Resident cardiac macrophages are not required for normal atrioventricular node conduction

Al-Othman, S.; Wu, Y.; Fontanaud, P.; Puttur, F.; Conesa, D.; Zhu, C.; Moore, S.; Tikhomirov, R.; Francis, A.; Nair, S.; Chowdhury, R. A.; Husain, M.; Boyle, J. J.; Oceandy, D.; Niederer, S. A.; Walton, R.; Howell, G.; Roberts, L.; Boyett, M. R.; Colman, M. A.; Mangoni, M. E.; D'Souza, A.

doi:10.64898/2026.02.11.704506

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bioRxiv · 10.64898/2026.02.11.704506

Resident cardiac macrophages are not required for normal atrioventricular node conduction

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Abstract

Resident cardiac macrophages are understood to facilitate atrioventricular (AV) node conduction because they purportedly couple to AV node myocytes via connexin43 (Cx43) containing gap junctions. We tested this mechanism using biophysical modelling, high-resolution imaging of mouse and human AV conduction tissue, and pharmacological macrophage depletion. In silico, coupling macrophage membrane phenotypes to HCN4+ AV node myocytes imposed an electrotonic load that suppressed pacemaking and promoted conduction slowing, including stable 2:1 block in strand simulations. Anatomically, HCN4-defined components of the mouse AV conduction axis were essentially devoid of Cx43 and overlap of CD68+ macrophages and Cx43 was negligible in both mouse AV node and human penetrating bundle. Finally, near-complete macrophage depletion with CSF1R inhibition (PLX5622) did not alter AV electrical activity in vivo or ex vivo. Together, these data argue against a physiologically relevant role for Cx43-mediated macrophage-myocyte electrical coupling in normal AV node function. HIGHLIGHTSO_LIModelling predicts that AV node automaticity and conduction would be suppressed if macrophages coupled to AV node myocytes C_LIO_LIThe mouse AV conduction axis is essentially devoid of Cx43, currently considered responsible for macrophage-AV node myocyte coupling C_LIO_LIOverlap of macrophages and Cx43 expression is not discernible in the Cx43-expressing human distal AV node C_LIO_LIMacrophage depletion by CSF1R inhibition does not impact AV electrical activity in vivo or ex vivo C_LI

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Al-Othman, S., Wu, Y., Fontanaud, P., Puttur, F., Conesa, D., Zhu, C., Moore, S., Tikhomirov, R., Francis, A., Nair, S., Chowdhury, R. A., Husain, M., Boyle, J. J., Oceandy, D., Niederer, S. A., Walton, R., Howell, G., Roberts, L., Boyett, M. R., Colman, M. A., Mangoni, M. E., D'Souza, A.. 2026-02-12. Resident cardiac macrophages are not required for normal atrioventricular node conduction. https://doi.org/10.64898/2026.02.11.704506

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