Remodeling of Transverse Tubular System: A Major Factor Inducing Heart Failure in Myocarditis?

Objectives: Viruses are the main cause of acute myocarditis in childhood. Although cardiac inflammation has been shown to be the cause of heart failure in many studies, the mechanism leading to a decline in contractile strength remains completely nonunderstood. The myocardial tubular system (t-system) is required for efficient electromechanical coupling by activating Ca²⁺ release channels and thus for sufficient contractility. In this study, we examined for the first time the remodeling of the t-system in myocarditis and its influence on myocardial contractility: myocardial cells of a 2-year-old child with fulminant myocarditis were examined initially and after recovery to analyze changes in the t-system taking into account the contractility at the respective time points.

Methods: Two myocardial biopsies from a child with fulminant myocarditis were taken during implantation and explantation of LVAD. Four biopsies of same aged children with good contractility removed during AVSD-closure surgery were used as controls. Three-dimensional confocal microscopy analysis were applied to assess density of t-system, Ca²⁺ release channel and ryanodine receptor (RyR) and the distance of ryanodine receptor cluster to the t-system. According to the literature it was assumed that a distance of more than 1 µm inhibits formation of calcium channels. Echocardiographic strain deformation imaging (SDI) was obtained initially and after explantation of the LVAD (GE E95-scanner, Norway).

Result: Histology showed a fulminant acute lymphocytic myocarditis with the detection of adenovirus. Compared with controls, the amount Ca²⁺ release channels and RyR were dramatically reduced (p < 0.01) with simultaneous strong reduction of the deformation force (LV-strain &−2%). The transverse tubular (t-tubular) system showed a significant regeneration in the myocardial cells 4 months later (p < 0.01), which correlates with an increase in deformation (LV-strain &−15%). It could be also shown that the distance of ryanodine receptor cluster to the t-system is initially significantly greater in comparison to recovery (1.7 + &−0.3 vs. 0.8 + &−0.4, p < 0.01).

Conclusion: It could be demonstrated that the inflammatory process in severe myocarditis causes cellular changes with significant reduction of t-tubules and Ca²⁺ channel proteins leading to a greater distance between proteins forming Ca²⁺ channels. These changes can be an explanation for the reduced myocardial deformation and terminal heart insufficiency. It could also be shown that these changes were reversible after recovery.