title: Unloaded rat hearts in vivo express a hypertrophic phenotype of cardiac repolarization.
abstract: Cardiac unloading with left ventricular assist devices is increasingly used to treat patients with severe heart failure. Unloading has been shown to improve systolic and diastolic function, but its impact on the repolarization of left ventricular myocytes is not known. Unloaded hearts exhibit similar patterns of gene expression as hearts subjected to an increased hemodynamic load. We therefore hypothesized that cardiac unloading also replicates the alterations in action potential and underlying repolarizing ionic currents found in pressure-overload induced cardiac hypertrophy. Left ventricular unloading was induced by heterotopic heart transplantation in syngenic male Lewis rats. Action potentials and underlying K+ and Ca2+ currents were investigated using whole-cell patch-clamp technique. Real-time RT-PCR was used to quantify mRNA expression of Kv4.2, Kv4.3, and KChIP2. Unloading markedly prolonged cardiac action potentials and suppressed the amplitude of several repolarizing K+ currents, in particular of the transient outward K+ current I(to), in both, epicardial and endocardial myocytes. The reduction of I(to) was associated with significantly lower levels of Kv4.2 and Kv4.3 mRNAs in epicardial myocytes, and of KChIP2 mRNA in endocardial myocytes. Concomitantly, the L-type Ca2+ current was increased in myocytes of unloaded hearts. Collectively, these results show that left ventricular unloading induces a profound remodelling of cardiac repolarization with action potential prolongation, downregulation of repolarizing K+ currents and upregulation of the L-type Ca2+ current. This indicates that unloaded rat hearts in vivo express a hypertrophic phenotype of cardiac repolarization at the cellular and the molecular level.
authors: Institut für Vegetative Physiologie und Pathophysiologie, Universitätsklinikum Hamburg Eppendorf, Germany. schwoere@uke.uni-hamburg.de
authors: Alexander Peter
authors: AP
authors: Schwoerer
authors: Ivan
authors: I
authors: Melnychenko
authors: Diane
authors: D
authors: Goltz
authors: Nils
authors: N
authors: Hedinger
authors: Irene
authors: I
authors: Broichhausen
authors: Ali
authors: A
authors: El-Armouche
authors: Thomas
authors: T
authors: Eschenhagen
authors: Tilmann
authors: T
authors: Volk
authors: Heimo
authors: H
authors: Ehmke
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology*; D004699:Endocardium / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000378:metabolism; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051672:Shal Potassium Channels / Q000378:metabolism
chemical_list: C496758:Kcnip2 protein, rat; D051605:Kv Channel-Interacting Proteins; D012333:RNA, Messenger; D051672:Shal Potassium Channels; D011188:Potassium