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NT Pro-BNP can be used as a Risk Predictor of Clinical Atrial Fibrillation with or without Left Atrial Enlargement
ISSN: 2329-9517

Journal of Cardiovascular Diseases & Diagnosis
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  • Research Article   
  • J Cardiovasc Dis Diagn 2019, Vol 7(3): 370

NT Pro-BNP can be used as a Risk Predictor of Clinical Atrial Fibrillation with or without Left Atrial Enlargement

Zhao X1, Li H2, Liu C1, Ren Y3 and Sun C4*
1Health Science Center, Xi’an Jiaotong University, Shaanxi Province, P.R. China
2Department of Rehabilitation and Treatment, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi Province, P.R. China
3Medical Science Center, Yan’an University, Shaanxi Province, P.R. China
4Cardiovascular Department, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi Province, P.R. China
*Corresponding Author: Sun C, Doctoral Supervisor, Cardiovascular Department, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi Province, P.R. China, Tel: + 8618191273192, Email: [email protected]

Received Date: May 17, 2019 / Accepted Date: May 29, 2019 / Published Date: Jun 06, 2019

Abstract

Background: NT Pro-BNP is a blood marker secreted from myocardial. The main stimulus for cardiac NT Pro- BNP secretion is myocardial stretch. NT Pro-BNP is a significant risk factor for stroke of cardiac insufficiency and pulmonary embolism. Patients with normal levels of NT–pro-BNP have low risks for death. So, does atrial stretch occur when patients have atrial fibrillation? Whether atrial fibrillation accompanied by changes in atrial muscle stretch may lead to NT Pro-BNP increase is unknown. The purpose of this experiment is to explore the relationship between NT Pro-BNP and atrial fibrillation.

Hypothesis: Atrial fibrillation may cause changes in atrial muscle stretch. Change of myocardial stretch may lead to NT Pro-BNP secretion increase. We hypothesized that NT Pro-BNP might be increased in AF with or without LAD enlargement.

Methods: Atrial fibrillation may cause changes in atrial muscle stretch. Change of myocardial stretch may lead to NT Pro-BNP secretion increase. We hypothesized that NT Pro-BNP might be increased in AF with or without LAD enlargement.

Results: We draw the results that NT Pro-BNP have a statistical relationship with the occurrence of atrial fibrillation after adjusting age, gender, left atrial diameter, hypertension, diabetes, coronary heart diseases and cerebral infarction.

Conclusion: The NT Pro-BNP of AF group is significantly higher than that of non-AF group with or without left atrial enlargement.

Keywords: NT Pro-BNP; Left atrial; Atrial fibrillation; Risk factor

Introduction

It is anticipated that over the next four decades the prevalence of atrial fibrillation (AF) will increase dramatically due to an aging population, improved therapies and longer survival with heart disease [1-3]. Atrial fibrillation (AF) is one of the most common arrhythmias in clinical practice [4] and a major source of cardiovascular morbidity and mortality [5]. AF is also associated with higher rates of stroke and hospitalization [6,7], diminished quality of life [8], increased risk of heart failure and worsened mortality, meanwhile AF is thought to account for nearly half of all embolic strokes [9]. Identifying risk factors of AF are important tasks for public health [10,11]. The supplement of risk factors related to atrial fibrillation are conducive to early identification, early intervention and treatment to prevent the occurrence of stroke. However, the traditional risk factors do not explain all stroke risks of AF, which suggest a need for improvement in risk prediction factors to understand the pathophysiology of AF [12,13]. Blood biomarkers are potential tools for AF risk prediction and to provide insights into the disease’s pathophysiology. The 108 amino-acid precursor molecule BNP is a polypeptide encoded by a gene on chromosome 1. On secretion from both the atria and the ventricles [14]. The intracellular prohormone of brain natriuretic peptide (pro BNP) is split into the biologically active brain natriuretic peptide (BNP) (the 32 amino-acid of the C-terminal fragment, biologically active BNP) and the remaining inactive N-terminal fragment of pro BNP (NT Pro-BNP) (the 76 amino-acid, biologically inactive NT Pro-BNP). NT Pro-BNP has a longer plasma half-life than BNP, and may provide a better diagnostic resolution [15,16]. The main stimulus for cardiac NT Pro-BNP secretion is myocardial stretch [17,18] and pressure or volume overload [19]. Brain-type natriuretic peptide (BNP) is usually a marker of ventricular dysfunction. This hormone is released in response to ventricular stretch [1]. Meanwhile, Patients with pulmonary embolism were also observed to be associated with a significant increase in NT Pro-BNP. NT Pro-BNP is a significant risk factor for stroke of cardiac insufficiency and pulmonary embolism [1]. Patients with normal levels of NT–pro-BNP have low risks for death as well as for hemodynamic deterioration resulting in any adverse events [1]. Atrial fibrillation is usually accompanied by changes in atrial stretch, which may also cause changes in NT Pro- BNP secretion. Stroke and embolism are also risk factors for atrial fibrillation. The purpose of this experiment was to explore whether atrial fibrillation can cause changes in NT Pro-BNP secretion and whether NT Pro-BNP can be considered as a risk factor for the occurrence of atrial fibrillation.

Methodology

Enrollment and subgroup analysis of patients with atrial fibrillation

Figure 1 shows the entire process of the experiment.

cardiovascular-diseases-diagnosis-design-inclusion

Figure 1: The above flow chart shows the design of inclusion and exclusion of AF and non-AF groups. Subgroups are made to explain the relationship of NT pro-BNP and AF.

The inclusion and exclusion criteria of AF and non-AF

Inclusion criteria for patients with atrial fibrillation: Atrial fibrillation has been diagnosed in patients aged 18 to 80.

Exclusion criteria for patients with atrial fibrillation: Valvular heart disease, cardiomyopathy, hyperthyroidism, anemia, congenital heart disease and severe cardiac dysfunction (EF<35%) were excluded.

The criterion of NT Pro-BNP

The normal range of NT Pro-BNP is 0-125 pg/ml, and once it is above 125 pg/ml, we define it as the increase of NT Pro-BNP.

Case Selection

This experiment aims to explore the role of NT Pro-BNP in atrial fibrillation. A total of 1243 patients were enrolled in the First Affiliated Hospital of Xi'an Jiaotong University. According to the inclusion and exclusion criteria, 679 patients with atrial fibrillation and 546 patients without atrial fibrillation were included. We also conducted subgroup analysis on the atrial fibrillation group and non-atrial fibrillation group, we divided them into the NT Pro-BNP elevation group and the NT Pro-BNP non-elevation group according to whether there was an increase of NT Pro-BNP. When exploring the relationship between NT Pro-BNP and atrial fibrillation, the influence of left ventricular diastolic diameter and left atrial diastolic diameter must be excluded. The relationship between NT Pro-BNP and atrial fibrillation were observed when the diameter of the heart was normal.

Statistical Analysis

We used two independent sample t tests for continuous data and chi-square tests for discontinuous data. Univariate analysis model was used for preliminary screening of related risk factors, and literature search was conducted to incorporate meaningful factors into the multivariate logistic regression model for further analysis. Multivariate regression analysis was conducted on the premise of the establishment of the model and good fitting of the model.

Results

NT Pro-BNP in AF and non-AF groups

Through the Table 1, we observed that NT Pro-BNP elevated in the patients with atrial fibrillation compared with the non-atrial fibrillation group.

Category AF Non-AF OR (95% CI) p value
Gender Male (378,55.7%)
Female (301,44.3%)
Male (287,50.8%)
Female (278,49.2%)
1.212
(0.969-1.516)
p=0.092
Age (r) 66.57 ± 11.923 57.85 ± 13.033 1.058
(1.047-1.068)
p<0.001***
BMI (Kg/m2) 25.08 ± 4.909 25.12 ± 3.355 1
(0.993-1.027)
p=0.999
Heart rates (times/min) 77.64 ± 19.125 77.36 ± 12.818 1.001
(0.994-0.008)
p=0.773
SBP (mmHg) 125.59 ± 18.571 138.08 ± 24.487 0.973
(0.967-0.978)
p<0.001***
DBP (mmHg) 76.91 ± 14.581 83.01 ± 15.593 0.972
(0.963-0.980)
p<0.001***
AST (U/L) 23.97 ± 14.5 23.54 ± 23.91 1.001
(0.995-1.007)
p=0.706
ALT (U/L) 25.97 ± 25.75 26.95 ± 32.87 0.999
(0.995-1.003)
p=0.563
CHOL (mmol/L) 4.33 ± 3.52 5.34 ± 4.50 0.928
(0.895-0.963)
p<0.001***
TG (mmol/L) 1.31 ± 0.92 1.74 ± 2.64 0.715
(0.627-0.817)
p<0.001***
LDL (mmol/L) 2.84 ± 20.27 2.30 ± 0.79 1.003
(0.992-1.004)
p=0.588
HDL (mmol/L) 1.05 ± 0.38 1.33 ± 6.13 0.956
(0.765-1.194)
p=0.690
BUN (mmol/L) 6.34 ± 2.91 5.58 ± 1.88 1.192
(1.118-1.271)
p<0.001***
CRE (umol/L) 69.1 ± 23.66 65.09 ± 27.22 1.007
(1.002-1.013)
p=0.008**
CK (U/L) 86.57 ± 54.02 96.04 ± 80.44 0.998
(0.996-1.000)
p=0.020*
CKMB (U/L) 13.31 ± 8.65 12.84 ± 15.50 1.003
(0.993-1.013)
p=0.520
INR 1.43 ± 2.94 1.19 ± 3.97 1.03
(0.975-1.088)
p=0.288
FDP (mg/L) 2.61 ± 9.51 1.42 ± 1.12 1.208
(1.103-1.323)
p<0.001***
Hemoglobin a1c (%) 5.92 ± 0.88 5.72 ± 0.75 1.384
(1.178-1.627)
p<0.001***
K+ (mmol/L) 4.63 ± 15.63 3.88 ± 0.41 2.191
(1.649-2.911)
p<0.001***
Na+ (mmol/L) 142.3 ± 40.23 142.80 ± 4.63 0.999
(0.996-1.003)
p=0.775
Cl (mmol/L) 100.67 ± 10.16 100.26 ± 6.70 1.005
(0.992-1.019)
p=0.421
FT4 (pmmol/L) 14.74 ± 3.97 14.71 ± 3.16 1.002
(0.969-1.035)
p=0.918
FT3 (pmmol/L) 4.84 ± 7.04 4.78 ± 0.99 1.002
(0.979-1.026)
p=0.856
TSH (uIU/L) 3.13 ± 5.18 2.75 ± 3.20 1.024
(0.9891.060)
p=0.183
QRS (s) 0.097 ± 0.020 0.1 ± 0.013 0
(0.000-0.030)
p=0.003**
Left atrial diameter (mm) 39.14 ± 6.59 31.75 ± 3.90 1.326
(1.281-1.372)
p<0.001***
Left ventricular diameter (mm) 46.37 ± 5.83 45.56 ± 4.4 1.031
(1.006-1.057)
p=0.016*
EF (%) 64.37 ± 8.25 67.99 ± 5.94 0.928
(0.911-0.946)
p<0.001***
CO (L/min) 5.97 ± 1.69 5.61 ± 1.36 1.164
(1.072-1.263)
p<0.001***
Nt pro-BNP (pg/mL) Yes 576 (84.83%)
No 103 (15.17%)
Yes 147 (26.06%)
No 417 (73.94%)
15.864
(11.970-21.024)
p<0.001***
Cerebral infarction Yes 50 (7.4)
No 628 (92.5)
Yes 8  (1.4)
No 556 (98.6)
5.533
(2.601-11.773)
p<0.001***
Hypertension Yes 351 (51.7)
No 328 (48.3)
Yes 455 (80.7)
No 109 (19.3)
0.256
(0.198-0.332)
p<0.001***
Diabetes Yes 120 (17.7)
No 559 (82.3)
Yes 80  (14.2)
No 484 (85.8)
1.299
(0.955-1.767)
p=0.096
Coronary heart disease (CHD) Yes 145  (21.4)
No 533 (78.5)
Yes 56  (9.9)
No 508 (90.1)
2.463
(1.768-3.431)
p<0.001***
Kidney disease (CKD) Yes 9  (1.3)
No 670 (98.7)
Yes 13  (2.3)
No 551 (97.7)
0.569
(0.242-1.342)
p=0.191

Table 1: Results of univariate analysis between AF and non-AF groups.

Univariate analysis between atrial fibrillation group and non-atrial fibrillation group

We collected the patient's age, gender, weight, height, respiration, pulse, heart rate, body temperature, blood pressure, blood routine, urine routine, liver function, kidney function, thyroid function, coagulation, electrocardiogram, cardiac ultrasound, holter, drugs and other factors. Univariate analysis was performed on factors that might be associated with atrial fibrillation. Univariate results are shown in Table 2.

Category Univariate analysis Multivariate analysis regression 95% CI for Exp(B)
NT Pro-BNP (pg/mL) p<0.001*** p<0.001*** 8.389
(5.656-12.443)
Age (r) p<0.001*** p=0.261 1.009
(0.993-1.025)
Gender(male) p=0.092 p=0.218 1.26
(0.872-1.821)
Left atrial diameter (mm) p<0.001*** p<0.001*** 1.231
(1.183-1.280)
Cerebral infarction p<0.001*** p=0.046* 2.886
(1.107-8.194)
hypertension p<0.001*** p<0.001*** 0.138
(0.091-0.209)
Coronary heart disease (CHD) p<0.001*** p=0.032* 1.722
(1.048-2.830)
Diabetes p=0.096 p=0.294 1.297
(0.798-2.108)

Table 2: Shows the results of further statistical analysis by incorporating the factors with statistical significance into the multifactor analysis model after single-factor regression.

Single factor results show that the NT Pro-BNP, age, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, urea nitrogen, creatinine, creatine kinase, potassium ion, glycosylated hemoglobin, fibrin degradation products, QRS interphase, Left atrial diameter, Left ventricular diameter and ejection fraction, cardiac output, cerebral infarction, hypertension and coronary heart disease may be associated with atrial fibrillation (p<0.05).

Multivariate logistic regression analysis between atrial fibrillation group and non-atrial fibrillation group.

We selected related factors into the multivariate logistic regression model by consulting relevant literature and the results of univariate analysis. Finally, we selected NT pro-BNP, age, gender, hypertension, coronary heart disease, cerebral infarction, diabetes, and Left atrial diameter into the multi-factor logistic regression model.

Before the binary logistic regression analysis of the relevant factors, we first tested whether the multi-factor regression model was reasonably established and whether the goodness of fit is suitable for the model. The results showed that after these factors were included, the model was established reasonably (the p value of omnibus test is p<0.001) and the goodness of fit of the model was proper (the P value of HL test is p>0.05).

As it is shown in Table 2, after incorporating the above factors into the binary logistic regression model, the NT pro-BNP (95% CI 8.389 5.656-12.443, p<0.001), Left atrial diameter (95% CI 1.231 1.183-1.280, p<0.001), and cerebral infarction (95% CI 2.886 1.017-8.194, p<0.05) were observed.

Hypertension (95% CI 0.128 0.091 0.209, p<0.001), coronary heart diseases (95% CI 1.722 1.048 2.83, p<0.05) are statistically significant. After adjusting for age, gender, hypertension, coronary heart disease, cerebral infarction, diabetes, and Left atrial diameter, NT pro-BNP still associated with a relative risk of 8.389 with atrial fibrillation (95% CI 8.389 5.656-12.443, p<0.001).

Sub-group analysis of AF with and without left ventricular enlargement

In order to rule out that the influence of NT Pro-BNP increase caused by ventricular enlargement. Firstly, we defined whether the left ventricle was enlarged according to the range of left ventricular diameter in the end diastolic stage of cardiac ultrasound. Male patients with left ventricular end-diastolic diameter greater than 55 mm and female patients with left ventricular end-diastolic diameter greater than 50 mm can then be defined as the left ventricle enlargement.

Secondly, we conducted subgroup analysis between the atrial fibrillation group and the control group and divided them into four subgroups: the left ventricular enlargement group in AF, the left ventricular enlargement group in non-AF, the left ventricular normal group in AF, the left ventricular normal group in non-AF. The chi-square test was performed to determine whether the left ventricle of the atrial fibrillation group and the non-atrial fibrillation group increased (Table 3).

Variables AF NON-AF p-value
LVEDD (mm) 46.26 ± 5.85 45.15 ± 4.75 p=0.106
LVEDD enlargerment 56 32
LVEDD without enlargerment 553 458

Table 3: Shows subgroup analysis of the NT-Pro BNP of LVEDD associated with AF and non-AF group.

According to the above Table 3, we found that the left ventricular end-diastolic diameter of the atrial fibrillation group was 46.26 ± 5.85 mm. The left ventricular end-diastolic diameter was 45.15 ± 4.75 in the non-atrial fibrillation group. The chi-square test results of patients with left ventricular enlargement in the atrial fibrillation group and patients with left ventricular enlargement in the non-atrial fibrillation group showed no statistically significance in left ventricular end-diastolic diameter between the atrial fibrillation group and the non-atrial fibrillation group.

Sub-group analysis of AF with and without left atrial enlargement

To further analyze whether NT Pro-BNP increase in the AF group was caused by the enlargement of the left atrium, or even if the left atrium did not increase, atrial fibrillation could still increase NT Pro- BNP. Therefore, we conducted subgroup analysis between the atrial fibrillation group and the control group and divided them into four subgroups: the left atrial enlargement group in AF, the left atrial enlargement group in non-AF, the left atrial normal group in AF, the left atrial normal group in non-AF. Comparison was made between the left atrial enlargement group in AF and the left atrial enlargement group in non-AF, the left atrial normal group in AF and the left atrial normal group in non-AF, the left atrial enlargement group in AF and the left atrial normal group in AF: Subgroup analysis was performed on the AF group and non-AF group as Table 4. We found that compared with the Left atrial normal group in AF, the Left atrial enlargement group in AF experienced an increase in NT Pro-BNP. Enlargement of the left atrium does lead to an increase in NT Pro-BNP.

Subgroup analysis of the diseases associated with atrial fibrillation
Subgroup NT Pro - BNP increase No NT Pro - BNP increase p-value
Left atrial enlargement in AF 269 15 p<0.05*
Left atrial enlargement in non-AF 14 3
  NT Pro - BNP increase No NT Pro - BNP increase  
Left atrial normal in AF 305 90 p<0.001***
Left atrial normal in non-AF 131 416
  NT Pro - BNP increase No NT Pro - BNP increase  
Left atrial enlargement in AF 269 15 p<0.001***
Left atrial normal in AF 305 90

Table 4: Subgroup analysis of the diseases associated with atrial fibrillation.

Compared with the Left atrial enlargement group in AF and the Left atrial enlargement group in non-AF, the NT Pro-BNP of the Left atrial enlargement group in AF was significantly increased, and atrial fibrillation made the patients' NT Pro-BNP increase on the original basis. Compared the Left atrial normal group in AF and the Left atrial normal group in non-AF, the levels of NT Pro-BNP of the Left atrial normal group in AF were also significantly increased. In this subgroup, although atrial fibrillation did not cause left atrial enlargement, however, irregular and asynchronous atrial myocardial contraction during atrial fibrillation may still lead to changes in myocardial tension, which may also lead to the increase of NT Pro-BNP. In comparison with the non-atrial fibrillation groups, the NT Pro-BNP of the atrial fibrillation group is increased in both the presence and absence of increased left atrium.

Discussion

Atrial fibrillation (AF) is one of the most common arrhythmias in clinical practice [4] and a major source for cardiovascular and cerebrovascular morbidity and mortality [5]. AF is also associated with higher rates of stroke and hospitalization [6,7], with diminished quality of life [8], increased risk of heart failure and worsened mortality, and it is thought to account for nearly half of all embolic strokes [9]. Identifying risk factors for AF is an important task for public health [10,11]. The supplement the risk factors of atrial fibrillation is conducive to early identification, early intervention and early treatment for atrial fibrillation to prevent the occurrence of stroke and embolism. Blood biomarkers are potential tools to enhance AF risk prediction and to provide insights into the disease ’ s pathophysiology. NT Pro-BNP may provide a better diagnostic resolution [15,16].

In the past, B-type natriuretic peptide (BNP) has emerged as a powerful diagnostic tool for detecting acute HF and LV systolic and/or diastolic dysfunction [20,21], a high BNP level was associated with left atrial appendage (LAA) thrombi [22], and it also might be a predictor of thromboembolism in patients with Pulmonary embolism. Patients with normal levels of NT–pro-BNP have low risks for death as well as for hemodynamic deterioration resulting in any adverse events [1]. However, with the development of research in recent years, it has been reported that NT pro BNP is also produced in the atrial wall [18], the main stimulus for cardiac NT Pro-BNP secretion is myocardial stretch [17]; However, Atrial fibrillation is usually accompanied by changes in atrial stretch, which may also cause changes in NT Pro-BNP secretion. Stroke and embolism are also risk factors for atrial fibrillation. The purpose of this experiment was to explore whether atrial fibrillation can cause changes in NT Pro-BNP secretion and whether NT Pro-BNP can be considered as a risk factor for the occurrence of atrial fibrillation. This study systematically reviewed 1243 patients with AF and non-AF. We found that compared with the non-AF group the NT Pro-BNP in atrial fibrillation group is increased (p<0.001).

In order to exclude the increase of NT Pro-BNP caused by left ventricular enlargement, we first need to verify whether there is left ventricular enlargement in the atrial fibrillation group and the non-atrial fibrillation group. Statistical analysis of left ventricular end-diastolic diameter between the atrial fibrillation group and the non-atrial fibrillation group revealed no statistical difference between the two groups.

Whether NT Pro-BNP increased in the AF group is caused by the enlargement of the left atrium, or even if the left atrium did not increase, atrial fibrillation could still increase the NT Pro-BNP. Therefore, Subgroup analysis was performed on the AF group and non-AF group. We found that compared with the Left atrial normal group in AF, the Left atrial enlargement group in AF experienced an increase in NT Pro-BNP. Enlargement of the left atrium leads to an increase in NT Pro-BNP. The main stimulus for cardiac NT Pro-BNP secretion is myocardial stretch. The enlargement of the left atrium usually stimulates the increase of NT Pro-BNP. The experimental results also prove that when the left atrium expands, NT Pro-BNP increases. But how does NT Pro-BNP change in AF patients who don't have left atrial enlargement, we compared the Left atrial normal group in AF and the Left atrial normal group in non-AF, the level of NT Pro- BNP in the Left atrial normal group in AF were also significantly increased. Through the above result, although atrial fibrillation does not cause obvious left atrial enlargement. However, minor, irregular and asynchronous atrial myocardial stretch during atrial fibrillation may still lead to changes in myocardial stretch, which may also lead to the increase of NT Pro-BNP. To sum up, in comparison with the non- AF groups, no matter with or without the left atrium enlargement, the NT Pro-BNP of the atrial fibrillation group is increased.

Conclusion

The results of this experiment showed that regardless of the presence or absence of enlarged left atrium, the NT Pro-BNP in the AF group was significantly higher than that of the non-AF group. NT Pro- BNP can be a risk factor for the occurrence of atrial fibrillation, no matter with or without the influence of enlarged left atrium. NT pro- BNP can be used as a risk factor for atrial fibrillation with or without left atrial enlargement.

Limitation of the Study

This study is an observational study in a single center. The research center is relatively single, and the sample representation is not enough.

Acknowledgement

Thanks very much for the guidance from my doctoral supervisor, for the recommendations of data collection and article writing from all the co-authors, for the sincere help from my friends in all aspects, for the company of my dearest husband, and for all the wonderful things in life.

Conflicts of Interest

This is a joint work of our team and the authors declare no conflict of interest.

References

Citation: Zhao X, Li H, Liu C, Ren Y, Sun C (2019) NT Pro-BNP can be used as a Risk Predictor of Clinical Atrial Fibrillation with or without Left Atrial Enlargement. J Cardiovasc Dis Diagn 7:370.

Copyright: © 2019 Zhao X, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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