Dasí Albert, Berg Lucas Arantes, Martinez-Navarro Hector, Bueno-Orovio Alfonso, Rodriguez Blanca
Department of Computer Science, University of Oxford, Oxford, UK.
J Physiol. 2024 Nov 18. doi: 10.1113/JP287124.
Virtual evaluation of medical therapy through human-based modelling and simulation can accelerate and augment clinical investigations. Treatment of the most common cardiac arrhythmia, atrial fibrillation (AF), requires novel approaches. This study prospectively evaluates and mechanistically explains three novel pharmacological therapies for AF through in silico trials, including single and combined SK and KP channel block. AF and pharmacological action were assessed in a large cohort of 1000 virtual patients, through 2962 multiscale simulations. Extensive calibration and validation with experimental and clinical data support their credibility. Sustained AF was observed in 654 virtual patients. In this cohort, cardioversion efficacy increased to 82% (535 of 654) through combined SK+KP channel block, from 33% (213 of 654) and 43% (278 of 654) for single SK and KP blocks, respectively. Drug-induced prolongation of tissue refractoriness, dependent on the virtual patient's ionic current profile, explained cardioversion efficacy (atrial refractory period increase: 133.0 ± 48.4 ms for combined vs. 45.2 ± 43.0 and 71.0 ± 55.3 ms for single SK and KP block, respectively). Virtual patients cardioverted by SK channel block presented lower KP densities, while lower SK densities favoured the success of KP channel inhibition. Both ionic currents had a crucial role on atrial repolarization, and thus a synergism resulted from the multichannel block. All three strategies, including the multichannel block, preserved atrial electrophysiological function (i.e. conduction velocity and calcium transient dynamics) and thus its contractile properties (safety). In silico trials identify key factors determining treatment success and the combined SK+KP channel block as a promising strategy for AF management. KEY POINTS: This is a large-scale in silico trial study involving 2962 multiscale simulations. A population of 1000 virtual patients underwent three treatments for atrial fibrillation. Single and combined SK+KP channel block were assessed prospectively. The multi-ion channel inhibition resulted in 82% cardioversion efficacy. In silico trials have broad implications for precision medicine.
通过基于人体的建模和模拟对药物治疗进行虚拟评估，可以加速和增强临床研究。治疗最常见的心律失常——心房颤动（AF），需要新的方法。本研究通过计算机模拟试验前瞻性地评估并从机制上解释了三种用于治疗AF的新型药物疗法，包括单独和联合的SK和KP通道阻滞。通过2962次多尺度模拟，在1000名虚拟患者的大型队列中评估了AF和药物作用。与实验和临床数据进行的广泛校准和验证支持了它们的可信度。在654名虚拟患者中观察到持续性AF。在该队列中，通过联合SK+KP通道阻滞，复律成功率从单独SK阻滞的33%（654例中的213例）和单独KP阻滞的43%（654例中的278例）提高到82%（654例中的535例）。药物诱导的组织不应期延长，取决于虚拟患者的离子电流分布，解释了复律成功率（联合阻滞时心房不应期增加：133.0±48.4毫秒，单独SK和KP阻滞时分别为45.2±43.0毫秒和71.0±55.3毫秒）。通过SK通道阻滞复律的虚拟患者呈现较低的KP密度，而较低的SK密度有利于KP通道抑制的成功。两种离子电流在心房复极化中都起关键作用，因此多通道阻滞产生了协同作用。所有三种策略，包括多通道阻滞，都保留了心房电生理功能（即传导速度和钙瞬变动力学），从而保留了其收缩特性（安全性）。计算机模拟试验确定了决定治疗成功的关键因素，并确定联合SK+KP通道阻滞是一种有前景的AF管理策略。要点：这是一项涉及2962次多尺度模拟的大规模计算机模拟试验研究。1000名虚拟患者群体接受了三种心房颤动治疗。前瞻性评估了单独和联合SK+KP通道阻滞。多离子通道抑制导致82%的复律成功率。计算机模拟试验对精准医学具有广泛意义。
