Objective: Previously we reported that the beneficial effects of -adrenergic blockade in chronic mitral regurgitation (MR) were in part due to induction of bradycardia, which obviously effects myocardial energy requirements. From this observation we hypothesized that part of the pathophysiology of MR may involve faulty energy substrate utilization, which in turn might lead to potentially harmful lipid accumulation observed in other models of heart failure. Methods: To explore this hypothesis, we measured triglyceride accumulation in the myocardium of dogs with chronic MR and then attempted to enhance myocardial metabolism by chronic administration of a PPAR agonist, rosiglitazone. Cardiac tissues were obtained from 3 groups of dogs: controls, dogs with MR for 3 months without treatment, and dogs with 6 months of MR treated with rosiglitazone 8mg/day for the last 3 months of observation. Hemodynamics and contractile function (end-systolic stress-strain relationship; K-index) were assessed at baseline, 3 months of MR, and 6 months of MR (3 months of the treatment). Results: Lipid accumulation in MR (Oil-Red-O staining score and thin layer chromatography) was marked and showed an inverse correlation with the LV contractility. LV contractility was significantly restored after PPAR therapy (K-index; 3.01 ±0.11* (therapy) vs. 2.12 ± 0.34 (3 mo MR) vs. 4.01 ± 0.29 (baseline), ANOVA p = 0.038, *p<0.05 vs. 3 mo MR). At the same time, therapy resulted in a marked reduction of intramyocyte lipid. Conclusion: We conclude that (1) chronic MR leads to intramyocyte myocardial lipid accumulation and contractile dysfunction and (2) administration of the PPAR agonist, rosiglitazone ameliorates MR-induced LV dysfunction accompanied by a decline in lipid content.