Report on Task 3.3 activities Clinical research on biomarkers

This document is an additional report, not included within the DoW, but derived by the extended observation of patients until the end of the project, in order to increase the number as well as to have all the possible important information from clinical arena. It must be underlined that all the data within the activities of the Task 3.3 reported in this document have been collected and analyzed by the SensorART Heart Recovery Focus Group, totally represented by a CNR multidisciplinary team, within the collaboration with HONIG partner. The main scope of the report has been the evaluation of different biomarkers implicated in the clinical outcome and cardiac functional recovery of end-stage heart failure (ESHF) patients supported by left ventricular assist device (LVAD) implantation. There are two distinct periods in the LVAD patient management: the immediate postoperative in-hospital phase and the later phase after discharge. The immediate post-operative phase is characterized by adverse events like post-surgical bleeding, tamponade, multiple-organ failure and possibly death. Some of these adverse events are heavily influenced by the condition of the patient at the moment of surgery. It is intuitive that inflammatory parameters can play an important indicative role in this first phase. Although not negligible, altered inflammatory signals during chronic phase of LVAD support might affect biological systems, such as von Willebrand factor system and coagulation, that impact on long-term outcome. Indeed, in the second phase of care during follow up, major adverse events in patients with mechanical circulatory support (MCS) are LVAD malfunction, bleeding and infection (driveline or device infection). There are numerous biomarkers which reflect the general medical condition of a patient supported with a LVAD. In this work we specifically analyzed biomarkers that can be expected to be related with LVAD related adverse outcomes: 1) the role of inflammatory biomarkers and new biomarkers associated to cardiac injury and catabolic state, particularly, in the early postoperative phase after LVAD implantation, and 2) the role of inflammatory biomarkers in the chronic phase. The analysis was done by prospective plasma/serum/urine sample collection and data analysis of patients groups undergoing LVAD implantation at HONIG. The first part of this report includes an analysis of the role of the inflammatory-, catabolic- and cardiac injury-related parameters in the first phase (first four weeks) after LVAD implantation and their predictive value towards outcome and develop of severe multi-organ failure, the main life-threatening complication in the acute phase of LVAD-based therapy. Moreover, the report describes the inflammatory profiles which are monitored also during the chronic phase of LVAD patients, characterized from different complications, such as infections and LVAD malfunctioning, with respect the acute phase. It proved that plasma levels of interleukin (IL)-8 and tumor necrosis factor (TNF)-?, immediately after surgery, and the amount of release in the first postoperative week, are associated to unfavorable evolution of LVAD patients that, after intervention in intensive care unit (ICU) stay, developed a severe multi-organ failure. In addition, the study proved that specific markers of cardiac injury (NT-proCNP and h-FABP) and catabolic state (adinopectin) are differently distributed between survivors and nonsurvivors in the early phase of LVAD support suggesting that combined evaluation of specific inflammatory cytokines and new cardiac injury markers can provide additional and better information on clinical outcome of LVAD patients, with respect biomarkers routinary used to monitor inflammation and cardiac injury, such as C-reactive protein and NT-proBNP. A second group of studies examined the effect of LV-unloading by LVAD on extracellular matrix (ECM) modulation and apoptosis. The analysis was done by myocardial sample collection and data analysis of patients groups undergoing LVAD implantation and heart transplantation (HT) at HONIG. These studies proved that metalloproteinase (MMPs)-2 and -9 are down-regulated in LVAD patients, resulting in minor MMPs activity, with respect failing heart without previous mechanical circulatory assistance, and, furthermore demonstrate that redox state, in particular the levels of myocardial glutathione, affects the MMPs activity, suggesting a relationship among redox state, ECM modulation and cardiac remodeling. Instead the role of LVAD on markers of apoptosis is contradictory since increment of both pro- and anti-apoptotic markers were observed in failing hearts of LVAD patients, with an increment of ICEBERG, an inhibitor of caspase-1 system involved both in apoptosis and inflammation crucial in cytokine processing, despite elevated levels of pro-inflammatory cytokines found in failing heart of LVAD patients. A major study has also focused on the evaluation of pattern of microRNAs (miRNAs), endogenous, single-stranded, non-coding RNAs that act as endogenous repressors of target genes, in failing hearts of LVAD patients. The study proved that miRNAs are differently distributed in failing hearts of ESHF patients supported by LVAD with respect failing hearts non-MCS supported, with specific miRNAs down- or up-regulated in LVAD patients, whose a few have been previously indicated in literature as potentially deregulated in HF or other cardiovascular diseases, while for some other miRNAs, revealed from our analysis, scarce information is presently available in literature. Of note, for some miRNAs it has been possible to find a relationship between their levels and hemodynamic parameters associated with the degree of cardiac remodeling, highlithing the potential interest of these microRNAs as important players in the reverse remodeling process.