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.
|Ellis, K L; Zhou, Y; Beshansky, J R et al. (2015) Genetic modifiers of response to glucose-insulin-potassium (GIK) infusion in acute coronary syndromes and associations with clinical outcomes in the IMMEDIATE trial. Pharmacogenomics J 15:488-95|
|Ellis, K L; Zhou, Y; Beshansky, J R et al. (2015) Genetic variation at glucose and insulin trait loci and response to glucose-insulin-potassium (GIK) therapy: the IMMEDIATE trial. Pharmacogenomics J 15:55-62|
|Gottesman, Omri; Drill, Esther; Lotay, Vaneet et al. (2012) Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk? PLoS One 7:e46419|