Computational modeling identifies embolic stroke of undetermined source patients with potential arrhythmic substrate.
Computational modeling identifies embolic stroke of undetermined source patients with potential arrhythmic substrate.
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DOI：
10.7554/elife.64213
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发表时间：
2021-05-04
期刊：
影响因子：
7.7
通讯作者：
Boyle PM
中科院分区：
文献类型：
--
作者：
Bifulco SF;Scott GD;Sarairah S;Birjandian Z;Roney CH;Niederer SA;Mahnkopf C;Kuhnlein P;Mitlacher M;Tirschwell D;Longstreth WT;Akoum N;Boyle PM
心脏磁共振成像（MRI）显示，来源不明（ESUS）患者的栓塞性卒中中的纤维化水平与房颤（AFib）中观察到的水平相当。我们使用计算模型来理解尽管存在肺促纤维化，但ESUS中不存在心律失常。对45例ESUS和45例AFib患者进行了基于MRI的心房模型重建。通过计算评估每个患者的纤维化基质的促炎能力。在24/45（53%）ESUS和22/45（49%）AFib模型中诱导了折返驱动器。诱导型模型的纤维化（16.7 ± 5.45%）多于非诱导型模型（11.07 ± 3.61%; p<0.0001）;然而，ESUS和AFib模型的诱导型亚组具有相似的纤维化水平（p=0.90），这意味着ESUS和AFib中纤维化的内在促纤维化底物性质是不可区分的。这表明，一些ESUS患者具有潜在的临床前纤维化基质，可能是未来的致炎性来源。因此，我们的工作提示了这样一个假设，即ESUS伴纤维化心房的患者由于没有心律失常触发因素而免于AFib。心脏通常以有规律的节奏跳动，以泵送血液，将氧气和营养物质输送到不同的器官。有时，心脏节律的改变被称为心律失常。心房颤动，也称为AFib，是一种心律失常，其中心脏跳动迅速且不规则，导致血流异常，从而导致血栓形成。如果其中一个血块进入大脑，它会阻塞血管，导致中风。然而，许多中风发生时没有任何AFib的证据。与AFib无关的卒中的一个子集是来源不明的栓塞性卒中（ESUS），占所有卒中的25%。根据定义，ESUS和AFib不会一起发生，但两者都与疾病相关重塑的相似水平升高相关（即，纤维化），这出现在心脏受伤时。纤维化损害心脏的正常电活动。Bifulco等人希望确定AFib患者和发生ESUS事件的患者之间的纤维化是否存在根本性差异。为此，他们使用计算方法对45名ESUS患者和45名AFib患者的心脏纤维化的几何形状和模式进行建模，基本上产生了每个患者心脏的虚拟版本。然后，Bifulco等人对每个心脏模型应用虚拟起搏器（在除颤模式下工作），以确定可能导致房颤的电输入是否对ESUS和房颤患者产生不同的影响。结果表明，电输入在所有心脏模型中具有相似的效果。这使得Bifulco等人得出结论，ESUS和AFib患者具有不可区分的纤维化模式。关键的区别在于，ESUS患者缺少启动纤颤过程的触发器-如果心房纤维化是谚语中的火绒箱，那么这些触发器就是点燃火焰所需的火花。进一步的研究，包括确认Bifulco et al.在活体患者中的发现，将需要证实ESUS患者缺乏AFib主要是由于缺乏触发因素的假设。如果情况确实如此，这些发现可能更容易识别出AFib或进一步卒中风险较高的ESUS患者。此外，更好地了解纤维化作为中风和AFib之间的联系将有助于临床医生提供更好，更个性化的治疗，例如指导患者是否应该服用血液稀释剂或进行更严格的心脏监测。
Cardiac magnetic resonance imaging (MRI) has revealed fibrosis in embolic stroke of undetermined source (ESUS) patients comparable to levels seen in atrial fibrillation (AFib). We used computational modeling to understand the absence of arrhythmia in ESUS despite the presence of putatively pro-arrhythmic fibrosis. MRI-based atrial models were reconstructed for 45 ESUS and 45 AFib patients. The fibrotic substrate’s arrhythmogenic capacity in each patient was assessed computationally. Reentrant drivers were induced in 24/45 (53%) ESUS and 22/45 (49%) AFib models. Inducible models had more fibrosis (16.7 ± 5.45%) than non-inducible models (11.07 ± 3.61%; p<0.0001); however, inducible subsets of ESUS and AFib models had similar fibrosis levels (p=0.90), meaning that the intrinsic pro-arrhythmic substrate properties of fibrosis in ESUS and AFib are indistinguishable. This suggests that some ESUS patients have latent pre-clinical fibrotic substrate that could be a future source of arrhythmogenicity. Thus, our work prompts the hypothesis that ESUS patients with fibrotic atria are spared from AFib due to an absence of arrhythmia triggers. The heart usually beats with a regular rhythm to pump the blood that carries oxygen and nutrients to different organs. Sometimes, alterations in the heart’s rhythm known as arrhythmias can occur. Atrial fibrillation, also called AFib, is a type of arrhythmia in which the heart beats rapidly and irregularly, causing abnormal blood-flow that can lead to the formation of blood clots. If one of these blood clots travels to the brain, it can block a blood vessel, causing a stroke. However, many strokes occur without any evidence of AFib. One subset of strokes that are not associated with AFib are embolic strokes of undetermined source (ESUS), which account for 25% of all strokes. By definition ESUS and AFib do not occur together, but both are associated with similar elevated levels of disease-related remodeling (i.e., fibrosis) in the heart tissue, which appears when the heart is injured. Fibrosis impairs the heart’s normal electrical activity. Bifulco et al. wanted to determine whether there is some fundamental difference in fibrosis between people with AFib and those who have had an ESUS event. To do this, they used a computational approach to model the geometries and patterns of fibrosis of the hearts of 45 ESUS patients and 45 patients with AFib, essentially producing a virtual version of each patient’s heart. Bifulco et al. then applied a virtual pace-maker (working in overdrive mode) to each heart model to determine whether electrical inputs that can lead to AFib had different effects on ESUS and AFib patients. The results showed that the electrical inputs had similar effects in all of the heart models. This led Bifulco et al. to conclude that ESUS and AFib patients have indistinguishable patterns of fibrosis. The key difference is that ESUS patients are missing the trigger to initiate the fibrillation process – if atrial fibrosis is the proverbial tinderbox, these triggers are the spark needed to ignite a fire. Further research, including confirmation of Bifulco et al.’s findings in live patients, will be needed to confirm the hypothesis that ESUS patients lack AFib primarily due to an absence of triggers. If this is indeed the case, these findings may make it easier to identify ESUS patients at higher risk for AFib or further strokes. Additionally, a better understanding of fibrosis as a link between stroke and AFib will help clinicians provide better, more personalized treatments, for example guiding whether a patient should take blood thinners or undergo more rigorous cardiac monitoring.