K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca(2+) leak from the sarcoplasmic reticulum

In heart failure, intracellular Ca(2+) leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca(2+) from the sarcoplasmic reticulum (SR) potentially contributing to decreased function. Experimental data suggest that the 1,4-benzothiazepine K201 (JTV-519) may stabilise RyR2s and thereby reduce detrimental intracellular Ca(2+) leak. Whether K201 exerts beneficial effects in human failing myocardium is unknown. Therefore, we have studied the effects of K201 on muscle preparations from failing human hearts. K201 (0.3 μM; extracellular [Ca(2+)](e) 1.25 mM) showed no effects on contractile function and micromolar concentrations resulted in negative inotropic effects (K201 1 μM; developed tension −9.8 ± 2.5% compared to control group; P < 0.05). Interestingly, K201 (0.3 μM) increased the post-rest potentiation (PRP) of failing myocardium after 120 s, indicating an increased SR Ca(2+) load. At high [Ca(2+)](e) concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30 s). Strikingly, treatment with K201 (0.3 μM) prevented diastolic dysfunction (diastolic tension at 5 mmol/L [Ca(2+)](e) normalised to 1 mmol/L [Ca(2+)](e): control 1.26 ± 0.06, K201 1.01 ± 0.03, P < 0.01). In addition at high [Ca(2+)](e,) K201 (0.3 μM) treatment significantly improved systolic function [developed tension +27 ± 8% (K201 vs. control); P < 0.05]. The beneficial effects on diastolic and systolic functions occurred throughout the physiological frequency range of the human heart rate from 1 to 3 Hz. Upon elevated intracellular Ca(2+) concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00395-009-0057-8) contains supplementary material, which is available to authorized users.