TNFα Modulates Cardiac Conduction by Altering Electrical Coupling between Myocytes.

Area of Science:

• Cardiovascular Physiology
• Cardiac Electrophysiology
• Inflammation Biology

Background:

• Tumor Necrosis Factor α (TNFα) is upregulated during acute inflammation, affecting cardiac function.
• TNFα may alter cardiac gap junctional (GJ) coupling and ephaptic coupling by modulating Connexin43 and vascular permeability.
• This study investigates TNFα's impact on cardiac electrical coupling and conduction velocity (CV).

Purpose of the Study:

• To test the hypothesis that acute pathophysiological TNFα levels modulate cardiac CV by altering GJ and ephaptic coupling.
• To investigate the effects of elevated extracellular calcium on TNFα-induced changes in cardiac electrical properties.
• To explore a potential therapeutic strategy for inflammation-induced cardiac conduction slowing.

Main Methods:

• Optical mapping of guinea pig hearts to measure CV (longitudinal and transverse) under control, TNFα, and TNFα + high calcium conditions.
• Transmission electron microscopy to quantify changes in the extracellular nanodomain-perinexus (Wp) adjacent to gap junctions.
• Western blotting for Cx43 expression/phosphorylation and confocal immunofluorescence for Cx43 distribution.

Main Results:

• TNFα alone slowed transverse CV (CVt) and increased Wp, indicating altered electrical coupling.
• Increasing extracellular calcium during TNFα exposure rapidly restored CVt and reduced Wp to control levels.
• Combined TNFα and high calcium treatment also improved GJ coupling, contributing to enhanced CV.

Conclusions:

• Elevating extracellular calcium during acute TNFα exposure mitigates perinexal expansion.
• This intervention enhances both ephaptic and GJ coupling, leading to improved cardiac CV.
• High extracellular calcium may represent a novel strategy to prevent inflammation-induced cardiac conduction slowing.