Abstract 517: Intracoronary Mesenchymal Stem Cells (MSCs) Improve Regional Function with a Differential Effect on Glycolytic and Mitochondrial Metabolic Enzymes in Chronic Hibernating Myocardium
Background: Statins and fibroblast growth factor improve function without altering myocardial perfusion by normalizing the downregulation of mitochondrial metabolic enzymes that are characteristic of hibernating myocardium. Since MSCs also improve function without altering blood flow, we tested the hypothesis that their beneficial effects are related to an improvement in mitochondrial enzyme expression.
Methods: Swine (n=10) chronically instrumented with a 1.5 mm stenosis on the proximal LAD were treated with autologous i.c. MSCs (4.5 x 106 cells) and compared to swine with untreated hibernating myocardium. Physiological studies to assess flow and function were performed 2– 4 weeks after MSCs and subendocardial protein samples subjected to 2D DIGE. Differential expression was quantified (LAD/Normal) and proteins identified using MALDI-TOF mass spectrometry.
Results: MSCs increased regional wall thickening from 2.3 ± 0.4 mm to 4.4 ± 0.6 mm (p<0.05) vs. 3.2 ± 0.3 mm to 2.7 ± 0.4 mm in untreated hibernating myocardium (p-ns) without increasing coronary flow during adenosine vasodilation ( LAD/Normal 0.20 ± 0.02 vs. 0.18 ± 0.02, p-ns). Mitochondrial oxidative enzymes were downregulated in untreated hibernating myocardium (LAD/Normal, Table⇓). After i.c. MSCs, cytosolic proteins involved in glycolysis and anaerobic glucose metabolism increased in expression but the reductions in mitochondrial enzymes persisted.
Conclusion: In contrast to other interventions that improve hibernating myocardium, MSCs increase glycolytic enzymes but reductions in mitochondrial oxidative enzyme expression persist. Thus, MSCs have a differential effect on metabolic pathways that indicate a distinct mechanism whereby MSCs may improve ventricular function in the failing heart.