Functional Effects and Heterogeneity of T-System Remodeling in Human Failing Hearts

Objectives: Failing human hearts exhibit great regional variability of ventricular remodeling and contractility. A possible explanation is the local loss and remodeling of the normally dense membrane system in cardiomyocytes, the transverse tubular (t-) system. Assuring efficient Ca²⁺ cycling and hence contractility, the t-system has been suggested as a histological biomarker. However, if regional t-system remodeling affects regional contraction and relaxation in human failing hearts remains elusive. It is also unknown how t-system remodeling varies regionally in failing hearts. This study investigated contraction at increasing stimulation rates and T-system heterogeneity in failing human myocardium.

Methods: Transmural cardiac samples were obtained from the left ventricular base, center, and apex of explanted hearts from patients undergoing transplantation due to terminal heart failure (n = 23). Contractile force was measured from cultivated tissue slices stimulated with frequencies between 0.2 and 3 Hz. Contraction force, time to peak (TTP), time to relaxation (TTR), and 90% contraction duration (CD90) were detected. Samples were further dissected into sub-endocardial and sub-epicardial wall layers, stained for extracellular matrix and t-tubules, and analyzed by 3D confocal microscopy. T-system distance (∆TT) was calculated as a measure of t-system remodeling.

Result: Basal contractile force and ∆TT were highly variable between samples from different patients. Interestingly, increasing stimulation frequencies led to force decrease in samples with high ∆TT (T-system loss), but not in samples with low ∆TT (preserved t-system, R ² = 0.8, p < 0.01). Furthermore, TTR and CD90 were prolonged in samples with high ∆TT (p < 0.05), indicating slower contraction in these samples. Given the association of ∆TT with myocardial function, we assessed regional variation of the t-system. The variance of ∆TT within different cardiac regions was lower than among different patients and no difference was found in ∆TT between endo- and epicardial sites.

Conclusion: T-system remodeling might contribute to cardiac force depression, particularly at high heart rates. T-system abundance is heterogeneous within failing hearts, but also patient-specific. This study may help not only to understand the mechanisms underlying regional variation of contractility in failing hearts, but also to herald for the t-system as a histological biomarker.

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Publikationsverlauf

Artikel online veröffentlicht:
19. Februar 2021