Age-related structural and functional changes of the intracardiac nervous system

Hortells, L.; Zgierski-Johnston, C. M.; Kohl, P.; Schneider-Warme, F.; Ravens, U.; Preissl, S.; Cameron, B. A.; Koch, M.; Brennan, T. A.; Madl, J.; Iaconianni, P.; Fernandez, M. C.; Stefanovska, D.; Tumlinson, G.; Sassu, E.

doi:10.1101/2023.11.24.568538

bioRxiv · 10.1101/2023.11.24.568538

Age-related structural and functional changes of the intracardiac nervous system

Hortells, L.·Zgierski-Johnston, C. M.·Kohl, P.·Schneider-Warme, F.·Ravens, U.·Preissl, S.·Cameron, B. A.·Koch, M.·Brennan, T. A.·Madl, J.·Iaconianni, P.·Fernandez, M. C.·Stefanovska, D.·Tumlinson, G.·Sassu, E.

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Abstract

BackgroundAlthough aging is known to be associated with an increased incidence of both atrial and ventricular arrhythmias, there is limited knowledge about how Schwann cells (SC) and the intracardiac nervous system (iCNS) remodel with age. Here we investigate the differences in cardiac SC, parasympathetic nerve fibers, and muscarinic acetylcholine receptor M2 (M2R) expression in young and old mice. Additionally, we examine age-related changes in cardiac responses to sympathomimetic and parasympathomimetic drugs. Methods and ResultsLower SC density, lower SC proliferation and fewer parasympathetic nerve fibers were observed in cardiac and, as a control sciatic nerves from old (20-24 months) compared to young mice (2-3 months). In old mice, CSPG4 was increased in sciatic but not cardiac nerves. Expression of M2R was lower in ventricular myocardium and ventricular conduction system from old mice compared to young mice, while no significant difference was seen in M2R expression in sino-atrial or atrio-ventricular node pacemaker tissue. Heart rate was slower and PQ intervals were longer in Langendorff-perfused hearts from old mice. Ventricular tachycardia and fibrillation were more frequently observed in response to carbachol administration in hearts from old mice versus those from young mice. ConclusionsOn the background of reduced presence of SC and parasympathetic nerve fibers, and of lower M2R expression in ventricular cardiomyocytes and conduction system of aged hearts, the propensity of ventricular arrhythmogenesis upon parasympathomimetic drug application is increased. Whether this is caused by an increase in heterogeneity of iCNS structure and function remains to be elucidated. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/568538v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@11dbccdorg.highwire.dtl.DTLVardef@1563d75org.highwire.dtl.DTLVardef@dcda58org.highwire.dtl.DTLVardef@182e598_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Hortells, L., Zgierski-Johnston, C. M., Kohl, P., Schneider-Warme, F., Ravens, U., Preissl, S., Cameron, B. A., Koch, M., Brennan, T. A., Madl, J., Iaconianni, P., Fernandez, M. C., Stefanovska, D., Tumlinson, G., Sassu, E.. 2023-11-24. Age-related structural and functional changes of the intracardiac nervous system. https://doi.org/10.1101/2023.11.24.568538

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