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

描述（由申请人提供）： 尽管有积极的再灌注策略，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患者的结局，正在进行的IMMEDIATE（急诊初始评估和治疗期间立即心肌代谢增强）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试验是一项由NIH支持的、15，450例受试者、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后立即给予GIK的临床影响。尽管有实验证据表明，在缺血性应激的情况下，葡萄糖、胰岛素和钾的联合给药可保护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，编码葡萄糖转运和氧化共同途径的基因变异（GLUT 4和PDK 1），胰岛素信号传导和降解（IRS 1和IDE），脂肪酸代谢调节心脏中的PRKAA 2、PPARA和PPARG和钾通道活性（KCNJ 11和ABCC 9）将与ACS背景下给予GIK治疗的即时和长期反应相关。为了验证这一假设，我们将从8,000名入组即刻试验的受试者中收集DNA样本。将在约412例确诊ACS病例的子集中检测候选基因变异与住院和短期血浆和左心室功能标志物的药物遗传学关系，这些病例接受广泛评价并返回接受30天随访。为了确定遗传变异与ACS后生存率之间的相关性，我们将研究GIK和基因携带状态对输液后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一些患者更容易受到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，这项研究将为理解GIK治疗对心脏的影响提供一种机制，未来的研究应有助于将这些发现转化为临床实践。尽管积极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患者的结局，已经探索了静脉内葡萄糖-胰岛素-钾（GIK）代谢支持-结果存在争议。这项拟议的研究旨在调查患者的遗传组成是否与ACS背景下对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性化方法。(End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)