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Articles in PresS, published online ahead of print October 31, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00619.2002
Submitted on July 18, 2002
Accepted on October 15, 2002
1 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA
2 Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA
3 Department of Surgery, Duke University Medical Center, Durham, NC, USA
* To whom correspondence should be addressed. E-mail: leslie.leinwand{at}colorado.edu.
Familial Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disease characterized by varying degrees of ventricular hypertrophy and myofibrillar disarray. Mutations in cardiac contractile proteins cause HCM. However, there is unexplained wide variability in the clinical phenotype and it is likely that there are multiple contributing factors. Since mitochondrial dysfunction has been described in heart disease, we tested the hypothesis that mitochondrial dysfunction contributes to the varying HCM phenotypes. Mitochondrial function was assessed in two transgenic models of HCM: mutant MyHC and missense mutant cTnT (R92Q) mice. Despite mitochondrial ultrastructural abnormalities in both models, the rate of State 3 respiration was significantly decreased only in the mutant MyHC mice by approximately 23%. Notably, this decrease in State 3 respiration preceded hemodynamic dysfunction. The maximum activity of 
-ketogutarate dehydrogenase as assayed in isolated disrupted mitochondria was decreased by 28% as compared to isolated control mitochondria. In addition, Complexes I and IV were decreased in mutant MyHC transgenic mice. Inhibition of the 
-adrenergic receptor kinase, which is elevated in mutant MyHC mouse hearts can prevent mitochondrial respiratory impairment in mutant MyHC mice. Thus, our results suggest that mitochondria may contribute to hemodynamic dysfunction seen in some forms of HCM and offer a plausible mechanism responsible for some of the heterogeneity of the disease phenotypes.
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