Abstract 15497: Genetic Modifiers of Glucose Response to GIK and Their Association With Cardiovascular Outcomes
Modifiers of response to glucose, insulin and potassium (GIK) infusion may affect clinical outcomes in acute coronary syndrome (ACS). The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial compared out-of-hospital initiation of GIK to Placebo in patients with suspected ACS. In an IMMEDIATE sub-study (n=318), we explored genetic effects on plasma glucose during 12hr GIK infusion. Patients were genotyped for 132,634 variants (minor allele frequency, MAF≥0.05) assayed on Cardiometabochip and Exome Chip. Associations between glucose-associated variants and progression to myocardial infarction (MI, 66.7%) and infarct size (n=66) were assessed. Blood glucose was measured shortly after infusion initiation, and at 6hrs and 12hrs. Regressions adjusted for treatment, time between treatment initiation and blood draw, age, sex, race, and diabetes. Glucose was higher with GIK than placebo at 6hrs (P=0.002; 159.6 vs. 218.7 mg/dL), but not 12hrs (P=0.60; 152.9 vs. 174.3 mg/dL). A variant near ADCYAP1, rs7229849 (MAF=0.14), modified glucose response to intervention. In GIK, but not placebo, each copy of the rs7229849 minor allele conferred a 1.5-fold initial-to-6hr rise (P for interaction, P-int=2.9x10-6) and a 1.2-fold 6-12hr fall (P-int=0.04) in glucose. This allele was also associated with a larger infarct in GIK (13.3% of LV per copy) and a smaller infarct in Placebo (-5.9% LV per copy; P-int=0.045). ADCYAP1 increases glucose-stimulated insulin release in vitro and in vivo. Near ACSL1, rs12641551 (MAF=0.38) was associated with differences in 6-to-12hr glucose (P-int=2.8x10-5; 1.38-fold rise per copy in GIK, no difference in placebo) and showed an opposite effect on infarct size by treatment (P-int=0.01; GIK=10.0%, Placebo= -7.0% of LV per copy). ACSL1 is implicated in insulin resistance and cardiac arrest resuscitation success. Differences in glucose, but not outcomes, were observed for 12 SNPs within or near SETX, XPO4, STRADA, TAS1R3, DNAH5, AKAP12, PTPRG, LCA5, MAGI1, ARFGEF2, PTCSC3, and ABCB11 (P≤5.0x10-7). Our findings suggest that gene variants in glucose metabolism pathways may modify glucose response to 12hr GIK infusion, and contribute to cardiovascular outcomes in ACS.
- © 2013 by American Heart Association, Inc.