Circulation Research. 2004
Published online before print December 23, 2004, doi: 10.1161/01.RES.0000154079.20681.B9
Published online before print December 23, 2004, doi: 10.1161/01.RES.0000154079.20681.B9
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Submitted on February 26, 2004
Revised on December 9, 2004
Accepted on December 13, 2004
Transgenic Expression of FATP1 in the Heart Causes Lipotoxic Cardiomyopathy
Hsiu-Chiang Chiu ;
From the Center for Cardiovascular Research (H.-C.C., A.K., R.M.B., X.H., M.C., C.J.W., K.A.Y., N.S., K.M.O., D.S.O., J.E.S.) and Departments of Molecular Biology and Pharmacology (S.B., H.X., J.M.N., J.E.S.) and Radiology (M.J.W., N.M.F., T.L.S.) and Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Internal Medicine (X.H.), Washington University School of Medicine, St Louis, Mo.
* To whom correspondence should be addressed. E-mail: jschaff{at}wustl.edu.
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 QTc intervals, reflecting reductions in the densities of repolarizing, voltage-gated K+ 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 • metabolism • cardiomyopathy
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