ArticleCirculation research2023
Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction.
Article in Circulation research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 21 citations in OpenAlex.
- Heterozygous Loss of Scn1b Results in Concealed Conduction Phenotype Unmasked by Osmotic Stress.bioRxiv : the preprint server for biology · 2026Article
- Cardiac Impulse Propagation: An Integrated View.JACC. Basic to translational science · 2026Review
- Prioritizing Discovery and Advancements in Arrhythmia Therapies: NIH/NHLBI Workshop.JACC. Clinical electrophysiology · 2026Review
- Nanoscale organization in the cell membrane dynamically modulates the biophysics of voltage-gated sodium channels.Nature communications · 2026Article
- Ephaptic coupling and the source-sink effect of cardiac conduction.The Journal of physiology · 2026Article
- Article
- Connexin43 Deficiency Leads to Ventricular Arrhythmias by Reprogramming Proline Metabolism.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Dissecting Gap Junctional and Ephaptic Contributions to Electrical Conduction in a Novel Cardiomyocyte Pair Model.bioRxiv : the preprint server for biology · 2026Article
- Emerging Regulatory Mechanisms in Sinoatrial Node Automaticity.Journal of cellular and molecular medicine · 2026Review
- Gap junctional and ephaptic coupling in cardiac electrical propagation: homocellular and heterocellular perspectives.The Journal of physiology · 2026Review
- Models of cardiomyocyte-non-myocyte electrical interactions.The Journal of physiology · 2026Review
- Hypernatremia Enhances Transient Outward Potassium and Late Sodium Currents in a Mouse Model of Long QT Syndrome Type 3.bioRxiv : the preprint server for biology · 2025Article
- Evidence for intermittent coupling of intramyocardial small, engineered heart tissues acutely implanted into rabbit myocardium.Cardiovascular research · 2025Article
- Intercalated Disc Abnormalities Are Linked to Arrhythmias in Inflammatory Cardiomyopathy.JACC. Clinical electrophysiology · 2025Article
- Viral Infection and Connexin Dysfunction in the Heart.Current cardiology reports · 2025Review
- Ultrastructure and cardiac impulse propagation: scaling up from microscopic to macroscopic conduction.The Journal of physiology · 2025Review
- Sequence-Dependent Repolarization Is Modulated by Endogenous Action Potential Duration Gradients Rather Than Electrical Coupling in Ventricular Myocardium.Journal of the American Heart Association · 2025Article
- New focus on cardiac voltage-gated sodium channel β1 and β1B: Novel targets for treating and understanding arrhythmias?Heart rhythm · 2025Review
- Development and characterization of the mode-of-action of inhibitory and agonist peptides targeting the voltage-gated sodium channel SCN1B beta-subunit.Journal of molecular and cellular cardiology · 2024Article
- Mannitol and hyponatremia regulate cardiac ventricular conduction in the context of sodium channel loss of function.American journal of physiology. Heart and circulatory physiology · 2024Article
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 7 countries.
Funding
Abstract
backgroundCardiac 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.
methodsConduction 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.
resultsCV 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.
conclusionsCardiac 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.