IL-33/ST2 Pathway and Classical Cytokines in End-Stage Heart Failure Patients Submitted to Left Ventricular Assist Device Support: A Paradoxic Role for Inflammatory Mediators?

Abstract

Background. Inflammation is a critical process contributing to heart failure (HF). We hypothesized that IL-33/ST2 pathway, a new mechanism regulated during cardiac stress, may be involved in the functional worsening of end-stage HF patients, candidates for left ventricular assist device (LVAD) implantation, and potentially responsible for their outcome. Methods. IL-33, ST2, and conventional cytokines (IL-6, IL-8, and TNF-α) were determined in cardiac biopsies and plasma of 22 patients submitted to LVAD implantation (pre-LVAD) and compared with (1) control stable chronic HF patients on medical therapy at the moment of heart transplantation without prior circulatory support (HT); (2) patients supported by LVAD at the moment of LVAD weaning (post-LVAD). Results. Cardiac expression of ST2/IL-33 and cytokines was lower in the pre-LVAD than in the HT group. LVAD determined an increase of inflammatory mediators comparable to levels of the HT group. Only ST2 correlated with outcome indices after LVAD implantation. Conclusions. IL-33/ST2 and traditional cytokines were involved in decline of cardiac function of ESHF patients as well as in hemodynamic recovery induced by LVAD. IL-33/ST2 pathway was also associated to severity of clinical course. Thus, a better understanding of inflammation is the key to achieving more favorable outcome by new specific therapies.

Tumor necrosis factor-α levels and non-surgical bleeding in continuous-flow left ventricular assist devices

“…45 Notably, the angiogenic effect of TNF-α appears paradoxical: escalating doses of TNF-α induce more vessel growth until a boundary is reached, where the effect is abolished and toxicity follows. 36,46 In this study, we have confirmed TNF-α elevation in plasma from LVAD patients, 21–25 and we have extended this knowledge by demonstrating that TNF-α induces pericyte apoptosis, suppresses Ang-1, drives angiogenesis, and may increase NSB synergically with Ang-2. Therefore, TNF-α/Ang-2 inhibition may help prevent or treat angiodysplasia in LVAD patients.…”

“…In paired analyses (pre- and post-LVAD), myocardial TNF-α decreases after LVAD implantation, 54 whereas LVAD patients have higher plasma levels of TNF-α compared with similar HF patients. 21–25 We speculate that differences between control groups could explain these discrepancies; patients awaiting LVAD are often very sick and therefore may have high TNF-α levels, 55 which are reduced by LVAD placement, whereas ambulatory HF patients who are functionally similar to LVAD patients may have lower TNF-α. Still, the source of TNF-α in LVAD patients remains unclear.…”

“…17 TNF-α also induces endothelial expression of tissue factor (TF, Factor III), 18 which leads to thrombin production and is augmented in synergy with thrombin itself. 19,20 Plasma TNF-α 21–25 and TF 26 are elevated after LVAD implantation and experts have theorized that TF may drive angiodysplasia in LVAD patients through thrombin and Ang-2. 27 However, the interplay of TNF-α with angiogenic and coagulation pathways in LVAD patients is not known.…”

Soluble ST2 in heart failure

“…sST2 was determined in endstage chronic HF patients submitted to left ventricular assist device implantation as bridge to heart transplantation [76]. Interestingly, sST2 was involved in the decline of HF patients as well as in hemodynamic recovery induced by left ventricular assist device and associated with the severity of the clinical course [76].…”

Circulating biomarker responses to medical management vs. mechanical circulatory support in severe inotrope‐dependent acute heart failure

“…It has been proposed as a valuable serial marker of progressive decongestion in AHF . In the setting of MCS treatment, circulating ST2 levels were found to decrease after 1 month of left ventricular assist device support and remained constant thereafter in end‐stage CHF patients . Our data not only support this observation but also indicate that stabilization of ST2 levels occurs within 7 days of MCS unloading ( Figure ).…”