Acute ischaemia and gap junction modulation modify propagation patterns across Purkinje-myocardial junctions

Richard J. Jabbour; Elham Behradfar; Michael Debney; Anders Nygren; Adam Hartley; Igor Efimov; Mélèze Hocini; Nicholas S. Peters; Fu Siong Ng; Edward J. Vigmond

doi:10.3389/fphys.2025.1540400

Acute ischaemia and gap junction modulation modify propagation patterns across Purkinje-myocardial junctions

Richard J. Jabbour, Elham Behradfar, Michael Debney, Anders Nygren, Adam Hartley, Igor Efimov, Mélèze Hocini, Nicholas S. Peters, Fu Siong Ng, Edward J. Vigmond^*

^*Corresponding author for this work

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

Abstract

Background: The Purkinje network is essential for normal electrical impulse propagation in the heart but has also been implicated in ventricular arrhythmias. Previous experimental work has suggested that not all Purkinje-myocardial junctions (PMJs) are active at rest due to source-sink mismatch at the PMJs. Objective: We hypothesized that pathological conditions that cause gap junction uncoupling (e.g., acute ischaemia), would increase the number of active PMJs, leading to more complex activation patterns. Methods: We investigated this using a whole-heart intact Purkinje system preparation that allowed direct high-resolution endocardial mapping to interrogate PMJ function. Twelve (7 control, five rotigaptide) Langendorff-perfused hearts from New Zealand white rabbits were subjected to an ischaemia-reperfusion protocol and optically mapped. Computational modelling was performed to determine the effects of gap junction coupling on PMJ function, and on the complexity of endocardial activation. Results: During ischaemia, the percentage of right ventricle area activated within the first 5 ms decreased from baseline 62% ± 7% to 52% ± 8% during early ischaemia (p = 0.04), consistent with slowing of conduction. This was followed by a paradoxical increase in late-ischaemia (60% ± 8%) due to extra regions of early activation. Gap junction enhancement with rotigaptide during ischaemia abolished the aforementioned pattern. Parallel computational experiments replicated experimental findings only when the number of functional PMJs was increased during ischaemia. With more active PMJs, there were more breakthrough sites with increased complexity of activation, as also measured in biological preparations. Conclusion: Normally-quiescent PMJs can become active in the context of gap junction uncoupling during acute ischaemia. Pharmacological gap junction modulation may alter propagation patterns across PMJs and may be used as a therapeutic strategy for Purkinje system associated arrhythmias.

Original language	English (US)
Article number	1540400
Journal	Frontiers in Physiology
Volume	16
DOIs	https://doi.org/10.3389/fphys.2025.1540400
State	Published - 2025

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. FN was funded by the British Heart Foundation (FS/11/69/29017, RG/16/3/32175 and RG/F/22/110078), The UK National Institute for Health Research (NIHR Clinical Lectureship CL-2011-21-011 and Imperial Biomedical Research Centre) and an Academy of Medical Sciences Starter Grant (AMS-SGCL8-Ng). EV was funded by National Research Agency (ANR), Grant reference ANR-10-IAHU-04 and the National Institutes of Health, grant number R01HL101196. EV and IE were supported by the LeDucq Foundation 23CVD04. ANR - EV salary BHF - experiment costs/fellows NIH - experiments LeDucq - collaborative travel.

Keywords

Purkinje-myocardial junction
cardiac electrophysiology
computer modelling
ischaemia
purkinje system

ASJC Scopus subject areas

Physiology
Physiology (medical)

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10.3389/fphys.2025.1540400

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@article{e0862ce599f64d509bc79c2886d141db,

title = "Acute ischaemia and gap junction modulation modify propagation patterns across Purkinje-myocardial junctions",

abstract = "Background: The Purkinje network is essential for normal electrical impulse propagation in the heart but has also been implicated in ventricular arrhythmias. Previous experimental work has suggested that not all Purkinje-myocardial junctions (PMJs) are active at rest due to source-sink mismatch at the PMJs. Objective: We hypothesized that pathological conditions that cause gap junction uncoupling (e.g., acute ischaemia), would increase the number of active PMJs, leading to more complex activation patterns. Methods: We investigated this using a whole-heart intact Purkinje system preparation that allowed direct high-resolution endocardial mapping to interrogate PMJ function. Twelve (7 control, five rotigaptide) Langendorff-perfused hearts from New Zealand white rabbits were subjected to an ischaemia-reperfusion protocol and optically mapped. Computational modelling was performed to determine the effects of gap junction coupling on PMJ function, and on the complexity of endocardial activation. Results: During ischaemia, the percentage of right ventricle area activated within the first 5 ms decreased from baseline 62% ± 7% to 52% ± 8% during early ischaemia (p = 0.04), consistent with slowing of conduction. This was followed by a paradoxical increase in late-ischaemia (60% ± 8%) due to extra regions of early activation. Gap junction enhancement with rotigaptide during ischaemia abolished the aforementioned pattern. Parallel computational experiments replicated experimental findings only when the number of functional PMJs was increased during ischaemia. With more active PMJs, there were more breakthrough sites with increased complexity of activation, as also measured in biological preparations. Conclusion: Normally-quiescent PMJs can become active in the context of gap junction uncoupling during acute ischaemia. Pharmacological gap junction modulation may alter propagation patterns across PMJs and may be used as a therapeutic strategy for Purkinje system associated arrhythmias.",

keywords = "Purkinje-myocardial junction, cardiac electrophysiology, computer modelling, ischaemia, purkinje system",

author = "Jabbour, {Richard J.} and Elham Behradfar and Michael Debney and Anders Nygren and Adam Hartley and Igor Efimov and M{\'e}l{\`e}ze Hocini and Peters, {Nicholas S.} and Ng, {Fu Siong} and Vigmond, {Edward J.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 Jabbour, Behradfar, Debney, Nygren, Hartley, Efimov, Hocini, Peters, Ng and Vigmond.",

year = "2025",

doi = "10.3389/fphys.2025.1540400",

language = "English (US)",

volume = "16",

journal = "Frontiers in Physiology",

issn = "1664-042X",

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TY - JOUR

T1 - Acute ischaemia and gap junction modulation modify propagation patterns across Purkinje-myocardial junctions

AU - Jabbour, Richard J.

AU - Behradfar, Elham

AU - Debney, Michael

AU - Nygren, Anders

AU - Hartley, Adam

AU - Efimov, Igor

AU - Hocini, Mélèze

AU - Peters, Nicholas S.

AU - Ng, Fu Siong

AU - Vigmond, Edward J.

PY - 2025

Y1 - 2025

N2 - Background: The Purkinje network is essential for normal electrical impulse propagation in the heart but has also been implicated in ventricular arrhythmias. Previous experimental work has suggested that not all Purkinje-myocardial junctions (PMJs) are active at rest due to source-sink mismatch at the PMJs. Objective: We hypothesized that pathological conditions that cause gap junction uncoupling (e.g., acute ischaemia), would increase the number of active PMJs, leading to more complex activation patterns. Methods: We investigated this using a whole-heart intact Purkinje system preparation that allowed direct high-resolution endocardial mapping to interrogate PMJ function. Twelve (7 control, five rotigaptide) Langendorff-perfused hearts from New Zealand white rabbits were subjected to an ischaemia-reperfusion protocol and optically mapped. Computational modelling was performed to determine the effects of gap junction coupling on PMJ function, and on the complexity of endocardial activation. Results: During ischaemia, the percentage of right ventricle area activated within the first 5 ms decreased from baseline 62% ± 7% to 52% ± 8% during early ischaemia (p = 0.04), consistent with slowing of conduction. This was followed by a paradoxical increase in late-ischaemia (60% ± 8%) due to extra regions of early activation. Gap junction enhancement with rotigaptide during ischaemia abolished the aforementioned pattern. Parallel computational experiments replicated experimental findings only when the number of functional PMJs was increased during ischaemia. With more active PMJs, there were more breakthrough sites with increased complexity of activation, as also measured in biological preparations. Conclusion: Normally-quiescent PMJs can become active in the context of gap junction uncoupling during acute ischaemia. Pharmacological gap junction modulation may alter propagation patterns across PMJs and may be used as a therapeutic strategy for Purkinje system associated arrhythmias.

AB - Background: The Purkinje network is essential for normal electrical impulse propagation in the heart but has also been implicated in ventricular arrhythmias. Previous experimental work has suggested that not all Purkinje-myocardial junctions (PMJs) are active at rest due to source-sink mismatch at the PMJs. Objective: We hypothesized that pathological conditions that cause gap junction uncoupling (e.g., acute ischaemia), would increase the number of active PMJs, leading to more complex activation patterns. Methods: We investigated this using a whole-heart intact Purkinje system preparation that allowed direct high-resolution endocardial mapping to interrogate PMJ function. Twelve (7 control, five rotigaptide) Langendorff-perfused hearts from New Zealand white rabbits were subjected to an ischaemia-reperfusion protocol and optically mapped. Computational modelling was performed to determine the effects of gap junction coupling on PMJ function, and on the complexity of endocardial activation. Results: During ischaemia, the percentage of right ventricle area activated within the first 5 ms decreased from baseline 62% ± 7% to 52% ± 8% during early ischaemia (p = 0.04), consistent with slowing of conduction. This was followed by a paradoxical increase in late-ischaemia (60% ± 8%) due to extra regions of early activation. Gap junction enhancement with rotigaptide during ischaemia abolished the aforementioned pattern. Parallel computational experiments replicated experimental findings only when the number of functional PMJs was increased during ischaemia. With more active PMJs, there were more breakthrough sites with increased complexity of activation, as also measured in biological preparations. Conclusion: Normally-quiescent PMJs can become active in the context of gap junction uncoupling during acute ischaemia. Pharmacological gap junction modulation may alter propagation patterns across PMJs and may be used as a therapeutic strategy for Purkinje system associated arrhythmias.

KW - Purkinje-myocardial junction

KW - cardiac electrophysiology

KW - computer modelling

KW - ischaemia

KW - purkinje system

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JO - Frontiers in Physiology

JF - Frontiers in Physiology

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ER -

Acute ischaemia and gap junction modulation modify propagation patterns across Purkinje-myocardial junctions

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