title: Metformin prevents the development of chronic heart failure in the SHHF rat model.
abstract: Insulin resistance is a recently identified mechanism involved in the pathophysiology of chronic heart failure (CHF). We investigated the effects of two insulin-sensitizing drugs (metformin and rosiglitazone) in a genetic model of spontaneously hypertensive, insulin-resistant rats (SHHF). Thirty SHHF rats were randomized into three treatment groups as follows: 1) metformin (100 mg/kg per day), 2) rosiglitazone (2 mg/kg per day), and 3) no drug. Ten Sprague-Dawley rats served as normal controls. At the end of the treatment period (12 months), the cardiac phenotype was characterized by histology, echocardiography, and isolated perfused heart studies. Metformin attenuated left ventricular (LV) remodeling, as shown by reduced LV volumes, wall stress, perivascular fibrosis, and cardiac lipid accumulation. Metformin improved both systolic and diastolic indices as well as myocardial mechanical efficiency, as shown by improved ability to convert metabolic energy into mechanical work. Metformin induced a marked activation of AMP-activated protein kinase, endothelial nitric oxide synthase, and vascular endothelial growth factor and reduced tumor necrosis factor-α expression and myocyte apoptosis. Rosiglitazone did not affect LV remodeling, increased perivascular fibrosis, and promoted further cardiac lipid accumulation. In conclusion, long-term treatment with metformin, but not with rosiglitazone, prevents the development of severe CHF in the SHHF model by a wide-spectrum interaction that involves molecular, structural, functional, and metabolic-energetic mechanisms.
authors.affiliation: Department of Clinical Medicine and Cardiovascular and ImmunologicalSciences, University Federico II, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cittadini
authors.forename: Raffaele
authors.initials: R
authors.lastname: Napoli
authors.forename: Maria Gaia
authors.initials: MG
authors.lastname: Monti
authors.forename: Domenica
authors.initials: D
authors.lastname: Rea
authors.forename: Salvatore
authors.initials: S
authors.lastname: Longobardi
authors.forename: Paolo Antonio
authors.initials: PA
authors.lastname: Netti
authors.forename: Marion
authors.initials: M
authors.lastname: Walser
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Samà
authors.forename: Gianluca
authors.initials: G
authors.lastname: Aimaretti
authors.forename: Jörgen
authors.initials: J
authors.lastname: Isgaard
authors.forename: Luigi
authors.initials: L
authors.lastname: Saccà
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure; D002908:Chronic Disease; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin; D007333:Insulin Resistance; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D000077154:Rosiglitazone; D008687:Metformin; D040301:Vascular Endothelial Growth Factor Receptor-2