Abstract 13074: Impact of Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia: The MAP-MI Study

Abstract

Rationale: During acute coronary syndromes (ACS) adrenergic receptor (AR) signaling may have major effects on cardiac arrhythmias including VF. AR gene products are highly polymorphic, and minor variants exhibit potentially important pharmacologic differences compared to receptors encoded by major allele homozygotes ( mah ). Objective: We tested the general hypothesis that polymorphic variants in the ADRB1 , ADRB2 or ADRA2C genes affect incident VF during ACS. Methods and Results: We recruited 953 subjects with a proven MI and no previous history of AC. In a case-control design 477 VF patients were compared to 476 controls without VF who did not differ in baseline characteristics. DNA collection and subsequent genotyping for ADRB1 389/49, ADRB2 27/16 and ADRA2C 322-325 Ins/Del were available in 718-779 patients. Results were expressed as Odds Ratios (OR) for VF vs. No-VF subjects by comparing each mah to minor allele monotype genotypes, genotype combinations or haplotypes. The entire cohort OR (95% CI) for patients receiving (41%) vs. not receiving beta-blockade (BB) was (0.70 (0.53, 0.93), P=0.014), dictating a BB adjustment in the genotype-VF analyses. No minor allele genotype was associated with increased incident VF. Monotypes with statistically significant ORs and their mah comparators were: ADRB2 monotypes and ADRB1 or ADRB2 haplotypes were not associated with VF reduction. Two of 3 ADRB1 and 3 of 4 ADRB2 monotypes or genotype combinations associated with VF reduction encoded ARs that exhibit increased agonist-induced internalization. Conclusions: In acute MI AR variants associated with reduced incident VF are those that mediate increased adrenergic drive ( ADRA2 C Del) and beta-AR internalization. This combination would be predicted to redirect beta-AR signaling from canonical pathways to "biased" EGFR and ERK1/2 mediated cardioprotection.