Early remodeling of repolarizing K currents in the αMHC mouse model of familial hypertrophic cardiomyopathy.

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 αMHC 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 αMHC 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 (I) 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, I, I and I, were significantly lower in αMHC, compared with WT, septum cells, whereas I amplitudes were similar. The amplitudes/densities of I and I were also lower in αMHC, compared with WT, LV wall and LV apex myocytes, whereas I was attenuated in αMHC LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the αMHC 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) αMHC mice, although this transcriptional remodeling was not correlated with the observed decreases in K current amplitudes.