Metformin prevents the development of chronic heart failure in the SHHF rat model.

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Nyckelord

Animals

Blood Glucose

Blood Pressure

Chronic Disease

Gene Expression Regulation

drug effects

Heart Failure

prevention & control

Hypoglycemic Agents

pharmacology

therapeutic use

Insulin

Insulin Resistance

Metformin

pharmacology

therapeutic use

Rats

Rats

Inbred SHR

Rats

Sprague-Dawley

Thiazolidinediones

pharmacology

Vascular Endothelial Growth Factor A

genetics

metabolism

Vascular Endothelial Growth Factor Receptor-2

genetics

metabolism

Ventricular Remodeling

drug effects

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)