Department of Physiology & Cell Biology, Bob and Corrine Frick Center for Heart Failure and Arrhythmia, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Arrhythmology Research Department, Almazov National Medical Research Centre, Saint-Petersburg, Russia.
Department of Physiology & Cell Biology, Bob and Corrine Frick Center for Heart Failure and Arrhythmia, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
J Mol Cell Cardiol. 2021 Feb;151:56-71. doi: 10.1016/j.yjmcc.2020.10.012. Epub 2020 Oct 29.
Atrial fibrillation (AF) occurrence and maintenance is associated with progressive remodeling of electrophysiological (repolarization and conduction) and 3D structural (fibrosis, fiber orientations, and wall thickness) features of the human atria. Significant diversity in AF etiology leads to heterogeneous arrhythmogenic electrophysiological and structural substrates within the 3D structure of the human atria. Since current clinical methods have yet to fully resolve the patient-specific arrhythmogenic substrates, mechanism-based AF treatments remain underdeveloped. Here, we review current knowledge from in-vivo, ex-vivo, and in-vitro human heart studies, and discuss how these studies may provide new insights on the synergy of atrial electrophysiological and 3D structural features in AF maintenance. In-vitro studies on surgically acquired human atrial samples provide a great opportunity to study a wide spectrum of AF pathology, including functional changes in single-cell action potentials, ion channels, and gene/protein expression. However, limited size of the samples prevents evaluation of heterogeneous AF substrates and reentrant mechanisms. In contrast, coronary-perfused ex-vivo human hearts can be studied with state-of-the-art functional and structural technologies, such as high-resolution near-infrared optical mapping and contrast-enhanced MRI. These imaging modalities can resolve atrial arrhythmogenic substrates and their role in reentrant mechanisms maintaining AF and validate clinical approaches. Nonetheless, longitudinal studies are not feasible in explanted human hearts. As no approach is perfect, we suggest that combining the strengths of direct human atrial studies with high fidelity approaches available in the laboratory and in realistic patient-specific computer models would elucidate deeper knowledge of AF mechanisms. We propose that a comprehensive translational pipeline from ex-vivo human heart studies to longitudinal clinically relevant AF animal studies and finally to clinical trials is necessary to identify patient-specific arrhythmogenic substrates and develop novel AF treatments.
心房颤动（AF）的发生和维持与人心房的电生理（复极和传导）和 3D 结构（纤维化、纤维方向和壁厚度）特征的进行性重构有关。AF 的病因存在显著差异，导致人心房的 3D 结构内存在异质性的致心律失常电生理和结构基质。由于目前的临床方法尚未完全解决患者特定的致心律失常基质，基于机制的 AF 治疗仍未得到充分发展。在这里，我们回顾了来自体内、离体和体外人心研究的现有知识，并讨论了这些研究如何为 AF 维持中心房电生理和 3D 结构特征的协同作用提供新的见解。在离体研究中，对手术获取的人心房样本进行研究，为研究广泛的 AF 病理学提供了很好的机会，包括单细胞动作电位、离子通道和基因/蛋白表达的功能变化。然而，样本的有限大小阻止了对异质 AF 基质和折返机制的评估。相比之下，冠状灌注的离体人心可以使用最新的功能和结构技术进行研究，例如高分辨率近红外光学映射和对比增强 MRI。这些成像方式可以解决心房致心律失常基质及其在维持 AF 的折返机制中的作用，并验证临床方法。尽管如此，在离体人心上进行纵向研究是不可行的。由于没有一种方法是完美的，我们建议将直接人心房研究的优势与实验室中可用的高保真方法以及现实的患者特定计算机模型相结合，以阐明 AF 机制的更深层次知识。我们提出，从离体人心研究到具有临床相关性的 AF 动物纵向研究，最后到临床试验的全面转化管道是必要的，以确定患者特定的致心律失常基质并开发新的 AF 治疗方法。
