title: Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure.
abstract: Metformin 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(-1)·day(-1)). 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 ± 3.2 vs. 38.0 ± 2.2%, P < 0.05). Moreover, metformin resulted in less left ventricular dilatation (6.0 ± 0.4 vs. 7.6 ± 0.6 mm, P < 0.05) and preservation of left ventricular ejection fraction (65.8 ± 3.7% vs. 48.6 ± 5.6%, P < 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 < 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.
authors.affiliation: University Medical Center Groningen, Thorax Center, Department of Cardiology, University of Groningen, The Netherlands.
authors.forename: Meimei
authors.initials: M
authors.lastname: Yin
authors.forename: Iwan C C
authors.initials: IC
authors.lastname: van der Horst
authors.forename: Joost P
authors.initials: JP
authors.lastname: van Melle
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Herman H W
authors.initials: HH
authors.lastname: Silljé
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D009320:Atrial Natriuretic Factor; D008687:Metformin; D055372:AMP-Activated Protein Kinases