Abstract 4881: Interaction of Genetic and Pharmacologic β -adrenergic Signaling Inhibitors Determines Long-term Mortality after Acute Coronary Ischemia

Abstract

Introduction: While chronic β-blocker (BB) therapy after myocardial infarction (MI) reduces the long-term risk of death, recent studies suggest that BB within 24h after MI is associated with increased death from cardiogenic shock. We have described a naturally-occurring G-protein Receptor Kinase ( GRK )5 L41 polymorphism that mimics BB effects in experimental models and human heart failure raising the possibility that pre-existing “genetic β-blockade” might also affect outcomes after MI. Methods: 3,244 patients hospitalized with acute coronary ischemic syndromes (ACS; 2,943 MI; 301 unstable angina) were followed for an average of 2.7 years. Primary endpoint was time to death. A sub-cohort (n=973) was followed for time to rehospitalization. Independent variables were antecedent BB therapy (a-BB), discharge BB therapy (d-BB), and GRK5 Q41L genotype. Differences were assessed with Kaplan Meier curves, log-rank tests, and Cox proportional hazards modeling (HR). Results: Complete data were available for 2,732 subjects (24% African American [AA], 33% female, 32% a-BB, 87% d-BB). Overall mortality rate was 12%, and rehospitalization occurred in 41%. AA had increased mortality risk (HR=1.32, CI= 1.017–1.71, p=0.037). a-BB significantly increased mortality in both AA (HR=1.69, CI=1.006–2.84, p=0.047) and Caucasians (HR=1.98, CI=1.523–2.57, p=0.00000033). GRK5 L41 is more common in AA. GRK5 L41 carrier status did not significantly affect mortality in AA or Caucasian non-BB subjects, but protected against death in AA with a-BB (HR=0.456, CI= 0.256 – 0.812, p=0.0076; p value for gene-drug interaction=0.041). In the rehospitalization sub-study, GRK5 L41 protected AA from rehospitalization, independent of BB use (HR=0.605, CI=0.388 – 0.943, p=0.026). d-BB status was not associated with mortality or rehospitalization after discharge. Conclusions: Antecedent, but not discharge, treatment with BB is associated with adverse long-term outcomes in ACS patients requiring hospitalization. In contrast, AA patients carrying the GRK5 L41 polymorphism are protected against death and rehospitalization. “Genetic β-blockade” may have advantages over, and can oppose some untoward consequences of, pharmacological β-receptor antagonism in ACS patients.