@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 {707, title = {Left atrial dimensions determined by M-mode echocardiography in black and white older (> or =65 years) adults (The Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {90}, year = {2002}, month = {2002 Nov 01}, pages = {983-7}, abstract = {

Stroke and atrial fibrillation are common and serious illnesses in the elderly, the risks of which are substantially increased by left atrial (LA) enlargement. Despite growing recognition of the importance of LA enlargement, the distribution and correlates of LA dimension in the elderly have not been well defined. A total of 3,882 women and men aged >65 years were studied. Increased LA dimension was independently associated with increased weight, mitral annular calcium, regional wall motion abnormalities, mitral early peak inflow velocity, and left ventricular (LV) fractional shortening. Increased LA dimension was negatively associated with aortic leaflet thickening. The relation with LV fractional shortening was curvilinear with a nadir at 35\% to 40\%. LA dimension in black men was approximately 1.9 mm less than in white men in multivariate analyses. Adjustment for spirometric lung volumes and chest dimensions appeared to diminish the race-LA dimension relation. Thus, LA dimension is strongly associated with weight and with several echocardiographic valvular abnormalities; its relation with LV fractional shortening is U-shaped with a nadir at the borderline of LV functional impairment.

}, keywords = {African Continental Ancestry Group, Age Factors, Aged, Blood Flow Velocity, Body Weight, Cardiovascular Diseases, Echocardiography, Electrocardiography, European Continental Ancestry Group, Evidence-Based Medicine, Female, Heart Atria, Heart Ventricles, Humans, Male, Multivariate Analysis, Prospective Studies, Risk Factors, Statistics as Topic, Ventricular Function, Left}, issn = {0002-9149}, doi = {10.1016/s0002-9149(02)02665-6}, author = {Manolio, Teri A and Gottdiener, John S and Tsang, Teresa S M and Gardin, Julius M} } @article {705, title = {Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study.}, journal = {Ann Intern Med}, volume = {137}, year = {2002}, month = {2002 Oct 15}, pages = {631-9}, abstract = {

BACKGROUND: Most persons with congestive heart failure are elderly, and many elderly persons with congestive heart failure have normal left ventricular systolic function.

OBJECTIVE: To evaluate the relationship between left ventricular systolic function and outcome of congestive heart failure in elderly persons.

DESIGN: Population-based longitudinal study of coronary heart disease and stroke.

SETTING: Four U.S. sites: Forsyth County, North Carolina; Sacramento County, California; Allegheny County, Pennsylvania; and Washington County, Maryland.

PARTICIPANTS: 5888 persons who were at least 65 years of age and were recruited from the community.

MEASUREMENTS: Total mortality and cardiovascular morbidity and mortality.

RESULTS: Of 5532 participants, 269 (4.9\%) had congestive heart failure. Among these, left ventricular function was normal in 63\%, borderline decreased in 15\%, and overtly impaired in 22\%. The mortality rate was 25 deaths per 1000 person-years in the reference group (no congestive heart failure and normal left ventricular function at baseline); 154 deaths per 1000 person-years in participants with congestive heart failure and impaired left ventricular systolic function; 87 and 115 deaths per 1000 person-years in participants with congestive heart failure and normal or borderline systolic function, respectively; and 89 deaths per 1000 person-years in persons with impaired left ventricular function but no congestive heart failure. Although the risk for death from congestive heart failure was lower in persons with normal systolic function than in those with impaired function, more deaths were associated with normal systolic function because more persons with heart failure fall into this category.

CONCLUSIONS: Community-dwelling elderly persons, especially those with impaired left ventricular function, have a substantial risk for death from congestive heart failure. However, more deaths occur from heart failure in persons with normal systolic function because left ventricular function is more often normal than impaired in elderly persons with heart failure.

}, keywords = {Aged, Cause of Death, Echocardiography, Female, Heart Failure, Humans, Longitudinal Studies, Male, Myocardial Infarction, Prevalence, Prognosis, Risk Factors, Stroke, Ventricular Dysfunction, Right, Ventricular Function, Left}, issn = {1539-3704}, doi = {10.7326/0003-4819-137-8-200210150-00006}, author = {Gottdiener, John S and McClelland, Robyn L and Marshall, Robert and Shemanski, Lynn and Furberg, Curt D and Kitzman, Dalane W and Cushman, Mary and Polak, Joseph and Gardin, Julius M and Gersh, Bernard J and Aurigemma, Gerard P and Manolio, Teri A} } @article {674, title = {The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study.}, journal = {Br J Ophthalmol}, volume = {86}, year = {2002}, month = {2002 Jan}, pages = {84-90}, abstract = {

AIMS: To describe the association of retinopathy with atherosclerosis and atherosclerotic risk factors in people with diabetes.

METHODS: 296 of the 558 people classified as having diabetes by the American Diabetes Association criteria, from a population based cohort of adults (ranging in age from 69 to 102 years) living in four United States communities (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were studied from 1997 to 1998. Lesions typical of diabetic retinopathy were determined by grading a 45 degrees colour fundus photograph of one eye of each participant, using a modification of the Airlie House classification system.

RESULTS: Retinopathy was present in 20\% of the diabetic cohort, with the lowest prevalence (16\%), in those 80 years of age or older. Retinopathy was detected in 20.3\% of the 296 people with diabetes; 2.7\% of the 296 had signs of proliferative retinopathy and 2.1\% had signs of macular oedema. The prevalence of diabetic retinopathy was higher in black people (35.4\%) than white (16.0\%). Controlling for age, sex, and blood glucose, retinopathy was more frequent in black people than white (odds ratio (OR) 2.26, 95\% confidence interval (CI) 1.01, 5.05), in those with longer duration of diabetes (OR (per 5 years of diabetes) 1.42, 95\% CI 1.18, 1.70), in those with subclinical cardiovascular disease (OR 1.49, 95\% CI 0.51, 4.31), or coronary heart disease or stroke (OR 3.23, 95\% CI 1.09, 9.56) than those without those diseases, in those with higher plasma low density lipoprotein (LDL) cholesterol (OR (per 10 mg/dl of LDL cholesterol) 1.12, 95\% CI 1.02, 1.23), and in those with gross proteinuria (OR 4.76, 95\% CI 1.53, 14.86).

CONCLUSION: Data from this population based study suggest a higher prevalence of retinopathy in black people than white people with diabetes and the association of cardiovascular disease, elevated plasma LDL cholesterol, and gross proteinuria with diabetic retinopathy. However, any conclusions or explanations regarding associations described here must be made with caution because only about one half of those with diabetes mellitus were evaluated.

}, keywords = {Age of Onset, Aged, Aged, 80 and over, Arteriosclerosis, Black People, Blood Pressure, Cohort Studies, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Female, Humans, Longitudinal Studies, Male, Odds Ratio, Prospective Studies, Regression Analysis, Risk Factors, Time Factors, White People}, issn = {0007-1161}, doi = {10.1136/bjo.86.1.84}, author = {Klein, Ronald and Marino, Emily K and Kuller, Lewis H and Polak, Joseph F and Tracy, Russell P and Gottdiener, John S and Burke, Gregory L and Hubbard, Larry D and Boineau, Robin} } @article {708, title = {Time trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {162}, year = {2002}, month = {2002 Nov 11}, pages = {2325-32}, abstract = {

BACKGROUND: Control of high blood pressure (BP) in older adults is an important part of public health efforts at prevention.

OBJECTIVE: To assess recent time trends in the awareness, treatment, and control of high BP and in the use of medications to treat high BP.

METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline, participants underwent an extensive examination that included the measurement of BP, use of medications, and other risk factors. Participants were followed up with annual visits that assessed BP and medication use from baseline in 1989-1990 through the examination in 1998-1999. The primary outcome measures were control of BP to levels lower than than 140/90 mm Hg and the prevalence of use of various classes of antihypertensive medications.

RESULTS: The awareness, treatment, and control of high BP improved during the 1990s. The proportions aware and treated were higher among blacks than whites, though control prevalences were similar. For both groups combined, the control of high BP to lower than 140/90 mm Hg increased from 37\% at baseline to 49\% in 1999. The 51\% whose BP was not controlled generally had isolated mild to moderate elevations in systolic BP. Among treated persons, the improvement in control was achieved in part by a mean increase of 0.2 antihypertensive medications per person over the course of 9 years. Improved control was also achieved by increasing the proportion of the entire Cardiovascular Health Study population that was treated for hypertension, from 34.5\% in 1990 to 51.1\% in 1999. Time trends in antihypertensive drug use were pronounced. Among those without coronary disease, the use of low-dose diuretics and beta-blockers decreased, while the use of newer agents, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers increased.

CONCLUSIONS: While control of high BP improved in the 1990s, about half the participants with hypertension had uncontrolled BP, primarily mild to moderate elevations in systolic BP. Low-dose diuretics and beta-blockers--the preferred agents since 1993 according to the recommendations of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure--remained underused. More widespread use of these agents will be an important intervention to prevent the devastating complications of hypertension, including stroke, myocardial infarction, and heart failure.

}, keywords = {Age Factors, Aged, Antihypertensive Agents, Awareness, Cohort Studies, Drug Therapy, Female, Health Knowledge, Attitudes, Practice, Humans, Hypertension, Male, Prospective Studies, Time Factors}, issn = {0003-9926}, doi = {10.1001/archinte.162.20.2325}, author = {Psaty, Bruce M and Manolio, Teri A and Smith, Nicholas L and Heckbert, Susan R and Gottdiener, John S and Burke, Gregory L and Weissfeld, Joel and Enright, Paul and Lumley, Thomas and Powe, Neil and Furberg, Curt D} } @article {761, title = {The association between the length of the QT interval and mortality in the Cardiovascular Health Study.}, journal = {Am J Med}, volume = {115}, year = {2003}, month = {2003 Dec 15}, pages = {689-94}, abstract = {

PURPOSE: A long QT interval is a risk factor for arrhythmic events and sudden death. Whether moderate QT prolongation is associated with clinical events in community-dwelling elderly patients is uncertain.

METHODS: We measured the QT interval in a population-based sample of 5888 men and women at least 65 years of age who were participants in the Cardiovascular Health Study. The association between Bazett{\textquoteright}s rate-corrected QT (QTc, in ms) and mortality during the subsequent 10 years was evaluated. We stratified participants by the presence or absence of coronary heart disease status at baseline, and adjusted for coronary heart disease risk factors.

RESULTS: The rates of all-cause and coronary heart disease mortality were greater in participants with longer QTc intervals. Among participants without known coronary heart disease, those whose QTc interval was >450 ms were at increased risk of all-cause mortality (relative risk [RR] = 1.34; 95\% confidence interval [CI]: 1.07 to 1.67) and coronary heart disease mortality (RR = 1.6; 95\% CI: 1.0 to 2.5) when compared with participants whose QTc interval was <410 ms. The associations were stronger among those with known coronary heart disease (RR for all-cause mortality = 2.3; 95\% CI: 1.6 to 3.3; and RR for coronary heart disease mortality = 2.0; 95\% CI: 1.1 to 3.7).

CONCLUSIONS: The QT interval from the standard electrocardiograms is of value for identification of elderly persons at increased risk of coronary heart disease and total mortality. A QTc interval >450 ms should prompt clinical evaluation and possible interventions to reduce the risk of coronary events.

}, keywords = {Aged, Arrhythmias, Cardiac, Cause of Death, Coronary Disease, Electrocardiography, Female, Follow-Up Studies, Heart Rate, Humans, Male, Randomized Controlled Trials as Topic, Risk Factors, Statistics as Topic, Survival Analysis, United States}, issn = {0002-9343}, doi = {10.1016/j.amjmed.2003.07.014}, author = {Robbins, John and Nelson, Jennifer Clark and Rautaharju, Pentti M and Gottdiener, John S} } @article {734, title = {The prevalence and risk factors of retinal microvascular abnormalities in older persons: The Cardiovascular Health Study.}, journal = {Ophthalmology}, volume = {110}, year = {2003}, month = {2003 Apr}, pages = {658-66}, abstract = {

PURPOSE: To describe the prevalence of retinal microvascular characteristics and their associations with atherosclerosis in elderly, nondiabetic persons.

DESIGN AND PARTICIPANTS: Population-based, cross-sectional study comprising 2050 men and women aged 69 to 97 years without diabetes, living in four communities.

METHODS: Participants underwent retinal photography and standardized grading of retinal microvascular characteristics, including retinopathy (e.g., microaneurysms, retinal hemorrhages), focal arteriolar narrowing, and arteriovenous nicking. In addition, calibers of retinal arterioles and venules were measured on digitized photographs to obtain an estimate of generalized arteriolar narrowing. Atherosclerosis and its risk factors were obtained from clinical examination and laboratory investigations.

MAIN OUTCOME MEASURES: Prevalence of retinal microvascular abnormalities and their associations with measures of atherosclerosis.

RESULTS: The prevalence of retinal microvascular abnormalities was 8.3\% for retinopathy, 9.6\% for focal arteriolar narrowing, and 7.7\% for arteriovenous nicking. All retinal lesions were associated with hypertension (odds ratios [OR] were 1.8 for retinopathy, 2.1 for focal arteriolar narrowing, 1.5 for arteriovenous nicking, and 1.7 for generalized arteriolar narrowing). After controlling for age, gender, race, mean arterial blood pressure, and antihypertensive medication use, retinopathy was associated with prevalent coronary heart disease (OR, 1.7), prevalent myocardial infarction (OR, 1.7), prevalent stroke (OR, 2.0), presence of carotid artery plaque (OR, 1.9), and increased intima-media thickness of the common carotid (OR, 2.3; fourth vs. first quartile) and internal carotid (OR, 1.8; fourth vs. first quartile) arteries. In contrast, focal arteriolar narrowing, arteriovenous nicking, and generalized arteriolar narrowing were not associated with any measures of atherosclerosis.

CONCLUSIONS: Retinal microvascular abnormalities are common in older persons without diabetes and are related to hypertension. Retinopathy is associated with prevalent coronary heart disease, stroke, and carotid artery thickening, but focal and generalized arteriolar narrowing and arteriovenous nicking are not related to most measures of atherosclerosis. These data suggest that retinal microvascular abnormalities reflect processes associated with hypertension but distinct from atherosclerosis.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, Coronary Artery Disease, Cross-Sectional Studies, Female, Humans, Hypertension, Male, Prevalence, Retinal Diseases, Retinal Vessels, Risk Factors, United States}, issn = {0161-6420}, doi = {10.1016/S0161-6420(02)01931-0}, author = {Wong, Tien Yin and Klein, Ronald and Sharrett, A Richey and Manolio, Teri A and Hubbard, Larry D and Marino, Emily K and Kuller, Lewis and Burke, Gregory and Tracy, Russell P and Polak, Joseph F and Gottdiener, John S and Siscovick, David S} } @article {735, title = {Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals.}, journal = {J Am Coll Cardiol}, volume = {41}, year = {2003}, month = {2003 Apr 16}, pages = {1364-72}, abstract = {

OBJECTIVES: This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events.

BACKGROUND: End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear.

METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl in men or > or =1.3 mg/dl in women.

RESULTS: An elevated creatinine level was present in 648 (11.2\%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine.

CONCLUSIONS: Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.

}, keywords = {Aged, Cardiovascular Diseases, Confidence Intervals, Creatinine, Female, Heart Failure, Humans, Intermittent Claudication, Kidney Failure, Chronic, Male, Odds Ratio, Predictive Value of Tests, Survival Analysis}, issn = {0735-1097}, doi = {10.1016/s0735-1097(03)00163-3}, author = {Fried, Linda F and Shlipak, Michael G and Crump, Casey and Bleyer, Anthony J and Gottdiener, John S and Kronmal, Richard A and Kuller, Lewis H and Newman, Anne B} } @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 {771, title = {Congestive heart failure in the elderly: the Cardiovascular Health Study.}, journal = {Am J Geriatr Cardiol}, volume = {13}, year = {2004}, month = {2004 Mar-Apr}, pages = {61-8}, abstract = {

Congestive heart failure in the elderly is recognized as a national public health priority; however, clinical diagnosis can be problematic in elderly persons, many of whom have a history of heart failure in the presence of normal or only minimally decreased ejection fraction. Findings of the Cardiovascular Health Study have underscored the common substrate and predictors underlying heart failure both with decreased ejection fraction and with normal ejection fraction (i.e., diastolic heart failure). Coronary heart disease, systolic blood pressure, and C-reactive protein (a measure of inflammation) are predictive of heart failure independent of ejection fraction. Left atrial size, arguably a marker of the effects of impaired diastolic filling over time, is increased in both systolic and diastolic heart failure of the elderly, as is atrial natriuretic peptide. The outcome of heart failure in elderly persons is poor both for systolic and diastolic heart failure. Moreover, many community-dwelling elderly persons have decreased ejection fraction without heart failure. In these persons the chance of death is similar to that of participants with diastolic heart failure. Since most clinical trials have studied younger patients with predominantly systolic heart failure, the appropriate therapy for heart failure in elderly persons remains to be determined.

}, keywords = {Aged, Aged, 80 and over, Atrial Natriuretic Factor, Blood Pressure, Diagnosis, Differential, Female, Geriatric Assessment, Heart Atria, Heart Failure, Heart Rate, Humans, Incidence, Male, Prevalence, Risk Factors, Stroke Volume, United States, Ventricular Dysfunction, Left}, issn = {1076-7460}, doi = {10.1111/j.1076-7460.2004.02121.x}, author = {Mathew, Sunil T and Gottdiener, John S and Kitzman, Dalane and Aurigemma, Gerard} } @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 {787, title = {Predictors of falling cholesterol levels in older adults: the Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {14}, year = {2004}, month = {2004 May}, pages = {325-31}, abstract = {

PURPOSE: To estimate 4-year change in serum total cholesterol levels in a population-based sample of older adults and identify independent predictors of cholesterol decline.

METHODS: Prospective study of 2837 adults aged 65 years and older with serum cholesterol measured in 1992-1993 and 1996-1997.

RESULTS: Mean serum cholesterol levels declined 6.3 mg/dl between the two examinations. Declines were greater in white (-7.3 mg/dl) than black (-1.4 mg/dl) participants and in those in good/excellent health (-0.9 mg/dl) vs. fair/poor health (-3.1 mg/dl; both p < 0.01). Factors associated with greater decline on multivariate analysis included age, male gender, and higher white cell count, albumin, and baseline cholesterol. Cholesterol levels declined 2.0 mg/dl per 6 year increment in baseline age and 6.8 mg/dl more in men than women after adjustment for other factors. C-reactive protein levels were unrelated to cholesterol change.

CONCLUSION: Declining cholesterol levels were associated with male gender, advanced age, weight loss, and white blood cell count but not with C-reactive protein levels. The role of declining cholesterol synthesis, due to as yet undefined age-related changes or to cytokine-mediated reductions related to illness, should be examined to help clarify the mechanisms of the sometimes marked declines in cholesterol levels observed at advanced ages.

}, keywords = {African Americans, Age Factors, Aged, Cardiovascular Diseases, Cholesterol, European Continental Ancestry Group, Female, Forecasting, Health Status, Humans, Male, Medicare, Prospective Studies, Risk Factors, Sex Distribution, Sex Factors, United States}, issn = {1047-2797}, doi = {10.1016/j.annepidem.2003.09.006}, author = {Manolio, Teri A and Cushman, Mary and Gottdiener, John S and Dobs, Adrian and Kuller, Lewis H and Kronmal, Richard A} } @article {807, title = {Time trends in the use of beta-blockers and other pharmacotherapies in older adults with congestive heart failure.}, journal = {Am Heart J}, volume = {148}, year = {2004}, month = {2004 Oct}, pages = {710-7}, abstract = {

BACKGROUND: Evidence supporting pharmacotherapy of congestive heart failure (CHF) has grown substantially over the past decade and includes large, placebo-controlled trials with mortality end points. We describe beta-blocker and other medication temporal treatment trends of CHF in the Cardiovascular Health Study, a community-based cohort study of 5888 adults > or =65 years of age.

METHODS: Prescription medication data were collected from hospital discharge summaries for incident CHF events and at in-study annual clinic visits for prevalent CHF cases from 1989 to 2000. Change in use of agents over time was estimated by using generalized estimating equations while adjusting for potential confounding factors of age, sex, race, and cardiovascular and pulmonary comorbidities.

RESULTS: Among 1033 incident CHF events, beta-blocker use after diagnosis increased an average of 2.4 percentage points annually (95\% CI, 1.5 to 3.4 points) from 1989 to 2000. The increasing trend was consistent throughout follow-up. Among participants with coronary disease and/or hypertension and among those with low ejection fractions (<45\%), beta-blocker use remained flat from 1989 to 1994 and increased 4.7 points annually (2.5 to 6.9) and 10.0 points annually (6.1 to 13.8), respectively, from 1995 to 2000. Among participants without coronary disease or hypertension, there was no overall increase in use. Use of renin-angiotensin system inhibitors increased 2.3 points annually (1.0 to 3.5), digoxin use decreased 2.4 points annually (-3.6 to -1.1), and loop diuretic use remained flat between 1989 and 2000. In general, treatment trends were similar for prevalent CHF.

CONCLUSIONS: Treatment of CHF has changed gradually in the 1990s and may in part reflect the influence of CHF clinical trial evidence.

}, keywords = {Adrenergic beta-Antagonists, Aged, Angiotensin II Type 1 Receptor Blockers, Angiotensin-Converting Enzyme Inhibitors, Cohort Studies, Drug Therapy, Drug Therapy, Combination, Female, Heart Failure, Humans, Male, Multivariate Analysis, Prevalence}, issn = {1097-6744}, doi = {10.1016/j.ahj.2004.04.002}, author = {Smith, Nicholas L and Chan, Jeannie D and Rea, Thomas D and Wiggins, Kerri L and Gottdiener, John S and Lumley, Thomas and Psaty, Bruce M} } @article {895, title = {Cardiovascular morbidity and mortality in community-dwelling elderly individuals with calcification of the fibrous skeleton of the base of the heart and aortosclerosis (The Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {97}, year = {2006}, month = {2006 May 01}, pages = {1281-6}, abstract = {

In the elderly, mitral annular calcification (MAC) and aortic valve sclerosis (AVS) are associated with increased cardiovascular morbidity and mortality. Aortic annular calcification (AAC) commonly occurs with MAC. However, the prognostic value of AAC, singly or in combination with MAC and AVS, for incident cardiovascular disease and mortality is unknown. From the Cardiovascular Health Study, we analyzed 3,782 participants (76 +/- 5 years of age, 60\% women) who had an echocardiogram at the 1994 to 1995 examination and who were prospectively followed for an average of 6.6 years (range 0.01 to 8.5). All 3 calcification categories were associated with incident congestive heart failure (MAC: hazard ratio [HR] 1.71, 95\% confidence interval [CI] 1.35 to 2.18, AAC: HR 1.62, 95\% CI 1.28 to 2.06, and AVS: HR 1.50, 95\% CI 1.19 to 1.89) and death. A stronger association with incident cardiovascular disease and mortality was observed with a larger number of calcification categories and with increased MAC severity. Moreover, in the participants with prevalent cardiovascular disease at echocardiographic examination (n = 1,054), MAC and AAC were still associated with cardiovascular mortality (MAC: HR 1.91, 95\% CI 1.04 to 3.50; AAC: HR 2.11, 95\% CI 1.16 to 3.85) even in fully adjusted models. In conclusion, MAC, AAC, and AVS are associated with a significant risk of incident congestive heart failure, cardiovascular and all-cause mortalities, and worse outcome in older patients with preexisting cardiovascular disease. Elderly patients with these findings represent a high-risk group and may require close medical attention.

}, keywords = {Aged, Aortic Valve, Calcinosis, Echocardiography, Female, Follow-Up Studies, Heart Failure, Heart Valve Diseases, Humans, Male, Mitral Valve, Prospective Studies, Risk Factors, Sclerosis, Severity of Illness Index, United States}, issn = {0002-9149}, doi = {10.1016/j.amjcard.2005.11.065}, author = {Barasch, Eddy and Gottdiener, John S and Marino Larsen, Emily K and Chaves, Paulo H M and Newman, Anne B} } @article {874, title = {Clinical significance of calcification of the fibrous skeleton of the heart and aortosclerosis in community dwelling elderly. The Cardiovascular Health Study (CHS).}, journal = {Am Heart J}, volume = {151}, year = {2006}, month = {2006 Jan}, pages = {39-47}, abstract = {

BACKGROUND: Mitral annular calcification (MAC), aortic annular calcification (AAC), and aortic valve sclerosis (AVS) are associated with aging, and MAC and AVS are markers of advanced atherosclerosis. No studies have examined the prevalence and the clinical relevance of all 3 forms of calcification in a single free-living elderly population.

METHODS: We used 2-dimensional echocardiography to evaluate MAC, AAC, AVS and all 3 combined in 3929 participants, mean age 76 +/- 5 years, 60\% women, in the Cardiovascular Health Study, a prospective community-based observational study designed to assess cardiovascular disease (CVD) risk factors and outcomes in elderly persons.

RESULTS: Mitral annular calcification was found in 1640 (42 \%) subjects, AAC in 1710 (44 \%), AVS in 2114 (54 \%), and all 3 combined in 662 (17 \%). The participants with these findings were older than those without them, and those with MAC had worse cardiovascular, renal, metabolic, and functional profile than those with AAC and AVS. Age-, sex-, and race-adjusted logistic regression analysis found a significant association between the 3 calcification categories and CVD, the strongest being between the combined group with congestive heart failure (odds ratio 2.04, 95\% CI 1.34-3.09). In highly adjusted models, only MAC was associated with CVD, and the strength of association was related to the severity of MAC.

CONCLUSIONS: In free-living elderly, MAC, AAC, and AVS are highly prevalent and are associated with CVD. Mitral annular calcification in particular has strong association with CVD, and with an adverse biomedical profile.

}, keywords = {Aged, Aortic Valve, Calcinosis, Female, Heart Valve Diseases, Humans, Male, Mitral Valve, Prevalence, Prospective Studies, Risk Factors, Sclerosis, Ultrasonography}, issn = {1097-6744}, doi = {10.1016/j.ahj.2005.03.052}, author = {Barasch, Eddy and Gottdiener, John S and Larsen, Emily K Marino and Chaves, Paulo H M and Newman, Anne B and Manolio, Teri A} } @article {887, title = {Comparison of mortality risk for electrocardiographic abnormalities in men and women with and without coronary heart disease (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {97}, year = {2006}, month = {2006 Feb 01}, pages = {309-15}, abstract = {

Mortality risk associated with electrocardiographic (ECG) abnormalities has been commonly reported to be lower in women than in men. We compared coronary heart disease (CHD) and all-cause mortality risk for ECG variables during a mean 9.1-year follow-up in 4,912 participants in the Cardiovascular Health Study who were > or = 65 years of age. The hypothesis was that mortality risk for ECG abnormalities is not lower in women than in men. Five ECG variables were significant mortality predictors in Cox regression models that were adjusted for demographic, clinical, and medication variables. Gender differences were significant and mortality risk was higher in women for ECG estimates of left ventricular mass for both end points and for nondipolar QRS voltage for all-cause mortality. When evaluated simultaneously in multiple ECG variable risk models in subgroups that were stratified by baseline CHD status, no gender difference was significant. In the latter models, ST depression was a strong predictor of CHD mortality in groups with and without previous CHD. Other significant ECG predictors were previous myocardial infarction in the previous CHD group and nondipolar QRS voltage in the CHD-free group. Four ECG abnormalities were significant predictors of all-cause mortality in the CHD-free group, with risk increases of 18\% to 50\%. The risk of all-cause mortality in the previous CHD group was significantly increased for ST depression (by 64\%), the ECG estimate of left ventricular mass (by 48\%), and previous myocardial infarction (by 34\%). In conclusion, we found no evidence that the relative risk of mortality for ECG abnormalities is lower in women than in men.

}, keywords = {Aged, Coronary Disease, Electrocardiography, Female, Humans, Male, Risk}, issn = {0002-9149}, doi = {10.1016/j.amjcard.2005.08.046}, author = {Rautaharju, Pentti M and Ge, Sijian and Nelson, Jennifer C and Marino Larsen, Emily K and Psaty, Bruce M and Furberg, Curt D and Zhang, Zhu-Ming and Robbins, John and Gottdiener, John S and Chaves, Paulo H M} } @article {879, title = {Costs for heart failure with normal vs reduced ejection fraction.}, journal = {Arch Intern Med}, volume = {166}, year = {2006}, month = {2006 Jan 09}, pages = {112-8}, abstract = {

BACKGROUND: Among the elderly population, heart failure (HF) with normal ejection fraction (EF) is more common than classic HF with low EF. However, there are few data regarding the costs of HF with normal EF. In a prospective, population-based cohort of elderly participants, we compared the costs and resource use of patients with HF and normal and reduced EF.

METHODS: A total of 4549 participants (84.5\% white; 40.6\% male) in the National Heart, Lung, and Blood Institute Cardiovascular Health Study were linked to Medicare claims from 1992 through 1998. By protocol echo examinations or clinical EF assessments, 881 participants with HF were characterized as having abnormal or normal EF. We applied semiparametric estimators to calculate mean costs per subject for a 5-year period.

RESULTS: There were 495 HF participants with normal EF (186 prevalent at study entry and 309 incident during the study period) and 386 participants with abnormal EF (166 prevalent and 220 incident). Participants with abnormal EF had more cardiology encounters and cardiac procedures. However, compared with abnormal EF participants, the 5-year costs for normal EF participants were similar in both the prevalent ($33,023 with abnormal EF and $32,580 with normal EF; P=.93) and incident ($49,128 with abnormal EF and $45,604 with normal EF; P=.55) groups. In models accounting for comorbid conditions, the costs with normal and abnormal EF remained similar.

CONCLUSIONS: Over a 5-year period, patients with HF and normal EF consume as many health care resources as those with reduced EF. These data highlight the substantial financial burden of HF with normal EF among the elderly population.

}, keywords = {Aged, Aged, 80 and over, Comorbidity, Echocardiography, Health Care Costs, Heart Failure, Humans, Incidence, Medicare, Prevalence, Prospective Studies, Regression Analysis, Statistics, Nonparametric, Stroke Volume, Systole, United States, Ventricular Function, Left}, issn = {0003-9926}, doi = {10.1001/archinte.166.1.112}, author = {Liao, Lawrence and Jollis, James G and Anstrom, Kevin J and Whellan, David J and Kitzman, Dalane W and Aurigemma, Gerard P and Mark, Daniel B and Schulman, Kevin A and Gottdiener, John S} } @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 {875, title = {Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons > or =65 years of age (the cardiovascular health study).}, journal = {Am J Cardiol}, volume = {97}, year = {2006}, month = {2006 Jan 01}, pages = {83-9}, abstract = {

The left atrium enlarges in association with many factors, including aging, atrial fibrillation, hypertension, diastolic dysfunction, and heart failure (HF) with low ejection fraction. However, left atrial (LA) volume, geometry, and emptying have not been compared between diastolic and systolic HF, nor has the association of LA volume for new HF been determined in older subjects, many of whom have normal ejection fraction. We used echocardiography to measure the LA volume, geometry, and emptying in 851 community-dwelling subjects > or =65 years of age, including 180 with HF at baseline and 255 participants who subsequently developed HF. The LA volume, area, and linear dimensions were higher in the prevalent and incident HF groups than in controls and did not differ between those with systolic versus diastolic HF, independent of co-morbidities and Doppler measures of diastolic function. The fractional area change was associated with prevalent, but not incident, HF. In conclusion, in population-based older subjects, the LA size is increased and LA emptying decreased in patients with either systolic or diastolic HF. LA size is associated with the new development of HF. These findings highlight the important role of the left atrium in HF, with or without a decreased ejection fraction.

}, keywords = {Aged, Atrial Function, Left, Case-Control Studies, Diastole, Echocardiography, Female, Heart Atria, Heart Failure, Humans, Male, Multivariate Analysis, Systole}, issn = {0002-9149}, doi = {10.1016/j.amjcard.2005.07.126}, author = {Gottdiener, John S and Kitzman, Dalane W and Aurigemma, Gerard P and Arnold, Alice M and Manolio, Teri A} } @article {939, title = {Alcohol consumption and risk and prognosis of atrial fibrillation among older adults: the Cardiovascular Health Study.}, journal = {Am Heart J}, volume = {153}, year = {2007}, month = {2007 Feb}, pages = {260-6}, abstract = {

BACKGROUND: The relationship of alcohol consumption with risk of atrial fibrillation (AF) is inconsistent in previous studies, and its relationship with prognosis of AF is undetermined.

METHODS: As part of the Cardiovascular Health Study, a population-based cohort of adults 65 years and older from 4 US communities, 5609 participants reported their use of beer, wine, and spirits yearly. We identified cases of AF with routine study electrocardiograms and validated discharge diagnoses from hospitalizations.

RESULTS: A total of 1232 cases of AF were documented during a mean of 9.1 years of follow-up. Compared with long-term abstainers, the multivariable-adjusted hazard ratios were 1.25 (95\% CI, 1.02-1.54) among former drinkers, 1.09 (95\% CI, 0.94-1.28) among consumers of less than 1 drink per week, 1.00 (95\% CI, 0.84-1.19) among consumers of 1 to 6 drinks per week, 1.06 (95\% CI, 0.82-1.37) among consumers of 7 to 13 drinks per week, and 1.09 (95\% CI, 0.88-1.37) among consumers of 14 or more drinks per week (P trend = 0.64). In analyses of mortality among participants with AF, the hazard ratios were 1.27 (95\% CI, 1.06-1.52) among former drinkers, 0.94 (95\% CI, 0.76-1.18) among consumers of less than 1 drink per week, 0.98 (95\% CI, 0.78-1.23) among consumers of 1 to 6 drinks per week, 0.73 (95\% CI, 0.51-1.03) among consumers of 7 to 13 drinks per week, and 0.81 (95\% CI, 0.59-1.11) among consumers of 14 or more drinks per week (P trend = 0.12).

CONCLUSIONS: Current moderate alcohol consumption is not associated with risk of AF or with risk of death after diagnosis of AF, but former drinking identifies individuals at higher risk.

}, keywords = {Aged, Alcohol Drinking, Atrial Fibrillation, Female, Follow-Up Studies, Humans, Incidence, Longitudinal Studies, Male, Prognosis, Risk Factors}, issn = {1097-6744}, doi = {10.1016/j.ahj.2006.10.039}, author = {Mukamal, Kenneth J and Psaty, Bruce M and Rautaharju, Pentti M and Furberg, Curt D and Kuller, Lewis H and Mittleman, Murray A and Gottdiener, John S and Siscovick, David S} } @article {997, title = {Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study.}, journal = {J Am Coll Cardiol}, volume = {50}, year = {2007}, month = {2007 Nov 13}, pages = {1992-8}, abstract = {

OBJECTIVES: The purpose of this study was to examine the relationship between C-reactive protein (CRP) and calcific aortic valve disease in a large, randomly selected, population-based cohort.

BACKGROUND: The pathobiology of calcific aortic stenosis involves an active inflammatory, atheromatous, osteogenic process. Elevations in CRP, a measure of systemic inflammation, have been associated with aortic stenosis.

METHODS: Two-dimensional and Doppler echocardiography and CRP measurement were performed at baseline in 5,621 participants in the Cardiovascular Health Study. Multivariable analysis was used to identify CRP as a predictor of baseline and incident aortic stenosis.

RESULTS: At a mean echocardiographic follow-up of 5 years, 9\% of subjects with aortic sclerosis progressed to some degree of aortic stenosis. Increasing age (odds ratio [OR] 1.13, 95\% confidence interval [CI] 1.09 to 1.16; p < 0.001) and male gender (OR 3.05, 95\% CI 1.76 to 5.27; p < 0.001) were related to risk of incident aortic stenosis, whereas increasing height (OR 0.96, 95\% CI 0.94 to 0.99; p = 0.013) and African-American ethnicity conveyed a lower risk (OR 0.49, 95\% CI 0.25 to 0.95; p = 0.035). C-reactive protein, treated as a continuous variable, was not associated with baseline aortic stenosis, progression to aortic sclerosis (adjusted OR 0.93, 95\% CI 0.85 to 1.02; p = 0.107), or progression to aortic stenosis (adjusted OR 0.85, 95\% CI 0.70 to 1.03; p = 0.092).

CONCLUSIONS: In this large population-based cohort, approximately 9\% of subjects with aortic sclerosis progressed to aortic stenosis over a 5-year follow-up period. There was no association between CRP levels and the presence of calcific aortic-valve disease or incident aortic stenosis. C-reactive protein appears to be a poor predictor of subclinical calcific aortic-valve disease.

}, keywords = {Aged, Aged, 80 and over, Aortic Valve, Aortic Valve Stenosis, C-Reactive Protein, Calcinosis, Cardiovascular Diseases, Cohort Studies, Disease Progression, Female, Follow-Up Studies, Heart Valve Diseases, Humans, Male, Risk Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2007.07.064}, author = {Novaro, Gian M and Katz, Ronit and Aviles, Ronnier J and Gottdiener, John S and Cushman, Mary and Psaty, Bruce M and Otto, Catherine M and Griffin, Brian P} } @article {969, title = {Costs of the metabolic syndrome in elderly individuals: findings from the Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {30}, year = {2007}, month = {2007 Oct}, pages = {2553-8}, abstract = {

OBJECTIVE: The cardiovascular consequences of the metabolic syndrome and its component risk factors have been documented in elderly individuals. Little is known about how the metabolic syndrome and its individual components translate into long-term medical costs.

RESEARCH DESIGN AND METHODS: We used log-linear regression models to assess the independent contributions of the metabolic syndrome and its individual components to 10-year medical costs among 3,789 individuals aged > or = 65 years in the Cardiovascular Health Study.

RESULTS: As defined by the National Cholesterol Education Program Third Adult Treatment Panel report, the metabolic syndrome was present in 47\% of the sample. Total costs to Medicare were 20\% higher among participants with the metabolic syndrome ($40,873 vs. $33,010; P < 0.001). Controlling for age, sex, race/ethnicity, and other covariates, we found that abdominal obesity, low HDL cholesterol, and elevated blood pressure were associated with 15\% (95\% CI 4.3-26.7), 16\% (1.7-31.8), and 20\% (10.1-31.7) higher costs, respectively. When added to the model, the metabolic syndrome composite variable did not contribute significantly (P = 0.32).

CONCLUSIONS: Abdominal obesity, low HDL cholesterol, and hypertension but not the metabolic syndrome per se are important predictors of long-term costs in the Medicare population.

}, keywords = {Aged, Aged, 80 and over, Cholesterol, HDL, Continental Population Groups, Cost of Illness, Diabetic Angiopathies, Female, Humans, Hypertension, Interviews as Topic, Male, Medicare, Metabolic Syndrome, Multivariate Analysis, Obesity, Patient Education as Topic, Prospective Studies, Regression Analysis, United States}, issn = {1935-5548}, doi = {10.2337/dc07-0460}, author = {Curtis, Lesley H and Hammill, Bradley G and Bethel, M Angelyn and Anstrom, Kevin J and Gottdiener, John S and Schulman, Kevin A} } @article {938, title = {Long-term costs and resource use in elderly participants with congestive heart failure in the Cardiovascular Health Study.}, journal = {Am Heart J}, volume = {153}, year = {2007}, month = {2007 Feb}, pages = {245-52}, abstract = {

BACKGROUND: Although heart failure (HF) afflicts nearly 5 million Americans, the long-term cost of HF care has not been described previously. In a prospective, longitudinal cohort of community-dwelling elderly from 4 regions, we examined the long-term costs and resource use of elderly patients with HF.

METHODS: We linked 4860 elderly participants in the National Heart, Lung, and Blood Institute Cardiovascular Health Study to Medicare part A and part B claims from 1992 to 2003. Costs were calculated from Medicare payments and discounted at 3\% annually. We applied nonparametric estimators to calculate mean costs and resource use per patient for a 10-year period. To describe the relationship between patient characteristics and long-term costs, we constructed censoring-adjusted regression models.

RESULTS: There were 343 participants (84.8\% white; 50.1\% men; mean age, 78.2 years) with prevalent HF and 4517 participants without HF at study entry. Mean follow-up was 6.7 years (median, 6.4 years). The 10-year survival rates were 33\% and 63\% for the prevalent HF and nonprevalent HF groups (P < .001), respectively. The mean 10-year medical costs were significantly higher for the prevalent HF cohort (54,704 dollars vs 41 dollars,780, P < .001). The higher costs associated with HF were also reflected in greater resource use with more hospitalizations (P < .05) and more intensive care unit days (P < .05). Participants with HF had more physician visits (P < .05), with most of these encounters involving noncardiology physicians. However, in multivariate models, prevalent HF was not an independent predictor of higher costs.

CONCLUSION: Patients with HF consume substantially more health care resources than their elderly peers, and these higher costs persist through 10 years of follow-up. Many of these costs may be related to other comorbid conditions.

}, keywords = {Aged, Costs and Cost Analysis, Female, Health Resources, Heart Failure, Humans, Male, Medicare, Prospective Studies, Time Factors}, issn = {1097-6744}, doi = {10.1016/j.ahj.2006.11.010}, author = {Liao, Lawrence and Anstrom, Kevin J and Gottdiener, John S and Pappas, Paul A and Whellan, David J and Kitzman, Dalane W and Aurigemma, Gerard P and Mark, Daniel B and Schulman, Kevin A and Jollis, James G} } @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 {1012, title = {Cystatin C concentration as a predictor of systolic and diastolic heart failure.}, journal = {J Card Fail}, volume = {14}, year = {2008}, month = {2008 Feb}, pages = {19-26}, abstract = {

BACKGROUND: Risk factors for heart failure (HF) may differ according to ejection fraction (EF). Higher cystatin C, a marker of kidney dysfunction, is associated with incident HF, but previous studies did not determine EF at diagnosis. We hypothesized that kidney dysfunction would predict diastolic HF (DHF) better than systolic HF (SHF) in the Cardiovascular Health Study.

METHODS AND RESULTS: Cystatin C was measured in 4453 participants without HF at baseline. Incident HF was categorized as DHF (EF > or = 50\%) or SHF (EF < 50\%). We compared the association of cystatin C with the risk for DHF and SHF, after adjustment for age, sex, race, medications, and HF risk factors. During 8 years of follow-up, 167 participants developed DHF and 206 participants developed SHF. After adjustment, sequentially higher quartiles of cystatin C were associated with risk for SHF (competing risks hazard ratios 1.0 [reference], 1.99 [95\% confidence interval 1.14-3.48], 2.32 [1.32-4.07], 3.17 [1.82-5.50], P for trend < .001). The risk for DHF was apparent only at the highest cystatin C quartile (hazard ratios 1.0 [reference], 1.09 [0.62-1.89], 1.08 [0.61-1.93], and 1.83 [1.07-3.11]).

CONCLUSIONS: Cystatin C levels are linearly associated with the incidence of systolic HF, whereas only the highest concentrations of cystatin C predict diastolic HF.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Confidence Intervals, Cystatin C, Cystatins, Echocardiography, Female, Heart Failure, Diastolic, Heart Failure, Systolic, Humans, Longitudinal Studies, Male, Predictive Value of Tests, Probability, Proportional Hazards Models, Risk Assessment, Sensitivity and Specificity, Stroke Volume, Survival Analysis}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2007.09.002}, author = {Moran, Andrew and Katz, Ronit and Smith, Nicolas L and Fried, Linda F and Sarnak, Mark J and Seliger, Stephen L and Psaty, Bruce and Siscovick, David S and Gottdiener, John S and Shlipak, Michael G} } @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 {1010, title = {Left ventricular mass predicts heart failure not related to previous myocardial infarction: the Cardiovascular Health Study.}, journal = {Eur Heart J}, volume = {29}, year = {2008}, month = {2008 Mar}, pages = {741-7}, abstract = {

AIMS: The relationship of left ventricular hypertrophy (LVH) to incident heart failure (HF) not attributable to myocardial infarction (MI) has not been defined. We assessed whether LVH is an independent predictor of MI-independent HF.

METHODS AND RESULTS: LVH was assessed by echocardiographic LV mass index (in g/m2.7) and excess of LV mass (eLVM, in \% of the observed value) relative to the amount predicted by sex, stroke work, and height, using a prognostically validated equation in 2078 participants of Cardiovascular Health Study without prevalent MI and normal systolic function. Increasing eLVM was associated with progressively increasing left atrial dimension and concentric geometry, decreasing systolic (P < 0.0001), and diastolic function (P < 0.04). After adjustment for age, sex, obesity, diabetes, hypertension, and antihypertensive therapy, and accounting for by incident MI, hazard of HF increased by 1\% for each 1\% increase in eLVM and by 3\% for each g/m2.7 increase in LV mass index (both P < 0.0001). The results were confirmed when also C-reactive protein and measures of systolic (endocardial shortening) and diastolic function (categories of E/A ratio) were added to the Cox models.

CONCLUSION: In an elderly population, LVH, measured as LV mass index or eLVM is an independent predictor of incident HF not related to prevalent or incident MI.

}, keywords = {Aged, Aged, 80 and over, Diabetic Angiopathies, Echocardiography, Female, Heart Failure, Humans, Hypertension, Hypertrophy, Left Ventricular, Male, Myocardial Infarction, Obesity, Risk Factors}, issn = {0195-668X}, doi = {10.1093/eurheartj/ehm605}, author = {de Simone, Giovanni and Gottdiener, John S and Chinali, Marcello and Maurer, Mathew S} } @article {1030, title = {Left ventricular morphology and systolic function in sleep-disordered breathing: the Sleep Heart Health Study.}, journal = {Circulation}, volume = {117}, year = {2008}, month = {2008 May 20}, pages = {2599-607}, abstract = {

BACKGROUND: Whether sleep-disordered breathing (SDB) is a risk factor for left ventricular (LV) hypertrophy and dysfunction is controversial. We assessed the relation of SDB to LV morphology and systolic function in a community-based sample of middle-aged and older adults.

METHODS AND RESULTS: The present study was a cross-sectional observational study of 2058 Sleep Heart Health Study participants (mean age 65+/-12 years; 58\% women; 44\% ethnic minorities) who had technically adequate echocardiograms. A polysomnographically derived apnea-hypopnea index (AHI) and hypoxemia index (percent of sleep time with oxyhemoglobin saturation < 90\%) were used to quantify SDB severity. LV mass index was significantly associated with both AHI and hypoxemia index after adjustment for age, sex, ethnicity, study site, body mass index, current and prior smoking, alcohol consumption, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and prevalent myocardial infarction. Adjusted LV mass index was 41.3 (SD 9.90) g/m(2.7) in participants with AHI < 5 (n=957) and 44.1 (SD 9.90) g/m(2.7) in participants with AHI > or = 30 (n=84) events per hour. Compared with participants with AHI < 5, those with AHI > or = 30 had an adjusted odds ratio of 1.78 (95\% confidence interval 1.14 to 2.79) for LV hypertrophy. A higher AHI and higher hypoxemia index were also associated with larger LV diastolic dimension and lower LV ejection fraction, with a trend toward lower LV fractional shortening. LV wall thickness was significantly associated with the hypoxemia index but not with AHI. Left atrial diameter was not associated with either SDB measure.

CONCLUSIONS: In a community-based cohort, SDB is associated with echocardiographic evidence of increased LV mass and reduced LV systolic function.

}, keywords = {Aged, Echocardiography, Female, Humans, Hypertrophy, Left Ventricular, Hypoxia, Male, Middle Aged, Odds Ratio, Sleep Apnea Syndromes, Systole, Ventricular Dysfunction, Left}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.107.717892}, author = {Chami, Hassan A and Devereux, Richard B and Gottdiener, John S and Mehra, Reena and Roman, Mary J and Benjamin, Emelia J and Gottlieb, Daniel J} } @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 {999, title = {Pancreatic beta-cell function as a predictor of cardiovascular outcomes and costs: findings from the Cardiovascular Health Study.}, journal = {Curr Med Res Opin}, volume = {24}, year = {2008}, month = {2008 Jan}, pages = {41-50}, abstract = {

OBJECTIVE: To explore relationships between beta-cell function and incident cardiovascular events, death, and medical costs among elderly individuals.

RESEARCH DESIGN AND METHODS: In a prospective, population-based cohort of 4555 elderly individuals, we examined the effect of beta-cell function on incident cardiovascular events and mortality. We also examined costs for 3715 of these individuals. We used the computer-based homeostasis model assessment (HOMA) to calculate indices of beta-cell function (HOMA-\%B) and insulin sensitivity (HOMA-\%S) using baseline fasting glucose and insulin levels. All subjects were followed from 1992/1993 for 6 years or until death.

MAIN OUTCOME MEASURES: Discrete-time survival model of the effects of beta-cell function on incident cardiovascular events and all-cause mortality; and semiparametric estimators for calculations of mean 6-year costs.

RESULTS: Controlling for HOMA-\%S, a 20\% decrease in HOMA-\%B was associated with increased odds of incident cardiovascular events (odds ratio [OR], 1.09; 95\% confidence interval [CI], 1.05-1.14) and death (OR, 1.10; 95\% CI, 1.07-1.14). The relationships persisted after controlling for clinical and sociodemographic confounders. A 20\% decrease in HOMA-\%B was also associated with increased costs (cost ratio, 1.03; 95\% CI, 1.01-1.05). The significant association did not persist after controlling for confounders.

LIMITATIONS: The sample comprises relatively healthy elderly individuals and is based on data from 1992 through 1999, which may not reflect current experience. The measure of beta-cell function is an estimate generated from single measures of glucose and insulin.

CONCLUSIONS: Beta-cell function as measured by HOMA-\%B is a significant predictor of incident cardiovascular events and mortality but not of costs, controlling for HOMA-\%S and sociodemographic and clinical confounders.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Female, Follow-Up Studies, Health Care Costs, Heart Failure, Humans, Insulin-Secreting Cells, Male, Myocardial Infarction, Outcome Assessment, Health Care, Prognosis, Prospective Studies, Stroke}, issn = {1473-4877}, doi = {10.1185/030079908x253573}, author = {Curtis, Lesley H and Hammill, Bradley G and Bethel, M Angelyn and Anstrom, Kevin J and Liao, Lawrence and Gottdiener, John S and Schulman, Kevin A} } @article {1053, title = {Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.}, journal = {J Am Coll Cardiol}, volume = {52}, year = {2008}, month = {2008 Sep 30}, pages = {1152-9}, abstract = {

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities.

BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited.

METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism.

RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95\% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF.

CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Echocardiography, Female, Heart, Heart Failure, Heart Function Tests, Humans, Hyperthyroidism, Hypertrophy, Left Ventricular, Hypothyroidism, Male, Risk Factors, Time Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2008.07.009}, author = {Rodondi, Nicolas and Bauer, Douglas C and Cappola, Anne R and Cornuz, Jacques and Robbins, John and Fried, Linda P and Ladenson, Paul W and Vittinghoff, Eric and Gottdiener, John S and Newman, Anne B} } @article {1134, title = {Association between elevated fibrosis markers and heart failure in the elderly: the cardiovascular health study.}, journal = {Circ Heart Fail}, volume = {2}, year = {2009}, month = {2009 Jul}, pages = {303-10}, abstract = {

BACKGROUND: Myocardial fibrosis reflects excess collagen deposition in the extracellular left ventricular matrix, which has been associated with heart failure (HF). No studies have addressed the relation between fibrosis biomarkers and HF in the elderly.

METHODS AND RESULTS: Serum fibrosis markers were measured in 880 participants of the Cardiovascular Health Study (mean age 77+/-6 years, 48\% women). Participants with systolic HF (n=131, left ventricular ejection fraction <55\%) and those with diastolic HF (n=179, left ventricular ejection fraction > or =55\%) were compared with controls (280 with cardiovascular risk factors, and 279 healthy individuals) using a nested case-control design. Fibrosis markers included carboxyl-terminal peptide of procollagen type I, carboxyl-terminal telopeptide of collagen type I, and amino-terminal peptide of procollagen type III. Echocardiography was used to document systolic and diastolic function parameters. Analysis of variance and logistic regression analysis (per tertile odds ratios [OR]), adjusted by age, gender, race, hypertension, atrial fibrillation, coronary heart disease, baseline serum glucose, serum cystatin C, serum creatinine, C-reactive protein, any angiotensin-converting enzyme inhibitor, spironolactone or any diuretic, NT-proBNP, and total bone mineral density were performed. Systolic HF was associated with significantly elevated carboxyl-terminal telopeptide of collagen type I (OR=2.6; 95\% CI=1.2 to 5.7) and amino-terminal peptide of procollagen type III (OR=3.3; 95\% CI=1.6 to 5.8), when adjusting for covariates. Associations of diastolic HF were significant for carboxyl-terminal telopeptide of collagen type I (OR=3.9; 95\% CI=1.9 to 8.3) and amino-terminal peptide of procollagen type III (OR=2.7; 95\% CI=1.4 to 5.4). HF was not associated with elevated carboxyl-terminal peptide of procollagen type I (P>0.10), and fibrosis markers did not significantly differ between HF with diastolic versus those with systolic dysfunction (P>0.10) whereas NT-proBNP mean values were higher in systolic heart failure than in diastolic heart failure (P<0.0001).

CONCLUSIONS: Fibrosis markers are significantly elevated in elderly individuals with diastolic or systolic HF. These associations remained significant when adjusting for covariates relevant to the aging process.

}, keywords = {Aged, Aged, 80 and over, Female, Fibrosis, Heart Failure, Humans, Male, Myocardium, Ultrasonography}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.108.828343}, author = {Barasch, Eddy and Gottdiener, John S and Aurigemma, Gerard and Kitzman, Dalane W and Han, Jing and Kop, Willem J and Tracy, Russell P} } @article {1056, title = {Association of renal function with cardiac calcifications in older adults: the cardiovascular health study.}, journal = {Nephrol Dial Transplant}, volume = {24}, year = {2009}, month = {2009 Mar}, pages = {834-40}, abstract = {

BACKGROUND: Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are highly prevalent in patients with end-stage renal disease. It is less well established whether milder kidney disease is associated with cardiac calcifications. We evaluated the relationships between renal function and MAC, aortic annular calcification (AAC) and AVS in the elderly.

METHODS: From the Cardiovascular Health Study, a community-based cohort of ambulatory adults >or= age 65, a total of 3929 individuals (mean +/- SD age 74 +/- 5 years, 60\% women) were evaluated with two-dimensional echocardiography. Renal function was assessed by means of creatinine-based estimated glomerular filtration rate (eGFR) and cystatin C.

RESULTS: The prevalences of MAC and AAC were significantly higher in individuals with an eGFR < 45 mL/ min/1.73 m(2) (P < 0.01 for each), and cystatin C levels were significantly higher in individuals with MAC or AAC compared to individuals without these cardiac calcifications (P < 0.001 for each). After multivariate-adjustment, an eGFR <45 mL/min/1.73 m(2) was significantly associated with MAC [odds ratio 1.54 (95\% CI 1.16-2.06), P = 0.003] and not associated with AAC [1.30 (0.97-1.74), P = 0.085] and AVS [1.15 (0.86-1.53), P = 0.355]. In addition, cystatin C levels were independently associated with MAC [odds ratio per SD 1.12 (1.05-1.21), P = 0.001] and not associated with AAC [1.07 (1.00-1.15), P = 0.054] and AVS [0.99 (0.93-1.06), P = 0.82]. Furthermore, the prevalence of multiple cardiac calcifications was higher in subjects with an eGFR < 45 mL/ min/1.73 m(2) and increased per quartile of cystatin C (P-values < 0.001). In addition, a significant trend was observed between an eGFR < 45 mL/min/1.73 m(2), increasing levels of cystatin C and the number of cardiac calcifications (P < 0.05).

CONCLUSIONS: In a community-based cohort of the elderly, moderate kidney disease as defined by an eGFR <45 mL/min/1.73m(2) and elevated levels of cystatin C was associated with prevalent MAC. In addition, a significant trend was observed between an eGFR <45 mL/min/1.73m(2), increasing levels of cystatin C and the number of cardiac calcifications. No associations were found between renal function and AAC or AVS.

}, keywords = {Aged, Aortic Valve, Calcinosis, Case-Control Studies, Cohort Studies, Creatinine, Cystatin C, Female, Glomerular Filtration Rate, Heart Valve Diseases, Humans, Kidney Diseases, Male, Mitral Valve, Risk Factors}, issn = {1460-2385}, doi = {10.1093/ndt/gfn544}, author = {Asselbergs, Folkert W and Mozaffarian, Dariush and Katz, Ronit and Kestenbaum, Bryan and Fried, Linda F and Gottdiener, John S and Shlipak, Michael G and Siscovick, David S} } @article {1113, title = {External validity of the cardiovascular health study: a comparison with the Medicare population.}, journal = {Med Care}, volume = {47}, year = {2009}, month = {2009 Aug}, pages = {916-23}, abstract = {

BACKGROUND: The Cardiovascular Health Study (CHS), a population-based prospective cohort study, has been used to identify major risk factors associated with cardiovascular disease and stroke in the elderly.

OBJECTIVE: To assess the external validity of the CHS.

RESEARCH DESIGN: Comparison of the CHS cohort to a national cohort of Medicare beneficiaries and to Medicare beneficiaries residing in the CHS geographic regions.

SUBJECTS: CHS participants and a 5\% sample of Medicare beneficiaries.

MEASURES: Demographic and administrative characteristics, comorbid conditions, resource use, and mortality.

RESULTS: Compared with both Medicare cohorts, the CHS cohort was older and included more men and African American participants. CHS participants were more likely to be enrolled in Medicare managed care than beneficiaries in the national Medicare cohort. Compared with the Medicare cohorts, mortality in the CHS was more than 40\% lower at 1 year, approximately 25\% lower at 5 years, and approximately 15\% lower at 10 years. There were minimal differences in comorbid conditions and health care resource use.

CONCLUSION: The CHS cohort is comparable with the Medicare population, particularly with regard to comorbid conditions and resource use, but had lower mortality. The difference in mortality may reflect the CHS recruitment strategy or volunteer bias. These findings suggest it may not be appropriate to project absolute rates of disease and outcomes based on CHS data to the entire Medicare population. However, there is no reason to expect that the relative risks associated with physiologic processes identified by CHS data would differ for nonparticipants.

}, keywords = {Aged, Cardiovascular Diseases, Cohort Studies, Comorbidity, Female, Humans, Male, Medicare, Randomized Controlled Trials as Topic, Reproducibility of Results, Socioeconomic Factors, United States}, issn = {1537-1948}, doi = {10.1097/MLR.0b013e318197b104}, author = {DiMartino, Lisa D and Hammill, Bradley G and Curtis, Lesley H and Gottdiener, John S and Manolio, Teri A and Powe, Neil R and Schulman, Kevin A} } @article {1108, title = {Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.}, journal = {JAMA}, volume = {302}, year = {2009}, month = {2009 Jul 08}, pages = {168-78}, abstract = {

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55\% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1\% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1\%-3\% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

}, keywords = {Adult, Aged, Aged, 80 and over, Aorta, Cardiovascular Diseases, Echocardiography, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genotype, Heart Atria, Heart Ventricles, Humans, Male, Middle Aged, Organ Size, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Ventricular Dysfunction, Left, Ventricular Function, Left}, issn = {1538-3598}, doi = {10.1001/jama.2009.978-a}, author = {Vasan, Ramachandran S and Glazer, Nicole L and Felix, Janine F and Lieb, Wolfgang and Wild, Philipp S and Felix, Stephan B and Watzinger, Norbert and Larson, Martin G and Smith, Nicholas L and Dehghan, Abbas and Grosshennig, Anika and Schillert, Arne and Teumer, Alexander and Schmidt, Reinhold and Kathiresan, Sekar and Lumley, Thomas and Aulchenko, Yurii S and K{\"o}nig, Inke R and Zeller, Tanja and Homuth, Georg and Struchalin, Maksim and Aragam, Jayashri and Bis, Joshua C and Rivadeneira, Fernando and Erdmann, Jeanette and Schnabel, Renate B and D{\"o}rr, Marcus and Zweiker, Robert and Lind, Lars and Rodeheffer, Richard J and Greiser, Karin Halina and Levy, Daniel and Haritunians, Talin and Deckers, Jaap W and Stritzke, Jan and Lackner, Karl J and V{\"o}lker, Uwe and Ingelsson, Erik and Kullo, Iftikhar and Haerting, Johannes and O{\textquoteright}Donnell, Christopher J and Heckbert, Susan R and Stricker, Bruno H and Ziegler, Andreas and Reffelmann, Thorsten and Redfield, Margaret M and Werdan, Karl and Mitchell, Gary F and Rice, Kenneth and Arnett, Donna K and Hofman, Albert and Gottdiener, John S and Uitterlinden, Andr{\'e} G and Meitinger, Thomas and Blettner, Maria and Friedrich, Nele and Wang, Thomas J and Psaty, Bruce M and van Duijn, Cornelia M and Wichmann, H-Erich and Munzel, Thomas F and Kroemer, Heyo K and Benjamin, Emelia J and Rotter, Jerome I and Witteman, Jacqueline C and Schunkert, Heribert and Schmidt, Helena and V{\"o}lzke, Henry and Blankenberg, Stefan} } @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 {1136, title = {Left atrial volume and geometry in healthy aging: the Cardiovascular Health Study.}, journal = {Circ Cardiovasc Imaging}, volume = {2}, year = {2009}, month = {2009 Jul}, pages = {282-9}, abstract = {

BACKGROUND: The left atrium is a validated marker of clinical and subclinical cardiovascular disease. Left atrial enlargement is often seen among older individuals; however, there are few population-based data regarding normal left atrial size among older persons, especially from those who are healthy, and from women. Furthermore, because the left atrium is a 3D structure, the commonly used parasternal long-axis diastolic diameter often underdiagnoses left atrial enlargement.

METHODS AND RESULTS: We evaluated left atrial size in 230 healthy participants (mean age, 76+/-5 years) free of prevalent cardiac disease, rhythm abnormality, hypertension, and diabetes selected from the Cardiovascular Health Study, a prospective community-based study of risk factors for cardiovascular disease in 5888 elderly participants. In addition to the standard long-axis measurement, we obtained left atrial superoinferior and lateral diameters and used these dimensions to estimate left atrial volume. These measurements were used to generate reference ranges for determining left atrial enlargement in older men and women, based on the 95\% percentiles of the left atrial dimensions in healthy participants, both unadjusted, and after adjustment for age, height, and weight. In healthy elderly subjects, indices of left atrial size do not correlate with age or height but with weight and other measures of body build.

CONCLUSIONS: These data provide normative reference values for left atrial size in healthy older women and men. The results should be useful for refining diagnostic criteria for left atrial dilation in the older population and may be relevant for cardiovascular risk stratification.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Atrial Function, Left, Body Size, Body Surface Area, Echocardiography, Three-Dimensional, Female, Heart Atria, Humans, Linear Models, Male, Models, Biological, Organ Size, Population Surveillance, Prospective Studies, Reference Values, Sex Factors, United States}, issn = {1942-0080}, doi = {10.1161/CIRCIMAGING.108.826602}, author = {Aurigemma, Gerard P and Gottdiener, John S and Arnold, Alice M and Chinali, Marcello and Hill, Jeffrey C and Kitzman, Dalane} } @article {1138, title = {N-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {120}, year = {2009}, month = {2009 Nov 03}, pages = {1768-74}, abstract = {

BACKGROUND: Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and healthcare expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, AF, and mortality.

METHODS AND RESULTS: The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5445 Cardiovascular Health Study participants with the use of relative risk regression for predicting prevalent AF and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95\% confidence interval, 17.9 to 913.3; P<0.001) and adjusted prevalence ratio of 147 for the highest quintile (95\% confidence interval, 20.4 to 1064.3; P<0.001) compared with the lowest. After a median follow-up of 10 years (maximum of 16 years), there were 1126 cases of incident AF (a rate of 2.2 per 100 person-years). NT-proBNP was highly predictive of incident AF, with an unadjusted hazard ratio of 5.2 (95\% confidence interval, 4.3 to 6.4; P<0.001) for the development of AF for the highest quintile compared with the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes mellitus, and heart failure, with an adjusted hazard ratio of 4.0 (95\% confidence interval, 3.2 to 5.0; P<0.001).

CONCLUSIONS: In a community-based population of older adults, NT-proBNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.

}, keywords = {Aged, Aged, 80 and over, Atrial Fibrillation, Female, Humans, Immunoassay, Longitudinal Studies, Male, Natriuretic Peptide, Brain, Peptide Fragments, Predictive Value of Tests, Prevalence, Proportional Hazards Models, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.109.873265}, author = {Patton, Kristen K and Ellinor, Patrick T and Heckbert, Susan R and Christenson, Robert H and DeFilippi, Christopher and Gottdiener, John S and Kronmal, Richard A} } @article {1090, title = {Race, gender, and mortality in adults > or =65 years of age with incident heart failure (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {103}, year = {2009}, month = {2009 Apr 15}, pages = {1120-7}, abstract = {

In patients with heart failure (HF), mortality is lower in women versus men. However, it is unknown whether the survival advantage in women compared with men is present in both whites and African Americans with HF. The inception cohort consisted of adults > or =65 years with incident HF after enrollment in the CHS, a prospective population-based study of cardiovascular disease. Of 5,888 CHS subjects, 1,264 developed new HF and were followed up for 3 years. Subjects were categorized into 4 race-gender groups, and Cox proportional hazard regression models were used to examine whether 3-year total and cardiovascular mortality differed among the 4 groups after adjusting for sociodemographic factors, co-morbidities, and treatment. A gender-race interaction was also tested for each outcome. In subjects with incident HF, African Americans had more hypertension and diabetes than whites, and white men had more coronary heart disease than other gender-race groups. Receipt of cardiovascular treatments among the 4 groups was similar. Mortality rates after HF were lower in women compared with men (for white women, African-American women, African-American men, and white men, total mortality was 35.5, 33.6, 44.4, and 40.5/100 person-years, and cardiovascular mortality was 18.4, 19.5, 20.2, and 22.7/100 person-years, respectively). After adjusting for covariates, women had a 15\% to 20\% lower risk of total and cardiovascular mortality compared with men, but there was no significant difference in outcome by race. The gender-race interaction for either outcome was not significant. In conclusion, in older adults with HF, women had significantly better survival than men irrespective of race, suggesting that gender-based survival differences may be more important than race-based differences.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Cohort Studies, Continental Population Groups, European Continental Ancestry Group, Female, Heart Failure, Humans, Incidence, Male, Proportional Hazards Models, Sex Factors, United States}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2008.12.043}, author = {Parashar, Susmita and Katz, Ronit and Smith, Nicholas L and Arnold, Alice M and Vaccarino, Viola and Wenger, Nanette K and Gottdiener, John S} } @article {1132, title = {Association between depressive symptoms and fibrosis markers: the Cardiovascular Health Study.}, journal = {Brain Behav Immun}, volume = {24}, year = {2010}, month = {2010 Feb}, pages = {229-35}, abstract = {

OBJECTIVE: Fibrosis plays an important role in heart failure (HF) and other diseases that occur more frequently with increasing age. Depression is associated with an increased risk of heart failure and other age-related diseases. This study examined the association between depressive symptoms and fibrosis markers in adults aged 65 years and above.

METHODS: Fibrosis markers and depressive symptoms were assessed in 870 participants (age=80.9+/-5.9 yrs, 49\% women) using a case-control design based on heart failure status (307 HF patients and 563 age- and sex-matched controls, of whom 284 with CVD risk factors (hypertension, diabetes mellitus, or hypercholesterolemia) and 279 controls without these CVD risk factors). Fibrosis markers were procollagen type I (PIP), type I collagen (CITP), and procollagen type III (PIIINP). Inflammation markers included C-reactive protein, white blood cell counts and fibrinogen. Depression was assessed using the Center for Epidemiological Studies-Depression (CES-D) scale using a previously validated cut-off point for depression (CES-D > or = 8). Covariates included demographic and clinical variables.

RESULTS: Depression was associated with higher levels of PIP (median=411.0, inter-quartile range (IQR)=324.4-472.7 ng/mL vs. 387.6, IQR=342.0-512.5 ng/mL, p=0.006) and CITP (4.99, IQR=3.53-6.85 vs. 4.53, IQR=3.26-6.22 microg/L, p=0.024), but not PIIIINP (4.07, IQR=2.75-5.54 microg/L vs. 3.58, IQR=2.71-5.01 microg/L, p=0.29) compared to individuals without depression. Inflammation markers were also elevated in depressed participants (CRP, p=0.014; WBC, p=0.075; fibrinogen, p=0.074), but these inflammation markers did not account for the relationship between depression and fibrosis markers.

CONCLUSIONS: Depression is associated with elevated fibrosis markers and may therefore adversely affect heart failure and other age-related diseases in which extra-cellular matrix formation plays a pathophysiological role.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Collagen Type I, Depression, Electrocardiography, Endomyocardial Fibrosis, Fatigue, Female, Fibrosis, Health Surveys, Heart Failure, Humans, Inflammation Mediators, Male, Multivariate Analysis, Peptide Fragments, Procollagen, Psychiatric Status Rating Scales, Risk Factors, Socioeconomic Factors}, issn = {1090-2139}, doi = {10.1016/j.bbi.2009.09.017}, author = {Kop, Willem J and Kuhl, Emily A and Barasch, Eddy and Jenny, Nancy S and Gottlieb, Stephen S and Gottdiener, John S} } @article {1197, title = {Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Jun}, pages = {256-66}, abstract = {

BACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12\%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16\%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.

CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cohort Studies, Endopeptidases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Heart Failure, Humans, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk, Ubiquitin-Specific Proteases}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.895763}, author = {Smith, Nicholas L and Felix, Janine F and Morrison, Alanna C and Demissie, Serkalem and Glazer, Nicole L and Loehr, Laura R and Cupples, L Adrienne and Dehghan, Abbas and Lumley, Thomas and Rosamond, Wayne D and Lieb, Wolfgang and Rivadeneira, Fernando and Bis, Joshua C and Folsom, Aaron R and Benjamin, Emelia and Aulchenko, Yurii S and Haritunians, Talin and Couper, David and Murabito, Joanne and Wang, Ying A and Stricker, Bruno H and Gottdiener, John S and Chang, Patricia P and Wang, Thomas J and Rice, Kenneth M and Hofman, Albert and Heckbert, Susan R and Fox, Ervin R and O{\textquoteright}Donnell, Christopher J and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Willerson, James T and Levy, Daniel and van Duijn, Cornelia M and Psaty, Bruce M and Witteman, Jacqueline C M and Boerwinkle, Eric and Vasan, Ramachandran S} } @article {1245, title = {Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.}, journal = {JAMA}, volume = {304}, year = {2010}, month = {2010 Dec 08}, pages = {2494-502}, abstract = {

CONTEXT: Older adults comprise the majority of new-onset heart failure (HF) diagnoses, but traditional risk-factor prediction models have limited accuracy in this population to identify those at highest risk for hospitalization or death.

OBJECTIVES: To determine if cardiac troponin T (cTnT) measured by a highly sensitive assay would be detectable in the majority of community-dwelling older adults, and if serial measures were associated with risk of HF hospitalization and cardiovascular death.

DESIGN, SETTING, AND PARTICIPANTS: A longitudinal nationwide cohort study (Cardiovascular Health Study) of 4221 community-dwelling adults aged 65 years or older without prior HF who had cTnT measured using a highly sensitive assay at baseline (1989-1990) and repeated after 2 to 3 years (n = 2918).

MAIN OUTCOME MEASURES: New-onset HF and cardiovascular death were examined through June 2008 with respect to cTnT concentrations, accounting for clinical risk predictors.

RESULTS: Cardiac troponin T was detectable (>=3.00 pg/mL) in 2794 participants (66.2\%). During a median follow-up of 11.8 years, 1279 participants experienced new-onset HF and 1103 cardiovascular deaths occurred, with a greater risk of both end points associated with higher cTnT concentrations. Among those participants with the highest cTnT concentrations (>12.94 pg/mL), there was an incidence rate per 100 person-years of 6.4 (95\% confidence interval [CI], 5.8-7.2; adjusted hazard ratio [aHR], 2.48; 95\% CI, 2.04-3.00) for HF and an incidence rate of 4.8 (95\% CI, 4.3-5.4; aHR, 2.91; 95\% CI, 2.37-3.58) for cardiovascular death compared with participants with undetectable cTnT levels (incidence rate, 1.6; 95\% CI, 1.4-1.8 and 1.1; 95\% CI, 0.9-1.2 for HF and cardiovascular death, respectively). Among individuals with initially detectable cTnT, a subsequent increase of more than 50\% (n = 393, 22\%) was associated with a greater risk for HF (aHR, 1.61; 95\% CI, 1.32-1.97) and cardiovascular death (aHR, 1.65; 95\% CI, 1.35-2.03) and a decrease of more than 50\% (n = 247, 14\%) was associated with a lower risk for HF (aHR, 0.73; 95\% CI, 0.54-0.97) and cardiovascular death (aHR, 0.71; 95\% CI, 0.52-0.97) compared with participants with 50\% or less change. Addition of baseline cTnT measurements to clinical risk factors was associated with only modest improvement in discrimination, with change in C statistic of 0.015 for HF and 0.013 for cardiovascular death.

CONCLUSION: In this cohort of older adults without known HF, baseline cTnT levels and changes in cTnT levels measured with a highly sensitive assay were significantly associated with incident HF and cardiovascular death.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Cohort Studies, Female, Heart Failure, Humans, Incidence, Male, Predictive Value of Tests, Risk, Sensitivity and Specificity, Troponin T, United States}, issn = {1538-3598}, doi = {10.1001/jama.2010.1708}, author = {deFilippi, Christopher R and de Lemos, James A and Christenson, Robert H and Gottdiener, John S and Kop, Willem J and Zhan, Min and Seliger, Stephen L} } @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 {1164, title = {Dynamic cardiovascular risk assessment in elderly people. The role of repeated N-terminal pro-B-type natriuretic peptide testing.}, journal = {J Am Coll Cardiol}, volume = {55}, year = {2010}, month = {2010 Feb 02}, pages = {441-50}, abstract = {

OBJECTIVES: This study sought to determine whether serial measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in community-dwelling elderly people would provide additional prognostic information to that from traditional risk factors.

BACKGROUND: Accurate cardiovascular risk stratification is challenging in elderly people.

METHODS: NT-proBNP was measured at baseline and 2 to 3 years later in 2,975 community-dwelling older adults free of heart failure in the longitudinal CHS (Cardiovascular Health Study). This investigation examined the risk of new-onset heart failure (HF) and death from cardiovascular causes associated with baseline NT-proBNP and changes in NT-proBNP levels, adjusting for potential confounders.

RESULTS: NT-proBNP levels in the highest quintile (>267.7 pg/ml) were independently associated with greater risks of HF (hazard ratio [HR]: 3.05; 95\% confidence interval [CI]: 2.46 to 3.78) and cardiovascular death (HR: 3.02; 95\% CI: 2.36 to 3.86) compared with the lowest quintile (<47.5 pg/ml). The inflection point for elevated risk occurred at NT-proBNP 190 pg/ml. Among participants with initially low NT-proBNP (<190 pg/ml), those who developed a >25\% increase on follow-up to >190 pg/ml (21\%) were at greater adjusted risk of HF (HR: 2.13; 95\% CI: 1.68 to 2.71) and cardiovascular death (HR: 1.91; 95\% CI: 1.43 to 2.53) compared with those with sustained low levels. Among participants with initially high NT-proBNP, those who developed a >25\% increase (40\%) were at higher risk of HF (HR: 2.06; 95\% CI: 1.56 to 2.72) and cardiovascular death (HR: 1.88; 95\% CI: 1.37 to 2.57), whereas those who developed a >25\% decrease to

CONCLUSIONS: NT-proBNP levels independently predict heart failure and cardiovascular death in older adults. NT-proBNP levels frequently change over time, and these fluctuations reflect dynamic changes in cardiovascular risk.

}, keywords = {Aged, Biomarkers, Female, Heart Failure, Humans, Male, Natriuretic Peptide, Brain, Peptide Fragments, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, United States}, issn = {1558-3597}, doi = {10.1016/j.jacc.2009.07.069}, author = {deFilippi, Christopher R and Christenson, Robert H and Gottdiener, John S and Kop, Willem J and Seliger, Stephen L} } @article {1292, title = {Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study.}, journal = {J Am Coll Cardiol}, volume = {57}, year = {2011}, month = {2011 May 24}, pages = {2172-80}, abstract = {

OBJECTIVES: The objective of this study was to investigate the associations of mitral annular calcification, aortic annular calcification, and aortic valve sclerosis with covert magnetic resonance imaging (MRI)-defined brain infarcts.

BACKGROUND: Clinically silent brain infarcts defined by MRI are associated with increased risk for cognitive decline, dementia, and future overt stroke. Left-sided cardiac valvular and annular calcifications are suspected as risk factors for clinical ischemic stroke.

METHODS: A total of 2,680 CHS (Cardiovascular Health Study) participants without clinical histories of stroke or transient ischemic attack underwent brain MRI in 1992 and 1993, 1 to 2 years before echocardiographic exams (1994 to 1995).

RESULTS: The mean age of the participants was 74.5 {\textpm} 4.8 years, and 39.3\% were men. The presence of any annular or valvular calcification (mitral annular calcification, aortic annular calcification, or aortic valve sclerosis), mitral annular calcification alone, or aortic annular calcification alone was significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular or valve calcification remained associated with covert brain infarcts (risk ratio: 1.24; 95\% confidence interval: 1.05 to 1.47). The degree of annular or valvular calcification severity showed a direct relation with the presence of covert MRI findings.

CONCLUSIONS: Left-sided cardiac annular and valvular calcifications are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening in the progression of annular and valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk for cognitive impairment and future stroke.

}, keywords = {Aged, Aortic Valve Stenosis, Brain, Brain Infarction, Calcinosis, Cohort Studies, Female, Humans, Magnetic Resonance Imaging, Male, Mitral Valve Stenosis, Retrospective Studies}, issn = {1558-3597}, doi = {10.1016/j.jacc.2011.01.034}, author = {Rodriguez, Carlos J and Bartz, Traci M and Longstreth, W T and Kizer, Jorge R and Barasch, Eddy and Lloyd-Jones, Donald M and Gottdiener, John S} } @article {1290, title = {Comparison of characteristics and outcomes of asymptomatic versus symptomatic left ventricular dysfunction in subjects 65 years old or older (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {107}, year = {2011}, month = {2011 Jun 01}, pages = {1667-74}, abstract = {

Although asymptomatic left ventricular (LV) systolic dysfunction (ALVSD) is common, its phenotype and prognosis for incident heart failure (HF) and mortality are insufficiently understood. Echocardiography was done in 5,649 participants in the Cardiovascular Health Study (age 73.0 {\textpm} 5.6 years, 57.6\% women). The clinical characteristics and cardiovascular risk factors of the participants with ALVSD were compared to those with normal LV function (ejection fraction >=55\%) and with symptomatic LV systolic dysfunction (SLVSD; ejection fraction <55\% and a history of HF). Cox proportional hazards models were used to estimate the risk of incident HF and mortality in those with ALVSD. Also, comparisons were made among the LV ejection fraction subgroups using previously validated cutoff values (<45\% and 45\% to 55\%), adjusting for the demographic and cardiovascular disease risk factors. Those with ALVSD (7.3\%) were more likely to have cardiovascular risk factors than those in the reference group (without LV dysfunction or symptomatic HF) but less likely than those with SLVSD. The HF rate was 24 occurrences per 1,000 person-years in the reference group and 57 occurrences per 1,000 person-years in those with ALVSD. The HF rate was 45 occurrences per 1,000 person-years for those with ALVSD and mildly impaired LV dysfunction and 93 occurrences per 1,000 person-years for those with ALVSD and moderate to severe LV dysfunction. The mortality rate was 51 deaths per 1,000 person-years in the reference group, 90 deaths per 1,000 person-years in the ALVSD group, and 156 deaths per 1,000 person-years in the SLVSD group. Adjusting for covariates, compared to the reference group, ALVSD was associated with an increased risk of incident HF (hazard ratio 1.60, 95\% confidence interval 1.35 to 1.91), cardiovascular mortality (hazard ratio 2.13, 95\% confidence interval 1.81 to 2.51), and all-cause mortality (hazard ratio 1.46, 95\% confidence interval 1.29 to 1.64). In conclusion, subjects with ALVSD are characterized by a greater prevalence of cardiovascular risk factors and co-morbidities than those with normal LV function and without HF. However, the prevalence is lower than in those with SLVSD. Patients with ALVSD are at an increased risk of HF and mortality, particularly those with greater severity of LV impairment.

}, keywords = {Aged, Female, Heart Failure, Systolic, Humans, Male, Prevalence, Risk Factors, Ultrasonography, Ventricular Dysfunction, Left}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2011.01.051}, author = {Pandhi, Jay and Gottdiener, John S and Bartz, Traci M and Kop, Willem J and Mehra, Mandeep R} } @article {1270, title = {Depressive symptoms, physical inactivity and risk of cardiovascular mortality in older adults: the Cardiovascular Health Study.}, journal = {Heart}, volume = {97}, year = {2011}, month = {2011 Mar}, pages = {500-5}, abstract = {

BACKGROUND: Depressed older individuals have a higher mortality than older persons without depression. Depression is associated with physical inactivity, and low levels of physical activity have been shown in some cohorts to be a partial mediator of the relationship between depression and cardiovascular events and mortality.

METHODS: A cohort of 5888 individuals (mean 72.8 {\textpm} 5.6 years, 58\% female, 16\% African-American) from four US communities was followed for an average of 10.3 years. Self-reported depressive symptoms (10-item Center for Epidemiological Studies Depression Scale) were assessed annually and self-reported physical activity was assessed at baseline and at 3 and 7 years. To estimate how much of the increased risk of cardiovascular mortality associated with depressive symptoms was due to physical inactivity, Cox regression with time-varying covariates was used to determine the percentage change in the log HR of depressive symptoms for cardiovascular mortality after adding physical activity variables.

RESULTS: At baseline, 20\% of participants scored above the cut-off for depressive symptoms. There were 2915 deaths (49.8\%), of which 1176 (20.1\%) were from cardiovascular causes. Depressive symptoms and physical inactivity each independently increased the risk of cardiovascular mortality and were strongly associated with each other (all p < 0.001). Individuals with both depressive symptoms and physical inactivity had greater cardiovascular mortality than those with either individually (p < 0.001, log rank test). Physical inactivity reduced the log HR of depressive symptoms for cardiovascular mortality by 26\% after adjustment. This was similar for persons with (25\%) and without (23\%) established coronary heart disease.

CONCLUSIONS: Physical inactivity accounted for a significant proportion of the risk of cardiovascular mortality due to depressive symptoms in older adults, regardless of coronary heart disease status.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Depression, Epidemiologic Methods, Female, Humans, Male, Motor Activity, Psychiatric Status Rating Scales, United States}, issn = {1468-201X}, doi = {10.1136/hrt.2010.209767}, author = {Win, Sithu and Parakh, Kapil and Eze-Nliam, Chete M and Gottdiener, John S and Kop, Willem J and Ziegelstein, Roy C} } @article {1330, title = {Left ventricular ejection fraction assessment in older adults: an adjunct to natriuretic peptide testing to identify risk of new-onset heart failure and cardiovascular death?}, journal = {J Am Coll Cardiol}, volume = {58}, year = {2011}, month = {2011 Sep 27}, pages = {1497-506}, abstract = {

OBJECTIVES: The goal of this paper was to determine whether assessment of left ventricular ejection fraction (LVEF) enhances prediction of new-onset heart failure (HF) and cardiovascular mortality over and above N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in older adults.

BACKGROUND: Elevated NT-proBNP levels are common in older adults and are associated with increased risk of HF.

METHODS: NT-proBNP and LVEF were measured in 4,137 older adults free of HF. Repeat measures of NT-proBNP were performed 2 to 3 years later and echocardiography was repeated 5 years later (n = 2,375), with a median follow-up of 10.7 years. The addition of an abnormal (<55\%) LVEF (n = 317 [7.7\%]) to initially elevated or rising NT-proBNP levels was evaluated to determine risk of HF or cardiovascular mortality. Changes in NT-proBNP levels were also assessed for estimating the risk of conversion from a normal to abnormal LVEF.

RESULTS: For participants with a low baseline NT-proBNP level (<190 pg/ml; n = 2,918), addition of an abnormal LVEF did not improve the estimation of risk of HF and identified a moderate increase in adjusted risk for cardiovascular mortality (hazard ratio: 1.69 [95\% confidence interval: 1.22 to 2.31]). Among those whose NT-proBNP subsequently increased >=25\% to >=190 pg/ml, an abnormal LVEF was likewise associated with an increased risk of cardiovascular mortality but not HF. Participants with an initially high NT-proBNP level (>=190 pg/ml) were at greater risk overall for both outcomes, and those with an abnormal LVEF were at the highest risk. However, an abnormal LVEF did not improve model classification or risk stratification for either endpoint when added to demographic factors and change in NT-proBNP. An initially elevated NT-proBNP or rising level was associated with an increased risk of developing an abnormal LVEF.

CONCLUSIONS: Assessment of LVEF in HF-free older adults based on NT-proBNP levels should be considered on an individual basis, as such assessments do not routinely improve prognostication.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Death, Female, Follow-Up Studies, Heart Failure, Humans, Male, Natriuretic Peptide, Brain, Peptide Fragments, Prospective Studies, Risk Factors, Stroke Volume, Survival Rate, Ventricular Function, Left}, issn = {1558-3597}, doi = {10.1016/j.jacc.2011.06.042}, author = {deFilippi, Christopher R and Christenson, Robert H and Kop, Willem J and Gottdiener, John S and Zhan, Min and Seliger, Stephen L} } @article {1277, title = {Longitudinal association of depressive symptoms with rapid kidney function decline and adverse clinical renal disease outcomes.}, journal = {Clin J Am Soc Nephrol}, volume = {6}, year = {2011}, month = {2011 Apr}, pages = {834-44}, abstract = {

BACKGROUND AND OBJECTIVES: Depression is a risk indicator for adverse outcomes in dialysis patients, but its prognostic impact in individuals who are not yet on dialysis is unknown. This study examines whether depressive symptoms are longitudinally associated with renal function decline, new-onset chronic kidney disease (CKD), ESRD, or hospitalization with acute kidney injury (AKI).

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Depressive symptoms were measured in a longitudinal cohort study with the 10-item Centers for Epidemiologic Studies Depression scale using a previously validated cut-off value (>=8). CKD at study entry and during follow-up was defined as an estimated GFR (eGFR) < 60 ml/min per m(2). Outcomes were rapid decline in eGFR (>3 ml/min per m(2) per year), new-onset CKD, ESRD (U.S. Renal Data System-based), and AKI (based on adjudicated medical record review). The median follow-up duration was 10.5 years.

RESULTS: Depressed participants (21.2\%) showed a higher prevalence of CKD at baseline compared with nondepressed participants in multivariable analysis. Depression was associated with a subsequent risk of rapid decline in eGFR, incident ESRD, and AKI, but not incident CKD in unadjusted models. In multivariable analyses, only associations of depressive symptoms with AKI remained significant.

CONCLUSIONS: Elevated depressive symptoms are associated with subsequent adverse renal disease outcomes. The depression-related elevated risk of AKI was independent of traditional renal disease risk factors and may in part be explained by the predictive value of depression for acute coronary syndromes and heart failure hospitalizations that can be complicated by AKI.

}, keywords = {Acute Kidney Injury, Aged, Chronic Disease, Cohort Studies, Comorbidity, Depression, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney Diseases, Longitudinal Studies, Male}, issn = {1555-905X}, doi = {10.2215/CJN.03840510}, author = {Kop, Willem J and Seliger, Stephen L and Fink, Jeffrey C and Katz, Ronit and Odden, Michelle C and Fried, Linda F and Rifkin, Dena E and Sarnak, Mark J and Gottdiener, John S} } @article {1242, title = {N-terminal pro-B-type natriuretic peptide is associated with sudden cardiac death risk: the Cardiovascular Health Study.}, journal = {Heart Rhythm}, volume = {8}, year = {2011}, month = {2011 Feb}, pages = {228-33}, abstract = {

BACKGROUND: Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality as well as with sudden death in women.

OBJECTIVE: The purpose of this study was to examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.

METHODS: The risk of SCD associated with baseline NT-proBNP was examined in 5,447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP.

RESULTS: Over a median follow-up of 12.5 years (maximum 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95\% confidence interval [2.9, 6.1]; P <.001) in the highest quintile compared with in the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the fifth versus the first quintile of 2.5 (95\% confidence interval [1.6, 3.8]; P <.001).

CONCLUSION: NT-proBNP provides information regarding the risk of SCD in a community-based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.

}, keywords = {Age Distribution, Aged, Biomarkers, Cardiovascular Diseases, Cohort Studies, Confidence Intervals, Death, Sudden, Cardiac, Female, Humans, Incidence, Kaplan-Meier Estimate, Male, Middle Aged, Natriuretic Peptide, Brain, Peptide Fragments, Predictive Value of Tests, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Sex Distribution, Time Factors, United States}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2010.10.038}, author = {Patton, Kristen K and Sotoodehnia, Nona and DeFilippi, Christopher and Siscovick, David S and Gottdiener, John S and Kronmal, Richard A} } @article {1268, title = {Predictive value of depressive symptoms and B-type natriuretic peptide for new-onset heart failure and mortality.}, journal = {Am J Cardiol}, volume = {107}, year = {2011}, month = {2011 Mar 01}, pages = {723-9}, abstract = {

Depression and natriuretic peptides predict heart failure (HF) progression, but the unique contributions of depression and biomarkers associated with HF outcomes are not known. The present study determined the additive predictive value of depression and aminoterminal pro-B-type natriuretic peptide (NT-proBNP) for new-onset HF in HF-free subjects and mortality in patients with HF. The participants in the Cardiovascular Health Study were assessed for depressive symptoms using the Center for Epidemiologic Studies Depression Scale and NT-proBNP using an electrochemiluminescence immunoassay. The validated cutoff values for depression (Center for Epidemiologic Studies Depression Scale >=8) and NT-proBNP (>=190 pg/ml) were used. The risks of incident HF and mortality (cardiovascular disease-related and all-cause) were examined during a median follow-up of 11 years, adjusting for demographics, clinical factors, and health behaviors. In patients with HF (n = 208), depression was associated with an elevated risk of cardiovascular disease mortality (hazard ratios [HR] 2.07, 95\% confidence interval [CI] 1.31 to 3.27) and all-cause mortality (HR 1.49, 95\% CI 1.05 to 2.11), independent of the NT-proBNP level and covariates. The combined presence of depression and elevated NT-proBNP was associated with substantially elevated covariate-adjusted risks of cardiovascular disease mortality (HR 5.42, 95\% CI 2.38 to 12.36) and all-cause mortality (HR 3.72, 95\% CI 2.20 to 6.37). In the 4,114 HF-free subjects, new-onset HF was independently predicted by an elevated NT-proBNP level (HR 2.27, 95\% CI 1.97 to 2.62) but not depression (HR 1.08, 95\% CI 0.92 to 1.26) in covariate-adjusted analysis. In conclusion, depression and NT-proBNP displayed additive predictive value for mortality in patients with HF. These associations can be explained by complementary pathophysiologic mechanisms. The presence of both elevated depression and NT-proBNP levels might improve the identification of patients with HF with a high risk of mortality.

}, keywords = {Aged, Depression, Disease Progression, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Natriuretic Peptide, Brain, Prognosis, Retrospective Studies, Risk Factors, Survival Rate, United States}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2010.10.055}, author = {van den Broek, Krista C and deFilippi, Christopher R and Christenson, Robert H and Seliger, Stephen L and Gottdiener, John S and Kop, Willem J} } @article {1321, title = {The relationship between serum markers of collagen turnover and cardiovascular outcome in the elderly: the Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {4}, year = {2011}, month = {2011 Nov}, pages = {733-9}, abstract = {

BACKGROUND: The deposition of collagen fibrils in the myocardial extracellular matrix increases with age and plays a key role in the pathophysiology of heart failure (HF). We sought to determine the predictive value of serum markers of collagen turnover for incident HF and cardiovascular (CV) morbidity, mortality, and all-cause mortality in elderly individuals.

METHODS AND RESULTS: In 880 participants in the Cardiovascular Health Study (mean age, 77{\textpm}6 years; 48\% women), serum levels of carboxyl-terminal peptide of procollagen type I (PIP), carboxyl-terminal telopeptide of collagen type I (CITP), and amino-terminal peptide of procollagen type III (PIIINP) were measured in 4 groups: HF with reduced ejection fraction (HFREF; n=146, EF <55\%); HF with preserved EF (HFPEF; n=175, EF >=55\%), control subjects with CV risk factors but not HF (CVD; n=280), and healthy control subjects free of CV disease (n=279). Relationships between these serum markers and outcome at follow-up of 12{\textpm}4 years (range, 3-17 years) was determined in six models including those adjusted for conventional risk factors, renal function, NT-proBNP and agents which interfere with collagen synthesis. For the entire cohort, in unadjusted and adjusted models, both PIIINP and CITP were associated with myocardial infarction, incident HF, hospitalization for HF, cardiovascular and all-cause mortality. In healthy control subjects, CITP and PIIINP were associated with all-cause death. In control subjects with risk factors, CITP was associated with incident HF, and in participants with HFPEF, CITP was associated with hospitalization for HF. No collagen biomarker was associated with outcome in participants with HFREF, and PIP was not associated with outcome in the cohort or its subgroups.

CONCLUSIONS: In both healthy and elderly individuals with CV disease at risk of developing HF, CITP and PIIINP are significantly associated with multiple adverse cardiac outcomes including myocardial infarction, HF, and death. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, keywords = {Aged, Aged, 80 and over, Aging, Biomarkers, Cardiovascular Diseases, Case-Control Studies, Cohort Studies, Collagen, Collagen Type I, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Peptide Fragments, Peptides, Predictive Value of Tests, Procollagen, Prospective Studies, Stroke Volume, Survival Rate}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.111.962027}, author = {Barasch, Eddy and Gottdiener, John S and Aurigemma, Gerard and Kitzman, Dalane W and Han, Jing and Kop, Willem J and Tracy, Russell P} } @article {1344, title = {Adiposity and incident heart failure in older adults: the cardiovascular health study.}, journal = {Obesity (Silver Spring)}, volume = {20}, year = {2012}, month = {2012 Sep}, pages = {1936-41}, abstract = {

While several studies have reported a positive association between overall adiposity and heart failure (HF) risk, limited and inconsistent data are available on the relation between central adiposity and incident HF in older adults. We sought to examine the association between waist circumference (WC) and incident HF and assess whether sex modifies the relation between WC and HF. Prospective study using data on 4,861 participants of the Cardiovascular Health Study (1989-2007). HF was adjudicated by a committee using information from medical records and medications. We used Cox proportional hazard models to compute hazard ratio (HR). The mean age was 73.0 years for men and 72.3 years for women; 42.5\% were men and 15.3\% were African Americans. WC was positively associated with an increased risk of HF: each standard deviation of WC was associated with a 14\% increased risk of HF (95\% CI: 3\%-26\%) in a multivariable model. There was not a statistically significant sex-by-WC interaction (P = 0.081). BMI was positively associated with incident HF (HR: 1.22 (95\% CI: 1.15-1.29) per standard deviation increase of BMI); however, this association was attenuated and became nonstatistically significant upon additional adjustment for WC (HR: 1.09 (95\% CI: 0.99-1.21)). In conclusion, a higher WC is associated with an increased risk of HF independent of BMI in community-living older men and women.

}, keywords = {Adiposity, Aged, Aging, Body Fat Distribution, Body Mass Index, Female, Heart Failure, Humans, Incidence, Independent Living, Male, Obesity, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Factors, United States, Waist Circumference}, issn = {1930-739X}, doi = {10.1038/oby.2011.320}, author = {Djouss{\'e}, Luc and Bartz, Traci M and Ix, Joachim H and Zieman, Susan J and Delaney, Joseph A and Mukamal, Kenneth J and Gottdiener, John S and Siscovick, David S and Kizer, Jorge R} } @article {1389, title = {Cardiac microinjury measured by troponin T predicts collagen metabolism in adults aged >=65 years with heart failure.}, journal = {Circ Heart Fail}, volume = {5}, year = {2012}, month = {2012 Jul 01}, pages = {406-13}, abstract = {

BACKGROUND: Repeated myocardial microinjuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition.

METHODS AND RESULTS: Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N=353; mean age, 74{\textpm}6 years; 52\% women) at baseline and at 3 years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I, carboxyterminal telopeptide of type I collagen, and aminoterminal propeptide of procollagen III. Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of carboxyterminal telopeptide of type I collagen (β=0.22, P<0.001) and aminoterminal propeptide of procollagen III (β=0.12, P=0.035) at follow-up when adjusting for demographic, clinical, and biochemical covariates including baseline cTnT. These associations were stronger in patients with heart failure than in control subjects. Conclusions- Increases in myocardial microinjury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Case-Control Studies, Chi-Square Distribution, Collagen, Collagen Type I, Female, Fibrosis, Heart Failure, Humans, Linear Models, Longitudinal Studies, Male, Multivariate Analysis, Myocardium, Peptide Fragments, Peptides, Predictive Value of Tests, Procollagen, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, Troponin T, Up-Regulation}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.111.965327}, author = {Kop, Willem J and Gottdiener, John S and deFilippi, Christopher R and Barasch, Eddy and Seliger, Stephen L and Jenny, Nancy S and Christenson, Robert H} } @article {1337, title = {Echocardiographic diastolic parameters and risk of atrial fibrillation: the Cardiovascular Health Study.}, journal = {Eur Heart J}, volume = {33}, year = {2012}, month = {2012 Apr}, pages = {904-12}, abstract = {

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia in the elderly, and shares several risk factors with diastolic dysfunction, including hypertension and advanced age. The purpose of this study is to examine diastolic dysfunction as a risk for incident AF.

METHODS AND RESULTS: We examined the association of echocardiographic parameters of diastolic function with the incidence of AF in 4480 participants enrolled in the Cardiovascular Health Study, an ongoing cohort of community-dwelling older adults from four US communities. Participants underwent baseline echocardiography in 1989-1990 and were followed for incident AF on routine follow-up and hospitalizations. After 50 941 person-years of follow-up (median follow-up time 12.1 years), 1219 participants developed AF. In multivariable-adjusted age-stratified Cox models, diastolic echocardiographic parameters were significantly associated with the risk of incident AF. The most significant parameters were the Doppler peak E-wave velocity and left atrial diameter, which demonstrated a positive nonlinear association [HR 1.5 (CI 1.3-1.9) and HR 1.7 (CI 1.4-2.1) for highest vs. lowest quintile, respectively], and Doppler A-wave velocity time integral, which displayed a U-shaped relationship with the risk of AF [HR 0.7 (CI 0.6-0.9) for middle vs. lowest quintile]. Each diastolic parameter displayed a significant association with adjusted NT-proBNP levels, although the nature of the association did not entirely parallel the risk of AF. Further cluster analysis revealed unique patterns of diastolic function that may identify patients at risk for AF.

CONCLUSION: In a community-based population of older adults, echocardiographic measures of diastolic function are significantly associated with an increased risk of AF.

}, keywords = {Aged, Atrial Fibrillation, Blood Flow Velocity, Diastole, Echocardiography, Doppler, Female, Humans, Kaplan-Meier Estimate, Longitudinal Studies, Male, Natriuretic Peptide, Brain, Peptide Fragments, Risk Factors, United States, Ventricular Dysfunction, Left}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehr378}, author = {Rosenberg, Michael A and Gottdiener, John S and Heckbert, Susan R and Mukamal, Kenneth J} } @article {1365, title = {Echocardiography, natriuretic peptides, and risk for incident heart failure in older adults: the Cardiovascular Health Study.}, journal = {JACC Cardiovasc Imaging}, volume = {5}, year = {2012}, month = {2012 Feb}, pages = {131-40}, abstract = {

OBJECTIVES: This study sought to examine the potential utility of echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for heart failure (HF) risk stratification in concert with a validated clinical HF risk score in older adults.

BACKGROUND: Without clinical guidance, echocardiography and natriuretic peptides have suboptimal test characteristics for population-wide HF risk stratification. However, the value of these tests has not been examined in concert with a clinical HF risk score.

METHODS: We evaluated the improvement in 5-year HF risk prediction offered by adding an echocardiographic score and/or NT-proBNP levels to the clinical Health Aging and Body Composition (ABC) HF risk score (base model) in 3,752 participants of the CHS (Cardiovascular Health Study) (age 72.6 {\textpm} 5.4 years; 40.8\% men; 86.5\% white). The echocardiographic score was derived as the weighted sum of independent echocardiographic predictors of HF. We assessed changes in Bayesian information criterion (BIC), C index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). We examined also the weighted NRI across baseline HF risk categories under multiple scenarios of event versus nonevent weighting.

RESULTS: Reduced left ventricular ejection fraction, abnormal E/A ratio, enlarged left atrium, and increased left ventricular mass were independent echocardiographic predictors of HF. Adding the echocardiographic score and NT-proBNP levels to the clinical model improved BIC (echocardiography: -43, NT-proBNP: -64.1, combined: -68.9; all p < 0.001) and C index (baseline: 0.746; echocardiography: +0.031, NT-proBNP: +0.027, combined: +0.043; all p < 0.01), and yielded robust IDI (echocardiography: 43.3\%, NT-proBNP: 42.2\%, combined: 61.7\%; all p < 0.001), and NRI (based on Health ABC HF risk groups; echocardiography: 11.3\%; NT-proBNP: 10.6\%, combined: 16.3\%; all p < 0.01). Participants at intermediate risk by the clinical model (5\% to 20\% 5-yr HF risk; 35.7\% of the cohort) derived the most reclassification benefit. Echocardiography yielded modest reclassification when used sequentially after NT-proBNP.

CONCLUSIONS: In older adults, echocardiography and NT-proBNP offer significant HF risk reclassification over a clinical prediction model, especially for intermediate-risk individuals.

}, keywords = {Aged, Biomarkers, Cardiomegaly, Echocardiography, Female, Heart Failure, Humans, Male, Natriuretic Peptide, Brain, Peptide Fragments, Risk, Risk Assessment, Ventricular Function, Left}, issn = {1876-7591}, doi = {10.1016/j.jcmg.2011.11.011}, author = {Kalogeropoulos, Andreas P and Georgiopoulou, Vasiliki V and deFilippi, Christopher R and Gottdiener, John S and Butler, Javed} } @article {1393, title = {Heart rate response to a timed walk and cardiovascular outcomes in older adults: the cardiovascular health study.}, journal = {Cardiology}, volume = {122}, year = {2012}, month = {2012}, pages = {69-75}, abstract = {

OBJECTIVES: To determine the relationship between heart rate response during low-grade physical exertion (6-min walk) with mortality and adverse cardiovascular outcomes in the elderly.

METHODS: Participants in the Cardiovascular Health Study who completed a 6-min walk test were included. We used delta heart rate (difference between postwalk heart rate and resting heart rate) as a measure of chronotropic response and examined its association with (1) all-cause mortality and (2) incident coronary heart disease event, using multivariable Cox regression models.

RESULTS: We included 2,224 participants (mean age 77 {\textpm} 4 years; 60\% women; 85\% white). The average delta heart rate was 26 beats/min. Participants in the lowest tertile of delta heart rate (<20 beats/min) had higher risk-adjusted mortality [hazard ratio (HR) 1.18, 95\% confidence interval (CI) 1.00-1.40] and incident coronary heart disease (HR 1.37, 95\% CI 1.05-1.78) compared to subjects in the highest tertile (>=30 beats/min), with a significant linear trend across tertiles (p for trend <0.05 for both outcomes). This relationship was not significant after adjustment for distance walked.

CONCLUSION: Impaired chronotropic response during a 6-min walk test was associated with an increased risk of mortality and incident coronary heart disease among the elderly. This association was attenuated after adjusting for distance walked.

}, keywords = {Aged, Cause of Death, Coronary Disease, Exercise Test, Female, Heart Rate, Humans, Male, Physical Exertion, Prognosis, Prospective Studies, Risk Factors, Time Factors, Walking}, issn = {1421-9751}, doi = {10.1159/000338736}, author = {Girotra, Saket and Kitzman, Dalane W and Kop, Willem J and Stein, Phyllis K and Gottdiener, John S and Mukamal, Kenneth J} } @article {5860, title = {Hemoglobin A1c and arterial and ventricular stiffness in older adults.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e47941}, abstract = {

OBJECTIVE: Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA(1c), an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes.

RESEARCH DESIGN \& METHODS: Baseline HbA(1c) was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged >= 65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA(1c) and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures.

RESULTS: HbA(1c) was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA(1c) was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM.

CONCLUSIONS: In this sample of older adults without diabetes, HbA(1c) was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers.

}, keywords = {Adult, African Continental Ancestry Group, Aged, Ankle Brachial Index, Arteries, Blood Glucose, Blood Pressure, Body Mass Index, Cross-Sectional Studies, Fasting, Female, Genetic Association Studies, Glycated Hemoglobin A, Glycation End Products, Advanced, Heart Ventricles, Humans, Male, Middle Aged, Ultrasonography, Vascular Stiffness}, issn = {1932-6203}, doi = {10.1371/journal.pone.0047941}, author = {Zieman, Susan J and Kamineni, Aruna and Ix, Joachim H and Barzilay, Joshua and Djouss{\'e}, Luc and Kizer, Jorge R and Biggs, Mary L and de Boer, Ian H and Chonchol, Michel and Gottdiener, John S and Selvin, Elizabeth and Newman, Anne B and Kuller, Lewis H and Siscovick, David S and Mukamal, Kenneth J} } @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 {1547, title = {Physical activity, change in biomarkers of myocardial stress and injury, and subsequent heart failure risk in older adults.}, journal = {J Am Coll Cardiol}, volume = {60}, year = {2012}, month = {2012 Dec 18}, pages = {2539-47}, abstract = {

OBJECTIVES: The aim of this study was to evaluate the association between physical activity and changes in levels of highly sensitive troponin T (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the subsequent risk of the development of heart failure (HF) in community-dwelling older adults.

BACKGROUND: Higher baseline levels of cTnT and NT-proBNP and increases over time correlate with the risk of HF in older adults. Factors modifying these levels have not been identified.

METHODS: NT-proBNP and cTnT were measured at baseline and 2 to 3 years later in adults 65 years of age and older free of HF participating in the Cardiovascular Health Study. Self-reported physical activity and walking pace were combined into a composite score. An increase was prespecified for NT-proBNP as a >25\% increment from baseline to >=190 pg/ml and for cTnT as a >50\% increment from baseline in participants with detectable levels (>=3 pg/ml).

RESULTS: A total of 2,933 participants free of HF had NT-proBNP and cTnT measured at both time points. The probability of an increase in biomarker concentrations between baseline and follow-up visits was inversely related to the physical activity score. Compared with participants with the lowest score, those with the highest score had an odds ratio of 0.50 (95\% confidence interval: 0.33 to 0.77) for an increase in NT-proBNP and an odds ratio of 0.30 (95\% confidence interval: 0.16 to 0.55) for an increase in cTnT, after adjusting for comorbidities and baseline levels. A higher activity score associated with a lower long-term incidence of HF. Moreover, at each level of activity, an increase in either biomarker still identified those at higher risk.

CONCLUSIONS: These findings suggest that moderate physical activity has protective effects on early heart failure phenotypes, preventing cardiac injury and neurohormonal activation.

}, keywords = {Aged, Biomarkers, Female, Heart Failure, Humans, Male, Motor Activity, Natriuretic Peptide, Brain, Peptide Fragments, Risk Assessment, Troponin}, issn = {1558-3597}, doi = {10.1016/j.jacc.2012.08.1006}, author = {deFilippi, Christopher R and de Lemos, James A and Tkaczuk, Andrew T and Christenson, Robert H and Carnethon, Mercedes R and Siscovick, David S and Gottdiener, John S and Seliger, Stephen L} } @article {6166, title = {Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study.}, journal = {Ann Intern Med}, volume = {159}, year = {2013}, month = {2013 Dec 03}, pages = {721-8}, abstract = {

BACKGROUND: Atrial fibrillation (AF) prediction models have unclear clinical utility given the absence of AF prevention therapies and the immutability of many risk factors. Premature atrial contractions (PACs) play a critical role in AF pathogenesis and may be modifiable.

OBJECTIVE: To investigate whether PAC count improves model performance for AF risk.

DESIGN: Prospective cohort study.

SETTING: 4 U.S. communities.

PATIENTS: A random subset of 1260 adults without prevalent AF enrolled in the Cardiovascular Health Study between 1989 and 1990.

MEASUREMENTS: The PAC count was quantified by 24-hour electrocardiography. Participants were followed for the diagnosis of incident AF or death. The Framingham AF risk algorithm was used as the comparator prediction model.

RESULTS: In adjusted analyses, doubling the hourly PAC count was associated with a significant increase in AF risk (hazard ratio, 1.17 [95\% CI, 1.13 to 1.22]; P < 0.001) and overall mortality (hazard ratio, 1.06 [CI, 1.03 to 1.09]; P < 0.001). Compared with the Framingham model, PAC count alone resulted in similar AF risk discrimination at 5 and 10 years of follow-up and superior risk discrimination at 15 years. The addition of PAC count to the Framingham model resulted in significant 10-year AF risk discrimination improvement (c-statistic, 0.65 vs. 0.72; P < 0.001), net reclassification improvement (23.2\% [CI, 12.8\% to 33.6\%]; P < 0.001), and integrated discrimination improvement (5.6\% [CI, 4.2\% to 7.0\%]; P < 0.001). The specificity for predicting AF at 15 years exceeded 90\% for PAC counts more than 32 beats/h.

LIMITATION: This study does not establish a causal link between PACs and AF.

CONCLUSION: The addition of PAC count to a validated AF risk algorithm provides superior AF risk discrimination and significantly improves risk reclassification. Further study is needed to determine whether PAC modification can prospectively reduce AF risk.

PRIMARY FUNDING SOURCE: American Heart Association, Joseph Drown Foundation, and National Institutes of Health.

}, keywords = {Aged, Atrial Fibrillation, Atrial Function, Cause of Death, Electrocardiography, Female, Humans, Male, Models, Statistical, Myocardial Contraction, Prospective Studies, Risk Assessment}, issn = {1539-3704}, doi = {10.7326/0003-4819-159-11-201312030-00004}, author = {Dewland, Thomas A and Vittinghoff, Eric and Mandyam, Mala C and Heckbert, Susan R and Siscovick, David S and Stein, Phyllis K and Psaty, Bruce M and Sotoodehnia, Nona and Gottdiener, John S and Marcus, Gregory M} } @article {6071, title = {Cardiomyocyte injury assessed by a highly sensitive troponin assay and sudden cardiac death in the community: the Cardiovascular Health Study.}, journal = {J Am Coll Cardiol}, volume = {62}, year = {2013}, month = {2013 Dec 03}, pages = {2112-20}, abstract = {

OBJECTIVES: This study sought to determine the association between markers of cardiomyocyte injury in ambulatory subjects and sudden cardiac death (SCD).

BACKGROUND: The pathophysiology of SCD is complex but is believed to be associated with an abnormal cardiac substrate in most cases. The association between biomarkers of cardiomyocyte injury in ambulatory subjects and SCD has not been investigated.

METHODS: Levels of cardiac troponin T, a biomarker of cardiomyocyte injury, were measured by a highly sensitive assay (hsTnT) in 4,431 ambulatory participants in the Cardiovascular Health Study, a longitudinal community-based prospective cohort study. Serial measures were obtained in 3,089 subjects. All deaths, including SCD, were adjudicated by a central events committee.

RESULTS: Over a median follow-up of 13.1 years, 246 participants had SCD. Baseline levels of hsTnT were significantly associated with SCD (hazard ratio [HR] for +1 log(hsTnT): 2.04, 95\% confidence interval [CI]: 1.78 to 2.34]. This association persisted in covariate-adjusted Cox analyses accounting for baseline risk factors (HR: 1.30, 95\% CI: 1.05 to 1.62), as well as for incident heart failure and myocardial infarction (HR: 1.26, 95\% CI: 1.01 to 1.57). The population was also categorized into 3 groups based on baseline hsTnT levels and SCD risk [fully adjusted HR: 1.89 vs. 1.55 vs. 1 (reference group) for hsTnT >=12.10 vs. 5.01 to 12.09 vs. <= 5.00 pg/ml, respectively; p trend = 0.005]. On serial measurements, change in hsTnT levels was also associated with SCD risk (fully adjusted HR for +1 pg/ml per year increase from baseline: 1.03, 95\% CI: 1.01 to 1.06).

CONCLUSIONS: The findings suggest an association between cardiomyocyte injury in ambulatory subjects and SCD risk beyond that of traditional risk factors.

}, keywords = {Aged, Ambulatory Care, Biomarkers, Death, Sudden, Cardiac, Female, Heart Arrest, Humans, Longitudinal Studies, Male, Middle Aged, Myocardium, Myocytes, Cardiac, Proportional Hazards Models, Risk Assessment, Troponin T}, issn = {1558-3597}, doi = {10.1016/j.jacc.2013.07.049}, author = {Hussein, Ayman A and Gottdiener, John S and Bartz, Traci M and Sotoodehnia, Nona and DeFilippi, Christopher and Dickfeld, Timm and Deo, Rajat and Siscovick, David and Stein, Phyllis K and Lloyd-Jones, Donald} } @article {1565, title = {Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study.}, journal = {Eur J Heart Fail}, volume = {15}, year = {2013}, month = {2013 Apr}, pages = {394-9}, chapter = {394}, abstract = {

AIM: To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure.

METHODS AND RESULTS: In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95\% confidence interval (CI) 1.25-1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95\% CI 1.01-1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion.

CONCLUSION: An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cohort Studies, Fatty Acid-Binding Proteins, Female, Follow-Up Studies, Glomerular Filtration Rate, Heart Failure, Humans, Male, Proportional Hazards Models, Prospective Studies, Risk Factors, United States, Ventricular Function, Left}, issn = {1879-0844}, doi = {10.1093/eurjhf/hfs196}, author = {Djouss{\'e}, Luc and Bartz, Traci M and Ix, Joachim H and Kochar, Jinesh and Kizer, Jorge R and Gottdiener, John S and Tracy, Russell P and Mozaffarian, Dariush and Siscovick, David S and Mukamal, Kenneth J and Zieman, Susan J} } @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 {6279, title = {Long-term trajectory of two unique cardiac biomarkers and subsequent left ventricular structural pathology and risk of incident heart failure in community-dwelling older adults at low baseline risk.}, journal = {JACC Heart Fail}, volume = {1}, year = {2013}, month = {2013 Aug}, pages = {353-360}, abstract = {

OBJECTIVES: This study sought to determine whether the combined trajectories of cardiac biomarkers identify those older adults with initial low levels who have an increased risk for structural heart disease, incident heart failure (HF), and cardiovascular (CV) death.

BACKGROUND: Initial low levels of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) identify older adults at lower risk for CV events.

METHODS: We performed an observational study among older adults without prevalent HF in the CHS (Cardiovascular Health Study). NT-proBNP and hs-cTnT were measured at baseline and after 2 to 3 years. In those with low baseline levels, a significant increase was defined as cardiac troponin T (cTnT) >50\% and NT-proBNP >25\% increase to >190 pg/ml. Left ventricular ejection fraction and left ventricular mass were measured by echocardiography at baseline and 5 years. Cox regression was used to estimate the association of change in biomarkers with HF and CV mortality.

RESULTS: Among 2,008 participants with initially low biomarker concentrations, significant increases occurred in 14.8\% for cTnT only, 13.2\% for NT-proBNP only, and 6.1\% for both. After 10 years, cumulative HF incidence was 50.4\% versus 12.2\% among those with both biomarkers versus neither biomarker increased. The adjusted relative risk comparing those with increases in both biomarkers versus neither biomarker was 3.56 for incident HF (95\% confidence interval: 2.56 to 4.97) and 2.98 for CV mortality (95\% confidence interval: 2.98 to 4.26). Among 1,340 participants with serial echocardiography, the frequency of new abnormal left ventricular ejection fraction was 11.8\% versus 4\% for those with increases in both biomarkers versus neither biomarker (p = 0.007).

CONCLUSIONS: Among older adults without HF with initially low cTnT and NT-proBNP, the long-term trajectory of both biomarkers predicts systolic dysfunction, incident HF, and CV death.

}, keywords = {Aged, Biomarkers, Female, Heart Failure, Heart Ventricles, Humans, Male, Natriuretic Peptide, Brain, Peptide Fragments, Prospective Studies, Risk Assessment, Time Factors, Troponin T, Ultrasonography}, issn = {2213-1787}, doi = {10.1016/j.jchf.2013.04.007}, author = {Glick, Danielle and deFilippi, Christopher R and Christenson, Robert and Gottdiener, John S and Seliger, Stephen L} } @article {6064, title = {Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {6}, year = {2013}, month = {2013 Sep 01}, pages = {964-9}, abstract = {

BACKGROUND: Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF).

METHODS AND RESULTS: To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12\% (95\% confidence interval, 6\%-19\%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95\% confidence interval, 1.09-1.23]).

CONCLUSIONS: A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Comorbidity, Fatty Acids, Nonesterified, Female, Heart Failure, Humans, Incidence, Kaplan-Meier Estimate, Linear Models, Male, Multivariate Analysis, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Time Factors, United States}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.113.000521}, author = {Djouss{\'e}, Luc and Benkeser, David and Arnold, Alice and Kizer, Jorge R and Zieman, Susan J and Lemaitre, Rozenn N and Tracy, Russell P and Gottdiener, John S and Mozaffarian, Dariush and Siscovick, David S and Mukamal, Kenneth J and Ix, Joachim H} } @article {1559, title = {Relation of vitamin D and parathyroid hormone to cardiac biomarkers and to left ventricular mass (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {111}, year = {2013}, month = {2013 Feb 01}, pages = {418-24}, abstract = {

Vitamin D and parathyroid hormone (PTH) may affect cardiovascular health in patients with kidney disease and in the general population. The aim of this study was to investigate associations of serum 25-hydroxyvitamin D (25(OH)D) and PTH concentrations with a comprehensive set of biochemical, electrocardiographic, and echocardiographic measurements of cardiac structure and function in the Cardiovascular Health Study. A total of 2,312 subjects who were free of cardiovascular disease at baseline were studied. Serum 25(OH)D and intact PTH concentrations were measured using mass spectrometry and a 2-site immunoassay. Outcomes were N-terminal pro-B-type natriuretic peptide, cardiac troponin T, electrocardiographic measures of conduction, and echocardiographic measures of left ventricular mass and diastolic dysfunction. At baseline, subjects had a mean age of 73.9 {\textpm} 4.9 years, 69.7\% were women, and 21\% had chronic kidney disease (glomerular filtration rate <60 ml/min). Mean 25(OH)D was 25.2 {\textpm} 10.2 ng/ml, and median PTH was 51 pg/ml (range 39 to 65). After adjustment, 25(OH)D was not associated with any of the biochemical, conduction, or echocardiographic outcomes. Serum PTH levels >=65 pg/ml were associated with greater N-terminal pro-B-type natriuretic peptide, cardiac troponin T, and left ventricular mass in patients with chronic kidney disease. The regression coefficients were: 120 pg/ml (95\% confidence interval 36.1 to 204), 5.2 pg/ml (95\% confidence interval 3.0 to 7.4), and 17 g (95\% confidence interval 6.2 to 27.8) (p <0.001). In subjects with normal kidney function, PTH was not associated with the outcomes. In conclusion, in older adults with chronic kidney disease, PTH excess is associated with higher N-terminal pro-B-type natriuretic peptide, cardiac troponin T, and left ventricular mass. These findings suggest a role for PTH in cardiovascular health and the prevention of cardiac diseases.

}, keywords = {Adult, Aged, Biomarkers, Cardiovascular Diseases, Echocardiography, Electrocardiography, Female, Follow-Up Studies, Heart Ventricles, Humans, Incidence, Male, Mass Spectrometry, Middle Aged, Parathyroid Hormone, Prospective Studies, United States, Vitamin D}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2012.10.021}, author = {van Ballegooijen, Adriana J and Visser, Marjolein and Kestenbaum, Bryan and Siscovick, David S and de Boer, Ian H and Gottdiener, John S and deFilippi, Christopher R and Brouwer, Ingeborg A} } @article {5878, title = {Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium.}, journal = {J Am Heart Assoc}, volume = {2}, year = {2013}, month = {2013 Mar 18}, pages = {e000102}, abstract = {

BACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.

METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19\% African Americans, 81\% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95\% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95\% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95\% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95\% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95\% CI, 0.664 to 0.747) and calibration was adequate.

CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Atrial Fibrillation, Cohort Studies, Diabetes Mellitus, European Continental Ancestry Group, Female, Heart Failure, Humans, Hypertension, Iceland, Incidence, Male, Middle Aged, Myocardial Infarction, Netherlands, Proportional Hazards Models, Risk Assessment, Smoking, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.112.000102}, author = {Alonso, Alvaro and Krijthe, Bouwe P and Aspelund, Thor and Stepas, Katherine A and Pencina, Michael J and Moser, Carlee B and Sinner, Moritz F and Sotoodehnia, Nona and Fontes, Jo{\~a}o D and Janssens, A Cecile J W and Kronmal, Richard A and Magnani, Jared W and Witteman, Jacqueline C and Chamberlain, Alanna M and Lubitz, Steven A and Schnabel, Renate B and Agarwal, Sunil K and McManus, David D and Ellinor, Patrick T and Larson, Martin G and Burke, Gregory L and Launer, Lenore J and Hofman, Albert and Levy, Daniel and Gottdiener, John S and K{\"a}{\"a}b, Stefan and Couper, David and Harris, Tamara B and Soliman, Elsayed Z and Stricker, Bruno H C and Gudnason, Vilmundur and Heckbert, Susan R and Benjamin, Emelia J} } @article {6139, title = {Total and high-molecular-weight adiponectin and risk of coronary heart disease and ischemic stroke in older adults.}, journal = {J Clin Endocrinol Metab}, volume = {98}, year = {2013}, month = {2013 Jan}, pages = {255-63}, abstract = {

CONTEXT: Adiponectin is atheroprotective in the laboratory, but prospective studies have shown opposite associations with cardiovascular disease (CVD) in healthy middle-aged populations (protective) and older cohorts (adverse). Whether this relates to different proportions of high-molecular-weight (HMW) adiponectin is unknown.

OBJECTIVE: The aim of the study was to test the hypothesis that total adiponectin is directly associated, but HMW adiponectin is inversely related, with CVD in older adults.

DESIGN, SETTING, AND PARTICIPANTS: We evaluated 3290 participants free of prevalent CVD in a longitudinal cohort study of U.S. adults aged 65 yr and older.

MAIN OUTCOME MEASURES: We measured incident CVD (n = 1291), comprising coronary heart disease and ischemic stroke.

RESULTS: Total and HMW adiponectin were tightly correlated (r = 0.94). Cubic splines adjusted for potential confounders revealed that the associations of total and HMW adiponectin with CVD were U-shaped, with inflection points of 20 and 10 mg/liter, respectively. After controlling for potential confounding, levels of total and HMW adiponectin below these cutpoints tended to be inversely associated with incident CVD, driven by their significant or near-significant relations with coronary heart disease [hazard ratio (HR), 0.85 per sd increase; 95\% confidence interval (CI), 0.75-96; and HR, 0.87; 95\% CI, 0.75-1.01, respectively]. These associations were abrogated by additional inclusion of putative metabolic intermediates. Above these cutpoints, however, both total and HMW adiponectin were significantly directly associated with CVD after adjustment for confounders and, particularly, mediators (HR, 1.20 per sd increase; 95\% CI, 1.06-1.35; and HR, 1.12; 95\% CI, 1.02-1.24, respectively).

CONCLUSION: In community-living elders, total and HMW adiponectin showed similar U-shaped relationships with CVD. The inverse relation in the lower range, but not the direct association at the higher end, disappeared after inclusion of putative intermediates, suggesting that high levels may reflect adverse processes separate from adiponectin{\textquoteright}s beneficial glycometabolic properties.

}, keywords = {Adiponectin, Adult, Aged, Aged, 80 and over, Brain Ischemia, Cardiovascular Diseases, Case-Control Studies, Cohort Studies, Coronary Disease, Female, Humans, Male, Molecular Weight, Residence Characteristics, Risk Factors, Stroke}, issn = {1945-7197}, doi = {10.1210/jc.2012-2103}, author = {Kizer, Jorge R and Benkeser, David and Arnold, Alice M and Djouss{\'e}, Luc and Zieman, Susan J and Mukamal, Kenneth J and Tracy, Russell P and Mantzoros, Christos S and Siscovick, David S and Gottdiener, John S and Ix, Joachim H} } @article {6601, title = {B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies.}, journal = {Europace}, volume = {16}, year = {2014}, month = {2014 Oct}, pages = {1426-33}, abstract = {

AIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.

METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95\% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95\% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95\% CI, 0.022-0.032), a relative IDI of 41.5\%, and a continuous NRI of 0.389 (95\% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.

CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.

}, keywords = {Aged, Atrial Fibrillation, Biomarkers, C-Reactive Protein, Europe, Female, Humans, Incidence, Male, Natriuretic Peptide, Brain, Peptide Fragments, Predictive Value of Tests, Risk Assessment, Risk Factors, United States}, issn = {1532-2092}, doi = {10.1093/europace/euu175}, author = {Sinner, Moritz F and Stepas, Katherine A and Moser, Carlee B and Krijthe, Bouwe P and Aspelund, Thor and Sotoodehnia, Nona and Fontes, Jo{\~a}o D and Janssens, A Cecile J W and Kronmal, Richard A and Magnani, Jared W and Witteman, Jacqueline C and Chamberlain, Alanna M and Lubitz, Steven A and Schnabel, Renate B and Vasan, Ramachandran S and Wang, Thomas J and Agarwal, Sunil K and McManus, David D and Franco, Oscar H and Yin, Xiaoyan and Larson, Martin G and Burke, Gregory L and Launer, Lenore J and Hofman, Albert and Levy, Daniel and Gottdiener, John S and K{\"a}{\"a}b, Stefan and Couper, David and Harris, Tamara B and Astor, Brad C and Ballantyne, Christie M and Hoogeveen, Ron C and Arai, Andrew E and Soliman, Elsayed Z and Ellinor, Patrick T and Stricker, Bruno H C and Gudnason, Vilmundur and Heckbert, Susan R and Pencina, Michael J and Benjamin, Emelia J and Alonso, Alvaro} } @article {6541, title = {Fibrosis-related biomarkers and incident cardiovascular disease in older adults: the cardiovascular health study.}, journal = {Circ Arrhythm Electrophysiol}, volume = {7}, year = {2014}, month = {2014 Aug}, pages = {583-9}, abstract = {

BACKGROUND: Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown.

METHODS AND RESULTS: We determined the associations of 2 biomarkers of fibrosis, transforming growth factor- β (TGF-β), and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction, and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1371) and PIIINP (n=2568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β{\textquoteright}s pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per SD=1.07; 95\% confidence interval [CI], 1.01-1.14) and heart failure (HR per SD=1.08; CI, 1.01-1.16) but not myocardial infarction or stroke. TGF-β was not associated with any CVD outcomes in the full cohort but was associated with total CVD (HR per SD=1.16; CI, 1.02-1.31), heart failure (HR per SD=1.16; CI, 1.01-1.34), and stroke (HR per SD=1.20; CI, 1.01-1.42) among individuals with C-reactive protein above the median, 2.3 mg/L (P interaction <0.05).

CONCLUSIONS: Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Female, Fibrosis, Heart Failure, Humans, Incidence, Male, Myocardial Infarction, Peptide Fragments, Procollagen, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Stroke, Time Factors, Transforming Growth Factor beta, United States}, issn = {1941-3084}, doi = {10.1161/CIRCEP.114.001610}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Biggs, Mary L and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Sicovick, David S and Tracy, Russell P and Mukamal, Kenneth J} } @article {6336, title = {Fibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study.}, journal = {Am J Epidemiol}, volume = {179}, year = {2014}, month = {2014 Jun 01}, pages = {1331-9}, abstract = {

Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996-2010). We measured circulating TGF-β and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-β and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-β and PIIINP were 1.09 (95\% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-β and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-β and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cause of Death, Female, Fibrosis, Follow-Up Studies, Humans, Likelihood Functions, Male, Multivariate Analysis, Peptide Fragments, Procollagen, Proportional Hazards Models, Prospective Studies, Risk Factors, Transforming Growth Factor beta}, issn = {1476-6256}, doi = {10.1093/aje/kwu067}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Biggs, Mary L and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and Tracy, Russell P and Zieman, Susan J and Mukamal, Kenneth J} } @article {6137, title = {Relations of plasma total and high-molecular-weight adiponectin to new-onset heart failure in adults >=65 years of age (from the Cardiovascular Health study).}, journal = {Am J Cardiol}, volume = {113}, year = {2014}, month = {2014 Jan 15}, pages = {328-34}, abstract = {

Adiponectin exhibits cardioprotective properties in experimental studies, but elevated levels have been linked to increased mortality in older adults and patients with chronic heart failure (HF). The adipokine{\textquoteright}s association with new-onset HF remains less well defined. The aim of this study was to investigate the associations of total and high-molecular weight (HMW) adiponectin with incident HF (n = 780) and, in a subset, echocardiographic parameters in a community-based cohort of adults aged >=65 years. Total and HMW adiponectin were measured in 3,228 subjects without prevalent HF, atrial fibrillation or CVD. The relations of total and HMW adiponectin with HF were nonlinear, with significant associations observed only for concentrations greater than the median (12.4 and 6.2 mg/L, respectively). After adjustment for potential confounders, the hazard ratios per SD increment in total adiponectin were 0.93 (95\% confidence interval 0.72 to 1.21) for concentrations less than the median and 1.25 (95\% confidence interval 1.14 to 1.38) higher than the median. There was a suggestion of effect modification by body mass index, whereby the association appeared strongest in participants with lower body mass indexes. Consistent with the HF findings, higher adiponectin tended to be associated with left ventricular systolic dysfunction and left atrial enlargement. Results were similar for HMW adiponectin. In conclusion, total and HMW adiponectin showed comparable relations with incident HF in this older cohort, with a threshold effect of increasing risk occurring at their median concentrations. High levels of adiponectin may mark or mediate age-related processes that lead to HF in older adults.

}, keywords = {Adiponectin, Age of Onset, Aged, Biomarkers, Cross-Sectional Studies, Echocardiography, Doppler, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Prognosis, Prospective Studies, Recurrence, Severity of Illness Index, United States, Ventricular Function, Left}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2013.09.027}, author = {Karas, Maria G and Benkeser, David and Arnold, Alice M and Bartz, Traci M and Djouss{\'e}, Luc and Mukamal, Kenneth J and Ix, Joachim H and Zieman, Susan J and Siscovick, David S and Tracy, Russell P and Mantzoros, Christos S and Gottdiener, John S and deFilippi, Christopher R and Kizer, Jorge R} } @article {6805, title = {Associations between metabolic dysregulation and circulating biomarkers of fibrosis: the Cardiovascular Health Study.}, journal = {Metabolism}, volume = {64}, year = {2015}, month = {2015 Oct}, pages = {1316-23}, abstract = {

AIM: Fibrosis is one postulated pathway by which diabetes produces cardiac and other systemic complications. Our aim was to determine which metabolic parameters are associated with circulating fibrosis-related biomarkers transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP).

METHODS: We used linear regression to determine the cross-sectional associations of diverse metabolic parameters, including fasting glucose, fasting insulin, body mass index, fatty acid binding protein 4, and non-esterified fatty acids, with circulating levels of TGF-β (n = 1559) and PIIINP (n = 3024) among community-living older adults in the Cardiovascular Health Study.

RESULTS: Among the main metabolic parameters we examined, only fasting glucose was associated with TGF-β (P = 0.03). In contrast, multiple metabolic parameters were associated with PIIINP, including fasting insulin, body mass index, and non-esterified fatty acids (P<0.001, P<0.001, P=0.001, respectively). These associations remained statistically significant after mutual adjustment, except the association between BMI and PIIINP.

CONCLUSIONS: Isolated hyperglycemia is associated with higher serum concentrations of TGF-β, while a broader phenotype of insulin resistance is associated with higher serum PIIINP. Whether simultaneous pharmacologic targeting of these two metabolic phenotypes can synergistically reduce the risk of cardiac and other manifestations of fibrosis remains to be determined.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Blood Glucose, Cardiovascular System, Cross-Sectional Studies, Diabetes Complications, Diabetes Mellitus, Fatty Acids, Nonesterified, Female, Fibrosis, Health, Humans, Insulin, Insulin Resistance, Male, Metabolic Diseases, Peptide Fragments, Procollagen, Transforming Growth Factor beta}, issn = {1532-8600}, doi = {10.1016/j.metabol.2015.07.013}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Djouss{\'e}, Luc and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and King, George L and Mukamal, Ken J} } @article {6768, title = {Burden of Comorbidities and Functional and Cognitive Impairments in Elderly Patients at the Initial Diagnosis of Heart Failure and Their Impact on Total Mortality: The Cardiovascular Health Study.}, journal = {JACC Heart Fail}, volume = {3}, year = {2015}, month = {2015 Jul}, pages = {542-50}, abstract = {

OBJECTIVES: The purpose of this study was to determine the prevalence of clinically relevant comorbidities and measures of physical and cognitive impairment in elderly persons with incident heart failure (HF).

BACKGROUND: Comorbidities and functional and cognitive impairments are common in the elderly and often associated with greater mortality risk.

METHODS: We examined the prevalence of 9 comorbidities and 4 measures of functional and cognitive impairments in 558 participants from the Cardiovascular Health Study who developed incident HF between 1990 and 2002. Participants were followed prospectively until mid-2008 to determine their mortality risk.

RESULTS: Mean age of participants was 79.2 {\textpm} 6.3 years with 52\% being men. Sixty percent of participants had >=3 comorbidities, and only 2.5\% had none. Twenty-two percent and 44\% of participants had >=1 activity of daily living (ADL) and >=1 instrumental activity of daily living (IADL) impaired respectively. Seventeen percent of participants had cognitive impairment (modified mini-mental state exam score <80, scores range between 0 and 100). During follow up, 504 participants died, with 1-, 5-, and 10-year mortality rates of 19\%, 56\%, and 83\%, respectively. In a multivariable-adjusted model, the following were significantly associated with greater total mortality risk: diabetes mellitus (hazard ratio [HR]: 1.64; 95\% confidence interval [CI]: 1.33 to 2.03), chronic kidney disease (HR: 1.32; 95\% CI: 1.07 to 1.62 for moderate disease; HR: 3.00; 95\% CI: 1.82 to 4.95 for severe), cerebrovascular disease (HR: 1.53; 95\% CI: 1.22 to 1.92), depression (HR: 1.44; 95\% CI: 1.09 to 1.90), functional impairment (HR: 1.30; 95\% CI: 1.04 to 1.63 for 1 IADL impaired; HR: 1.49; 95\% CI: 1.07 to 2.04 for >=2 IADL impaired), and cognitive impairment (HR: 1.33; 95\% CI: 1.02 to 1.73). Other comorbidities (hypertension, coronary heart disease, peripheral arterial disease, atrial fibrillation, and obstructive airway disease) and measures of functional impairments (ADLs and 15-ft walk time) were not associated with mortality.

CONCLUSIONS: Elderly patients with incident HF have a high burden of comorbidities and functional and cognitive impairments. Some of these conditions are associated with greater mortality risk.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Atrial Fibrillation, Cognition Disorders, Cohort Studies, Comorbidity, Coronary Disease, Female, Heart Failure, Humans, Hypertension, Incidence, Longitudinal Studies, Male, Peripheral Arterial Disease, Physical Fitness, Prevalence, Proportional Hazards Models, Pulmonary Disease, Chronic Obstructive}, issn = {2213-1787}, doi = {10.1016/j.jchf.2015.03.004}, author = {Murad, Khalil and Goff, David C and Morgan, Timothy M and Burke, Gregory L and Bartz, Traci M and Kizer, Jorge R and Chaudhry, Sarwat I and Gottdiener, John S and Kitzman, Dalane W} } @article {6665, title = {Fibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {239}, year = {2015}, month = {2015 Apr}, pages = {539-46}, abstract = {

OBJECTIVE: Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels.

METHODS: We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998.

RESULTS: After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR]~=~1.36 per doubling of TGF-β, 95\% confidence interval [CI]~=~1.04, 1.78) and retinal venular diameter (1.63~μm per doubling of TGF-β, CI~=~0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102~mm per doubling of PIIINP, CI~=~0.029, 0.174) and impaired brachial artery reactivity (-0.20\% change per doubling of PIIINP, CI~=~-0.39,~-0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy.

CONCLUSIONS: Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.

}, keywords = {Aged, Ankle Brachial Index, Biomarkers, Brachial Artery, Carotid Artery Diseases, Carotid Intima-Media Thickness, Cross-Sectional Studies, Female, Fibrosis, Humans, Incidence, Male, Peptide Fragments, Peripheral Arterial Disease, Predictive Value of Tests, Procollagen, Prognosis, Prospective Studies, Retinal Diseases, Risk Factors, Transforming Growth Factor beta, United States, Vasodilation}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2015.02.020}, author = {Agarwal, Isha and Arnold, Alice and Glazer, Nicole L and Barasch, Eddy and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Jensen, Richard A and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and Tracy, Russell P and Wong, Tien Y and Mukamal, Kenneth J} } @article {6878, title = {Prognostic Significance of High-Sensitivity Cardiac Troponin T Concentrations between the Limit of Blank and Limit of Detection in Community-Dwelling Adults: A Metaanalysis.}, journal = {Clin Chem}, volume = {61}, year = {2015}, month = {2015 Dec}, pages = {1524-31}, abstract = {

BACKGROUND: There is controversy regarding whether to report concentrations of high-sensitivity cardiac troponin T (hs-cTnT) to the limit of blank (LOB) (3 ng/L) or the limit of detection (LOD) (5 ng/L) of the assay in community-based cohorts. We hypothesized that hs-cTnT concentrations between the LOB and LOD would be associated with poorer cardiovascular outcomes compared to concentrations below the LOB.

METHODS: hs-cTnT was analyzed in a total of 10 723 participants from the Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) study, and Dallas Heart Study (DHS). Participants were divided into 2 groups, those with hs-cTnT concentrations below the limit of blank (LOB) (<3 ng/L) and those with hs-cTnT between the LOB and limit of detection (LOD) (3-4.99 ng/L). Cross-sectional associations with traditional cardiovascular risk factors and cardiac structural measurements, and longitudinal associations with long-term cardiovascular outcomes of incident heart failure and cardiovascular death, were determined.

RESULTS: Participants with hs-cTnT between the LOB and LOD for all 3 cohorts were older, more likely to be male, and have a higher burden of cardiovascular risk factors and structural pathology. A metaanalysis of the 3 cohorts showed participants with hs-cTnT between the LOB and LOD were at increased risk of new-onset heart failure (hazard ratio, 1.18; 95\% CI, 1.02-1.38) and cardiovascular mortality (hazard ratio, 1.29; 95\% CI, 1.06-1.57).

CONCLUSIONS: hs-cTnT concentrations between the LOB and LOD (3-4.99 ng/L) are associated with a higher prevalence of traditional risk factors, more cardiac pathology, and worse outcomes than concentrations below the LOB (<3 ng/L).

}, keywords = {Aged, Atherosclerosis, Biomarkers, Cross-Sectional Studies, Female, Heart Failure, Humans, Independent Living, Limit of Detection, Longitudinal Studies, Male, Middle Aged, Myocardial Infarction, Prognosis, Risk Assessment, Risk Factors, Sex Factors, Troponin T}, issn = {1530-8561}, doi = {10.1373/clinchem.2015.244160}, author = {Parikh, Ravi H and Seliger, Stephen L and de Lemos, James and Nambi, Vijay and Christenson, Robert and Ayers, Colby and Sun, Wensheng and Gottdiener, John S and Kuller, Lewis H and Ballantyne, Christie and deFilippi, Christopher R} } @article {6702, title = {Serial measures of cardiac troponin T levels by a highly sensitive assay and incident atrial fibrillation in a prospective cohort of ambulatory older adults.}, journal = {Heart Rhythm}, volume = {12}, year = {2015}, month = {2015 May}, pages = {879-85}, abstract = {

BACKGROUND: Various mechanisms in cardiac remodeling related to atrial fibrillation (AF) lead to elevated circulating cardiac troponin levels, but little is known about such elevations upstream to AF onset.

OBJECTIVE: The purpose of this study was to study the association between circulating troponin levels as assessed by a highly sensitive cardiac troponin T (hs-cTnT) assay and incident atrial fibrillation (AF).

METHODS: In a large prospective cohort of ambulatory older adults [the Cardiovascular Health Study (CHS)], hs-cTnT levels were measured in sera that were collected at enrollment from 4262 participants without AF (2871 with follow-up measurements). Incident AF was identified by electrocardiograms during CHS visits, hospital discharge diagnoses, and Medicare files, including outpatient and physician claims diagnoses.

RESULTS: Over median follow-up of 11.2 years (interquartile range 6.1-16.5), 1363 participants (32.0\%) developed AF. Higher baseline levels of hs-cTnT were associated with incident AF in covariate-adjusted analyses accounting for demographics, traditional risk factors, and incident heart failure in time-dependent analyzes (hazard ratio for 3rd tertile vs undetectable 1.75, 95\% confidence interval 1.48-2.08). This association was statistically significant in analyses that additionally adjusted for biomarkers of inflammation and hemodynamic strain (hazard ratio for 3rd tertile vs undetectable 1.38, 95\% confidence interval 1.16-1.65). Significant associations were also found when hs-cTnT levels were treated as a continuous variable and when examining change from baseline of hs-cTnT levels and incident AF.

CONCLUSION: The findings show a significant association of circulating troponin levels in ambulatory older adults with incident AF beyond that of traditional risk factors, incident heart failure, and biomarkers of inflammation and hemodynamic strain.

}, keywords = {Aged, Atrial Fibrillation, Biomarkers, Electrocardiography, Female, Heart Failure, Humans, Incidence, Longitudinal Studies, Male, Outpatients, Risk Assessment, Risk Factors, Statistics as Topic, Troponin T, United States}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2015.01.020}, author = {Hussein, Ayman A and Bartz, Traci M and Gottdiener, John S and Sotoodehnia, Nona and Heckbert, Susan R and Lloyd-Jones, Donald and Kizer, Jorge R and Christenson, Robert and Wazni, Oussama and DeFilippi, Christopher} } @article {6767, title = {Ventricular Ectopy as a Predictor of Heart Failure and Death.}, journal = {J Am Coll Cardiol}, volume = {66}, year = {2015}, month = {2015 Jul 14}, pages = {101-9}, abstract = {

BACKGROUND: Studies of patients presenting for catheter ablation suggest that premature ventricular contractions (PVCs) are a modifiable risk factor for congestive heart failure (CHF). The relationship among PVC frequency, incident CHF, and mortality in the general population remains unknown.

OBJECTIVES: The goal of this study was to determine whether PVC frequency ascertained using a 24-h Holter monitor is a predictor of a decrease in the left ventricular ejection fraction (LVEF), incident CHF, and death in a population-based cohort.

METHODS: We studied 1,139 Cardiovascular Health Study (CHS) participants who were randomly assigned to 24-h ambulatory electrocardiography (Holter) monitoring and who had a normal LVEF and no history of CHF. PVC frequency was quantified using Holter studies, and LVEF was measured from baseline and 5-year echocardiograms. Participants were followed for incident CHF and death.

RESULTS: Those in the upper quartile versus the lowest quartile of PVC frequency had a multivariable-adjusted, 3-fold greater odds of a 5-year decrease in LVEF (odds ratio [OR]: 3.10; 95\% confidence interval [CI]: 1.42 to 6.77; p = 0.005), a 48\% increased risk of incident CHF (HR: 1.48; 95\% CI: 1.08 to 2.04; p = 0.02), and a 31\% increased risk of death (HR: 1.31; 95\% CI: 1.06 to 1.63; p = 0.01) during a median follow-up of >13 years. Similar statistically significant results were observed for PVCs analyzed as a continuous variable. The specificity for the 15-year risk of CHF exceeded 90\% when PVCs included at least 0.7\% of ventricular beats. The population-level risk for incident CHF attributed to PVCs was 8.1\% (95\% CI: 1.2\% to 14.9\%).

CONCLUSIONS: In a population-based sample, a higher frequency of PVCs was associated with a decrease in LVEF, an increase in incident CHF, and increased mortality. Because of the capacity to prevent PVCs through medical or ablation therapy, PVCs may represent a modifiable risk factor for CHF and death.

}, keywords = {Aged, Catheter Ablation, Echocardiography, Electrocardiography, Ambulatory, Female, Forecasting, Heart Failure, Humans, Male, Risk Factors, Stroke Volume, Ventricular Premature Complexes}, issn = {1558-3597}, doi = {10.1016/j.jacc.2015.04.062}, author = {Dukes, Jonathan W and Dewland, Thomas A and Vittinghoff, Eric and Mandyam, Mala C and Heckbert, Susan R and Siscovick, David S and Stein, Phyllis K and Psaty, Bruce M and Sotoodehnia, Nona and Gottdiener, John S and Marcus, Gregory M} } @article {6707, title = {Years of able life in older persons--the role of cardiovascular imaging and biomarkers: the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {4}, year = {2015}, month = {2015 Apr}, abstract = {

BACKGROUND: As the U.S. population grows older, there is greater need to examine physical independence. Previous studies have assessed risk factors in relation to either disability or mortality, but an outcome that combines both is still needed.

METHODS AND RESULTS: The Cardiovascular Health Study is a population-based, prospective study where participants underwent baseline echocardiogram, measurement of carotid intima-media thickness (IMT), and various biomarkers, then followed for up to 18 years. Years of able life (YAL) constituted the number of years the participant was able to perform all activities of daily living. Linear regression was used to model the relationship between selected measures and outcomes, adjusted for confounding variables. Among 4902 participants, mean age was 72.6 {\textpm} 5.4 years, median YAL for males was 8.8 (interquartile range [IQR], 4.3 to 13.8) and 10.3 (IQR, 5.8 to 15.8) for females. Reductions in YAL in the fully adjusted model for females and males, respectively, were: -1.34 (95\% confidence interval [CI], -2.18, -0.49) and -1.41 (95\% CI, -2.03, -0.8) for abnormal left ventricular (LV) ejection fraction, -0.5 (95\% CI, -0.78, -0.22) and -0.62 (95\% CI, -0.87, -0.36) per SD increase in LV mass, -0.5 (95\% CI, -0.7, -0.29) and -0.79 (95\% CI, -0.99, -0.58) for IMT, -0.5 (95\% CI, -0.64, -0.37) and -0.79 (95\% CI, -0.94, -0.65) for N-terminal pro-brain natriuretic peptide, -1.08 (95\% CI, -1.34, -0.83) and -0.73 (95\% CI, -0.97, -0.5) for high-sensitivity troponin-T, and -0.26 (95\% CI, -0.42, -0.09) and -0.23 (95\% CI, -0.41, -0.05) for procollagen-III N-terminal propeptide. Most tested variables remained significant even after adjusting for incident cardiovascular (CV) disease.

CONCLUSIONS: In this population-based cohort, variables obtained by CV imaging and biomarkers of inflammation, coagulation, atherosclerosis, myocardial injury and stress, and cardiac collagen turnover were associated with YAL, an important outcome that integrates physical ability and longevity in older persons.

}, keywords = {Activities of Daily Living, Aged, Biomarkers, Cardiovascular Diseases, Carotid Intima-Media Thickness, Echocardiography, Female, Humans, Independent Living, Male, Natriuretic Peptide, Brain, Peptide Fragments, Procollagen, Prospective Studies, Stroke Volume, Troponin I}, issn = {2047-9980}, doi = {10.1161/JAHA.114.001745}, author = {Alshawabkeh, Laith I and Yee, Laura M and Gardin, Julius M and Gottdiener, John S and Odden, Michelle C and Bartz, Traci M and Arnold, Alice M and Mukamal, Kenneth J and Wallace, Robert B} } @article {7120, title = {Association of inflammatory, lipid and mineral markers with cardiac calcification in older adults.}, journal = {Heart}, year = {2016}, month = {2016 Jul 13}, abstract = {

OBJECTIVE: Calcification of the aortic valve and adjacent structures involves inflammatory, lipid and mineral metabolism pathways. We hypothesised that circulating biomarkers reflecting these pathways are associated with cardiac calcification in older adults.

METHODS: We investigated the associations of various biomarkers with valvular and annular calcification in the Cardiovascular Health Study. Of the 5888 participants, up to 3585 were eligible after exclusions for missing biomarker, covariate or echocardiographic data. We evaluated analytes reflecting lipid (lipoprotein (Lp) (a), Lp-associated phospholipase A2 (LpPLA2) mass and activity), inflammatory (interleukin-6, soluble (s) CD14) and mineral metabolism (fetuin-A, fibroblast growth factor (FGF)-23) pathways that were measured within 5 years of echocardiography. The relationships of plasma biomarkers with aortic valve calcification (AVC), aortic annular calcification (AAC) and mitral annular calcification (MAC) were assessed with relative risk (RR) regression.

RESULTS: Calcification was prevalent: AVC 59\%, AAC 45\% and MAC 41\%. After adjustment, Lp(a), LpPLA2 mass and activity and sCD14 were positively associated with AVC. RRs for AVC per SD (95\% CI) were as follows: Lp(a), 1.051 (1.022 to 1.081); LpPLA2 mass, 1.036 (1.006 to 1.066) and LpPLA2 activity, 1.037 (1.004 to 1.071); sCD14, 1.039 (1.005 to 1.073). FGF-23 was positively associated with MAC, 1.040 (1.004 to 1.078) and fetuin-A was negatively associated, 0.949 (0.911 to 0.989). No biomarkers were significantly associated with AAC.

CONCLUSION: This study shows novel associations of circulating FGF-23 and fetuin-A with MAC, and LpPLA2 and sCD14 with AVC, confirming that previously reported for Lp(a). Further investigation of Lp and inflammatory pathways may provide added insight into the aetiology of AVC, while study of phosphate regulation may illuminate the pathogenesis of MAC.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2016-309404}, author = {Bortnick, Anna E and Bartz, Traci M and Ix, Joachim H and Chonchol, Michel and Reiner, Alexander and Cushman, Mary and Owens, David and Barasch, Eddy and Siscovick, David S and Gottdiener, John S and Kizer, Jorge R} } @article {7242, title = {Longitudinal assessment of N-terminal pro-B-type natriuretic peptide and risk of diabetes in older adults: The cardiovascular health study.}, journal = {Metabolism}, volume = {65}, year = {2016}, month = {2016 Oct}, pages = {1489-97}, abstract = {

INTRODUCTION: Natriuretic peptides have a well-recognized role in cardiovascular homeostasis. Recently, higher levels of B-type natriuretic peptide (BNP) have also been associated with decreased risk of diabetes in middle-aged adults. Whether this association persists into older age, where the pathophysiology of diabetes changes, has not been established, nor has its intermediate pathways.

METHODS: We investigated the relationship between N-terminal (NT)-proBNP and incident diabetes in 2359 older adults free of cardiovascular disease or chronic kidney disease in the Cardiovascular Health Study.

RESULTS: We documented 348 incident cases of diabetes over 12.6years of median follow-up. After adjusting for age, sex, race, body mass index, systolic blood pressure, anti-hypertensive treatment, smoking, alcohol use, and LDL, each doubling of NT-proBNP was associated with a 9\% lower risk of incident diabetes (HR=0.91 [95\% CI: 0.84-0.99]). Additional adjustment for waist circumference, physical activity, estimated glomerular filtration rate or C-reactive protein did not influence the association. Among putative mediators, HDL and triglycerides, adiponectin, and especially homeostasis model assessment of insulin resistance, all appeared to account for a portion of the lower risk associated with NT-proBNP.

CONCLUSION: In older adults without prevalent cardiovascular or kidney disease, higher NT-proBNP is associated with decreased risk of incident diabetes even after adjustment for traditional risk factors. These findings suggest that the metabolic effects of natriuretic peptides persist late in life and offer a potential therapeutic target for prevention of diabetes in older people.

}, issn = {1532-8600}, doi = {10.1016/j.metabol.2016.06.002}, author = {Brutsaert, Erika F and Biggs, Mary L and Delaney, Joseph A and Djouss{\'e}, Luc and Gottdiener, John S and Ix, Joachim H and Kim, Francis and Mukamal, Kenneth J and Siscovick, David S and Tracy, Russell P and de Boer, Ian H and deFilippi, Christopher R and Kizer, Jorge R} } @article {7123, title = {Measures of Body Size and Composition and Risk of Incident Atrial Fibrillation in Older People: The Cardiovascular Health Study.}, journal = {Am J Epidemiol}, volume = {183}, year = {2016}, month = {2016 Jun 1}, pages = {998-1007}, abstract = {

Various anthropometric measures, including height, have been associated with atrial fibrillation (AF). This raises questions about the appropriateness of using ratio measures such as body mass index (BMI), which contains height squared in its denominator, in the evaluation of AF risk. Among older adults, the optimal anthropometric approach to risk stratification of AF remains uncertain. Anthropometric and bioelectrical impedance measures were obtained from 4,276 participants (mean age = 72.4 years) free of cardiovascular disease in the Cardiovascular Health Study. During follow-up (1989-2008), 1,050 cases of AF occurred. BMI showed a U-shaped association, whereas height, weight, waist circumference, hip circumference, fat mass, and fat-free mass were linearly related to incident AF. The strongest adjusted association occurred for height (per each 1-standard-deviation increment, hazard ratio = 1.38, 95\% confidence interval: 1.25, 1.51), which exceeded all other measures, including weight (hazard ratio = 1.21, 95\% confidence interval: 1.13, 1.29). Combined assessment of log-transformed weight and height showed regression coefficients that departed from the 1 to -2 ratio inherent in BMI, indicating a loss of predictive information. Risk estimates for AF tended to be stronger for hip circumference than for waist circumference and for fat-free mass than for fat mass, which was explained largely by height. These findings highlight the prominent role of body size and the inadequacy of BMI as determinants of AF in older adults.

}, issn = {1476-6256}, doi = {10.1093/aje/kwv278}, author = {Karas, Maria G and Yee, Laura M and Biggs, Mary L and Djouss{\'e}, Luc and Mukamal, Kenneth J and Ix, Joachim H and Zieman, Susan J and Siscovick, David S and Gottdiener, John S and Rosenberg, Michael A and Kronmal, Richard A and Heckbert, Susan R and Kizer, Jorge R} } @article {7140, title = {Predicting Heart Failure With Preserved and Reduced Ejection Fraction: The International Collaboration on Heart Failure Subtypes.}, journal = {Circ Heart Fail}, volume = {9}, year = {2016}, month = {2016 Jun}, abstract = {

BACKGROUND: Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF).

METHODS AND RESULTS: Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2:1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95\% confidence interval [CI], 0.78-0.82) and validation samples (internal: 0.79; 95\% CI, 0.77-0.82 and external: 0.76; 95\% CI: 0.71-0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95\% CI, 0.80-0.84) and validation samples (internal: 0.80; 95\% CI, 0.78-0.83 and external: 0.76; 95\% CI, 0.71-0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF (P value for each comparison <=0.02).

CONCLUSIONS: We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes.

}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.115.003116}, author = {Ho, Jennifer E and Enserro, Danielle and Brouwers, Frank P and Kizer, Jorge R and Shah, Sanjiv J and Psaty, Bruce M and Bartz, Traci M and Santhanakrishnan, Rajalakshmi and Lee, Douglas S and Chan, Cheeling and Liu, Kiang and Blaha, Michael J and Hillege, Hans L and van der Harst, Pim and van Gilst, Wiek H and Kop, Willem J and Gansevoort, Ron T and Vasan, Ramachandran S and Gardin, Julius M and Levy, Daniel and Gottdiener, John S and de Boer, Rudolf A and Larson, Martin G} } @article {7130, title = {Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community-Dwelling Population.}, journal = {J Am Heart Assoc}, volume = {5}, year = {2016}, month = {2016 Aug}, abstract = {

BACKGROUND: Soluble ST2 (sST2), a marker of myocyte stretch and fibrosis, has prognostic value in many cardiovascular diseases. We hypothesized that sST2 levels are associated with incident heart failure (HF), including subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fraction, and cardiovascular death.

METHODS AND RESULTS: Baseline serum sST2 was measured in 3915 older, community-dwelling subjects from the Cardiovascular Health Study without prevalent HF. sST2 levels were associated with older age, male sex, black race, traditional cardiovascular risk factors, other biomarkers of inflammation, cardiac stretch, myocardial injury, and fibrosis, and abnormal echocardiographic parameters. In longitudinal analysis, greater sST2 was associated with a higher risk of incident HF and cardiovascular death; however, in multivariate models adjusting for other cardiac risk factors and the cardiac-specific biomarker, N-terminal pro-type B natriuretic peptide, these associations were attenuated. In these models, an sST2 level above the US Food and Drug Administration-approved cut-off value (>35~ng/mL) was significantly associated with incident HF (hazard ratio [HR], 1.20; 95\% CI, 1.02-1.43) and cardiovascular death (HR, 1.21; 95\% CI, 1.02-1.44), and greater sST2 was continuously associated with cardiovascular death (per 1-ln increment: HR, 1.24; 95\% CI, 1.02-1.50). sST2 was not associated with the HF subtypes of HFpEF and HFrEF in adjusted analysis. Addition of sST2 to existing risk models of HF and cardiovascular death modestly improved discrimination and reclassification into a higher risk.

CONCLUSIONS: The predictive value of sST2 for HF of all subtypes and cardiovascular death is modest in an elderly population despite strong cross-sectional associations with risk factors and underlying cardiac pathology.

}, issn = {2047-9980}, doi = {10.1161/JAHA.115.003188}, author = {Parikh, Ravi H and Seliger, Stephen L and Christenson, Robert and Gottdiener, John S and Psaty, Bruce M and deFilippi, Christopher R} } @article {6932, title = {Study of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study.}, journal = {Circulation}, volume = {133}, year = {2016}, month = {2016 Jan 12}, pages = {156-64}, abstract = {

BACKGROUND: Increasingly, the diagnostic codes from administrative claims data are being used as clinical outcomes.

METHODS AND RESULTS: Data from the Cardiovascular Health Study (CHS) were used to compare event rates and risk factor associations between adjudicated hospitalized cardiovascular events and claims-based methods of defining events. The outcomes of myocardial infarction (MI), stroke, and heart failure were defined in 3 ways: the CHS adjudicated event (CHS[adj]), selected International Classification of Diseases, Ninth Edition diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare \& Medicaid Services (CMS[1st]), and the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values but low sensitivities. For instance, the positive predictive value of International Classification of Diseases, Ninth Edition code 410.x1 for a new acute MI in the first position was 90.6\%, but this code identified only 53.8\% of incident MIs. The observed event rates for CMS[1st] were low. For MI, the incidence was 14.9 events per 1000 person-years for CHS[adj] MI, 8.6 for CMS[1st] MI, and 12.2 for CMS[any] MI. In general, cardiovascular disease risk factor associations were similar across the 3 methods of defining events. Indeed, traditional cardiovascular disease risk factors were also associated with all first hospitalizations not resulting from an MI.

CONCLUSIONS: The use of diagnostic codes from claims data as clinical events, especially when restricted to primary diagnoses, leads to an underestimation of event rates. Additionally, claims-based events data represent a composite end point that includes the outcome of interest and selected (misclassified) nonevent hospitalizations.

}, keywords = {Blood Glucose, Cardiovascular Diseases, Female, Follow-Up Studies, Health Surveys, Hospitalization, Hospitals, Veterans, Humans, Insurance Claim Review, International Classification of Diseases, Lipids, Male, Managed Care Programs, Medicare, Risk Factors, Sampling Studies, Treatment Outcome, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.115.018610}, author = {Psaty, Bruce M and Delaney, Joseph A and Arnold, Alice M and Curtis, Lesley H and Fitzpatrick, Annette L and Heckbert, Susan R and McKnight, Barbara and Ives, Diane and Gottdiener, John S and Kuller, Lewis H and Longstreth, W T} } @article {7122, title = {Usefulness of Left Ventricular Mass and Geometry for Determining 10-Year Prediction of Cardiovascular Disease in Adults Aged >65~Years (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {118}, year = {2016}, month = {2016 Sep 1}, pages = {684-90}, abstract = {

Left ventricular (LV) mass and geometry are associated with risk of cardiovascular disease (CVD). We sought to determine whether LV mass and geometry contribute to risk prediction for CVD in adults aged >=65~years of the Cardiovascular Health Study. We indexed LV mass to body size, denoted as LV mass index (echo-LVMI), and we defined LV geometry as normal, concentric remodeling, and eccentric or concentric LV hypertrophy. We added echo-LVMI and LV geometry to separate 10-year risk prediction models containing traditional risk factors and determined the net reclassification improvement (NRI) for incident coronary heart disease (CHD), CVD (CHD, heart failure [HF], and stroke), and HF alone. Over 10~years of follow-up in 2,577 participants (64\% women, 15\% black, mean age 72~years) for CHD and CVD, the adjusted hazards ratios for a 1-SD higher echo-LVMI were 1.25 (95\% CI 1.14 to 1.37), 1.24 (1.15 to 1.33), and 1.51 (1.40 to 1.62), respectively. Addition of echo-LVMI to the standard model for CHD resulted in an event NRI of~-0.011 (95\% CI~-0.037 to 0.028) and nonevent NRI of 0.034 (95\% CI 0.008 to 0.076). Addition of echo-LVMI and LV geometry to the standard model for CVD resulted in an event NRI of 0.013 (95\% CI~-0.0335 to 0.0311) and a nonevent NRI of 0.043 (95\% CI 0.011 to 0.09). The nonevent NRI was also significant with addition of echo-LVMI for HF risk prediction (0.10, 95\% CI 0.057 to 0.16). In conclusion, in adults aged >=65~years, echo-LVMI improved risk prediction for CHD, CVD, and HF, driven primarily by improved reclassification of nonevents.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2016.06.016}, author = {Desai, Chintan S and Bartz, Traci M and Gottdiener, John S and Lloyd-Jones, Donald M and Gardin, Julius M} } @article {7489, title = {Ectopy on a Single 12-Lead ECG, Incident Cardiac Myopathy, and Death in the Community.}, journal = {J Am Heart Assoc}, volume = {6}, year = {2017}, month = {2017 Aug 03}, abstract = {

BACKGROUND: Atrial fibrillation and heart failure are 2 of the most common diseases, yet ready means to identify individuals at risk are lacking. The 12-lead ECG is one of the most accessible tests in medicine. Our objective was to determine whether a premature atrial contraction observed on a standard 12-lead ECG would predict atrial fibrillation and mortality and whether a premature ventricular contraction would predict heart failure and mortality.

METHODS AND RESULTS: We utilized the CHS (Cardiovascular Health) Study, which followed 5577 participants for a median of 12~years, as the primary cohort. The ARIC (Atherosclerosis Risk in Communities Study), the replication cohort, captured data from 15~792 participants over a median of 22~years. In the CHS, multivariable analyses revealed that a baseline 12-lead ECG premature atrial contraction predicted a 60\% increased risk of atrial fibrillation (hazard ratio, 1.6; 95\% CI, 1.3-2.0; P<0.001) and a premature ventricular contraction predicted a 30\% increased risk of heart failure (hazard ratio, 1.3; 95\% CI, 1.0-1.6; P=0.021). In the negative control analyses, neither predicted incident myocardial infarction. A premature atrial contraction was associated with a 30\% increased risk of death (hazard ratio, 1.3; 95\% CI, 1.1-1.5; P=0.008) and a premature ventricular contraction was associated with a 20\% increased risk of death (hazard ratio, 1.2; 95\% CI, 1.0-1.3; P=0.044). Similarly statistically significant results for each analysis were also observed in ARIC.

CONCLUSIONS: Based on a single standard ECG, a premature atrial contraction predicted incident atrial fibrillation and death and a premature ventricular contraction predicted incident heart failure and death, suggesting that this commonly used test may predict future disease.

}, issn = {2047-9980}, doi = {10.1161/JAHA.117.006028}, author = {Nguyen, Kaylin T and Vittinghoff, Eric and Dewland, Thomas A and Dukes, Jonathan W and Soliman, Elsayed Z and Stein, Phyllis K and Gottdiener, John S and Alonso, Alvaro and Chen, Lin Y and Psaty, Bruce M and Heckbert, Susan R and Marcus, Gregory M} } @article {7549, title = {Predictors and outcomes of heart failure with mid-range ejection fraction.}, journal = {Eur J Heart Fail}, year = {2017}, month = {2017 Dec 11}, abstract = {

AIMS: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.

METHODS AND RESULTS: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49\%], HFpEF (EF >=50\%), and HFrEF (EF <=40\%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P~<= 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P~<= 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95\% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95\% CI 1.20-1.90, P~= 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95\% CI 1.41-1.73, P~= 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P~= 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P~= 0.78).

CONCLUSIONS: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.

}, issn = {1879-0844}, doi = {10.1002/ejhf.1091}, author = {Bhambhani, Vijeta and Kizer, Jorge R and Lima, Jo{\~a}o A C and van der Harst, Pim and Bahrami, Hossein and Nayor, Matthew and de Filippi, Christopher R and Enserro, Danielle and Blaha, Michael J and Cushman, Mary and Wang, Thomas J and Gansevoort, Ron T and Fox, Caroline S and Gaggin, Hanna K and Kop, Willem J and Liu, Kiang and Vasan, Ramachandran S and Psaty, Bruce M and Lee, Douglas S and Brouwers, Frank P and Hillege, Hans L and Bartz, Traci M and Benjamin, Emelia J and Chan, Cheeling and Allison, Matthew and Gardin, Julius M and Januzzi, James L and Levy, Daniel and Herrington, David M and van Gilst, Wiek H and Bertoni, Alain G and Larson, Martin G and de Boer, Rudolf A and Gottdiener, John S and Shah, Sanjiv J and Ho, Jennifer E} } @article {7350, title = {Relation of the Myocardial Contraction Fraction, as Calculated from M-Mode Echocardiography, With Incident Heart Failure, Atherosclerotic Cardiovascular Disease and Mortality (Results from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {119}, year = {2017}, month = {2017 Mar 15}, pages = {923-928}, abstract = {

We evaluated the association between 2-dimensional (2D) echocardiography (echo)-determined myocardial contraction fraction (MCF) and adverse cardiovascular outcomes including incident heart failure (HF), atherosclerotic cardiovascular disease (ASCVD), and mortality. The MCF, the ratio of left ventricular (LV) stroke volume (SV) to myocardial volume (MV), is a volumetric measure of myocardial shortening that can distinguish pathologic from physiological hypertrophy. Using 2D echo-guided M-mode data from the~Cardiovascular Health Study, we calculated MCF in subjects with LV ejection fraction (EF) >=55\% and used Cox models to evaluate its association with incident HF, ASCVD, and all-cause mortality after adjusting for clinical and echo parameters. We assessed whether log2(SV) and log2(MV) were consistent with the expected 1:-1 ratio used in the definition of MCF. Among 2,147 participants (age 72 {\textpm} 5 years), average MCF was 59 {\textpm} 13\%. After controlling for clinical and echo variables, each 10\% absolute increment in MCF was associated with lower risk of HF (hazard ratio [HR] 0.88; 95\% confidence interval [CI] 0.82, 0.94), ASCVD (HR 0.90; 95\% CI 0.85, 0.95), and death (HR 0.93; 95\% CI 0.89, 0.97). Moreover, the MCF was still significantly associated with ASCVD and mortality, but not HF, after adjustment for percent-predicted LV mass. Significant departure from the 1:-1 ratio was not observed for ASCVD or death, but did occur for HF, driven by a stronger association for MV than SV. In conclusion, among older adults without CVD or low LV ejection fraction, 2D echo-guided M-mode-derived MCF was independently associated with lower risk of adverse cardiovascular outcomes, but this ratiometric index may not capture the full relation that is apparent when its components are modeled separately in the~case of HF.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2016.11.048}, author = {Maurer, Mathew S and Koh, William J H and Bartz, Traci M and Vullaganti, Sirish and Barasch, Eddy and Gardin, Julius M and Gottdiener, John S and Psaty, Bruce M and Kizer, Jorge R} } @article {7488, title = {Relationship of bone mineral density with valvular and annular calcification in community-dwelling older people: The Cardiovascular Health Study.}, journal = {Arch Osteoporos}, volume = {12}, year = {2017}, month = {2017 Dec}, pages = {52}, abstract = {

Associations between bone mineral density and aortic valvular, aortic annular, and mitral annular calcification were investigated in a cross-sectional analysis of a population-based cohort of 1497 older adults. Although there was no association between continuous bone mineral density and outcomes, a significant association between osteoporosis and aortic valvular calcification in men was found.

INTRODUCTION: The process of cardiac calcification bears a resemblance to skeletal bone metabolism and its regulation. Experimental studies suggest that bone mineral density (BMD) and valvular calcification may be reciprocally related, but epidemiologic data are sparse.

METHODS: We tested the hypothesis that BMD of the total hip and femoral neck measured by dual-energy X-ray absorptiometry (DXA) is inversely associated with prevalence of three echocardiographic measures of cardiac calcification in a cross-sectional analysis of 1497 older adults from the Cardiovascular Health Study. The adjusted association of BMD with aortic valve calcification (AVC), aortic annular calcification (AAC), and mitral annular calcification (MAC) was assessed with relative risk (RR) regression.

RESULTS: Mean (SD) age was 76.2 (4.8)~years; 58\% were women. Cardiac calcification was highly prevalent in women and men: AVC, 59.5 and 71.0\%; AAC 45.1 and 46.7\%; MAC 42.8 and 39.5\%, respectively. After limited and full adjustment for potential confounders, no statistically significant associations were detected between continuous BMD at either site and the three measures of calcification. Assessment of WHO BMD categories revealed a significant association between osteoporosis at the total hip and AVC in men (adjusted RR compared with normal BMD~=~1.24 (1.01-1.53)). In graded sensitivity analyses, there were apparent inverse associations between femoral neck BMD and AVC with stenosis in men, and femoral neck BMD and moderate/severe MAC in women, but these were not significant.

CONCLUSION: These findings support further investigation of the sex-specific relationships between low BMD and cardiac calcification, and whether processes linking the two could be targeted for therapeutic ends.

}, issn = {1862-3514}, doi = {10.1007/s11657-017-0347-y}, author = {Massera, Daniele and Xu, Shuo and Bartz, Traci M and Bortnick, Anna E and Ix, Joachim H and Chonchol, Michel and Owens, David S and Barasch, Eddy and Gardin, Julius M and Gottdiener, John S and Robbins, John R and Siscovick, David S and Kizer, Jorge R} } @article {7570, title = {Subclinical Atherosclerosis, Cardiac and Kidney Function, Heart Failure, and Dementia in the Very Elderly.}, journal = {J Am Heart Assoc}, volume = {6}, year = {2017}, month = {2017 Jul 22}, abstract = {

BACKGROUND: Heart failure (HF) and dementia are major causes of disability and death among older individuals. Risk factors and biomarkers of HF may be determinants of dementia in the elderly. We evaluated the relationship between biomarkers of cardiovascular disease and HF and risk of dementia and death. Three hypotheses were tested: (1) higher levels of high-sensitivity cardiac troponin T, N-terminal of prohormone brain natriuretic peptide, and cystatin C predict risk of death, cardiovascular disease, HF, and dementia; (2) higher levels of cardiovascular disease biomarkers are associated with increased risk of HF and then secondary increased risk of dementia; and (3) risk of dementia is lower among participants with a combination of lower coronary artery calcium, atherosclerosis, and lower high-sensitivity cardiac troponin T (myocardial injury).

METHODS AND RESULTS: The Cardiovascular Health Study Cognition Study was a continuation of the Cardiovascular Health Study limited to the Pittsburgh, PA, center from 1998-1999 to 2014. In 1992-1994, 924 participants underwent magnetic resonance imaging of the brain. There were 199 deaths and 116 developed dementia before 1998-1999. Of the 609 participants eligible for the Pittsburgh Cardiovascular Health Study Cognition Study, 87.5\% (n=532) were included in the study. There were 120 incident HF cases and 72\% had dementia. In 80 of 87, dementia preceded HF. A combination of low coronary artery calcium score and low high-sensitivity cardiac troponin T was significantly associated with reduced risk of dementia and HF.

CONCLUSIONS: Most participants with HF had dementia but with onset before HF. Lower high-sensitivity cardiac troponin T and coronary artery calcium was associated with low risk of dementia based on a small number of events.

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

}, issn = {2047-9980}, doi = {10.1161/JAHA.116.005353}, author = {Kuller, Lewis H and Lopez, Oscar L and Gottdiener, John S and Kitzman, Dalane W and Becker, James T and Chang, Yuefang and Newman, Anne B} } @article {7603, title = {Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction.}, journal = {JAMA Cardiol}, year = {2018}, month = {2018 Jan 10}, abstract = {

Importance: Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood.

Objective: To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population.

Design, Setting, and Participants: This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017.

Exposures: The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6.

Main Outcomes and Measures: Development of incident HFpEF and incident HFrEF.

Results: Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95\% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95\% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95\% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95\% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95\% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95\% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95\% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95\% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95\% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95\% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95\% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF.

Conclusions and Relevance: Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2017.4987}, author = {de Boer, Rudolf A and Nayor, Matthew and deFilippi, Christopher R and Enserro, Danielle and Bhambhani, Vijeta and Kizer, Jorge R and Blaha, Michael J and Brouwers, Frank P and Cushman, Mary and Lima, Jo{\~a}o A C and Bahrami, Hossein and van der Harst, Pim and Wang, Thomas J and Gansevoort, Ron T and Fox, Caroline S and Gaggin, Hanna K and Kop, Willem J and Liu, Kiang and Vasan, Ramachandran S and Psaty, Bruce M and Lee, Douglas S and Hillege, Hans L and Bartz, Traci M and Benjamin, Emelia J and Chan, Cheeling and Allison, Matthew and Gardin, Julius M and Januzzi, James L and Shah, Sanjiv J and Levy, Daniel and Herrington, David M and Larson, Martin G and van Gilst, Wiek H and Gottdiener, John S and Bertoni, Alain G and Ho, Jennifer E} } @article {7678, title = {Association of lipoprotein-associated phospholipase A and risk of incident atrial fibrillation: Findings from 3 cohorts.}, journal = {Am Heart J}, volume = {197}, year = {2018}, month = {2018 Mar}, pages = {62-69}, abstract = {

BACKGROUND: Multiple prospective studies have established an association between inflammation and higher risk of atrial fibrillation (AF), but the association between lipoprotein-associated phospholipase A (Lp-PLA) mass and activity and incident AF has not been extensively evaluated.

METHODS: Using data from 10,794 Atherosclerosis Risk In Communities (ARIC) study participants aged 53-75 years, 5,181 Cardiovascular Health Study (CHS) participants aged 65 to 100 years, and 5,425 Multi-Ethnic Study of Atherosclerosis (MESA) participants aged 45-84 years, we investigated the association between baseline Lp-PLA levels and the risk of developing AF. Incident AF was identified in each cohort by follow-up visit electrocardiograms, hospital discharge coding of AF, or Medicare claims data.

RESULTS: Over a mean of 13.1, 11.5, and 10.0 years of follow-up, 1,439 (13\%), 2,084 (40\%), and 615 (11\%) incident AF events occurred in ARIC, CHS, and MESA, respectively. In adjusted analyses, each SD increment in Lp-PLA activity was associated with incident AF in both ARIC (hazard ratio [HR] 1.13, 95\% CI 1.06-1.20) and MESA (HR 1.24, 95\% CI 1.05-1.46). Each SD increment in Lp-PLA mass was also associated with incident AF in MESA (HR 1.25, 95\% CI 1.11-1.41). No significant associations were observed among CHS participants.

CONCLUSIONS: Although higher Lp-PLA mass and activity were associated with development of AF in ARIC and MESA, this relationship was not observed in CHS, a cohort of older individuals.

}, issn = {1097-6744}, doi = {10.1016/j.ahj.2017.11.010}, author = {Garg, Parveen K and Bartz, Traci M and Norby, Faye L and Jorgensen, Neal W and McClelland, Robyn L and Ballantyne, Christie M and Chen, Lin Y and Gottdiener, John S and Greenland, Philip and Hoogeveen, Ron and Jenny, Nancy S and Kizer, Jorge R and Rosenson, Robert S and Soliman, Elsayed Z and Cushman, Mary and Alonso, Alvaro and Heckbert, Susan R} } @article {7812, title = {The Association of Obesity and Cardiometabolic Traits With Incident~HFpEF and HFrEF.}, journal = {JACC Heart Fail}, volume = {6}, year = {2018}, month = {2018 Aug}, pages = {701-709}, abstract = {

OBJECTIVES: This study evaluated the associations of obesity and cardiometabolic traits with incident heart failure with preserved versus reduced ejection fraction (HFpEF vs. HFrEF). Given known sex differences in HF subtype, we examined men and women separately.

BACKGROUND: Recent studies suggest that obesity confers greater risk of HFpEF versus HFrEF. Contributions of associated metabolic traits to HFpEF are less clear.

METHODS: We studied 22,681 participants from 4 community-based cohorts followed for incident HFpEF versus HFrEF (ejection fraction >=50\% vs.~<50\%). We evaluated the association of body mass index (BMI) and cardiometabolic traits with incident HF subtype using Cox models.

RESULTS: The mean age was 60 {\textpm} 13 years, and 53\% were women. Over a median follow-up of 12 years, 628 developed incident HFpEF and 835 HFrEF. Greater BMI portended higher risk of HFpEF compared with HFrEF (hazard ratio [HR]: 1.34 per 1-SD increase in BMI; 95\% confidence interval [CI]: 1.24 to 1.45 vs. HR: 1.18; 95\% CI: 1.10 to 1.27). Similarly, insulin resistance (homeostatic model assessment of insulin resistance) was associated with HFpEF (HR: 1.20 per 1-SD; 95\% CI: 1.05 to 1.37), but not HFrEF (HR: 0.99; 95\% CI: 0.88 to 1.11; p~< 0.05 for difference HFpEF vs. HFrEF). We found that the differential association of BMI with HFpEF versus HFrEF was more pronounced among women (p for difference HFpEF vs. HFrEF~= 0.01) when compared with men (p~= 0.34).

CONCLUSIONS: Obesity and related cardiometabolic traits including insulin resistance are more strongly associated with risk of future HFpEF versus HFrEF. The differential risk of HFpEF with obesity seems particularly pronounced among~women and may underlie sex differences in HF subtypes.

}, issn = {2213-1787}, doi = {10.1016/j.jchf.2018.05.018}, author = {Savji, Nazir and Meijers, Wouter C and Bartz, Traci M and Bhambhani, Vijeta and Cushman, Mary and Nayor, Matthew and Kizer, Jorge R and Sarma, Amy and Blaha, Michael J and Gansevoort, Ron T and Gardin, Julius M and Hillege, Hans L and Ji, Fei and Kop, Willem J and Lau, Emily S and Lee, Douglas S and Sadreyev, Ruslan and van Gilst, Wiek H and Wang, Thomas J and Zanni, Markella V and Vasan, Ramachandran S and Allen, Norrina B and Psaty, Bruce M and van der Harst, Pim and Levy, Daniel and Larson, Martin and Shah, Sanjiv J and de Boer, Rudolf A and Gottdiener, John S and Ho, Jennifer E} } @article {7685, title = {Sex and Race Differences in Lifetime Risk of Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction.}, journal = {Circulation}, volume = {137}, year = {2018}, month = {2018 Apr 24}, pages = {1814-1823}, abstract = {

BACKGROUND: Lifetime risk of heart failure has been estimated to range from 20\% to 46\% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.

METHODS: Participant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF >=45\%) and HFrEF (EF <45\%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.

RESULTS: We included 12 417 participants >45 years of age (22.2\% blacks, 44.8\% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4\% versus 23.8\%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6\% versus 5.8\%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9\% versus 22.4\%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2\% versus 7.7\%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.

CONCLUSIONS: Lifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.117.031622}, author = {Pandey, Ambarish and Omar, Wally and Ayers, Colby and LaMonte, Michael and Klein, Liviu and Allen, Norrina B and Kuller, Lewis H and Greenland, Philip and Eaton, Charles B and Gottdiener, John S and Lloyd-Jones, Donald M and Berry, Jarett D} } @article {7814, title = {Temporal Trends in the Incidence of~and~Mortality Associated With Heart~Failure With Preserved and Reduced Ejection Fraction.}, journal = {JACC Heart Fail}, volume = {6}, year = {2018}, month = {2018 Aug}, pages = {678-685}, abstract = {

OBJECTIVES: This study aimed to determine temporal trends in the incidence of and mortality associated with heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart rate with preserved ejection fraction [HFpEF]) in the community.

BACKGROUND: Major shifts in cardiovascular disease risk factor prevalence and advances in therapies may have influenced HF incidence and mortality.

METHODS: In the FHS (Framingham Heart Study) and CHS (Cardiovascular Health Study), for participants who were~>=60 years of age and free of HF (n~= 15,217; 60\% women; 2,524 incident HF cases; 115,703 person-years of follow-up), we estimated adjusted incidence rate ratios of HF, HFrEF, and HFpEF from 1990 to 1999 and 2000 to 2009. We compared the cumulative incidence of and mortality associated with HFrEF versus HFpEF within and between decades.

RESULTS: Across the 2 decades, HF incidence rate ratio was similar (p~= 0.13). The incidence rate ratio of HFrEF declined (p~= 0.0029), whereas HFpEF increased (p~< 0.001). Although HFrEF incidence declined more in men than in women, men had a higher incidence of HFrEF than women in each decade (p~< 0.001). The incidence of HFpEF significantly increased over time in both men and women (p~< 0.001 and p~= 0.02, respectively). During follow-up after HF, 1,701 individuals died (67.4\%; HFrEF, n~= 557 [33\%]; HFpEF, n~= 474 [29\%]). There were no significant differences in mortality~rates (overall, cardiovascular disease, and noncardiovascular disease) across decades within HF subtypes or between HFrEF and HFpEF within decade.

CONCLUSIONS: In several U.S. community-based samples from 1990 to 2009, we observed divergent trends of decreasing HFrEF and increasing HFpEF incidence, with stable overall HF incidence and high risk for mortality. Our~findings highlight the need to elucidate factors contributing to these observations.

}, issn = {2213-1787}, doi = {10.1016/j.jchf.2018.03.006}, author = {Tsao, Connie W and Lyass, Asya and Enserro, Danielle and Larson, Martin G and Ho, Jennifer E and Kizer, Jorge R and Gottdiener, John S and Psaty, Bruce M and Vasan, Ramachandran S} } @article {8008, title = {NT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure.}, journal = {J Am Heart Assoc}, volume = {8}, year = {2019}, month = {2019 Apr 02}, pages = {e010868}, abstract = {

Background Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N-terminal pro-B-type natriuretic peptide ( NT -pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT -pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT -pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12~418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT -pro BNP ( CHS : 40\% higher than blacks; 95\% CI , 29-53; ARIC : 39\% higher; 95\% CI , 33-46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95\% CI , 1.31-1.93; ARIC : hazard ratio, 1.93; 95\% CI , 1.57-2.27). NT -pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2\%; 95\% CI , 23.2-69.2\%; ARIC : 24.6\%; 95\% CI , 14.8-39.6\%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95\% CI , 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95\% CI , 0.94-1.23), CHF -related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT -pro BNP levels. No consistent relationship between race and CHF was observed.

}, issn = {2047-9980}, doi = {10.1161/JAHA.118.010868}, author = {Whitman, Isaac R and Vittinghoff, Eric and deFilippi, Christopher R and Gottdiener, John S and Alonso, Alvaro and Psaty, Bruce M and Heckbert, Susan R and Hoogeveen, Ron C and Arking, Dan E and Selvin, Elizabeth and Chen, Lin Y and Dewland, Thomas A and Marcus, Gregory M} } @article {8441, title = {Orthostatic Hypotension, Dizziness, Neurology Outcomes, and Death in Older Adults.}, journal = {Neurology}, year = {2020}, month = {2020 Jul 30}, abstract = {

OBJECTIVE: To test the hypothesis that orthostatic hypotension (OH) might cause cerebral hypoperfusion and injury, we examined the longitudinal relationship between orthostatic hypotension (OH) or orthostatic symptoms and incident neurologic outcomes in a community population of older adults.

METHODS: Cardiovascular Health Study (CHS) participants (>=65yrs) without dementia or stroke had blood pressure (BP) measured after lying 20-minutes and after standing 3-minutes. Participants reported dizziness immediately upon standing and any dizziness in the past 2wks. OH was defined as a drop in standing systolic/diastolic BP >=20/>=10mmHg. We determined the association between OH or dizziness with (1) MRI brain findings (ventricular size, white matter hyperintensities, brain infarcts) using linear or logistic regression, (2) cognitive function (baseline and over time) using generalized estimating equations, and (3) prospective adjudicated events (dementia, stroke, death) using Cox models. Models were adjusted for demographic characteristics and OH risk factors. We used multiple imputation to account for missing OH or dizziness (N=534).

RESULTS: Prior to imputation, there were 5,007 participants (mean age 72.7{\textpm}5.5yrs, 57.6\% women, 10.9\% black, 16\% with OH). OH was modestly associated with death (HR=1.11; 95\%CI:1.02,1.20), but not MRI findings, cognition, dementia, or stroke. In contrast, dizziness upon standing was associated with lower baseline cognition (β=-1.20;-1.94,-0.47), incident dementia (HR=1.32;1.04,1.62), incident stroke (HR=1.22;1.06,1.41), and death (HR=1.13; 1.06,1.21). Similarly, dizziness over the past two weeks was associated with higher white matter grade (β=0.16;0.03,0.30), brain infarcts (OR=1.31;1.06,1.63), lower baseline cognition (β=-1.18;-2.01,-0.34), and death (HR=1.13;1.04,1.22).

CONCLUSIONS: Dizziness was more consistently associated with neurologic outcomes than OH 3-minutes after standing. Delayed OH assessments may miss pathologic information related to cerebral injury.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000010456}, author = {Juraschek, Stephen P and Longstreth, W T and Lopez, Oscar L and Gottdiener, John S and Lipsitz, Lewis A and Kuller, Lewis H and Mukamal, Kenneth J} } @article {8482, title = {Relation of Biomarkers of Cardiac Injury, Stress, and Fibrosis With Cardiac Mechanics in Patients >= 65 Years of Age.}, journal = {Am J Cardiol}, year = {2020}, month = {2020 Sep 16}, abstract = {

High sensitivity cardiac troponin T (hscTnT), soluble ST2 (sST2), N-terminal B-type natriuretic peptide (NT-proBNP), and galectin-3 are biomarkers of cardiac injury, stress, myocardial stretch, and fibrosis. Elevated levels are associated with poor outcomes. However, their association with cardiac mechanics in older persons is unknown. Associations between these biomarkers and cardiac mechanics derived from speckle tracking echocardiography, including left ventricular longitudinal strain (LVLS), early diastolic strain, and left atrial reservoir strain (LARS) were evaluated using standardized beta coefficients () in a cross sectional analysis with cardiac biomarkers in older patients without cardiovascular disease, low ejection fraction, or wall motion abnormalities. Biomarker associations with strain were attenuated by demographics and risk factors. In adjusted models, LVLS was associated with continuous measures of hscTnT (β-0.06, p = 0.020), sST2 (β -0.05, p = 0.024) and NT-proBNP (β -0.06, p = 0.007). "High" levels (i.e., greater than prognostic cutpoint) of hscTnT (>13 ng/ml), sST2 (>35 ng/ml), and NT-proBNP (>190 pg/ml) were also associated with worse LVLS. In risk factor adjusted models, LARS was associated with hscTnT (β -0.08, p = 0.003) and NT-proBNP (β-0.18, p <0.0001). High hscTnT (>13 ng/ml) and high NT-proBNP (>190 pg/ml) were also both associated with worse LARS. Gal-3 was not associated with any strain measure. In conclusion, in persons >= 65 years of age, without cardiovascular disease, low ejection fraction, or wall motion abnormalities, hscTnT, sST2, and NT-proBNP are associated with worse LVLS. HscTnT and NT-proBNP are associated with worse LARS. In conclusion, these subclinical increases in blood biomarkers, and their associations with subtle diastolic and systolic dysfunction, may represent pre-clinical heart failure.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2020.09.013}, author = {Gottdiener, John S and Seliger, Stephen and DeFilippi, Christopher and Christenson, Robert and Baldridge, Abigail S and Kizer, Jorge R and Psaty, Bruce M and Shah, Sanjiv J} } @article {8488, title = {Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart~Failure.}, journal = {J Am Coll Cardiol}, volume = {76}, year = {2020}, month = {2020 Sep 22}, pages = {1455-1465}, abstract = {

BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear.

OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF.

METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio.

RESULTS: Among 22,756 participants (mean age 60 {\textpm} 13 years, 53\% women), HF occurred in 2,095 participants (47\% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p~<~0.001), and the combined clinical model had good discrimination in men (C-statistic~=~0.80) and in women (C-statistic~=~0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic~=~0.006; likelihood ratio chi-square~=~146; p~<~0.001), and after adding cardiac troponins in women (ΔC-statistic~=~0.003; likelihood ratio chi-square~=~73; p~<~0.001).

CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in~a~clinical HF risk prediction model is limited in both sexes.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.07.044}, author = {Suthahar, Navin and Lau, Emily S and Blaha, Michael J and Paniagua, Samantha M and Larson, Martin G and Psaty, Bruce M and Benjamin, Emelia J and Allison, Matthew A and Bartz, Traci M and Januzzi, James L and Levy, Daniel and Meems, Laura M G and Bakker, Stephan J L and Lima, Jo{\~a}o A C and Cushman, Mary and Lee, Douglas S and Wang, Thomas J and deFilippi, Christopher R and Herrington, David M and Nayor, Matthew and Vasan, Ramachandran S and Gardin, Julius M and Kizer, Jorge R and Bertoni, Alain G and Allen, Norrina B and Gansevoort, Ron T and Shah, Sanjiv J and Gottdiener, John S and Ho, Jennifer E and de Boer, Rudolf A} } @article {8376, title = {Soluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults.}, journal = {J Card Fail}, volume = {26}, year = {2020}, month = {2020 May}, pages = {410-419}, abstract = {

BACKGROUND: CD14 is a membrane glycoprotein primarily expressed by myeloid cells that plays a key role in inflammation. Soluble CD14 (sCD14) levels carry a poor prognosis in chronic heart failure (HF), but whether elevations in sCD14 precede HF is unknown. We tested the hypothesis that sCD14 is associated with HF incidence and its subtypes independent of major inflammatory biomarkers among older adults.

METHODS AND RESULTS: We included participants in the Cardiovascular Health Study without preexisting HF and available baseline sCD14. We evaluated the associations of sCD14, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and white blood cell count (WBC) with incident HF and subtypes using Cox regression. Among 5217 participants, 1878 had incident HF over 13.6 years (609 classifiable as HF with preserved ejection fraction [HFpEF] and 419 as HF with reduced ejection fraction [HFrEF]). After adjusting for clinical and laboratory covariates, sCD14 was significantly associated with incident HF (hazard ratio [HR]: 1.56 per doubling, 95\% confidence interval [CI]: 1.29-1.89), an association that was numerically stronger than for hsCRP (HR per doubling: 1.10, 95\% CI: 1.06-1.15), IL-6 (HR: 1.18, 95\% CI: 1.10-1.25), and WBC (HR: 1.24, 95\% CI: 1.09-1.42), and that remained significant after adjustment for the other markers of inflammation. This association for sCD14 was observed with HFpEF (HR: 1.50, 95\% CI: 1.07-2.10) but not HFrEF (HR: 0.99, 95\% CI: 0.67-1.49).

CONCLUSIONS: Plasma sCD14 was associated with incident HF independently and numerically more strongly than other major inflammatory markers. This association was only observed with HFpEF in the subset with classifiable HF subtypes. Pending replication, these findings have potentially important therapeutic implications.

}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2020.03.003}, author = {Al-Kindi, Sadeer G and B{\r u}zkov{\'a}, Petra and Shitole, Sanyog G and Reiner, Alex P and Garg, Parveen K and Gottdiener, John S and Psaty, Bruce M and Kizer, Jorge R} } @article {8833, title = {Adverse cardiac mechanics and incident coronary heart disease in the Cardiovascular Health Study.}, journal = {Heart}, year = {2021}, month = {2021 Jul 13}, abstract = {

OBJECTIVES: Speckle-tracking echocardiography enables detection of abnormalities in cardiac mechanics with higher sensitivity than conventional measures of left ventricular (LV) dysfunction and may provide insight into the pathogenesis of coronary heart disease (CHD). We investigated the relationship of LV longitudinal strain, LV early diastolic strain rate (SR) and left atrial (LA) reservoir strain with long-term CHD incidence in community-dwelling older adults.

METHODS: The association of all three strain measures with incidence of non-fatal and fatal CHD (primary outcome of revascularisation, non-fatal and fatal myocardial infarction) was examined in the population-based Cardiovascular Health Study using multivariable Cox proportional hazards models. Follow-up was truncated at 10 years.

RESULTS: We included 3313 participants (mean (SD) age 72.6 (5.5) years). During a median follow-up of 10.0 (25th-75th percentile 7.7-10.0) years, 439 CHD events occurred. LV longitudinal strain (HR=1.25 per SD decrement, 95\% CI 1.09 to 1.43) and LV early diastolic SR (HR=1.31 per SD decrement, 95\% CI 1.14 to 1.50) were associated with a significantly greater risk of incident CHD after adjustment for potential confounders. By contrast, LA reservoir strain was not associated with incident CHD (HR=1.06 per SD decrement, 95\% CI 0.94 to 1.19). Additional adjustment for biochemical and echocardiographic measures of myocardial stress, dysfunction and remodelling did not meaningfully alter these associations.

CONCLUSION: We found an association between echocardiographic measures of subclinically altered LV mechanics and incident CHD. These findings inform the underlying biology of subclinical LV dysfunction and CHD. Early detection of asymptomatic myocardial dysfunction may offer an opportunity for prevention and early intervention.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2021-319296}, author = {Massera, Daniele and Hu, Mo and Delaney, Joseph A and Bartz, Traci M and Bach, Megan E and Dvorak, Stephen J and deFilippi, Christopher R and Psaty, Bruce M and Gottdiener, John S and Kizer, Jorge R and Shah, Sanjiv J} } @article {8787, title = {Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults.}, journal = {Heart}, year = {2021}, month = {2021 Jun 02}, abstract = {

OBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up.

METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods.

RESULTS: The cohort comprised 5795 participants (age 73{\textpm}6, 42.2\% male, 14.3\% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69\% (probable/definite) to 4.67\% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88\% to 3.71\%. Of incident cases, about 85\% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95\% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95\% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95\% CI 0.23 to 0.81]).

CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2021-319025}, author = {Owens, David S and Bartz, Traci M and B{\r u}zkov{\'a}, Petra and Massera, Daniele and Biggs, Mary L and Carlson, Selma D and Psaty, Bruce M and Sotoodehnia, Nona and Gottdiener, John S and Kizer, Jorge R} } @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 {9154, title = {The association of aortic valve sclerosis, aortic annulus increased reflectivity, and mitral annular calcification with subsequent aortic stenosis in older individuals. Findings from the Cardiovascular Health Study.}, journal = {J Am Soc Echocardiogr}, year = {2022}, month = {2022 Sep 09}, abstract = {

BACKGROUND: While aortic valve sclerosis (AVS) is well-described as preceding aortic stenosis (AS), the association of AS with antecedent mitral aortic annular calcification and aortic annulus increased reflectivity (MAC and AAIR, respectively) has not been characterized. In a population-based prospective study, we evaluated whether MAC, AAIR, and AVS are associated with the risk of incident AS.

METHODS: Among participants of the Cardiovascular Health Study (CHS) free of AS at the 1994-1995 visit, the presence of MAC, AAIR, AVS, and the combination of all three were evaluated in 3041 participants. Cox proportional hazards regression was used to assess the association between the presence of calcification and the incidence of moderate/severe AS in three nested models adjusting for factors associated with atherosclerosis and inflammation both relevant to the pathogenesis of AS.

RESULTS: Over a median follow-up of 11.5 years (IQR 6.7 to 17.0), 110 cases of incident moderate/severe AS were ascertained. Strong positive associations with incident moderate/severe AS were found for all calcification sites after adjustment for the main model covariates: AAIR (HR=2.90, 95\% CI=[1.95, 4.32], p<0.0005), AVS (HR=2.20, 95\% CI=[1.44, 3.37], p<0.0005), MAC (HR=1.67, 95\% CI=[1.14, 2.45], p=0.008), and the combination of MAC, AAIR, and AVS (HR=2.50, 95\% CI=[1.65, 3.78], p<0.0005). In a secondary analysis, the risk of AS increased with the number of sites at which calcification was present.

CONCLUSIONS: In a large cohort of community-dwelling elderly individuals, there were strong associations between each of AAIR, AVS, MAC, and the combination of MAC, AAIR, and AVS with incident moderate/severe AS. The novel finding that AAIR had a particularly strong association with incident AS, even after adjusting for other calcification sites, suggests its value in identifying individuals at risk for AS, and potential inclusion in the routine assessment by transthoracic echocardiography.

}, issn = {1097-6795}, doi = {10.1016/j.echo.2022.08.013}, author = {Barasch, Eddy and Gottdiener, John S and Tressel, William and Bartz, Traci M and B{\r u}zkov{\'a}, Petra and Massera, Daniele and DeFilippi, Christopher and Biggs, Mary L and Psaty, Bruce M and Kizer, Jorge R and Owens, David} } @article {9043, title = {Body Composition and Incident Heart Failure in Older Adults: Results From 2 Prospective Cohorts.}, journal = {J Am Heart Assoc}, volume = {11}, year = {2022}, month = {2022 01 04}, pages = {e023707}, abstract = {

Background Aging is associated with central fat redistribution and skeletal muscle decline, yet the relationships of tissue compartments with heart failure (HF) remain incompletely characterized. We assessed the contribution of body composition to incident HF in elders. Methods and Results Participants from 2 older cohorts who completed dual-energy X-ray absorptiometry (DEXA) and, in one cohort, computed tomography were included. We evaluated associations with incident HF for DEXA principal components (PCs) and total lean, appendicular lean, total fat and trunk fat mass; and for computed tomography measures of abdominal visceral and subcutaneous fat, thigh muscle, intermuscular fat area and thigh muscle density. DEXA analysis included 3621, and computed tomography analysis 2332 participants. During median follow-up of 11.8~years, 927 participants developed HF. DEXA principal components showed no relationship with HF. After adjustment for height, weight, and cardiovascular risk factors, total lean mass was near significantly associated with higher HF (hazard ratio [HR], 1.25 per SD [1.00-1.56]), whereas total fat mass and thigh muscle density were significantly related to lower HF (HR, 0.82 [0.68-0.99] and HR, 0.87 [0.78-0.97], respectively). Patterns were similar for HF subtypes. The relationships with HF for total lean and fat mass were attenuated after adjusting for intercurrent atrial fibrillation or excluding high natriuretic peptide levels. Conclusions Total lean mass was positively associated, while total fat mass and thigh muscle density were inversely associated, with incident HF. These findings highlight the limitations of DEXA for assessment of HF risk in elders and support the preeminence of computed tomography-measured skeletal muscle quality over mass as a determinant of HF incidence.

}, keywords = {Absorptiometry, Photon, Aged, Aging, Body Composition, Body Mass Index, Heart Failure, Humans, Muscle, Skeletal, Prospective Studies}, issn = {2047-9980}, doi = {10.1161/JAHA.121.023707}, author = {Zhang, Lili and Bartz, Traci M and Santanasto, Adam and Djouss{\'e}, Luc and Mukamal, Kenneth J and Forman, Daniel E and Hirsch, Calvin H and Newman, Anne B and Gottdiener, John S and Kizer, Jorge R} } @article {9256, title = {Circulating Androgen Concentrations and Risk of Incident Heart Failure in Older Men: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {11}, year = {2022}, month = {2022 Nov}, pages = {e026953}, abstract = {

Background Circulating androgen concentrations in men decline with age and have been linked to diabetes and atherosclerotic cardiovascular disease (ASCVD). A similar relationship has been reported for low total testosterone and incident heart failure (HF) but remains unstudied for free testosterone or the more potent androgen dihydrotestosterone (DHT). We hypothesized that total/free testosterone are inversely related, sex hormone-binding globulin is positively related, and total/free DHT bear a U-shaped relationship with incident HF. Methods and Results In a sample of men from the CHS (Cardiovascular Health Study) without atherosclerotic cardiovascular disease or HF, serum testosterone and DHT concentrations were measured by liquid chromatography-tandem mass spectrometry, and sex hormone-binding globulin by immunoassay. Free testosterone or DHT was calculated from total testosterone or total DHT, sex hormone-binding globulin, and albumin. We used Cox regression to estimate relative risks of HF after adjustment for potential confounders. In 1061 men (aged 76{\textpm}5 years) followed for a median of 9.6 years, there were 368 HF events. After adjustment, lower calculated free testosterone was significantly associated with higher risk of HF (hazard ratio [HR], 1.14 [95\% CI, 1.01-1.28]). Risk estimates for total testosterone (HR, 1.12 [95\% CI, 0.99-1.26]), total DHT (HR, 1.10 [95\% CI, 0.97-1.24]), calculated free dihydrotestosterone (HR, 1.09 [95\% CI, 0.97-1.23]), and sex hormone-binding globulin (HR, 1.07 [95\% CI, 0.95-1.21]) were directionally similar but not statistically significant. Conclusions Calculated free testosterone was inversely associated with incident HF, suggesting a contribution of testosterone deficiency to HF incidence among older men. Additional research is necessary to determine whether testosterone replacement therapy might be an effective strategy to lower HF risk in older men.

}, keywords = {Aged, Androgens, Cardiovascular Diseases, Dihydrotestosterone, Estradiol, Heart Failure, Humans, Male, Sex Hormone-Binding Globulin, Testosterone}, issn = {2047-9980}, doi = {10.1161/JAHA.122.026953}, author = {Njoroge, Joyce N and Tressel, William and Biggs, Mary L and Matsumoto, Alvin M and Smith, Nicholas L and Rosenberg, Emily and Hirsch, Calvin H and Gottdiener, John S and Mukamal, Kenneth J and Kizer, Jorge R} } @article {9092, title = {Glucose dysregulation and subclinical cardiac dysfunction in older adults: The Cardiovascular Health Study.}, journal = {Cardiovasc Diabetol}, volume = {21}, year = {2022}, month = {2022 Jun 20}, pages = {112}, abstract = {

OBJECTIVE: We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population.

METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics.

RESULTS: Mean age for the 2433 included participants was 72.0~years, 33.6\% were male, and 3.7\% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95\% confidence interval = 0.03-0.33).

CONCLUSION: In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity.

}, keywords = {Aged, Cross-Sectional Studies, Female, Glucose, Humans, Insulin Resistance, Male, Ventricular Dysfunction, Left, Ventricular Function, Left}, issn = {1475-2840}, doi = {10.1186/s12933-022-01547-z}, author = {Garg, Parveen K and Biggs, Mary L and Kizer, Jorge R and Shah, Sanjiv J and Psaty, Bruce and Carnethon, Mercedes and Gottdiener, John S and Siscovick, David and Mukamal, Kenneth J} } @article {8974, title = {Relation of Cigarette Smoking and Heart Failure in Adults >=65~Years of Age (From the Cardiovascular Health Study).}, journal = {Am J Cardiol}, year = {2022}, month = {2022 Jan 16}, abstract = {

Cigarette smoking is associated with adverse cardiac outcomes, including incident heart failure (HF). However, key components of potential pathways from smoking to HF have not been evaluated in older adults. In a community-based study, we studied cross-sectional associations of smoking with blood and imaging biomarkers reflecting mechanisms of cardiac disease. Serial nested, multivariable Cox models were used to determine associations of smoking with HF, and to assess the influence of biochemical and functional (cardiac strain) phenotypes on these associations. Compared with never smokers, smokers had higher levels of inflammation (C-reactive protein and interleukin-6), cardiomyocyte injury (cardiac troponin T [hscTnT]), myocardial "stress"/fibrosis (soluble suppression of tumorigenicity 2 [sST2], galectin 3), and worse left ventricle systolic and diastolic function. In models adjusting for age, gender, and race (DEMO) and for clinical factors potentially in the causal pathway (CLIN), smoking exposures were associated with C-reactive protein and interleukin-6, sST2, hscTnT, and with N-terminal pro-brain natriuretic protein (in Whites). In DEMO adjusted models, the cumulative burden of smoking was associated with worse left ventricle systolic strain. Current smoking and former smoking were associated with HF in DEMO models (hazard ratio 1.41, 95\% confidence interval 1.22 to 1.64 and hazard ratio 1.14, 95\% confidence interval 1.03 to 1.25, respectively), and with current smoking after CLIN adjustment. Adjustment for time-varying myocardial infarction, inflammation, cardiac strain, hscTnT, sST2, and galectin 3 did not materially alter the associations. Smoking was associated with HF with preserved and decreased ejection fraction. In conclusion, in older adults, smoking is associated with multiple blood and imaging biomarker measures of pathophysiology previously linked to HF, and to incident HF even after adjustment for clinical intermediates.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2021.12.021}, author = {Gottdiener, John S and B{\r u}zkov{\'a}, Petra and Kahn, Peter A and DeFilippi, Christopher and Shah, Sanjiv and Barasch, Eddy and Kizer, Jorge R and Psaty, Bruce and Gardin, Julius M} } @article {9320, title = {Cardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study.}, journal = {Kidney360}, year = {2023}, month = {2023 Mar 08}, abstract = {

BACKGROUND: Clinical heart failure frequently coexists with chronic kidney disease (CKD) and may precipitate kidney function decline. However, whether earlier-stage myocardial dysfunction assessable by speckle tracking echocardiography is a contributor to kidney function decline remains unknown.

METHODS: We studied 2135 Cardiovascular Health Study (CHS) participants who were free of clinical heart failure and had Year 2-baseline 2D speckle tracking echocardiography and two measurements of estimated glomerular filtration rate (eGFR) (Year 2 and Year 9). "Archival" speckle tracking of digitized echocardiogram videotapes was utilized to measure left ventricular longitudinal strain (LVLS), LV early diastolic strain rate (EDSR), left atrial reservoir strain (LARS), right ventricular free wall strain (RVFWS), and mitral annular velocity (e{\textquoteright}). Multivariable Poisson regression models that adjusted for demographics and cardiovascular risk factors were used to investigate the independent associations of cardiac mechanics indices and decline in kidney function defined as a 30\% decline in eGFR over 7 years.

RESULTS: In risk factor (RF) models LVLS, EDSR, RVFWS, and e{\textquoteright} were all significantly associated with the prevalence of kidney disease. After multivariable adjustment, left atrial dysfunction (RR 1.18 [95\% CI 1.01, 1.38] per SD lower LARS] and left ventricular diastolic dysfunction (RR 1.21 [95\% CI 1.04, 1.41] per SD lower EDSR) were each significantly associated with 30\% decline in eGFR.

CONCLUSIONS: Subclinical myocardial dysfunction suggesting abnormal diastolic function detected by 2D speckle-tracking echocardiography was independently associated with decline in kidney function over time. Further studies are needed to understand the mechanisms of these associations and to test whether interventions that may improve subclinical myocardial dysfunction can prevent decline of kidney function.

}, issn = {2641-7650}, doi = {10.34067/KID.0000000000000100}, author = {Mehta, Rupal and B{\r u}zkov{\'a}, Petra and Patel, Harnish and Cheng, Jeanette and Kizer, Jorge R and Gottdiener, John S and Psaty, Bruce and Khan, Sadiya S and Ix, Joachim H and Isakova, Tamara and Shlipak, Michael G and Bansal, Nisha and Shah, Sanjiv J} } @article {9382, title = {Effect of 2022 ACC/AHA/HFSA Criteria on Stages of Heart~Failure in a Pooled Community Cohort.}, journal = {J Am Coll Cardiol}, volume = {81}, year = {2023}, month = {2023 Jun 13}, pages = {2231-2242}, abstract = {

BACKGROUND: The 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart~Failure Society of America (HFSA) clinical practice guideline proposed an updated definition for heart failure (HF) stages.

OBJECTIVES: This study aimed to compare prevalence and prognosis of HF stages according to classification/definition originally described in 2013 and 2022 ACC/AHA/HFSA definitions.

METHODS: Study participants from 3 longitudinal cohorts (the MESA [Multi-Ethnic Study of Atherosclerosis], CHS [Cardiovascular Health Study], and the FHS [Framingham Heart Study]), were categorized into 4 HF stages according to the 2013 and 2022 criteria. Cox proportional hazards regression was used to assess predictors of progression to symptomatic HF and adverse clinical outcomes associated with each HF stage.

RESULTS: Among 11,618 study participants, according to the 2022 staging, 1,943 (16.7\%) were healthy, 4,348 (37.4\%) were in stage A (at risk), 5,019 (43.2\%) were in stage B (pre-HF), and 308 (2.7\%) were in stage C/D (symptomatic HF). Compared to the classification/definition originally described in 2013, the 2022 ACC/AHA/HFSA approach resulted in a higher proportion of individuals with stage B HF (increase from 15.9\% to 43.2\%); this shift disproportionately involved women as well as Hispanic and Black individuals. Despite the 2022 criteria designating a greater proportion of individuals as stage B, the relative risk of progression to symptomatic HF remained similar (HR: 10.61; 95\%~CI: 9.00-12.51; P~< 0.001).

CONCLUSIONS: New standards for HF staging resulted in a substantial shift of community-based individuals from stage A to stage B. Those with stage B HF in the new system were at high risk for progression to symptomatic HF.

}, keywords = {American Heart Association, Atherosclerosis, Cardiology, Female, Heart Failure, Humans, Longitudinal Studies, Prognosis, United States}, issn = {1558-3597}, doi = {10.1016/j.jacc.2023.04.007}, author = {Mohebi, Reza and Wang, Dongyu and Lau, Emily S and Parekh, Juhi K and Allen, Norrina and Psaty, Bruce M and Benjamin, Emelia J and Levy, Daniel and Wang, Thomas J and Shah, Sanjiv J and Gottdiener, John S and Januzzi, James L and Ho, Jennifer E} } @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 {9288, title = {Lifestyle habits associated with cardiac conduction disease.}, journal = {Eur Heart J}, year = {2023}, month = {2023 Jan 20}, abstract = {

AIMS: Cardiac conduction disease can lead to syncope, heart failure, and death. The only available therapy is pacemaker implantation, with no established prevention strategies. Research to identify modifiable risk factors has been scant.

METHODS AND RESULTS: Data from the Cardiovascular Health Study, a population-based cohort study of adults >= 65 years with annual 12-lead electrocardiograms obtained over 10 years, were utilized to examine relationships between baseline characteristics, including lifestyle habits, and conduction disease. Of 5050 participants (mean age 73 {\textpm} 6 years; 52\% women), prevalent conduction disease included 257 with first-degree atrioventricular block, 99 with left anterior fascicular block, 9 with left posterior fascicular block, 193 with right bundle branch block (BBB), 76 with left BBB, and 102 with intraventricular block at baseline. After multivariable adjustment, older age, male sex, a larger body mass index, hypertension, and coronary heart disease were associated with a higher prevalence of conduction disease, whereas White race and more physical activity were associated with a lower prevalence. Over a median follow-up on 7 (interquartile range 1-9) years, 1036 developed incident conduction disease. Older age, male sex, a larger BMI, and diabetes were each associated with incident conduction disease. Of lifestyle habits, more physical activity (hazard ratio 0.91, 95\% confidence interval 0.84-0.98, P = 0.017) was associated with a reduced risk, while smoking and alcohol did not exhibit a significant association.

CONCLUSION: While some difficult to control comorbidities were associated with conduction disease as expected, a readily modifiable lifestyle factor, physical activity, was associated with a lower risk.

}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehac799}, author = {Frimodt-M{\o}ller, Emilie K and Soliman, Elsayed Z and Kizer, Jorge R and Vittinghoff, Eric and Psaty, Bruce M and Biering-S{\o}rensen, Tor and Gottdiener, John S and Marcus, Gregory M} } @article {9241, title = {Multiple Prior Live Births are Associated with Cardiac Remodeling and Heart Failure Risk in Women.}, journal = {J Card Fail}, year = {2023}, month = {2023 Jan 10}, abstract = {

INTRODUCTION: Greater parity has been associated with cardiovascular disease risk, though effects on cardiac remodeling and heart failure risk remain unclear.

METHODS: We examined the association of number of live births and echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of n=12,635 participants of FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major CVD, MI, and stroke.

RESULTS: Among n=3931 FHS participants (mean age 48 {\textpm} 13 years), higher number of live births was associated with worse LV fractional shortening (multivariable β -1.11 (0.31), p= 0.0005 in >= 5 live births vs nulliparous women) and worse cardiac mechanics including global circumferential strain and longitudinal and radial dyssynchrony (p< 0.01 for all comparing >= 5 live births vs nulliparity). When examining HF subtypes, women with >=5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95\% CI 1.19-3.12, p=0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95\% CI 0.37-0.91, p=0.02).

CONCLUSIONS: Greater number of live births are associated with worse cardiac structure and function. While there was no association with overall HF, a higher number of live births was associated with greater risk for incident HFrEF.

}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2022.12.014}, author = {Sarma, Amy A and Paniagua, Samantha M and Lau, Emily S and Wang, Dongyu and Liu, Elizabeth E and Larson, Martin G and Hamburg, Naomi M and Mitchell, Gary F and Kizer, Jorge and Psaty, Bruce M and Allen, Norrina B and Lely, A Titia and Gansevoort, Ronald T and Rosenberg, Emily and Mukamal, Kenneth and Benjamin, Emelia J and Vasan, Ramachandran S and Cheng, Susan and Levy, Daniel and de Boer, Rudolf A and Gottdiener, John S and Shah, Sanjiv J and Ho, Jennifer E} } @article {9416, title = {Traditional and novel risk factors for incident aortic stenosis in community-dwelling older adults.}, journal = {Heart}, year = {2023}, month = {2023 Jul 18}, abstract = {

OBJECTIVES: Calcific aortic stenosis (AS) is the most common valvular disease in older adults, yet its risk factors remain insufficiently studied in this population. Such studies are necessary to enhance understanding of mechanisms, disease management and therapeutics.

METHODS: The Cardiovascular Health Study is a population-based investigation of older adults that completed adjudication of incident AS over long-term follow-up. We evaluated traditional cardiovascular risk factors or disease, as well as novel risk factors from lipid, inflammatory and mineral metabolism pathways, in relation to incident moderate or severe AS (including AS procedures) and clinically significant AS (severe AS, including procedures).

RESULTS: Of 5390 participants (age 72.9{\textpm}5.6 years, 57.6\% female, 12.5\% black), 287 developed moderate or severe AS, and 175 clinically significant AS, during median follow-up of 13.1 years. After full adjustment, age (HR=1.66 per SD (95\% CI=1.45, 1.91)), male sex (HR=1.41 (1.06, 1.87)), diabetes (HR=1.53 (1.10, 2.13)), coronary heart disease (CHD, HR=1.36 (1.01, 1.84)), lipoprotein-associated phospholipase-A (LpPLA) activity (HR=1.21 per SD (1.07, 1.37)) and sCD14 (HR=1.16 per SD (1.01, 1.34)) were associated with incident moderate/severe AS, while black race demonstrated an inverse association (HR=0.40 (0.24, 0.65)), and creatinine-based estimated glomerular filtration rate (eGFR) showed a U-shaped relationship. Findings were similar for clinically significant AS, although CHD and sCD14 fell short of significance, but interleukin-(IL) 6 showed a positive association.

CONCLUSION: This comprehensive evaluation of risk factors for long-term incidence of AS identified associations for diabetes and prevalent CHD, LpPLA activity, sCD14 and IL-6, and eGFR. These factors may hold clues to biology, preventive efforts and potential therapeutics for those at highest risk.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2023-322709}, author = {Massera, Daniele and Bartz, Traci M and Biggs, Mary L and Sotoodehnia, Nona and Reiner, Alexander P and Semba, Richard D and Gottdiener, John S and Psaty, Bruce M and Owens, David S and Kizer, Jorge R} } @article {9910, title = {Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.}, journal = {Nat Genet}, year = {2025}, month = {2025 Mar 04}, abstract = {

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

}, issn = {1546-1718}, doi = {10.1038/s41588-024-02064-3}, author = {Henry, Albert and Mo, Xiaodong and Finan, Chris and Chaffin, Mark D and Speed, Doug and Issa, Hanane and Denaxas, Spiros and Ware, James S and Zheng, Sean L and M{\"a}larstig, Anders and Gratton, Jasmine and Bond, Isabelle and Roselli, Carolina and Miller, David and Chopade, Sandesh and Schmidt, A Floriaan and Abner, Erik and Adams, Lance and Andersson, Charlotte and Aragam, Krishna G and Arnl{\"o}v, Johan and Asselin, Geraldine and Raja, Anna Axelsson and Backman, Joshua D and Bartz, Traci M and Biddinger, Kiran J and Biggs, Mary L and Bloom, Heather L and Boersma, Eric and Brandimarto, Jeffrey and Brown, Michael R and Brunak, S{\o}ren and Bruun, Mie Topholm and Buckbinder, Leonard and Bundgaard, Henning and Carey, David J and Chasman, Daniel I and Chen, Xing and Cook, James P and Czuba, Tomasz and de Denus, Simon and Dehghan, Abbas and Delgado, Graciela E and Doney, Alexander S and D{\"o}rr, Marcus and Dowsett, Joseph and Dudley, Samuel C and Engstr{\"o}m, Gunnar and Erikstrup, Christian and Esko, T{\~o}nu and Farber-Eger, Eric H and Felix, Stephan B and Finer, Sarah and Ford, Ian and Ghanbari, Mohsen and Ghasemi, Sahar and Ghouse, Jonas and Giedraitis, Vilmantas and Giulianini, Franco and Gottdiener, John S and Gross, Stefan and Gu{\dh}bjartsson, Dan{\'\i}el F and Gui, Hongsheng and Gutmann, Rebecca and H{\"a}gg, Sara and Haggerty, Christopher M and Hedman, {\r A}sa K and Helgadottir, Anna and Hemingway, Harry and Hillege, Hans and Hyde, Craig L and Aagaard Jensen, Bitten and Jukema, J Wouter and Kardys, Isabella and Karra, Ravi and Kavousi, Maryam and Kizer, Jorge R and Kleber, Marcus E and K{\o}ber, Lars and Koekemoer, Andrea and Kuchenbaecker, Karoline and Lai, Yi-Pin and Lanfear, David and Langenberg, Claudia and Lin, Honghuang and Lind, Lars and Lindgren, Cecilia M and Liu, Peter P and London, Barry and Lowery, Brandon D and Luan, Jian{\textquoteright}an and Lubitz, Steven A and Magnusson, Patrik and Margulies, Kenneth B and Marston, Nicholas A and Martin, Hilary and M{\"a}rz, Winfried and Melander, Olle and Mordi, Ify R and Morley, Michael P and Morris, Andrew P and Morrison, Alanna C and Morton, Lori and Nagle, Michael W and Nelson, Christopher P and Niessner, Alexander and Niiranen, Teemu and Noordam, Raymond and Nowak, Christoph and O{\textquoteright}Donoghue, Michelle L and Ostrowski, Sisse Rye and Owens, Anjali T and Palmer, Colin N A and Par{\'e}, Guillaume and Pedersen, Ole Birger and Perola, Markus and Pigeyre, Marie and Psaty, Bruce M and Rice, Kenneth M and Ridker, Paul M and Romaine, Simon P R and Rotter, Jerome I and Ruff, Christian T and Sabatine, Marc S and Sallah, Neneh and Salomaa, Veikko and Sattar, Naveed and Shalaby, Alaa A and Shekhar, Akshay and Smelser, Diane T and Smith, Nicholas L and S{\o}rensen, Erik and Srinivasan, Sundararajan and Stefansson, Kari and Sveinbj{\"o}rnsson, Gar{\dh}ar and Svensson, Per and Tammesoo, Mari-Liis and Tardif, Jean-Claude and Teder-Laving, Maris and Teumer, Alexander and Thorgeirsson, Gu{\dh}mundur and Thorsteinsdottir, Unnur and Torp-Pedersen, Christian and Tragante, Vinicius and Trompet, Stella and Uitterlinden, Andr{\'e} G and Ullum, Henrik and van der Harst, Pim and van Heel, David and van Setten, Jessica and van Vugt, Marion and Veluchamy, Abirami and Verschuuren, Monique and Verweij, Niek and Vissing, Christoffer Rasmus and V{\"o}lker, Uwe and Voors, Adriaan A and Wallentin, Lars and Wang, Yunzhang and Weeke, Peter E and Wiggins, Kerri L and Williams, L Keoki and Yang, Yifan and Yu, Bing and Zannad, Faiez and Zheng, Chaoqun and Asselbergs, Folkert W and Cappola, Thomas P and Dub{\'e}, Marie-Pierre and Dunn, Michael E and Lang, Chim C and Samani, Nilesh J and Shah, Svati and Vasan, Ramachandran S and Smith, J Gustav and Holm, Hilma and Shah, Sonia and Ellinor, Patrick T and Hingorani, Aroon D and Wells, Quinn and Lumbers, R Thomas} }