The Role And Mechanism Of Cardiac Insulin Resistance In The Development Of Heart Failure Coursed By Myocardial Ischemia

Objective: Recent Clinical research suggests that systemic insulin resistance (IR) isan independent predictor of heart failure (HF) and cardiovascular mortality. However,it is not clear whether IR also affects the heart. It can not be determined whethercardiac insulin resistance is an independent risk factor for heart failure. Our aims were:First, to assess whether cardiac insulin signaling is impaired in HF through rats afterligation of the left coronary artery. Second, to determine that cardiac IR is associatedwith diminished substrate oxidation (SOX) and the development of HF.Methods: HF was induced in rats by ligation of the left anterior descending artery(LAD). Two weeks after LAD ligation, cardiac size and function were determined byechocardiography. The hyperinsulinemic, euglycemic clamp was used to determinewhole body insulin sensitivity. Glucose (GO) and fatty acid (FAO) oxidation rates aswell as insulin response were measured in the isolated working heart. The proteinexpression of p38mitogen-activated protein kinase(MAPK) was evaluated byWestern blotting, ultrastructure by electron microscope.Results: The infarcted hearts were dilated and had a reduced ejection fraction(ejection fraction<50%). The basal glucose oxidation was preserved, but the fatty acidoxidation was significantly reduced. Insulin’s effect on substrate oxidation wassignificantly impaired for both the decrease in fatty acid oxidation and the increase inglucose oxidation. The hyperinsuliemic, euglycemic clamp demonstrated normalwhole body glucose utilization, suggesting the presence of cardiac IR in the absenceof systemic IR. The protein expression of p38mitogen-activated protein kinase ininfracted hearts was significantly reduced, which resulted in mitochondrial dysfunction. Observed by electron microscope, we found that infarcted myocardialcells were swelling, mitochondria were seriously damage.Conclusion: Myocardial infarction in rats caused partial insulin resistance at thelevel of substrate oxidation, which was associated with mitochondrial and cardiaccontractile dysfunction. Mitochondrial dysfunction was characterized by a reducedcapacity to oxidize fatty acids and might have resulted from impaired mitochondrialbiogenesis through the lack of p38mitogen-activated protein kinase. Cardiac insulinresistance appears to be a risk factor for heart failure, independent of systemic IR.