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| Cardiac Insulin Resistance as a Risk Factor for Heart Failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Paulo Amorim, T. Dung Nguyen, Andrea Schrepper, Claudia Hain, Yasushige Shingu, Friedrich W. Mohr, Torsten Doenst; Herzzentrum Leipzig, Leipzig, Germany Objective: Pressure overload and ischemic heart disease are the two most common causes of heart failure (HF). Defects in mitochondrial substrate oxidation (SOX) are thought to play a causal role (Neubauer NEJM 2009). Insulin resistance (IR) affects SOX and mitochondrial function. Clinically, systemic IR is an independent predictor of HF and cardiovascular mortality. However, it is not clear whether IR also affects the heart. Our aims were: First, to assess whether cardiac insulin signaling is impaired in HF. Second, to determine that cardiac IR is associated with diminished SOX and the development of HF. Methods: HF was induced in rats by either ligation of the left anterior descending artery (LAD) or transverse aortic constriction (TAC). Two weeks after LAD ligation or 2, 10 and 20 weeks after TAC, cardiac size and function were determined by echocardiography, glucose (GO) and fatty acid (FAO) oxidation rates as well as insulin response were measured in the isolated working heart using radioactive tracers, and the hyperinsulinemic, euglycemic clamp was used to determine whole body insulin sensitivity. Finally, maximal respiratory capacity (state 3) was measured in isolated mitochondria. Results: The Table summarizes the key results (*=p<0,05). Echocardiography revealed left ventricular dilation, and impaired contractility two weeks after LAD ligation and 20 weeks after TAC. Animals presented dyspnea and pleural effusions as signs of HF. At 2 and 10 weeks of TAC, hearts were hypertrophied with normal contractile function. Both LAD ligation and TAC caused less power generation and reduced fatty acid and glucose oxidation in the isolated working heart. Importantly, insulin response was dramatically reduced in HF. However, the expected increase in GO (ΔGO) and decrease in FAO (ΔFAO) were already significantly blunted at 10 weeks of TAC, where contractile and mitochondrial function were still preserved. In contrast, the hyperinsuliemic, euglycemic clamp demonstrated normal whole body glucose utilization (Sham: 25,1±6,2; PO: 27,7±3,9; p=NS), suggesting the presence of cardiac IR in the absence of systemic IR. Conclusion: Cardiac insulin resistance appears to be a risk factor for heart failure (in both ischemic and pressure overload HF), independent of systemic IR. The temporal sequence of events suggests that the onset of cardiac IR may trigger mitochondrial and contractile dysfunction.
Control: Correspond to 10 weeks TAC-Sham since there were no significant differences between Sham groups. n.d.: not determined yet. Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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