Illuminating Myocyte-Fibroblast Homotypic and Heterotypic Gap Junction Dynamics Using Dynamic Clamp

Area of Science:

• Cardiovascular physiology
• Cardiac electrophysiology
• Computational biology

Background:

• Cardiac fibroblasts contribute to heart dysfunction through extracellular matrix deposition and direct electrical signaling.
• Fibroblast-cardiomyocyte interactions via gap junctions (GJ) are an emerging mechanism for arrhythmogenesis.
• Connexin (Cx) isoforms (Cx40, Cx43, Cx45) form cell-type-specific GJ channels with unique gating properties.

Purpose of the Study:

• To investigate how different myocyte-fibroblast (M-F) GJ channel compositions affect cardiac electrophysiology.
• To elucidate the electrophysiological contributions of fibroblasts to cardiac arrhythmia.
• To explore the impact of GJ channel gating on M-F coupling at cellular and tissue levels.

Main Methods:

• Coupled native cardiomyocytes with in silico fibroblast and GJ channel models using dynamic-clamp.
• Developed cell-specific models of dynamic-clamp experiments to analyze membrane currents.
• Performed 2D tissue sheet simulations of cardiac fibrosis incorporating cell-type-specific GJ channels.

Main Results:

• GJ channel gating reduced the early peak of junctional current during cardiomyocyte action potential upstroke.
• Cardiomyocyte action potential morphology was unaffected by GJ channel type (Cx43, Cx45, Cx43/Cx45).
• GJ channel gating did not significantly alter conduction velocity in fibrotic tissue compared to static coupling.

Conclusions:

• While GJ channel gating modulates junctional currents, its impact on conduction velocity in fibrotic hearts is minimal.
• Fibroblast electrical interactions, particularly GJ channel gating, have complex effects on cardiac electrophysiology.
• Findings provide insights into the electrophysiological interplay between cardiac fibroblasts and myocytes in disease states.