Combined Therapy With Simvastatin and Bone Marrow–Derived Mesenchymal Stem Cells Increases Benefits in Infarcted Swine Hearts

Abstract

Objective— Widespread death of implanted cells hampers stem cell therapy for acute myocardial infarction (AMI). Based on the pleiotropic beneficial effects of statins, we examined whether simvastatin (SIMV) increased the efficacy of mesenchymal stem cell (MSC) transplantation after AMI. Methods and Results— Chinese miniswine (n=28) were randomized to 1 of 4 groups (n=7 per group): control, SIMV (0.25 mg/kg · d), MSC transplantation, and SIMV+MSCs. AMI was created by ligating the left anterior descending coronary artery; MSCs were injected immediately into the cyanotic myocardium. At 6 weeks, MRI showed the number of dyskinetic segments and the infarct size were significantly decreased in the SIMV group. Cardiac function improved and the perfusion defect decreased significantly in the SIMV+MSC group but not in the MSC-only group ( P <0.05, versus control group). MSC survival and differentiation were significantly better in the combination group than in the MSC-only group ( P <0.01). Cell apoptosis decreased significantly in both the SIMV and the SIMV+MSC groups but not in the MSC-only group when compared with controls ( P <0.05). Furthermore, oxidative stress and inflammatory response was significantly reduced in the infarcted regions in both the SIMV and the SIMV+MSCs groups. Conclusions— SIMV treatment improves the therapeutic efficacy of MSC transplantation in acutely infarcted hearts by promoting cell survival and cardiovascular differentiation.