The effect of metformin therapy on cardiac function and survival in volume-overload model of heart failure in rats

Jan Benes (1) , Ludmila Kazdova , Zdenek Drahota , Josef Houstek , Dasa Medrikova , Jan Kopecky , Nikola Kovarova , Marek Vrbacky , David Sedmera , Hynek Strnad , Michal Kolář , Jiri Petrak , Oldřich Benada , Petra Skaroupkova , Luděk Červenka , Vojtech Melenovsky

1 IKEM

Aims: Advanced heart failure (HF) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. Antihyperglycemic drug metformin (MET) affects substrate metabolism and its use might be associated with improved outcome in diabetic HF. The aim of the study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Methods: Volume overload HF was induced in male Wistar rats by creating aorto-caval fistula (ACF). Animals were randomized to placebo/MET (300mg/kg/day, 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6-12/group) in advanced HF stage (21st week). A separate cohort served for survival analysis (n=10-90/group). Results: The ACF group had marked cardiac hypertrophy, increased LVEDP and lung weight confirming decompensated HF, increased circulating free fatty acids (FFA), intraabdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triglyceride content and attenuated myocardial 14C-glucose and 14C-palmitate oxidation, but preserved mitochondrial respiratory function, glucose tolerance and insulin sensitivity. MET therapy normalized serum FFA, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival despite reaching therapeutic serum level (2.2 ± 0.7 μg/ml). Conclusion: MET-induced enhancement of myocardial fatty acid oxidation had neutral effect on cardiac function and survival. Recently reported cardioprotective effects of MET may not be universal to all forms of HF and may require AMPK activation or ATP depletion. No increase in mortality on MET supports its safe use in diabetic HF.

Mots clés: Medicine

Domaines: Médecine humaine et pathologie

Jan Benes, Ludmila Kazdova, Zdenek Drahota, Josef Houstek, Dasa Medrikova, et al.. The effect of metformin therapy on cardiac function and survival in volume-overload model of heart failure in rats. Clinical Science, 2011, 121 (1), pp.29-41. ⟨10.1042/CS20100527⟩. ⟨hal-00680184⟩