# Role of the Extracellular Space as a Modulator of the Cardiac Gap Junction - Conduction Velocity Relationship

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2020 · $517,280

## Abstract

Project Abstract
While studies of gap junctions often cite their fundamental importance to normal electrical activation of the
heart, there is little agreement on the degree of gap junction remodeling required to slow electrical activation.
Our prior work has made the following seminal observations. First, the degree of cardiac hydration can
modulate whether gap junction uncoupling will be associated with measurable conduction slowing and
increased arrhythmia risk. Second, the microdomain adjacent to gap junction plaques is rich in the cardiac
sodium channel isoform Nav1.5, is nominally 150 nm long and 10-20 nm wide. Through the use of super-
resolution microscopy, electron microscopy, optical mapping, and cutting edge computations simulations, we
provided evidence that the perinexus is a strong candidate structure as the cardiac ephapse. Third, we
demonstrate that the buffer used to perform ex vivo whole-heart studies can modulate both perinexal width and
the relationship between cardiac conduction and gap junctions. In short, altering extracellular sodium and
potassium can compensate for a 50% loss of connexin43 such that conduction appears normal. These findings
are entirely consistent with the various groups that have analyzed the relationship between conduction velocity
and gap junctions, so much so that it is possible by post-hoc literature analysis to determine whether a group
will find conduction slowing secondary to loss of Cx43 simply by the buffer used. This work is not just important
for understanding alternative modes of electrical communication, but it points out an even more sobering issue:
the foundational tool of ex vivo and in vitro biology (buffers) may yield investigator dependent results simply
based on ionic buffer composition. In this application we will test three new aims. 1. We will test unique
computational predictions of gap junctional and ephaptic coupling to demonstrate that the conduction reserve
hypothesis is unique to continuous “cable-like” propagation, and ephaptic coupling can self-attenuate
conduction when intercellular widths are very narrow. 2. We will demonstrate how changing interfibrillar and
perinexal separation separately alters cardiac conduction. These findings will be compared to models of
ephaptic coupling in order to further support the hypothesis that ephaptic coupling is an alternative form of
electrical coupling between myocytes. 3. We provide evidence that altering perfusate ion concentration can
rescue conduction to the same degree as gap junction based therapy during acidosis. In this final aim, we will
determine how perfusate composition modulates electrical coupling during no-flow ischemia and complete
coronary artery ligation. Also, we will test whether perfusate composition can agonize the effects of gap
junction therapy during ischemia.

## Key facts

- **NIH application ID:** 9838769
- **Project number:** 5R01HL102298-09
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Steven Poelzing
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $517,280
- **Award type:** 5
- **Project period:** 2011-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838769

## Citation

> US National Institutes of Health, RePORTER application 9838769, Role of the Extracellular Space as a Modulator of the Cardiac Gap Junction - Conduction Velocity Relationship (5R01HL102298-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838769. Licensed CC0.

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