Interaction of implantable defibrillator therapy with angiotensin-converting enzyme deletion/insertion polymorphism

INTRODUCTION: The angiotensin-converting enzyme deletion allele (ACE D) decreases survival in patients with advanced heart failure. Whether the adverse impact on survival reflects an increased risk of pump failure or arrhythmic sudden death remains uncertain. If the ACE D genotype increases the risk of sudden death, implantable cardioverter defibrillator (ICD) therapy should diminish its negative impact. We sought to evaluate the effect of ICD therapy on ACE D genetic risk. METHODS AND RESULTS: The Genetic Risk Assessment of Cardiac Events (GRACE) study enrolled 479 patients at the University of Pittsburgh between 1996 and 2001. Blood was genotyped for the ACE D/I (deletion/insertion) polymorphism. Of the 479 patients, 82 (77% male, 84% Caucasian, age 56 +/- 11 years, 60% ischemic, left ventricular ejection fraction 0.23 +/- 0.08) received an ICD and were selected for outcomes analysis (mean follow-up 871 +/- 538 days). Transplant-free survival and survival alone were compared in ACE DD patients (n = 24, 29%) versus ACE DI/II patients (n = 58, 71%). Survival was significantly improved in ACE DI/II patients compared to those without an ICD (1 year: 93% vs 87%; 2 year: 89% vs 77%; P = 0.02) but not in ACE DD patients. Transplant-free survival among patients with an ICD was significantly worse in ACE DD versus ACE DI/II (1 year: 67% vs 88%, 2 year: 55% vs 80%, P = 0.03). Analysis of survival as a single endpoint revealed a similar result (1 year = 78% vs 94%; 2 year: 72% vs 88%; P = 0.05). ICD telemetry data showed a nonsignificant trend toward fewer individuals with arrhythmias in the ACE-DD group (46% vs 65%, P = 0.22) CONCLUSION: ICDs do not diminish the adverse influence of the ACE DD genotype on survival. This finding suggests that mortality in this high-risk genetic subset of patients is due to progression of heart failure rather than arrhythmic sudden death.