Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats
Language English Country England, Great Britain Media print
Document type Journal Article
PubMed
21275906
DOI
10.1042/cs20100527
PII: CS20100527
Knihovny.cz E-resources
- MeSH
- Survival Analysis MeSH
- Glycogen metabolism MeSH
- Hemodynamics drug effects MeSH
- Hypoglycemic Agents blood therapeutic use MeSH
- AMP-Activated Protein Kinase Kinases MeSH
- Blood Glucose metabolism MeSH
- Rats MeSH
- Lipid Metabolism drug effects MeSH
- Metformin blood therapeutic use MeSH
- Disease Models, Animal MeSH
- Myocardium metabolism pathology MeSH
- Lung pathology MeSH
- Rats, Wistar MeSH
- Drug Evaluation, Preclinical MeSH
- Protein Kinases metabolism MeSH
- Mitochondria, Heart physiology MeSH
- Heart Failure diagnostic imaging drug therapy physiopathology MeSH
- Body Weight drug effects MeSH
- Ultrasonography MeSH
- Organ Size drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Glycogen MeSH
- Hypoglycemic Agents MeSH
- AMP-Activated Protein Kinase Kinases MeSH
- Blood Glucose MeSH
- Metformin MeSH
- Protein Kinases MeSH
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.
References provided by Crossref.org
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Metabolic characterization of volume overload heart failure due to aorto-caval fistula in rats