Long-term pharmacological activation of PPARgamma does not prevent left ventricular remodeling in dogs with advanced heart failure.

Abstract

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPARgamma activator, GW347845 (GW), on the progression of heart failure. METHODS AND RESULTS: Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n = 7), low-dose GW (3 mg/Kg daily, n = 7), or no therapy (control, n = 7). In control dogs, EF significantly decreased (28 +/- 1 vs. 22 +/- 1%, p < 0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the follow-up period (64 +/- 4 vs. 76 +/- 5; p = 0.003, 46 +/- 3 vs. 59 +/- 4 ml, p = 0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69 +/- 4 vs.81 +/- 5 ml, p = 0.01), whereas ESV remained statistically unchanged (50 +/- 3 vs. 54 +/- 3 ml, p = 0.10) resulting in modestly increased ejection fraction (27 +/- 1 vs. 32 +/- 3%, p = 0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72 +/- 4 vs. 79 +/- 5 ml, p = 0.04; 53 +/- 3 vs. 62 +/- 5 ml, p = 0.04) and EF decreased (26 +/- 1 vs. 23 +/- 1%, p = 0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPARgamma, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy. CONCLUSIONS: Long-term PPARgamma activation with GW did not prevent progressive LV remodeling in dogs with advanced heart failure.