Nona Sotoodehnia

Heart Disease and Stroke Statistics—2012 Update A Report From the American Heart Association

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e3 1. About These Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e7 2. American Heart Associations 2020 Impact Goals. . . . . . . . . . . . . . . . .e10 3. Cardiovascular Diseases . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . .e21 4. Subclinical Atherosclerosis . . . . . . . . . . . . . . . . . . . . .e45 5. Coronary Heart Disease, Acute Coronary Syndrome, and Angina Pectoris . . . . . . . . .e54 6. Stroke (Cerebrovascular Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . .e68 7. High Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .e88 8. Congenital Cardiovascular Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . .e97 9. Cardiomyopathy and Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . .e102 10. Disorders …

Systematic Localization of Common Disease-Associated Variation in Regulatory DNA

Predictions of Genetic Disease Many genome-wide association studies (GWAS) have identified loci and variants associated with disease, but the ability to predict disease on the basis of these genetic variants remains small. Maurano et al. (p. 1190; see the Perspective by Schadt and Chang; see the cover) characterize the location of GWAS variants in the genome with respect to their proximity to regulatory DNA [marked by deoxyribonuclease I (DNase I) hypersensitive sites] by tissue type, disease, and enrichments in physiologically relevant transcription factor binding sites and networks. They found many noncoding disease associations in regulatory DNA, indicating tissue and developmental-specific regulatory roles for many common genetic variants and thus enabling links to be made between gene regulation and adult-onset disease. Genetic variants that have been associated with diseases are concentrated in regulatory regions of the genome. Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure–related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn’s disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.

Common variants at ten loci influence QT interval duration in the QTGEN Study.

QT interval duration reflecting myocardial repolarization on the electrocardiogram is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of 3 genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study. We observed associations at P < 5×10−8 with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and Mendelian Long QT Syndromes. Associations at five novel loci included 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RIFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4–6.5% of variation in QT interval. Identifying the causal variants and defining their impact on myocardial repolarization may add incrementally to the prevention of sudden cardiac death and drug-induced arrhythmias.QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 × 10−8 with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4–6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

Meta-analysis identifies six new susceptibility loci for atrial fibrillation

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10−8). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

Sudden Cardiac Death Prediction and Prevention Report From a National Heart, Lung, and Blood Institute and Heart Rhythm Society Workshop

Despite the significant decline in coronary artery disease (CAD) mortality in the second half of the 20th century,1 sudden cardiac death (SCD) continues to claim 250 000 to 300 000 US lives annually.2 In North America and Europe the annual incidence of SCD ranges between 50 to 100 per 100 000 in the general population.3,–,6 Because of the absence of emergency medical response systems in most world regions, worldwide estimates are currently not available.7 However, even in the presence of advanced first responder systems for resuscitation of out-of-hospital cardiac arrest, the overall survival rate in a recent North American analysis was 4.6%.8 SCD can manifest as ventricular tachycardia (VT), ventricular fibrillation (VF), pulseless electric activity (PEA), or asystole. In a significant proportion of patients, SCD can present without warning or a recognized triggering mechanism. The mean age of those affected is in the mid 60s, and at least 40% of patients will suffer SCD before the age of 65.4 Consequently, enhancement of methodologies for prediction and prevention of SCD acquires a unique and critical importance for management of this significant public health issue. Prediction and prevention of SCD is an area of active investigation, but considerable challenges persist that limit the efficacy and cost-effectiveness of available methodologies.7,9,10 It was recognized early on that optimization of SCD risk stratification will require integration of multi-disciplinary efforts at the bench and bedside, with studies in the general population.11,–,13 This integration has yet to be effectively accomplished. There is also increasing awareness that more investigation needs to be directed toward identification of early predictors of SCD.14 Significant advancements have occurred for risk prediction in the inherited channelopathies15,–,17 and …

Genome-wide association study of PR interval

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 × 10−8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 × 10−7). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 × 10−11; combined RR = 1.25; combined P = 1.8 × 10−15).

Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium

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.

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.

Plasma phospholipid Trans fatty acids, fatal ischemic heart disease, and sudden cardiac death in older adults : The cardiovascular health study

Background— Intake of trans fatty acids is associated with increased risk of coronary heart disease. Whether different classes of trans fatty acids show similar associations is unclear. We previously reported an association of sudden cardiac death with red cell membrane trans-18:2 but not trans-18:1 fatty acids. To extend these findings, we investigated the associations of plasma phospholipid trans fatty acids with fatal ischemic heart disease (IHD) and sudden cardiac death. Methods and Results— We conducted a case-control study nested in the Cardiovascular Health Study. We identified 214 cases of fatal IHD (fatal myocardial infarction and coronary heart disease death) between 1992 and 1998. We randomly selected 214 controls, matched to cases on demographics, prevalent cardiovascular disease, and timing of blood draw. Plasma phospholipid fatty acids were assessed in blood samples collected earlier. Higher levels of plasma phospholipid trans-18:2 fatty acids were associated with higher risk of fatal IHD (odds ratio [OR] for interquintile range 1.68, 95% confidence interval [CI] 1.21 to 2.33) after adjustment for risk factors and trans-18:1 levels. Trans-18:1 levels above the 20th percentile were associated with lower risk (OR 0.34, 95% CI 0.18 to 0.63). In analyses limited to cases of sudden cardiac death (n=95), higher levels of trans-18:2 fatty acids were associated with higher risk (OR 2.34, 95% CI 1.27 to 4.31) and higher trans-18:1 with lower risk (OR 0.18, 95% CI 0.06 to 0.54). Conclusions— Higher levels of trans-18:2 and lower levels of trans-18:1 fatty acids are associated with higher risks of fatal IHD and sudden cardiac death. If confirmed, these findings suggest that current efforts at decreasing trans fatty acid intake in foods should take into consideration the trans-18:2 content.