@article {675, title = {Fasting and 2-hour postchallenge serum glucose measures and risk of incident cardiovascular events in the elderly: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {162}, year = {2002}, month = {2002 Jan 28}, pages = {209-16}, abstract = {

BACKGROUND: The contributions of fasting and 2-hour postchallenge glucose level to cardiovascular events remain ill-defined, especially for nondiabetic adults. This study examined the relative predictive power of fasting and 2-hour glucose level on cardiovascular event risk.

METHODS: A total of 4014 community-dwelling adults 65 years or older who participated in the baseline visit of the Cardiovascular Health Study and who were without treated diabetes or previous myocardial infarction or stroke were eligible for analyses. Participants with treated diabetes at baseline were excluded. Incident myocardial infarction or stroke, or coronary death, was the outcome of interest. Age-, sex-, and race-adjusted proportional hazards regression models described individual and joint associations between baseline measures of fasting and 2-hour postchallenge glucose level and event risk.

RESULTS: There were 764 incident cardiovascular events during 8.5 years of follow-up. Fasting glucose level of 115 mg/dL (6.4 mmol/L) or more was associated with an increased cardiovascular risk (hazard ratio [HR], 1.66 [95\% confidence interval (CI), 1.39-1.98]) in adjusted analyses compared with fasting glucose level less than 115 mg/dL. Two-hour glucose level was associated with a linear risk (HR, 1.02 [95\% CI, 1.00-1.04] per 10 mg/dL [0.6 mmol/L]) that included an additional increase in risk for 2-hour glucose level of 154 mg/dL (8.5 mmol/L) or more (HR, 1.29 [95\% CI, 1.04-1.59]) in adjusted analyses. In joint fasting and 2-hour glucose models, only 2-hour glucose level remained predictive of event risk.

CONCLUSIONS: Two-hour glucose level was better than fasting glucose level alone at identifying older adults at increased risk of major incident cardiovascular events.

}, keywords = {Aged, Blood Glucose, Cardiovascular Diseases, Fasting, Female, Glucose Tolerance Test, Humans, Male, Myocardial Infarction, Predictive Value of Tests, Proportional Hazards Models, Risk Assessment, Stroke}, issn = {0003-9926}, doi = {10.1001/archinte.162.2.209}, author = {Smith, Nicholas L and Barzilay, Joshua I and Shaffer, Douglas and Savage, Peter J and Heckbert, Susan R and Kuller, Lewis H and Kronmal, Richard A and Resnick, Helaine E and Psaty, Bruce M} } @article {685, title = {Glucose, blood pressure, and lipid control in older people with and without diabetes mellitus: the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {50}, year = {2002}, month = {2002 Mar}, pages = {416-23}, abstract = {

OBJECTIVES: To determine the prevalence of cardiovascular risk-factor treatment and control in older adults with normal fasting glucose, impaired fasting glucose, and diabetes mellitus and whether those with diabetes mellitus had better risk factor control than older adults with normal fasting glucose.

DESIGN: Secondary analysis of data from population-based, prospective cohort study of risk factors for cardio-vascular and cerebrovascular disease in older people (Cardiovascular Health Study).

SETTING: Community-based.

PARTICIPANTS: Community-dwelling adults aged 65 and older.

MEASUREMENTS: Fasting plasma glucose, serum cholesterol and its subfractions, systolic and diastolic blood pressures, and body mass index.

RESULTS: There were 579 (18\%) cohort members with diabetes mellitus (77\% receiving antidiabetic medication, 23\% with fasting glucose > or =126 mg/dL and no treatment), 213 (6\%) with impaired fasting glucose, and 2,582 (77\%)with normal fasting glucose. Of diabetic participants, 12\% had recommended fasting glucose levels of less than 110 mg/dL. Of participants with hypertension, a larger proportion of diabetic participants than nondiabetic participants (89\% versus 75\%, P < .01) was treated with antihypertensive agents, but a smaller proportion of diabetic participants had recommended blood pressure levels of 129/85 mmHg or lower than nondiabetic participants had recommended blood pressure levels of 139/89 mmHg or lower (27\% vs 48\%, P < .01). Diabetic dyslipidemic participants were treated less often with lipid-lowering therapy (26\% versus 55\%, P < .01) and achieved recommended low-density lipoprotein goals less often (8\%versus 54\%, P < .01) than nondiabetic dyslipidemic participants.

CONCLUSIONS: Overall, treatment and control of cardiovascular risk factors were suboptimal in this older population, especially among those with diabetes mellitus. Optimizing risk-factor control can improve health outcomes in older adults with and without diabetes mellitus.

}, keywords = {Age Factors, Aged, Blood Glucose, Blood Pressure, Cardiovascular Diseases, Cholesterol, LDL, Cross-Sectional Studies, Diabetes Complications, Diabetes Mellitus, Female, Humans, Male, Prevalence, Prospective Studies, Risk Factors}, issn = {0002-8614}, doi = {10.1046/j.1532-5415.2002.50103.x}, author = {Smith, Nicholas L and Savage, Peter J and Heckbert, Susan R and Barzilay, Joshua I and Bittner, Vera A and Kuller, Lewis H and Psaty, Bruce M} } @article {791, title = {The association of fasting glucose levels with congestive heart failure in diabetic adults > or =65 years: the Cardiovascular Health Study.}, journal = {J Am Coll Cardiol}, volume = {43}, year = {2004}, month = {2004 Jun 16}, pages = {2236-41}, abstract = {

OBJECTIVES: The purpose of this study was to determine if fasting glucose levels are an independent risk factor for congestive heart failure (CHF) in elderly individuals with diabetes mellitus (DM) with or without coronary heart disease (CHD).

BACKGROUND: Diabetes mellitus and CHF frequently coexist in the elderly. It is not clear whether fasting glucose levels in the setting of DM are a risk factor for incident CHF in the elderly.

METHODS: A cohort of 829 diabetic participants, age > or =65 years, without prevalent CHF, was followed for five to eight years. The Cox proportional hazards modeling was used to determine the risk of CHF by fasting glucose levels. The cohort was categorized by the presence or absence of prevalent CHD.

RESULTS: For a 1 standard deviation (60.6 mg/dl) increase in fasting glucose, the adjusted hazard ratios for incident CHF among participants without CHD at baseline, with or without an incident myocardial infarction (MI) or CHD event on follow-up, was 1.41 (95\% confidence interval 1.24 to 1.61; p < 0.0001). Among those with prevalent CHD at baseline, with or without another incident MI or CHD event on follow-up, the corresponding adjusted hazard ratio was 1.27 (95\% confidence interval 1.02 to 1.58; p < 0.05).

CONCLUSIONS: Among older adults with DM, elevated fasting glucose levels are a risk factor for incident CHF. The relationship of fasting glucose to CHF differs somewhat by the presence or absence of prevalent CHD.

}, keywords = {Aged, Biomarkers, Blood Glucose, Blood Pressure, Coronary Disease, Diabetes Mellitus, Diabetic Angiopathies, Fasting, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Proportional Hazards Models, Risk Factors, Statistics as Topic, Stroke Volume, Ventricular Function, Left}, issn = {0735-1097}, doi = {10.1016/j.jacc.2003.10.074}, author = {Barzilay, Joshua I and Kronmal, Richard A and Gottdiener, John S and Smith, Nicholas L and Burke, Gregory L and Tracy, Russell and Savage, Peter J and Carlson, Michelle} } @article {794, title = {The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study.}, journal = {Am J Kidney Dis}, volume = {44}, year = {2004}, month = {2004 Jul}, pages = {25-34}, abstract = {

BACKGROUND: Microalbuminuria is a risk factor for coronary heart disease (CHD). It occurs most commonly in the settings of diabetes and hypertension. The mechanisms by which it increases CHD risk are uncertain.

METHODS: We examined the cross-sectional association of microalbuminuria with a broad range of CHD risk factors in 3 groups of adults aged 65 years or older with and without microalbuminuria: those with (1) no diabetes or hypertension (n = 1,098), (2) hypertension only (n = 1,450), and (3) diabetes with or without hypertension (n = 465).

RESULTS: Three factors were related to microalbuminuria in all 3 groups: age, elevated systolic blood pressure, and markers of systemic inflammation. In patients with neither diabetes nor hypertension, increasing C-reactive protein levels were associated with microalbuminuria (odds ratio per 1-mg/L increase, 1.46; 95\% confidence interval [CI], 1.15 to 1.84). Among those with diabetes, an increase in white blood cell (WBC) count was associated with microalbuminuria (odds ratio per 1,000-cell/mL increase, 2.57; 95\% CI, 1.12 to 5.89). Among those with hypertension, an increase in WBC count (odds ratio per 1,000-cell/mL increase, 1.83; 95\% CI, 1.04 to 3.23) and fibrinogen level (odds ratio per 10-mg/dL increase, 1.02; 95\% CI, 1.00 to 1.05) were significantly associated with microalbuminuria. In all 3 groups, prevalent CHD was related to an elevated WBC count. In none of the 3 groups was brachial artery reactivity to ischemia, an in vivo marker of endothelial function, related to microalbuminuria.

CONCLUSION: Microalbuminuria is associated with age, systolic blood pressure, and markers of inflammation. These associations reflect potential mechanisms by which microalbuminuria is related to CHD risk.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Albuminuria, Biomarkers, Brachial Artery, Comorbidity, Coronary Disease, Cross-Sectional Studies, Diabetes Mellitus, Female, Humans, Hypertension, Inflammation, Logistic Models, Male, Multivariate Analysis, Odds Ratio, Risk Factors, Smoking, Ultrasonography}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2004.03.022}, author = {Barzilay, Joshua I and Peterson, Do and Cushman, Mary and Heckbert, Susan R and Cao, Jie J and Blaum, Caroline and Tracy, Russell P and Klein, Ronald and Herrington, David M} } @article {789, title = {The relationship of fasting serum radioimmune insulin levels to incident coronary heart disease in an insulin-treated diabetic cohort.}, journal = {J Clin Endocrinol Metab}, volume = {89}, year = {2004}, month = {2004 Jun}, pages = {2852-8}, abstract = {

It is not known whether insulin levels, in the setting of insulin treatment, are an independent risk factor for coronary heart disease (CHD). We studied a cohort of 116 insulin-treated individuals, 65 yr or older, who were followed for 5.6-9 yr. All were free of CHD at baseline. There were 47 incident CHD events. In Cox proportional hazards modeling, with fasting immune-reactive insulin levels as a continuous variable, the hazard ratio for CHD was statistically significant (P < 0.0001). When insulin levels were divided into intervals, those in the third interval [43-150 microU/ml (258-900 pmol/liter)] had an adjusted 30\% increased relative risk (95\% confidence interval, 0.57, 2.98) compared with those in the first interval [<20 microU/ml (<120 pmol/liter)]. Those in the fourth interval [151-400 microU/ml (906-2400 pmol/liter)] had an adjusted 5.6-fold increased risk (2.3-13.1; P < 0.0001). Approximately 15\% of the cohort had such elevated insulin levels. Immune-reactive insulin levels were strongly correlated with specific insulin, proinsulin, and insulin antibody levels. Markedly elevated fasting immune-reactive insulin levels were an independent risk factor for CHD in this study of insulin-treated older adults. These observational findings should be confirmed through larger prospective studies, given their implications for insulin therapy.

}, keywords = {Aged, Cohort Studies, Coronary Disease, Diabetes Mellitus, Type 1, Fasting, Female, Follow-Up Studies, Humans, Hypoglycemic Agents, Incidence, Insulin, Male, Radioimmunoassay, Risk Factors}, issn = {0021-972X}, doi = {10.1210/jc.2003-031822}, author = {Kronmal, Richard A and Barzilay, Joshua I and Tracy, Russell P and Savage, Peter J and Orchard, Trevor J and Burke, Gregory L} } @article {863, title = {The association of microalbuminuria with clinical cardiovascular disease and subclinical atherosclerosis in the elderly: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {187}, year = {2006}, month = {2006 Aug}, pages = {372-7}, abstract = {

PURPOSE: Microalbuminuria (MA) is a risk factor for cardiovascular disease (CVD). It is not known whether this association is due to the effect of MA on the development of subclinical atherosclerosis or whether MA destabilizes subclinical atherosclerosis, leading to clinical events.

METHODS: In a cross-sectional analysis we evaluated 3312 Cardiovascular Health Study participants, age >or=65 years, who had MA testing. Participants were divided into three groups: those without diabetes or hypertension (33\%), those with hypertension (52\%) and those with diabetes, with or without hypertension (15\%). Clinical CVD was defined as presence of coronary heart disease (angina, MI, CABG, PTCA), cerebrovascular disease (stroke, TIA) and peripheral arterial disease (requiring intervention). Among those without clinical disease, subclinical atherosclerosis was defined as increased carotid artery intima-media thickness, decreased ankle arm index or increased left ventricular mass.

RESULTS: In each of the three groups of participants, the adjusted odds of prevalent clinical CVD in the presence of MA was 1.70-1.80-fold increased, independent of other risk factors. MA was not associated with risk of subclinical atherosclerosis in those without hypertension or diabetes (OR 1.14 [95\% CI 0.59, 2.23]), whereas it was associated with subclinical atherosclerosis in those with hypertension (OR 1.58 [95\% CI 1.08, 2.30]) or diabetes (OR 2.51 [95\% CI 1.27, 4.94]).

CONCLUSION: In the absence of hypertension or diabetes, MA was associated with clinical CVD but not with subclinical atherosclerosis. Thus, a hypothesis may be made that the mechanism of association of MA with clinical vascular disease involves destabilization of the vasculature, leading to clinical disease.

}, keywords = {Aged, Aged, 80 and over, Albuminuria, Atherosclerosis, Cardiovascular Diseases, Coronary Disease, Diabetes Mellitus, Female, Humans, Hypertension, Male, Peripheral Vascular Diseases, Prevalence, Risk Factors, Stroke, United States}, issn = {0021-9150}, doi = {10.1016/j.atherosclerosis.2005.09.015}, author = {Cao, Jie J and Barzilay, Joshua I and Peterson, Do and Manolio, Teri A and Psaty, Bruce M and Kuller, Lewis and Wexler, Jason and Bleyer, Anthony J and Cushman, Mary} } @article {918, title = {Metabolic syndrome and cardiovascular disease in older people: The cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {54}, year = {2006}, month = {2006 Sep}, pages = {1317-24}, abstract = {

OBJECTIVES: To assess the prospective association between metabolic syndrome (MetS) and cardiovascular disease (CVD) in older people and to evaluate the effect of lowering the threshold for impaired fasting glucose (IFG) on the prevalence of IFG and MetS and the risk of CVD.

DESIGN: Prospective cohort study.

SETTING: Four field centers in U.S. communities.

PARTICIPANTS: Three thousand five hundred eighty-five subjects in the Cardiovascular Health Study free of diabetes mellitus and CVD at baseline (mean age 72, 62\% female, 14\% black).

MEASUREMENTS: Baseline measures of MetS components and adjudicated incident CVD events. MetS (2001) was defined first using the original criteria from the Third Adult Treatment Panel Report of the National Cholesterol Education Program (> or =3 of the following: large waist circumference (women >88 cm, men >102 cm), elevated triglycerides (> or =1.70 mmol/L), low high-density lipoprotein cholesterol (men <1.04 mmol/L, women <1.30 mmol/L), elevated fasting glucose (6.1-6.9 mmol/L), and high blood pressure (> or =130/85 mmHg or self-reported use of medications for hypertension). Subjects were also classified according to the revised definition of the MetS (2005) that applies the lower threshold for fasting glucose (5.6-6.9 mmol/L).

RESULTS: During follow-up (median 11 years), 818 coronary heart disease (CHD), 401 stroke, and 554 congestive heart failure (CHF) events occurred. Age- and race-adjusted hazard ratios (HRs) for CHD, stroke, and CHF were 1.30 (95\% confidence interval (CI) = 1.07-1.57), 0.94 (95\% CI = 0.73-1.21), and 1.40 (95\% CI = 1.12-1.76) for women and 1.35 (95\% CI = 1.10-1.66), 1.51 (95\% CI = 1.08-2.12), and 1.47 (95\% CI = 1.14-1.90) for men, respectively. Overall, women and men with MetS (2005) were 20\% to 30\% more likely to experience any CVD event than subjects without MetS (2005). Using the lower cut-point for IFG resulted in a near tripling in IFG prevalence (16\% to 46\%) and an additional 9\% classified with MetS (2005) but HRs similar to those estimated from the original MetS (2001) criteria. High blood pressure was the component most strongly associated with incident CHD.

CONCLUSION: Results from this study of an elderly, population-based cohort provide support for earlier investigations in primarily middle-aged populations that link the presence of MetS with the development of CVD and further underscore the importance of recognizing and treating its individual components, particularly high blood pressure.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Blood Glucose, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Fasting, Female, Humans, Incidence, Male, Metabolic Syndrome, Risk Factors, Sex Factors}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2006.00862.x}, author = {McNeill, Ann Marie and Katz, Ronit and Girman, Cynthia J and Rosamond, Wayne D and Wagenknecht, Lynne E and Barzilay, Joshua I and Tracy, Russell P and Savage, Peter J and Jackson, Sharon A} } @article {923, title = {Mortality in pharmacologically treated older adults with diabetes: the Cardiovascular Health Study, 1989-2001.}, journal = {PLoS Med}, volume = {3}, year = {2006}, month = {2006 Oct}, pages = {e400}, abstract = {

BACKGROUND: Diabetes mellitus (DM) confers an increased risk of mortality in young and middle-aged individuals and in women. It is uncertain, however, whether excess DM mortality continues beyond age 75 years, is related to type of hypoglycemic therapy, and whether women continue to be disproportionately affected by DM into older age.

METHODS AND FINDINGS: From the Cardiovascular Health Study, a prospective study of 5,888 adults, we examined 5,372 participants aged 65 y or above without DM (91.2\%), 322 with DM treated with oral hypoglycemic agents (OHGAs) (5.5\%), and 194 with DM treated with insulin (3.3\%). Participants were followed (1989-2001) for total, cardiovascular disease (CVD), coronary heart disease (CHD), and non-CVD/noncancer mortality. Compared with non-DM participants, those treated with OHGAs or insulin had adjusted hazard ratios (HRs) for total mortality of 1.33 (95\% confidence interval [CI], 1.10 to 1.62) and 2.04 (95\% CI, 1.62 to 2.57); CVD mortality, 1.99 (95\% CI, 1.54 to 2.57) and 2.16 (95\% CI, 1.54 to 3.03); CHD mortality, 2.47 (95\% CI, 1.89 to 3.24) and 2.75 (95\% CI, 1.95 to 3.87); and infectious and renal mortality, 1.35 (95\% CI, 0.70 to 2.59) and 6.55 (95\% CI, 4.18 to 10.26), respectively. The interaction of age (65-74 y versus > or =75 y) with DM was not significant. Women treated with OHGAs had a similar HR for total mortality to men, but a higher HR when treated with insulin.

CONCLUSIONS: DM mortality risk remains high among older adults in the current era of medical care. Mortality risk and type of mortality differ between OHGA and insulin treatment. Women treated with insulin therapy have an especially high mortality risk. Given the high absolute CVD mortality in older people, those with DM warrant aggressive CVD risk factor reduction.

}, keywords = {Administration, Oral, Aged, Cardiovascular Diseases, Coronary Disease, Diabetes Mellitus, Female, Humans, Hypoglycemic Agents, Insulin, Male, Proportional Hazards Models, Prospective Studies, Risk Assessment, Sex Distribution}, issn = {1549-1676}, doi = {10.1371/journal.pmed.0030400}, author = {Kronmal, Richard A and Barzilay, Joshua I and Smith, Nicholas L and Psaty, Bruce M and Kuller, Lewis H and Burke, Gregory L and Furberg, Curt} } @article {914, title = {New-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {29}, year = {2006}, month = {2006 Sep}, pages = {2012-7}, abstract = {

OBJECTIVE: Cardiovascular risk associated with new-onset diabetes is not well characterized. We hypothesized that risk of all-cause and cardiovascular mortality would be similar among participants with and without new-onset diabetes in the first years of follow-up and rise over time for new-onset diabetes.

RESEARCH DESIGN AND METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of cardiovascular risk factors in adults aged > or =65 years. We used CHS participants to define a cohort (n = 282) with new-onset diabetes during 11 years of follow-up. New-onset diabetes was defined by initiation of antidiabetes medication or by fasting plasma glucose >125 mg/dl among CHS participants without diabetes at study entry. Three CHS participants without diabetes were matched for age, sex, and race to each participant with new-onset diabetes at the time of diabetes identification (n = 837). Survival analysis provided adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality.

RESULTS: During a median of 5.9 years of follow-up, there were 352 deaths, of which 41\% were cardiovascular. In adjusted analyses, new-onset diabetes was associated with an HR of 1.9 (95\% CI 1.4-2.5) for all-cause and 2.2 (1.4-3.4) for cardiovascular mortality compared with no diabetes. Mortality risks were elevated within 2 years of onset, especially cardiovascular risk (4.3 [95\% CI 1.7-10.8]), and did not increase over time.

CONCLUSIONS: Our findings indicate that there may be a mortality differential soon after diabetes onset in older adults and suggest that long-term macrovascular damage from atherosclerosis may not be primarily responsible for increased risk.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Blood Glucose, Cardiovascular Diseases, Diabetes Complications, Diabetes Mellitus, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Risk Factors, Survival Rate, Time Factors}, issn = {0149-5992}, doi = {10.2337/dc06-0574}, author = {Smith, Nicholas L and Barzilay, Joshua I and Kronmal, Richard and Lumley, Thomas and Enquobahrie, Daniel and Psaty, Bruce M} } @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 {961, title = {Longitudinal association between depressive symptoms and incident type 2 diabetes mellitus in older adults: the cardiovascular health study.}, journal = {Arch Intern Med}, volume = {167}, year = {2007}, month = {2007 Apr 23}, pages = {802-7}, abstract = {

BACKGROUND: Prospective studies indicate that a single self-report of high depressive symptoms is associated with an increased risk of developing type 2 diabetes mellitus.

METHODS: We tested whether a single report of high depressive symptoms, an increase in depressive symptoms, or persistently high depressive symptoms over time were associated with the development of diabetes in adults 65 years and older. Participants from the Cardiovascular Health Study completed the 10-item Center for Epidemiological Studies-Depression Scale (CES-D) annually from 1989 to 1999. A single report of high depressive symptoms (CES-D score, >/=8), an increase in symptoms during follow-up (>/=5 from baseline), and persistently high symptoms (2 consecutive scores >/=8) were each studied in relation to incident diabetes, defined by initiation of diabetes control medications among participants who were free from diabetes at baseline (n = 4681).

RESULTS: The mean CES-D score at baseline was 4.5 (SD, 4.5). The incidence rate of diabetes was 4.4 per 1000 person-years. Following adjustment for baseline demographic characteristics and measures of physical activity, smoking, alcohol intake, body mass index, and C-reactive protein during follow-up, each measure of depressive symptoms was significantly associated with incident diabetes (high baseline CES-D score: hazard ratio, 1.6 [95\% confidence interval, 1.1-2.3]; CES-D score increase: hazard ratio, 1.5 [95\% confidence interval, 1.1-2.2]; and persistently high symptoms: hazard ratio, 1.5 [95\% confidence interval, 1.1-2.3]).

CONCLUSION: Older adults who reported higher depressive symptoms were more likely to develop diabetes than their counterparts; this association was not fully explained by risk factors for diabetes.

}, keywords = {Aged, Body Mass Index, C-Reactive Protein, Depression, Diabetes Mellitus, Type 2, Drinking, Female, Humans, Longitudinal Studies, Male, Smoking}, issn = {0003-9926}, doi = {10.1001/archinte.167.8.802}, author = {Carnethon, Mercedes R and Biggs, Mary L and Barzilay, Joshua I and Smith, Nicholas L and Vaccarino, Viola and Bertoni, Alain G and Arnold, Alice and Siscovick, David} } @article {1038, title = {Adiponectin and risk of coronary heart disease in older men and women.}, journal = {J Clin Endocrinol Metab}, volume = {93}, year = {2008}, month = {2008 Sep}, pages = {3357-64}, abstract = {

CONTEXT: Despite established insulin-sensitizing and antiatherogenic preclinical effects, epidemiological investigations of adiponectin have yielded conflicting findings, and its relationship with coronary heart disease (CHD) remains uncertain.

OBJECTIVE: Our objective was to investigate the relationship between adiponectin and CHD in older adults.

DESIGN, SETTING, AND PARTICIPANTS: This was a case-control study (n = 1386) nested within the population-based Cardiovascular Health Study from 1992--2001. Controls were frequency-matched to cases by age, sex, race, subclinical cardiovascular disease, and center.

MAIN OUTCOME MEASURES: Incident CHD was defined as angina pectoris, percutaneous or surgical revascularization, nonfatal myocardial infarction (MI), or CHD death. A more restrictive CHD endpoint was limited to nonfatal MI and CHD death.

RESULTS: Adiponectin exhibited significant negative correlations with baseline adiposity, insulin resistance, dyslipidemia, inflammatory markers, and leptin. After controlling for matching factors, adjustment for waist to hip ratio, hypertension, smoking, alcohol, low-density lipoprotein cholesterol, creatinine, and leptin revealed a modestly increased risk of incident CHD with adiponectin concentrations at the upper end [odds ratio = 1.37 (quintile 5 vs. 1-4), 95\% confidence interval 1.02-1.84]. This association was stronger when the outcome was limited to nonfatal MI and fatal CHD (odds ratio = 1.69, 95\% confidence interval 1.23-2.32). The findings were not influenced by additional adjustment for weight change, health status, or cystatin C, nor were they abolished by adjustment for potential mediators.

CONCLUSIONS: This study shows an association between adiponectin and increased risk of first-ever CHD in older adults. Further research is needed to elucidate the basis for the concurrent beneficial and detrimental aspects of this relationship, and under what circumstances one or the other may predominate.

}, keywords = {Adiponectin, Age Factors, Aged, Aged, 80 and over, Body Weight, Case-Control Studies, Cohort Studies, Coronary Disease, Female, Humans, Longitudinal Studies, Male, Odds Ratio, Risk Factors}, issn = {0021-972X}, doi = {10.1210/jc.2008-0640}, author = {Kizer, Jorge R and Barzilay, Joshua I and Kuller, Lewis H and Gottdiener, John S} } @article {1032, title = {Albuminuria and dementia in the elderly: a community study.}, journal = {Am J Kidney Dis}, volume = {52}, year = {2008}, month = {2008 Aug}, pages = {216-26}, abstract = {

BACKGROUND: Dementia is associated with microvascular disease of the retina. In this study, we examine whether cognitive status (normal cognition, mild cognitive impairment, and dementia) is associated with albuminuria, a microvascular disorder of the kidney.

STUDY DESIGN: Cross-sectional analysis.

SETTING \& PARTICIPANTS: 2,316 participants from the Cardiovascular Health Cognition Study who underwent brain magnetic resonance imaging and testing for albuminuria.

PREDICTOR: Doubling of albuminuria.

OUTCOME: Dementia defined according to neuropsychological and clinical evaluation.

MEASUREMENTS: Multinomial logistic modeling was used to estimate odds ratios (ORs) and 95\% confidence intervals (CIs) of dementia and mild cognitive impairment with doubling of albuminuria compared with the odds with normal cognition.

RESULTS: 283 participants (12.2\%) had dementia, 344 (14.9\%) had mild cognitive impairment, and 1,689 (72.9\%) had normal cognition. Compared with participants with normal cognition, doubling of albuminuria was associated with increased odds of dementia (OR, 1.22; 95\% CI, 1.15 to 1.29). Adjustment for prevalent cardiovascular disease and cardiovascular risk factors, lipid levels, C-reactive protein level, estimated glomerular filtration rate, and apolipoprotein E-4 genotype attenuated this association, but it remained statistically significant (OR, 1.12; 95\% CI, 1.03 to 1.22). Mild cognitive impairment was associated with albuminuria on unadjusted analysis, but not with adjustment for other factors.

LIMITATIONS: Results are cross-sectional; causality cannot be imputed.

CONCLUSIONS: The odds of dementia increased in the presence of albuminuria. These findings suggest a role of shared susceptibility for microvascular disease in the brain and kidney in older adults.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Albuminuria, Brain, Cognition, Cross-Sectional Studies, Dementia, Female, Humans, Incidence, Magnetic Resonance Imaging, Male, Odds Ratio, Population Surveillance, Prognosis, Retrospective Studies, Risk Factors}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2007.12.044}, author = {Barzilay, Joshua I and Fitzpatrick, Annette L and Luchsinger, Jose and Yasar, Sevil and Bernick, Charles and Jenny, Nancy S and Kuller, Lewis H} } @article {1008, title = {Higher levels of inflammation factors and greater insulin resistance are independently associated with higher heart rate and lower heart rate variability in normoglycemic older individuals: the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 Feb}, pages = {315-21}, abstract = {

OBJECTIVES: To explore the relationship between (1) insulin resistance and inflammation factors with (2) higher heart rate (HR) and lower heart rate variability (HRV) in normoglycemic older adults.

DESIGN: Cross-sectional population-based study.

PARTICIPANTS: Five hundred forty-five adults aged 65 and older with normoglycemia (fasting glucose <100 mg/dL) who participated in the Cardiovascular Health Study.

MEASUREMENTS: Serum levels of three inflammation proteins (C-reactive protein (CRP), interleukin 6 (IL-6), and fibrinogen); insulin resistance, quantified according to the homeostasis assessment model (HOMA-IR); HR; and four representative measures of HRV (the standard deviation of normal beat to beat intervals (SDNN), the root mean square of successive differences (rMSSD), very low frequency power (VLF), and the low- to high-frequency power ratio (LF/HF)) derived from 24-hour Holter recordings.

RESULTS: High CRP and IL-6 levels were associated with higher HR and lower SDNN and VLF after adjustment for multiple covariates, including HOMA-IR and clinical cardiovascular disease. High IL-6 was also associated with lower LF/HF. Significant univariate inverse relationships between HOMA-IR and HR and HRV were also found, but the strengths of these relationships were attenuated after adjustment for inflammation factors.

CONCLUSION: Increased levels of inflammation markers and HOMA-IR are associated with higher HR and lower HRV. These findings suggest that inflammation may contribute to the pathogenesis of cardiovascular autonomic decline in older adults.

}, keywords = {Aged, C-Reactive Protein, Cardiovascular Diseases, Cross-Sectional Studies, Electrocardiography, Ambulatory, Female, Fibrinogen, Heart Rate, Humans, Inflammation Mediators, Insulin Resistance, Interleukin-6, Male, Risk Factors}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2007.01564.x}, author = {Stein, Phyllis K and Barzilay, Joshua I and Chaves, Paulo H M and Traber, Jennifer and Domitrovich, Peter P and Heckbert, Susan R and Gottdiener, John S} } @article {1042, title = {Novel measures of heart rate variability predict cardiovascular mortality in older adults independent of traditional cardiovascular risk factors: the Cardiovascular Health Study (CHS).}, journal = {J Cardiovasc Electrophysiol}, volume = {19}, year = {2008}, month = {2008 Nov}, pages = {1169-74}, abstract = {

UNLABELLED: Novel HRV Predicts CV Mortality in the Elderly.

BACKGROUND: It is unknown whether abnormal heart rate turbulence (HRT) and abnormal fractal properties of heart rate variability identify older adults at increased risk of cardiovascular death (CVdth).

METHODS: Data from 1,172 community-dwelling adults, ages 72 +/- 5 (65-93) years, who participated in the Cardiovascular Health Study (CHS), a study of risk factors for CV disease in people >or=65 years. HRT and the short-term fractal scaling exponent (DFA1) derived from 24-hour Holter recordings. HRT categorized as: normal (turbulence slope [TS] and turbulence onset [TO] normal) or abnormal (TS and/or TO abnormal). DFA1 categorized as low (1). Cox regression analyses stratified by Framingham Risk Score (FRS) strata (low = <10, mid = 10-20, and high >20) and adjusted for prevalent clinical cardiovascular disease (CVD), diabetes, and quartiles of ventricular premature beat counts (VPCs).

RESULTS: CVdths (N = 172) occurred over a median follow-up of 12.3 years. Within each FRS stratum, low DFA1 + abnormal HRT predicted risk of CVdth (RR = 7.7 for low FRS; 3.6, mid FRS; 2.8, high FRS). Among high FRS stratum participants, low DFA1 alone also predicted CVdth (RR = 2.0). VPCs in the highest quartile predicted CVdth, but only in the high FRS group. Clinical CV disease predicted CVdth at each FRS stratum (RR = 2.9, low; 2.6, mid; and 1.9, high). Diabetes predicted CVdth in the highest FRS group only (RR = 2.2).

CONCLUSIONS: The combination of low DFA1 + abnormal HRT is a strong risk factor for CVdth among older adults even after adjustment for conventional CVD risk measures and the presence of CVD.

}, keywords = {Aged, Aged, 80 and over, Arrhythmias, Cardiac, Death, Sudden, Cardiac, Electrocardiography, Ambulatory, Female, Heart Rate, Humans, Male, Maryland, Reproducibility of Results, Risk Assessment, Risk Factors, Sensitivity and Specificity, Survival Analysis, Survival Rate}, issn = {1540-8167}, doi = {10.1111/j.1540-8167.2008.01232.x}, author = {Stein, Phyllis K and Barzilay, Joshua I and Chaves, Paulo H M and Mistretta, Stephanie Q and Domitrovich, Peter P and Gottdiener, John S and Rich, Michael W and Kleiger, Robert E} } @article {1069, title = {Heart rate variability and its changes over 5 years in older adults.}, journal = {Age Ageing}, volume = {38}, year = {2009}, month = {2009 Mar}, pages = {212-8}, abstract = {

PURPOSE: to characterise the association between age, ageing and heart rate variability (HRV) in older individuals, 585 adults age >65 years with two 24-h Holter recordings in the Cardiovascular Health Study were studied.

METHODS: heart rate (HR), ventricular premature contractions (VPCs), atrial premature contractions (APCs), frequency-domain, ratio-based and non-linear HRV and heart rate turbulence (HRT) were examined cross-sectionally by 5-year age groups and prospectively over 5 years. Analyses adjusted for gender, lower versus elevated cardiovascular (CV) risk and for the change in CV risk.

RESULTS: HR declined, and VPCs and APCs increased per 5-year increase in age. Frequency-domain HRV decreased more at 65-69, less at 70-74 and minimally at > or =75 years, independent of CVD risk or change in CVD risk. Ratio and non-linear HRV continued to decline to > or =75 years old. Ratio HRV and HRT slope were more strongly related to CVD risk than frequency-domain HRV.

CONCLUSIONS: cardiac autonomic function, assessed by frequency-domain HRV, declines most at 65-70 and levels off at age >75. The decline is independent of CVD risk or change in CVD risk. Ratio-based and non-linear HRV and HRT slope continued to change with increasing age and were more closely related to CVD risk than frequency-domain HRV.

}, keywords = {Age Distribution, Aged, Aging, Atrial Premature Complexes, Autonomic Nervous System, Cardiovascular Diseases, Cross-Sectional Studies, Electrocardiography, Ambulatory, Female, Heart Rate, Humans, Hypertension, Male, Nonlinear Dynamics, Prevalence, Prospective Studies, Risk Factors, Ventricular Premature Complexes}, issn = {1468-2834}, doi = {10.1093/ageing/afn292}, author = {Stein, Phyllis K and Barzilay, Joshua I and Chaves, Paulo H M and Domitrovich, Peter P and Gottdiener, John S} } @article {1216, title = {Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression.}, journal = {Psychosom Med}, volume = {72}, year = {2010}, month = {2010 Sep}, pages = {626-35}, abstract = {

OBJECTIVE: To investigate prospectively whether autonomic nervous system (ANS) dysfunction and inflammation play a role in the increased cardiovascular disease (CVD)-related mortality risk associated with depression.

METHODS: Participants in the Cardiovascular Health Study (n = 907; mean age, 71.3 {\textpm} 4.6 years; 59.1\% women) were evaluated for ANS indices derived from heart rate variability (HRV) analysis (frequency and time domain HRV, and nonlinear indices, including detrended fluctuation analysis (DFA(1)) and heart rate turbulence). Inflammation markers included C-reactive protein, interleukin-6, fibrinogen, and white blood cell count). Depressive symptoms were assessed, using the 10-item Centers for Epidemiological Studies Depression scale. Cox proportional hazards models were used to investigate the mortality risk associated with depression, ANS, and inflammation markers, adjusting for demographic and clinical covariates.

RESULTS: Depression was associated with ANS dysfunction (DFA(1), p = .018), and increased inflammation markers (white blood cell count, p = .012, fibrinogen p = .043) adjusting for covariates. CVD-related mortality occurred in 121 participants during a median follow-up of 13.3 years. Depression was associated with an increased CVD mortality risk (hazard ratio, 1.88; 95\% confidence interval, 1.23-2.86). Multivariable analyses showed that depression was an independent predictor of CVD mortality (hazard ratio, 1.72; 95\% confidence interval, 1.05-2.83) when adjusting for independent HRV and inflammation predictors (DFA(1), heart rate turbulence, interleukin-6), attenuating the depression-CVD mortality association by 12.7\% (p < .001).

CONCLUSION: Autonomic dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression, but a large portion of the predictive value of depression remains unexplained by these neuroimmunological measures.

}, keywords = {Aged, Autonomic Nervous System Diseases, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cause of Death, Cohort Studies, Comorbidity, Depressive Disorder, Electrocardiography, Female, Follow-Up Studies, Heart Rate, Humans, Inflammation, Interleukin-6, Leukocyte Count, Male, Risk Factors}, issn = {1534-7796}, doi = {10.1097/PSY.0b013e3181eadd2b}, author = {Kop, Willem J and Stein, Phyllis K and Tracy, Russell P and Barzilay, Joshua I and Schulz, Richard and Gottdiener, John S} } @article {1254, title = {Measures of adiposity and future risk of ischemic stroke and coronary heart disease in older men and women.}, journal = {Am J Epidemiol}, volume = {173}, year = {2011}, month = {2011 Jan 01}, pages = {10-25}, abstract = {

The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989-2007) in 3,754 community-dwelling US adults aged 65-100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (>= 30 kg/m{\texttwosuperior}) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25-29.9 kg/m{\texttwosuperior} was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95\% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95\% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.

}, keywords = {Adiposity, Age Factors, Aged, Aged, 80 and over, Brain Ischemia, Coronary Disease, Female, Humans, Incidence, Male, Middle Aged, Obesity, Prevalence, Retrospective Studies, Risk Factors, Sex Factors, United States}, issn = {1476-6256}, doi = {10.1093/aje/kwq311}, author = {Kizer, Jorge R and Biggs, Mary L and Ix, Joachim H and Mukamal, Kenneth J and Zieman, Susan J and de Boer, Ian H and Mozaffarian, Dariush and Barzilay, Joshua I and Strotmeyer, Elsa S and Luchsinger, Jos{\'e} A and Elkind, Mitchell S V and Longstreth, W T and Kuller, Lewis H and Siscovick, David S} } @article {1255, title = {Relationship of abnormal heart rate turbulence and elevated CRP to cardiac mortality in low, intermediate, and high-risk older adults.}, journal = {J Cardiovasc Electrophysiol}, volume = {22}, year = {2011}, month = {2011 Feb}, pages = {122-7}, abstract = {

INTRODUCTION: We examined whether heart rate turbulence (HRT) and C-reactive protein (CRP) add to traditional risk factors for cardiac mortality in older adults at low, intermediate, and high risk.

METHODS AND RESULTS: One thousand two hundred and seventy-two individuals, age >= 65 years, with 24-hour Holter recordings were studied. HRT, which quantifies heart rate response to ventricular premature contractions, was categorized as: both turbulence onset (TO) and turbulence slope (TS) normal; TO abnormal; TS abnormal; or both abnormal. Independent risks for cardiac mortality associated with HRT or, for comparison, elevated CRP (>3.0 mg/L), were calculated using Cox regression analysis adjusted for traditional cardiovascular disease risk factors and stratified by the presence of no, isolated subclinical (i.e., intermediate risk) or clinical cardiovascular disease. Having TS + TO abnormal compared to both normal was associated with cardiac mortality in the low-risk group [HR 7.9, 95\% confidence interval (CI) 2.8-22.5, (P < 0.001)]. In the high and intermediate risk groups, abnormal TS and TS + TO ([HR 2.2, 95\% CI 1.5-4.0, P = 0.016] and [HR 2.7, 95\% CI 1.2-5.9, P = 0.012]), respectively, were also significantly associated with cardiac mortality. In contrast, elevated CRP was associated with increased cardiac mortality risk only in low-risk individuals [HR 2.5, 95\% CI 1.3-5.1, P = 0.009]. Among low risk, the c-statistic was 0.706 for the base model, 0.725 for the base model with CRP, and 0.767 for the base model with HRT.

CONCLUSIONS: Abnormal HRT independently adds to risk stratification of low, intermediate and high-risk individuals, but HRT and CRP appear to both add to stratification of those considered low risk.

}, keywords = {Aged, C-Reactive Protein, Cardiovascular Diseases, Comorbidity, Electrocardiography, Ambulatory, Female, Humans, Incidence, Male, Risk Assessment, Risk Factors, Statistics as Topic, Survival Analysis, Survival Rate, United States, Ventricular Premature Complexes}, issn = {1540-8167}, doi = {10.1111/j.1540-8167.2010.01967.x}, author = {Stein, Phyllis K and Barzilay, Joshua I} } @article {1356, title = {Total and high-molecular-weight adiponectin and risk of incident diabetes in older people.}, journal = {Diabetes Care}, volume = {35}, year = {2012}, month = {2012 Feb}, pages = {415-23}, abstract = {

OBJECTIVE: To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults.

RESEARCH DESIGN AND METHODS: Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals.

RESULTS: Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95\% CI 0.39-0.63]) and HMW adiponectin (0.42 [0.32-0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables.

CONCLUSIONS: In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation.

}, keywords = {Adiponectin, Aged, Diabetes Mellitus, Female, Humans, Male, Risk Factors}, issn = {1935-5548}, doi = {10.2337/dc11-1519}, author = {Kizer, Jorge R and Arnold, Alice M and Benkeser, David and Ix, Joachim H and Djouss{\'e}, Luc and Zieman, Susan J and Barzilay, Joshua I and Tracy, Russell P and Mantzoros, Christos S and Siscovick, David S and Mukamal, Kenneth J} } @article {6555, title = {Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {374-382}, abstract = {

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.

METHODS AND RESULTS: Sequencing (mean depth, 38{\texttimes}) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9\% of which were rare (minor allele frequency <1\%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73{\texttimes}10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28{\texttimes}10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6\% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.

CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

}, keywords = {Aged, Aged, 80 and over, Aging, Blood Glucose, Chromosomes, Human, Pair 11, Cohort Studies, Death Domain Receptor Signaling Adaptor Proteins, Diabetes Mellitus, Type 2, Fasting, Female, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genomics, Guanine Nucleotide Exchange Factors, Heart Diseases, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000169}, author = {Cornes, Belinda K and Brody, Jennifer A and Nikpoor, Naghmeh and Morrison, Alanna C and Chu, Huan and Ahn, Byung Soo and Wang, Shuai and Dauriz, Marco and Barzilay, Joshua I and Dupuis, Jos{\'e}e and Florez, Jose C and Coresh, Josef and Gibbs, Richard A and Kao, W H Linda and Liu, Ching-Ti and McKnight, Barbara and Muzny, Donna and Pankow, James S and Reid, Jeffrey G and White, Charles C and Johnson, Andrew D and Wong, Tien Y and Psaty, Bruce M and Boerwinkle, Eric and Rotter, Jerome I and Siscovick, David S and Sladek, Robert and Meigs, James B} } @article {6375, title = {Circulating levels of carboxy-methyl-lysine (CML) are associated with hip fracture risk: the Cardiovascular Health Study.}, journal = {J Bone Miner Res}, volume = {29}, year = {2014}, month = {2014}, pages = {1061-6}, abstract = {

Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy-methyl-lysine (CML) are associated with risk of hip fracture.We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68{\textendash}102 years; 39.8\% male) for a median of 9.22 years (range, 0.01{\textendash}12.07 years). Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD)measurement. There were 348 hip fractures during follow-up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant-years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/mL) of CML level (hazard ratio, 1.27; 95\% confidence interval [CI], 1.16{\textendash}1.40]; p<0.001). Sequential adjustment for age, gender, race/ethnicity,body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture (1.17; 95\% CI, 1.05{\textendash}1.31; p=0.006).In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.

}, keywords = {Age Factors, Aged, Female, Follow-Up Studies, Glycation End Products, Advanced, Hip Fractures, Humans, Incidence, Lysine, Male, Prospective Studies, Retrospective Studies, Risk Factors}, issn = {1523-4681}, author = {Barzilay, Joshua I and B{\r u}zkov{\'a}, Petra and Zieman, Susan J and Kizer, Jorge R and Djouss{\'e}, Luc and Ix, Joachim H and Tracy, Russell P and Siscovick, David S and Cauley, Jane A and Mukamal, Kenneth J} } @article {6625, title = {Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Nov}, pages = {4116-23}, abstract = {

CONTEXT: Microvascular disease is a leading cause of cognitive impairment. Approximately 50\% of people with a hip fracture have cognitive impairment.

OBJECTIVE: We tested the hypothesis that microvascular diseases of the brain (lacunar infarcts and white matter disease [WMD]), kidney (albuminuria [>= 30 mg/g creatinine] and albumin creatinine ratio [ACR]), and eye (retinal vascular disorders) attenuate the association of cognitive impairment with hip fracture risk.

SETTING: The Cardiovascular Health Cognition Study.

PATIENTS: Three thousand, one-hundred six participants (mean age, \~{} 79 y; 8.84 y median follow-up) with cognitive testing. Subsets received ACR testing (n=2389), brain magnetic resonance imaging scans (n = 2094), and retinal photography (n = 1098).

MAIN OUTCOME MEASURE: Incident hip fracture.

RESULTS: There were 488 participants (16\%) with mild cognitive impairment (MCI) and 564 (18\%) with dementia. There were 337 incident hip fractures, of which 19\% occurred in participants with MCI and 26\% in participants with dementia. Adjusted hazard ratios (HR) and 95\% confidence interval for hip fracture in participants with MCI were 2.45 (1.67-3.61) and for dementia 2.35 (1.57-3.52). With doubling of ACR, the HR for fracture was attenuated in participants with dementia compared with participants with normal cognition [interaction HR 0.70 (0.55-0.91)]. No such effect was found in participants with MCI. Albuminuria, lacunar infarcts, WMD, and retinal vascular disease (RVD) did not modify the association of dementia or MCI with hip fracture risk.

CONCLUSIONS: ACR attenuates part of the risk of hip fracture in people with dementia, suggesting that these disorders share a common pathogenesis.

}, keywords = {Aged, Aged, 80 and over, Albuminuria, Creatinine, Dementia, Female, Hip Fractures, Humans, Incidence, Magnetic Resonance Imaging, Male, Mild Cognitive Impairment, Neuropsychological Tests, Prospective Studies, Risk}, issn = {1945-7197}, doi = {10.1210/jc.2014-2409}, author = {B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Fink, Howard A and Robbins, John A and Cauley, Jane A and Fitzpatrick, Annette L} } @article {6666, title = {Association of Fetuin-A With Incident Fractures in Community-Dwelling Older Adults: The Cardiovascular Health Study.}, journal = {J Bone Miner Res}, volume = {30}, year = {2015}, month = {2015 Aug}, pages = {1394-402}, abstract = {

Fetuin-A, a serum protein that regulates calcium mineralization, has been associated with bone mineral density (BMD) in several cross-sectional human studies, suggesting a possible beneficial effect on clinically important measures of bone health. Fetuin-A and incidence of subsequent fracture was assessed in 4714 men and women >=65 years of age. Proportional hazards models were used to estimate risk of incident hip (hospital discharge ICD-9 codes) and composite fracture (hip, pelvis, humerus, or proximal forearm; hospital discharge ICD-9 codes and Medicare claims data). A total of 576 participants had an incident hip fracture (median follow-up 11.2 years) and 768 had an incident composite fracture (median follow-up 6.9 years). In unadjusted analyses, there was no association between fetuin-A (per SD increase) and risk of hip fracture (hazard ratio [HR], 0.96; 95\% CI, 0.88 to 1.05) or composite fracture (HR, 0.99; 95\% CI, 0.92 to 1.06). Results were not significantly changed after adjustment for potential confounding variables. Analyses modeling fetuin-A in quartiles or within a subset with available BMD measures also showed no statistically significant association with risk of hip or composite fracture. Though fetuin-A was positively associated with areal BMD in partially adjusted models (total hip: β, 0.013 g/cm(2) ; 95\% CI, 0.005 to 0.021; femoral neck: β, 0.011 g/cm(2) ; 95\% CI, 0.004 to 0.018; and lumbar spine: β, 0.007 g/cm(2) ; 95\% CI, 0.001 to 0.028), these associations were no longer significant after further adjustment for BMI and in final multivariate models. In this large sample of community-dwelling older adults, a small positive association between fetuin-A and areal BMD appeared attributable to confounding variables and we found no evidence of an association between fetuin-A and risk of clinical fracture.

}, keywords = {Adult, Aged, Aged, 80 and over, alpha-2-HS-Glycoprotein, Bone Density, Cross-Sectional Studies, Female, Follow-Up Studies, Fractures, Bone, Humans, Incidence, Male, Models, Biological}, issn = {1523-4681}, doi = {10.1002/jbmr.2475}, author = {Fink, Howard A and B{\r u}zkov{\'a}, Petra and Garimella, Pranav S and Mukamal, Kenneth J and Cauley, Jane A and Kizer, Jorge R and Barzilay, Joshua I and Jalal, Diana I and Ix, Joachim H} } @article {6679, title = {Atherosclerotic cardiovascular disease in older adults with diabetes mellitus.}, journal = {Clin Geriatr Med}, volume = {31}, year = {2015}, month = {2015 Feb}, pages = {29-39, vii}, abstract = {

Diabetes mellitus exerts a strong effect on atherosclerotic cardiovascular disease risk into older age (beyond ages 70-74 years). This effect is particularly noticeable with regard to coronary artery disease and cerebral microvascular disease. Thus, diabetes mellitus in older adults deserves the same careful medical attention as it does in middle age.

}, keywords = {Age Factors, Aged, Coronary Artery Disease, Diabetes Mellitus, Type 2, Female, Humans, Male, Risk Factors, Survival Rate}, issn = {1879-8853}, doi = {10.1016/j.cger.2014.09.001}, author = {Barzilay, Joshua I and Mukamal, Kenneth J and Kizer, Jorge R} } @article {6850, title = {Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {71}, year = {2016}, month = {2016 Mar}, pages = {370-7}, abstract = {

BACKGROUND: Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse.

METHODS: Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic.

RESULTS: Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models.

CONCLUSION: In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life.

}, keywords = {Aged, Aging, Blood Glucose, Cardiovascular Diseases, Fasting, Female, Follow-Up Studies, Glucose, Glucose Tolerance Test, Health Surveys, Humans, Incidence, Male, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Survival Rate, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glv106}, author = {Brutsaert, Erika F and Shitole, Sanyog and Biggs, Mary Lou and Mukamal, Kenneth J and deBoer, Ian H and Thacker, Evan L and Barzilay, Joshua I and Djouss{\'e}, Luc and Ix, Joachim H and Smith, Nicholas L and Kaplan, Robert C and Siscovick, David S and Psaty, Bruce M and Kizer, Jorge R} } @article {8258, title = {Comment on Davis et al. Development and Validation of a Simple Hip Fracture Risk Prediction Tool for Type 2 Diabetes: The Fremantle Diabetes Study Phase I. Diabetes Care 2018;42:102-109.}, journal = {Diabetes Care}, volume = {42}, year = {2019}, month = {2019 06}, pages = {e100}, keywords = {Diabetes Mellitus, Type 2, Hip Fractures, Humans}, issn = {1935-5548}, doi = {10.2337/dc19-0204}, author = {B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I} } @article {9004, title = {Cardiovascular autonomic nervous system function and hip fracture risk: the Cardiovascular Health Study.}, journal = {Arch Osteoporos}, volume = {16}, year = {2021}, month = {2021 10 31}, pages = {163}, abstract = {

Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15~years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants.

PURPOSE: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans.

METHODS: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8~years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7~years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95\% confidence intervals, CI).

RESULTS: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24~h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95\% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95\% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other{\textquoteright}s association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95\% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men.

CONCLUSIONS: In older women, increased heart rate variation is associated with hip fracture risk.

}, keywords = {Aged, Autonomic Nervous System, Female, Heart Rate, Hip Fractures, Humans, Osteoporosis, Proportional Hazards Models}, issn = {1862-3514}, doi = {10.1007/s11657-021-01028-y}, author = {Stein, Phyllis K and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Robbins, John A and Mukamal, Kenneth J and Cauley, Jane A and Carbone, Laura and Elam, Rachel and McMillan, David W and Valderrabano, Rodrigo and Barzilay, Joshua I} } @article {9155, title = {The Association of Measures of Cardiovascular Autonomic Function, Heart Rate, and Orthostatic Hypotension With Incident Glucose Disorders: The Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {45}, year = {2022}, month = {2022 10 01}, pages = {2376-2382}, abstract = {

OBJECTIVE: The autonomic nervous system (ANS) innervates pancreatic endocrine cells, muscle, and liver, all of which participate in glucose metabolism. We tested whether measures of cardiovascular ANS function are independently associated with incident diabetes and annual change in fasting glucose (FG) levels as well as with insulin secretion and insulin sensitivity in older adults without diabetes.

RESEARCH DESIGN AND METHODS: Heart rate (HR) and measures of HR variability (HRV) were derived from 24-h electrocardiographic monitoring. Blood pressure, seated and standing, was measured. Cox proportional hazards models and linear mixed models were used to analyze the associations between HRV, HR, and orthostatic hypotension (SBP >20 mmHg decline) and incident diabetes or longitudinal FG change.

RESULTS: The mean annual unadjusted FG change was 1 mg/dL. Higher detrended fluctuation analyses (DFA) values, averaged over 4-11 (DFA1) or 12-20 beats (DFA2)-reflecting greater versus less organization of beat-to-beat intervals-were associated with less FG increase over time (per 1-SD increment: DFA1: -0.49 mg/dL/year [-0.96, -0.03]; DFA2: -0.55 mg/dL/year [-1.02, -0.09]). In mutually adjusted analyses, higher SD of the N-N interval (SDNN) was associated with less FG increase over time (per 1-SD increment: SDNN: -0.62 mg/dL/year [-1.22, -0.03]). Higher values of DFA1, DFA2, and SDNN were each associated with greater insulin secretion and insulin sensitivity but not with incident diabetes. We observed no association of HR or orthostatic hypotension with diabetes or FG change.

CONCLUSIONS: Specific measures of cardiac autonomic function are prospectively related to FG level changes and insulin secretion and action.

}, keywords = {Aged, Autonomic Nervous System, Blood Glucose, Diabetes Mellitus, Glucose, Heart Rate, Humans, Hypotension, Orthostatic, Insulin Resistance}, issn = {1935-5548}, doi = {10.2337/dc22-0553}, author = {Barzilay, Joshua I and Tressel, William and Biggs, Mary L and Stein, Phyllis K and Kizer, Jorge R and Shitole, Sanyog G and Bene-Alhasan, Yakubu and Mukamal, Kenneth J} } @article {9089, title = {Trimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study.}, journal = {Bone}, volume = {161}, year = {2022}, month = {2022 08}, pages = {116431}, abstract = {

CONTEXT: Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain.

OBJECTIVE: Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults.

DESIGN AND SETTING: Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study.

PARTICIPANTS: 5019~U.S. adults aged >=65~years.

EXPOSURE: Plasma TMAO.

MAIN OUTCOME MEASURES: Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n~=~1400).

RESULTS: Six hundred sixty-six incident hip fractures occurred during up to 26~years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95\% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95\% CI] of 0.42~g/cm*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P~<~0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI~>=~25) (HR [95\% CI]:1.17[1.05,1.31]), but not normal or underweight.

CONCLUSIONS: Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.

}, keywords = {Absorptiometry, Photon, Aged, Bone Density, Female, Hip Fractures, Humans, Male, Methylamines, Risk Factors}, issn = {1873-2763}, doi = {10.1016/j.bone.2022.116431}, author = {Elam, Rachel E and B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Wang, Zeneng and Nemet, Ina and Budoff, Matthew J and Cauley, Jane A and Fink, Howard A and Lee, Yujin and Robbins, John A and Wang, Meng and Hazen, Stanley L and Mozaffarian, Dariush and Carbone, Laura D} } @article {9242, title = {Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study.}, journal = {Osteoporos Int}, volume = {34}, year = {2023}, month = {2023 Jan}, pages = {91-99}, abstract = {

UNLABELLED: Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture.

INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture.

METHODS: A prospective cohort of 3373 community-dwelling adults aged >= 65~years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive).

RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8~years. The demographic-adjusted hazard of incident hip fracture was 32\% higher among participants with >= 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95\% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95\% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95\% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95\% CI, 0.98-1.23); risk in individuals whose largest infarct was >= 20~mm versus 3 to < 20~mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95\% CI, 1.09-1.66) and 1.83 (95\% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95\% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95\% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95\% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95\% CI, 0.95-1.90).

CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.

}, keywords = {Aged, Brain Infarction, Frailty, Hip Fractures, Humans, Prospective Studies, Risk Factors, White Matter}, issn = {1433-2965}, doi = {10.1007/s00198-022-06565-x}, author = {Sheets, Kerry M and B{\r u}zkov{\'a}, Petra and Chen, Zhao and Carbone, Laura D and Cauley, Jane A and Barzilay, Joshua I and Starks, Jamie L and Miller, Lindsay M and Fink, Howard A} } @article {9316, title = {The associations of markers of endothelial dysfunction with hip fracture risk.}, journal = {Arch Osteoporos}, volume = {18}, year = {2023}, month = {2023 Mar 02}, pages = {39}, abstract = {

UNLABELLED: Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them.

PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk.

METHODS: Participants for this study were 2792 individuals (mean age 78.6~years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3~years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7~years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group.

RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1\% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80\% of FMD (<= 4.5\%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20\% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable.

CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

}, keywords = {Aged, Forearm, Hip Fractures, Humans, Osteoporotic Fractures, Vascular Diseases}, issn = {1862-3514}, doi = {10.1007/s11657-023-01226-w}, author = {Barzilay, Joshua I and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Cauley, Jane A and Carbone, Laura and Elam, Rachel and Robbins, John A and Stein, Phyllis and Sheets, Kerry and Jalal, Diana and Mukamal, Kenneth J} } @article {9701, title = {Association of serum levels of phenylalanine and tyrosine with hip fractures and frailty in older adults: The cardiovascular health study.}, journal = {Arch Osteoporos}, volume = {19}, year = {2024}, month = {2024 Jun 20}, pages = {51}, abstract = {

UNLABELLED: This study examined if the amino acids phenylalanine or tyrosine contribute to risk of hip fracture or frailty in older adults. We determined that neither phenylalanine nor tyrosine are important predictors of hip fracture or frailty. We suggest advice on protein intake for skeletal health consider specific amino acid composition.

PURPOSE: Protein is essential for skeletal health, but the specific amino acid compositions of protein may have differential associations with fracture risk. The aim of this study was to determine the association of serum levels of the aromatic amino acids phenylalanine and tyrosine with risk for incident hip fractures over twelve years of follow-up and cross sectional associations with frailty.

METHODS: We included 131 older men and women from the Cardiovascular Health Study (CHS) who sustained a hip fracture over twelve years of follow-up and 131 men and women without an incident hip fracture over this same period of time. 42\% of this cohort were men and 95\% were Caucasian. Weighted multivariable Cox hazards molecules were used to estimate the hazard ratios (HR) and 95\% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher serum level of phenylalanine or tyrosine. Relative risk regression was used to determine the cross-sectional association of these amino acids with Freid{\textquoteright}s frailty index.

RESULTS: Neither serum levels of phenylalanine (HR 0.85 (95\% CI 0.62-1.16) or tyrosine (HR 0.82 (95\% CI 0.62-1.1) were significantly associated with incident hip fractures or cross sectionally with frailty (frail compared with prefrail/not frail) (HR 0.92 (95\% CI 0.48-1.76) and HR (0.86 (95\% CI 0.46-1.61) respectively.

CONCLUSION: Phenylalanine and tyrosine are not significant contributors to hip fractures or frailty in older men and women.

}, keywords = {Aged, Aged, 80 and over, Cross-Sectional Studies, Female, Frail Elderly, Frailty, Hip Fractures, Humans, Male, Phenylalanine, Risk Factors, Tyrosine}, issn = {1862-3514}, doi = {10.1007/s11657-024-01408-0}, author = {Carbone, Laura and B{\r u}zkov{\'a}, Petra and Robbins, John A and Fink, Howard A and Barzilay, Joshua I and Elam, Rachel E and Isales, Carlos} }