Project Details
Projekt
P1: Principal Categories of Interstitial Non-Myocyte Electrophysiological Effects on Cardiac Action Potential Propagation In Vitro and In Silico
Subject Area
Cardiology, Angiology
Anatomy and Physiology
Cell Biology
Anatomy and Physiology
Cell Biology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564978926
Traditional concepts describe the heart as a functional syncytium of cardiomyocytes (CM), electrically coupled via connexin-containing gap junctions, while the interstitium is regarded as a passive structural scaffold. Recent evidence challenges this CM-centric view, demonstrating that interstitial non-myocytes (NM), including fibroblasts or macrophages, also express connexins, and form functional gap junctions with CM. These findings suggest that the interstitium actively contributes to cardiac electrophysiology, with implications for normal conduction and arrhythmogenesis.We have proposed three motifs of NM–CM coupling: 0-sided (where there is no electrical contact), 1-sided (where NM connect in parallel to CM), and 2-sided (where NM serially link otherwise unconnected CM clusters). These structural motifs can support different modes of NM-affected action potential (AP) propagation:- active AP conduction resembles the classic understanding of CM-based propagation, but with the addition of NM–CM coupling in fibrotic myocardium, where NM form an electrotonic load that may cause conduction slowing or failure;- passive conduction of AP-like signals through non-excitable NM, which may link otherwise disconnected CM over short distances (10^-4 m);- hybrid active/passive conduction where CM, dispersed among NM, act as “repeater stations” that regenerate AP signal amplitudes, and thereby extend the distance over which excitation may be passed on through NM-rich tissue (10^-2 m).Our project aims to define the basic biophysical principles underlying the various scenarios of NM–CM interactions in cardiac electrical propagation, using integrated in vitro and in silico models. Understanding these processes is of clinical relevance, as interstitially mediated trans-scar conduction may contribute to phenomena such as electrical reconnection of heart tissue after ablation or surgery. We will:quantify the passive cable properties (time and space constants) of CM-CM and NM–CM based electrical conduction in native, hiPSC-derived, and computational 1D tissue strands;experimentally and computationally assess the potential of saltatory excitation across NM or temporarily non-excitable CM in the above models;determine the presence and utility of CM “repeater stations”, embedded in NM networks, and their effect on long-range trans-scar conduction of electrical excitation.Our research will provide a unifying framework to explain: the conduction slowing in areas of diffuse interstitial fibrosis; the repeatedly observed acceleration of conduction in areas of focal replacement fibrosis; and trans-scar conduction of excitation across long distances.By quantitatively linking interstitial structure to electrophysiological function, this project will establish new mechanistic insights and prepare the ground for interstitial tissue engineering to steer or restore cardiac conduction in remodelled hearts.
DFG Programme
Research Units
