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Concept: Coronary artery disease

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Background Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown. Methods Using a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts - 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women’s Genome Health Study (WGHS), and 22,389 in the Malmö Diet and Cancer Study (MDCS) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet. Results The relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category. Conclusions Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.).

Concepts: Genetics, Epidemiology, Nutrition, Atherosclerosis, Angina pectoris, Coronary artery disease, Atheroma, Artery

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To determine whether dietary pattern assessed by a simple self-administered food frequency questionnaire is associated with major adverse cardiovascular events (MACE) in high-risk patients with stable coronary artery disease.

Concepts: Atherosclerosis, Coronary artery disease, Heart, Blood vessel, Heart disease, Artery, Coronary circulation, Cardiovascular system

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We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population. Next, we used iGWAS to harness information from 14 meta-analyses of disease and trait GWAS to identify longevity loci in two studies of long-lived humans. In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40) when controlling the false discovery rate (FDR) at 10%. With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity at FDR < 10%. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated (FDR < 5%) included APOE/TOMM40 (associated with Alzheimer's disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease). Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits, including coronary artery disease and Alzheimer's disease. iGWAS provides a new analytical strategy for uncovering SNPs that influence extreme longevity, and can be applied more broadly to boost power in other studies of complex phenotypes.

Concepts: Alzheimer's disease, Gene, Cancer, Senescence, Atherosclerosis, Coronary artery disease, Gerontology, Aging-associated diseases

233

A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.

Concepts: Gene, Genetics, Epidemiology, Natural selection, Evolution, Atherosclerosis, Coronary artery disease, United Kingdom

173

Volumes of paracardial adipose tissue (PAT) and epicardial adipose tissue (EAT) are greater after menopause. Interestingly, PAT but not EAT is associated with estradiol decline, suggesting a potential role of menopause in PAT accumulation. We assessed whether volumes of heart fat depot (EAT and PAT) were associated with coronary artery calcification (CAC) in women at midlife and whether these associations were modified by menopausal status and estradiol levels.

Concepts: Hormone replacement therapy, Coronary artery disease, Middle age, Heart, Menopause, Estrogen, Luteinizing hormone, Menstrual cycle

169

BACKGROUND: Approximately 2/3 of Veterans admitting to Veterans Health Administration (VHA) facilities present >12 hours after symptom onset of acute myocardial infarction (AMI) (“late presenters”). Veterans admitted to VHA facilities with AMI may delay hospital presentation for different reasons compared to their general population counter parts. Despite the large descriptive literature on factors associated with delayed presentation in the general population, the literature describing these factors among the Veteran AMI population is limited. The purpose of this analysis is to identify predictors of late presentation in the Veteran population presenting with AMI to VHA facilities. Identifying predictors will help inform and target interventions for Veterans at a high risk of late presentation. METHODS: In our cross-sectional study, we analyzed a cohort of 335 male Veterans from nine VHA facilities with physician diagnosed AMI between April 2005 and December 2006. We compared demographics, presentation characteristics, medical history, perceptions of health, and access to health care between early and late presenting Veterans. We used standard descriptive statistics for bivariate comparisons and multivariate logistic regression to identify independent predictors of late presentation. RESULTS: Our cohort was an average of 64 +/- 10.5 years old and was 88% white. Sixty-eight percent of our cohort were late presenters. Bivariate comparisons found that fewer late presenters had attended at least some college or vocational school (late 53.2% vs. early 66%, p = 0.02). Multivariate analysis showed that presentation with ST-elevation myocardial infarction (STEMI) was associated with early presentation (OR = 0.43 95%CI [0.2, 0.9]) and >=2 angina episodes in the prior 24 hours (versus 0-1 episode) was associated with late presentation (OR = 7.5 95%CI [3.6,15.6]). CONCLUSIONS: A significant majority of Veterans presenting to VHA facilities with AMI were late presenters. We found few differences between early and late presenters. Having a STEMI was independently associated with early presentation and reporting >=2 angina episodes in the 24 hours prior to hospital admission was independently associated with late presentation. These independent predictors of early and late presentation are similar to what has been reported for the general population. Despite these similarities to the general population, there may be untapped opportunities for patient education within the VHA to decrease late presentation.

Concepts: Myocardial infarction, Atherosclerosis, Coronary artery disease, Infarction, Troponin, United States Department of Veterans Affairs, Veterans Health Administration, Cardiac stress test

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Although drug-eluting stents have dramatically reduced angiographic restenosis and clinical need for repeat revascularization procedures, some adverse effects, such as late stent thrombosis, have been described. We evaluated clinical performance of paclitaxel-eluting stents coated with a new bioactive polymer system (P-5) based on a copolymer of an acrylic derivative of triflusal in patients with coronary artery disease.

Concepts: Atherosclerosis, Coronary artery disease, Cardiology, Atheroma, Artery, Stent, Cardiovascular system, Drug-eluting stent

162

The objective of this prospective study was to assess the prevalence of anxiety and depression disorders and their association with quality of life (QoL), clinical parameters and survival in patients with pulmonary hypertension (PH).

Concepts: Pulmonology, Myocardial infarction, Coronary artery disease, Cardiology, Blood pressure, Chronic obstructive pulmonary disease, Pulmonary artery, Pulmonary hypertension

151

Prolonged QRS duration is a predictor of poor prognosis in patients with coronary artery disease. The association between the duration of QRS and myocardial reperfusion is not very well understood. Our aim was to assess the relationship between the measurements of QRS duration and myocardial blush grade (MBG) in patients with ST elevation myocardial infarction (STEMI) who were treated with a primary percutaneous intervention.

Concepts: Myocardial infarction, Atherosclerosis, Angina pectoris, Coronary artery disease, Heart, Percutaneous coronary intervention, Atheroma, Artery

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Background In patients with coronary artery disease who receive metallic drug-eluting coronary stents, adverse events such as late target-lesion failure may be related in part to the persistent presence of the metallic stent frame in the coronary-vessel wall. Bioresorbable vascular scaffolds have been developed to attempt to improve long-term outcomes. Methods In this large, multicenter, randomized trial, 2008 patients with stable or unstable angina were randomly assigned in a 2:1 ratio to receive an everolimus-eluting bioresorbable vascular (Absorb) scaffold (1322 patients) or an everolimus-eluting cobalt-chromium (Xience) stent (686 patients). The primary end point, which was tested for both noninferiority (margin, 4.5 percentage points for the risk difference) and superiority, was target-lesion failure (cardiac death, target-vessel myocardial infarction, or ischemia-driven target-lesion revascularization) at 1 year. Results Target-lesion failure at 1 year occurred in 7.8% of patients in the Absorb group and in 6.1% of patients in the Xience group (difference, 1.7 percentage points; 95% confidence interval, -0.5 to 3.9; P=0.007 for noninferiority and P=0.16 for superiority). There was no significant difference between the Absorb group and the Xience group in rates of cardiac death (0.6% and 0.1%, respectively; P=0.29), target-vessel myocardial infarction (6.0% and 4.6%, respectively; P=0.18), or ischemia-driven target-lesion revascularization (3.0% and 2.5%, respectively; P=0.50). Device thrombosis within 1 year occurred in 1.5% of patients in the Absorb group and in 0.7% of patients in the Xience group (P=0.13). Conclusions In this large-scale, randomized trial, treatment of noncomplex obstructive coronary artery disease with an everolimus-eluting bioresorbable vascular scaffold, as compared with an everolimus-eluting cobalt-chromium stent, was within the prespecified margin for noninferiority with respect to target-lesion failure at 1 year. (Funded by Abbott Vascular; ABSORB III ClinicalTrials.gov number, NCT01751906 .).

Concepts: Myocardial infarction, Atherosclerosis, Angina pectoris, Coronary artery disease, Cardiology, Heart, Atheroma, Artery