Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.
Cardiovasc Res. 2011 Mar 1;89(4):744-53. doi: 10.1093/cvr/cvq329. Epub 2010 Oct 20.
Cardiac fibroblasts account for about 75% of all cardiac cells, but because of their small size contribute only ∼10-15% of total cardiac cell volume. They play a crucial role in cardiac pathophysiology. For a long time, it has been recognized that fibroblasts and related cell types are the principal sources of extracellular matrix (ECM) proteins, which organize cardiac cellular architecture. In disease states, fibroblast production of increased quantities of ECM proteins leads to tissue fibrosis, which can impair both mechanical and electrical function of the heart, contributing to heart failure and arrhythmogenesis. Atrial fibrosis is known to play a particularly important role in atrial fibrillation (AF). This review article focuses on recent advances in understanding the molecular electrophysiology of cardiac fibroblasts. Cardiac fibroblasts express a variety of ion channels, in particular voltage-gated K(+) channels and non-selective cation channels of the transient receptor potential (TRP) family. Both K(+) and TRP channels are important determinants of fibroblast function, with TRP channels acting as Ca(2+)-entry pathways that stimulate fibroblast differentiation into secretory myofibroblast phenotypes producing ECM proteins. Fibroblasts can couple to cardiomyocytes and substantially affect their cellular electrical properties, including conduction, resting potential, repolarization, and excitability. Co-cultured preparations of cardiomyocytes and fibroblasts generate arrhythmias by a variety of mechanisms, including spontaneous impulse formation and rotor-driven reentry. In addition, the excess ECM proteins produced by fibroblasts can interrupt cardiomyocyte-bundle continuity, leading to local conduction disturbances and reentrant arrhythmias. A better understanding of the electrical properties of fibroblasts should lead to an improved comprehension of AF pathophysiology and a variety of novel targets for antiarrhythmic intervention.
心肌成纤维细胞约占所有心肌细胞的 75%，但其体积仅占心肌细胞总体积的 10-15%。它们在心脏病理生理学中发挥着至关重要的作用。长期以来，人们一直认为成纤维细胞和相关细胞类型是细胞外基质（ECM）蛋白的主要来源，这些蛋白组织了心脏的细胞结构。在疾病状态下，成纤维细胞产生的 ECM 蛋白增加，导致组织纤维化，这会损害心脏的机械和电功能，导致心力衰竭和心律失常的发生。心房纤维化被认为在心房颤动（AF）中起着特别重要的作用。这篇综述文章重点介绍了对心脏成纤维细胞分子电生理学的最新认识。心肌成纤维细胞表达多种离子通道，特别是电压门控 K(+)通道和瞬时受体电位（TRP）家族的非选择性阳离子通道。K(+)和 TRP 通道都是成纤维细胞功能的重要决定因素，TRP 通道作为 Ca(2+)进入途径，刺激成纤维细胞分化为产生 ECM 蛋白的分泌型肌成纤维细胞表型。成纤维细胞可以与心肌细胞偶联，并显著影响其细胞电特性，包括传导、静息电位、复极化和兴奋性。培养的心肌细胞和成纤维细胞的共培养物通过多种机制产生心律失常，包括自发性冲动形成和转子驱动的折返。此外，成纤维细胞产生的过量 ECM 蛋白会中断心肌细胞束的连续性，导致局部传导障碍和折返性心律失常。更好地理解成纤维细胞的电特性应该有助于提高对 AF 病理生理学的认识，并为抗心律失常干预提供各种新的靶点。
