Biomarkers Of Heart Failure Patients

Abstract 1 The correlation of NT-proANP,NT-proBNP and NT-proCNP with clinical and echocardiographic parameters of heart function in heart failure patients[Background]Natriuretic peptides family consists of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP),C-type natriuretic peptide(CNP),urodilatin and dendroaspis natriuetic.ANP and BNP are mainly secreted from the atrium and ventricle of the heart respectively to act as cardiac hormones whereas CNP is secreted from the endothelium to act as an endothelium-derived relaxing peptide.Atrial natriuretic peptide and brain natriuretic peptide are similar in their ability to promote natriuresis and diuresis, inhibit the renin-angiotensin-aldosterone axis.Understanding of the actions of C-type natriuretic peptide is incomplete.Recent study demonstrate that CNP is a novel endothelium-derived hyperpolarizing factor(EDHF) that can modulate the phenotype of vascular smooth muscle cells to regulate vascular remodeling.[Objective]To evaluate the correlation of plasma NT-proANP,NT-proBNP and NT-proCNP level with clinical,New York Heart Association(NYHA) functional class and echocardiographic functional parameters,and evaluate the prognostic value of NT-proANP,NT-proBNP and NT-proCNP in heart failure patients.[Methods]The blood plasma of NT-proANP,NT-proBNP and NT-proCNP were measured with enzyme immunoassay method in 112 left ventricular heart failure patients and 44 normal control subjects.The correlation analysis was made between NT-proANP,NT-proBNP,NT-proCNP and NYHA functional class,left atrium diameter(LAD),left ventricular end-diastolic diameter(LVEDD) and left ventricular ejection fraction(LVEF) respectively.[Result]In heart failure group,the plasma concentration of NT-proANP,NT-proBNP and NT-proCNP were significantly higher than in control group(all P＜0.005).and the NT-proANP,NT-proBNP and NT-proCNP was related to each other in heart failure group. Correlation analysis showed that there was a strong correlation between NT-proANP with NT-proBNP(r=0.790,p=0.000),while weak correlation between NT-proCNP with NT-proBNP(r=0.278,p=0.003);and NT-proCNP with NT-proANP(r=0.236,p=0.012) In univariant analysis,NT-proANP,NT-proBNP was positively related to LAD,LVEDD and negatively related to LVEF respectively(all P＜0.05),but NT-proCNP showed no significant relation to this echocardiographic functional parameters.In heart failure group, multivariate stepwise regression analysis including following six factors:age,gender, NYHA classification,LAD,LVEDD and LVEF revealed that NYHA classification,LVEF, LAD and age were independent correlative maker for NT-proANP;while NYHA classification,LVEF and age were independent correlative marker for NT-proBNP;but there was no independent correlative factor for NT-proCNP.[Conclusion]In heart failure patients,the plasma concentration of NT-proANP,NT-proBNP and NT-proCNP were significantly higher than in control group(all P＜0.005),and they were related to each other.NT-proCNP showed no significant relation to NYHA classification and the echocardiographic functional parameters including LAD,LVEF and LVEDD no matter in univariate analysis or multivariate regression analysis.Abstract 2 Prognostic value Comparison of NT-proANP,T-proBNP and NT-proCNP in heart failure patients[Background]natriuretic peptides(ANP) and brain natriuretic peptides(BNP) are powerful neurohormonal indicators and prognostic factors of left-ventricular function in heart failure(HF).C-type natriuretic peptide(CNP) belongs to the natriuretic peptide family and is structurally related with a 17 amino-acid ring linked by a disulfide bond. ANP and BNP are mainly cardiovascular hormones.However,CNP plays roles in wide variety of tissues,which is commonly considered to be an endothelial hormone and acts locally as an autocrine/paracrine regulator.But the prognostic value of CNP is not clear yet.[Objective]To compare the prognostic value of NT-proANP,NT-proBNP and NT-proCNP in heart failure patients.[Methods]The NT-proANP,NT-proBNP and NT-proCNP in the blood plasma were measured using enzyme immunoassay method in 112 left ventricular heart failure patients.All the patients were followed up for about 16.8 months.The primary clinical end points were cardiac death,heart transplantation or first re-admission for CHF.We used the ROC curve to evaluate the prognostic value of NT-proANP,NT-proBNP and NT-proCNP in heart failure group[HF],compensate(NYHAⅠ,Ⅱ) heart failure subgroup [CHF]and decompensate(NYHAⅢ,Ⅳ) heart failure subgroup[DHF].Univariant and multivariate Cox regression analysis were used to find the predictors of the cardiac event.[Result]The plasma level of NT-proANP[6.56(4.54,8.61) vs 3.62(2.64, 5.49)]and NT-proBNP[165.55(78.62,271.96) vs 43.28(12.94,105.91)]in cardiac event group was significantly higher than that in the none cardiac event group(both P＜0.05).Meanwhile,The level of NT-proCNP had a tendency of increase in cardiac event group[6.25(4.03,8.39) vs 5.22(4.09,7.20)],but had no statistics meaning(P＞0.05).From the ROC curve,we could find that NT-proANP and NT-proBNP could distinguish the cardiac events in HF group and DHF group,and the value of NT-proBNP is higher.NT-proCNP could not predict the cardiac mortality,the re-admission or the necessity for heart transplant in HF group and DHF group.In CHF group,none of NT-proANP,NT-proBNP and NT-proCNP could distinguish the cardiac event(P＞0.05).NT-proANP,NT-proBNP,NT-proCNP,age,gender,NYHA classification,LAD,LVEDD,LVEF,Atrial fibrillation/atrial flutter,ventricular tachycardia and diabetes were introduced as evaluation factors.LogNT-proANP,LogNT-proBNP,NYHA classification,LVEF,LVEDD and Ventricular tachycardia were revealed associated with the adverse outcome in univariant COX analysis But in multivariate COX analysis,only LogNT-proBNP[B(SE):1.103(0.539);P=0.041]and LVEF[B(SE):-0.042(0.021);P=0.046]were the significant independent predictors of the cardiac event.[Conclusion]In the three natriuretic peptides,NT-proANP and NT-proBNP can predict the cardic death,readmission and heart transplantation in the heart failure group and decompensate heart failure group.Meanwhile the NT-proCNP showed poor predict value in heart failure patients. Abstract 3 The correlation of NT-proANP,NT-proBNP and NT-proCNP with bilirubin in heart failure patients[Background]In heart failure patients,the liver abnormalities,especially the serum bilirubin level can always be seen elevated.Passive hepatic congestion due to increased central venous pressure is believed to cause elevations of both direct and indirect serum bilirubin.In 2001,Javier Padillo reported that the plasma levels of ANP and BNP were increased in newly diagnosed obstructive jaundice patients who had no previous heart,lung or renal disease.After biliary drainage,the levels of serum bilirubin and ANP and BNP were all declined.So it is wonder whether the natriuretic peptide were correlated with the concentrations of bilirubin in heart failure patients?[Objective]To observe whether there is a correlation between the NT-proANP,NT-proBNP and NT-proCNP with the bilirubin and other liver function indicators in heart failure patients.And to analysis the correlation between the bilirubin with the cardiac function and echocardiographic parameters.[Methods]The blood plasma of NT-proANP,NT-proBNP,NT-proCNP and bilirubin were measured in 112 left ventricular heart failure patients and 44 normal control subjects.Elisa kits from BIOMEDICA company was applied to test the plasma level of NT-proANP,NT-proBNP and NT-proCNP.The Pearson correlation analysis was done and multiple stepwise regression was used to analysis the association between the bilirubin with clinical cardiac function and echocardiographic parameters.[Result]The serum level of total bilirubin(TBIL),direct bilirubin(DBIL),indirect bilirubin(IBIL),γ-glutamyltransferase(GGT),alkaline phosphatase(ALP) were significantly higher in heart failure group than in control group(P all＜0.05).As well as the glutamic oxalacetic transaminase(GOT) and glutamic pyruvic transaminase(GPT) showed no significant difference between the two groups(P＞0.05).Among heart failure patients,LogNT-proANP,LogNT-proBNP were positively correlated with LogTBIL, LogDBIL,LogIBIL,LogGGT and LogALP respectively.However the LogNT-proCNP showed no correlation with the bilirubin and other liver functions.In univariate analysis, LVEF and age were negatively related with the bilirubin;while NYHA classification, LAD,LVEDD were positively related with the bilirubin in heart failure patients. However,in multiple regression analyses,only age and NYHA were independently associated with LogTBIL;LogDBIL and LogIBIL respectively,and NYHA was the strongest impact factor.[Conclusion]The bilirubin level was significantly increased in heart failure patients, and the bilirubin level was positively correlated with NT-proANP and NT-proBNP. However the NT-proCNP show no correlation with bilirubin.The bilirubin level of heart failure patients also demonstrated good correlation with the cardiac function and echocardiography parameters,in multiple regression analysis,only NYHA function and age were independent correlated with bilirubin.Abstract 4 The correlation of NT-proANP,NT-proBNP and NT-proCNP with renal function in heart failure patients[Background]Heart failure and renal dysfunction are closely related.Chronic heart failure is caused by a loss of ventricular function and leads to adaptive responses, including neurohormonal activation,peripheral vasoconstriction,and reduced renal perfusion pressure.And all this factors can cause renal dysfunction.Renal insufficiency leads to further increase the cardiac load,and the vicious circle ensues.Now we know the natriuretic peptides are activated in both heart failure patients and severe renal insufficiency patients.But it is not clear whether there is a correlation between the natriuretic peptide and renal function in heart failure patients with mild renal insufficiency.[Objective]The aim of the study was to observe whether there is a correlation between the NT-proANP,NT-proBNP,NT-proCNP with the renal function in heart failure patients who had serum creatinine＜2mg/dl.[Methods]We measured the serum creatinine(Cr),blood urea nitrogen(BUN),and blood plasma of NT-proANP,NT-proBNP,NT-proCNP in 112 heart failure patients and 44 normal control subjects.We analysis the correlation between the NT-proANP,NT-proBNP,NT-proCNP and Cr,BUN,eGFR respectively.And use multiple stepwise regression analysis the clinical and renal function to find the independent predictor of NT-proANP,NT-proBNP and NT-proCNP.[Result]The serum level of Cr[85.50(73.00,101.00) umol/L],BUN[5.10(4.20,6.70) mmol/L]in heart failure group were significantly higher than that in the control group{Cr[75.50(65.00,88.00) umol/L],BUN[4.65(3.86,5.99) mmol/L} respectively(both P＜0.05),meanwhile the eGFR[87.59(71.33,102.69)ml/min]in heart failure group was signicicantly lower than that in control group [94.42(79.96,112.60)ml/min](P＜0.05).Among heart failure patients,NT-proANP,NT-proBNP and NT-proCNP were positively correlated with Cr and BUN respectively(all P＜0.05);and negative correlation with eGFR respectively(all P＜0.05).In multiple stepwise regression analysis,when including following five factors:age,gender, Cr,BUN and eGFR,only BUN was the independent correlative maker for NT-proANP and NT-proBNP;while Cr was the independent correlative maker for NT-proCNP.When further draw into NYHA and diuretic as the addition factors,the result reveal that NYHA, BUN and diuretic become the independent correlative maker for NT-proANP and NT-proBNP;while only Cr was the independent correlative maker for NT-proCNP.[Conclusion]The serum level of Cr,BUN in heart failure patients(Cr＜2mg/dl) were significantly increased,while the eGFR significantly decreased.Even in the heart failure patients without obviously increased renal function,the level of NT-proANP,NT-proBNP and NT-proCNP were effected with renal function.Abstract 5 The correlation of GDF-15 with cardiac function, echocardiographic functional parameters and N-terminal natriuretic peptide in heart failure patients[Background]Growth-differentiation factor-15(GDF-15),a member of the transforming growth factor-βcytokine superfamily,was initially cloned from an activated macrophage cell line.While GDF-15 is weakly expressed in most tissues under physiological conditions,its expression levels may increase in response to pathological stress associated with inflammation or tissue injury.Studies have shown that GDF-15 was significantly increased in non-ST segment elevation or ST segment elevation myocardial infarcion.The study about GDF-15 in heart failure patient has not been reported in China. [Objective]To evaluate the correlation of plasma GDF-15 with New York Heart Association(NYHA) functional class and echocardiographic functional parameters.As the natriuretic peptide is thought to be the classic biomarker of heart failure,we compare the correlation between the GDF-15 with NT-proANP,NT-proBNP and NT-proCNP in heart failure patients.[Methods]We measured the plasma level of GDF-15,NT-proANP,NT-proBNP and NT-proCNP with enzyme immunoassay method in 102 left ventricular heart failure patients and 38 normal control subjects.The correlation analysis was made between GDF-15 and NYHA functional class,NT-proANP,NT-proBNP,NT-proCNP,left atrium diameter(LAD),left ventricular end-diastolic diameter(LVEDD) and left ventricular ejection fraction(LVEF) respectively.[Result]In heart failure group,the plasma concentration of GDF-15 [1231.9(798.8,2038.6) vs 615.8(413.0,765.26) pg/ml,P＜0.01]was significantly higher than in control group.The plasma GDF-15 of heart failure patients were gradually and significantly increased with the NYHA functional class except to the patients between NYHAⅠand NYHAⅡ.Correlation analysis showed that there were correlation between GDF-15 with NT-proANP(r=0.389,p=0.000),NT-proBNP(r=0.413,p=0.000) and NT-proCNP(r=0.245,p=0.013).In univariant analysis,GDF-15 was positively related to NYHA,LVEDD and negatively related to LVEF respectively(all P＜0.05),in multivariate stepwise regression analysis including following six factors:age,gender, NYHA classification,LAD,LVEDD and LVEF,only NYHA classification[B(SE): 0.155(0.029);P=0.000]was independent correlative maker for GDF-15.[Conclusion]In heart failure patients,the plasma concentration of GDF-15 were significantly increased,and it correlated with NT-proANP,NT-proBNP and NT-proCNP. GDF-15 show good correlation with cardiac function and echocardiographic functional parameters. Abstract 6 The prognostic value of GDF-15 in heart failure patients[Background]Growth-differentiation factor-15(GDF-15),a member of the transforming growth factor-βcytokine superfamily,was initially cloned from an activated macrophage cell line.While GDF-15 is weakly expressed in most tissues under physiological conditions,its expression level may increase in response to pathological stress associated with inflammation or tissue injury.Studies have shown that GDF-15 increased significantly in heart failure patients.But the data showing the prognostic value of GDF-15 in heart failure patients is insufficient.[Objective]The aim of the study was to evaluate prognostic value of GDF-15,and to compare the prognostic value of GDF-15 with NT-proBNP in heart failure patients.[Methods]We measured the blood plasma level of GDF-15 and NT-proBNP with enzyme immunoassay method in 102 left ventricular heart failure patients.All the patients were followed up for about 16.6 months.The primary clinical end points were cardiac death,heart transplantation or first re-admission for CHF.We use the area under the ROC curve(AUC) to evaluate GDF-15 and NT-proBNP's discriminative power of cardiac event in heart failure group.Univariant and multivariate Cox regression analysis were used to find the predictors of the cardiac event.[Result]The plasma level of GDF-15[1588.86(1146.12,2719.01) pg/ml]in cardiac event group was significantly higher than that in the none cardiac event group[1125.81 (780.40,1841.13) fmol/ml](P＜0.01).The measured AUC by NT-proBNP[0.778(95 %confidence interval:0.676 to 0.879;P＜0.01]is higher than those using GDF-15[0.642 (95%Confidence interval:0.518 to 0.765;P＜0.05].In univariant COX analysis, including following factors:GDF-15,NT-proBNP,age,gender,NYHA classification, LVEF,Atrial fibrillation/atrial flutter,Ventricular tachycardia and diabetes,revealed that GDF-15,LogNT-proBNP,NYHA classification,LVEF and Ventricular tachycardia were correlated to the adverse outcome.But in multivariate COX analysis,only LogNT-proBNP[B(SE):1.804(0.452),P=0.000]was the significant independent predictors of the cardiac event.[Conclusion]GDF-15 can predict the cardic death,readmission and heart transplant in heart failure group and decompensate heart failure group,but it's prognostic value seem not to be better than NT-proBNP's.Abstract 7 The correlation of red blood cell distribution width with natriuretic peptide,hs-CPR and GDF-15[Background]Red blood cell distribution width(RDW),a numerial measurement of the variability in size of circulating erythrocytes,has recently been shown to be a strong predictor of adverse outcomes in patients with heart failure independent of anemia and in patients with coronary artery disease,but the underlying mechanism is unknown.We hypothesized that higher RDW may reflect neurohumoral activation and a chronic inflammatory state,and Growth-differentiation factor-15(GDF-15) may affect the variability in size of circulating erythrocytes in heart failure patients.[Objective]To evaluate the correlation of RDW-Standard deviation(RDW-SD) and RDW-Coefficient of variation(RDW-CV) with New York Heart Association(NYHA) functional class and echocardiographic functional parameters in heart failure patients,to analyze the correlation between the increased RDW and natriuretic peptide, inflammatory factors,growth-differentiation factor.[Methods]We measured the RDW-SD,RDW-CV and plasma levels of NT-proANP, NT-proBNP,NT-proCNP,hs-CRP,GDF-15 in 102 consecutive left ventricular heart failure patients and 44 normal control subjects.The correlation analysis was made between RDW-SD,RDW-CV with NYHA functional class,left atrium diameter(LAD), left ventricular end-diastolic diameter(LVEDD) and left ventricular ejection fraction(LVEF) respectively.And further analyze the correlation between the RDW-SD, RDW-CV with GDF-15,hs-CRP,NT-proANP,NT-proBNP and NT-proCNP.[Result]In heart failure group,the level of RDW-SD,RDW-CV were significantly higher than those in control group(P＜0.05).There was a correlation between RDW-SD, RDW-CV and NHYA functional class in heart failure patients.In the analysis of RDW with echocardiographic functional parameters,the RDW-SD,RDW-CV was positively related to LVEDD and negatively related to LVEF respectively(all P＜0.05),but there was no significant correlation between the RDW and LAD.In heart failure group,RDW-SD and RDW-CV has a positive correlation with NT-proANP,NT-proBNP,GDF-15 and hs-CRP respectively.[Conclusion]In heart failure patients,the level of RDW was significantly increased. RDW has a good correlation with NYHA functional class and the echocardiographic functional parameters.We think that increased RDW may reflect meurohumoral activation and a chronic inflammatory state,and Growth-differentiation factor-15(GDF-15) may affect the variability in size of circulating erythrocytes in heart failure patients.