Aims Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital-twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. Methods and Results Computational models of human HCM cardiomyocytes, tissue and ventricles were used to simulate outcomes of phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n=12 cells, N=5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N=28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarisation, and (iii) ischaemia, impaired repolarisation, and diffuse fibrosis. HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of c.a. 75,000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia-fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. Conclusions HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.

中文翻译：

---

肥厚型心肌病缺血诱发心律失常的机制：大规模计算研究

肥厚型心肌病 (HCM) 中的致死性心律失常广泛归因于心肌缺血和纤维化。这些因素如何调节心律失常风险仍然很大程度上未知，特别是因为这些患者不常规使用侵入性标测方案。通过利用多尺度数字孪生技术，我们的目标是研究 HCM 心律失常风险增加的缺血机制。方法和结果 人类 HCM 心肌细胞、组织和心室的计算模型用于模拟 1A 期急性心肌缺血的结果。细胞反应预测通过人 HCM 心肌细胞（n=12 个细胞，N=5 名患者）的膜片钳研究进行了验证。通过灌注扫描分析的心内膜下/透壁缺血的典型分布来进行心室模拟（N=28 名患者）。 S1-S2 起搏方案用于量化间隔阻塞性肥大区域受到 (i) 缺血，(ii) 缺血和复极受损，以及 (iii) 缺血、复极受损和弥漫性纤维化影响的情况下的心律失常风险。 HCM 心肌细胞表现出动作电位增强和缺血性损伤异常有效不应期缩短。对大约 75,000 个折返诱导病例的分析表明，与健康心肌相比，异常的 HCM 细胞反应能够在较轻度缺血的情况下形成心律失常，因为更大的不应梯度会促进传导阻滞。透壁缺血比心内膜下缺血更容易持续心律失常。缺血-纤维化相互作用的机制强烈依赖于电生理学。纤维化导致不对称折返模式并分解为持续性室性心动过速。结论 HCM 心室表现出非持续和持续折返的风险增加，这主要是由于细胞反应受损以及与弥漫性纤维化基质的有害相互作用所致。