The Degree of t-System Remodeling Predicts Negative Force-Frequency Relationship and Prolonged Relaxation Time in Failing Human Myocardium

Abu-Khousa M, Fiegle D, Sommer ST, Minabari G, Milting H, Heim C, Weyand M, Tomasi R, Dendorfer A, Volk T, Seidel T (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Frontiers in Physiology Frontiers Media

Book Volume: 11

Article Number: 182

DOI: 10.3389/fphys.2020.00182

Abstract

The normally positive cardiac force-frequency relationship (FFR) becomes flat or negative in chronic heart failure (HF). Here we explored if remodeling of the cardiomyocyte transverse tubular system (t-system) is associated with alterations in FFR and contractile kinetics in failing human myocardium. Left-ventricular myocardial slices from 13 failing human hearts were mounted into a biomimetic culture setup. Maximum twitch force (F), 90% contraction duration (CD90), time to peak force (TTP) and time to relaxation (TTR) were determined at 37°C and 0.2–2 Hz pacing frequency. F1Hz/F0.5Hz and F2Hz/F0.5Hz served as measures of FFR, intracellular cardiomyocyte t-tubule distance (ΔTT) as measure of t-system remodeling. Protein levels of SERCA2, NCX1, and PLB were quantified by immunoblotting. F1Hz/F0.5Hz (R2 = 0.82) and F2Hz/F0.5Hz (R2 = 0.5) correlated negatively with ΔTT, i.e., samples with severe t-system loss exhibited a negative FFR and reduced myocardial wall tension at high pacing rates. PLB levels also predicted F1Hz/F0.5Hz, but to a lesser degree (R2 = 0.49), whereas NCX1 was not correlated (R2 = 0.02). CD90 correlated positively with ΔTT (R2 = 0.39) and negatively with SERCA2/PLB (R2 = 0.42), indicating that both the t-system and SERCA activity are important for contraction kinetics. Surprisingly, ΔTT was not associated with TTP (R2 = 0) but rather with TTR (R2 = 0.5). This became even more pronounced when interaction with NCX1 expression was added to the model (R2 = 0.79), suggesting that t-system loss impairs myocardial relaxation especially when NCX1 expression is low. The degree of t-system remodeling predicts FFR inversion and contraction slowing in failing human myocardium. Moreover, together with NCX, the t-system may be important for myocardial relaxation.

Authors with CRIS profile

Dominik Fiegle Professur für Herz-Kreislaufphysiologie Christian Heim Department of Cardiac Surgery Michael Weyand Lehrstuhl für Herzchirurgie Tilmann Volk Professur für Herz-Kreislaufphysiologie Thomas Seidel Professur für Herz-Kreislaufphysiologie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung (IZKF)

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

Klinikum der Universität München DE Germany (DE) Herz- und Diabeteszentrum Nordrhein-Westfalen DE Germany (DE)

How to cite

APA:

Abu-Khousa, M., Fiegle, D., Sommer, S.T., Minabari, G., Milting, H., Heim, C.,... Seidel, T. (2020). The Degree of t-System Remodeling Predicts Negative Force-Frequency Relationship and Prolonged Relaxation Time in Failing Human Myocardium. Frontiers in Physiology, 11. https://doi.org/10.3389/fphys.2020.00182

MLA:

Abu-Khousa, Maha, et al. "The Degree of t-System Remodeling Predicts Negative Force-Frequency Relationship and Prolonged Relaxation Time in Failing Human Myocardium." Frontiers in Physiology 11 (2020).

BibTeX: Download