Genetic Markers of GIK Effect in Acute Coronary Syndrome in the IMMEDIATE Trial

立即试验中 GIK 对急性冠脉综合征影响的遗传标记

基本信息

批准号：
7502213
负责人：
Inga Peter
金额：
$ 37.52万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7502213
关键词：
Affect Ancillary Study Arrhythmia Biochemical Bioinformatics Biometry Candidate Disease Gene Cardiac Cardiovascular Diseases Cessation of life Clinical Clinical Trials Clinical Trials Design Code Coupled DNA Development Drug Delivery Systems Emergency Care Emergency medical service Enrollment Enzymes Evaluation Funding Future GLUT4 gene Generations Genes Genetic Genetic Markers Genetic Polymorphism Genetic Variation Glucose Glycolysis Haplotypes Heart Heart failure Hospitalization Hospitals Human IRS1 gene Individual Infarction Infusion procedures Insulin Intravenous Laboratories Left Left Ventricular Function Link Linkage Disequilibrium Maps Measurable Membrane Metabolic Mutation Myocardial Myocardial Ischemia N-3 polyunsaturated fatty acid Nonesterified Fatty Acids Nucleic Acid Regulatory Sequences Outcome PDPK1 gene PPARG gene Pathway interactions Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Physiological Placebos Plasma Play Potassium Potassium Channel Randomized Clinical Trials Regulation Reperfusion Therapy Role Sampling Serum Single Nucleotide Polymorphism Stress Symptoms Testing Time Translating United States National Institutes of Health Variant Ventricular Ventricular Arrhythmia Work abstracting acute coronary syndrome base clinical practice cohort defined contribution design disability fatty acid metabolism fatty acid oxidation follow-up genetic association genetic variant glucose metabolism glucose transport heart rate variability improved insulin signaling novel oxidation receptor response therapeutic effectiveness tool

项目摘要

DESCRIPTION (provided by applicant): Despite aggressive reperfusion strategies, significant disability and death remain common consequences of acute coronary syndrome (ACS). To improve outcomes of patients with ACS, myocardial metabolic support in the form of intravenous Glucose-Insulin-Potassium (GIK) therapy is explored by the ongoing IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) Trial. IMMEDIATE Trial is an NIH supported, 15,450-subject, multicenter, emergency medical service-based clinical trial, designed to assess GIK clinical impact when administered immediately upon the patient's presentation with ACS. Despite experimental evidence that co-administration of glucose, insulin and potassium in the setting of ischemic stress preserves cellular viability and reduces ventricular arrhythmias, an overall impact of GIK in clinical trials continues to be controversial. Given accumulating evidence strongly suggesting that mutations in genes encoding drug targets can be linked to drug responses, we hypothesize that variations in genes encoding common pathways related to glucose transport and oxidation (GLUT4 and PDK1), insulin signaling and degradation (IRS1 and IDE), fatty acid metabolism regulation (PRKAA2, PPARA, and PPARG), and potassium channel activity (KCNJ11 and ABCC9) in the heart will be associated with the immediate and long-term response to GIK therapy administered in the setting of ACS. To test this hypothesis, we will collect DNA samples from 8,000 subjects being enrolled in the IMMEDIATE Trial. Pharmacogenetic relationship of variants in the candidate genes with in-hospital and short-term plasma and left ventricular function markers will be tested in a subset of ~412 confirmed ACS cases who get extensive evaluation and return for a 30-day follow-up. To determine the association between the genetic variants and survival following an ACS, we will examine the interactive effect of GIK and gene carrier status on the composite endpoint of hospitalization, heart failure, and death at 30 days and 1 year post-infusion. As genetic variations are highly likely to render some patients more susceptible to the harmful or beneficial effects of GIK, it is of critical importance to identify individuals for whom GIK therapy would be most effective. Moreover, this study will provide a mechanism for understanding the effects of GIK treatment on the heart, and future studies should help translate these findings into clinical practice. Despite advances in the development of aggressive reperfusion strategies, significant disability and death remain common consequences of acute coronary syndromes (ACS). To improve outcomes for patients with ACS, intravenous Glucose-Insulin-Potassium (GIK) metabolic support has been explored - with controversial results. The proposed study aims to investigate whether a patient's genetic make-up is associated with the immediate and long-term response to GIK therapy administered in the setting of ACS, whereas future studies would help translate these findings into an individualized approach to curing cardiovascular disease. (End of Abstract)

描述（由申请人提供）：尽管有积极的再灌注策略，但急性冠状动脉综合征（ACS）的显着残疾和死亡仍然是普遍的后果。为了改善ACS患者的预后，持续的即时（在急诊初步评估和初步评估期间立即进行心肌代谢增强）探索了静脉内葡萄糖 - 胰岛素 - 胰岛 - 胰岛素（GIK）疗法的形式的心肌代谢支持）。立即试验是NIH支持的15,450个受试者，多中心，紧急医疗服务的临床试验，旨在评估GIK临床影响，当时患者在患者使用ACS介绍后立即给予临床影响。尽管实验性证据表明，在缺血性胁迫的情况下，葡萄糖，胰岛素和钾的共同给药可保留细胞活力并降低心室心律不齐，但GIK在临床试验中的总体影响仍然引起争议。给定积累的证据，强烈表明编码药物靶标的基因突变可以与药物反应联系在一起，我们假设编码与葡萄糖转运和氧化相关的基因的变化（GLUT4和PDK1），胰岛素和降解和降解和降解（IRS1和IDE），脂肪酸代理Parka和ParkaA 2，PARAA 2，PARAA 2，PARAA 2，PARAA 2，心脏中的通道活性（KCNJ11和ABCC9）将与ACS环境中对GIK治疗的直接和长期反应有关。为了检验这一假设，我们将收集8,000名受试者的DNA样本，即立即进行试验。在〜412个确认的ACS病例中，将测试候选基因与院内和短期等离子体和左心室功能标记的候选基因的药物遗传学关系，这些标志物将在约412个确认的ACS病例中进行测试，这些病例获得了广泛的评估并进行了30天的随访。为了确定ACS之后的遗传变异和生存之间的关联，我们将检查GIK和GENE载体状态对入院后30天和1年后住院，心力衰竭和死亡复合终点的互动效应。由于遗传变异极有可能使某些患者更容易受到GIK的有害或有益作用的影响，因此确定对GIK治疗最有效的人至关重要。此外，这项研究将提供一种理解GIK治疗对心脏影响的机制，未来的研究应有助于将这些发现转化为临床实践。尽管发展了积极再灌注策略的发展，但急性冠状动脉综合征（AC）的显着残疾和死亡仍然是常见的后果。为了改善ACS患者的结局，已经探索了静脉葡萄糖 - 胰岛素 - 胰岛胰岛胰岛素（GIK）代谢支持 - 有争议的结果。拟议的研究旨在调查患者的遗传构成是否与ACS环境中对GIK治疗的直接和长期反应有关，而未来的研究将有助于将这些发现转化为康复心血管疾病的个性化方法。（抽象的结尾）