TY - JOUR

T1 - Muscarinic acetylcholine receptors M2 are upregulated in the atrioventricular nodal tract in horses with a high burden of second-degree atrioventricular block

AU - Nissen, Sarah Dalgas

AU - Saljic, Arnela

AU - Carstensen, Helena

AU - Braunstein, Thomas Hartig

AU - Hesselkilde, Eva Melis

AU - Kjeldsen, Sofie Troest

AU - Hopster-Iversen, Charlotte

AU - D’Souza, Alicia

AU - Jespersen, Thomas

AU - Buhl, Rikke

N1 - Publisher Copyright: 2023 Nissen, Saljic, Carstensen, Braunstein, Hesselkilde, Kjeldsen, Hopster-Iversen, D'Souza, Jespersen and Buhl.

PY - 2023

Y1 - 2023

N2 - Background: Second-degree atrioventricular (AV) block at rest is very common in horses. The underlying molecular mechanisms are unexplored, but commonly attributed to high vagal tone. Aim: To assess whether AV block in horses is due to altered expression of the effectors of vagal signalling in the AV node, with specific emphasis on the muscarinic acetylcholine receptor (M2) and the G protein-gated inwardly rectifying K+ (GIRK4) channel that mediates the cardiac IK,ACh current. Method: Eighteen horses with a low burden of second-degree AV block (median 8 block per 20 h, IQR: 32 per 20 h) were assigned to the control group, while 17 horses with a high burden of second-degree AV block (median: 408 block per 20 h, IQR: 1,436 per 20 h) were assigned to the AV block group. Radiotelemetry ECG recordings were performed to assess PR interval and incidence of second-degree AV block episodes at baseline and on pharmacological blockade of the autonomic nervous system (ANS). Wenckebach cycle length was measured by intracardiac pacing (n = 16). Furthermore, the expression levels of the M2 receptor and the GIRK4 subunit of the IKACh channel were quantified in biopsies from the right atrium, the AV node and right ventricle using immunohistochemistry and machine learning-based automated segmentation analysis (n = 9 + 9). Results: The AV block group had a significantly longer PR interval (mean ± SD, 0.40 ± 0.05 s; p < 0.001) and a longer Wenckebach cycle length (mean ± SD, 995 ± 86 ms; p = 0.007) at baseline. After blocking the ANS, all second-degree AV block episodes were abolished, and the difference in PR interval disappered (p = 0.80). The AV block group had significantly higher expression of the M2 receptor (p = 0.02), but not the GIRK4 (p = 0.25) in the AV node compared to the control group. Both M2 and GIRK4 were highly expressed in the AV node and less expressed in the atria and the ventricles. Conclusion: Here, we demonstrate the involvement of the m2R-IK,ACh pathway in underlying second-degree AV block in horses. The high expression level of the M2 receptor may be responsible for the high burden of second-degree AV blocks seen in some horses.

AB - Background: Second-degree atrioventricular (AV) block at rest is very common in horses. The underlying molecular mechanisms are unexplored, but commonly attributed to high vagal tone. Aim: To assess whether AV block in horses is due to altered expression of the effectors of vagal signalling in the AV node, with specific emphasis on the muscarinic acetylcholine receptor (M2) and the G protein-gated inwardly rectifying K+ (GIRK4) channel that mediates the cardiac IK,ACh current. Method: Eighteen horses with a low burden of second-degree AV block (median 8 block per 20 h, IQR: 32 per 20 h) were assigned to the control group, while 17 horses with a high burden of second-degree AV block (median: 408 block per 20 h, IQR: 1,436 per 20 h) were assigned to the AV block group. Radiotelemetry ECG recordings were performed to assess PR interval and incidence of second-degree AV block episodes at baseline and on pharmacological blockade of the autonomic nervous system (ANS). Wenckebach cycle length was measured by intracardiac pacing (n = 16). Furthermore, the expression levels of the M2 receptor and the GIRK4 subunit of the IKACh channel were quantified in biopsies from the right atrium, the AV node and right ventricle using immunohistochemistry and machine learning-based automated segmentation analysis (n = 9 + 9). Results: The AV block group had a significantly longer PR interval (mean ± SD, 0.40 ± 0.05 s; p < 0.001) and a longer Wenckebach cycle length (mean ± SD, 995 ± 86 ms; p = 0.007) at baseline. After blocking the ANS, all second-degree AV block episodes were abolished, and the difference in PR interval disappered (p = 0.80). The AV block group had significantly higher expression of the M2 receptor (p = 0.02), but not the GIRK4 (p = 0.25) in the AV node compared to the control group. Both M2 and GIRK4 were highly expressed in the AV node and less expressed in the atria and the ventricles. Conclusion: Here, we demonstrate the involvement of the m2R-IK,ACh pathway in underlying second-degree AV block in horses. The high expression level of the M2 receptor may be responsible for the high burden of second-degree AV blocks seen in some horses.

KW - acetylcholine-dependent inwardly rectifying potassium channel

KW - atrioventricular node

KW - cardiac conduction

KW - equine

KW - muscarinic receptor

KW - parasympathetic activity

KW - second-degree AV block

KW - vagus

U2 - 10.3389/fcvm.2023.1102164

DO - 10.3389/fcvm.2023.1102164

M3 - Journal article

C2 - 38034369

AN - SCOPUS:85178195260

VL - 10

JO - Frontiers in Cardiovascular Medicine

JF - Frontiers in Cardiovascular Medicine

SN - 2297-055X

M1 - 1102164

ER -