Department of Computer Science, University of Oxford, Wolfson Building, Parks Road, Oxford, OX1 3QD, UK.
Discovery Toxicology, Bristol Myers Squibb, Lawrenceville, NJ, USA.
Sci Rep. 2024 Jul 29;14(1):17351. doi: 10.1038/s41598-024-65249-0.
Chronic heart failure is one of the most common reasons for hospitalization. Current risk stratification is based on ejection fraction, whereas many arrhythmic events occur in patients with relatively preserved ejection fraction. We aim to investigate the mechanistic link between proarrhythmic abnormalities, reduced contractility and diastolic dysfunction in heart failure, using electromechanical modelling and simulations of human failing cardiomyocytes. We constructed, calibrated and validated populations of human electromechanical models of failing cardiomyocytes, that were able to reproduce the prolonged action potential, reduced contractility and diastolic dysfunction as observed in human data, as well as increased propensity to proarrhythmic incidents such as early afterdepolarization and beat-to-beat alternans. Our simulation data reveal that proarrhythmic incidents tend to occur in failing myocytes with lower diastolic tension, rather than with lower contractility, due to the relative preserved SERCA and sodium calcium exchanger current. These results support the inclusion of end-diastolic volume to be potentially beneficial in the risk stratifications of heart failure patients.
慢性心力衰竭是住院的最常见原因之一。目前的风险分层基于射血分数，而许多心律失常事件发生在射血分数相对保留的患者中。我们旨在使用人类衰竭心肌细胞的机电建模和模拟来研究心律失常异常、收缩力降低和舒张功能障碍之间的机制联系。我们构建、校准和验证了人类衰竭心肌细胞机电模型的群体，这些模型能够再现人类数据中观察到的动作电位延长、收缩力降低和舒张功能障碍，以及增加早期后除极和搏动间交替等致心律失常事件的倾向。我们的模拟数据表明，由于相对保留的 SERCA 和钠钙交换体电流，致心律失常事件往往发生在舒张张力较低的衰竭心肌细胞中，而不是收缩力较低的细胞中。这些结果支持将舒张末期容积纳入心力衰竭患者的风险分层中可能具有益处。
