Clinical Application Of Protein Markers In Patients With Heart Failure

Part 1:Prognostic value of plasma soluble ST2 in hospitalized Chinese patients with heart failureObjectives:ST2 was a member of IL-1 receptor family. In response to mechanical stimulation, the transcript for both sST2 and ST2L are up-regulated, and sST2 can act as a decoy receptor for IL-33 competitively inhibiting the cardioprotective function of IL-32/ST2 signaling system. sST2 has been shown to be a risk predictor in heart failure (HF) in studies of Western patients. The prognostic value of sST2 in an Asian population is not well established. Our aim was to explore the characteristics and prognostic value of sST2 in hospitalized Chinese patients with HF.Methods:Between March 2009 and April 2013, we consecutively enrolled 1528 hospitalized patients with HF according to current Chinese guidelines. Adverse events were defined as all-cause death and cardiac transplantation. Demographic data from medical records are abstracted. The plasma concentrations of sST2 within 24 hours of hospitalization were measured by enzyme-linked immunosorbent assay. Multivariable Cox proportional hazards analysis were used to assess the association between sST2 and adverse events. Receiver operating characteristic (ROC) were performed to determine the prognostic ability of sST2 for events. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were performed to evaluate the added predictive value of sST2 when combined with NT-proBNP.Results:During a median follow-up of 19.1 months,325 patients experienced adverse events (300 patients died,25 patients underwent cardiac transplantation). Compared with patients free of events, sST2 concentrations were significantly higher in patients with events (P< 0.001). Univariable and multivariable Cox regression analyses showed sST2 concentrations were significantly associated with adverse events (P< 0.001). An sST2 concentration in the highest quartiles (> 55.6 ng/mL) independently predicted events in comparison to the lowest quartile (≤25.2 ng/mL) when adjusted by multivariable model. In ROC analysis, the area under the curve for sST2 was not different from that for NT-proBNP in short and longer term. Over time, sST2 also improved discrimination and reclassification of risk beyond NT-proBNP.Conclusions:sST2 is a strong independent risk predictor in Chinese patients hospitalized with HF and can significantly provide additional prognostic value to NT- proBNP in risk prediction.Part 2:Characteristic of galectin-3 in hospitalized patients with heart failureObjectives Galectin-3 is a β-galactoside-binding lectin and expressed in a wide range of species and tissues. Under pathophysiologic conditions, the expression of galectin-3 may change substantially and act as a promoter to interact with relative receptors. Galectin-3 has been shown to involve in the process of cardiac fibroblast proliferation, collagen deposition and ventricular dysfunction, and predict adverse events in heart failure (HF). However, the association of galectin-3 with cause-specific death has not been well established. The purpose of this study was to investigate the prognostic value of baseline galectin-3 for all-cause, cardiovascular (CV) and in hospital death in patients with HF.Methods:Between March 2009 and April 2013, we consecutively measured galectin-3 in a large cohort of 1440 hospitalized patients with HF according to current Chinese guidelines. The endpoints were defined as cause-specific death. Concentrations of galectin-3 within 24 hours of hospitalization were determined by enzyme-linked immunosorbent assay. Cox proportional hazards analysis were used to assess the association between galectin-3 and cause-specific death. Receiver operating characteristic (ROC) were performed to determine the prognostic ability of galectin-3 for events. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were performed to evaluate the added predictive value of galectin-3 to predefined risk models.Results During a median follow-up of 582 days,283 deaths were identified [259 of all deaths resulted from CV cause (91.5%),169 were due to progressive HF (59.7%),43 were due to sudden death (15.2%)]. Of which,64 patients died during hospitalization. Compared with the lowest galectin-3 tertile, the highest two tertiles were significantly associated with all-cause, CV, and progressive HF death, but not significant for sudden and in-hospital death when analyzed by multivariable Cox regression. The utility of combining galectin-3 and NT-proBNP was assessed by dichotomized these two biomarkers according to their median values, respectively. The highest risk of death due to all-cause, CV, and progressive HF was observed when both biomarkers were elevated after adjustment for established risk factors. In NRI and IDI analysis, addition of galectin-3 to prediction model for all-cause and CV death significantly improved discrimination and reclassification.Conclusions Galectin-3 independently predicted death and added additional prognostic value beyond established risk factors in hospitalized patients with HF. The utility of galectin-3 as a risk predictor was not strong to assess sudden or in-hospital death. biomarkers according to their median values, respectively. The highest risk of death due to all-cause, CV, and progressive HF was observed when both biomarkers were elevated after adjustment for established risk factors. In NRI and IDI analysis, addition of galectin-3 to prediction model for all-cause and CV death significantly improved discrimination and reclassification.Part 3:The prognostic value of sST2 and galectin-3 for death relative to renal function in patients hospitalized with heart failureObjectives:soluble ST2 (sST2) and galectin-3 are two promising biomarkers that have been shown to be involved in cardiac fibrosis and associated with adverse events in patients hospitalized with heart failure (HF). Whether the prognostic value of these two biomarkers was affected by renal function was unclear. We aimed to evaluate the associations of sST2 and galectin-3 with death relative to renal function in patients with HF.Methods:Between March 2009 and June 2012, patients with HF as their primary diagnosis and 1-year follow up were recruited for analysis. sST2, galectin-3 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined in all patients. Receiver operating characteristic (ROC), multiple Cox proportional hazards analysis, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were performed to evaluate the association between biomarkers and death in every subgroups predefined.Results A total of 1161 patients were studied to evaluate the associations of sST2 and galectin-3 with death relative to renal function.174 deaths were identified during 1-year follow-up. In correlation analysis, r value between eGFR and sST2 was -0.10 (P< 0.001), while for galectin-3 it was -0.46 (P< 0.001). Patients were divided into two groups based on eGFR of either>or≤60 mL/min/1.73m2. Across NYHA grouping, sST2 was only significantly higher in NYHA Class IV patients with impaired renal function, whereas, galectin-3 concentrations were routinely significantly higher in patients with lower value of eGFR across all NYHA groups. sST2 was independently associated with 1-year mortality in both categories of renal function, while galectin-3 lost this significance after addition of NT-proBNP to the model of patients with eGFR ≤60 mL/min/1.73m2. In receiver operating characteristic analyses, the area under the curve (AUC) for sST2 was 0.79, which was similar to that for galectin-3 (0.74) when eGFR> 60 mL/min/1.73m2 (P=0.175), but higher when eGFR< 60 mL/min/1.73m2 (0.74 vs.0.61, P= 0.004). sST2 added reclassification of risk regardless of eGFR. However, incorporation of galectin-3 only yielded additional prognostic value in patients with eGFR> 60 mL/min/1.73m2. 1020 patients with understandable HF etiology were selected for assessing the associations between prognostic value of sST2 and galectin-3 and death relative to HF etiology. After 1-year follow-up,162 deaths were identified (151 deaths were CV,107 were progressive HF, and 9 were due to myocardial infarction). Given the underlying biological differences between ischemic and nonischemic HF, patients were divided into two groups. Multivariable Cox regression showed sST2 and NT-proBNP were independently predictive of death due to all-cause, cardiovascular (CV), and progressive HF after adjustment in both groups of patients; the association between galectin-3 and death was not significant when sST2 and NT-proBNP were incorporated into model in patients with ischemic HF. Incorporation of sST2 to model for death improved area under the curve only in patients with non-ischemic HF. After classifying patients according to biomarker median and HF etiology, patients with non-ischemic HF and higher sST2 levels had the highest cumulative hazard for all-cause and CV death. Similarly, the highest cumulative hazard for progressive HF death was observed in patients with non-ischemic HF and higher galectin-3 levels. NT-proBNP concentrations comparably predicted risk of death in patients with ischemic and non-ischemic HF.Conclusions:In patients with HF, both sST2 and galectin-3 improved prediction for death beyond risk factors above an eGFR of 60 mL/min/1.73m2, however, the prognostic value of galectin-3 is less clear below an eGFR of 60 mL/min/1.73m2. Furthermore, high levels of sST2 and galectin-3 might be more predictive for death in non-ischemic HF compared with ischemic HF, while the prognostic value of NT-proBNP was not affected by HF etiology.Part 4:The performance of multiple biomarkers for cardiovascular risk prediction in patients with advanced heart failureObjective The purpose of this study was to investigate the change in multiple biomarkers concentrations during treatment and explore the prognostic value of them for predicting risk in patients with advanced heart failure (HF).Methods From October 2013 to January 2014, patients who were admitted to FuWai Hospital HF center, with advanced HF, were consecutively enrolled in this study. We serially measured N-terminal pro-B-type natriuretic peptide (NT-proBNP), BNP and soluble ST2 (sST2) levels from baseline,3rd days and 6th days during treatment in 64 HF patients. All patients were followed up for 6 months, and the endpoint was hospitalization for worsening HF, cardiac transplantation or cardiovascular death.Results During 6 month follow-up,24 patients experienced cardiovascular (CV) events. All three biomarkers were not change significantly during 6-days treatment in patients who experienced CV events. With respect to patients free of events, NT-proBNP and BNP declined significantly, but sST2 did not change. In receiver operating characteristic analyses, the ability of all three biomarkers to discriminate patients with or without events was more powerful after 6-days treatment than their values in the baseline, respectively. The area under the curve for sST2 was higher than that of NT-proBNP and BNP in every stage of observation.Conclusions The values of biomarkers after treatment could be more powerful to predict risk than those in the baseline in patients with advanced HF. sST2 might be useful in early risk assessment because it did not change significantly than other markers during treatment.