Abstract 11650: Adcy9Inactivation Improves Cardiac Function After Myocardial Infarction in Absence of Cholesterol Ester Transfer Protein

Pharmacogenomic studies have shown that polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the effects of dalcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, on cardiovascular events after an acute coronary syndrome. We hypothesized that Adcy9inactivation could improve cardiac function and remodeling after myocardial infarction (MI) in the absence of CETP activity.Wild-type (WT) and Adcy9-inactivated (Adcy9Gt) mice, transgenic (tg) or not for human CETP, were subjected to MI by permanent left anterior descending coronary artery ligation (n=22-24/genotype) and studied for 4 weeks. There was no significant difference between groups in cardiac troponin I in serum and left ventricular (LV) wall motion score index (WMSI) on echocardiography at 24 hours post-MI. Mice with insufficient myocardial damage (WMSI?1.2) at 24 hours were excluded. The total mortality rate was 45%, without difference between genotypes (p=0.98), which resulted in 11 mice with each genotype (n=44) undergoing echocardiography at baseline, weeks 1 and 4 post-MI. All of these mice developed LV hypertrophy, dilation and systolic dysfunction over time, but Adcy9Gtmice exhibited reduced pathological LV remodeling and better LV function compared to WT after MI (p<0.05, Table). Histology analyses performed at 4-week follow-up indicated smaller cardiomyocyte size (p<0.01) and reduced infarct size (p=0.07) in Adcy9Gtversus WT mice. There were no significant differences between CETPtg and Adcy9Gt-CETPtg mice, which both exhibited intermediate responses compared to those of WT and Adcy9Gtmice.In conclusion, Adcy9inactivation reduces pathological LV remodeling and improves cardiac function after MI, but only in the absence of CETP activity.