Relaxin and endothelin-1 axis in heart failure patients: First evidence of their transcriptional profiling in during left ventric- ular assist device support

Background-aim Left ventricular assist devices (LVAD) are implanted in patients with end-stage heart failure (HF) as bridge to transplantation and are able to active neurohormonal system that entails the compen- satory rise of vasocostrincting and vasodilating mediators, such as endothelin (ET) system and relaxin (RLX). RLX acts as compensatory mediator in HF and inhibits the stimulation of ET-1 probably via ET receptors enhancing ET-1 clearance and leading to improve cardiac compliance. The aim was to evaluate whether LVAD is able to modulate the RLX and ET-1 system in the heart of end-stage HF patients undergoing LVAD implant by measuring their cardiac expression. Methods In this study were enrolled patient candidates for LVAD implantation collected at baseline (pre-LVAD, n = 22), patients who underwent elective heart transplantation (HTx, n = 7) on medical therapy, and patients supported by LVAD as a bridge-to- heart transplantation (post-LVAD, n = 6). The pre-LVAD and the HTx patients median age was comparable [58 (48-64) vs 55 (46-62) years, respectively] as well as etiology and LV ejection fraction (b25%). In post-LVAD, the median support time prior to heart transplantation was 367 days. Biopsies were collected from LV area at the time of surgical procedures and the cardiac expression of ET-1, RLX, ET-A, ET-B and ET converting enzyme (ECE)-1 was evaluated by Real-Time PCR. Results RLX expression resulted similar in pre-LVAD and HTx (0.32 ± 0.06 vs. 0.10 ± 0.04) but was significantly increased in post-LVAD (1.35 ± 0.95; p = .02 vs. HTx and p = .01 vs. pre-LVAD). Similar to RLX no significant changes in cardiac expression of ET-1 system was found in pre-LVAD and HTx, even though ET-1 and ECE-1 were up- regulated in HTx (0.31 ± 0.06 vs. 0.51 ± 0.47; 0.64 ± 0.12 vs. 0.91 ± 0.84, respectively). In post-LVAD only ET-1 (1.94 ± 0.47) and ECE- 1 (2.48 ± 0.66) increased reaching statistical significance (p = .007 vs. HTx and p = .0002 vs. pre-LVAD and p = .016 vs. HTx and p = .0002 vs. pre-LVAD; respectively) while while ET-A (0.77 ± 0.5) and ET-B (0.87 ± 0.17) mRNA expression resulted similar to those obtained in pre-LVAD (ET-A:0.63 ± 0.13, ET-B:0.70 ± 0.15) and HTx (ET-A:0.33 ± 0.09, ET-B:0.79 ± 0.68). Conclusions Our results show the involvement of RLX and ET-1 axis in end stage HF patients supported by LVAD, evidencing a different regulation in LVAD group with respect to HTx. The increase of RLX expression evidenced in the post-LVAD patients might support its role as a compensatory mediator in HF also after mechanical assistance. Probably this increase, resulting in systemic vasodilata- tion, counterbalance the vasopressor effect of ET-1 system evidenc- ing the effect of LVAD on phenotypic and functional changes in failing myocardium.