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

Maha Abu-Khousa; Dominik J Fiegle; Sophie T Sommer; Ghazali Minabari; Hendrik Milting; Christian Heim; Michael Weyand; Roland Tomasi; Andreas Dendorfer; Tilmann Volk; Thomas Seidel

doi:10.3389/fphys.2020.00182

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

Front Physiol. 2020 Mar 13:11:182. doi: 10.3389/fphys.2020.00182. eCollection 2020.

Authors

Maha Abu-Khousa¹, Dominik J Fiegle¹, Sophie T Sommer¹, Ghazali Minabari², Hendrik Milting³, Christian Heim², Michael Weyand^{2

4}, Roland Tomasi^{5

6}, Andreas Dendorfer^{5

7}, Tilmann Volk^{1

4}, Thomas Seidel^{1

4}

Affiliations

¹ Institute of Cellular and Molecular Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
² Department of Cardiac Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
³ Erich and Hanna Klessmann Institute, Clinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany.
⁴ Muscle Research Center Erlangen (MURCE), Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁵ Walter Brendel Centre of Experimental Medicine, University Hospital, LMU Munich, Munich, Germany.
⁶ Department of Anaesthesiology, University Hospital, LMU Munich, Munich, Germany.
⁷ German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.

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. F₁ _Hz/F₀.₅ _Hz and F₂ _Hz/F₀.₅ _Hz 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. F₁ _Hz/F₀.₅ _Hz (R ² = 0.82) and F₂ _Hz/F₀.₅ _Hz (R ² = 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 F₁ _Hz/F₀.₅ _Hz, but to a lesser degree (R ² = 0.49), whereas NCX1 was not correlated (R ² = 0.02). CD₉₀ correlated positively with ΔTT (R ² = 0.39) and negatively with SERCA2/PLB (R ² = 0.42), indicating that both the t-system and SERCA activity are important for contraction kinetics. Surprisingly, ΔTT was not associated with TTP (R ² = 0) but rather with TTR (R ² = 0.5). This became even more pronounced when interaction with NCX1 expression was added to the model (R ² = 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.

Keywords: cardiac excitation-contraction coupling; cardiac remodeling; force frequency relationship; heart failure; human heart; transverse tubular system.