通过在梗死心室模型上的计算机模拟应用评估工程心脏组织贴片的致心律失常风险。
Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models.
机构信息
School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK; National Heart and Lung Institute, Imperial College London, London, UK.
School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK.
出版信息
Comput Biol Med. 2023 Mar;154:106550. doi: 10.1016/j.compbiomed.2023.106550. Epub 2023 Jan 13.
BACKGROUND
Post myocardial infarction (MI) ventricles contain fibrotic tissue and may have disrupted electrical properties, both of which predispose to an increased risk of life-threatening arrhythmias. Application of epicardial patches obtained from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a potential long-term therapy to treat heart failure resulting from post MI remodelling. However, whether the introduction of these patches is anti- or pro-arrhythmic has not been studied.
METHODS
We studied arrhythmic risk using in silico engineered heart tissue (EHT) patch engraftment on human post-MI ventricular models. Two patient models were studied, including one with a large dense scar and one with an apparent channel of preserved viability bordered on both sides by scar. In each heart model a virtual EHT patch was introduced as a layer of viable tissue overlying the scarred area, with hiPSC-CMs electrophysiological properties. The incidence of re-entrant and sustained activation in simulations with and without EHT patches was assessed and the arrhythmia inducibility compared in the context of different EHT patch properties (conduction velocity (CV) and action potential duration (APD)). The impact of the EHT patch on the likelihood of focal ectopic impulse propagation was estimated by assessing the minimum stimulus strength and duration required to generate a propagating impulse in the scar border zone (BZ) with and without patch.
RESULTS
We uncovered two main mechanisms by which ventricular tachycardia (VT) risk could be either augmented or attenuated by the interaction of the patch with the tissue. In the case of isthmus-related VT, our simulations predict that EHT patches can prevent the induction of VT when the, generally longer, hiPSC-CMs APD is reduced towards more physiological values. In the case of large dense scar, we found that, an EHT patch with CV similar to the host myocardium does not promote VT, while EHT patches with lower CV increase the risk of VT, by promoting both non-sustained and sustained re-entry. Finally, our simulations indicate that electrically coupled EHT patches reduce the likelihood of propagation of focal ectopic impulses.
CONCLUSIONS
The introduction of EHT patches as a treatment for heart failure has the potential to augment or attenuate the risk of ventricular arrhythmias, and variations in the anatomic configuration of the substrate, the functional properties of the BZ and the electrophysiologic properties of the patch itself will determine the overall impact. Planning for delivery of this therapy will need to consider the possible impact on arrhythmia.
背景
心肌梗死后（MI）的心室包含纤维组织，并且可能具有紊乱的电特性，这两者都增加了发生危及生命的心律失常的风险。应用源自人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）的心外膜贴片是治疗 MI 后重塑引起心力衰竭的潜在长期治疗方法。然而，尚未研究引入这些贴片是抗心律失常还是致心律失常。
方法
我们使用基于人类 MI 后心室模型的心脏组织工程（EHT）贴片移植的计算机模拟来研究心律失常风险。研究了两种患者模型，包括一个大的致密瘢痕和一个具有明显的存活带的模型，该存活带两侧均有瘢痕。在每个心脏模型中，将虚拟 EHT 贴片作为覆盖瘢痕区域的存活组织层引入，其具有 hiPSC-CMs 的电生理特性。评估了有无 EHT 贴片的情况下折返和持续激活的发生率，并比较了不同 EHT 贴片特性（传导速度（CV）和动作电位持续时间（APD））下的心律失常诱导能力。通过评估有无贴片时在瘢痕边界区（BZ）中产生传播冲动所需的最小刺激强度和持续时间，估计 EHT 贴片对局灶性异位冲动传播可能性的影响。
结果
我们揭示了两种主要机制，通过这些机制，EHT 贴片与组织相互作用可增强或减弱室性心动过速（VT）的风险。在与峡部相关的 VT 的情况下，我们的模拟预测，当一般较长的 hiPSC-CMs APD 向更生理值降低时，EHT 贴片可防止 VT 的诱导。在大的致密瘢痕的情况下，我们发现，与宿主心肌的 CV 相似的 EHT 贴片不会促进 VT，而 CV 较低的 EHT 贴片通过促进非持续性和持续性折返，增加了 VT 的风险。最后，我们的模拟表明，电耦合的 EHT 贴片降低了局灶性异位冲动传播的可能性。
结论
将 EHT 贴片作为心力衰竭的治疗方法引入可能会增加或减轻室性心律失常的风险，而基质的解剖结构，BZ 的功能特性和贴片本身的电生理特性的变化将决定整体影响。进行这种治疗的计划需要考虑对心律失常的可能影响。
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