Abstract 3692: PPARA Genotype is Associated with Differential Response to Beta-Blocker Therapy in Patients Following Acute Coronary Syndromes
Background: After an acute coronary syndrome (ACS), β-blockers (BB) are recommended for all patients without contraindications; however, not all patients may benefit. The causes of variable response to BB remain unknown. Given that myocardial ischemia and BB influence metabolic processes regulated by peroxisome proliferator-activated receptor alpha (PPARα), we hypothesized that polymorphisms of the PPARα gene (PPARA) would correlate with variability in BB-related outcomes following ACS.
Methods and Results: 735 patients hospitalized with ACS were genotyped. Cardiac rehospitalization through 1 year was analyzed in relation to PPARA genotype and BB prescription at discharge. Significantly different outcomes associated with BB therapy were observed according to PPARA genotype (p = 0.002 for interaction). After multivariable adjustment, patients with PPARA IVS7 2498 GG discharged on BB had decreased cardiac rehospitalization (HR 0.52, 95% CI 0.32 - 0.86, p=0.011), compared with patients not on BB, while PPARA C allele carriers discharged on BB had nearly 3-fold increased cardiac rehospitalization (HR 2.92, 95% CI 1.32– 6.92, p= 0.015; genotype interaction p=0.0005) compared with patients not on BB. In transgenic mice with cardiac-specific overexpression of PPARα (MHC-PPARα), myocardial contractile and chronotropic responses to the β-sympathomimetic dobutamine were blunted compared with wild-type littermates (p<0.05).
Conclusions: PPARA IVS7 2498 genotype is associated with heterogeneity in 1-year outcome in response to BB among patients following ACS and may predict which patients benefit from BB therapy. This heterogeneity in clinical outcome may be related to the influence of cardiac PPARα on hemodynamic response to β-adrenergic activation.