Objectives: Glucocorticoids have been shown to increase cardiomyocyte Ca2+ currents and may prevent remodeling of structures related to cardiac excitation-contraction coupling. However, most results stem from animal models and cell culture experiments, and it is therefore unclear if glucocorticoids exert similar effects in human myocardium. Furthermore, assessing direct effects of glucocorticoids in vivo is hampered by systemic adverse effects. Here, we investigated inotropic effects of glucocorticoids in human myocardium in vitro.
Methods: We obtained myocardial tissue samples from 11 patients undergoing heart transplantation or left ventricular (LV) assist device implantation. As healthy control, we used LV tissue from 6 rabbit hearts. Tissues were sliced into 300-µm-thick sections and kept in culture under constant electromechanical stimulation for 5 to 7 days. Pacing rates ranged from 30/min to 120/min. Slices were treated with either 100 nmol/L dexamethasone (DEX) or with vehicle only as control. Maximum force (Fmax), contraction duration (CD), time to peak force (TTP), and time to relaxation (TTR) were analyzed. After culture, we used RT qPCR to quantify mRNA expression of the L-type Ca2+ channel subunit α-1C (CACNA1C).
Result: DEX-treated human myocardial slices showed a nearly 2-fold increase in contractile force (Fmax = 1780 ± 621 µN) when compared with control slices (Fmax = 893 ± 170 µN, p < 0.01). Furthermore, DEX significantly decreased contraction time (CD90 = 665 ± 53 vs. 783 ± 81 milliseconds, p < 0.05). This acceleration of the contraction cycle resulted from faster force development (TTP = 285 ± 27 vs. 365 ± 44 milliseconds, p < 0.01) rather from than a change in relaxation velocity (TTR = 380 ± 31 vs. 418 ± 42 milliseconds, p = 0.14). These functional changes were accompanied by a 23 ± 8% increase in CACNA1C mRNA in DEX-treated slices (p < 0.05, n = 8). Functional results could be recapitulated in healthy rabbit myocardium, where in DEX-treated slices Fmax was greater than in control slices (2,300 ± 562 µN, vs. 767 ± 240 µN, p < 0.001), CD (459 ± 95 vs. 677 ± 70 milliseconds, p < 0.05) and TTP (223 ± 61 vs. 381 ± 51 milliseconds, p < 0.01) were shorter, and TTR was unaltered (236 ± 40 vs. 296 ± 25 milliseconds, p = 0.23).
Conclusion: Glucocorticoids directly increase contractile force and contraction kinetics in failing human and healthy rabbit myocardium, which may be mediated by upregulation of L-type Ca2+ channel expression. We suggest to further explore the role of the glucocorticoid receptor and related signaling pathways in the setting of heart failure.
