, Matthias and Pankow, James S and Polasek, Ozren and Prokopenko, Inga and Ramos, Paula S and Rasmussen-Torvik, Laura and Rathmann, Wolfgang and Rich, Stephen S and Robertson, Neil R and Roden, Michael and Roussel, Ronan and Rudan, Igor and Scott, Robert A and Scott, William R and Sennblad, Bengt and Siscovick, David S and Strauch, Konstantin and Sun, Liang and Swertz, Morris and Tajuddin, Salman M and Taylor, Kent D and Teo, Yik-Ying and Tham, Yih Chung and T{\"o}njes, Anke and Wareham, Nicholas J and Willemsen, Gonneke and Wilsgaard, Tom and Hingorani, Aroon D and Egan, Josephine and Ferrucci, Luigi and Hovingh, G Kees and Jula, Antti and Kivimaki, Mika and Kumari, Meena and Nj{\o}lstad, Inger and Palmer, Colin N A and Serrano R{\'\i}os, Manuel and Stumvoll, Michael and Watkins, Hugh and Aung, Tin and Bl{\"u}her, Matthias and Boehnke, Michael and Boomsma, Dorret I and Bornstein, Stefan R and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chen, Yduan-Tsong and Cheng, Ching-Yu and Cucca, Francesco and de Geus, Eco J C and Deloukas, Panos and Evans, Michele K and Fornage, Myriam and Friedlander, Yechiel and Froguel, Philippe and Groop, Leif and Gross, Myron D and Harris, Tamara B and Hayward, Caroline and Heng, Chew-Kiat and Ingelsson, Erik and Kato, Norihiro and Kim, Bong-Jo and Koh, Woon-Puay and Kooner, Jaspal S and K{\"o}rner, Antje and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lin, Xu and Liu, Yongmei and Loos, Ruth J F and Magnusson, Patrik K E and M{\"a}rz, Winfried and McCarthy, Mark I and Oldehinkel, Albertine J and Ong, Ken K and Pedersen, Nancy L and Pereira, Mark A and Peters, Annette and Ridker, Paul M and Sabanayagam, Charumathi and Sale, Michele and Saleheen, Danish and Saltevo, Juha and Schwarz, Peter Eh and Sheu, Wayne H H and Snieder, Harold and Spector, Timothy D and Tabara, Yasuharu and Tuomilehto, Jaakko and van Dam, Rob M and Wilson, James G and Wilson, James F and Wolffenbuttel, Bruce H R and Wong, Tien Yin and Wu, Jer-Yuarn and Yuan, Jian-Min and Zonderman, Alan B and Soranzo, Nicole and Guo, Xiuqing and Roberts, David J and Florez, Jose C and Sladek, Robert and Dupuis, Jos{\'e}e and Morris, Andrew P and Tai, E-Shyong and Selvin, Elizabeth and Rotter, Jerome I and Langenberg, Claudia and Barroso, In{\^e}s and Meigs, James B} } @article {7365, title = {Incident atrial fibrillation and the risk of fracture in the cardiovascular health study.}, journal = {Osteoporos Int}, volume = {28}, year = {2017}, month = {2017 Feb}, pages = {719-725}, abstract = {

In this prospective cohort of 4462 older adults, incident atrial fibrillation (AF) was not statistically significantly associated with subsequent risk of incident fracture.

INTRODUCTION: AF is associated with stroke, heart failure, dementia, and death, but its association with fracture is unknown. Therefore, we examined the association of incident AF with the risk of subsequent fracture in the Cardiovascular Health Study (CHS) cohort.

METHODS: Of the CHS participants aged >=65~years, 4462 were followed between 1991 and 2009, mean follow-up 8.8~years. Incident AF was identified by annual study electrocardiogram (ECG), hospital discharge diagnosis codes, or Medicare claims. Fractures of the hip, distal forearm, humerus, or pelvis were identified using hospital discharge diagnosis codes or Medicare claims. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95~\% confidence intervals (CIs) for the association between incident AF (time-varying) and the risk of subsequent fracture. We also evaluated whether AF was associated with risk of sustaining a fall.

RESULTS: Crude incident fracture rate was 22.9 per 1000 person-years in participants with AF and 17.7 per 1000 person-years in participants without AF. Individuals with incident AF were not at significantly higher risk of hip fracture (adjusted HR~=~1.09, 95~\% CI 0.83-1.42) or fracture at any selected site (adjusted HR~=~0.97, 95~\% CI 0.77-1.22) or risk of sustaining a fall (adjusted HR~=~1.00, 95~\% CI~=~0.87-1.16) compared with those without AF.

CONCLUSION: In this cohort of older, community-dwelling adults, incident AF was not shown to be associated with falls or hip or other fractures.

}, issn = {1433-2965}, doi = {10.1007/s00198-016-3778-1}, author = {Wallace, E R and Siscovick, D S and Sitlani, C M and Dublin, S and Mitchell, P and Robbins, J A and Fink, H A and Cauley, J A and B{\r u}{\v z}kov{\'a}, P and Carbone, L and Chen, Z and Heckbert, S R} } @article {7799, title = {Impact of lung-function measures on cardiovascular disease events in older adults with metabolic syndrome and diabetes.}, journal = {Clin Cardiol}, volume = {41}, year = {2018}, month = {2018 Jul}, pages = {959-965}, abstract = {

BACKGROUND: Individuals with metabolic syndrome (MetS) and diabetes (DM) are more likely to have decreased lung function and are at greater risk of cardiovascular disease (CVD).

HYPOTHESIS: Lung-function measures can predict CVD events in older persons with MetS, DM, and neither condition.

METHODS: We followed 4114 participants age >= 65 years with and without MetS or DM in the Cardiovascular Health Study. Cox regression examined the association of forced vital capacity (FVC) and 1-second forced expiratory volume (FEV ; percent of predicted values) with incident coronary heart disease and CVD events over 12.9 years.

RESULTS: DM was present in 537 (13.1\%) and MetS in 1277 (31.0\%) participants. Comparing fourth vs first quartiles for FVC, risk of CVD events was 16\% (HR: 0.84, 95\% CI: 0.59-1.18), 23\% (HR: 0.77, 95\% CI: 0.60-0.99), and 30\% (HR: 0.70, 95\% CI: 0.58-0.84) lower in DM, MetS, and neither disease groups, respectively. For FEV , CVD risk was lower by 2\% (HR: 0.98, 95\% CI: 0.70-1.37), 26\% (HR: 0.74, 95\% CI: 0.59-0.93), and 31\% (HR: 0.69, 95\% CI: 0.57-0.82) in DM. Findings were strongest for predicting congestive heart failure (CHF) in all disease groups. C-statistics increased significantly with addition of FEV or FVC over risk factors for CVD and CHF among those with neither MetS nor DM.

CONCLUSIONS: FEV and FVC are inversely related to CVD in older adults with and without MetS, but not DM (except for CHF); however, their value in incremental risk prediction beyond standard risk factors is limited mainly to metabolically healthier persons.

}, issn = {1932-8737}, doi = {10.1002/clc.22985}, author = {Lee, Hwa Mu and Zhao, Yanglu and Liu, Michael A and Yanez, David and Carnethon, Mercedes and Graham Barr, R and Wong, Nathan D} } @article {8531, title = {{The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE)}, journal = {PLoS One}, volume = {14}, year = {2019}, pages = {e0219668}, abstract = {Apolipoprotein E is a glycoprotein best known as a mediator and regulator of lipid transport and uptake. The APOE-{\^I}{\textmu}4 allele has long been associated with increased risks of Alzheimer{\textquoteright}s disease and mortality, but the effect of the less prevalent APOE-{\^I}{\textmu}2 allele on diseases in the elderly and survival remains elusive.\ We aggregated data of 38,537 individuals of European ancestry (mean age 65.5 years; 55.6\% women) from six population-based cohort studies (Rotterdam Study, AGES-Reykjavik Study, Cardiovascular Health Study, Health-ABC Study, and the family-based Framingham Heart Study and Long Life Family Study) to determine the association of APOE, and in particular APOE-{\^I}{\textmu}2, with survival in the population.\ During a mean follow-up of 11.7 years, 17,021 individuals died. Compared with homozygous APOE-{\^I}{\textmu}3 carriers, APOE-{\^I}{\textmu}2 carriers were at lower risk of death (hazard ratio,95\% confidence interval: 0.94,0.90-0.99; P = 1.1*10-2), whereas APOE-{\^I}{\textmu}4 carriers were at increased risk of death (HR 1.17,1.12-1.21; P = 2.8*10-16). APOE was associated with mortality risk in a dose-dependent manner, with risk estimates lowest for homozygous APOE-{\^I}{\textmu}2 (HR 0.89,0.74-1.08), and highest for homozygous APOE-{\^I}{\textmu}4 (HR 1.52,1.37-1.70). After censoring for dementia, effect estimates remained similar for APOE-{\^I}{\textmu}2 (HR 0.95,0.90-1.01), but attenuated for APOE-{\^I}{\textmu}4 (HR 1.07,1.01-1.12). Results were broadly similar across cohorts, and did not differ by age or sex. APOE genotype was associated with baseline lipid fractions (e.g. mean difference(95\%CI) in LDL(mg/dL) for {\^I}{\textmu}2 versus {\^I}{\textmu}33: -17.1(-18.1-16.0), and {\^I}{\textmu}4 versus {\^I}{\textmu}33: +5.7(4.8;6.5)), but the association between APOE and mortality was unaltered after adjustment for baseline LDL or cardiovascular disease. Given the European ancestry of the study population, results may not apply to other ethnicities.\ Compared with APOE-{\^I}{\textmu}3, APOE-{\^I}{\textmu}2 is associated with prolonged survival, whereas mortality risk is increased for APOE-{\^I}{\textmu}4 carriers. Further collaborative efforts are needed to unravel the role of APOE and in particular APOE-{\^I}{\textmu}2 in health and disease.}, author = {Wolters, F. J. and Yang, Q. and Biggs, M. L. and Jakobsdottir, J. and Li, S. and Evans, D. S. and Bis, J. C. and Harris, T. B. and Vasan, R. S. and Zilhao, N. R. and Ghanbari, M. and Ikram, M. A. and Launer, L. and Psaty, B. M. and Tranah, G. J. and Kulminski, A. M. and Gudnason, V. and Seshadri, S.} } @article {8525, title = {{The impact of both spousal caregivers{\textquoteright} and care recipients{\textquoteright} health on relationship satisfaction in the Caregiver Health Effects Study}, journal = {J Health Psychol}, volume = {24}, year = {2019}, month = {10}, pages = {1744{\textendash}1755}, abstract = {This study examined, with a sample of older adult, caregiving couples, whether each spouse{\textquoteright}s health was associated with their own and their partner{\textquoteright}s relationship satisfaction. Dyads (n = 233; age = 64-99 years) in the Caregiver Health Effects Study, ancillary to the Cardiovascular Health Study, reported relationship satisfaction, depressive symptoms, disability, and self-reported health. The cross-sectional Actor-Partner Interdependence Model showed that for both caregivers and care recipients, greater depressive symptoms and lower self-reported health related to lower relationship satisfaction (actor effects). Caregivers had lower relationship satisfaction when they were more disabled (actor effect) and when care recipients were more depressed (partner effect).}, author = {Monin, J. K. and Levy, B. and Doyle, M. and Schulz, R. and Kershaw, T.} } @article {8205, title = {Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Oct 03}, pages = {706-718}, abstract = {

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12\% in African-Americans, MAF = 2\% in Hispanics) lowered HbA1c (-0.88\% in hemizygous males, -0.34\% in heterozygous females) and explained 23\% of HbA1c variance in African-Americans and 4\% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5\%; -0.98\% in hemizygous males, -0.46\% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.08.010}, author = {Sarnowski, Chloe and Leong, Aaron and Raffield, Laura M and Wu, Peitao and de Vries, Paul S and DiCorpo, Daniel and Guo, Xiuqing and Xu, Huichun and Liu, Yongmei and Zheng, Xiuwen and Hu, Yao and Brody, Jennifer A and Goodarzi, Mark O and Hidalgo, Bertha A and Highland, Heather M and Jain, Deepti and Liu, Ching-Ti and Naik, Rakhi P and O{\textquoteright}Connell, Jeffrey R and Perry, James A and Porneala, Bianca C and Selvin, Elizabeth and Wessel, Jennifer and Psaty, Bruce M and Curran, Joanne E and Peralta, Juan M and Blangero, John and Kooperberg, Charles and Mathias, Rasika and Johnson, Andrew D and Reiner, Alexander P and Mitchell, Braxton D and Cupples, L Adrienne and Vasan, Ramachandran S and Correa, Adolfo and Morrison, Alanna C and Boerwinkle, Eric and Rotter, Jerome I and Rich, Stephen S and Manning, Alisa K and Dupuis, Jos{\'e}e and Meigs, James B} } @article {8405, title = {Incorporating sampling weights into robust estimation of Cox proportional hazards regression model, with illustration in the Multi-Ethnic Study of Atherosclerosis.}, journal = {BMC Med Res Methodol}, volume = {20}, year = {2020}, month = {2020 03 14}, pages = {62}, abstract = {

BACKGROUND: Cox proportional hazards regression models are used to evaluate associations between exposures of interest and time-to-event outcomes in observational data. When exposures are measured on only a sample of participants, as they are in a case-cohort design, the sampling weights must be incorporated into the regression model to obtain unbiased estimating equations.

METHODS: Robust Cox methods have been developed to better estimate associations when there are influential outliers in the exposure of interest, but these robust methods do not incorporate sampling weights. In this paper, we extend these robust methods, which already incorporate influence weights, so that they also accommodate sampling weights.

RESULTS: Simulations illustrate that in the presence of influential outliers, the association estimate from the weighted robust method is closer to the true value than the estimate from traditional weighted Cox regression. As expected, in the absence of outliers, the use of robust methods yields a small loss of efficiency. Using data from a case-cohort study that is nested within the Multi-Ethnic Study of Atherosclerosis (MESA) longitudinal cohort study, we illustrate differences between traditional and robust weighted Cox association estimates for the relationships between immune cell traits and risk of stroke.

CONCLUSIONS: Robust weighted Cox regression methods are a new tool to analyze time-to-event data with sampling, e.g. case-cohort data, when exposures of interest contain outliers.

}, issn = {1471-2288}, doi = {10.1186/s12874-020-00945-9}, author = {Sitlani, Colleen M and Lumley, Thomas and McKnight, Barbara and Rice, Kenneth M and Olson, Nels C and Doyle, Margaret F and Huber, Sally A and Tracy, Russell P and Psaty, Bruce M and C Delaney, Joseph A} } @article {8638, title = {{An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms}, journal = {Sci Rep}, volume = {10}, year = {2020}, month = {11}, pages = {19111}, abstract = {{In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck{\textquoteright}s Depression Inventory (BDI) scale (range 0-63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65\% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 ({\^A}{\textpm} 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95\% confidence interval = - 0.17 to 0.76}, author = {Wildisen, L. and Del Giovane, C. and Moutzouri, E. and Beglinger, S. and Syrogiannouli, L. and Collet, T. H. and Cappola, A. R. and ?svold, B. O. and Bakker, S. J. L. and Yeap, B. B. and Almeida, O. P. and Ceresini, G. and Dullaart, R. P. F. and Ferrucci, L. and Grabe, H. and Jukema, J. W. and Nauck, M. and Trompet, S. and V?lzke, H. and Westendorp, R. and Gussekloo, J. and Kl?ppel, S. and Aujesky, D. and Bauer, D. and Peeters, R. and Feller, M. and Rodondi, N.} } @article {8621, title = {Inherited causes of clonal haematopoiesis in 97,691 whole genomes.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {763-768}, abstract = {

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is~termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP~driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

}, issn = {1476-4687}, doi = {10.1038/s41586-020-2819-2}, author = {Bick, Alexander G and Weinstock, Joshua S and Nandakumar, Satish K and Fulco, Charles P and Bao, Erik L and Zekavat, Seyedeh M and Szeto, Mindy D and Liao, Xiaotian and Leventhal, Matthew J and Nasser, Joseph and Chang, Kyle and Laurie, Cecelia and Burugula, Bala Bharathi and Gibson, Christopher J and Lin, Amy E and Taub, Margaret A and Aguet, Francois and Ardlie, Kristin and Mitchell, Braxton D and Barnes, Kathleen C and Moscati, Arden and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Silverman, Edwin K and Weiss, Scott T and Palmer, Nicholette D and Vasan, Ramachandran S and Burchard, Esteban G and Kardia, Sharon L R and He, Jiang and Kaplan, Robert C and Smith, Nicholas L and Arnett, Donna K and Schwartz, David A and Correa, Adolfo and de Andrade, Mariza and Guo, Xiuqing and Konkle, Barbara A and Custer, Brian and Peralta, Juan M and Gui, Hongsheng and Meyers, Deborah A and McGarvey, Stephen T and Chen, Ida Yii-Der and Shoemaker, M Benjamin and Peyser, Patricia A and Broome, Jai G and Gogarten, Stephanie M and Wang, Fei Fei and Wong, Quenna and Montasser, May E and Daya, Michelle and Kenny, Eimear E and North, Kari E and Launer, Lenore J and Cade, Brian E and Bis, Joshua C and Cho, Michael H and Lasky-Su, Jessica and Bowden, Donald W and Cupples, L Adrienne and Mak, Angel C Y and Becker, Lewis C and Smith, Jennifer A and Kelly, Tanika N and Aslibekyan, Stella and Heckbert, Susan R and Tiwari, Hemant K and Yang, Ivana V and Heit, John A and Lubitz, Steven A and Johnsen, Jill M and Curran, Joanne E and Wenzel, Sally E and Weeks, Daniel E and Rao, Dabeeru C and Darbar, Dawood and Moon, Jee-Young and Tracy, Russell P and Buth, Erin J and Rafaels, Nicholas and Loos, Ruth J F and Durda, Peter and Liu, Yongmei and Hou, Lifang and Lee, Jiwon and Kachroo, Priyadarshini and Freedman, Barry I and Levy, Daniel and Bielak, Lawrence F and Hixson, James E and Floyd, James S and Whitsel, Eric A and Ellinor, Patrick T and Irvin, Marguerite R and Fingerlin, Tasha E and Raffield, Laura M and Armasu, Sebastian M and Wheeler, Marsha M and Sabino, Ester C and Blangero, John and Williams, L Keoki and Levy, Bruce D and Sheu, Wayne Huey-Herng and Roden, Dan M and Boerwinkle, Eric and Manson, JoAnn E and Mathias, Rasika A and Desai, Pinkal and Taylor, Kent D and Johnson, Andrew D and Auer, Paul L and Kooperberg, Charles and Laurie, Cathy C and Blackwell, Thomas W and Smith, Albert V and Zhao, Hongyu and Lange, Ethan and Lange, Leslie and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Scheet, Paul and Kitzman, Jacob O and Lander, Eric S and Engreitz, Jesse M and Ebert, Benjamin L and Reiner, Alexander P and Jaiswal, Siddhartha and Abecasis, Goncalo and Sankaran, Vijay G and Kathiresan, Sekar and Natarajan, Pradeep} } @article {8403, title = {Innate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts.}, journal = {Atherosclerosis}, volume = {300}, year = {2020}, month = {2020 05}, pages = {47-53}, abstract = {

BACKGROUND AND AIMS: Cell-mediated immunity is implicated in atherosclerosis. We evaluated whether innate and adaptive immune cell subsets in peripheral blood are risk factors for coronary heart disease.

METHODS: A nested case-cohort study (n~=~2155) was performed within the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). Cases of incident myocardial infarction (MI) and incident angina (n~=~880 total cases) were compared with a cohort random sample (n~=~1275). Immune cell phenotypes (n~=~34, including CD14 monocytes, natural killer cells, γδ T cells, CD4, CD8 and CD19 lymphocyte subsets) were measured from cryopreserved cells by flow cytometry. Cox proportional hazards models with adjustment for cardiovascular disease risk factors were used to evaluate associations of cell phenotypes with incident MI and a composite phenotype of incident MI or incident angina (MI-angina) over a median 9.3 years of follow-up. Th1, Th2, Th17, T regulatory (CD4CD25CD127), naive (CD4CD45RA), memory (CD4CD45RO), and CD4CD28 cells were specified as primary hypotheses. In secondary analyses, 27 additional cell phenotypes were investigated.

RESULTS: After correction for multiple testing, there were no statistically significant associations of CD4 naive, memory, CD28, or T helper cell subsets with MI or MI-angina in MESA, CHS, or combined-cohort meta analyses. Null associations were also observed for monocyte subsets, natural killer cells, γδ T cells, CD19 B cell and differentiated CD4 and CD8 cell subsets.

CONCLUSIONS: The proportions of peripheral blood monocyte and lymphocyte subsets are not strongly related to the future occurrence of MI or angina in adults free of autoimmune disease.

}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2020.03.011}, author = {Olson, Nels C and Sitlani, Colleen M and Doyle, Margaret F and Huber, Sally A and Landay, Alan L and Tracy, Russell P and Psaty, Bruce M and Delaney, Joseph A} } @article {8487, title = {Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes?}, journal = {J Clin Endocrinol Metab}, volume = {105}, year = {2020}, month = {2020 Dec 01}, abstract = {

CONTEXT: Higher fibroblast growth factor-23 (FGF23) concentrations are associated with heart failure and mortality in diverse populations, but the strengths of associations differ markedly depending up on which assay is used.

OBJECTIVE: We sought to evaluate whether iron deficiency, inflammation, or kidney function account for differences in the strengths of associations between these 2 FGF23 assays with clinical outcomes.

DESIGN: Case cohort study from the Cardiovascular Health Study.

SETTING: A total of 844 community-dwelling individuals aged 65 years or older with and without chronic kidney disease were followed for 10 years.

OUTCOMES: Outcomes included death, incident heart failure (HF), and incident myocardial infarction (MI). Exposure was baseline intact and C-terminal FGF23. Using modified Cox models, adjusting sequentially we tested whether observed associations of each assay with outcomes were attenuated by iron status, inflammation, kidney function, or their combinations.

RESULTS: FGF23 measured by either assay was associated with mortality in unadjusted analysis (intact FGF23 hazard ratio [HR] per 2-fold higher 1.45; 95\% CI, 1.25-1.68; C-terminal FGF23 HR 1.38; 95\% CI, 1.26-1.50). Adjustment for kidney function completely attenuated associations of intact FGF23 with mortality (HR 1.00; 95\% CI, 0.85-1.17), but had much less influence on the association of C-terminal FGF23, for which results remained significant after adjustment (HR 1.15; 95\% CI, 1.04-1.28). Attenuation was much less with adjustment for iron status or inflammation. Results were similar for the HF end point. Neither C-terminal or intact FGF23 was associated with MI risk.

CONCLUSIONS: The relationship of FGF23 with clinical end points is markedly different depending on the type of FGF23 assay used. The associations of biologically active FGF23 with clinical end points may be confounded by kidney disease, and thus much weaker than previously thought.

}, issn = {1945-7197}, doi = {10.1210/clinem/dgaa665}, author = {Sharma, Shilpa and Katz, Ronit and Bullen, Alexander L and Chaves, Paulo H M and de Leeuw, Peter W and Kroon, Abraham A and Houben, Alfons J H M and Shlipak, Michael G and Ix, Joachim H} } @article {9007, title = {Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations With Atrial Fibrillation.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 12}, pages = {e003460}, abstract = {

BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive.

METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI.

RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in and 3 previously reported loci at , , and . One known locus at was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6\% increase in hs-cTnT levels (minor allele frequency, 0.18; =2.80{\texttimes}10). We observed pleiotropic loci located at and . The proportions of variances explained by single-nucleotide polymorphisms were 10.15\% and 7.74\% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with expression in heart tissues and hs-cTnT and with expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95\% CI, 1.25-1.54] for hs-cTnT and 1.21 [95\% CI, 1.06-1.37] for hs-cTnI).

CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.121.003460}, author = {Yang, Yunju and Bartz, Traci M and Brown, Michael R and Guo, Xiuqing and Zilh{\~a}o, Nuno R and Trompet, Stella and Weiss, Stefan and Yao, Jie and Brody, Jennifer A and deFilippi, Christopher R and Hoogeveen, Ron C and Lin, Henry J and Gudnason, Vilmundur and Ballantyne, Christie M and D{\"o}rr, Marcus and Jukema, J Wouter and Petersmann, Astrid and Psaty, Bruce M and Rotter, Jerome I and Boerwinkle, Eric and Fornage, Myriam and Jun, Goo and Yu, Bing} } @article {8836, title = {Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.}, journal = {PLoS One}, volume = {16}, year = {2021}, month = {2021}, pages = {e0253611}, abstract = {

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12\%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0253611}, author = {Sarnowski, Chloe and Chen, Han and Biggs, Mary L and Wassertheil-Smoller, Sylvia and Bressler, Jan and Irvin, Marguerite R and Ryan, Kathleen A and Karasik, David and Arnett, Donna K and Cupples, L Adrienne and Fardo, David W and Gogarten, Stephanie M and Heavner, Benjamin D and Jain, Deepti and Kang, Hyun Min and Kooperberg, Charles and Mainous, Arch G and Mitchell, Braxton D and Morrison, Alanna C and O{\textquoteright}Connell, Jeffrey R and Psaty, Bruce M and Rice, Kenneth and Smith, Albert V and Vasan, Ramachandran S and Windham, B Gwen and Kiel, Douglas P and Murabito, Joanne M and Lunetta, Kathryn L} } @article {8778, title = {Identification of putative causal loci in whole-genome sequencing data via knockoff statistics.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 05 25}, pages = {3152}, abstract = {

The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer{\textquoteright}s Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

}, keywords = {Algorithms, Causality, Computer Simulation, Data Interpretation, Statistical, Datasets as Topic, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Markov Chains, Models, Genetic, Polymorphism, Single Nucleotide, Reproducibility of Results, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-021-22889-4}, author = {He, Zihuai and Liu, Linxi and Wang, Chen and Le Guen, Yann and Lee, Justin and Gogarten, Stephanie and Lu, Fred and Montgomery, Stephen and Tang, Hua and Silverman, Edwin K and Cho, Michael H and Greicius, Michael and Ionita-Laza, Iuliana} } @article {8837, title = {Incidence, Determinants and Mortality of Heart Failure Associated With Medical-Surgical Procedures in Patients >= 65 Years of Age (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {153}, year = {2021}, month = {2021 Aug 15}, pages = {71-78}, abstract = {

Heart failure (HF) and myocardial infarction are serious complications of major noncardiac surgery in older adults. Many factors can contribute to the development of HF during the postoperative period. The incidence of, and risk factors for, procedure-associated heart failure (PHF) occurring at the time of, or shortly after, medical procedures in a population-based sample >= 65 years of age have not been fully characterized, particularly in comparison with HF not proximate to medical procedures. This analysis comprises 5,121 men and women free of HF at baseline from the Cardiovascular Health Study who were followed up for 12.0 years (median). HF events were documented by self-report at semi-annual contacts and confirmed by a formal adjudication committee using a review of the participants{\textquoteright} medical records and standardized criteria for HF. Incident HF events were additionally adjudicated as either being related or unrelated to a medical procedure (PHF and non-PHF, respectively). We estimated cause-specific hazards ratios for the association of covariates with PHF and non-PHF. There were 1,728 incident HF events in the primary analysis: 168 (10\%) classified as PHF, 1,526 (88\%) as non-PHF, and 34 unclassified (2\%). For those 1,045 participants in whom LV ejection fraction was known at the time of the HF event, it was >=45\% in 89 of 118 participants (75\%) with PHF, compared to 517 of 927 participants (55\%) with non-PHF (p < 0.001). Increased age, male gender, diabetes, and angina at baseline were associated with both PHF and non-PHF (range of hazard ratios (HR): 1.04-2.05]. Being Black was inversely associated with PHF [HR: 0.46, 95\% confidence interval: 0.25-0.86]. Participants with increased age, without baseline angina, and with baseline LVEF<55\% were at a significantly lower risk for PHF compared to non-PHF. Among those with PHF, surgical procedures-including cardiac, orthopedic, gastrointestinal, vascular, and urologic-comprised 83.3\%, while percutaneous procedures comprised 8.9\% (including 6.5\% represented by cardiac catheterizations and pacemaker placements). Another group composed of a variety of procedures commonly requiring large fluid volume administration comprised 7.7\%. There was a lower all-cause 30-day mortality in the PHF versus the non-PHF group (2.2\% vs 5.7\%), with a nonsignificant odds ratio of 0.39 in a minimally adjusted model. When individuals with prior myocardial infarction (MI) were excluded in a sensitivity analysis, the proportion of incident HF with concurrent MI was greater~for PHF (32.9\%) than for non-PHF (19.8\%). In conclusion, PHF in older adults is a common entity with relatively low 30-day mortality. Baseline angina, lower age, and LVEF >= 55\% were associated with a higher risk of PHF compared to non-PHF. Being Black was associated with a lower risk of PHF and PHF as a proportion of HF was lower in Black than in non-Black participants. Compared to non-PHF, PHF more frequently presented with concurrent MI and with preserved LV ejection fraction.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2021.05.017}, author = {Shah, Monali and Rodriguez, Carlos J and Bartz, Traci M and Lyles, Mary F and Kizer, Jorge R and Aurigemma, Gerard P and Gardin, Julius M and Gottdiener, John S} } @article {8665, title = {Individual non-esterified fatty acids and incident atrial fibrillation late in life.}, journal = {Heart}, year = {2021}, month = {2021 Jan 22}, abstract = {

OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Expansion of fat depots is associated with increased circulating total non-esterified fatty acids (NEFAs), elevated levels of which are associated with incident AF. We undertook comprehensive serum measurement of individual NEFA to identify specific associations with new-onset AF late in life.

METHODS: The present study focused on participants with available serum and free of AF selected from the Cardiovascular Health Study, a community-based longitudinal investigation of older US adults. Thirty-five individual NEFAs were measured by gas chromatography. Cox regression was used to evaluate the association of individual NEFAs with incident AF.

RESULTS: The study sample included 1872 participants (age 77.7{\textpm}4.4). During median follow-up of 11.3 years, 715 cases of incident AF occurred. After concurrent adjustment of all NEFAs and full adjustment for potential confounders, higher serum concentration of nervonic acid (24:1 n-9), a long-chain monounsaturated fatty acid, was associated with higher risk of AF (HR per SD: 1.18, 95\% CI 1.08 to 1.29; p<0.001). Conversely, higher serum concentration of gamma-linolenic acid (GLA) (18:3 n-6), a polyunsaturated n-6 fatty acid, was associated with lower risk of AF (HR per SD: 0.81, 95\% CI 0.71 to 0.94; p=0.004). None of the remaining NEFAs was significantly associated with AF.

CONCLUSIONS: Among older adults, serum levels of non-esterified nervonic acid were positively associated, while serum levels of non-esterified GLA were inversely associated, with incident AF. If confirmed, these results could offer new strategies for AF prevention and early intervention in this segment of the population at highest risk.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2020-317929}, author = {Pellegrini, Cara N and B{\r u}zkov{\'a}, Petra and Lichtenstein, Alice H and Matthan, Nirupa R and Ix, Joachim H and Siscovick, David S and Heckbert, Susan R and Tracy, Russell P and Mukamal, Kenneth J and Djouss{\'e}, Luc and Kizer, Jorge R} } @article {9247, title = {Immune cell subpopulations as risk factors for atrial fibrillation: The Cardiovascular Health Study and Multi-Ethnic Study of Atherosclerosis.}, journal = {Heart Rhythm}, year = {2022}, month = {2022 Oct 18}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2022.10.012}, author = {Floyd, James S and Sitlani, Colleen M and Doyle, Margaret F and Feinstein, Matthew J and Olson, Nels C and Heckbert, Susan R and Huber, Sally A and Tracy, Russell P and Psaty, Bruce M and Delaney, Joseph A C} } @article {9260, title = {The Impact of Time Horizon on Classification Accuracy: Application of Machine Learning to Prediction of Incident Coronary Heart Disease.}, journal = {JMIR Cardio}, volume = {6}, year = {2022}, month = {2022 Nov 02}, pages = {e38040}, abstract = {

BACKGROUND: Many machine learning approaches are limited to classification of outcomes rather than longitudinal prediction. One strategy to use machine learning in clinical risk prediction is to classify outcomes over a given time horizon. However, it is not well-known how to identify the optimal time horizon for risk prediction.

OBJECTIVE: In this study, we aim to identify an optimal time horizon for classification of incident myocardial infarction (MI) using machine learning approaches looped over outcomes with increasing time horizons. Additionally, we sought to compare the performance of these models with the traditional Framingham Heart Study (FHS) coronary heart disease gender-specific Cox proportional hazards regression model.

METHODS: We analyzed data from a single clinic visit of 5201 participants of a cardiovascular health study. We examined 61 variables collected from this baseline exam, including demographic and biologic data, medical history, medications, serum biomarkers, electrocardiographic, and echocardiographic data. We compared several machine learning methods (eg, random forest, L1 regression, gradient boosted decision tree, support vector machine, and k-nearest neighbor) trained to predict incident MI that occurred within time horizons ranging from 500-10,000 days of follow-up. Models were compared on a 20\% held-out testing set using area under the receiver operating characteristic curve (AUROC). Variable importance was performed for random forest and L1 regression models across time points. We compared results with the FHS coronary heart disease gender-specific Cox proportional hazards regression functions.

RESULTS: There were 4190 participants included in the analysis, with 2522 (60.2\%) female participants and an average age of 72.6 years. Over 10,000 days of follow-up, there were 813 incident MI events. The machine learning models were most predictive over moderate follow-up time horizons (ie, 1500-2500 days). Overall, the L1 (Lasso) logistic regression demonstrated the strongest classification accuracy across all time horizons. This model was most predictive at 1500 days follow-up, with an AUROC of 0.71. The most influential variables differed by follow-up time and model, with gender being the most important feature for the L1 regression and weight for the random forest model across all time frames. Compared with the Framingham Cox function, the L1 and random forest models performed better across all time frames beyond 1500 days.

CONCLUSIONS: In a population free of coronary heart disease, machine learning techniques can be used to predict incident MI at varying time horizons with reasonable accuracy, with the strongest prediction accuracy in moderate follow-up periods. Validation across additional populations is needed to confirm the validity of this approach in risk prediction.

}, issn = {2561-1011}, doi = {10.2196/38040}, author = {Simon, Steven and Mandair, Divneet and Albakri, Abdel and Fohner, Alison and Simon, Noah and Lange, Leslie and Biggs, Mary and Mukamal, Kenneth and Psaty, Bruce and Rosenberg, Michael} } @article {9250, title = {{Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis}, journal = {Genome Biol}, volume = {23}, year = {2022}, month = {Dec}, pages = {268}, abstract = {Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.\ 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5\% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.\ Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.}, author = {Kanoni, S. and Graham, S. E. and Wang, Y. and Surakka, I. and Ramdas, S. and Zhu, X. and Clarke, S. L. and Bhatti, K. F. and Vedantam, S. and Winkler, T. W. and Locke, A. E. and Marouli, E. and Zajac, G. J. M. and Wu, K. H. and Ntalla, I. and Hui, Q. and Klarin, D. and Hilliard, A. T. and Wang, Z. and Xue, C. and Thorleifsson, G. and Helgadottir, A. and Gudbjartsson, D. F. and Holm, H. and Olafsson, I. and Hwang, M. Y. and Han, S. and Akiyama, M. and Sakaue, S. and Terao, C. and Kanai, M. and Zhou, W. and Brumpton, B. M. and Rasheed, H. and Havulinna, A. S. and Veturi, Y. and Pacheco, J. A. and Rosenthal, E. A. and Lingren, T. and Feng, Q. and Kullo, I. J. and Narita, A. and Takayama, J. and Martin, H. C. and Hunt, K. A. and Trivedi, B. and Haessler, J. and Giulianini, F. and Bradford, Y. and Miller, J. E. and Campbell, A. and Lin, K. and Millwood, I. Y. and Rasheed, A. and Hindy, G. and Faul, J. D. and Zhao, W. and Weir, D. R. and Turman, C. and Huang, H. and Graff, M. and Choudhury, A. and Sengupta, D. and Mahajan, A. and Brown, M. R. and Zhang, W. and Yu, K. and Schmidt, E. M. and Pandit, A. and Gustafsson, S. and Yin, X. and Luan, J. and Zhao, J. H. and Matsuda, F. and Jang, H. M. and Yoon, K. and Medina-Gomez, C. and Pitsillides, A. and Hottenga, J. J. and Wood, A. R. and Ji, Y. and Gao, Z. and Haworth, S. and Yousri, N. A. and Mitchell, R. E. and Chai, J. F. and Aadahl, M. and Bjerregaard, A. A. and Yao, J. and Manichaikul, A. and Hwu, C. M. and Hung, Y. J. and Warren, H. R. and Ramirez, J. and Bork-Jensen, J. and rhus, L. L. and Goel, A. and Sabater-Lleal, M. and Noordam, R. and Mauro, P. and Matteo, F. and McDaid, A. F. and Marques-Vidal, P. and Wielscher, M. and Trompet, S. and Sattar, N. and llehave, L. T. and Munz, M. and Zeng, L. and Huang, J. and Yang, B. and Poveda, A. and Kurbasic, A. and Lamina, C. and Forer, L. and Scholz, M. and Galesloot, T. E. and Bradfield, J. P. and Ruotsalainen, S. E. and Daw, E. and Zmuda, J. M. and Mitchell, J. S. and Fuchsberger, C. and Christensen, H. and Brody, J. A. and Vazquez-Moreno, M. and Feitosa, M. 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W. and Chen, Z. and Li, L. and Kawaguchi, T. and Thiery, J. and Bis, J. C. and Launer, L. J. and Li, H. and Nalls, M. A. and Raitakari, O. T. and Ichihara, S. and Wild, S. H. and Nelson, C. P. and Campbell, H. and ger, S. and Nabika, T. and Al-Mulla, F. and Niinikoski, H. and Braund, P. S. and Kolcic, I. and Kovacs, P. and Giardoglou, T. and Katsuya, T. and de Kleijn, D. and de Borst, G. J. and Kim, E. K. and Adams, H. H. H. and Ikram, M. A. and Zhu, X. and Asselbergs, F. W. and Kraaijeveld, A. O. and Beulens, J. W. J. and Shu, X. O. and Rallidis, L. S. and Pedersen, O. and Hansen, T. and Mitchell, P. and Hewitt, A. W. and nen, M. and russe, L. and Bouchard, C. and njes, A. and Chen, Y. I. and Pennell, C. E. and Mori, T. A. and Lieb, W. and Franke, A. and Ohlsson, C. and m, D. and Cho, Y. S. and Lee, H. and Yuan, J. M. and Koh, W. P. and Rhee, S. Y. and Woo, J. T. and Heid, I. M. and Stark, K. J. and Zimmermann, M. E. and lzke, H. and Homuth, G. and Evans, M. K. and Zonderman, A. B. and Polasek, O. and Pasterkamp, G. and Hoefer, I. E. and Redline, S. and Pahkala, K. and Oldehinkel, A. J. and Snieder, H. and Biino, G. and Schmidt, R. and Schmidt, H. and Bandinelli, S. and Dedoussis, G. and Thanaraj, T. A. and Kardia, S. L. R. and Peyser, P. A. and Kato, N. and Schulze, M. B. and Girotto, G. and ger, C. A. and Jung, B. and Joshi, P. K. and Bennett, D. A. and De Jager, P. L. and Lu, X. and Mamakou, V. and Brown, M. and Caulfield, M. J. and Munroe, P. B. and Guo, X. and Ciullo, M. and Jonas, J. B. and Samani, N. J. and Kaprio, J. and Pajukanta, P. and -Luna, T. and Aguilar-Salinas, C. A. and Adair, L. S. and Bechayda, S. A. and de Silva, H. J. and Wickremasinghe, A. R. and Krauss, R. M. and Wu, J. Y. and Zheng, W. and Hollander, A. I. and Bharadwaj, D. and Correa, A. and Wilson, J. G. and Lind, L. and Heng, C. K. and Nelson, A. E. and Golightly, Y. M. and Wilson, J. F. and Penninx, B. and Kim, H. L. and Attia, J. and Scott, R. J. and Rao, D. C. and Arnett, D. K. and Hunt, S. C. and Walker, M. and Koistinen, H. A. and Chandak, G. R. and Mercader, J. M. and Costanzo, M. C. and Jang, D. and Burtt, N. P. and Villalpando, C. G. and Orozco, L. and Fornage, M. and Tai, E. and van Dam, R. M. and ki, T. and Chaturvedi, N. and Yokota, M. and Liu, J. and Reilly, D. F. and McKnight, A. J. and Kee, F. and ckel, K. H. and McCarthy, M. I. and Palmer, C. N. A. and Vitart, V. and Hayward, C. and Simonsick, E. and van Duijn, C. M. and Jin, Z. B. and Qu, J. and Hishigaki, H. and Lin, X. and rz, W. and Gudnason, V. and Tardif, J. C. and Lettre, G. and Hart, L. M. {\textquoteright} and Elders, P. J. M. and Damrauer, S. M. and Kumari, M. and Kivimaki, M. and van der Harst, P. and Spector, T. D. and Loos, R. J. F. and Province, M. A. and Parra, E. J. and Cruz, M. and Psaty, B. M. and Brandslund, I. and Pramstaller, P. P. and Rotimi, C. N. and Christensen, K. and Ripatti, S. and n, E. and Hakonarson, H. and Grant, S. F. A. and Kiemeney, L. A. L. M. and de Graaf, J. and Loeffler, M. and Kronenberg, F. and Gu, D. and Erdmann, J. and Schunkert, H. and Franks, P. W. and Linneberg, A. and Jukema, J. W. and Khera, A. V. and {\"o}, M. and Jarvelin, M. R. and Kutalik, Z. and Francesco, C. and Mook-Kanamori, D. O. and van Dijk, K. W. and Watkins, H. and Strachan, D. P. and Grarup, N. and Sever, P. and Poulter, N. and Chuang, L. M. and Rotter, J. I. and Dantoft, T. M. and Karpe, F. and Neville, M. J. and Timpson, N. J. and Cheng, C. Y. and Wong, T. Y. and Khor, C. C. and Li, H. and Sabanayagam, C. and Peters, A. and Gieger, C. and Hattersley, A. T. and Pedersen, N. L. and Magnusson, P. K. E. and Boomsma, D. I. and Willemsen, A. H. M. and Cupples, L. and van Meurs, J. B. J. and Ghanbari, M. and Gordon-Larsen, P. and Huang, W. and Kim, Y. J. and Tabara, Y. and Wareham, N. J. and Langenberg, C. and Zeggini, E. and Kuusisto, J. and Laakso, M. and Ingelsson, E. and Abecasis, G. and Chambers, J. C. and Kooner, J. S. and de Vries, P. S. and Morrison, A. C. and Hazelhurst, S. and Ramsay, M. and North, K. E. and Daviglus, M. and Kraft, P. and Martin, N. G. and Whitfield, J. B. and Abbas, S. and Saleheen, D. and Walters, R. G. and Holmes, M. V. and Black, C. and Smith, B. H. and Baras, A. and Justice, A. E. and Buring, J. E. and Ridker, P. M. and Chasman, D. I. and Kooperberg, C. and Tamiya, G. and Yamamoto, M. and van Heel, D. A. and Trembath, R. C. and Wei, W. Q. and Jarvik, G. P. and Namjou, B. and Hayes, M. G. and Ritchie, M. D. and Jousilahti, P. and Salomaa, V. and Hveem, K. and svold, B. O. and Kubo, M. and Kamatani, Y. and Okada, Y. and Murakami, Y. and Kim, B. J. and Thorsteinsdottir, U. and Stefansson, K. and Zhang, J. and Chen, Y. and Ho, Y. L. and Lynch, J. A. and Rader, D. J. and Tsao, P. S. and Chang, K. M. and Cho, K. and O{\textquoteright}Donnell, C. J. and Gaziano, J. M. and Wilson, P. W. F. and Frayling, T. M. and Hirschhorn, J. N. and Kathiresan, S. and Mohlke, K. L. and Sun, Y. V. and Morris, A. P. and Boehnke, M. and Brown, C. D. and Natarajan, P. and Deloukas, P. and Willer, C. J. and Assimes, T. L. and Peloso, G. M.} } @article {9099, title = {Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.}, journal = {Hypertension}, year = {2022}, month = {2022 Jun 02}, pages = {101161HYPERTENSIONAHA12219324}, abstract = {

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5{\texttimes}10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99{\texttimes}10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18{\texttimes}10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28{\texttimes}10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1{\texttimes}10 and <1{\texttimes}10, respectively).

DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.122.19324}, author = {Kelly, Tanika N and Sun, Xiao and He, Karen Y and Brown, Michael R and Taliun, Sarah A Gagliano and Hellwege, Jacklyn N and Irvin, Marguerite R and Mi, Xuenan and Brody, Jennifer A and Franceschini, Nora and Guo, Xiuqing and Hwang, Shih-Jen and de Vries, Paul S and Gao, Yan and Moscati, Arden and Nadkarni, Girish N and Yanek, Lisa R and Elfassy, Tali and Smith, Jennifer A and Chung, Ren-Hua and Beitelshees, Amber L and Patki, Amit and Aslibekyan, Stella and Blobner, Brandon M and Peralta, Juan M and Assimes, Themistocles L and Palmas, Walter R and Liu, Chunyu and Bress, Adam P and Huang, Zhijie and Becker, Lewis C and Hwa, Chii-Min and O{\textquoteright}Connell, Jeffrey R and Carlson, Jenna C and Warren, Helen R and Das, Sayantan and Giri, Ayush and Martin, Lisa W and Craig Johnson, W and Fox, Ervin R and Bottinger, Erwin P and Razavi, Alexander C and Vaidya, Dhananjay and Chuang, Lee-Ming and Chang, Yen-Pei C and Naseri, Take and Jain, Deepti and Kang, Hyun Min and Hung, Adriana M and Srinivasasainagendra, Vinodh and Snively, Beverly M and Gu, Dongfeng and Montasser, May E and Reupena, Muagututi{\textquoteright}a Sefuiva and Heavner, Benjamin D and LeFaive, Jonathon and Hixson, James E and Rice, Kenneth M and Wang, Fei Fei and Nielsen, Jonas B and Huang, Jianfeng and Khan, Alyna T and Zhou, Wei and Nierenberg, Jovia L and Laurie, Cathy C and Armstrong, Nicole D and Shi, Mengyao and Pan, Yang and Stilp, Adrienne M and Emery, Leslie and Wong, Quenna and Hawley, Nicola L and Minster, Ryan L and Curran, Joanne E and Munroe, Patricia B and Weeks, Daniel E and North, Kari E and Tracy, Russell P and Kenny, Eimear E and Shimbo, Daichi and Chakravarti, Aravinda and Rich, Stephen S and Reiner, Alex P and Blangero, John and Redline, Susan and Mitchell, Braxton D and Rao, Dabeeru C and Ida Chen, Yii-Der and Kardia, Sharon L R and Kaplan, Robert C and Mathias, Rasika A and He, Jiang and Psaty, Bruce M and Fornage, Myriam and Loos, Ruth J F and Correa, Adolfo and Boerwinkle, Eric and Rotter, Jerome I and Kooperberg, Charles and Edwards, Todd L and Abecasis, Goncalo R and Zhu, Xiaofeng and Levy, Daniel and Arnett, Donna K and Morrison, Alanna C} } @article {9025, title = {Intake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 Mar 01}, pages = {e225012}, abstract = {

Importance: Higher intake of dietary fiber has been associated with lower inflammation, but whether there are differences in this association by source of dietary fiber (ie, cereal, vegetable, or fruit) has not been studied to date.

Objectives: To evaluate the associations of total fiber intake and source (ie, cereal, vegetable, and fruit fiber intake) with inflammation and to evaluate whether inflammation mediates the inverse association between dietary fiber intake and cardiovascular disease (CVD).

Design, Setting, and Participants: At the baseline visit (1989-1990) of 4125 adults aged 65 years or older in an ongoing US cohort study, dietary intake was assessed by a food frequency questionnaire among study participants without prevalent CVD (stroke and myocardial infarction) at enrollment. Inflammation was assessed from blood samples collected at baseline with immunoassays for markers of inflammation. Multivariable linear regression models tested the association of dietary fiber intake with inflammation. Also assessed was whether each inflammatory marker and its composite derived from principal component analysis mediated the association of baseline cereal fiber intake with development of CVD (stroke, myocardial infarction, and atherosclerotic cardiovascular death) through June 2015. Data from June 1, 1989, through June 30, 2015, were analyzed.

Exposures: Total fiber intake and sources of fiber (cereal, vegetable, and fruit).

Main Outcomes and Measures: Systemic markers of inflammation. Cardiovascular disease was the outcome in the mediation analysis.

Results: Of 4125 individuals, 0.1\% (n = 3) were Asian or Pacific Islander, 4.4\% (n = 183) were Black, 0.3\% (n = 12) were Native American, 95.0\% (n = 3918) were White, and 0.2\% (n = 9) were classified as other. Among these 4125 individuals (2473 women [60\%]; mean [SD] age, 72.6 [5.5] years; 183 Black individuals [4.4\%]; and 3942 individuals of other races and ethnicitites [95.6\%] [ie, race and ethnicity other than Black, self-classified by participant]), an increase in total fiber intake of 5 g/d was associated with significantly lower concentrations of C-reactive protein (adjusted mean difference, -0.05 SD; 95\% CI, -0.08 to -0.01 SD; P = .007) and interleukin 1 receptor antagonist (adjusted mean difference, -0.04 SD; 95\% CI, -0.07 to -0.01 SD; P < .02) but with higher concentrations of soluble CD163 (adjusted mean difference, 0.05 SD; 95\% CI, 0.02-0.09 SD; P = .005). Among fiber sources, only cereal fiber was consistently associated with lower inflammation. Similarly, cereal fiber intake was associated with lower CVD incidence (adjusted hazard ratio, 0.90; 95\% CI, 0.81-1.00; 1941 incident cases). The proportion of the observed association of cereal fiber with CVD mediated by inflammatory markers ranged from 1.5\% for interleukin 18 to 14.2\% for C-reactive protein, and 16.1\% for their primary principal component.

Conclusions and Relevance: Results of this study suggest that cereal fiber intake was associated with lower levels of various inflammatory markers and lower risk of CVD and that inflammation mediated approximately one-sixth of the association between cereal fiber intake and CVD.

}, keywords = {Adult, Aged, Cardiovascular Diseases, Cohort Studies, Dietary Fiber, Female, Humans, Inflammation, Middle Aged, Risk Factors}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.5012}, author = {Shivakoti, Rupak and Biggs, Mary L and Djouss{\'e}, Luc and Durda, Peter Jon and Kizer, Jorge R and Psaty, Bruce and Reiner, Alex P and Tracy, Russell P and Siscovick, David and Mukamal, Kenneth J} } @article {9094, title = {Integrative analysis of clinical and epigenetic biomarkers of mortality.}, journal = {Aging Cell}, volume = {21}, year = {2022}, month = {2022 Jun}, pages = {e13608}, abstract = {

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n~=~15,013). During a mean follow-up of 10~years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p~<~1~{\texttimes}~10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5\% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta~=~1.2, P ~=~4.1~{\texttimes}~10 ) and negatively associated with longevity (Beta~=~-1.9, P ~=~0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

}, keywords = {Biomarkers, Cardiovascular Diseases, DNA Methylation, Epigenesis, Genetic, Epigenomics, Humans, Male, Neoplasms}, issn = {1474-9726}, doi = {10.1111/acel.13608}, author = {Huan, Tianxiao and Nguyen, Steve and Colicino, Elena and Ochoa-Rosales, Carolina and Hill, W David and Brody, Jennifer A and Soerensen, Mette and Zhang, Yan and Baldassari, Antoine and Elhadad, Mohamed Ahmed and Toshiko, Tanaka and Zheng, Yinan and Domingo-Relloso, Arce and Lee, Dong Heon and Ma, Jiantao and Yao, Chen and Liu, Chunyu and Hwang, Shih-Jen and Joehanes, Roby and Fornage, Myriam and Bressler, Jan and van Meurs, Joyce B J and Debrabant, Birgit and Mengel-From, Jonas and Hjelmborg, Jacob and Christensen, Kaare and Vokonas, Pantel and Schwartz, Joel and Gahrib, Sina A and Sotoodehnia, Nona and Sitlani, Colleen M and Kunze, Sonja and Gieger, Christian and Peters, Annette and Waldenberger, Melanie and Deary, Ian J and Ferrucci, Luigi and Qu, Yishu and Greenland, Philip and Lloyd-Jones, Donald M and Hou, Lifang and Bandinelli, Stefania and Voortman, Trudy and Hermann, Brenner and Baccarelli, Andrea and Whitsel, Eric and Pankow, James S and Levy, Daniel} } @article {9546, title = {{Identification of circulating proteins associated with general cognitive function among middle-aged and older adults}, journal = {Commun Biol}, volume = {6}, year = {2023}, month = {Nov}, pages = {1117}, abstract = {2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.}, author = {Tin, A. and Fohner, A. E. and Yang, Q. and Brody, J. A. and Davies, G. and Yao, J. and Liu, D. and Caro, I. and Lindbohm, J. V. and Duggan, M. R. and Meirelles, O. and Harris, S. E. and Gudmundsdottir, V. and Taylor, A. M. and Henry, A. and Beiser, A. S. and Shojaie, A. and Coors, A. and Fitzpatrick, A. L. and Langenberg, C. and Satizabal, C. L. and Sitlani, C. M. and Wheeler, E. and Tucker-Drob, E. M. and Bressler, J. and Coresh, J. and Bis, J. C. and Candia, J. and Jennings, L. L. and Pietzner, M. and Lathrop, M. and Lopez, O. L. and Redmond, P. and Gerszten, R. E. and Rich, S. S. and Heckbert, S. R. and Austin, T. R. and Hughes, T. M. and Tanaka, T. and Emilsson, V. and Vasan, R. S. and Guo, X. and Zhu, Y. and Tzourio, C. and Rotter, J. I. and Walker, K. A. and Ferrucci, L. and ki, M. and Breteler, M. M. B. and Cox, S. R. and Debette, S. and Mosley, T. H. and Gudnason, V. G. and Launer, L. J. and Psaty, B. M. and Seshadri, S. and Fornage, M.} } @article {9237, title = {Inflammation and Incident Conduction Disease.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Jan 03}, pages = {e027247}, keywords = {Cardiac Conduction System Disease, Electrocardiography, Heart Block, Humans, Inflammation}, issn = {2047-9980}, doi = {10.1161/JAHA.122.027247}, author = {Frimodt-M{\o}ller, Emilie K and Gottdiener, John S and Soliman, Elsayed Z and Kizer, Jorge R and Vittinghoff, Eric and Psaty, Bruce M and Biering-S{\o}rensen, Tor and Marcus, Gregory M} } @article {9287, title = {Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease.}, journal = {Neurobiol Aging}, volume = {122}, year = {2023}, month = {2023 Feb}, pages = {107-111}, abstract = {

A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer{\textquoteright}s disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4, was about 3-fold higher in AD cases than in cognitively intact controls (0.845\% vs. 0.277\%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95\% CI: 1.34 - 6.13;~=~0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95\% CI: 0.70 - 3.36; p~=~0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12\% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80\% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD.

}, keywords = {Alleles, Alzheimer Disease, Animals, Apolipoprotein E3, Apolipoprotein E4, Apolipoproteins E, Genotype, Heterozygote}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2022.11.007}, author = {Fan, KangHsien and Francis, Lily and Aslam, M Muaaz and Bedison, Margret A and Lawrence, Elizabeth and Acharya, Vibha and Snitz, Beth E and Ganguli, Mary and DeKosky, Steven T and Lopez, Oscar L and Feingold, Eleanor and Kamboh, M Ilyas} } @article {9615, title = {Iron Deficiency and Incident Heart Failure in Older Community-Dwelling Individuals.}, journal = {ESC Heart Fail}, year = {2024}, month = {2024 Feb 26}, abstract = {

AIMS: Among persons with prevalent heart failure (HF), iron deficiency has been linked to HF admissions, and intravenous iron replacement improves HF outcomes. Recent studies in persons with chronic kidney disease (CKD) demonstrate that iron deficiency is associated with incident HF. This study aimed to determine the relationship of iron status with incident HF in community-dwelling older adults irrespective of their kidney function.

METHODS: In this case-cohort study, 1,006 Cardiovascular Health Study participants (785 from the random sub-cohort [including 193 HF cases] and 221 additional HF cases [N~=~414 total HF cases]) aged >= 65~years without HF (41\% with CKD), we used weighted Cox models to evaluate associations of iron status with incident HF. Participants were categorized based on quartiles of transferrin saturation and ferritin as "iron replete" (27.3\%), "functional iron deficiency" (7.7\%), "iron deficiency" (11.8\%), "mixed iron deficiency" (5.6\%), "high iron" (9.3\%) and "non-classified" (38.1\%), consistent with prior studies.

RESULTS: Compared to older persons who were iron replete, those with iron deficiency were at higher risk of incident HF (HR 1.47; 1.02-2.11) in models adjusting for demographics, HF risk factors, and estimated glomerular filtration rate. Other iron categories did not associate with incident HF. The relationship of iron deficiency with incident HF did not differ by CKD status (interaction P value 0.2).

CONCLUSIONS: Among community-dwelling elders, iron deficiency is independently associated with incident HF, an association that was similar irrespective of CKD status. Our findings support conduct of clinical trials of iron replacement for prevention of HF in older adults with iron deficiency.

}, issn = {2055-5822}, doi = {10.1002/ehf2.14724}, author = {Sharma, Shilpa and Katz, Ronit and Chaves, Paulo H M and Hoofnagle, Andrew N and Kizer, Jorge R and Bansal, Nisha and Ganz, Tomas and Ix, Joachim H} }