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.

Comparative Safety and Effectiveness of Metformin in Patients With Diabetes Mellitus and Heart Failure

“…34 In addition, metformin has been shown to attenuate left ventricular remodeling, as well as improve cardiac mechanical efficiency and systolic and diastolic indices in insulin resistant rats. 35 Again, whether any of these observed mechanisms occur in humans is less clear.…”

Improvement of Insulin Sensitivity by a Novel Drug Candidate, BGP-15, in Different Animal Studies

“…The doses of these latter drugs were selected as described. 17 Effect of BGP-15 on insulin sensitivity in combination with a sulfonylurea antidiabetic drug in GK rats…”

The Effect of Metformin Use on Left Ventricular Ejection Fraction and Mortality Post-Myocardial Infarction

“…It is the only oral hypoglycemic agent that has been shown to reduce cardiovascular events and improve survival in patients with diabetes and significant cardiovascular risk factors [9][10][11]. The improvement in all-cause mortality correlates with improved LV function reported in animal models of heart failure following coronary occlusion or sustained hypertension [12][13][14]. Only one published study so far has demonstrated a beneficial effect of metformin on LV diastolic function as evident by improved isovolumetric LV relaxation times and longitudinal tissue velocities measured by tissue Doppler imaging in patients with DM [15].…”