Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure

Abstract

Yin M, van der Horst IC, van Melle JP, Qian C, van Gilst WH, Silljé HH, de Boer RA. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol 301: H459 -H468, 2011. First published May 13, 2011 doi:10.1152/ajpheart.00054.2011Metformin is the first choice drug for the treatment of patients with diabetes, but its use is debated in patients with advanced cardiorenal disease. Epidemiological data suggest that metformin may reduce cardiac events, in patients both with and without heart failure. Experimental evidence suggests that metformin reduces cardiac ischemia-reperfusion injury. It is unknown whether metformin improves cardiac function (remodeling) in a long-term post-MI remodeling model. We therefore studied male, nondiabetic, Sprague-Dawley rats that were subjected to either myocardial infarction (MI) or sham operation. Animals were randomly allocated to treatment with normal water or metformin-containing water (250 mg·kg Ϫ1 ·day Ϫ1 ). At baseline, 6 wk, and 12 wk, metabolic parameters were analyzed and oral glucose tolerance tests (OGTT) were performed. Echocardiography and hemodynamic parameters were assessed 12 wk after MI. In the MI model, infarct size was significantly smaller after 12-wk metformin treatment (29.6 Ϯ 3.2 vs. 38.0 Ϯ 2.2%, P Ͻ 0.05). Moreover, metformin resulted in less left ventricular dilatation (6.0 Ϯ 0.4 vs. 7.6 Ϯ 0.6 mm, P Ͻ 0.05) and preservation of left ventricular ejection fraction (65.8 Ϯ 3.7% vs. 48.6 Ϯ 5.6%, P Ͻ 0.05) compared with MI control. The improved cardiac function was associated with decreased atrial natriuretic peptide mRNA levels in the metformin-treated group (50% reduction compared with MI, P Ͻ 0.05). Insulin resistance did not occur during cardiac remodeling (as indicated by normal OGTT) and fasting glucose levels and the pattern of the OGTT were not affected by metformin. Molecular analyses suggested that altered AMP kinase phosphorylation status and low insulin levels mediate the salutary effects of metformin. Altogether our results indicate that metformin may have potential to attenuate heart failure development after myocardial infarction, in the absence of diabetes and independent of systemic glucose levels.

Les nouvelles promesses de la metformine

“…Contrairement à d'autres agents antidiabétiques (insuline ou sulfonylurés), la metformine entraîne une diminution d'environ 40 % de la mortalité liée aux pathologies cardiovasculaires, comme l'infarctus du myocarde ou les attaques cérébrales, indiquant que la protection cardiovasculaire de la metformine pourrait être dissociée de son action antihyperglycémique. Des travaux chez le rat non diabétique ont confirmé que la metformine amé-liore la fonction cardiaque et réduit la taille des lésions après l'induction d'un infarctus du myocarde [24]. Cet effet bénéfique résulte d'un phénomène de précondi-tionnement myocardique induit de manière plus ou moins permanente par la metformine.…”

Metformin and heart failure: never say never again

“…Three mechanisms have hitherto been proposed. Based on experimental evidence [30][31][32][33][34][35], the main mechanism appears to be the activation of adenosine monophosphate-activated protein kinase (AMPK) [36]. In experimental models of diabetes and HF, metformin activates AMPK, leading to its increased phosphorylation, which, in turn, results in increased phosphorylation of endothelial nitric oxide synthase (eNOS) [30][31][32][33]35].…”

“…Based on experimental evidence [30][31][32][33][34][35], the main mechanism appears to be the activation of adenosine monophosphate-activated protein kinase (AMPK) [36]. In experimental models of diabetes and HF, metformin activates AMPK, leading to its increased phosphorylation, which, in turn, results in increased phosphorylation of endothelial nitric oxide synthase (eNOS) [30][31][32][33]35]. Thus, plasma and myocardial levels of nitric oxide increase [30,31], ultimately resulting in improved endothelial function, preservation of left ventricular ejection fraction [30,31,33,35], reduced left ventricular dilatation [30,33,35], improved left ventricular end-diastolic pressure [31,35] and also reduced myocardial autophagy [34] and apoptosis [31].…”

“…Furthermore, although some workers have performed multivariate analyses to exclude potential confounding factors [20][21][22][23][24][25][26], the latter have not always been entirely convincingly accounted for. Fifth, and final, most of the information on the mechanisms of action for metformin are currently derived from experimental research [30][31][32][33][34][35]37,39] and need further clinical study.…”

“…In addition, metformin may exert cardioprotective actions, possibly by AMPK activation and reduced cardiac fibrosis [30][31][32][33][34][35]37]. However, we need longer follow-up data and more information as to the role of the severity of HF.…”