Inherited and acquired cardiomyopathies are associated with marked intracellular lipid accumulation in the heart. To test the hypothesis that mismatch between myocardial fatty acid uptake and utilization leads to the accumulation of cardiotoxic lipid species, and to establish a mouse model of metabolic cardiomyopathy, we generated transgenic mouse lines that overexpress long-chain acylCoA synthetase in the heart (MHC-ACS). This protein plays an important role in vectorial fatty acid transport across the plasma membrane. MHC-ACS mice demonstrate cardiac-restricted expression of the transgene and marked cardiac myocyte triglyceride accumulation. Lipid accumulation is associated with initial cardiac hypertrophy, followed by the development of left-ventricular dysfunction and premature death. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and cytochrome c release in transgenic hearts suggest that cardiac myocyte death occurs, in part, by lipid-induced programmed cell death. Taken together, our data demonstrate that fatty acid uptake/utilization mismatch in the heart leads to accumulation of lipid species toxic to cardiac myocytes. This novel mouse model will provide insight into the role of perturbations in myocardial lipid metabolism in the pathogenesis of inherited and acquired forms of heart failure.

Abstract-Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the ␣-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT c intervals, reflecting reductions in the densities of repolarizing, voltage-gated K ϩ currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo. Key Words: lipids Ⅲ metabolism Ⅲ cardiomyopathy C ardiomyopathy has been observed in a variety of metabolic disorders. In inherited disorders of ␤-oxidation, accumulation of unmetabolized lipid in cardiac myocytes is associated with ventricular systolic dysfunction. 1 In obesity, increased myocardial oxygen consumption and decreased efficiency may contribute to diastolic and systolic dysfunction. 2,3 In diabetes mellitus, heart failure in the absence of valvular or congenital heart disease, alcoholism, hypertension, or significant epicardial coronary atherosclerosis is defined as diabetic cardiomyopathy and accounts for significant morbidity and mortality in people with type 1 and type 2 diabetes. 4 Echocardiographic and hemodynamic studies suggest left ventricular (LV) diastolic impairment represents an early preclinical manifestation of diabetic cardiomyopathy that may progress over an extended period of time to both diastolic and systolic dysfunction. 5,6 In these metabolic disorders, systemic metabolic perturbations lead to myocyte dysfunction and/or loss. Glucotoxicity, 7 ATP depletion, 8 and maladaptive changes in metabolic substrate utilization 9 are mechanisms proposed to contribute to cardiac dysfunction. It has also been hypothesized that mismatch between tissue free fatty acid (FFA) import and utilization leads to lipid accumulation and results in lipotoxicity. In diabetes, this imbalance results from high-serum F...

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