Abstract 448: The Loss of Rad GTPase Protects Against Infarction-induced Myocardial Remodeling, Scar Formation, and Decompensatory Dilation

Abstract

Rationale: Myocardial infarction (MI) is a leading cause of death in the U.S. A non-contractile infarct compromises the overall mechanical function of the heart, reducing cardiac output and triggering decompensatory ventricular dilation. Rad GTPase, a member of the small GTPase RGK (Rem, Gem, Kir) family, is a calcium channel blocker that is endogenously expressed in the myocardium. We have previously shown that Rad deletion in mice results in increased Ca 2+ handling and a sustained non-pathological improvement in left ventricular function compared to wildtype. Hypothesis: Rad-ablation attenuates post-ischemic loss of function, resulting in reduced remodeling and improved long-term contractility. Methods and Results: We subjected Rad-deficient mice to ligation of the left anterior descending (LAD) coronary artery, and monitored cardiac function using echocardiography. We found that Rad deletion reduces both mortality and contractile dysfunction after MI, as well as ventricular dilation over five weeks. This improvement is also accompanied by preserved calcium handling in isolated myocytes. Histological and MRI examination of both ex vivo global ischemia and in vivo 24 hour LAD ligated myocardium revealed that initial infarct size is comparable between knockout and wildtype. We found that Rad loss reduced scar development and elongation independent of preserving tissue viability. Investigation of inflammatory pathways to account for this revealed increased expression of the anti-inflammatory protein thrombospondin accompanied by a reduction in neutrophil infiltration into the myocardium after MI. Conclusion: Rad deletion results in reduced cardiac remodeling, diminished myocardial inflammation, and improved contractile function after MI.