title: Early remodeling of repolarizing K+currents in the αMHC403/+mouse model of familial hypertrophic cardiomyopathy.
abstract: Familial hypertrophic cardiomyopathy (HCM), linked to mutations in myosin, myosin-binding proteins and other sarcolemmal proteins, is associated with increased risk of life threatening ventricular arrhythmias, and a number of animal models have been developed to facilitate analysis of disease progression and mechanisms. In the experiments here, we use the αMHC403/+mouse line in which one αMHC allele harbors a common HCM mutation (in βMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male αMHC403/+mice, well in advance of the onset of measurable left ventricular hypertrophy. Electrophysiological recordings from myocytes isolated from the interventricular septum of these animals revealed significantly (P<0.001) lower peak repolarizing voltage-gated K+(Kv) current (IK,peak) amplitudes, compared with cells isolated from wild type (WT) littermate controls. Analysis of Kv current waveforms revealed that the amplitudes of the inactivating components of the total outward Kv current, Ito,f, Ito,sand IK,slow, were significantly lower in αMHC403/+, compared with WT, septum cells, whereas Issamplitudes were similar. The amplitudes/densities of IK,peakand IK,slowwere also lower in αMHC403/+, compared with WT, LV wall and LV apex myocytes, whereas Ito,fwas attenuated in αMHC403/+LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the αMHC403/+mice would be expected to increase the dispersion of ventricular repolarization and be proarrhythmic. Quantitative RT-PCR analysis revealed reductions in the expression of transcripts encoding several K+channel subunits in the interventricular septum, LV free wall and LV apex of (10-12week) αMHC403/+mice, although this transcriptional remodeling was not correlated with the observed decreases in K+current amplitudes.
authors.affiliation: Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA; Department of Anesthesiology, Washington University Medical School, St. Louis, MO 63110-1093, USA.
authors.forename: Rocco
authors.initials: R
authors.lastname: Hueneke
authors.affiliation: Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Adenwala
authors.affiliation: Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA; Department of Medicine, Washington University Medical School, St. Louis, MO 63110-1093, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Mellor
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.affiliation: Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA; Department of Medicine, Washington University Medical School, St. Louis, MO 63110-1093, USA. Electronic address: jnerbonne@wustl.edu.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Nerbonne
mesh_terms: D000200:Action Potentials; D000818:Animals; D001706:Biopsy; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography; D004562:Electrocardiography; D015870:Gene Expression; D020869:Gene Expression Profiling; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D024723:Ventricular Myosins / Q000235:genetics*; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D015221:Potassium Channels; D024723:Ventricular Myosins
keywords: ECG; Electrical remodeling; Hypertrophy; Kv currents; QT interval; Repolarization; Transcriptional remodeling