Gemma Vilahur1, Laura Casani1, Esther Peña1, Oriol Juan-Babot1, Guiomar Mendieta1, Javier Crespo1, Lina Badimon2. 1. Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain. 2. Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; Cardiovascular Research Chair, UAB, Barcelona, Spain. Electronic address: lbadimon@csic-iccc.org.
Abstract
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.
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.
Authors: Stephanie L Thorn; Shayne C Barlow; Attila Feher; Mitchel R Stacy; Heather Doviak; Julia Jacobs; Kia Zellars; Jennifer M Renaud; Ran Klein; Robert A deKemp; Aarif Y Khakoo; TaeWeon Lee; Francis G Spinale; Albert J Sinusas Journal: Circ Cardiovasc Imaging Date: 2019-11-11 Impact factor: 7.792