Abstract 1128: Pravastatin Improves Function in Hibernating Myocardium by Restoring Mitochondrial Protein Expression in the Absence of Increased Perfusion
Background: Pravastatin improves myocardial function without increasing coronary flow reserve in hibernating myocardium but the mechanisms responsible for this are unclear. We used a proteomic approach to determine whether functional improvement is secondary to metabolic remodeling and an increase in the mitochondrial proteins chronically downregulated in hibernating myocardium.
Methods: Swine (n=11) chronically instrumented with a 1.5 mm stenosis on the proximal LAD were treated with pravastatin for 4 weeks and compared to swine with untreated hibernating myocardium. Physiological studies to assess flow and function were performed and the hearts excised for isolation of subendocardial protein. Differentially expressed proteins (LAD/Normal) were quantified using Cy3,Cy5 and 2D DIGE (using Cy2 as a pooled normal) with identification of protein spots using MALDI mass spectrometry.
Results: Pravastatin increased regional wall thickening from 3.8 ± 0.6 mm to 5.2 ± 0.5 mm, p<0.05 (vs. 3.5 ± 0.6 mm to 2.9 ± 0.4 mm in untreated) without changing coronary flow reserve which was severely reduced (adenosine/rest 1.8 ± 0.3 vs. 1.9 ± 0.5, p-ns). Mitochondrial respiratory enzymes including the entry points to oxidative metabolism were downregulated in hibernating myocardium (LAD/Normal, Table⇓). Pravastatin increased mitochondrial proteins associated with oxidative metabolism and the electron transport chain. In contrast, stress proteins and cytoskeletal proteins that were increased in hibernating LAD regions tended to normalize after pravastatin.
Conclusion: These data indicate that the improvement in regional function in the absence of angiogenesis after pravastatin is secondary to metabolic remodeling of the heart. These findings indicate a novel meachanism whereby statins may improve ventricular function in the globally failing heart.