Desmin is essential for the structure and function of the sinoatrial node: implications for increased arrhythmogenesis

Manolis Mavroidis*, Nikolaos C. Athanasiadis, Pavlos Rigas, Ioanna Kostavasili, Ismini Kloukina, Wouter P. Te Rijdt, Nikolaos Kavantzas, Dimitris Chaniotis, J. Peter van Tintelen, Irini Skaliora, Constantinos H. Davos

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    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 “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 Ca2+ 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.

    Original languageEnglish
    Pages (from-to)H557-H570
    Number of pages14
    JournalAMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
    Volume319
    Issue number3
    DOIs
    Publication statusPublished - Sept-2020

    Keywords

    • animal models
    • arrhythmogenic cardiomyopathy
    • cytoskeleton
    • desmin
    • desmosomes
    • electron micmscopy
    • heart rate variability
    • intercalated disks
    • CARDIAC SODIUM-CHANNEL
    • HEART-RATE-VARIABILITY
    • INTERCALATED DISK
    • CONDUCTION SYSTEM
    • JUNCTIONS
    • CARDIOMYOPATHY
    • CELLS
    • CARDIOMYOCYTES
    • HETEROGENEITY
    • ORGANIZATION

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