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

Background: Studies 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.

Objectives: To 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.

Methods: Pigs (n=24) fed a 10 day Western-type diet underwent a 90 min coronary-balloon occlusion (MI) being randomized to a single intravenous infusion of active β-hydroxy acid derivative of simvastatin (β-OH-S; 0.3 mg/kg) 15 min prior to reperfusion or vehicle. Animals were either sacrificed 2.5 h post-reperfusion or kept under the same regime ± simvastatin (p.o., 20 mg/day) for 3 weeks. Jeopardized and remote myocardium was obtained for molecular/histological studies. Echocardiography was assessed.

Results: β-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). 3 weeks 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.

Conclusions: Acute HMG-CoA-reductase inhibition during total ischemia and prior reperfusion limits reperfusion injury and prolonged oral simvastatin treatment thereafter improves cardiac healing post-MI.