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.

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