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Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial. In TRA 2°P-TIMI 50—a randomised, placebo-controlled, parallel trial—we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474). 17 779 of 26 449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2·5 years (IQR 2·0–2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8·1%vs 9·7%, HR 0·80, 95% CI 0·72–0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3·4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2·1%, 3-year Kaplan-Meier estimate], HR 1·61, 95% CI 1·31–1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups. For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding. Merck.

Although substantial progress has been made in the diagnosis and treatment of acute coronary syndromes, cardiovascular disease remains the leading cause of death globally, with nearly half of these deaths due to ischaemic heart disease. The broadening availability of high-sensitivity troponin assays has allowed for rapid rule-out algorithms in patients with suspected non-ST-segment elevated myocardial infarction (NSTEMI). Dual antiplatelet therapy is recommended for 12 months following an acute coronary syndrome in most patients, and additional secondary prevention measures including intensive lipid-lowering therapy (LDL-C <1·4 mmol/L), neurohormonal agents, and lifestyle modification, are crucial. The scientific evidence for diagnosis and management of acute coronary syndromes continues to evolve rapidly, including adapting to the COVID-19 pandemic, which has impacted all aspects of care. This Seminar provides a clinically relevant overview of the pathobiology, diagnosis, and management of acute coronary syndromes, and describes key scientific advances.

Searching for genes in which loss-of-function mutations confer protection against disease is a strategy to identity drug targets. This study reports an association between loss-of-function mutations in ANGPTL4 and protection against coronary artery disease. Although genomewide association studies have identified more than 56 loci associated with the risk of coronary artery disease, 1 – 3 the disease-associated variants are typically common (minor-allele frequency >5%) and located in noncoding sequences; this has made it difficult to pinpoint causal genes and affected pathways. This lack of a causal mechanism has in part hindered the immediate translation of the findings of genomewide association studies into new therapeutic targets. However, the discovery of rare or low-frequency coding-sequence variants that affect the risk of coronary artery disease has facilitated advances in the prevention and treatment of disease. The most recent example . . .

Inactivating mutations in NPC1L1 were identified on exon sequencing and genotyping in 16 cohorts of patients with coronary heart disease and controls. Mutation carriers had lower LDL cholesterol levels and a lower risk of coronary heart disease than did noncarriers. Ezetimibe, a drug that is commonly prescribed to reduce plasma levels of low-density lipoprotein (LDL) cholesterol, inhibits the function of the protein encoded by the Niemann–Pick C1-like 1 gene ( NPC1L1 ). 1 NPC1L1 protein, which is expressed in the small intestine and liver, functions as a transporter of dietary cholesterol from the gut lumen into intestinal enterocytes. 2 , 3 Because of its ability to block sterol absorption by about 50%, 4 ezetimibe lowers plasma LDL cholesterol levels by 15 to 20%. 5 However, it is uncertain whether inhibiting NPC1L1 — either through ezetimibe treatment or by other means — reduces the risk of . . .

The Tobacco and Genetics Consortium report meta-analyses of several smoking phenotypes across 16 cohorts including 74,053 individuals. They identify three loci associated with cigarettes smoked per day. Consistent but indirect evidence has implicated genetic factors in smoking behavior 1 , 2 . We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium ( n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions ( n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], β = 1.03, standard error (s.e.) = 0.053, P = 2.8 × 10 −73 ). Two 10q25 SNPs (rs1329650[G], β = 0.367, s.e. = 0.059, P = 5.7 × 10 −10 ; and rs1028936[A], β = 0.446, s.e. = 0.074, P = 1.3 × 10 −9 ) and one 9q13 SNP in EGLN2 (rs3733829[G], β = 0.333, s.e. = 0.058, P = 1.0 × 10 −8 ) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04–1.08, P = 1.8 × 10 −8 ). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08–1.18, P = 3.6 × 10 −8 ) was significantly associated with smoking cessation.

Aims/hypothesisWomen remain underrepresented in clinical trials and those with type 2 diabetes mellitus are at high risk for cardiovascular (CV) events. The sodium–glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin reduces the risk of CV death or heart failure hospitalisations in individuals with type 2 diabetes. Here, we performed a pre-specified analysis to examine whether sex modifies these effects.MethodsThe DECLARE-TIMI 58 trial randomised 17,160 patients with type 2 diabetes with or at risk for atherosclerotic disease to dapagliflozin or placebo (median follow-up 4.2 years). The dual efficacy outcomes were CV death or heart failure hospitalisations, and major adverse cardiovascular events (MACE; CV death, myocardial infarction or ischaemic stroke). The renal-specific composite outcome was a sustained ≥40% drop in eGFR to <60 ml min−1 [1.73 m]−2, new end-stage renal disease or renal death. Cox models were run separately by sex with treatment-by-sex interaction testing for each outcome.ResultsAt baseline, women (n = 6422, 37.4%) had higher HbA1c, longer type 2 diabetes duration, and were on fewer glucose-lowering medications. There was no evidence of modification of the effect of dapagliflozin by sex for (1) CV death or heart failure hospitalisations: women (3.8% vs 4.5%; HR 0.84, 95% CI 0.66, 1.07) and men (5.3% vs 6.4%; HR 0.83, 95% CI 0.71, 0.96; pinteraction = 0.90); (2) MACE: women (6.3% vs 6.8%; HR 0.93, 95% CI 0.77, 1.12) and men (10.0% vs 10.7%; HR 0.93, 95% CI 0.83, 1.05; pinteraction = 0.99); or (3) renal-specific composite: women (1.4% vs 2.8%; HR 0.50, 95% CI 0.35, 0.70) and men (1.5% vs 2.5%; HR 0.55, 95% CI 0.42, 0.73; pinteraction = 0.64). The overall safety profile of dapagliflozin was similar for women and men.Conclusions/interpretationDapagliflozin offers comparable CV and renal benefits and a comparable safety profile in women and men.FundingAstraZeneca.Trial registrationclinicaltrials.gov NCT01730534.

Jeanette Erdmann and colleagues identify a locus on chromosome 3q22.3 associated with coronary artery disease. The SNP with the strongest association is in MRAS , which encodes a membrane-anchored GTP-binding protein. We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in ∼25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS ( P = 7.44 × 10 −13 ; OR = 1.15, 95% CI = 1.11–1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 ( P = 4.81 × 10 −7 ; OR = 1.08, 95% CI = 1.05–1.11).

Atherosclerosis is a chronic and progressive inflammatory process beginning early in life with late clinical manifestation. This slow pathological trend underlines the importance to early identify high-risk patients and to treat intensively risk factors to prevent the onset and/or the progression of atherosclerotic lesions. In addition to the common Cardiovascular (CV) risk factors, new markers able to increase the risk of CV disease have been identified. Among them, high levels of Lipoprotein(a)—Lp(a)—lead to very high risk of future CV diseases; this relationship has been well demonstrated in epidemiological, mendelian randomization and genome-wide association studies as well as in meta-analyses. Recently, new aspects have been identified, such as its association with aortic stenosis. Although till recent years it has been considered an unmodifiable risk factor, specific drugs have been developed with a strong efficacy in reducing the circulating levels of Lp(a) and their capacity to reduce subsequent CV events is under testing in ongoing trials. In this paper we will review all these aspects: from the synthesis, clearance and measurement of Lp(a), through the findings that examine its association with CV diseases and aortic stenosis to the new therapeutic options that will be available in the next years.

The aim of this study was to assess recent trends in hospital mortality and in the treatment techniques for patients with ST-segment elevation myocardial infarction according to gender. Data on hospitalizations for ST-segment elevation myocardial infarction from 2000 to 2010 were extracted from hospital discharge record databases (International Classification of Diseases, Ninth Revision, Clinical Modification, codes) in the Lombardy Region of Italy. The impact of female gender on in-hospital mortality was assessed by multivariable regression after adjusting for invasive approach use (i.e., coronary angiography, angioplasty or coronary artery bypass graft), age, and co-morbidities. A total of 89,562 patients, men (66.5%) and women (33.5%), were enrolled. The use of an invasive approach increased over time in both sexes although it was higher in men (from 54.9% in 2000 to 91.9% in 2010 in men; from 36.8% in 2000 to 72.0% in 2010 in women). This pattern was driven by the subgroup of patients aged ≥75 years, whereas differences between sexes were not observed in patients <65 years and were small in patients aged 65 to 74 years. In-hospital mortality presented a small decrease from 7.6% in 2000 to 6.2% in 2010 in men (p for trend = 0.004), whereas it remained higher and substantially constant over time in women (16.6% in 2000, 15.5% in 2010, p for trend = 0.09). At multivariable regression, female gender did not emerge as an independent predictor of mortality (p = 0.13). However, a significant gender-age interaction was found, with female gender being a significant predictor of increased mortality in patients aged ≥75 years (odds ratio [OR] 1.33) while predicting a reduced mortality in patients aged <75 years (OR 0.93, p for interaction <0.0001). The use of an invasive approach was an independent predictor of mortality (OR 0.23, p <0.0001), the magnitude of mortality reduction being higher in men than in women and in patients aged <75 years than in those aged ≥75 years. In conclusion, a weak temporal trend in mortality reduction is observed in men only, which is driven by patients aged ≥75 years. In-hospital mortality remains higher in women than in men, although female gender is not a significant predictor of mortality. Despite temporal increases in the use of an invasive approach, women are more often treated conservatively.