Calcineurin inhibition ameliorates structural, contractile, and electrophysiologic consequences of postinfarction remodeling

Introduction: After myocardial infarction (MI), the heart undergoes an adap tive remodeling process characterized by hypertrophy of the noninfarcted my ocardium. Calcineurin, a Ca2+-calmodulin-regulated phosphatase, has been sh own to participate in hypertrophic signal transduction. Methods and Results: We investigated the effects of calcineurin inhibition by cyclosporin A on key structural, contractile, and electrophysiologic alt erations of post-MI remodeling. Male Sprague-Dawley rats were divided into four groups: (1) sham-operated; (2) sham + cyclosporin A; (3) post-MI (left anterior descending coronary artery ligation); and (4) MI + cyclosporin A. Cyclosporin A (25 mg/kg/day) was initiated 2 days before surgery and conti nued for 30 days. Hypertrophy was evaluated by echocardiography and by chan ges in membrane capacitance of isolated myocytes from noninfarcted left ven tricle (LV). The effects of cyclosporin A on hemodynamics and cardiac dimen sions were investigated, and changes in diastolic function were correlated with changes in protein phosphatase 1 activity and the basal level of phosp horylated phospholamban. The effects of cyclosporin A on Kv4.2/Kv4.3 genes expression and transient outward K+ current (I-to) density also were evalua ted. One of 12 rats in the post-MI group and 2 of 12 rats in the post-MI cyclosporin A group died within 48 hours after MI. There were no late death s in either MI group. There was no evidence of heart failure (lung congesti on and/or pleural effusion) in the two groups 4 weeks post-MI. Calcineurin phosphatase activity increased 1.9-fold in post-MI remodeled LV myocardium, and cyclosporin A administration resulted in an 86% decrease in activity. There were statistically significant decreases of LV end-diastolic pressure , LV end-diastolic diameter, and LV relative wall thickness in the post-MI + cyclosporin A group compared with the post-MI group. On the other hand, t here was no significant difference in LV end-systolic diameter or peak rate of LV pressure increase between the two post-MI groups. Protein phosphatas e 1 activity was elevated by 36% in the post-MI group compared with sham, a nd this correlated with a 79% decrease in basal level of p16-phospholamban. In the post-MI + cyclosporin A group, the increase in protein phosphatase I activity was much less (18% vs 36%; P<0.05), and the decrease in basal le vel of p16-phospholamban was markedly ameliorated (20% vs 79%; P<0.01). The decreases in mRNA levels of Kv4.2 and Kv4.3 and I-to density in the LV of the post-MI + cyclosporin A group were significantly less compared with the post-MI group. Conclusion: Our results show that calcineurin inhibition by cyclosporin A p artially ameliorated post-MI remodeled hypertrophy, diastolic dysfunction, decrease in basal level of phosphorylated phospholamban, down-regulation of key K+ genes expression, and decrease of K+ current, with no adverse effec ts on systolic function or mortality in the first 4 weeks after MI.