BACKGROUND: An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS: We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS: Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS: We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease

Background-Circulating cardiac troponin T, a marker of cardiomyocyte injury, predicts adverse outcome in patients with heart failure (HF) but is detectable in only a small fraction of those with chronic stable HF. We assessed the prognostic value of circulating cardiac troponin T in patients with stable chronic HF with a traditional (cTnT) and a new precommercial highly sensitive assay (hsTnT). Methods and Results-Plasma troponin T was measured in 4053 patients with chronic HF enrolled in the Valsartan HeartFailure Trial (Val-HeFT). Troponin T was detectable in 10.4% of the population with the cTnT assay (detection limit Յ0.01 ng/mL) compared with 92.0% with the new hsTnT assay (Յ0.001 ng/mL). Patients with cTnT elevation or with hsTnT above the median (0.012 ng/mL) had more severe HF and worse outcome. In Cox proportional hazards models adjusting for clinical risk factors, cTnT was associated with death (780 events; hazard ratioϭ2. Key Words: heart failure Ⅲ natriuretic peptides Ⅲ prognosis Ⅲ troponin C ardiac troponins I and T (cTnT) are sensitive and specific markers of myocardial injury used routinely for the diagnosis of acute coronary syndromes. 1-5 Elevated troponin blood levels have been reported in several cohorts of patients with heart failure (HF), and the magnitude of elevation has been correlated with the severity of the disease and with adverse outcomes. 6 -16 Because of their high cardiac specificity, elevated troponins in patients with HF may suggest ongoing myocardial damage and may serve as a marker for the progression of HF. Measurement of troponin has been proposed since 1997 to monitor patients with HF. 17,18 The prevalence of elevated troponin T in the general population is Ͻ1% and is associated with underlying cardiovascular disease or high-risk phenotypes. 19 Editorial p 1217 Clinical Perspective p 1249The levels of cardiac troponins in HF are generally lower than those in patients with acute coronary syndromes and lack the characteristic rise and fall pattern. 4 Few reports exist on cTnT elevations in chronic stable HF. 6,8,16,20 Previous studies included more frequently patients with severe HF (New York Heart Association [NYHA] class III and IV) and/or with decompensated HF, recruited in a single center. 6,8,10,11,15,16 As expected, lesser severity of HF is associated with a larger fraction of patients with undetectable troponin. The commercial assays for troponins have sufficient sensitivity (0.01 ng/mL) for screening patients with suspected myocardial infarction 21 but may be inadequate for risk stratification of patients with stable chronic HF who may have levels below Methods Study Design and PatientsVal-HeFT was a randomized, placebo-controlled, double-blind, parallel-arm multicenter trial of 5010 patients with stable, symptomatic HF, who were on prescribed HF therapy. The patients had a left ventricular ejection fraction (LVEF) Ͻ40% and a left ventricular diameter in diastole adjusted for body surface area (LVIDD/BSA) Ն2.9 cm/m 2 . Results of the main trial have been published....

BACKGROUNDThe risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail. METHODSWe analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter-defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization. RESULTSSudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P = 0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer-standing diagnosis. CONCLUSIONSRates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence-based medications on this cause of death. (Funded by the China Scholarship Council and the University of Glasgow.)A BS TR AC T

Serial determinations of NT-proBNP concentration and classification into few categories of changes according to threshold levels may be a superior strategy for risk stratification of patients with chronic and stable HF.

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Stratification by baseline severity of remodeling showed that patients with worse LVIDd and EF are at highest risk for an event, yet appear to gain the most anti-remodeling effect and clinical benefit with valsartan treatment.

In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. (Funded by Società Prodotti Antibiotici and others; ClinicalTrials.gov number, NCT00317707.).