PPAR-γ agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation

Abstract

Previously we reported that the beneficial effects of β-adrenergic blockade in chronic mitral regurgitation (MR) were in part due to induction of bradycardia, which obviously affects 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 as observed in other models of heart failure. To explore this hypothesis, we measured triglyceride accumulation in the myocardia of dogs with chronic MR and then attempted to enhance myocardial metabolism by chronic administration of the peroxisome proliferator-activated receptor (PPAR)-γ agonist rosiglitazone. Cardiac tissues were obtained from three groups of dogs that included control animals, dogs with MR for 3 mo without treatment, and dogs with MR for 6 mo that were treated with rosiglitazone (8 mg/day) for the last 3 mo of observation. Hemodynamics and contractile function (end-systolic stress-strain relationship, as measured by K index) were assessed at baseline, 3 mo of MR, and 6 mo of MR (3 mo of the treatment). Lipid accumulation in MR (as indicated by oil red O staining score and TLC analysis) was marked and showed an inverse correlation with the left ventricular (LV) contractility. LV contractility was significantly restored after PPAR therapy (K index: therapy, 3.01 ± 0.11*; 3 mo MR, 2.12 ± 0.34; baseline, 4.01 ± 0.29; ANOVA, P = 0.038; * P < 0.05 vs. 3 mo of MR). At the same time, therapy resulted in a marked reduction of intramyocyte lipid. We conclude that 1) chronic MR leads to intramyocyte myocardial lipid accumulation and contractile dysfunction, and 2) administration of the PPAR-γ agonist rosiglitazone ameliorates MR-induced LV dysfunction accompanied by a decline in lipid content.

Progressive nature of chronic mitral regurgitation and the role of tissue Doppler-derived indexes

“…However, in this model, there is no progressive change in the severity of the MR. These differences may relate to the severity of the initial insult: in previous studies initial induction of RF was ϳ60 -70% (25,26), whereas in our model initial RF was 50%.…”

Inactivation of peroxisome proliferator-activated receptor isoforms α, β/δ, and γ mediate distinct facets of hypertrophic transformation of adult cardiac myocytes

“…PPARα and PPARβ/δ on one hand, and PPARγ on the other hand, differ not only in their effects on the expression of regulatory proteins of fatty acid metabolism, but also in their modification of the hypertrophic response. This observation may be relevant for the development of therapeutic strategies designed to modify myocardial remodeling because restoration of fatty acid metabolism and attenuation of the hypertrophic response may differentially affect the remodeling process [24,48].…”

Long-Term Effects of Sildenafil in a Rat Model of Chronic Mitral Regurgitation

“…It has been suggested that inflammation and energy metabolism initiate cardiac remodeling. 29 Nemoto et al 30 showed that administration of the peroxisome proliferator-activated receptor-␥ agonist rosiglitazone ameliorates MR-induced LV dysfunction accompanied by a decline in lipid content. Similarly, in the volume overload model of aortocaval fistula, upregulation of genes was related to inflammation, the extracellular matrix, the cell cycle, and apoptosis.…”