Cellular Size, Gap Junctions, and Sodium Channel Properties Govern Developmental Changes in Cardiac Conduction

Abstract

Electrical conduction in cardiac ventricular tissue is regulated via sodium (Na+) channels and gap junctions (GJs). We and others have recently shown that Na+channels preferentially localize at the site of cell-cell junctions, the intercalated disc (ID), in adult cardiac tissue, facilitating coupling via the formation of intercellular Na+nanodomains, also termed ephaptic coupling (EpC). Several properties governing EpC vary with age, including Na+channel and GJ expression and distribution and cell size. Prior work has shown that neonatal cardiomyocytes have immature IDs with Na+channels and GJs diffusively distributed throughout the sarcolemma, while adult cells have mature IDs with preferentially localized Na+channels and GJs. In this study, we perform an in silico investigation of key age-dependent properties to determine developmental regulation of cardiac conduction. Simulations predict that conduction velocity (CV) biphasically depends on cell size, depending on the strength of GJ coupling. Total cell Na+channel conductance is predictive of CV in cardiac tissue with high GJ coupling, but not correlated with CV for low GJ coupling. We find that ephaptic effects are greatest for larger cells with low GJ coupling typically associated with intermediate developmental stages. Finally, simulations illustrate how variability in cellular properties during different developmental stages can result in a range of possible CV values, with a narrow range for both neonatal and adult myocardium but a much wider range for an intermediate developmental stage. Thus, we find that developmental changes predict associated changes in cardiac conduction.

Unraveling Chamber-specific Differences in Intercalated Disc Ultrastructure and Molecular Organization and Their Impact on Cardiac Conduction

“…This stems from current experimental methods lacking the spatial resolution to assess conduction at the scale of individual IDs. While conduction dependence on subcellular structure at such scales has been studied via computational models, most included no representation of the ID and even recent modeling studies have grossly oversimplified ID structure 3, 5, 7, 44, 64, 65 . We recently published the first computational model to incorporate 3D ID ultrastructure derived from electron microscopy, which revealed previously unappreciated dependence of conduction on ID structure: the presence of larger gap junctions at the ID periphery increased conduction velocity and intermembrane distance in the interplicate regions had a gap junction coupling-dependent biphasic influence on conduction 9 .…”

“…Structural differences between atrial and ventricular myocardium at the organ, tissue, and cellular levels are well established determinants of differences in action potential propagation under normal physiological conditions 1,2 , as well as determining chamber-specific arrhythmia susceptibility under pathological conditions. Intercalated discs (IDs), which are cell-cell contact sites specialized to provide electrical and mechanical coupling between adjacent cardiomyocytes, are thus a key focus of research into cardiac action potential propagation with a growing body of evidence highlighting the strong influence of ion channel localization to specialized ID nanodomains [3][4][5][6][7] . However, there is limited data on ID ultrastructural and molecular organization at subcellular through nano scales, while mounting evidence highlights their importance in determining function [3][4][5][6][7][8] .…”

“…Intercalated discs (IDs), which are cell-cell contact sites specialized to provide electrical and mechanical coupling between adjacent cardiomyocytes, are thus a key focus of research into cardiac action potential propagation with a growing body of evidence highlighting the strong influence of ion channel localization to specialized ID nanodomains [3][4][5][6][7] . However, there is limited data on ID ultrastructural and molecular organization at subcellular through nano scales, while mounting evidence highlights their importance in determining function [3][4][5][6][7][8] . Additionally, conventional modeling approaches cannot predict conduction changes in response to perturbations that alter ID ultrastructure or molecular organization.…”

Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals

“…Atrial and ventricular conduction velocity (CV) is spatially heterogeneous and depends on multiple factors, including cardiomyocyte size, fiber orientation, the expression level, and spatial distribution of gap junctions and Na + channels, the distribution of collagen, and the pattern of excitation ( 108 – 112 ). CV as a tissue property is ideally measured during electrical pacing to control the initiation of wavefronts and the cycle length, as CV slows at short coupling intervals (see Fig.…”

Frequency-dependent signaling in cardiac myocytes

“…Signaling activity at the membranes depends on global cell geometry parameters, such as the cellular aspect ratio (Haftbaradaran Esfahani et al, 2019), size (Nowak et al, 2021), membrane surface area, and membrane curvature (Haftbaradaran Esfahani and Knoll, 2020b). A recent paper by Rangamani et al (2013) has presented a "curvature-dependent mechanism of transient receptor activity enhancement," but its relevance for biology and medicine remains unclear.…”