Projects

• Introduction

The burden of heart failure affecting medical systems and society, the need to set effective diagnostic and prognostic clinical tools, and the need to develop new approaches to treatment are the current challenge for the scientific research into chronic heart failure. However, it is important to select and use sensitive clinical indicators and biological markers to evaluate the real effects of drug treatment. The study of new, reliable biological markers is of paramount importance for the optimization of heart failure management measures and the adjustment of medical care processes. The aim of the planned study is to evaluate the diagnostic and prognostic values of new biological marker sST2  for the presentation of possible mechanisms for the development of heart failure of various genesis based on clinical evidence.

Soluble suppression of tumorigenesis 2 protein (sST2) is the circulating form of the cellular receptor ST2L, expressed by cardiomyocytes and vascular endothelial cells together with its ligand interleukin-33 after cardiovascular injury. Binding between interleukin-33 and ST2L is likely to inhibit myocardial hypertrophy and fibrosis and mitigate adverse cardiac remodeling 1, 2. sST2 competes with ST2L for interleukin-33 binding, thus likely blunting the cardiovascular protective effects exerted by the interleukin-33/ST2L interaction 1, 2.

sST2 has elicited interest as a potential aid to predict prognosis and manage therapy of chronic heart failure (CHF) 3, 4. Although the characterization of the interleukin-33/ST2L axis in CHF is currently incomplete (4), sST2 plasma concentrations have been found to be generally higher in CHF patients than in healthy subjects (5).

In this review, the role of sST2 as a HF biomarker will be discussed, specifically addressing analytical considerations of measuring sST2 as well as the clinical applications of measurement of sST2 for the diagnosis, prognosis and monitoring of  chronic HF.

Methods

Study population

This study was designed as a  prospective  cohort  study . One hundred and seventy  consequently enrolled  CHF patients from May 2019 to  2022 January were divided into 2 subgroups  according sSt2 concentration.T1 (>35ng/ml ;N=99) and T 2 (<35 ng/ml; N=71). The patients were followed up for a median period of 21.0 months  for the development of primary endpoint. Cox proportional hazards model was performed to evaluate the prognostic value of sSt2 for the clinical outcome. This cohort study  was designed to evaluate more established biomarkers of  Heart Failure further. A total of  patients with chronic heart failure with reduced ejection fraction    enrolled consecutively. Participants with heart failure referred to Vivamedi Clinic selected through convenient sampling method and  randomly allocated to groups. We included patients over 18 years of age who were admitted with a diagnosis of CHF.  The present study has been approved by the local ethics committee of Vivamedi. Written consent was acquired from each patient after enrollment . The inclusion criteria were Informed consent form of the research participant, data from the National Heart Failure Registry for a specific patient, age + 18 years, established Chronic Heart Failure with NYHA functional class II-IV, elevated concentration of NT – proBNP (different for all three groups of patients, optimal medication therapy (OMT) with recommended medications and doses according to the guideline for at least the last 1 month, adequate therapy of comorbidities The exclusion criteria were Ongoing acute decompensated heart failure (ADHF) or urgent hospitalization for the last 4 weeks due to ADHF, symptomatic hypotension or systolic blood pressure <100 mm Hg, primary severe stenosis or defect of the aorta or mitral valve, any major cardiovascular events in the last 4 weeks, such as acute myocardial infarction, stroke, cardiac arrest, and resuscitation, calculated glomerular filtration rate eGFR  <30 ml / min / 1.73 m2,diagnosis of per partum, stress-induced or chemotherapy-induced cardiomyopathy or acute myocarditis in the last 12 months;

At baseline, detailed demographic and clinical data: age, sex, body mass index, and comorbidities  ( CKD, CAD, Arterial Hypertension , Diabetes Mellitus , atrial fibrillation metabolic syndrome ),Vital signs ( BP , HR , RR, SPO2 , t ), 12-lead electrocardiogram ( ecg abnormalities ), Echocardiographic examination and the following parameters were assessed: LV end-diastolic diameter, LV end-systolic diameter (LVESD), LV end-diastolic volume/BSA and LV end-systolic volume (LVESV/BSA), EF, LA volume/BSA, IVS.) ,Medication ( ACEi/ARB, ARNI , MRA, Beta-blockers , Sglt2 inhibitors , Diuretics , ivabradine, digoxin, Device therapy.),Kansas Questionary. Finally 170 patients with available blood samples for NT-proBNP and ST2 were included in the current study cohort. The primary endpoint was: composite rate of cardiovascular deaths and rehospitalizations with diagnosis of acute decompensated heart failure (ADHF) ,cardiovascular mortality, Number of rehospitalizations with ADHF diagnosis.

Serum measurement

Blood samples were collected within 1 h after admission. Samples for serum sSt2 were centrifuged for 15 m in at 3000 r/min and were collected in lyophilized tubes and stored at -80 C. Serum sSt2 levels were measured uniformly using enzyme –linked immunosorbent assay ( ELISA).

Collection of clinical and echocardiographic parameters.

Hospital records were reviewed to collect clinical, analytical, and echocardiographic data. Patients were followed up by telephone calls or clinical visits. The follow-up time was calculated from discharge to cardiovascular death or termination of the study.

Population baseline  Characteristics

Statistical Analyses

Continuous variables were presented as mean  ± standard deviation (SD) or median with interquartile range (IOR) and compared using ANOVA test if they conform normal distribution or Kruskal-Wallis test if not. Categorical variables were expressed as percentages and compared using the chi-square test. Correlations were analyzed with Pearson test or Spearman rank correlation coefficients. Survival curves were estimated and plotted using the Kaplan-Meier method, and the the long rank test was used to compare groups. The association between primary endpoint and variables was presented as hazard ratio (HR) and 95% confidence interval (CI). Because sSt2 and NT-proBNP have a skewed distribution, we performed logarithmic conversion on the data in the Cox regression analyses. P < 0.05 was considered statistically significant.

Results

Comparisons of Clinical Characteristics and Echocardiographic Parameters.

The  mean age of the patients in this study was 68 years, and 70 % were male . The mean sST2 level of the entire population was 28.7 ng/ml. all participants were divided into 2 subgroups according to sSt2 tertiles. Although left ventricular mass index (LVMI), Left atrium size did not differ groups. Spearmen correlation analysis revealed positive correlations of sSt2 with NT-proBNP and NYHA class among all patients (r=0.392 and 0.443.respectively; P< 0.01), while negative correlation was found with LVEF values ( r=-0.119; P=0.031).

Relationship Between sSt2 and NYHA Functional Class in CHF Patients.

Participants were divided into 3 subgroups according to NYHA classification; we found that sST2 and NT-proBNP concentrations were significantly different between groups and patients with Higher NYHA class displayed higher sSt2 levels ( P<0.001)  and higher NT-proBNP (p <0.001)

The Correlation and Prognostic Value of sSt2  for Outcome in CHF Patients.

We assessed the relationship between sSt2 levels and patient outcome. Kaplan-Meier curves estimating the event-free survival (cardiovascular mortality) were presented according to different sSt2 groups ( table 1). There were total of 53 cardiovascular deaths over a median follow up of 21 months . Patients in the upper tertile of sST2 has a lower survival in the upper tertile of ssT2 had  alower survival rate after discharge than those in the middle and lower tertiles (log-rank test P= 0.048).

                                                                                                                                                  Table 1