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

• 批准号: 7934556
• 负责人: Inga Peter
• 金额: $ 37.8万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 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/7934556
• 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 variant; glucose metabolism; glucose transport; heart rate variability; improved; insulin signaling; novel; oxidation; receptor; response; therapeutic effectiveness; tool

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）： 尽管采取了积极的再灌注策略，严重的残疾和死亡仍然是急性冠状动脉综合征（ACS）的常见后果。为了改善 ACS 患者的预后，正在进行的 IMMEDIATE（紧急护理初始评估和治疗期间立即增强心肌代谢）试验探索了静脉注射葡萄糖胰岛素钾 (GIK) 治疗形式的心肌代谢支持。 IMMEDIATE 试验是一项 NIH 支持的、15,450 名受试者、多中心、基于紧急医疗服务的临床试验，旨在评估患者出现 ACS 后立即施用 GIK 的临床影响。尽管实验证据表明在缺血应激情况下联合给予葡萄糖、胰岛素和钾可以保留细胞活力并减少室性心律失常，但 GIK 在临床试验中的总体影响仍然存在争议。鉴于越来越多的证据强烈表明编码药物靶点的基因突变可能与药物反应有关，我们假设编码与葡萄糖转运和氧化（GLUT4和PDK1）、胰岛素信号传导和降解（IRS1和IDE）、脂肪酸代谢调节（PRKAA2、PPARA和PPARG）以及钾相关的常见途径的基因发生变异。 心脏中的通道活性（KCNJ11 和 ABCC9）将与 ACS 患者对 GIK 治疗的即时和长期反应相关。为了检验这一假设，我们将从参加 IMMEDIATE 试验的 8,000 名受试者中收集 DNA 样本。候选基因变异与院内和短期血浆和左心室功能标志物的药物遗传学关系将在约 412 例确诊 ACS 病例的子集中进行测试，这些病例接受广泛评估并返回进行 30 天的随访。为了确定遗传变异与 ACS 后生存之间的关联，我们将检查 GIK 和基因携带者状态对输注后 30 天和 1 年住院、心力衰竭和死亡复合终点的相互作用。由于遗传变异很可能使某些患者更容易受到 GIK 的有害或有益影响，因此确定 GIK 治疗最有效的个体至关重要。此外，这项研究将提供一种机制来了解 GIK 治疗对心脏的影响，未来的研究应有助于将这些发现转化为临床实践。尽管积极的再灌注策略的发展取得了进展，但严重的残疾和死亡仍然是急性冠状动脉综合征（ACS）的常见后果。为了改善 ACS 患者的预后，人们对静脉注射葡萄糖-胰岛素-钾 (GIK) 代谢支持进行了探索，但结果存在争议。拟议的研究旨在调查患者的基因组成是否与 ACS 患者对 GIK 治疗的即时和长期反应有关，而未来的研究将有助于将这些发现转化为治疗心血管疾病的个体化方法。 （摘要完）