title: Decreased contractility due to energy deprivation in a transgenic rat model of hypertrophic cardiomyopathy.
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.
authors.affiliation: Department of Cardiology, University of Heidelberg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Luedde
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flögel
authors.forename: Maike
authors.initials: M
authors.lastname: Knorr
authors.forename: Christina
authors.initials: C
authors.lastname: Grundt
authors.forename: Hans-Joerg
authors.initials: HJ
authors.lastname: Hippe
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Derk
authors.initials: D
authors.lastname: Frank
authors.forename: Uta
authors.initials: U
authors.lastname: Haselmann
authors.forename: Claude
authors.initials: C
authors.lastname: Antony
authors.forename: Mirko
authors.initials: M
authors.lastname: Voelkers
authors.forename: Juergen
authors.initials: J
authors.lastname: Schrader
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
authors.forename: Bjoern
authors.initials: B
authors.lastname: Lemmer
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D048429:Cell Size; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000648:ultrastructure; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020107:Troponin T / Q000235:genetics
chemical_list: D020107:Troponin T; D010725:Phosphocreatine; D000255:Adenosine Triphosphate