Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization

Figures

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  FIGURE 1. Alterations of ventricular electrophysiology and function in Kcna1 ⎯/⎯ mice. (A) Representative surface ECG (lead I) and ventricular electrogram traces after pacing stimulation exhibiting no arrhythmia (top two traces) versus arrhythmia (bottom two traces) responses. (B‐C) Incidence of pacing‐induced ventricular arrhythmia (VA) (B) at baseline and (C) following isoproterenol (ISO) administration (4 mg/kg, i.p.) in WT (n = 29) and KO mice (n = 20). (D) Examples of M‐mode echocardiography images from WT and KO mice showing increased left ventricular internal diameter during systole (LVIDs; dotted white arrow) in KO animals that leads to decreased ejection fraction and fractional shortening. The following parameters are also indicated: left ventricular internal diameter during diastole (LVIDd; solid white arrow); left ventricular anterior and poster wall thickness during systole [(LVAWs; dotted orange arrow) and (LVPWs; dotted yellow arrow), respectively]; and left ventricular anterior and poster wall thickness during diastole [(LVAWd; solid orange arrow) and (LVPWd; solid yellow arrow), respectively]. *, p < 0.05 (Fisher's exact test)

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  FIGURE 2. Effects of Kv1.1 deletion and inhibition on action potential morphology of ventricular cardiomyocytes. (A) Representative whole‐cell patch‐clamp action potential recordings from wild‐type (WT) and Kcna1 ⎯/⎯ (KO) myocytes. (B) Average action potential duration (APD) in WT and KO cells at 30, 50, and 90% repolarization (APD30, APD50, and APD90, respectively) (C) Representative ventricular action potential recordings in a WT cell at baseline (black line) overlaid with the resulting action potential after the application of 10 nM DTX‐K (red line). (D) Average action potential duration (APD) in WT cells at APD30, APD50, and APD90 before (control) and after (DTX‐K) application of 10 nM DTX‐K. Sample numbers (n) indicate numbers of myocytes and mice. *, p < 0.05 (2‐tailed unpaired Student's t‐test); **, p < 0.01 (2‐tailed paired Student's t‐test).

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  FIGURE 3. Absence of obvious structural and expression remodeling in Kcna1 ⎯/⎯ mice. (A) Representative images of ventricular sections from WT (n = 5) and KO (n = 5) animals stained with Masson's trichrome to visualize fibrosis. Positive fibrosis staining appears light blue in color. The boxed regions in the upper panels are shown at higher magnification in the lower panels. (B) Relative mRNA expression profile of ion channel subunits important for action potential generation, as measured in left ventricular tissue from WT (n = 13) and KO (n = 10) animals. Expression levels were normalized to Hprt1 as a reference gene.

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  FIGURE 4. Kv1.1 protein is present in both human atria and ventricles. Representative western blot of Kv1.1 protein in two human right atrial (RA) and left ventricular (LV) samples with corresponding densitometric quantification (mean ± standard deviation) of protein levels normalized to GAPDH (loading control) and expressed relative to atrial Kv1.1 expression