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

Abstract

The effect of metformin therapy on cardiac function and survival in volume-overload model of heart failure in rats Short title: Metformin therapy in volume-overload heart failure in rats A c c e p t e d M a n u s c r i p t Licenced copy. Copying is not permitted, except with prior permission and as allowed by law.© 2011 The Authors Journal compilation © 2011 Portland Press Limited 2 Abstract 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 (21 st 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 14 C-glucose and 14 C-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. IntroductionAdvanced heart failure (HF) is characterized not only by a depression of heart mechanical performance but also by altered myocardial metabolism -attenuated expression of fatty acid oxidation genes [1,2] and by diminished oxidation of long chain fatty acids [1,[3][4][5], which may contribute to diminished metabolic flexibility and to energetic deficiency that further promotes worsening of HF [6]. Targeting energetic substrate metabolism might thus serve as a target for novel therapeutic approaches to HF [7,8]. Metformin (MET), a widely used antihyperglycemic drug with insulin-sensitizing properties, could be a suitable candidate for metabolic HF therapy. MET lowers serum glucose by inhibiting liver gluconeogenesis, lowers circulating free...

The role of mitochondria in cardiac development and protection

“…Another promising candidate for the promotion of oxidative metabolism could be the antidiabetic drug metformin, that influences the substrate metabolism for OXPHOS by promoting fatty-acid oxidation [136]. Metformin has been reported to increase myocardial palmitate oxidation in a volume-overload rodent model [137] and although the drug did not influence the overall survival of the animals in the study, it might be applied to influence the pathological reprogramming of cardiomyocytes.…”

Metformin Reduces Left Ventricular Eccentric Re-modeling In Experimental volume Overload in the Rat

“…In a recent study in a model of global heart volume overload caused by aortocaval fistulae (ACF) in rats, metformin was shown to have no impact on the heart and LV weight in ACF rats while echo data showed a trend similar to ours (less dilatation). In that study the dose of metformin was twice the one we used 15 (27). In another study in rats post-myocardial infarction, metformin was shown to decrease heart dilatation while limiting LV wall thinning [28].…”

AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases

“…Altered substrate metabolism is associated with advanced heart failure (HF), and metformin is known to affect substrate metabolism leading to improved outcome in diabetic HF. Kazdova et al ( 176 ) examined the effect of metformin on the improvement of cardiac function in nondiabetic volume-overload HF rat model and observed normalization of NEFA and increased palmitate oxidation but no effect on mitochondrial diacylglycerides contributing to insulin resistance ( 143 ). AMPK restores the AMP:ATP ratio through ATP production mediated by increased fatty acid uptake and lipid oxidation ( 113,141,142,144,145 ).…”