Microscopic Isthmuses and Fibrosis Within the Border Zone of Infarcted Hearts Promote Calcium-Mediated Ectopy and Conduction Block
Microscopic Isthmuses and Fibrosis Within the Border Zone of Infarcted Hearts Promote Calcium-Mediated Ectopy and Conduction Block
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DOI：
10.3389/fphy.2018.00057
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发表时间：
2018-06-07
影响因子：
3.1
通讯作者：
Bishop, Martin J.
中科院分区：
文献类型：
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作者：
Campos, Fernando O.;Shiferaw, Yohannes;Bishop, Martin J.
心肌梗死继发的室性心动过速仍然是成人猝死的主要原因。室性早搏（PVC）是部分心律失常的第一个起始搏动，由梗死边缘区（BZ）的触发活动引起。在细胞尺度上，自发钙释放（SCR）事件是触发活动的已知原因，并已在MI存活的细胞中报道。在组织尺度上，纤维化已被证明在形成VT的基质中发挥重要作用。然而，SCR介导的触发活动和纤维化之间的相互作用后，在梗死心脏VT形成尚未得到充分的研究。在这里，我们进行计算机模拟实验，以评估宏观和微观解剖特性的BZ可以创建一个SCR介导的VT形成的基板。为了研究这个问题，我们采用随机亚细胞尺度模型的SCR事件和动作电位来模拟不同的心脏准备。在具有理想化梗死瘢痕和BZ的2D片材模型中，我们发现在具有薄的传导峡部（0.2 mm）超越瘢痕的制剂中，PVC的概率更高，为55%。在一个解剖学上详细的模型，兔心室与一个现实的代表性壁内疤痕，我们表明，心脏的保护源-汇不匹配，防止异位。此外，我们证明纤维化破坏了这种抗肿瘤机制，使PVC更容易发生。当纤维化分别占2D表和3D解剖模型中BZ的60%和90%时，PVC概率最高（>= 25%）。高于这些阈值，PVC发生率降低，因为：（1）BZ中的肌细胞数量减少;（2）传导阻滞。阻滞是由BZ细胞与心肌断开连接或由于快速组织扩张区域的源-库不匹配引起的。此外，虽然向外传播到健康组织可能失败，但通过瘢痕向内行进的PVC可能遇到更有利的加载条件。这些室性心动过速可能会离开心肌，并重新进入阻滞区域。总的来说，我们的研究结果表明，细峡部和肌细胞散在纤维化可能是致瘤性的。消融这些微观结构可以防止VT形成。
Ventricular tachycardia secondary to myocardial infarction (MI) remain a major cause of sudden death in adults. Premature ventricular complexes (PVCs), the first initiating beats of a portion of these arrhythmias, arise from triggered activity in the infarct border zone (BZ). At the cellular scale, spontaneous calcium release (SCR) events are a known cause of triggered activity and have been reported in cells that survive MI. At the tissue scale, fibrosis has been shown to play an important role in creating the substrate for VT. However, the interplay between SCR-mediated triggered activity and fibrosis upon VT formation in infarcted hearts has not been fully investigated. Here, we conduct in-silico experiments to assess how macroscopic and microscopic anatomical properties of the BZ can create a substrate for SCR-mediated VT formation. To study this question, we employ a stochastic subcellular-scale model of SCR events and action potential to simulate different cardiac preparations. Within 2D sheet models with idealized infarct scars and BZ we show that the probability of PVCs is higher, 55%, in preparations with thin conducting isthmuses (0.2 mm) transcending the scar. In an anatomically-detailed model of the rabbit ventricles with a realistic representation of intramural scars, we show that the heart's protective source-sink mismatch prevents ectopy. Furthermore, we demonstrate that fibrosis disrupts this antiarrhythmic mechanism making PVCs more likely. PVC probability is highest (>= 25%) when fibrosis accounts for 60 and 90% of the BZ in the 2D sheet and the 3D anatomical model, respectively. Above these thresholds, PVC occurrence decreases because of: (1) the reduced number of myocytes in the BZ; (2) conduction block. Block is caused either by disconnection of BZ cells from the myocardium or due to source-sink mismatches at regions of rapid tissue expansion. Moreover, while outward propagation to healthy tissue may fail, PVCs traveling inward through the scar might encounter more favorable loading conditions. These PVCs may exit to the myocardium and reenter back at the region of block. Overall, our findings indicate that thin isthmuses and strands of myocytes interspersed with fibrosis can be arrhythmogenic. Ablation of these microscopic structures may prevent VT formation.