Abstract 18887: Ruboxistaurin Improves Cardiac Function in the Swine Heart After Myocardial Infarction

Abstract

Introduction: Myocardial Infarction (MI) is a major health problem that causes cardiac dysfunction and often leads to heart failure. Previously, we and others have demonstrated that protein kinase C alpha (PKCα) activity is up-regulated in cardiac disease. This enhanced PKCα activity has been linked to depressed cardiac contractility in the diseased heart. In the present study we tested the effects of Ruboxistaurin, a PKCα inhibitor, on cardiac contractile function in a swine MI model. Hypothesis: Increased PKCα activity is involved in the progression of myocardial contractility defects in the post MI heart. Methods and Results: MI was induced in female Göttingen mini- pigs (6-7 months of age) by occlusion of the left anterior descending coronary artery (LAD) using an inflated percutaneous transluminal coronary angioplasty (PTCA) balloon for 90 minutes, followed by reperfusion. Cardiac structure and function was evaluated using echocardiography before and 4, 8, and 12 weeks post MI. During the 12 weeks after MI there was a progressive depression of pump function (Ejection Fraction [EF] 66.52% ± 1.16 [baseline] to 32.66 % ± 1.02 [12 weeks after MI] p <0.0001) and dilation of the LV volumes (End-diastolic volume [EDV] was 40.38 ml ± 3.01[baseline] to 75.73 ml ± 3.18 [12 weeks post MI] p = 0.0123 and End-systolic volume [ESV] was 15.14 ml ± 2.32 to 50.75 ml ± 1.86 p= 0.0004). The acute inotropic effects of an oral dose of ruboxistaurin (20mg/kg) were tested in animals 12 weeks post MI. Ruboxistaurin treatment significantly increased EF (from 32.66% ± 1.02 to 41.43% ± 2.87 p =0.0282). Ruboxistaurin treatment also significantly reduced EDV and ESV (from 75.73 ml ± 3.18 to 63.58 ml ± 4.06 p =0.0494, and from 50.75 ml ± 1.86 to 37.45 ml ± 3.52 p =0.0156 respectively). Conclusion: These data show that acute administration of the PKCα inhibitor ruboxistaurin can increase cardiac contractility and reduce heart size in swine with post MI cardiac dysfunction. These results suggest that PKCα activity suppresses cardiac contractile function and that removal of this inhibitory activity enhances cardiac pump function.