Effects of recombinant human brain natriuretic peptide combined with tolvaptan on cardiac and renal function and serum inflammatory factors in patients with severe heart failure

Abstract

This study examined the effects of recombinant human brain natriuretic peptide (rhBNP) combined with tolvaptan on cardiac and renal function and serum inflammatory factors in patients with severe heart failure (HF). This retrospective study included 90 patients with severe HF who were treated at our hospital between January 2019 and August 2021. Patients treated with tolvaptan tablets were assigned to the control group, and those treated with rhBNP combined with tolvaptan were assigned to the observation group. Efficacy, cardiac function, levels of inflammatory factors, renal function, 6 minutes walking test, Minnesota Living with Heart Failure Questionnaire score, and adverse reactions were assessed. The curative effect (97.78% vs 77.78%) and improvement in cardiac function were greater in the observation group than in the control group (P < .05). Decreased levels of inflammatory factors were seen in both groups after treatment, and the levels of tumor necrosis factor-α, interleukin-33, and intercellular adhesion factor-1 in the observation group were lower than those in the control group (P < .05). The 6 minutes walking test was higher and the Minnesota Living with Heart Failure Questionnaire score was lower in the observation group compared with the control group (P < .05). The incidence of adverse reactions such as dry mouth, nausea, polyuria, hypotension, and headache in the observation group was lower than that in the control group (P < .05). In conclusion, for patients with severe HF, rhBNP combined with tolvaptan can improve cardiac function, alleviate symptoms of dyspnea, protect renal function, and reduce serum inflammatory factor levels when compared with tolvaptan alone.

1. Introduction

Heart failure (HF) is the final clinical outcome of various serious heart diseases and is characterized by severe systolic dysfunction and prolonged diastolic time.^[1] In developed countries, the prevalence of HF is 1.5%, and the prevalence in people aged 70 years and older is over 10%.^[2] Most patients admitted to hospital with noticeable clinical manifestations have already developed moderate-to-severe HF. Hyponatremia is a common electrolyte disorder observed in patients with severe HF. Previous studies have shown that serum sodium ions are negatively correlated with the prognosis of severe HF. Moreover, hyponatremia at admission is positively correlated with all-cause mortality, rehospitalization rates, and the incidence of shock within 24 months in patients with severe HF.^[3,4] However, high-dose diuretics usually result in a poor prognosis in patients with severe HF. Therefore, comprehensive management of patients with moderate and severe HF is a key clinical problem that needs addressing.^[3]

Currently, the treatment of HF includes cardiotonics, diuresis, vasodilation, heart rate, and blood pressure control, and other treatment measures,^[5] with the objective of reducing cardiac load and enhancing quality of life.^[6] Vasodilators are widely used because the resulting vasodilation increases the upper limit of individual volume load, reduces venous reflux, and reduces cardiac preload.^[7] However, the therapeutic outcomes for recurrent acute HF in patients with persistent HF remains unsatisfactory. Recombinant human brain natriuretic peptide (rhBNP) antagonizes the renin–angiotensin–aldosterone system (RAAS), vascular endothelin, catecholamine, and aldosterone,^[8,9] thereby improving the glomerular filtration rate and urinary sodium excretion, reducing the concentration of blood renin and aldosterone, and antagonizing the effect of vasopressin on water retention and hypertension. Moreover, rhBNP can reduce cardiac load and improve cardiac function by regulating blood pressure and water–salt balance. Tolvaptan, an oral vasopressin V2 receptor antagonist, acts on the distal end of renal tubules and can induce diuresis without increasing electrolyte loss.^[10] A study in patients with HF found that tolvaptan had a more noticeable effect on increasing chloride ion concentrations than on increasing sodium ion concentrations.^[11] While numerous studies have reported on the application of rhBNP or tolvaptan alone when treating HF, few have reported on their combined effects. In this context, further research is necessary to fully demonstrate the efficacy of this drug combination. Thus, the objective of this study was to assess the effects of rhBNP combined with tolvaptan tablets on cardiac and renal function and serum inflammatory factors in patients with severe HF.

2. Materials and methods

2.1. General information

This retrospective study used data extracted from the electronic records of 90 patients with severe HF who were treated at our hospital between January 2019 and August 2021. Of these, 45 were treated with tolvaptan tablets alone and assigned to the control group, whereas 45 were treated with rhBNP combined with tolvaptan and assigned to the observation group. This study was approved by the Ethics Committee of the Beijing Luhe Hospital.

The diagnostic criteria for severe HF were as follows^[12]: (1) major criteria: nocturnal paroxysmal dyspnea; jugular vein anger; pulmonary rale; heart enlargement; acute pulmonary edema; a galloping rhythm of the third heart sound; hemodynamic instability, shock, or symptomatic hypotension; and wet and cold limb ends; (2) minor criteria: ankle edema, nocturnal cough, dyspnea after exercise, hepatomegaly, pleural effusion with vital capacity reduced to 1/3 of maximum capacity, noticeable and difficult-to-correct electrolyte imbalance, and tachycardia (>120 beats/min); and (3) major or minor criteria: weight loss of ≥4.5 kg after treatment lasting more than 5 days. Diagnosis was established when the patient met 2 major criteria or 1 major and 2 minor criteria. Left HF was indicated by exertional dyspnea, cough, sitting breathing, paroxysmal nocturnal dyspnea, heart enlargement, wet rales at the bottom of the lung, galloping rhythm, and pulmonary venous blood stasis. Right HF was indicated by elevated venous pressure, hepatomegaly, and postural edema.

The inclusion criteria were as follows: (1) >18 years of age; (2) signed informed consent; (3) a previous history of HF, with a New York Heart Association (NYHA) cardiac function grade III or IV; (4) signs or symptoms of volume overload on admission or within 48 hours after admission (e.g., elevated jugular pressure, dyspnea, and lower limb edema); and 5) fulfillment of the diagnostic criteria of severe HF.

The exclusion criteria were as follows: (1) severe gastrointestinal diseases, (2) malignant tumors, (3) coma, (4) withdrawal from the trial, (5) refusal to sign the informed consent form, and (6) multiple organ failure.

2.2. Treatment methods

Patients were given basic anti-HF therapy, including oxygen inhalation, digoxin, diuretics, vasodilators, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, aldosterone receptor antagonists, and β-receptor blockers. Lipid-lowering and antiplatelet therapies were administered in accordance with diagnostic and treatment standards and guidelines. The control group was treated with tolvaptan tablets; the initial dose was 7.5 mg/day, and the highest dose was 15 mg/day. The observation group was treated with a combination of rhBNP and tolvaptan tablets. Tolvaptan dosages were the same as those used in the control group; for rhBNP, an initial dose of 1.5 μg/kg was injected intravenously, and then 0.01 μg/kg/min was administered for 1 day. During treatment, the infusion rate was adjusted promptly to maintain a systolic blood pressure > 90 mm Hg. The treatment cycle lasted for 2 weeks.

2.3. Observation indicators

2.3.1. Evaluation of curative effect.

The clinical efficacy of the treatment was evaluated after 2 weeks. Based on the following evaluation criteria, the treatment was categorized as significant effect, effective, or invalid: (1) significant effect: disappearance of dyspnea, fatigue, and other clinical symptoms; and a ≥2-point improvement of the NYHA grade; (2) effective: a noticeable improvement of clinical symptoms and a 1-point improvement of the NYHA grade; (3) invalid: no improvements in clinical symptoms or NYHA grade.^[13] The total effective rate was calculated as follows: total effective rate = (number of significant effect cases + effective cases)/total number of cases × 100%.

2.3.2. Cardiac function.

Before and 3 months after treatment, cardiac function was assessed using the NYHA cardiac function classification criteria^[14]:

Class I: heart disease with no restrictions in physical activity. Physical activity did not cause fatigue, palpitations, asthma, or angina pectoris.

Class II: heart disease with slight restrictions in physical activity. The rest of the body was asymptomatic, with no excessive fatigue, palpitations, asthma, or angina.

Class III: heart disease with obvious restrictions in physical activity. No symptoms were associated with rest; however, excessive fatigue, palpitations, asthma, or angina were experienced with physical activity.

Class IV: symptoms of cardiac insufficiency or angina pectoris at rest, with physical activity leading to increased discomfort.

2.3.3. Serum inflammatory factors.

The levels of the following serum inflammatory factors were measured before and 3 months after treatment: TNF- α, IL-33 and ICAM-1. Fasting venous blood (5 mL) was collected in the morning and centrifuged at 3000 rpm for 10 minutes at a radius of 15 cm. The supernatant was separated, and an enzyme-linked immunosorbent assay was used to determine TNF-α, IL-33, and ICAM-1 levels.

2.3.4. Renal function indicators.

The levels of 24hUp-ro, SCr, and BUN were measured before and 3 months after treatment. Fasting venous blood (5 mL) was collected in the morning and centrifuged for 10 minutes at 3000 rpm, with a radius of 15 cm. The supernatant was separated, and 24hUp-ro was detected using a radioimmunoassay. SCr and BUN levels were determined using an automatic biochemical analyzer.

2.3.5. 6 minutes walking test (6MWT) and quality of life.

The 6MWT and quality of life assessments were performed before and 3 months after treatment. The Minnesota Living with Heart Failure Questionnaire (MLHFQ)^[15] was used for evaluating quality of life. The scores ranged from 0 to 105, with a high score indicating poor quality of life. The evaluation criteria for the 6MWT were as follows: (1) severe cardiopulmonary insufficiency: the maximum walking distance in 6 minutes was <150 m; (2) moderate cardiopulmonary insufficiency: the maximum walking distance in 6 minutes was 150–425 m; and (3) mild cardiopulmonary insufficiency: the walking distance in 6 minutes was >425 m.

2.3.6. Incidence of adverse reactions.

Adverse reactions were collected during treatment and included dry mouth, nausea, polyuria, hypotension, and headaches. The incidence of adverse reactions was calculated as the sum of all adverse reactions/the total number of cases in the group × 100%.

2.4. Statistical analysis

The statistical analysis was conducted using SPSS (version 24.0). Measurement data with normal distributions are presented as mean ± standard deviation and were compared using the t-test. Count data are presented as n (%) and were compared using the χ² test. Statistical significance was set at P < .05.

3. Results

The control group included 25 men and 20 women, with a mean age of 68.52 ± 4.22 years (range: 56–81 years) and a mean body mass index (BMI) of 23.38 ± 2.10 kg/m² (range: 17.78–27.74 kg/m²). Disease duration ranged from 5 to 10 years (mean 7.48 ± 1.95 years); 31 patients had coronary heart disease, 12 had diabetes, and 16 had hyperlipidemia. The observation group included 23 men and 22 women, with a mean age of 68.62 ± 4.27 years (range: 57–83 years) and a mean BMI of 23.44 ± 2.14 kg/m² (range: 17.63–27.81 kg/m²). The disease duration was between 5 and 11 years, with a mean of 7.75 ± 1.54 years. A total of 35 patients had coronary heart disease, 11 had diabetes, and 15 had hyperlipidemia. No significant differences were observed between the 2 groups (P > .05), as shown in Table 1.

Table 1.

Comparison of general information between 2 groups.

Items	Observation group (n = 45)	Control group (n = 45)	χ2/t	P
Age (years)	68.62 ± 4.27	68.52 ± 4.22	0.724	.451
Gender (male/female)	23/22	25/20	0.179	.672
BMI (kg/m2)	23.44 ± 2.14	23.38 ± 2.10	0.615	.613
Course (years)	7.75 ± 1.54	7.48 ± 1.95	0.583	.496
Smoking history			0.498	.48
Yes	31 (68.89)	34 (75.55)
No	14 (31.11)	11 (24.45)
Drinking history			0.179	.672
Yes	23 (51.11)	25 (55.56)
No	22 (48.89)	20 (44.44)
Comorbidities
Diabetes	11 (24.44)	12 (26.67)	0.058	.809
Hypertension	27 (60.00)	30 (66.67)	0.431	.511
Coronary heart disease	35 (77.78)	31 (68.89)	0.909	.34
Hyperlipidemia	15 (33.33)	16 (35.56)	0.049	.825
NYHA classification			0.104	.747
III	5 (11.11)	6 (13.33)
IV	40 (88.89)	39 (86.67)

3.1. Comparison of curative effect

In the observation group, treatment outcomes were significant effect in 37 patients, effective in 7, and invalid in 1, with an effective rate of 97.78%. In the control group, treatment outcomes were significant effect in 24 patients, effective in 11, and invalid in 10, with an effective rate of 77.78%. Compared with the control group, a significantly greater efficacy was observed in the observation group (P = .004) (Fig. 1).

Figure 1.

Comparison of curative effect between 2 groups.

3.2. Comparison of cardiac function

Before treatment, the groups were not significantly different in terms of their cardiac function (P = .747). After treatment, the observation group had 0 patients with grade I, 5 with grade II, 31 with grade III, and 9 with grade IV. In the control group, there were 0, 1, 14, and 30 patients with grades I, II, III, and IV, respectively. The improvement in cardiac function was greater in the observation group than in the control group (P < .05) (Fig. 2).

Figure 2.

Grading of cardiac function. (A) Before treatment. (B) After treatment.

3.3. Comparison of inflammatory factors

Before treatment, the levels of inflammatory factors were not significantly different between the groups (P > .05). Compared with before treatment, the inflammatory factor levels decreased significantly following treatment (P < .05). Compared with the control group, TNF-α, IL-33, and ICAM-1 levels were significantly lower in the observation group (P < .05) (Table 2).

Table 2.

Comparison of inflammatory factors between 2 groups before and after treatment.

Group	TNF-α (ng/L)		IL-33 (ng/L)		ICAM-1 (μg/L)
	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Control group (n = 45)	37.59 ± 4.01	25.18 ± 2.29*	264.95 ± 23.86	167.92 ± 22.95*	661.92 ± 34.96	521.96 ± 22.44*
Observation group (n = 45)	37.19 ± 4.06	20.49 ± 3.10*	265.91 ± 23.91	123.96 ± 20.85*	661.91 ± 34.86	425.94 ± 34.97*
t	0.47	8.163	0.19	9.51	0.001	15.502
P	.873	.017	.581	.003	.622	<.001

^*Compared with the same group before treatment (P < .05).

3.4. Comparison of renal function indexes

Before treatment, renal function did not show any significant differences between the 2 groups (P > .05). After treatment, the levels of 24hUp-ro, SCr, and BUN significantly decreased in both groups (P < .05). The 24hUp-ro, SCr, and BUN levels in the observation group were significantly lower than those in the control group (P < .05) (Table 3).

Table 3.

Comparison of renal function indexes between 2 groups before and after treatment.

Group	24hup-ro (mg)		SCr (μmol/L)		BUN (nmol/L)
	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Control group (n = 45)	1875.84 ± 206.33	1653.86 ± 46.91*	153.95 ± 12.95	136.49 ± 22.44*	9.94 ± 1.21	7.48 ± 1.94*
Observation group (n = 45)	1875.94 ± 205.56	1439.82 ± 43.21*	153.49 ± 12.55	121.92 ± 23.95*	9.95 ± 1.24	6.49 ± 1.22*
t	0.002	22.512	0.171	2.978	0.038	2.897
P	.755	<.001	.419	.006	.351	.021

^*Compared with the same group before treatment (P < .05).

3.5. Comparison of 6MWT and MLHFQ scores

In terms of 6MWT and MLHFQ scores, no significant differences between the groups were observed before treatment (P > .05). After treatment, the 6MWT significantly increased and the MLHFQ score significantly decreased in both groups (P < .05). The 6MWT and MLHFQ scores of the observation group were significantly higher and lower, respectively, when compared with the control group (P < .05) (Table 4).

Table 4.

Comparison of 6 MWT and LHFQ scores between 2 groups before and after treatment.

Group	6 MWT (m)		LHFQ scoring (points)
	Before treatment	3 months after treatment	Before treatment	3 months after treatment
Control group (n = 45)	159.69 ± 23.95	184.96 ± 23.96*	84.96 ± 6.95	56.19 ± 8.95*
Observation group (n = 45)	159.56 ± 23.63	254.92 ± 21.04*	84.19 ± 6.53	43.19 ± 7.42*
t	0.025	14.717	0.541	7.501
P	.619	<.001	.273	.005

^*Compared with the same group before treatment (P < .05).

3.6. Comparison of the incidence of adverse reactions

The incidence of adverse reactions such as dry mouth, nausea, polyuria, hypotension, and headache in the observation group was lower than that in the control group (P < .05) (Fig. 3).

Figure 3.

Incidence of adverse reactions between 2 groups.

4. Discussion

End-stage HF is a severe cardiovascular disease with a high mortality rate and unfavorable prognosis.^[16] As the disease progresses, atrial sensitivity decreases, leading to elevated vasopressin levels and RAAS activation; this in turn activates the sympathetic nervous system, resulting in increased cardiac output that intensifies the cardiac load and induces renal injury.^[17] RAAS activation can also cause a noticeable increase in the circulating volume load. In vivo, natriuretic peptides counteract the water and sodium retention caused by angiotensin and endothelin by dilating blood vessels, inhibiting ventricular remodeling, and preventing cardiac decline.^[18] In response to the over-activation of the sympathetic nervous system and RAAS, the “Golden Triangle” of drugs has emerged to improve ventricular remodeling and includes angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, beta-blockers, and aldosterone receptor antagonists; however, therapeutic effects have been limited.^[19] Further treatment options that can improve cardiac function, reduce circulatory congestion and clinical symptoms, and ensure adequate organ blood supply^[20] are urgently needed to treat recurrent acute episodes of chronic HF and reduce the rates of rehospitalization and mortality and improve overall quality of life.^[21,22]

Tolvaptan is an oral non-peptide vasopressin V2 receptor antagonist that acts on the distal end of the renal tubule without increasing electrolyte loss during diuresis.^[23] The addition of tolvaptan to standard therapy has been shown to markedly ameliorate sodium and water retention, improve congestive symptoms and the prognosis of patients with HF, and prevent the exacerbation of acute renal injury.^[23,24] The current study has demonstrated that the curative effect of the combination of rhBNP and tolvaptan was higher than that of tolvaptan alone, and the cardiac function of the observation group was significantly improved. The incidence of adverse reactions such as dry mouth, nausea, polyuria, hypotension, and headache was noticeably lower in the observation group than in the control group. The analysis showed that rhBNP combined with tolvaptan can rapidly improve dyspnea in patients with severe HF, increase urine excretion, reduce the body weight of patients, and improve the symptoms and signs of hyperemia. Thus, better clinical outcomes can be achieved with the drug combination than with tolvaptan alone. The adverse reactions observed in other studies varied and were closely related to the severity of the disease, the drug dosage, and the treatment level of the study group.^[25] In the observation group of this study, there were no serious or difficult-to-correct adverse reactions, indicating that the drug combination is safe and reliable. The combination of rhBNP and tolvaptan tablets may improve the cardiac function of patients by enhancing the myocardial contractility without increasing the oxygen consumption of the heart. In addition, combination therapy can increase blood vessel volume and reduce heart load. Furthermore, rhBNP has been proposed as being regulated by endocrine negative feedback to inhibit NT-proBNP production. Other investigators have arrived at similar conclusions.^[26,27]

Inflammatory reactions can play important roles in the occurrence and development of severe HF. TNF-α is a cytokine with various biological activities, and cardiomyocytes can produce TNF-α under severe HF conditions. IL-33 is a clinical inflammatory factor commonly used for monitoring the progression of severe HF. ICAM-1 is a biological factor that promotes the adhesion of endothelial and inflammatory cells. In severe HF, the RAAS is overactivated, which stimulates cardiomyocytes to express ICAM-1, thus aggravating the inflammatory response and promoting myocardial remodeling.^[28] This study indicated that the serum levels of TNF- α, IL-33, and ICAM-1 in the observation group were lower 3 months after treatment than those in the control group. This is because the combination of rhBNP and tolvaptan protects the cardiovascular system, inhibits the RAAS, reduces angiotensin secretion and the expression of many serum inflammatory factors, and improves myocardial ischemia.^[29,30] The levels of 24hUp-ro, SCr, and BUN were lower in the observation group than in the control group. In this study, there was no overall deterioration in renal function after treatment, which confirms the safety of rhBNP combined with tolvaptan tablets. In addition, 3 months after treatment, the 6MWT was higher and the MLHFQ score was lower in the observation group compared with the control group, indicating that the adjuvant treatment of severe HF with a combination of rhBNP and tolvaptan can help enhance the quality of life of patients with severe HF.

In summary, rhBNP combined with tolvaptan improved cardiac function, alleviated the symptoms of dyspnea, protected renal function, and reduced serum inflammatory cytokine levels in patients with severe HF.

Author contributions

Conceptualization: Libin Zhang.

Data curation: Libin Zhang.

Formal analysis: Libin Zhang.

Funding acquisition: Libin Zhang, Ming Guo.

Investigation: Libin Zhang, Ming Guo.

Methodology: Jing Yang, Libin Zhang, Ming Guo.

Project administration: Jing Yang, Libin Zhang, Ming Guo, Minghui Hao.

Resources: Jing Yang, Libin Zhang, Ming Guo, Minghui Hao.

Software: Jing Yang, Libin Zhang, Ming Guo, Minghui Hao.

Supervision: Jing Yang, Ming Guo, Minghui Hao.

Validation: Jing Yang, Ming Guo, Minghui Hao.

Visualization: Jing Yang, Minghui Hao.

Writing – original draft: Jing Yang, Minghui Hao.

Writing – review & editing: Jing Yang, Minghui Hao.