Abstract 5386: The Development of Heart Failure in Rats is Associated with Impaired Insulin Response and Mitochondrial Dysfunction
Insulin regulates mitochondrial OXPHOS expression, and a link between mitochondrial dysfunction and insulin resistance (IR) has been established in various tissues. Recent reports demonstrated that IR and/or mitochondrial dysfunction can occur in failing hearts. We hypothesized that IR may precede onset of mitochondrial dysfunction in the development of heart failure following pressure overload. Male Sprague-Dawley rats were subjected to transverse aortic constriction (TAC) for 10 or 20 weeks, or rats were trained on a treadmill for 10 weeks. Left ventricular posterior wall thickness was increased (LVPWD: 2.6±0.2 vs. 1.4±0.2mm; p<0.05) and ejection fraction (EF) was unaltered (76%–63%) following 10 weeks of TAC, indicating compensated hypertrophy. In contrast, 20 weeks of TAC resulted in reduced EF (53±8 vs. 75±6%; p<0.05), indicating heart failure. Treadmill training resulted in increased LVPWD (1.7±0.1 vs. 1.9±0.1mm; p<0.05) and normal EF (75±3 vs. 70±1%), indicating physiologic hypertrophy. State 3 respiration of isolated mitochondria was unchanged in both types of hypertrophy but significantly reduced in heart failure (natomsO/min/mg protein: glutamate 200±16 vs. 585±92, palmitoyl-carnitine 193±15 vs. 802±75, pyruvate 198±29 vs. 549±87, succinate 405±39 vs. 720±80; all p<0.05). While insulin increased glucose oxidation in isolated working hearts of exercise-trained animals, this response was significantly blunted in animals with pressure overload hypertrophy and failure. The mitochondrial marker enzyme, citrate synthase, was significantly reduced in hearts with heart failure (U/g wet weight: 24.6±2.1 vs. 5.1±0.8). Hearts with physiologic hypertrophy demonstrated a normal mitochondrial geno- and phenotype associated with normal insulin sensitivity. Thus pressure overload causes insulin resistance which precedes the onset of mitochondrial and contractile dysfunction. It is tempting to speculate that the development of IR may be involved in the mechanism causing pressure overload induced heart failure.