Fibrosis Post Myocardial Infarction Research Articles

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

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.

Reduced Cardiac Remodeling and Function in Cardiac-Specific EP 4 Receptor Knockout Mice With Myocardial Infarction

We have shown previously that cyclooxygenase-2 inhibition reduces cardiac hypertrophy and fibrosis postmyocardial infarction (MI) in a mouse model and that prostaglandin E(2) stimulates cardiomyocyte hypertrophy in vitro through its EP(4) receptor. Because the role of cardiac myocyte EP(4) in cardiac function and hypertrophy in vivo is unknown, we generated mice lacking EP(4) only in cardiomyocytes (CM- EP(4) knockout [KO]). Twelve- to 14-week-old mice were evaluated using echocardiography and histology. There were no differences in ejection fraction, myocyte cross-sectional area, and interstitial collagen fraction between KO mice and littermate controls. To test the hypothesis that EP(4) is involved in cardiac remodeling after MI, we induced MI by ligating the left anterior descending coronary artery. Two weeks later, the mice were subjected to echocardiography, and hearts were removed for histology and Western blot. There was no difference in infarct size between KO mice and controls; however, KO mice showed less myocyte cross-sectional area and interstitial collagen fraction than controls. Also, CM-EP4 KO mice had reduced ejection fraction. Because the transcription factor Stat-3 is involved in hypertrophy and protection from ischemic injury, we tested whether it was activated in control and KO mouse hearts after MI. Western blot indicated that Stat-3 was activated in control hearts after MI but not in KO hearts. Thus, CM-EP4 deletion decreased hypertrophy, fibrosis, and activation of Stat-3. However, cardiac function was unexpectedly worsened in these mice. We conclude that cardiac myocyte EP(4) plays a role in hypertrophy via activation of Stat-3, a process that seems to be cardioprotective.