Early remodeling of repolarizing K⁺ currents in the αMHC^403/+ 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^403/+ 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 (10–12 week) male αMHC^403/+ 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_K,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, I_to,f, I_to,s and I_K,slow, were significantly lower in αMHC^403/+, compared with WT, septum cells, whereas I_ss amplitudes were similar. The amplitudes/densities of I_K,peak and I_K,slow were also lower in αMHC^403/+, compared with WT, LV wall and LV apex myocytes, whereas I_to,f was attenuated in αMHC^403/+ LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the αMHC^403/+ 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 (10–12 week) αMHC^403/+ mice, although this transcriptional remodeling was not correlated with the observed decreases in K⁺ current amplitudes.