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

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

JOURNAL=Frontiers in Physiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00182

DOI=10.3389/fphys.2020.00182

ISSN=1664-042X

ABSTRACT=<p>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 (CD<sub>90</sub>), time to peak force (TTP) and time to relaxation (TTR) were determined at 37°C and 0.2–2 Hz pacing frequency. F<sub>1</sub><sub>Hz</sub>/F<sub>0</sub>.<sub>5</sub><sub>Hz</sub> and F<sub>2</sub><sub>Hz</sub>/F<sub>0</sub>.<sub>5</sub><sub>Hz</sub> 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. F<sub>1</sub><sub>Hz</sub>/F<sub>0</sub>.<sub>5</sub><sub>Hz</sub> (<italic>R</italic><sup>2</sup> = 0.82) and F<sub>2</sub><sub>Hz</sub>/F<sub>0</sub>.<sub>5</sub><sub>Hz</sub> (<italic>R</italic><sup>2</sup> = 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 F<sub>1</sub><sub>Hz</sub>/F<sub>0</sub>.<sub>5</sub><sub>Hz</sub>, but to a lesser degree (<italic>R</italic><sup>2</sup> = 0.49), whereas NCX1 was not correlated (<italic>R</italic><sup>2</sup> = 0.02). CD<sub>90</sub> correlated positively with ΔTT (<italic>R</italic><sup>2</sup> = 0.39) and negatively with SERCA2/PLB (<italic>R</italic><sup>2</sup> = 0.42), indicating that both the t-system and SERCA activity are important for contraction kinetics. Surprisingly, ΔTT was not associated with TTP (<italic>R</italic><sup>2</sup> = 0) but rather with TTR (<italic>R</italic><sup>2</sup> = 0.5). This became even more pronounced when interaction with NCX1 expression was added to the model (<italic>R</italic><sup>2</sup> = 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.</p>