Muscarinic acetylcholine receptors M2 are upregulated in the atrioventricular nodal tract in horses with a high burden of second-degree atrioventricular block
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Muscarinic acetylcholine receptors M2 are upregulated in the atrioventricular nodal tract in horses with a high burden of second-degree atrioventricular block. / Nissen, Sarah Dalgas; Saljic, Arnela; Carstensen, Helena; Braunstein, Thomas Hartig; Hesselkilde, Eva Melis; Kjeldsen, Sofie Troest; Hopster-Iversen, Charlotte; D’Souza, Alicia; Jespersen, Thomas; Buhl, Rikke.
In: Frontiers in Cardiovascular Medicine, Vol. 10, 1102164, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 378838032