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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.
Abstract: 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. Unassigned: 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 (M) and the G protein-gated inwardly rectifying K (GIRK4) channel that mediates the cardiac current. Unassigned: 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 , 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 . 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 ( = 16). Furthermore, the expression levels of the M receptor and the GIRK4 subunit of the I channel were quantified in biopsies from the right atrium, the AV node and right ventricle using immunohistochemistry and machine learning-based automated segmentation analysis ( = 9 + 9). Unassigned: The AV block group had a significantly longer PR interval (mean ± SD, 0.40 ± 0.05 s; < 0.001) and a longer Wenckebach cycle length (mean ± SD, 995 ± 86 ms; = 0.007) at baseline. After blocking the ANS, all second-degree AV block episodes were abolished, and the difference in PR interval disappered ( = 0.80). The AV block group had significantly higher expression of the M receptor ( = 0.02), but not the GIRK4 ( = 0.25) in the AV node compared to the control group. Both M and GIRK4 were highly expressed in the AV node and less expressed in the atria and the ventricles. Unassigned: Here, we demonstrate the involvement of the mR- pathway in underlying second-degree AV block in horses. The high expression level of the M receptor may be responsible for the high burden of second-degree AV blocks seen in some horses.
© 2023 Nissen, Saljic, Carstensen, Braunstein, Hesselkilde, Kjeldsen, Hopster-Iversen, D'Souza, Jespersen and Buhl.
Publication Date: 2023-11-16 PubMed ID: 38034369PubMed Central: PMC10687567DOI: 10.3389/fcvm.2023.1102164Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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The research investigates the underlying causes of second-degree atrioventricular block in horses, focusing on the role of muscarinic acetylcholine receptors and to a lesser extent, G protein-gated inwardly rectifying potassium channels. It finds that an increased presence of these receptors may contribute to this common equine heart condition.
Background and Purpose
- The study wants to understand more about the second-degree atrioventricular (AV) block in horses, which is often attributed to high vagal tone. The focus is on the factors involved in vagal signaling in the AV node, namely the muscarinic acetylcholine receptor (M) and the G protein-gated inwardly rectifying K (GIRK4) channel.
- The AV block is common in horses and can significantly affect a horse’s performance and well-being. However, the exact molecular mechanisms causing this condition are still unclear.
Methodology
- The experimentation involved two groups of horses: 18 horses with a low burden of AV block and 17 horses with a high burden of AV block.
- Radiotelemetry ECG recordings were done to measure the heart rhythm of the horses both under normal conditions and under pharmacological blockade of the autonomic nervous system (ANS).
- The researchers specifically measured the incidence of AV block episodes and the length of the Wenckebach cycle, a cycle concerning cardiac conduction.
- Simultaneously, levels of M receptor and GIRK4 channel expression were examined in the heart tissue samples from the right atrium, the AV node, and the right ventricle.
Findings
- The horses with a higher burden of second-degree AV block exhibited a longer PR interval and Wenckebach cycle length, indicators of abnormal heart function. However, these differences in heart function disappeared when the ANS was pharmacologically blocked.
- Most notably, the high AV block group showed higher expression levels of the M receptor in the AV node as compared to the control group. Levels of GIRK4 expression, on the other hand, did not show a significant difference.
Conclusion
- The research concludes that an upregulated presence of M receptors in the AV node could be responsible for the high rate of second-degree AV block episodes in horses.
- By examining expression levels of M receptors, the study demonstrates the role of the muscarinic acetylcholine receptor pathway in the pathology of second-degree AV block in horses.
Cite This Article
APA
Nissen SD, Saljic A, Carstensen H, Braunstein TH, Hesselkilde EM, Kjeldsen ST, Hopster-Iversen C, D'Souza A, Jespersen T, Buhl R.
(2023).
Muscarinic acetylcholine receptors M2 are upregulated in the atrioventricular nodal tract in horses with a high burden of second-degree atrioventricular block.
Front Cardiovasc Med, 10, 1102164.
https://doi.org/10.3389/fcvm.2023.1102164 Publication
Researcher Affiliations
- Laboratory of Cardiac Physiology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Laboratory of Cardiac Physiology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Institute of Pharmacology, West German Heart and Vascular Centre, University Duisburg-Essen, Essen, Germany.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
- Core Facility for Integrated Microscopy, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Laboratory of Cardiac Physiology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
- Division of Cardiovascular Sciences, University of Manchester, 3.30 Core Technology, Manchester, United Kingdom.
- Laboratory of Cardiac Physiology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
This article includes 37 references
- Raekallio M. Long term ECG recording with Holter monitoring in clinically healthy horses.. Acta Vet Scand (1992) 33(1):71–5.
- Holmes JR, Alps BJ. Observations on partial atrio-ventricular heart block in the horse.. Can Vet J (1966) 7(12):280–90.
- Smetzer DL, Smith CR, Senta T. Second-degree atrioventricular block in the horse.. Am J Vet Res (1969) 30(6):933–46.
- Pedersen PJ, Moeller SB, Flethøj M, Kanters JK, Buhl R, Klaerke DA. Diurnal modulation and sources of variation affecting ventricular repolarization in Warmblood horses.. J Vet Cardiol (2014) 16(4):265–76.
- Nissen SD, Weis R, Krag-Andersen EK, Hesselkilde EM, Isaksen JL, Carstensen H. Electrocardiographic characteristics of trained and untrained standardbred racehorses.. J Vet Intern Med (2022) 36(3):1119–30.
- Verheyen T, Decloedt A, De Clerq D, Deprez P, Sys SU, van Loon G. Electrocardiography in horses—part 2: how to read the equine ECG.. Vlaams Diergeneeskundig Tijdschrift (2010) 79:337–44.
- Brooijmans AWM. Electrocardiography in horses and cattles: theoretical and clinical aspects.. Collected Papers from the Laboratory of Veterinary Physiology, State University of Utrecht, Netherlands (1957).
- Steel JD. Studies on the electrocardiogram of the racehorse.. Australasian Medical Publishing Sydney; (1963).
- Senta T, Smetzer DL, Smith CR. Effects of exercise on certain electrocardiographic parameters and cardiac arrhythmias in the horse. A radiotelemetric study.. Cornell Vet (1970) 60(4):552–69.
- Reef VB, Bonagura J, Buhl R, McGurrin MKJ, Schwarzwald CC, van Loon G. Recommendations for management of equine athletes with cardiovascular abnormalities.. J Vet Intern Med (2014) 28(3):749–61.
- van Loon G. Cardiac arrhythmias in horses.. Vet Clin North Am (2019) 35(1):85–102.
- Saljic A, Friederike Fenner M, Winters J, Flethøj M, Eggert Eggertsen C, Carstensen H. Increased fibroblast accumulation in the equine heart following persistent atrial fibrillation.. IJC Heart Vasc (2021) 35:100842.
- Hesselkilde EZ, Carstensen H, Flethøj M, Fenner M, Kruse DD, Sattler SM. Longitudinal study of electrical, functional and structural remodelling in an equine model of atrial fibrillation.. BMC Cardiovasc Disord (2019) 19(1):228.
- Fenner MF, Carstensen H, Dalgas Nissen S, Melis Hesselkilde E, Scott Lunddahl C, Adler Hess Jensen M. Effect of selective IK,ACh inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation.. Br J Pharmacol (2020) 177(16):3778–94.
- Mesirca P, Nakao S, Nissen SD, Forte G, Anderson C, Trussell T. Intrinsic electrical remodeling underlies atrioventricular block in athletes.. Circ Res (2021) 129(1):e1–e20.
- Li M, Chadda KR, Matthews GDK, Marr CM, Huang CL, Jeevaratnam K. Cardiac electrophysiological adaptations in the equine athlete—restitution analysis of electrocardiographic features.. PLoS One (2018) 13(3).
- Smetzer DL. Equine sinoatrial and second-degree atrioventricular heart-block.. University Microfilms, Inc. Ann Arbor, MI: (1967).
- Yamaya Y, Kubo K, Amada A, Sato K. Intrinsic atrioventricular conductive function in horses with a second degree atrioventricular block.. J Vet Med Sci (1997) 59(3):149–51.
- Saternos HC, Almarghalani DA, Gibson HM, Meqdad MA, Antypas RB, Lingireddy A. Distribution and function of the muscarinic receptor subtypes in the cardiovascular system.. Physiol Genomics (2018) 50(1):1–9.
- Logothetis DE, Kurachi Y, Galper J, Neer EJ, Clapham DE. The beta gamma subunits of GTP-binding proteins activate the muscarinic K + channel in heart.. Nature (1987) 325(6102):321–6.
- Drici MD, Diochot S, Terrenoire C, Romey G, Lazdunski M. The bee venom peptide tertiapin underlines the role of I(KACh) in acetylcholine-induced atrioventricular blocks.. Br J Pharmacol (2000) 131(3):569–77.
- Nishimura M, Habuchi Y, Hiromasa S, Watanabe Y. Ionic basis of depressed automaticity and conduction by acetylcholine in rabbit AV node.. Am J Physiol (1988) 255(1 Pt 2):H7–14.
- Hamlin RL, Klepinger WL, Gilpin KW, Smith CR. Autonomic control of heart rate in the horse.. Am J Physiol (1972) 222(4):976–8.
- Carstensen H, Nissen SD, Saljic A, Hesselkilde EM, van Hunnik A, Hohl M. Long-term training increases atrial fibrillation sustainability in standardbred racehorses.. J Cardiovasc Transl Res (2023) 16:1205–19.
- Fenner MF, Gatta G, Sattler S, Kuiper M, Hesselkilde EM, Adler DMT. Inhibition of small-conductance calcium-activated potassium current (IK,Ca) leads to differential atrial electrophysiological effects in a horse model of persistent atrial fibrillation.. Front Physiol (2021) 12(31).
- Mesirca P, Marger L, Toyoda F, Rizzetto R, Audoubert M, Dubel S. The G-protein-gated K + channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation.. J Gen Physiol (2013) 142(2):113–26.
- Bettahi I, Marker CL, Roman MI, Wickman K. Contribution of the Kir3.1 subunit to the muscarinic-gated atrial potassium channel IKACh*.. J Biol Chem (2002) 277(50):48282–8.
- Miyamoto T, Zhang L, Sekiguchi A, Hadama T, Shimada T. Structural differences in the cytoarchitecture and intercalated discs between the working myocardium and conduction system in the human heart.. Heart Vessels (2002) 16(6):232–40.
- Deighton NM, Motomura S, Borquez D, Zerkowski HR, Doetsch N, Brodde OE. Muscarinic cholinoceptors in the human heart: demonstration, subclassification, and distribution.. Naunyn Schmiedebergs Arch Pharmacol (1990) 341(1-2):14–21.
- Dhein S, van Koppen CJ, Brodde O-E. Muscarinic receptors in the mammalian heart.. Pharmacol Res (2001) 44(3):161–82.
- Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A. Tissue-based map of the human proteome.. Science (2015) 347(6220):1260419.
- Zoob M, Smith KS. The aetiology of complete heart-block.. Br Med J (1963) 2(5366):1149–53.
- Dhingra RC, Denes P, Wu D, Chuquimia R, Rosen KM. The significance of second degree atrioventricular block and bundle branch block.. Circulation (1974) 49(4):638–46.
- Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Crist T. The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation.. Circulation (2005) 112(24):3697–706.
- Anderson A, Kulkarni K, Marron Fernandez de Velasco E, Carlblom N, Xia Z, Nakano A. Expression and relevance of the G protein-gated K(+) channel in the mouse ventricle.. Sci Rep (2018) 8(1):1192–1192.
- Dobrzynski H, Marples DD, Musa H, Yamanushi TT, Henderson Z, Takagishi Y. Distribution of the muscarinic K + channel proteins Kir3.1 and Kir3.4 in the ventricle, atrium, and sinoatrial node of heart.. J Histochem Cytochem (2001) 49(10):1221–34.
- Darkow E, Nguyen TT, Stolina M, Kari FA, Schmidt C, Wiedmann F. Small conductance Ca2 + -activated K + (SK) channel mRNA expression in human atrial and ventricular tissue: comparison between donor, atrial fibrillation and heart failure tissue.. Front Physiol (2021) 12.
Citations
This article has been cited 2 times.- Natterson-Horowitz B, Wright K, Van Steenkiste G, Decloedt A, Gagnon AL, Cai X, Mazmanian A. Arrhythmias across the tree of life: comparative insights for human electrophysiology. Front Cardiovasc Med 2025;12:1652591.
- Nissen SD, Bastrup JA, Haugaard SL, Marion-Knudsen R, Schneider M, Kjeldsen ST, Carstensen H, Hopster-Iversen C, Nattel S, Jepps TA, Buhl R. Horse model of spontaneous atrial fibrillation share proteomic changes with humans. Sci Rep 2025 Aug 28;15(1):31694.
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