Document Detail

Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats.
MedLine Citation:
PMID:  21275906     Owner:  NLM     Status:  MEDLINE    
Advanced HF (heart failure) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. The antihyperglycaemic drug MET (metformin) affects substrate metabolism, and its use might be associated with improved outcome in diabetic HF. The aim of the present study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Volume-overload HF was induced in male Wistar rats by creating ACF (aortocaval fistula). Animals were randomized to placebo/MET (300 mg·kg(-1) of body weight·day(-1), 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6-12/group) in advanced HF stage (week 21). A separate cohort served for survival analysis (n=10-90/group). The ACF group had marked cardiac hypertrophy, increased LVEDP (left ventricular end-diastolic pressure) and lung weight confirming decompensated HF, increased circulating NEFAs (non-esterified 'free' fatty acids), intra-abdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triacylglycerol (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 NEFAs, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK (AMP-activated protein kinase) signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival, despite reaching therapeutic serum levels (2.2±0.7 μg/ml). In conclusion, MET-induced enhancement of myocardial fatty acid oxidation had a 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.
Jan Benes; Ludmila Kazdova; Zdenek Drahota; Josef Houstek; Dasa Medrikova; Jan Kopecky; Nikola Kovarova; Marek Vrbacky; David Sedmera; Hynek Strnad; Michal Kolar; Jiri Petrak; Oldrich Benada; Petra Skaroupkova; Ludek Cervenka; Vojtech Melenovsky
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Clinical science (London, England : 1979)     Volume:  121     ISSN:  1470-8736     ISO Abbreviation:  Clin. Sci.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-03-18     Completed Date:  2011-06-02     Revised Date:  2011-10-20    
Medline Journal Info:
Nlm Unique ID:  7905731     Medline TA:  Clin Sci (Lond)     Country:  England    
Other Details:
Languages:  eng     Pagination:  29-41     Citation Subset:  IM    
Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
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MeSH Terms
Blood Glucose / metabolism
Body Weight / drug effects
Disease Models, Animal
Drug Evaluation, Preclinical
Glycogen / metabolism
Heart Failure / drug therapy*,  physiopathology,  ultrasonography
Hemodynamics / drug effects
Hypoglycemic Agents / blood,  therapeutic use*
Lipid Metabolism / drug effects
Lung / pathology
Metformin / blood,  therapeutic use*
Mitochondria, Heart / physiology
Myocardium / metabolism,  pathology
Organ Size / drug effects
Protein Kinases / metabolism
Rats, Wistar
Survival Analysis
Reg. No./Substance:
0/Blood Glucose; 0/Hypoglycemic Agents; 657-24-9/Metformin; 9005-79-2/Glycogen; EC 2.7.-/Protein Kinases; EC 2.7.1.-/AMP-activated protein kinase kinase

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