HMG-CoA reductase inhibition prior reperfusion improves reparative fibrosis post-myocardial infarction in a preclinical experimental model

Abstract

BackgroundStudies in patients support a beneficial effect of statin treatment early after acute coronary syndrome and/or prior percutaneous coronary intervention. However, statin effect during total occlusion remains unknown. ObjectivesTo investigate whether infusion of activated simvastatin during ischemia and prior reperfusion and oral administration thereafter confers cardioprotection and improves cardiac healing in a preclinical model of myocardial infarction. MethodsPigs (n=24) fed a 10day Western-type diet underwent a 90min coronary-balloon occlusion (MI) being randomized to a single intravenous infusion of active β-hydroxy acid derivative of simvastatin (β-OH-S; 0.3mg/kg) 15min prior to reperfusion or vehicle. Animals were either sacrificed 2.5h post-reperfusion or kept under the same regime±simvastatin (p.o., 20mg/day) for 3weeks. Jeopardized and remote myocardium was obtained for molecular/histological studies. Echocardiography was assessed. Resultsβ-OH-S infusion prior to reperfusion reduced coronary and cardiac oxidative DNA-damage, diminished neutrophil infiltration at the site of ischemia, preserved mitochondrial membrane potential and reduced apoptosis in the ischemic myocardium (lower mRNA levels of Fas, casp8, p53, and casp3 and mitochondrial-p-Bcl2; and reduced TUNEL and active caspase-3; p<0.05 vs. vehicle/control). This treatment regime attenuated reperfusion-related arrhythmias and stunning leading to a 40% increased myocardial salvage (p<0.05 vs. vehicle/control). 3weeks post-MI simvastatin-treated animals showed P-PKCε increase, lower intramyocardial lipotoxicity, TβRII/Smad2/3 signaling restoration and subsequent myofibroblast differentiation and collagen-fibril formation in the evolving scar (p<0.05 vs. control). Simvastatin suppressed cardiac RhoA mobilization and triggered Akt/eNOS signaling. ConclusionsAcute HMG-CoA-reductase inhibition during total ischemia and prior reperfusion limits reperfusion injury and prolonged oral simvastatin treatment thereafter improves cardiac healing post-MI.