| BackgroundHeart failure(HF) is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. It is the terminal stage of many cardiovascular diseases,the survival rates for HF are approximately only 50% within 5 years of diagnosis.The cardinal manifestations of HF are dyspnea and fatigue,which may limit exercise tolerance and fluid retention. In the coming decades, as the population ages, the prevalence of hypertension, diabetes and obesity increase,the incidences of heart failure also increase. According to left ventricular ejection fraction (LVEF),patients with HF can be categorized into those with reduced ejection fraction (HFREF) and those with preserved ejection fraction(HFPEF). HFPEF refers to those who have symptoms and (or) signs of HF with a relatively normal left ventricular ejection fraction. In the general population, patients with HFPEF are usually older women with a history of hypertension,diabetes mellitus,obesity and atrial fibrillation. Many epidemiological reports estimate that the prevalence of HFpEF is approximately 50% and the mortality rates and rates of rehospitalization are not significantly different between 2 groups. Therapy in HFPEF is aimed at amelioration of symptoms. These patients are often treated for comorbidities and underlying risk factors. Several effective therapies have been identified for patients who have HFREF but none have been conclusively shown to be effective for HFPEF. Quickly understanding the likelihood for adverse outcome in patients with HF then tailoring therapeutic strategies to improve prognosis is meaningful.Soluble ST2 (sST2) is an interleukin-1 (IL-1) receptor family member and identified as a biomarker that is markedly induced by mechanical stretch in cardiomyocytes. It exists two major kinds of isoformers including a transmembrane receptor (ST2L) and a soluble receptor (sST2). The ligand of ST2 is IL-33, known to be involved in IL-33/ST2 signaling to reduce tissue fibrosis and myocyte hypertrophy in mechanically strained hearts. Through its ability to act as a decoy receptor, sST2 blocks the beneficial effects that occur when IL-33 attempts to bind to ST2L, experimentally, this leads to cardiac hypertrophy, fibrosis and ventricular dysfunction.Blood concentrations of sST2 are increased in various diseases such as inflammatory diseases,immune diseases and heart diseases.In multiple clinical trials, sST2 has emerged as a clinically useful prognostic biomarker in patients with cardiovascular diseases, including myocardial infarction and HF. It can also provide prognostic information in a low-risk community-based population. sST2 is notably associated with HF severity and poor outcome. sST2 as a novel biomarker integrating inflammation, fibrosis and cardiac stress has additive risk stratification value for patients with acute and chronic HF. The current gold standards for clinical HF biomarker testing are the natriuretic peptides (e.gB-type natriuretic peptide,BNP and its amino-terminal cleavage fragment, NT-proBNP).Induced by pressure or volume overload, BNP and NT-proBNP are related to the severity of abnormalities in cardiac structure and function,both BNP and NT-proBNP are now widely used for HF early diagnosis and are supported for prognosis as well. Unlike natriuretic peptides,some clinical trials suggest that sST2 levels were not related to age, body mass index, previous diagnosis of HF,renal function and atrial fibrillation.Comparative study about sST2 in patients with HFREF and HFPEF is rare in China. My study is to observe the early changes of levels of sST2 and NT-proBNP in patients with HFPEF compared with HFREF and explore the predictive value of the 2 biomarkers for the occurrence of cardiovascular events.Objective:1. To observe the early changes of levels of sST2 and NT-proBNP in patients with HFPEF compared with HFREF in the stage of treatment.2. To observe the correlation between sST2 and NT-proBNP,high-sensitivity c-reactive protein(hs-CRP), incides of echocardiography and explore the predictive value of the levels at admission,7 days after admission and the early changes of the 2 biomarkers for the occurrence of cardiovascular events.Methods1 Study populationA total of 85 patients with heart failure in Wuhan General hospital of Guangzhou Military Command from December 2014 to June 2015 were enrolled. There were 46 males and 39 females with the age of 45～82 years. They were divided into two groups according to left ventricular ejection fraction:HFPEF group (n=41, LVEF≥50%) and HFREF group (n=44, LVEF<50%). There were 42 cases of coronary artery disease,16 cases of hypertensive heart disease and 27 cases of dilated cardiomyopathy. Clinical data including demographic characteristics, vital signs, physical examination, primary HF etiologies, medical history and New York Heart Association (NYHA) functional class were recorded at the time of the hospitalization. Echocardiography was performed(including LVEF, left ventricular volume at end systole,left ventricular volume at end diastole) within 48 hours after admission. If there were no contraindications,all patients received angiotensin converting enzyme inhibitor (ACEI)/Angiotensin Ⅱ receptor blocker(ARB), β receptor blocker, mineralocorticoid receptor antagonists, loop diuretics and digoxin.Elbow venous blood samples were collected at admission and 7 days after admission for measurement of sST2 and NT-proBNP, immediately centrifuged and stored at 80℃in fridge. They were determined by blood samples subjected to no more than one freeze-thaw cycle and measured by enzyme linked immsorbant assay(ELISA). All patients signed a written informed consent.There were no significant difference between two groups except systolic blood pressure and LVEF.2 Research methods2.1 Observation of serum indexThe plasma levels of sST2 were measured by ELISA at admission and 7 days after admission. Compare the levels of sST2 and NT-proBNP in patients with HFPEF and patients with HFREF at admission,7 days after admission. Observe the correlation between sST2 and NT-proBNP, hs-CRP, incides of echocardiography. Observe the early changes of levels of sST2 and NT-proBNP between two groups in the stage of treatment.2.2 Observation of clinical indexThe patients were followed up for 6 months with outpatient visit or telephone call and the occurrence of cardiovascular events (including all cause motality, re-admission for worsening HF) were recorded. Analysis the predictive value of the levels at admission,7 days after admission and early changes of the 2 biomarkers for the occurrence of cardiovascular events.For patients with multiple admissions, only the first admission was included in this study.3 Statistical AnalysisAll data were processed and analyzed by SPSS 19.0 statistical software. Continuous variables were expressed by mean±D(x±s) for normally distributed variables or medians and interquartile range (IQR) for variables with skewed distribution.Categorical data were shown as percentages(%).Comparisons between two groups were performed by Student t-test for symmetrical continuous, Mann-Whitney U test for nonsymmetric continuous, and x2 tests for categorical variables. Univariable spearman or pearson correlation was used to evaluate the relationships among variables. Multivariable logistic regression analyses were then performed with stepwise method for the influence factors of cardiovascular events. Receiver operating characteristic(ROC) curves were performed to determine the prognostic ability of the early changes of levels of sST2 and NT-proBNP for events.Results1. Compare the plasma levels of sST2 between two groups at different time pointsThe sST2 levels were similar in patients with HFPEF at admission than 7 days after admission[0.36(0.30-0.54)VS0.34(0.31～0.47), P>0.05].The sST2 levels were similar in patients with HFREF at admission than 7 days after admission[0.63(0.44～0.92) VS 0.59(0.54～0.65), P>0.05].The sST2 levels were significantly lower in patients with HFPEF than those with HFREF at admission[0.36(0.30-0.54) VS 0.63(0.44～0.92), P<0.05] and 7days after admission[0.34(0.31～0.47)VS 0.59(0.54～0.65), P<0.05].2. Compare the plasma levels of NT-proBNP between two groups at different time pointsThe NT-proBNP levels were significantly greater in patients with HFPEF at admission than 7 days after admission[2740 (1612～5860) VS 512(236～1112),P< 0.05]The NT-proBNP levels were significantly greater in patients with HFREF at admission than 7 days after admission[5866(4205～9811)VS 1112(875～3238), P< 0.05]The NT-proBNP levels were significantly lower in patients with HFPEF than those with HFREF at admission[2740 (1612-5860) VS 5866(4205～9811), P<0.05] and 7days after admission[512(236～1112)VS 1112(875-3238), P<0.05].3. The correlation between sST2 levels at admission and clinical index, incides of echocardiography.Plasma sST2 levels at admission were positively related to NT-proBNP、hs-CRP (r value respectively 0.365、0.470,P< 0.05), negtively related to LVEF and glomerular fitration rate ((r value respectively -0.370、-0.275, P<0.05), not related to left ventricular volume at end systole and left ventricular volume at end diastole in HFPEF group.Plasma sST2 levels at admission were positively related to NT-proBNP、hs-CRP、 left ventricular volume at end systole (r value respectively 0.413% 0.545、0.501,P< 0.05), negtively related to LVEF and glomerular fitration rate(r value respectively-0.391、-0.357,P<0.05), not related to left ventricular volume at end diastole in HFREF group.4. The relationship between sST2 levels and cardiovascular events by multivariable logistic regression analysesDuring six month follow-up, there were 8 cases cardiovascular events in HFPEF group.1 patient died for worsening heart failure.1 patient suddenly died.6 patients were admitted to hospital for worsening heart failure. In HFREF group 4 patients died for worsening heart failure.1 patient suddenly died.10 patients were admitted to hospital for worsening heart failure.Multivariable logistic regression showed sST2 concentrations at admission were significantly associated with the primary end point after adjustment for gender, age, hemoglobin, hs-CRP, NYHA function class, LVEF, NT-proBNP, glomerular fitration rate(GFR) in two groups (HFPEF group:OR 1.411, 95%CI1.038-1.918, P<0.05; HFREF group:OR1.033,95%CI 1.009-1.058, P<0.001).5. Compare predictive value of the early changes of levels of sST2 and NT-proBNP for cardiovascular events.ROC analysis indicated that levels of sST2 at admission and 7 days after admission, levels of NT-proBNP 7days after admission, the change of NT-proBNP levels had predictive value for cardiovascular events(P<0.05),while the occurrences of cardiovascular events were not predicted by levels of NT-proBNP at admission and change of sST2 levels(P>0.05).Conclusion1.The sST2 levels and NT-proBNP levels were significantly lower in patients with HFPEF than in those with HFREF at admission and 7 days after admission. The NT-proBNP levels decreased obviously after treatment(P<0.05) in both groups,but sST2 levels remained similar.2. Plasma sST2 levels were positively related to NT-proBNP、hs-CRP,but negtively related to LVEF in patients with HFPEF.It can reflect the sevetity of HFPEF.3. Plasma sST2 levels remained an independent predictor of cardiovascular events,regardless of the left ventricular ejection fraction. It can be used for risk stratification in patients with HFPEF.4. Plasma sST2 levels at admission and 7 days after admission, Plasma NT-proBNP levels 7 days after admission, the short-term change of NT-proBNP levels had predictive value for cardiovascular events(P<0.05),while the occurrences of cardiovascular events were not predicted by levels of NT-proBNP at admission and change of short-term sST2 levels.They can provide information for treatment and prognosis. |
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