Comparative observation of changes in natriuretic peptides before and after interventional therapy for congenital heart disease

Abstract

OBJECTIVE:

To explore changes in the plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in patients with left-to-right shunt congenital heart disease (CHD) before and in the early stage after interventional occlusion and to evaluate the clinical significance.

METHODS:

Among 97 patients with left-to-right shunt CHD undergoing interventional occlusion, 34 cases had a VSD (ventricular septal defect), 35 cases had an ASD (atrial septal defect), and 28 cases had PDA (patent ductus arteriosus). Another 20 normal adults formed the control group. An ELISA was used to determine the plasma ANP and BNP levels before and on the third day after the operation to evaluate their correlations with cardiac functions and the defect size.

RESULTS:

The plasma ANP and BNP levels of patients with left-to-right shunt CHD were increased compared with those of the normal control group ( $P<$ 0.01), and the plasma ANP and BNP levels were decreased on the third day after interventional occlusion compared with the preoperative levels ( $P<$ 0.05). The plasma ANP and BNP levels were correlated with the New York Heart Association (NYHA) grade, left ventricular ejection fraction and defect diameter ( $P<$ 0.05).

CONCLUSION:

Patients with left-to-right congenital heart disease exhibit activation of ANP and BNP, which can be alleviated in the early stage after intervention occlusion. Left-to-right shunt congenital heart disease is given priority over atrial septal defect (ASD), ventricular septal defect (VSD) and patent ductus arteriosus (PDA). Early traditional methods included repair or correction by open heart surgery under extracorporeal circulation (also known as cardiopulmonary bypass, CPB). However, interventional therapy has become a developing trend for the treatment of congenital heart disease since 1967, when Porstmann et al. [1]. reported the transcatheter closure of ASD for the first time. The application of the AMPLATZER occluder, which is a simple and feasible method, has improved the safety of the treatment and enabled the therapeutic effect to reach ideal levels. The natriuretic peptide (NP) family consists of the atrial natriuretic polypeptide (ANP), the brain natriuretic peptide, which is also known as the B type natriuretic peptide (BNP), the C type natriuretic peptide (CNP), the renal natriuretic peptide (RNP) and the D type natriuretic peptide (DNP). These family members are similar in structure, have strong natriuretic, diuretic and vasodilative effects and antagonize the activity of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nerve.

Together, the natriuretic peptides sensitively and specifically reflect the ventricular function state. Although all types of congenital heart disease differ in anatomical structure, they all contain the common features of heart failure. This study detected changes in the serum ANP and BNP levels in patients with left-to-right shunt congenital heart disease before and on the third day after interventional occlusion to evaluate the early changes in left-to-right shunt congenital heart disease after interventional occlusion through neuroendocrine.

Keywords

Left-to-right shunt congenital heart disease atrial natriuretic peptide brain natriuretic peptide interventional occlusion

1. Materials and methods

1.1 Objects and methods

A total of 97 cases of patients with congenital heart disease (diagnosed based on a history of illness and echocardiography results) were selected from our hospital between March 2019 and October 2020. The type of anesthesia used for a congenital heart surgery depends on various factors such as the age of the patient, the complexity of the surgery, and the patient’s overall health. In typical, the types are general anesthesia, regional anesthesia, and cardiac anesthesia. The patients included 34 cases of VSD, 35 cases of ASD and 28 cases of PDA; there were 50 male patients and 47 female patients between 16 and 63 (36.2 $\pm$ 10.6) years of age. Twenty peer healthy adults were selected as the control group, including 10 men and 10 women between 19 and 65 (37 $\pm$ 12.5) years of age. The body weight, body height, heart rate, blood pressure, and regular liver and kidney function test results were recorded for all patients. The exclusion criteria were as follows: Kawasaki disease, arrhythmia, rheumatic heart disease, systemic lupus erythematosus, infective endocarditis, myocarditis, pericardial disease, endocardial fibroelastosis, aorto-arteritis, rheumatism, neoplastic disease, polycythemia, chronic hemolysis, hyperthyroidism or hypothyroidism, cerebrovascular accident, diabetes, renal failure (serum creatinine higher than 200 $\mu$ mol/l), and aspartate aminotransferase 2 times higher than the normal value (80 $\mu$ g/l). All patients were advised not to use drugs to antagonize or activate the autonomic nervous system (i.e., propranolol and epinephrine) and drugs that antagonize the RAAS 2 weeks before hospitalization. Drugs can antagonize or activate the autonomic nervous system in different ways depending on their mechanism of action and the specific receptors they target. It’s important for healthcare providers to carefully consider the potential benefits and risks of any medication before prescribing it to a patient. RAAS stands for Renin-Angiotensin-Aldosterone System. It is a complex hormonal system that helps regulate blood pressure, fluid balance, and electrolyte balance in the body. The system is activated in response to various stimuli such as low blood pressure, low blood volume, or low sodium levels.

1.2 Experimental methods

All patients were given routine interventional therapy for congenital heart disease [2]. The operation was performed under simple local anesthesia or a combination of anesthesia with an AMPLATZER occluder (SHANGHAI SHAPE MEMORY ALLOY CO., LTD, Shanghai, CHINA) under guidance by thoracic echocardiography. An AMPLATZER occluder is a medical device used to close abnormal openings or defects in the heart, such as atrial septal defects (ASDs) and patent ductus arteriosus (PDA). It is a type of transcatheter closure device, meaning it can be inserted into the heart without the requirement for open-heart surgery. It is used in the handling of certain types of congenital heart diseases, specifically atrial septal defects (ASDs) besides patent ductus arteriosus (PDA). Local anesthesia is a type of anesthesia that is used to numb a specific area of the body, typically a small area such as a tooth or a finger. It is administered by injecting a local anesthetic drug (such as lidocaine) into the tissue around the area that needs to be numbed. The type of anesthesia that is considered safe for a patient during an operation depends on various factors including the patient’s medical history, age, the type of surgery being performed, and the patient’s preference. The postoperative echocardiography showed good occluder positioning without an obvious residual shunt, and no serious complications occurred during hospitalization. In postoperative echocardiography after interventional occlusion of congenital heart disease, residual shunt refers to any abnormal blood flow that persists across the site of occlusion.

1.3 Plasma ANP and BNP detection

All patients rested for at least 20 min. Fasting blood was taken via the elbow or femoral vein on the second day after admission and on the third postoperative day. The blood was transferred to a centrifuge tube containing EDTA and centrifuged at 1000 r/min at 4 ${}^{\circ}$ C for 15 min. EDTA (ethylenediaminetetraacetic acid) is a chelating agent that is commonly used in laboratory settings as an anticoagulant to prevent blood from clotting. The amount of blood that can be transferred into a centrifuge tube containing EDTA depends on the size of the tube. Generally, a 5 mL or 10 mL tube is used for collecting blood samples for various laboratory tests, including complete blood count (CBC) and other hematological tests. Blood is typically collected in a centrifuge tube containing EDTA (ethylene diamine tetra-acetic acid) to prevent the blood from clotting. It is an anticoagulant that works by chelating (binding to) calcium ions in the blood, which are necessary for the blood to clot. The plasma and serum were stored in a freezer at $-$ 80 ${}^{\circ}$ C. An ELISA was used for the simultaneous determination of plasma ANP and BNP in pg/ml. ELISA, which stands for Enzyme-Linked Immunosorbent Assay, is a common laboratory technique employed to detect and quantify the presence of specific proteins or other molecules in a sample. It is widely used in biomedical research, clinical diagnostics, and food safety testing. The plasma ANP and BNP levels are typically reported in picograms per milliliter (pg/ml) because they are present in very small quantities in the plasma. ANP and BNP are released by the heart in response to various stimuli, and their levels can be used as biomarkers to assess cardiac function and diagnose heart failure. The types of ELISA are direct, indirect, sandwich, and competitive, in which, each has its own advantages and limitations depending on the specific application and the nature of the analyte being measured.

1.4 Measurement of cardiac function parameters

All patients were classified as grade I or II according to the cardiac function classification standard issued by the New York Heart Association (NYHA). Color Doppler echocardiography was used to measure the left ventricular ejection fraction and the defect diameter. The left ventricle is one of the four chambers of the heart and is responsible for pumping oxygenated blood to the rest of the body. The left ventricular function is critical to overall heart function, and any impairment can lead to heart failure and other serious complications. Color Doppler echocardiography is a non-invasive imaging technique that uses ultrasound waves to assess the blood flow in the heart and blood vessels. It is a type of echocardiography that uses color-coded images to show the direction and velocity of blood flow.

1.5 Statistical methods

SPSS 13.0 was used for the analysis. SPSS 13.0 used in this article because of user-friendly interface, comprehensive statistical analysis, Integration with other software, Data management, and Graphical representation. Enumeration data were analyzed with the $\chi^{2}$ test. When the measurement data assumed a non-normal distribution and exhibited heterogeneity of variance, the data were presented as the median ( $M$ ) and quartile ( $Q$ ) (i.e., $M_{(Q)}$ ). A non-parametric test was adopted for multiple independent samples (Kruskal-Wallis $H$ Test), whereas the Mann-Whitney U test was utilized for pairwise comparisons. Non-parametric tests are statistical tests that do not make assumptions about the underlying distribution of the data being analyzed. A non-parametric test called the Mann-Whitney U test, sometimes referred to as the Wilcoxon rank-sum test, is employed for comparing two separate sets of information. It is commonly used when the data do not meet the assumptions of a parametric test, such as the $t$ -test. Non-parametric tests can also be more robust than parametric tests in the face of outliers or skewed distributions. They are less sensitive to extreme values and can be more reliable in small sample sizes. A multiple linear regression analysis was used for the correlation analysis between parameters, with $P<$ 0.05 indicating significance. A statistical technique known as multiple linear regression analysis is employed to look at the connection among a dependent variable and two or more independent factors. It is a development of simple linear regression evaluation, that looks at how one independent variable and one variable that depends are related.

2. Results

No significant differences were found in age, gender, defect diameter, NYHA grade and left ventricular ejection fraction ( $P>$ 0.05) (Table 1).

The plasma ANP and BNP levels of patients with left-to-right shunt congenital heart disease were significantly increased compared with those of controls ( $P<$ 0.01) (Tables 2 and 3).

The plasma ANP and BNP levels on the 3rd postoperative day were significantly decreased compared with the preoperative levels ( $P<$ 0.01) (Tables 2 and 3).

The plasma ANP and BNP levels were correlated with the NYHA grade, left ventricular ejection fraction and defect diameter ( $P<$ 0.05) (Tables 4 and 5).

Table 1
Baseline characteristics of patients with interventional occlusion (% or $\bar{x}\pm s$ )

Intervention method	Gender	Age (y)	Ultrasonic defect size (mm)	Intraoperative defect size (mm)	Cardiac function classification (NYHA)	EF value (%)
Interventional occlusion	M 50 (57.1%)	36.2 $\pm$ 10.6	6.73 $\pm$ 2.30	7.89 $\pm$ 2.24	Grade I 80 (92.9%)	51.79 $\pm$ 4.26
( $n=$ 97)	F 47 (42.9%)				Grade II 17 (7.1%)
$P$ value	0.276	0.124	0.109	0.317	0.224	0.347

Note: Comparisons between groups for gender, age, defect diameter, cardiac function grade and ejection fraction ( $P>$ 0.05).

Table 2

Changes in patients’ ANP and BNP levels before and after interventional occlusion (pg/ml, $M_{(Q)}$ )

Indicator	Normal control group ( $n=$ 20)	Interventional occlusion group ( $n=$ 97)
		Before interventional occlusion	After interventional occlusion
ANP	0.199 (0.027)	0.355 (0.468)	0.219 (0.038)
BNP	0.274 (0.034)	0.301 (0.412)	0.298 (0.042)
$p$ value		0.001	0.010 ${}^{*}$

Note: Compared with the normal control group, $P<$ 0.05; compared with before interventional occlusion ${}^{*}P<$ 0.05.

Table 3

Changes in the ANP and BNP levels in patients with VSD, ASD and PDA before and after interventional occlusion (pg/ml, $M_{(Q)}$ )

Indicator	Normal control group ( $n=$ 20)	VSD group ( $n=$ 34)		ASD group ( $n=$ 35)		PDA group ( $n=$ 28)
		Before interventional occlusion	After interventional occlusion	Before interventional occlusion	After interventional occlusion	Before interventional occlusion	After interventional occlusion
ANP	0.199 (0.027)	0.372 (0.234)	0.212 (0.021)	0.313 (0.408)	0.197 (0.033)	0.325 (0.461)	0.2155 (0.024)
BNP	0.274 (0.034)	0.378 (0.932)	0.114 (0.113)	0.378 (0.8165)	0.114 (0.110)	0.598 (0.403)	0.115 (0.793)
$p$ value		0.001	0.010 ${}^{*}$	0.001	0.010 ${}^{*}$	0.001	0.010 ${}^{*}$

Note: Compared with the normal control group, $P<$ 0.05; compared with the before interventional occlusion ${}^{*}P<$ 0.05.

Table 4

Correlation analysis of ANP with gender, age and ultrasound indicators

Related factor	Value	Multiple correlation coefficient R	Standardized partial regression coefficient $\beta$	$t$ value	$p$ value
Gender	M: 50 (57.1%)	0.628	0.545	1.300	0.235
	F: 47 (42.9%)
Age (y)	36.2 $\pm$ 10.6		0.246	0.571	0.586
Ultrasonic defect size (mm)	6.73 $\pm$ 2.30		$-$ 1.003	$-$ 1.000	0.043
Cardiac function classification (NYHA)	Grade I, 80 (92.9%)		0.154	0.366	0.046
	Grade II, 17 (7.1%)
EF value (%)	51.79 $\pm$ 4.26		$-$ 0.065	$-$ 0.009	0.023

Table 5

Correlation analysis of BNP with gender, age, and gender, age and ultrasound indicators

Related factor	Value	Multiple correlation coefficient R	Standardized partial regression coefficient $\beta$	$t$ value	$p$ value
Gender	M: 50 (57.1%)	0.732	$-$ 0.659	$-$ 1.793	0.116
	F: 47 (42.9%)
Age (y)	36.2 $\pm$ 10.6		0.683	1.811	0.113
Ultrasonic defect size (mm)	5.89 $\pm$ 2.24		0.876	0.998	0.045
Cardiac function classification (NYHA)	Grade I, 80 (92.9%)		0.687	0.678	0.037
	Grade II, 17 (7.1%)
EF value (%)	51.79 $\pm$ 4.26		$-$ 0.112	$-$ 1.085	0.028

3. Discussion

Patients with congenital heart disease showed obvious activation of ANP and BNP. The ANP and BNP levels were closely associated with the ventricular filling pressure and ventricular remodeling. Ventricular filling pressure is a measure of the pressure inside the ventricles of the heart during diastole, when the heart is relaxed and filling with blood. Ventricular remodeling refers to the structural changes that occur in the heart in response to various stimuli, such as increased blood pressure, myocardial infarction, or chronic volume overload. Some common treatments are observation and monitoring, medications, interventional procedures, open-heart surgery and heart transplantation. Their expression levels were related to the increased ventricular volume load and pressure load, which reflected the abnormalities in the cardiac structure during heart failure.

This study confirmed that patients with congenital heart disease, even without symptoms, had significantly higher ANP and BNP levels than the controls, which was in line with the results of Schrier et al. [3]. The ANP and BNP levels were significantly decreased after interventional occlusion compared with the preoperative levels. The types are Atrial septal defects (ASDs), and Patent ductus arteriosus (PDA). After interventional occlusion with the AMPLATZER occluder, studies have also shown that ANP and BNP levels can be significantly decreased. This is because the occlusion of the defect restores normal blood flow and reduces the pressure and volume load on the heart, leading to a reduction in the release of these hormones. Although congenital heart disease types differ in anatomical structure, they all contain the common features of heart failure. The common features are enlarged heart, thickened walls, dilated ventricles, reduced ejection fraction and valve problems. Patients with chronic heart failure have high blood concentrations of several chemical messenger substances; these messengers are derived from the heart and other organs and are known as neuroendocrine hormones [4, 5]. Several chemical messenger substances are present in the heart, including norepinephrine, epinephrine, Atrial Natriuretic Peptide (ANP), Acetylcholine, Angiotensin II, Brain Natriuretic Peptide (BNP) and Prostaglandins. Its main job is to control blood pressure and volume by encouraging the kidneys to excrete salt and water and by preventing the production of renin and aldosterone, two additional hormones that control blood pressure. The renin-angiotensin-aldosterone system (RAAS) is a complex hormonal system that plays a critical role in regulating blood pressure and fluid balance in the body. When blood pressure falls or blood volume decreases, the RAAS is activated to help maintain cardiovascular homeostasis. Changes in the neuroendocrine hormone levels in patients with congenital heart disease have attracted widespread attention in recent years [6, 7], and neuroendocrine activation has become an independent cause [8]. The cause of increased preoperative ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) in patients with congenital heart disease (CHD) is related to the hemodynamic changes that occur as a result of the underlying heart defect.

ANP can rise even when patients with congenital heart disease are asymptomatic, and ANP further increases when failure occurs [9]. The mechanism in patients with congenital heart disease who have a left-to-right shunting is that ANP secretion increases when the pressure of the right atrium increases; additionally, the increase in angiotensin II during ventricular extraction can also promote ANP secretion. The elevated ANP level reduces the right ventricular preload and decreases the left-to-right shunt via natriuretic and dieresis effects; additionally, increased ANP expands the pulmonary artery and regulates pulmonary artery pressure by influencing the Ca ${}^{2+}$ levels in pulmonary vascular smooth muscle cells [10]. Elevated levels of ANP and BNP in heart disease are a sign of increased stress on the heart and indicate a need for the body to compensate for the decreased function. Measuring ANP and BNP levels can help diagnose and monitor heart disease, as well as guide treatment decisions.

BNP is a type of active peptide that is mainly synthesized and secreted by ventricular muscle cells and reflects changes in the ventricular pressure and load capacity. In congenital heart disease, the plasma BNP concentration is increased due to the increase in the ventricular wall and load capacity; Both ANP and BNP have important functions in regulating blood pressure and volume, BNP appears to have a greater effect on blocking fibrosis of myocardial cells and proliferation of smooth muscle cells, which may make it particularly beneficial in preventing and treating cardiovascular disease. BNP additionally inhibits the fibrosis of myocardial cells and the proliferation of smooth muscle cells, which prevents vascular re-modeling as well as the manufacturing of plasminogen activator inhibitor-1 (PAI-1) or vascular endothelial growth factor (VEGF) in hyperemic limitations.

Left-to-right shunt congenital heart disease (ASD, VSD and PDA) is characterized by anatomic deformities that lead to long-term left-to-right shunting and cause a high load capacity in the right ventricle. ASD can cause blood to flow from the left atrium to the right atrium, which can lead to an increased workload on the right side of the heart. VSD can cause blood to flow from the left ventricle to the right ventricle, which can lead to an increased workload on the right side of the heart. PDA can result in blood flowing from the pulmonary artery, which takes blood from the heart through the lungs, to the aorta, the major artery that distributes blood from the heart to the body. This can put more strain on the lungs. According to the Frank-Starling law, the contraction force of the right ventricular wall is increased in the early phase to adapt to changes in the right ventricular volume at the end of diastole, thereby inducing a hyperkinetic circulatory state in the right ventricle. Reducing the hyperkinetic circulatory state of the right ventricle can be achieved through several strategies are medications, lifestyle changes, oxygen therapy, interventional and surgical procedures. However, a chronic high load capacity will eventually result in irreversible pulmonary hypertension and right heart failure. The common abnormalities that can occur in heart failure include cardiomegaly, ventricular remodeling, reduced ejection fraction, valve abnormalities, pulmonary congestion, pericardial effusion. This situation was also the cause of the increased preoperative ANP and BNP in the CHD patients in this study compared with those of the normal controls. Interventional occlusion blocks, also known as interventional embolization, is a minimally invasive procedure that involves the use of a device to block or occlude blood vessels. The progressions are pre-operative preparation, anesthesia, access to blood vessels, placement of the occlusion, confirmation of successful occlusion and recovery. However, interventional occlusion blocks the abnormal shunt pathway to fundamentally correct the abnormal hemodynamic changes in the heart; theoretically, the right ventricular volume load is decreased, thereby reducing the hyperkinetic circulatory state of the right ventricle, and thus cardiac function recovers and improves [11, 12]. The changes are increased-cardiac output, heart rate, blood pressure, altered blood flow and changes in the workload of the heart. Monitoring and understanding these changes is important in the diagnosis, treatment, and management of heart disease. Interventional therapy to correct hemodynamic abnormalities can effectively relieve the hyperkinetic state during the early stage. The several factors are blood volume, vascular resistance, heart rate, blood viscosity, compliance of blood vessels, and cardiac function. Improving interventional therapy for correcting hemodynamic abnormalities in heart disease involves several strategies, including advancing technology, personalized approach, multidisciplinary team approach, follow-up care, and continued research. As a result, the right ventricular end-diastolic volume is decreased, and the right ventricular tension continues to decline due to the reduction of the load capacity. Subsequently, the ventricular remodeling caused by ventricular wall tension and ventricular hypertrophy is reversed. Therefore, interventional therapy has a long-term trend of improving the right ventricular structure and function. Improving interventional therapy for correcting hemodynamic abnormalities in heart disease involves several strategies, including advancing technology, personalized approach, multidisciplinary team approach, follow-up care, and continued research. Interventional therapy, such as percutaneous pulmonary valve implantation (PPVI), has shown long-term improvement in the right ventricular structure in patients with certain congenital heart defects.

This study confirmed that the activated levels of ANP and BNP were correlated with the NYHA grade, defect diameter and left ventricular ejection fraction. The normal ejection fraction of the left ventricle is generally considered to be between 50% and 70%. This means that during each heartbeat, the left ventricle pumps out between 50% and 70% of the blood that fills it. The normal diameter of the left ventricle varies depending on a person’s age, gender, and body size. In adults, the normal end-diastolic diameter of the left ventricle is typically between 4.0 and 5.6 cm, while the end-systolic diameter is typically between 2.0 and 4.0 cm. The activated ANP and BNP levels were positively correlated with the defect diameter; the ANP and BNP concentrations increased with the gradually elevated NYHA grades and were negatively correlated with the left ventricular ejection fraction, which was consistent with some domestic and foreign research results. Foreign study results have suggested [13] that the ANP and BNP concentrations in left-to-right shunt CHD are increased with the gradually elevated NYHA grade and that differences exist between NYHA grade I/II and ANP/BNP. Foreign researcher Ohuchi H reported [14, 15] that the ANP and BNP concentrations were negatively associated with the left ventricular ejection fraction and that activated ANP and BNP were positively associated with the defect diameter. Domestic researcher Ding Jian-dong [16] also reported that the ANP concentration was positively correlated with the atrial septal defect diameter. Therefore, a larger defect diameter indicates a higher plasma ANP concentration.

In conclusion, ANP and BNP, which are the key regulatory factors of the internal environment and blood pressure, can reduce sodium and water retention and inhibit the release of adrenaline. ANP and BNP have a high negative predictive value with high sensitivity and specificity for evaluations of early cardiac functions. Plasma ANP and BNP detection has the characteristics of rapid, economic and wide application and can determine patients with asymptomatic cardiac insufficiency and provide an effective clinical diagnostic method for the evaluation of cardiac functions in congenital heart disease and heart failure. Patients with left-to-right shunt congenital heart disease exhibit activation of ANP and BNP expression, which is decreased in the early stage after interventional occlusion; therefore, ANP and BNP are helpful for the assessment and judgment of the long-term curative effects of interventional occlusion for congenital heart disease.

Funding

This research was supported by the Foundation from the Department of Science and Technology of Guizhou Province (Qiankehechengguo-LC [2021]023) and the Youth Foundation of Guizhou Provincial People’s Hospital (No. GZSYQN [2019]06). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability statement

No datasets were generated or analyzed during the current study.

Footnotes

Conflict of interest

The authors do not have conflicts of interest to declare.

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