Emelia J. Benjamin

Heart Disease and Stroke Statistics—2013 Update A Report From the American Heart Association

Author(s): Go, Alan S; Mozaffarian, Dariush; Roger, Veronique L; Benjamin, Emelia J; Berry, Jarett D; Borden, William B; Bravata, Dawn M; Dai, Shifan; Ford, Earl S; Fox, Caroline S; Franco, Sheila; Fullerton, Heather J; Gillespie, Cathleen; Hailpern, Susan M; Heit, John A; Howard, Virginia J; Huffman, Mark D; Kissela, Brett M; Kittner, Steven J; Lackland, Daniel T; Lichtman, Judith H; Lisabeth, Lynda D; Magid, David; Marcus, Gregory M; Marelli, Ariane; Matchar, David B; McGuire, Darren K; Mohler, Emile R; Moy, Claudia S; Mussolino, Michael E; Nichol, Graham; Paynter, Nina P; Schreiner, Pamela J; Sorlie, Paul D; Stein, Joel; Turan, Tanya N; Virani, Salim S; Wong, Nathan D; Woo, Daniel; Turner, Melanie B; American Heart Association Statistics Committee and Stroke Statistics Subcommittee

Vitamin D Deficiency and Risk of Cardiovascular Disease

Background— Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes. A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. Methods and Results— We studied 1739 Framingham Offspring Study participants (mean age 59 years; 55% women; all white) without prior cardiovascular disease. Vitamin D status was assessed by measuring 25-dihydroxyvitamin D (25-OH D) levels. Prespecified thresholds were used to characterize varying degrees of 25-OH D deficiency (<15 ng/mL, <10 ng/mL). Multivariable Cox regression models were adjusted for conventional risk factors. Overall, 28% of individuals had levels <15 ng/mL, and 9% had levels <10 ng/mL. During a mean follow-up of 5.4 years, 120 individuals developed a first cardiovascular event. Individuals with 25-OH D <15 ng/mL had a multivariable-adjusted hazard ratio of 1.62 (95% confidence interval 1.11 to 2.36, P=0.01) for incident cardiovascular events compared with those with 25-OH D ≥15 ng/mL. This effect was evident in participants with hypertension (hazard ratio 2.13, 95% confidence interval 1.30 to 3.48) but not in those without hypertension (hazard ratio 1.04, 95% confidence interval 0.55 to 1.96). There was a graded increase in cardiovascular risk across categories of 25-OH D, with multivariable-adjusted hazard ratios of 1.53 (95% confidence interval 1.00 to 2.36) for levels 10 to <15 ng/mL and 1.80 (95% confidence interval 1.05 to 3.08) for levels <10 ng/mL (P for linear trend=0.01). Further adjustment for C-reactive protein, physical activity, or vitamin use did not affect the findings. Conclusions— Vitamin D deficiency is associated with incident cardiovascular disease. Further clinical and experimental studies may be warranted to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.

Lifetime Risk for Developing Congestive Heart Failure The Framingham Heart Study

Background—Congestive heart failure (CHF) is an increasing public health problem. Methods and Results—Among Framingham Heart Study subjects who were free of CHF at baseline, we determined the lifetime risk for developing overt CHF at selected index ages. We followed 3757 men and 4472 women from 1971 to 1996 for 124 262 person-years; 583 subjects developed CHF and 2002 died without prior CHF. At age 40 years, the lifetime risk for CHF was 21.0% (95% CI 18.7% to 23.2%) for men and 20.3% (95% CI 18.2% to 22.5%) for women. Remaining lifetime risk did not change with advancing index age because of rapidly increasing CHF incidence rates. At age 80 years, the lifetime risk was 20.2% (95% CI 16.1% to 24.2%) for men and 19.3% (95% CI 16.5% to 22.2%) for women. Lifetime risk for CHF doubled for subjects with blood pressure ≥160/100 versus <140/90 mm Hg. In a secondary analysis, we only considered those who developed CHF without an antecedent myocardial infarction; at age 40 years, the lifetime risk for CHF was 11.4% (95% CI 9.6% to 13.2%) for men and 15.4% (95% CI 13.5% to 17.3%) for women. Conclusions—When established clinical criteria are used to define overt CHF, the lifetime risk for CHF is 1 in 5 for both men and women. For CHF occurring in the absence of myocardial infarction, the lifetime risk is 1 in 9 for men and 1 in 6 for women, which highlights the risk of CHF that is largely attributable to hypertension. These results should assist in predicting the population burden of CHF and placing greater emphasis on prevention of CHF through hypertension control and prevention of myocardial infarction.

Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death

OBJECTIVESnThis study examined the relations of echocardiographically determined left ventricular (LV) mass and hypertrophy to the risk of sudden death.nnnBACKGROUNDnEchocardiographic LV hypertrophy is associated with increased risk for all-cause mortality and cardiovascular disease morbidity and mortality. However, little is known about the association of echocardiographic LV hypertrophy with sudden death.nnnMETHODSnWe examined the relations of LV mass and hypertrophy to the incidence of sudden death in 3,661 subjects enrolled in the Framingham Heart Study who were > or =40 years of age. The baseline examination was performed from 1979 to 1983 and LV hypertrophy was defined as LV mass (adjusted for height) > 143 g/m in men and > 102 g/m in women. During up to 14 years of follow-up there were 60 sudden deaths. Cox models examined the relations of LV mass and LV hypertrophy to sudden death risk after adjusting for known risk factors.nnnRESULTSnThe prevalence of LV hypertrophy was 21.5%. The risk factor-adjusted hazard ratio (HR) for sudden death was 1.45 (95% confidence interval [CI] 1.10 to 1.92, p=0.008) for each 50-g/m increment in LV mass. For LV hypertrophy, the risk factor-adjusted HR for sudden death was 2.16 (95% CI 1.22 to 3.81, p=0.008). After excluding the first 4 years of follow-up, both increased LV mass and LV hypertrophy conferred long-term risk of sudden death (HR 1.53, 95% CI 1.01 to 2.28, p=0.047 and HR 3.28, 95% CI 1.58 to 6.83, p=0.002, respectively).nnnCONCLUSIONSnIncreased LV mass and hypertrophy are associated with increased risk for sudden death after accounting for known risk factors.

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

Summary Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125u2008222 participants. We also compared the frequency of Asp358Ala in 51u2008441 patients with coronary heart disease and in 136u2008226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

Why Is Left Ventricular Hypertrophy So Predictive of Morbidity and Mortality

The prevalence, prognosis, and predictors of left ventricular hypertrophy (LVH) are reviewed, and theories of the pathogenesis of the relation between LVH and poor prognosis are summarized to highlight controversies in the field. In the Framingham Heart Study, which consists largely of white people, echocardiographic LVH has a prevalence of 14% in men and 18% in women. The prevalence of LVH is reported to be elevated in African Americans compared with whites, although the higher prevalence has been attributed to the increased prevalence of hypertension and obesity. Echocardiographic LVH is independently associated with a variety of cardiovascular endpoints, including coronary heart disease and stroke. Furthermore, after adjusting for other cardiovascular disease risk factors, LVH is associated with a doubling in mortality in both white and African American cohorts. Despite the intensive investigation of LVH, there remain many unanswered questions: To what extent do genetic or other factors account for the large portion of the variance in LVH that remains unexplained? What is the prognosis of LVH and left ventricular geometry in a population-based African American cohort? How does the development and progression of LVH relate to other risk factors and their treatment? What is the relation of LVH to poor prognosis? The proposed Jackson Heart Study will help address many important unanswered questions regarding LVH.

European Ancestry as a Risk Factor for Atrial Fibrillation in African Americans

Background— Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF. Methods and Results— We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results. Conclusions— European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.

Cardiovascular Risk Factors Predictive for Survival and Morbidity-Free Survival in the Oldest-Old Framingham Heart Study Participants

Objectives: To examine whether midlife cardiovascular risk factors predict survival and survival free of major comorbidities to the age of 85.

Risk factors for syncope in a community-based sample (the Framingham Heart Study).

The epidemiology of syncope has not been well described. Prior studies have examined risk factors for syncope in hospital-based or other acute or long-term care settings. To determine risk factors for syncope in a community-based sample, we performed a nested case-control study. We examined reports of syncope in Framingham Heart Study participants who underwent routine clinic visits from 1971 to 1990. For each syncope case (n = 543) 2 controls were matched for age, sex, and examination period. Mean age of subjects was 67 years (range 25 to 95); 59% were women. History of stroke or transient ischemic attack, history of myocardial infarction, high blood pressure, use of antihypertensive medication, use of other cardiac medication, smoking, alcohol intake, body mass index, systolic blood pressure, diastolic blood pressure, heart rate, atrial fibrillation, PR interval prolongation, interventricular block, and diabetes or elevated glucose level were examined as potential predictors. Using conditional logistic regression analysis, the predictors of syncope included a history of stroke or transient ischemic attack (odds ratio [OR] 2.56, 95% confidence interval [CI] 1.62 to 4.04), use of cardiac medication (OR 1.67, 95% CI 1.21 to 2. 30), and high blood pressure (OR 1.46, 95% CI 1.14 to 1.88). Lower body mass index was marginally associated with syncope (OR per 4 kg/m(2) decrement 1.10, 95% CI 0.99 to 1.22), as were increased alcohol intake (OR per 5 oz/week 1.11, 95% CI 0.99 to 1.26), and diabetes or an elevated glucose level (OR 1.29, 95% CI 0.96 to 1.75). To our knowledge, this study represents the first community-based study of risk factors for syncope.

Genetic association analyses highlight biological pathways underlying mitral valve prolapse

Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1−/− mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair.