Meier Stefan, Dobrev Dobromir, Volders Paul G A, Heijman Jordi
Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Health, Medicine, and Life Sciences, Maastricht University and Maastricht University Medical Center, Maastricht, The Netherlands.
Institute of Pharmacology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany.
J Physiol. 2025 Jul 20. doi: 10.1113/JP288659.
Small-conductance calcium-activated potassium (SK) channels are promising targets for atrial-specific antiarrhythmic therapies, with evidence suggesting tachycardia-dependent SK-channel upregulation. However, the dynamics of SK-channel gating and trafficking in human atrial electrophysiology remain unclear because of experimental limitations, including the availability of human cardiomyocytes and long patch clamp experiments. Although computational models help explore these mechanisms, none integrate SK-channel trafficking. In the present study, we expanded our K11.1 trafficking model to simulate rate-dependent SK-channel trafficking in a human atrial cardiomyocyte model. Calibrated against experimental data, our model replicates time- and rate-dependent SK-channel function, allowing simulations of SK-channel trafficking and its effects on action potentials. Tachypacing at 5 Hz increased SK-channel density, enhancing SK current and shortening action potential duration, with or without calcium buffering. Two-dimensional tissue simulations with physiological calcium handling showed that tachycardia increased re-entry duration and ectopic activity. SK-channel inhibition reduced re-entry duration but promoted ectopic activity, suggesting a reduction in atrial fibrillation burden rather than complete elimination. Our novel computational model highlights SK channels' role in re-entry-promoting effects of short atrial tachycardia episodes, offering insights into early atrial fibrillation progression and potential antiarrhythmic strategies. KEY POINTS: Small-conductance calcium-activated potassium (SK) channels have emerged as potential targets for atrial-specific antiarrhythmic therapies, especially in atrial fibrillation (AF). Emerging evidence suggests that tachycardia-induced SK-channel trafficking can regulate cardiac cellular electrophysiology over minutes, but investigating its impact on arrhythmogenesis in humans is experimentally challenging. We adapted our recent in silico K11.1 trafficking model to simulate SK-channel trafficking and incorporated it into a human atrial cardiomyocyte model, which was calibrated based on experimental results. Tachypacing at 5 Hz led to a substantial increase in SK channel-density at the membrane, resulting in enhanced SK current and a reduction in action potential duration. 2-D tissue simulations demonstrated that rapid pacing promoted both re-entry and ectopic (triggered) activity. Blocking SK channels reduced re-entry duration but increased ectopic activity, suggesting that SK channel inhibition could decrease AF burden, but may not eliminate AF per se.
小电导钙激活钾（SK）通道是心房特异性抗心律失常治疗的有前景的靶点，有证据表明心动过速依赖的SK通道上调。然而，由于实验限制，包括人类心肌细胞的可用性和长时间的膜片钳实验，SK通道门控和转运在人类心房电生理学中的动态仍不清楚。尽管计算模型有助于探索这些机制，但没有一个模型整合了SK通道的转运。在本研究中，我们扩展了我们的K11.1转运模型，以模拟人类心房心肌细胞模型中速率依赖性的SK通道转运。根据实验数据进行校准后，我们的模型复制了时间和速率依赖性的SK通道功能，从而能够模拟SK通道的转运及其对动作电位的影响。在5Hz的快速起搏下，无论有无钙缓冲，SK通道密度都会增加，增强SK电流并缩短动作电位持续时间。具有生理钙处理的二维组织模拟表明，心动过速会增加折返持续时间和异位活动。SK通道抑制减少了折返持续时间，但促进了异位活动，这表明房颤负担会减轻，但不会完全消除。我们的新型计算模型突出了SK通道在短阵房性心动过速发作的折返促进作用中的作用，为早期房颤进展和潜在的抗心律失常策略提供了见解。要点：小电导钙激活钾（SK）通道已成为心房特异性抗心律失常治疗的潜在靶点，尤其是在房颤（AF）中。新出现的证据表明，心动过速诱导的SK通道转运可在数分钟内调节心脏细胞电生理学，但研究其对人类心律失常发生的影响在实验上具有挑战性。我们改编了我们最近的计算机模拟K11.1转运模型以模拟SK通道转运，并将其纳入人类心房心肌细胞模型，该模型基于实验结果进行了校准。在5Hz的快速起搏下，膜上的SK通道密度大幅增加，导致SK电流增强，动作电位持续时间缩短。二维组织模拟表明，快速起搏促进了折返和异位（触发）活动。阻断SK通道减少了折返持续时间，但增加了异位活动，这表明抑制SK通道可减轻房颤负担，但可能无法消除房颤本身。
