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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 90 ), time to peak force (TTP) and time to relaxation (TTR) were determined at 37°C and 0.2–2 Hz pacing frequency. F 1  Hz /F 0 . 5  Hz  and F 2  Hz /F 0 . 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. F 1  Hz /F 0 . 5  Hz  ( R  2  = 0.82) and F 2  Hz /F 0 . 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 F 1  Hz /F 0 . 5  Hz , but to a lesser degree ( R  2  = 0.49), whereas NCX1 was not correlated ( R  2  = 0.02). CD 90  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.

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