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New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin.

ABSTRACT: Although a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events (MACE) in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI), these genotypes account for only a small fraction of the variation and evidence is insufficient. This study aims to identify new genetic variants associated with MACE end point during the 18-month follow-up period by a two-stage large-scale sequencing data, including high-depth whole exome sequencing of 168 patients in the discovery cohort and high-depth targeted sequencing of 1793 patients in the replication cohort. We discovered eight new genotypes and their genes associated with MACE in patients with ACS, including MYOM2 (rs17064642), WDR24 (rs11640115), NECAB1 (rs74569896), EFR3A (rs4736529), AGAP3 (rs75750968), ZDHHC3 (rs3749187), ECHS1 (rs140410716), and KRTAP10-4 (rs201441480). Notably, the expressions of MYOM2 and ECHS1 are downregulated in both animal models and patients with phenotypes related to MACE. Importantly, we developed the first superior classifier for predicting 18-month MACE and achieved high predictive performance (AUC ranged between 0.92 and 0.94 for three machine-learning methods). Our findings shed light on the pathogenesis of cardiovascular outcomes and may help the clinician to make a decision on the therapeutic intervention for ACS patients.

SUBMITTER: Liu X

PROVIDER: S-EPMC8602039 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin.

Liu Xiaomin X Xu Hanshi H Xu Huaiqian H Geng Qingshan Q Mak Wai-Ho WH Ling Fei F Su Zheng Z Yang Fang F Zhang Tao T Chen Jiyan J Yang Huanming H Wang Jian J Zhang Xiuqing X Xu Xun X Jia Huijue H Zhang Zhiwei Z Liu Xiao X Zhong Shilong S

The pharmacogenomics journal 20210622 6

Although a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events (MACE) in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI), these genotypes account for only a small fraction of the variation and evidence is insufficient. This study aims to identify new genetic variants associated with MACE end point during the 18-month follow-up period by a two-stage large-scale sequencing data, including h ...[more]

PMID: 34158603

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Project description:ImportanceGuidelines currently recommend ticagrelor over clopidogrel for patients with acute coronary syndrome (ACS) based on randomized clinical trial data in which ticagrelor reduced major adverse coronary events (MACE) vs clopidogrel but increased bleeding and dyspnea.ObjectiveTo compare the risk of MACE with ticagrelor vs clopidogrel in patients with ACS treated with percutaneous coronary intervention (PCI), to compare major bleeding and dyspnea, and to evaluate the association between P2Y12 inhibitor adherence and MACE.Design, setting, and participantsPopulation-based cohort study using data of patients discharged alive after PCI for ACS from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry from April 1, 2012, to March 31, 2016, with follow-up to 1 year. Analysis began April 2018.ExposuresOutpatient prescription for ticagrelor or clopidogrel within 31 days after PCI. Adherence was defined as a medication refill adherence value of 80% or higher.Main outcomes and measuresMajor adverse coronary events, a composite of all-cause death, hospitalization for ACS, unplanned coronary revascularization, or stent thrombosis within 365 days after index PCI. Secondary outcomes included hospitalization for major bleeding and emergency department visit for dyspnea.ResultsOf 11 185 individuals who underwent PCI, the median (interquartile range) age was 61 (54-71) years, and 2760 (24.7%) were women. Ticagrelor users (4076 [36.4%]) were generally younger and had fewer cardiac and noncardiac comorbidities than clopidogrel users. Ticagrelor was not associated with lower risk of MACE (adjusted hazard ratio [aHR], 0.97; 95% CI, 0.85-1.10); however, it was associated with an increased risk of major bleeding (aHR, 1.51; 95% CI, 1.29-1.78) and dyspnea (aHR, 1.98; 95% CI, 1.47-2.65). A total of 3328 ticagrelor users (81.6%) were adherent during the study vs 5256 of clopidogrel users (73.9%) (P < .001; χ2 = 86.4). In the full cohort, adherence was associated with a lower MACE risk (aHR, 0.79; 95% CI, 0.69-0.90 for adherence of ≥80% vs <80%). Differences in other secondary outcomes were not statistically significant. Sensitivity and subgroup analyses were consistent with primary analyses.Conclusions and relevanceIn this population-based cohort study of patients with ACS who underwent PCI, outpatient use of ticagrelor was not associated with a statistically significant reduction in MACE vs clopidogrel; however, it was associated with more major bleeding and dyspnea.

Project description:Background & aimsHepatic steatosis has been associated with increased risk of major adverse cardiovascular events (MACE) but it is not clear whether steatosis is independently associated with risk of MACE. We investigated whether steatosis is associated with risk of MACE independently of the presence and extent of baseline coronary artery disease, assessed by comprehensive contrast-enhanced computed tomography angiography (CTA).MethodsWe conducted a nested cohort study of 3756 subjects (mean age, 60.6 years; 48.4% men) who underwent coronary CTA at 193 sites in North America, from July 2010 through September 2013, as part of the PROMISE study, which included noninvasive cardiovascular analyses of symptomatic outpatients without coronary artery disease. Independent core laboratory readers measured hepatic and splenic attenuation, using non-contrast computed tomography images to identify steatosis, and evaluated coronary plaques and stenosis in coronary CTA images. We collected data on participants' cardiovascular risk factors, presence of metabolic syndrome, and body mass index. The primary endpoint was an adjudicated composite of MACE (death, myocardial infarction, or unstable angina) during a median follow-up time of 25 months.ResultsAmong the 959 subjects who had steatosis (25.5% of the cohort), 42 had MACE (4.4%), whereas among the 2797 subjects without steatosis, 73 had MACE (2.6%) (hazard ratio [HR] for MACE in subjects with steatosis, 1.69; 95% CI, 1.16-2.48; P = .006 for MACE in subjects with vs without steatosis). This association remained after adjustment for atherosclerotic cardiovascular disease risk scores, significant stenosis, and metabolic syndrome (adjusted HR, 1.72; 95% CI, 1.16-2.54; P = .007) or obesity (adjusted HR, 1.75; 95% CI, 1.19-2.59; P = .005). Steatosis remained independently associated with MACE after adjustment for all CTA measures of plaques and stenosis.ConclusionsHepatic steatosis is associated with MACE independently of other cardiovascular risk factors or extent of coronary artery disease. Strategies to reduce steatosis might reduce risk of MACE. ClinicalTrials.gov no: NCT01174550.

Project description:BackgroundThe number of models developed for predicting major adverse cardiovascular events (MACE) in patients undergoing percutaneous coronary intervention (PCI) is increasing, but the performance of these models is unknown. The purpose of this systematic review is to evaluate, describe, and compare existing models and analyze the factors that can predict outcomes.MethodsWe adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 during the execution of this review. Databases including Embase, PubMed, The Cochrane Library, Web of Science, CNKI, Wanfang Data, VIP, and SINOMED were comprehensively searched for identifying studies published from 1977 to 19 May 2023. Model development studies specifically designed for assessing the occurrence of MACE after PCI with or without external validation were included. Bias and transparency were evaluated by the Prediction Model Risk Of Bias Assessment Tool (PROBAST) and Transparent Reporting of a multivariate Individual Prognosis Or Diagnosis (TRIPOD) statement. The key findings were narratively summarized and presented in tables.ResultsA total of 5,234 articles were retrieved, and after thorough screening, 23 studies that met the predefined inclusion criteria were ultimately included. The models were mainly constructed using data from individuals diagnosed with ST-segment elevation myocardial infarction (STEMI). The discrimination of the models, as measured by the area under the curve (AUC) or C-index, varied between 0.638 and 0.96. The commonly used predictor variables include LVEF, age, Killip classification, diabetes, and various others. All models were determined to have a high risk of bias, and their adherence to the TRIPOD items was reported to be over 60%.ConclusionThe existing models show some predictive ability, but all have a high risk of bias due to methodological shortcomings. This suggests that investigators should follow guidelines to develop high-quality models for better clinical service and dissemination.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=400835, Identifier CRD42023400835.

Dataset Information

New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin.

Publications

New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin.

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