title: Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats.
abstract: 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.
authors.affiliation: Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. jan.benes@ikem.cz
authors.forename: Jan
authors.initials: J
authors.lastname: Benes
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kazdova
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Drahota
authors.forename: Josef
authors.initials: J
authors.lastname: Houstek
authors.forename: Dasa
authors.initials: D
authors.lastname: Medrikova
authors.forename: Jan
authors.initials: J
authors.lastname: Kopecky
authors.forename: Nikola
authors.initials: N
authors.lastname: Kovarova
authors.forename: Marek
authors.initials: M
authors.lastname: Vrbacky
authors.forename: David
authors.initials: D
authors.lastname: Sedmera
authors.forename: Hynek
authors.initials: H
authors.lastname: Strnad
authors.forename: Michal
authors.initials: M
authors.lastname: Kolar
authors.forename: Jiri
authors.initials: J
authors.lastname: Petrak
authors.forename: Oldrich
authors.initials: O
authors.lastname: Benada
authors.forename: Petra
authors.initials: P
authors.lastname: Skaroupkova
authors.forename: Ludek
authors.initials: L
authors.lastname: Cervenka
authors.forename: Vojtech
authors.initials: V
authors.lastname: Melenovsky
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006003:Glycogen / Q000378:metabolism; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000097:blood / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects; D008168:Lung / Q000473:pathology; D008297:Male; D008687:Metformin / Q000097:blood / Q000627:therapeutic use*; D008929:Mitochondria, Heart / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D014463:Ultrasonography
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D006003:Glycogen; D008687:Metformin; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases