Dexamethasone treatment of failing human myocardial slices caused a 2-fold increase in contraction force compared with control (p<0.01) and higher maximum beating rates (p<0.001).
Dexamethasone increases contractility and improves excitation-contraction coupling in failing human myocardium via the glucocorticoid receptor, suggesting a potential mechanism to oppose cellular electrophysiological changes in heart failure.
Effect estimate: 2-fold increase
p-value: p=<0.01
Abstract Background Glucocorticoids are key regulators of cardiac development, maturation of stem-cell derived cardiomyocytes. They were also shown to enhance excitation-contraction (EC) coupling in in isolated animal cardiomyocytes. However, our knowledge on direct effects of glucocorticoids on human myocardial tissue and human cardiomyocytes is limited. Here, we studied the influence of glucocorticoids on contractile parameters, transmembrane currents and EC coupling in living human myocardial slices. Methods Left-ventricular tissue from failing human hearts was obtained during assist device implantation or from explanted hearts. The use of human tissues was approved by institutional ethics committees, all patients or legal guardians gave written informed consent. Slices from 18 end-stage failing human heart samples were kept beating in culture for up to 30 days with 100 nM dexamethasone (DEX), 20 nM cortisol, +/- 1 µM spironolactone or 1 µM mifepristone, or vehicle as control (CTRL). After culture, slices underwent b-adrenergic stimulation, Ca2+ imaging (Calbryte), cell isolation to measure whole-cell ionic currents and action potentials, or were analyzed by qPCR and immunostaining. Results DEX treatment caused a 2-fold increase in contraction force when compared with CTRL (p0.01), higher maximum beating rates (p0.001), a more positive force-frequency relationship and faster contraction and relaxation. These effects were blocked by mifepristone, but not by spironolactone, and reproduced with cortisol treatment, albeit less pronounced. DEX caused a 38±6% increase in CACNA1c mRNA after 2d and a 23±8% increase after one week. DEX increased mRNA expressions of SERCA, Kv4.3, KChIP2, Kir2.1 and Kir2.3. Consistently, DEX increased ICaL density by 69% (p0.05), Ito 2.7fold (p0.001), IK1 1.5fold (p0.01) and caused a slightly more negative membrane potential. Current kinetics remained unchanged. Moreover, the contractile response to 100 nM isoprenaline was 2fold increased in DEX-treated slices. Ca2+ signal upstroke velocity was higher in DEX than in CTRL. Ca2+ signal amplitudes were unchanged at baseline, but increased in DEX after isoprenaline application. Confocal microscopy revealed no difference in cell size and fibrosis, but a slight increase in RyR cluster density in DEX. Conclusions DEX increases contractility in human failing myocardium via the glucocorticoid receptor and increases current densities of ICaL, Ito and IK1 in human failing myocardium without affecting kinetic parameters. DEX also increases the expression of the respective ion channel subunits and enhances Ca2+ signaling and b-adrenergic response. This suggests increased Ca2+ entry and subsequently improved EC coupling as a main mechanism of glucocorticoid-induced increase in inotropy and may oppose the cellular changes in electrophysiology and excitation-contraction coupling commonly observed in human heart failure.Dexamethason effects on human myocardiumFor image description, please refer to the figure legend and surrounding text.
Seidel et al. (Fri,) conducted a other in end-stage failing human heart (n=18). dexamethasone vs. vehicle was evaluated on contraction force (2-fold increase, p=<0.01). Dexamethasone treatment of failing human myocardial slices caused a 2-fold increase in contraction force compared with control (p<0.01) and higher maximum beating rates (p<0.001).