Circulating MIF, D-DT, and Soluble CD74 in End-Stage Heart Failure Patients Receiving LVAD: An Exploratory Clinical...

Background: Emerging evidence highlights the importance of the MIF-sCD74 axis in health and disease, including its role in regulating cell death. While studies in routine cardiac surgery suggest perioperative relevance, its role in end-stage heart failure (ESFH) patients undergoing left ventricular assist device (LVAD) implantation remains unexplored. Moreover, although MIF and sCD74 induce necroptosis in neonatal cardiac myofibroblasts, the effects of MIF, its paralog D-DT, and sCD74 on adult cardiac myofibroblasts (CMFs) are unknown. Methods: Plasma concentrations of sCD74, MIF and D-DT were measured perioperatively in a small cohort of patients with ESHF undergoing LVAD implantation (n = 20). As a preclinical model of ESHF, primary adult CMFs were treated with recombinant MIF, D-DT and sCD74 to evaluate their effects on cellular viability and health. Results: In LVAD patients, sCD74 and D-DT levels were significantly increased 24 h postoperatively, whereas MIF levels were reduced compared to baseline. ROC curve analysis demonstrated a good discriminatory power of 24 h post-OP sCD74 (AUC = 0.83), sCD74/MIF ratio (AUC = 0.82), and D-DT levels (AUC = 0.88) for acute kidney injury, composite outcome, and right heart failure (RHF), respectively. In adult CMFs, MIF and sCD74 synergistically reduced viable cell counts (p = 0.0083), whereas D-DT reduced cell counts in an sCD74-independent manner (p = 0.0004). Yet, measures of metabolism, proliferation, apoptosis and necrosis along with inflammatory gene expression remained unchanged. Conclusions: Our findings indicate that the balance of MIF, D-DT, and sCD74 during LVAD implantation may be clinically relevant. In particular, an imbalance characterized by elevated sCD74 or D-DT and reduced MIF levels 24 h post-surgery was associated with unfavorable clinical outcomes. Yet, the current findings are exploratory and hypothesis-generating because of a small sample size. Thus, the prognostic value of plasma levels for postoperative complications after LVAD implantation, and the effects of MIF/D-DT/sCD74 imbalance on cardiac myofibroblasts, need to be validated in larger cohorts and in advanced human experimental models.