Abstract 162 Cardiology: Mouse Models and Basic Mechanisms of Cardiac Disease Platform, Tuesday, 5/4

Mitochondrial myopathies are characterized by exercise intolerance, muscle weakness, lactic acidosis, hypertrophic cardiomyopathy, and ragged-red muscle fibers. Sengers syndrome is an example of a human mitochondrial myopathy which results from absent or abnormal expression of the adenine nucleotide translocator protein ANT1. Adenine nucleotide translocators (ANT) are a group of nuclear-encoded proteins responsible for exchange of ADP for ATP across the inner mitochondrial membrane. In cardiac myocytes ANT1 is the predominant member of this family. Its absence results in diminished oxidative phosphorylation and subsequent mitochondrial energy deficiency. Graham et. al [Nat Genet, 1997] reported the development of an Ant1-deficient mouse strain which develops the characteristic findings of a mitochondrial myopathy, including hypertrophic cardiomyopathy by six months of age. To characterize the in-vivo cardiac morphology and cardiac function of these mice, and the progression of cardiac disease, we studied three control and four Ant1-deficient mice at two years of age using echocardiography. A Hewlett Packard 5500 cardiac ultrasound system with a 12 MHz phased array transducer was used to obtain aortic pulsed-wave Doppler and long and short-axis 2-D images and M-mode tracings of the left ventricle. The following parameters were measured in systole and diastole: left ventricular inner diameter (LVIDs and LVIDd), left ventricular posterior wall thickness (PWs and PWd), and interventricular septum thickness (IVSs and IVSd). Estimated left ventricular mass (LVM), fractional shortening (%FS), and cardiac output (CO) were calculated. Two mutant mice showed evidence of severe dysfunction, with dilated, poorly contractile ventricles, and increased LVM. For the group, mean LVIDd was 0.68 (mutant) vs. 0.44 cm (control), LVM was 0.24 vs. 0.11 g, %FS was 20 vs. 41, and CO was 16.6 vs. 40.2 ml/min. Conclusion: We have demonstrated that bioenergetic insufficiency in the Ant1-deficient mouse strain can lead to development of dilated cardiomyopathy with hypertrophy of the left ventricle.