Key result
Osmotic modulation of perinexal width reveals biphasic effects on cardiac conduction velocity, supporting ephaptic coupling.
Why the study?
To determine the relationship between ventricular conduction velocity and structural changes to micro- and nanoscale extracellular spaces.
Does modulating extracellular perinexal volume with osmotic agents alter cardiac conduction velocity in isolated ventricular myocardium?
Does modulating extracellular perinexal volume with osmotic agents alter cardiac conduction velocity in isolated ventricular myocardium?
The structural regulation of perinexal nanodomains directly influences cardiac conduction through ephaptic mechanisms, identifying the perinexus as a potential target for arrhythmia management.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for perinexal targeting in arrhythmia; leaves open in vivo and human translation.
BACKGROUND: Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular resistance. By contrast, ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs such as the perinexus. Our objective was to determine the relationship between ventricular CV and structural changes to micro- and nanoscale extracellular spaces. METHODS: Conduction and Cx43 (connexin43) protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with the osmotic agents albumin, mannitol, dextran 70 kDa, or dextran 2 MDa. Peak sodium current was quantified in isolated guinea pig ventricular myocytes. Extracellular resistance was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs. RESULTS: CV primarily in the transverse direction of propagation was significantly reduced by mannitol and increased by albumin and both dextrans. The combination of albumin and dextran 70 kDa decreased CV relative to albumin alone. Extracellular resistance was reduced by mannitol, unchanged by albumin, and increased by both dextrans. Cx43 expression and conductance and peak sodium currents were not significantly altered by the osmotic agents. In response to osmotic agents, perinexal width, in order of narrowest to widest, was albumin with dextran 70 kDa; albumin or dextran 2 MDa; dextran 70 kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width. CONCLUSIONS: Cardiac conduction does not correlate with extracellular resistance but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.
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Adams et al. (2023) studied this question. Osmotic agents (albumin, mannitol, dextran 70 kDa, dextran 2 MDa) vs. Time control and paired pre-treatment baseline was evaluated on Cardiac conduction velocity (CV) and perinexal width. Osmotic agents modulated extracellular perinexal volume, demonstrating a biphasic relationship between perinexal separation and cardiac conduction velocity consistent with ephaptic coupling.
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