Data_Sheet_1_Morphological Substrates for Atrial Arrhythmogenesis in a Heart With Atrioventricular Septal Defect.docx

Due to advances in corrective surgery, congenital heart disease has an ever growing patient population. Atrial arrhythmias are frequently observed pre- and post-surgical correction. Pharmaceutical antiarrhythmic therapy is not always effective, therefore many symptomatic patients undergo catheter ablation therapy. In patients with atrioventricular septal defects (AVSD), ablation therapy itself has mixed success; arrhythmogenic recurrences are common, and because of the anatomical displacement of the atrioventricular node, 3-degree heart block post-ablation is a real concern. In order to develop optimal and safe ablation strategies, the field of congenital cardiac electrophysiology must combine knowledge from clinical electrophysiology with a thorough understanding of the anatomical substrates for arrhythmias. Using image-based analysis and multi-cellular mathematical modeling of electrical activation, we show how the anatomical alterations characteristic of an AVSD serve as arrhythmogenic substrates. Using ex-vivo contrast enhanced micro-computed tomography we imaged post-mortem the heart of a 5 month old male with AVSD at an isometric spatial resolution of 38 μm. Morphological analysis revealed the 3D disposition of the cardiac conduction system for the first time in an intact heart with this human congenital malformation. We observed displacement of the compact atrioventricular node inferiorly to the ostium of the coronary sinus. Myocyte orientation analysis revealed that the normal arrangement of the major atrial muscle bundles was preserved but was modified in the septal region. Models of electrical activation suggest the disposition of the myocytes within the atrial muscle bundles associated with the “fast pathway,” together with the displaced atrioventricular node, serve as potential substrates for re-entry and possibly atrial fibrillation. This study used archived human hearts, showing them to be a valuable resource for the mathematical modeling community, and opening new possibilities for the investigations of arrhythmogenesis and ablation strategies in the congenitally malformed heart.

鉴于矫正手术技术的不断进步，先天性心脏病患者群体呈持续增长态势。房性心律失常在手术矫正前后均较为常见。由于药物抗心律失常治疗并非始终有效，因此许多症状性患者接受了导管消融疗法。在房间隔缺损（AVSD）患者中，消融疗法本身的成功率参差不齐；心律失常的复发较为普遍，加之由于心房传导束的解剖位置改变，消融术后出现三度房室传导阻滞成为一项实际担忧。为了开发出最优且安全的消融策略，先天性心脏病电生理学领域必须将临床电生理学的知识与实践对该心律失常解剖基础的深入了解相结合。通过基于图像的分析和多细胞电活动数学建模，我们揭示了AVSD特有的解剖变化如何充当心律失常的基质。利用体外增强型微计算机断层扫描技术，我们对一名5个月大的AVSD男性患者的尸检心脏进行了成像，空间分辨率为38微米。形态学分析首次揭示了具有这种人类先天性畸形的完整心脏中心脏传导系统的三维排列。我们观察到，致密心房传导束向下移位至冠状窦口。肌细胞方向分析表明，主要心房肌束的正常排列得以保留，但在间隔区域有所改变。电活动模型表明，与“快速通路”相关的肌细胞在心房肌束中的分布，以及移位的心房传导束，可能成为折返和可能的心房颤动的潜在基质。本研究利用存档的人类心脏，证明了其对于数学建模领域是一项宝贵的资源，并为先天性畸形心脏中心律失常的发生机制和消融策略的研究开辟了新的可能性。