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.