Cyclosporine A reduces microvascular obstruction and preserves left ventricular function deterioration following myocardial ischemia and reperfusion

Abstract

Postconditioning and cyclosporine A prevent mitochondrial permeability transition pore opening providing cardioprotection during ischemia/reperfusion. Whether microvascular obstruction is affected by these interventions is largely unknown. Pigs subjected to coronary occlusion for 1 h followed by 3 h of reperfusion were assigned to control (n = 8), postconditioning (n = 9) or cyclosporine A intravenous infusion 10–15 min before the end of ischemia (n = 8). Postconditioning was induced by 8 cycles of repeated 30-s balloon inflation and deflation. After 3 h of reperfusion magnetic resonance imaging, triphenyltetrazolium chloride/Evans blue staining and histopathology were performed. Microvascular obstruction (MVO, percentage of gadolinium-hyperenhanced area) was measured early (3 min) and late (12 min) after contrast injection. Infarct size with double staining was smaller in cyclosporine (46.2 ± 3.1 %, P = 0.016) and postconditioning pigs (47.6 ± 3.9 %, P = 0.008) versus controls (53.8 ± 4.1 %). Late MVO was significantly reduced by cyclosporine (13.9 ± 9.6 %, P = 0.047) but not postconditioning (23.6 ± 11.7 %, P = 0.66) when compared with controls (32.0 ± 16.9 %). Myocardial blood flow in the late MVO was improved with cyclosporine versus controls (0.30 ± 0.06 vs 0.21 ± 0.03 ml/g/min, P = 0.002) and was inversely correlated with late-MVO extent (R2 = 0.93, P < 0.0001). Deterioration of left ventricular ejection fraction (LVEF) between baseline and 3 h of reperfusion was smaller with cyclosporine (−7.9 ± 2.4 %, P = 0.008) but not postconditioning (−12.0 ± 5.5 %, P = 0.22) when compared with controls (−16.4 ± 5.5 %). In the three groups, infarct size (β = −0.69, P < 0.001) and late MVO (β = −0.33, P = 0.02) were independent predictors of LVEF deterioration following ischemia/reperfusion (R2 = 0.73, P < 0.001). Despite both cyclosporine A and postconditioning reduce infarct size, only cyclosporine A infusion had a beneficial effect on microvascular damage and was associated with better preserved LV function when compared with controls.