Key result
In silico simulations of a transmural ventricular fiber indicated that SK channel block may prolong the QT interval and increase the transmural dispersion of repolarization, potentially increasing the risk of arrhythmia in heart failure.
Why the study?
The pathophysiological role and contribution of small conductance calcium-activated potassium (SK) channels to ventricular repolarization in human failing myocytes remain unclear.
Does SK channel inhibition alter ventricular repolarization and arrhythmic risk markers in an in silico model of failing human myocytes?
Does SK channel inhibition alter ventricular repolarization and arrhythmic risk markers in an in silico model of failing human myocytes?
In silico modeling suggests that SK channels play a crucial role in HF-induced ventricular remodeling, and their pharmacological inhibition could increase arrhythmic risk by prolonging the QT interval and increasing transmural dispersion of repolarization.
SK channel block may raise arrhythmia risk in HF; leaves open clinical relevance pending in vivo validation.
OBJECTIVE: The pathophysiological role of the small conductance calcium-activated potassium (SK) channels in human ventricular myocytes remains unclear. Experimental studies have reported upregulation of SK channels in pathological states, potentially contributing to ventricular repolarization. In heart failure (HF) patients, this upregulation could be an adaptive physiological response to shorten the action potential duration (APD) under conditions of reduced repolarization reserve. This work aimed to uncover the contribution of SK channels to ventricular repolarization in failing myocytes. METHODS: We extended an in silico electrophysiological model of human ventricular failing myocytes by including SK channel activity. To calibrate the maximal SK current conductance (G_SK), we simulated action potentials (APs) at different pacing frequencies and matched the AP duration changes induced by SK channel inhibition or activation to different available experimental data from human failing ventricles for adjustment. RESULTS: The optimal value obtained for G_SK was 4.288 μS/μF in mid-myocardial cells, and 6.4 μS/μF for endocardial and epicardial cells. The output of the models was compared with independent experimental data for validation. 1-D simulations of a transmural ventricular fiber indicated that SK channel block may prolong the QT interval and increase the transmural dispersion of repolarization, potentially increasing the risk of arrhythmia in HF. CONCLUSION: Our results highlight the importance of considering the SK channels to improve the characterization of HF-induced ventricular remodeling. Simulations across various single-cell and 1-D scenarios suggest that pharmacological SK channel inhibition could lead to adverse effects in failing ventricles.
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Gómez-Gómez et al. (2024) studied Heart failure. SK channel inhibition vs. Failing conditions without SK block was evaluated on Action potential duration (APD) and transmural dispersion of repolarization. In silico simulations of a transmural ventricular fiber indicated that SK channel block may prolong the QT interval and increase the transmural dispersion of repolarization, potentially increasing the risk of arrhythmia in heart failure.
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