Abstract 3917: High-dose Metformin Therapy Improves Myocardial Fatty Acid Oxidation, but Not Survival in Chronic Heart Failure Due to Volume Overload
Introduction: Advanced heart failure (HF) is associated with decreased fatty acid oxidation (FAO), but if modification of substrate utilisation will correct the course of HF remains unknown. The study examined whether chronic metformin therapy improves cardiac function, metabolism and survival in rat model of HF due to volume overload from aorto-caval fistula (ACF).
Methods: 3mo old male WR rats underwent ACF/sham procedure and then were randomized to placebo/metformin therapy (P/MET, 300 mg/kg/day, 0,5% in food). In advanced HF stage (24 week), animals (n=12/group) underwent cardiovascular and metabolic assessment. Separate rat cohort (n=180) served for survival analysis.
Results: Untreated ACF animals had markedly (p <0.01) increased heart weight/BW (5.4 vs 2.56 g/kg), reduced EF (75% vs. 93%) increased LVEDP (13.5 vs. 6.5 mmHg) and lung weight/BW compared to sham, confirming decompensated HF phenotype. Myocardial tissue incubation showed reduced myocardial oxidation of 14C-glucose (0.94 vs 2.38 nmol/min/g wet, p<0.01) and 14C-palmitate in ACF (fig 1⇓). Maximal respiratory rate of myocardial tissue homogenate (ADP, palmitylcarnitine) were preserved indicating pre-mitochondrial site of FAO impairment. Plasma MET levels were in therapeutic range (2.2ug/ml). MET therapy significantly increased myocardial tissue palmitate oxidation, with no effect on HW/BW, lung weight/BW, LV size/function and mortality (fig 2⇓).
Conclusion: Despite MET almost normalized attenuated FAO in ACF-HF animals, it had no effect on survival. Recently reported cardioprotective effects of MET may not be universal to all forms of heart failure, or they may depend on MET dose or timing.