Desmin is essential for the structure and function of the sinoatrial node; implications for increased arrhythmogenesis
Mavroidis, Manolis; Athanasiadis, Nikolaos C; Rigas, Pavlos Stavros; Kostavasili, Ioanna; Kloukina, Ismini; Te Rijdt, Wouter P; Kavantzas, Nikolaos; Chaniotis, Dimitris; van Tintelen, J Peter; Skaliora, Irini; Davos, Constantinos H
(2020) American Journal of Physiology-Heart and Circulatory Physiology, volume 319, issue 3, pp. H557 - H570
(Article)
Abstract
Our objective was to investigate the effect of desmin depletion on the structure and function of the sinoatrial pacemaker complex (SANcl) and its implication in arrhythmogenesis. Analysis of mice and humans (SANcl) indicated that the sinoatrial node exhibits high amounts of desmin, desmoplakin, N-cadherin, and β-catenin in structures we call
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“lateral intercalated disks” connecting myocytes side by side. Examination of the SANcl from an arrhythmogenic cardiomyopathy model, desmin-deficient (Des -/ -) mouse, by immunofluorescence, ultrastructural, and Western blot analysis showed that the number of these lateral intercalated disks was diminished. Also, electrophysiological recordings of the isolated compact sinoatrial node revealed increased pacemaker systolic potential and higher diastolic depolarization rate compared with wild-type mice. Prolonged interatrial conduction expressed as a longer P wave duration was also observed in Des-/mice. Upregulation of mRNA levels of both T-type Ca 2+ current channels, Cav3.1 and Cav3.2, in the Des-/ - myocardium (1.8- and 2.3-fold, respectively) and a 1.9-fold reduction of funny hyperpolarization-activated cyclic nucleotide-gated K + channel 1 could underlie these functional differences. To investigate arrhythmogenicity, electrocardiographic analysis of Des-deficient mice revealed a major increase in supraventricular and ventricular ectopic beats compared with wild-type mice. Heart rate variability analysis indicated a sympathetic predominance in Des-/ - mice, which may further contribute to arrhythmogenicity. In conclusion, our results indicate that desmin elimination leads to structural and functional abnormalities of the SANcl. These alterations may be enhanced by the sympathetic component of the cardiac autonomic nervous system, which is predominant in the desmin-deficient heart, thus leading to increased arrhythmogenesis.
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Keywords: Animal models, Arrhythmogenic cardiomyopathy, Cytoskeleton, Desmin, Desmosomes, Electron microscopy, Heart rate variability, Intercalated disks, Physiology, Cardiology and Cardiovascular Medicine, Physiology (medical)
ISSN: 0363-6135
Publisher: American Physiological Society
Note: Funding Information: Grants were awarded from the Hellenic Society of Cardiology and by intramural funding to M.M. and C.H.D. and from the Greek General Secretariat of Research and Technology to I.S. W.P.T.R. was supported by Young Talent Program (CVON PREDICT) Grant 2017T001 from the Dutch Heart Foundation and The Netherlands Heart Institute (DEMOS study). Publisher Copyright: Copyright © 2020 the American Physiological Society
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