Chronic heart failure (CHF) is a disorder associated with high mortality and prolonged hospitalization; it affects more than 10 million people in the countries represented by the European Society of Cardiology [
The natriuretic peptide family mainly includes A-type natriuretic peptide (ANP) or atrial natriuretic peptide, B-type natriuretic peptide (BNP) or brain natriuretic peptide, C-type natriuretic peptide (CNP), renal natriuretic peptide, and Dendroaspis natriuretic peptide (DNP). The ANP and BNP are mainly secreted by the atrium and ventricle, respectively, and have similar effects, which are natriuretic and can inhibit renin angiotensin aldosterone system, and BNP is useful as a principal biomarker for CHF [
Heart failure and renal dysfunction are closely related. The ventricular dysfunction caused by CHF may lead to a series of adaptive responses, such as the activation of neuroendocrine system, peripheral vasoconstriction, and reduced renal perfusion pressure. All these changes can cause renal dysfunction, and the deterioration of renal function further increases the capacity of the load of the heart and leads to a vicious circle. The natriuretic peptide system can be activated in both heart failure and severe renal insufficiency patients. Renal dysfunction is often present in CHF patients with reported CCR lower than 60 mL/min in up to 50% of patients [
Several studies have revealed that there is a relationship between NT-proBNP levels and clinical manifestations [
The investigation complied with the principles outlined in the Declaration of Helsinki [
Three hundred thirty-six consecutive symptomatic or nonsymptomatic Chinese heart failure patients for suspected myocardial ischemia scheduled for coronary angiography were recruited between July 2011 and October 2012 at the 6th People’s Hospital affiliated to Shanghai Jiaotong University Medical College, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, and General Hospital of Shenyang Military Area Command, China. Severity of CHF was clinically evaluated according to the NYHA classification.
Two hundred and one Chinese patients were grouped according to the New York Heart Association (NYHA) classification as NYHA 1-2 and 3-4 groups and 135 cases out of heart failure patients as control group. Patients in NYHA class 1 showed cardiac disease but result in no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. No cardiac disease, hypertension, or diabetes was diagnosed in control group.
A fasting venous blood sample was obtained for measurement of fasting glucose and HbA1c. Patients with HbA1c levels ≥6.5% were diagnosed as diabetic, even without previous history of diabetes. Body weight and height were measured to determine the body mass index (BMI; BMI, kg/m2 = weight (kg)/[height (m)]2) and blood pressure by standard methods.
Data were expressed as mean ± standard deviation (SD) for continuous variables, or as percentages (%) for categorical variables. Statistical analysis was performed using SPSS for Windows (version 13.0). Variables such as age, sex, and smoking status were adjusted by covariance analysis. Repeated measures one-way ANOVA was used to determine the significance of trends within groups, and further comparison between the two groups was done using least significant difference procedure (LSD). Numerical data was compared using the Chi-square test. Spearman single-factor correlation analysis and Spearman coefficient of rank correlation were used to evaluate linear relationship between biomarkers and NYHA classification. Logistic regression was used to identify independent risk factors for heart failure. Association between variables in NT-proBNP and CCR was examined using Pearson’s correlation coefficient and linear regression. Receiver operating characteristic (ROC) curves were used to obtain the biomarker cut-off points for predicting the prevalence of angiographic heart failure. The respective areas under the curve (AUC), sensitivity, and specificity were compared between biomarkers and NYHA classification. A value of
Fasting plasma glucose (FPG) was quantified by the glucose oxidase procedure and HbA1c was measured by ion-exchange high-performance liquid chromatography (HPLC, Bio-Rad, USA). Creatinine (Cr) and uric acid (UA) were measured by an enzymatic method with a chemical analyzer (Hitachi 7600-020, Tokyo, Japan); CCR was calculated using the Cockcroft-Gault formula. The chemiluminescence-based immunoanalytical system was used to determine plasma levels of NT-proBNP (VITROS 5600 integrated system, Johnson & Johnson Medical Company, USA).
Two-dimensional and Doppler echocardiography scans were performed using the HP77020A echocardiograph (Hewlett Packard Company, USA) to assess the left ventricular end-diastolic diameter (LVEDD).
The baseline characteristics of the patients are shown in Table
Characteristics of the control, NYHA classification 1-2, and 3-4 groups.
Groups | Control ( |
1-2 ( |
3-4 ( |
|
|
---|---|---|---|---|---|
Age, year (mean ± SD) | 65.84 ± 15.95 | 69.91 ± 13.14 | 68.27 ± 13.36 | 2.14 |
|
Male, % ( |
47.40 (64/135) | 54.43 (43/79) | 63.93 (78/122) | 3.59 |
|
BMI, kg/m2 (mean ± SD) | 23.48 ± 3.69 | 24.19 ± 4.31 | 24.05 ± 4.22 | 1.13 |
|
Current smokers, % ( |
27.40 (37/135) | 29.11 (23/79) | 17.21 (21/122) | 0.55 |
|
Hypertension, % ( |
49.63 (67/135) | 75.94 (60/79) | 71.31 (87/122) | 10.39 |
|
Diabetes, % ( |
16.30 (22/135) | 30.38 (24/79) | 38.52 (47/122) | 8.43 |
|
NT-proBNP, pg/mL (mean ± SD) | 78.83 ± 15.27 | 1611.54 ± 171.24 | 3162.19 ± 453.21 | 260.18 |
|
CCR, mL/min (mean ± SD) | 89.94 ± 16.39 | 59.43 ± 19.57 | 53.57 ± 17.41 | 154.87 |
|
Cr, mg/dL (mean ± SD) | 0.67 ± 0.15 | 1.07 ± 0.25 | 1.16 ± 0.23 | 195.55 |
|
UA, umol/L (mean ± SD) | 299.22 ± 56.12 | 418.91 ± 49.21 | 471.54 ± 64.72 | 88.80 |
|
LVEDD, mm (mean ± SD) | 45.21 ± 3.86 | 50.89 ± 6.65 | 52.85 ± 8.71 | 45.40 |
|
BMI: body mass index; CCR: creatinine clearance rate; Cr: creatinine; LVEDD: left ventricular end-diastolic diameter; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association; UA: uric acid.
There were no significant differences in age, BMI, and current smokers between any of heart failure groups and the control group (
The NT-proBNP, Cr, UA, and LVEDD levels were significantly higher in the NYHA class 1-2 and 3-4 groups than in the control group, and these variables in the NYHA class 3-4 group were significantly higher than that in the control and NYHA class 1-2 groups (all
Paired comparison for biology markers between control group and heart failure group.
Variable | NYHA | SE |
|
95% CI | ||
---|---|---|---|---|---|---|
Lower | Upper | |||||
Male | 0 | 2 | 0.07 | 0.32 | −0.21 | 0.07 |
3 | 0.06 | 0.01 | −0.29 | −0.04 | ||
2 | 3 | 0.07 | 0.18 | −2.24 | 0.05 | |
|
||||||
Hypertension | 0 | 2 | 0.07 | 0.00 | −0.39 | −0.13 |
3 | 0.06 | 0.00 | −0.33 | −0.10 | ||
2 | 3 | 0.07 | 0.49 | −0.09 | 0.18 | |
|
||||||
Diabetes | 0 | 2 | 0.06 | 0.02 | −0.26 | −0.02 |
3 | 0.05 | 0.00 | −0.33 | −0.11 | ||
2 | 3 | 0.06 | 0.20 | −0.21 | 0.04 | |
|
||||||
NT-proBNP | 0 | 2 | 153.31 | 0.00 | −1834.29 | −1231.12 |
3 | 135.20 | 0.00 | −3349.31 | −2817.41 | ||
2 | 3 | 156.30 | 0.00 | −1858.11 | −1243.20 | |
|
||||||
CCR | 0 | 2 | 2.49 | 0.00 | 25.62 | 35.40 |
3 | 2.19 | 0.00 | 32.06 | 40.69 | ||
2 | 3 | 2.53 | 0.02 | 0.88 | 10.85 | |
|
||||||
Cr | 0 | 2 | 0.03 | 0.00 | −0.46 | −0.35 |
3 | 0.04 | 0.00 | −0.54 | −0.44 | ||
2 | 3 | 0.03 | 0.01 | −0.14 | −0.02 | |
|
||||||
UA | 0 | 2 | 14.99 | 0.00 | −149.18 | −90.20 |
3 | 13.22 | 0.00 | −198.33 | −146.31 | ||
2 | 3 | 15.30 | 0.00 | −82.70 | −22.56 | |
|
||||||
LVEDD | 0 | 2 | 0.94 | 0.00 | −7.52 | −3.82 |
3 | 0.83 | 0.00 | −9.27 | −6.01 | ||
2 | 3 | 0.96 | 0.04 | −3.85 | −2.76 |
CCR: creatinine clearance rate; CI: confidence interval; Cr: creatinine; LVEDD: left ventricular end-diastolic diameter; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association; SE: standard error; UA: uric acid.
As shown in Table
Spearman correlation analysis of relations between variables and the NYHA classification (
Variable | Correlation coefficient | Sig (2-tailed) |
---|---|---|
NT-proBNP | 0.87 | 0.00 |
CCR | 0.74 | 0.00 |
Cr | 0.69 | 0.00 |
LVEDD | 0.44 | 0.00 |
UA | 0.64 | 0.00 |
CCR: creatinine clearance rate; Cr: creatinine; LVEDD: left ventricular end-diastolic diameter; NT-proBNP: N-terminal pro-B-type natriuretic peptide; UA: uric acid.
Logistic regression analysis of risk factors for heart failure.
Variable | Regression coefficient | wald |
|
|
Correct class |
---|---|---|---|---|---|
NT-proBNP | 0.03 | 4.52 | 265.55 | 0.03 | 87.50% |
CCR | 20.82 | 6.08 | 441.48 | 0.01 | 99.70% |
CCR: creatinine clearance rate; NT-proBNP: N-terminal pro-B-type natriuretic peptide.
The Pearson correlation analysis was carried out to determine the relationship between variables of NT-proBNP and CCR in control and heart failure groups. Table
Pearson correlation analysis for NT-proBNP and CCR (
Variable | NT-proBNP | CCR |
---|---|---|
NT-proBNP | ||
Correlation coefficient | 1.00 | −0.62 |
Sig (2-tailed) | 0.00 | |
CCR | ||
Correlation coefficient | −0.62 | 1.00 |
Sig (2-tailed) | 0.00 |
CCR: creatinine clearance rate; NT-proBNP: N-terminal pro-B-type natriuretic peptide.
In univariate linear regression analysis, CCR showed a significant negative correlation with NT-proBNP in the control and heart failure groups (
The ROC curves for NT-proBNP and CCR as indicators of heart failure are shown in Figure
Cut-off points, sensitivity, specificity, and area under the curves for biomarkers and NYHA classification.
Marker | NYHA classification | Cut-off point | Sensitivity | Specificity | Area under ROC curve | SE |
|
95% CI | |
---|---|---|---|---|---|---|---|---|---|
Lower | Upper | ||||||||
NT-proBNP | 1-2 | 329.05 pg/mL | 81.07% | 75.62% | 0.90 | 0.02 | 0.00 | 0.86 | 0.94 |
3-4 | 324.40 pg/mL | 82.34% | 85.90% | 0.92 | 0.02 | 0.00 | 0.89 | 0.96 | |
CCR | 1-2 | 61.39 mL/min | 74.71% | 63.02% | 0.86 | 0.03 | 0.00 | 0.81 | 0.91 |
3-4 | 63.13 mL/min | 82.42% | 78.33% | 0.88 | 0.02 | 0.00 | 0.85 | 0.92 |
CCR: creatinine clearance rate; CI: confidence interval; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association; ROC: receiver operating characteristic; SE: standard error.
Receiver operating characteristic curve analysis of NT-proBNP and CCR for diagnosis for heart failure. ROC curve shows NT-proBNP for the prediction of heart failure patients with NHYA class: (a) 1-2 and (b) 3-4 groups; ROC curve shows CCR for the prediction of heart failure patients with NHYA class: (c) 1-2 and (d) 3-4 groups.
Linear regression analysis of the level of NT-proBNP with CCR (
In this study, we observed that the variables, such as male, hypertension, diabetes, NT-pro BNP, CCR, Cr, UA, and LVEDD, were significantly different among all groups. Furthermore, we revealed that the biomarkers of NT-proBNP, Cr, UA, LVEDD, and CCR were positively correlated with the severity of heart failure.
The NT-proBNP level significantly increased and the value for CCR significantly decreased from control group to NYHA class 1-2 to 3-4 group. The levels of NT-proBNP and CCR were closely related to heart failure and were independent risk factors for patients with heart failure. At the same time, there was a significant negative correlation between the level of NT-proBNP and CCR. The area under the ROC curve suggested that the NT-proBNP and CCR have high accuracy in the diagnosis of heart failure with clinical diagnostic value.
Our findings are similar to the results of several previous studies where NT-proBNP plasma levels were closely related to the severity of heart failure [
Heart failure and renal dysfunction often coexist as the visceral damage in one organ will result in the other organ’s pathological changes accordingly. As two most important organs in the body, heart and kidney influence each other in the physiological and pathological processes, and the renal blood flow accounts for 20–25% of the total output of heart and plays an important role in regulating blood volume, blood vessels tension, and blood pressure change. In patients with heart failure, moderately elevated serum creatinine, without a history of chronic renal insufficiency, is often noticed. Therefore, our research focused on heart failure with no history of chronic kidney disease patients to observe the correlation between kidney index and cardiac function.
Determination of endogenous CCR can effectively evaluate the glomerular filtration function. The CCR can determine the degree of renal impairment and whether glomerular filtration function was damaged. Previous studies have shown that renal insufficiency is the risk factor for prognosis of patients with myocardial infarction, cardiac insufficiency, and hypertension [
Uric acid, a product of purine metabolism whose elevated concentration in CHF is a sign of damaged oxygen metabolism, is associated with the severity of cardiac dysfunction [
Left ventricular end-diastolic diameter is used to determine the abnormal changes of cardiac systolic function. Cardiac ischemia causes the interruption of coronary blood flow and decline of myocardial contraction ability. Cardiac contraction ability is closely related to the size of myocardial ischemic area. When ischemic area size exceeds 15%, LVEDD value increases. There is evidence to suggest that NT-proBNP levels may reflect increased left ventricular wall stress in the absence of cardiac ischemia; thus, in this study we observed that the LVEDD increased from control to NYHA class 1-2 to 3-4 group, associated with heart failure severity.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Zhigang Lu and Bo Wang contributed equally to this work.
This work was supported by Johnson & Johnson Medical. Data was analyzed at the 6th People’s Hospital affiliated to Shanghai Jiaotong University Medical College in Shanghai, China.