Severe T-System Remodeling in Pediatric Viral Myocarditis

Fiegle D, Schober M, Dittrich S, Cesnjevar R, Klingel K, Volk T, Alkassar M, Seidel T (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Frontiers in Cardiovascular Medicine Frontiers Media

Book Volume: 7

DOI: 10.3389/fcvm.2020.624776

Abstract

Chronic heart failure (HF) in adults causes remodeling of the cardiomyocyte transverse tubular system (t-system), which contributes to disease progression by impairing excitation-contraction (EC) coupling. However, it is unknown if t-system remodeling occurs in pediatric heart failure. This study investigated the t-system in pediatric viral myocarditis. The t-system and integrity of EC coupling junctions (co-localization of L-type Ca2+ channels with ryanodine receptors and junctophilin-2) were analyzed by 3D confocal microscopy in left-ventricular (LV) samples from 5 children with myocarditis (age 14 +/- 3 months), undergoing ventricular assist device (VAD) implantation, and 5 children with atrioventricular septum defect (AVSD, age 17 +/- 3 months), undergoing corrective surgery. LV ejection fraction (EF) was 58.4 +/- 2.3% in AVSD and 12.2 +/- 2.4% in acute myocarditis. Cardiomyocytes from myocarditis samples showed increased t-tubule distance (1.27 +/- 0.05 mu m, n = 34 cells) and dilation of t-tubules (volume-length ratio: 0.64 +/- 0.02 mu m(2)) when compared with AVSD (0.90 +/- 0.02 mu m, p < 0.001; 0.52 +/- 0.02 mu m(2), n = 61, p < 0.01). Intriguingly, 4 out of 5 myocarditis samples exhibited sheet-like t-tubules (t-sheets), a characteristic feature of adult chronic heart failure. The fraction of extracellular matrix was slightly higher in myocarditis (26.6 +/- 1.4%) than in AVSD samples (24.4 +/- 0.8%, p < 0.05). In one case of myocarditis, a second biopsy was taken and analyzed at VAD explantation after extensive cardiac recovery (EF from 7 to 56%) and clinical remission. When compared with pre-VAD, t-tubule distance and density were unchanged, as well as volume-length ratio (0.67 +/- 0.04 mu m(2) vs. 0.72 +/- 0.05 mu m(2), p = 0.5), reflecting extant t-sheets. However, junctophilin-2 cluster density was considerably higher (0.12 +/- 0.02 mu m(-3) vs. 0.05 +/- 0.01 mu m(-3), n = 9/10, p < 0.001), approaching values of AVSD (0.13 +/- 0.05 mu m(-3), n = 56), and the measure of intact EC coupling junctions showed a distinct increase (20.2 +/- 5.0% vs. 6.8 +/- 2.2%, p < 0.001). Severe t-system loss and remodeling to t-sheets can occur in acute HF in young children, resembling the structural changes of chronically failing adult hearts. T-system remodeling might contribute to cardiac dysfunction in viral myocarditis. Although t-system recovery remains elusive, recovery of EC coupling junctions may be possible and deserves further investigation.

Authors with CRIS profile

Dominik Fiegle Lehrstuhl für Physiologie (Vegetative Physiologie) Sven Dittrich Professur für Kinderkardiologie Robert Cesnjevar Professur für Herzchirurgie mit dem Schwerpunkt Kinderherzchirurgie Tilmann Volk Professur für Herz-Kreislaufphysiologie Thomas Seidel Professur für Herz-Kreislaufphysiologie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

IZKF-J65 (P2): Regulation of the t-system and associated proteins in cardiomyocytes by glucocorticoid receptor signaling Nov. 1, 2017 - Oct. 31, 2020

Involved external institutions

Universitätsklinikum Tübingen DE Germany (DE)

How to cite

APA:

Fiegle, D., Schober, M., Dittrich, S., Cesnjevar, R., Klingel, K., Volk, T.,... Seidel, T. (2021). Severe T-System Remodeling in Pediatric Viral Myocarditis. Frontiers in Cardiovascular Medicine, 7. https://doi.org/10.3389/fcvm.2020.624776

MLA:

Fiegle, Dominik, et al. "Severe T-System Remodeling in Pediatric Viral Myocarditis." Frontiers in Cardiovascular Medicine 7 (2021).

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