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Decreased contractility due to energy deprivation in a transgenic rat model of hypertrophic cardiomyopathy.

M. Luedde, U. Flögel, M. Knorr, C. Grundt, H. Hippe, B. Brors, D. Frank, U. Haselmann, C. Antony, M. Voelkers, J. Schrader, P. Most, B. Lemmer, H. Katus, and N. Frey. J Mol Med (Berl) 87 (4): 411--422 (April 2009)

Abstract

Hypertrophic cardiomyopathy (HCM) is associated with cardiac hypertrophy, diastolic dysfunction, and sudden death. Recently, it has been suggested that inefficient energy utilization could be a common molecular pathway of HCM-related mutations. We have previously generated transgenic Sprague-Dawley rats overexpressing a truncated cardiac troponin T (DEL-TNT) molecule, displaying typical features of HCM such as diastolic dysfunction and an increased susceptibility to ventricular arrhythmias. We now studied these rats using 31P magnetic resonance spectroscopy (MRS). MRS demonstrated that cardiac energy metabolism was markedly impaired, as indicated by a decreased phosphocreatine to ATP ratio (-31\%, p < 0.05). In addition, we assessed contractility of isolated cardiomyocytes. While DEL-TNT and control cardiomyocytes showed no difference under baseline conditions, DEL-TNT cardiomyocytes selectively exhibited a decrease in fractional shortening by 28\% after 1 h in glucose-deprived medium (p < 0.05). Moreover, significant decreases in contraction velocity and relaxation velocity were observed. To identify the underlying molecular pathways, we performed transcriptional profiling using real-time PCR. DEL-TNT hearts exhibited induction of several genes critical for cardiac energy supply, including CD36, CPT-1/-2, and PGC-1alpha. Finally, DEL-TNT rats and controls were studied by radiotelemetry after being stressed by isoproterenol, revealing a significantly increased frequency of arrhythmias in transgenic animals. In summary, we demonstrate profound energetic alterations in DEL-TNT hearts, supporting the notion that inefficient cellular ATP utilization contributes to the pathogenesis of HCM.

Links and resources

DOI:
10.1007/s00109-008-0436-x
URL:
http://dx.doi.org/10.1007/s00109-008-0436-x
BibTeX key:
Luedde2009
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