Cardiac Conduction in Physiology and Disease ― Gap Junction Biology, Immune Modulation, and Computational Electrophysiology ―
Year: 2026
Type: article
Abstract: Cardiac conduction is a central determinant of normal rhythm and arrhythmia susceptibility. Although arrhythmias have traditionally been attributed to abnormal automaticity, triggered activity, and re-entry, emerging evidence indicates that conduction abnormalities integrate structural, electrical, and immune-derived signals into a common arrhythmogenic substrate. This review summarizes multiscale mechanisms of impulse propagation, with an emphasis on gap junction-mediated coupling. Connexin 43 (Cx43), the principal ventricular connexin, maintains intercellular current flow through phosphorylation-dependent localization at intercalated discs; its remodeling leads to conduction slowing, heterogeneous propagation, and reentrant vulnerability. Recent studies have revealed that cardiac resident macrophages preserve ventricular conduction by promoting Cx43 phosphorylation via amphiregulin-epidermal growth factor receptor signaling. Loss of this macrophage-derived pathway causes Cx43 disorganization, atrioventricular block, ventricular fibrillation, and sudden death during cardiac stress, establishing an immune-electrical interface essential for conduction stability. This review further highlights conduction abnormalities in human disease, differences between mice and humans, and insights derived from electrocardiography and advanced computational modeling. Simulations linking molecular alterations to organ-level activation patterns provide a mechanistic bridge between cellular coupling, Purkinje network integrity, fibrosis distribution, and clinical electrophysiology. Together, these findings position conduction as a dynamic, regulated property of the ventricular myocardium and suggest that targeting gap junction and immune pathways may enable future conduction-based precision cardiology.
Source: Circulation Journal
Author: Katsuhito Fujiu
Institutions: Institute of Science Tokyo, The University of Tokyo
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7123875140