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

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.