Clinical efficacy of Jiawei Xiaoshui Shengyu Decoction in treating chronic heart failure and its effect on NO and inflammatory factors

Jiamin Chen, Xiaokang Ning,＊, Lianshe Li

1 Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China

2 Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China

Abstract

Key words: chronic heart failure; Jiawei Xiaoshui Shengyu Decoction; cardiac function; TCM symptom score; quality of life; inflammatory factor

Introduction

Chronic heart failure (CHF) refers to a group of syndromes that have impaired ventricular filling and/or ejection ability due to various cardiac structural and functional abnormalities[1].The main clinical symptoms include different levels of dyspnea, fluid retention and limited physical activity, and occur at the end stage of the development of various heart diseases.The epidemiological survey results show that the incidence of heart failure in Chinese population is 7% to 9% per 1,000 people, and the number of new heart failure patients is more than 500,000 per year.The incidence and mortality rate caused by heart failure are increasing year by year[2].At present,western medicine treatment in patients with heart failure includes cardiotonic, diuretic, vasodilator, neuroendocrine inhibitors and devices[3], but the long-term prognosis is still poor.TCM syndrome differentiation and treatment of heart failure has its unique characteristics, and plays an important role in improving clinical symptoms, delaying or even cutting off the process of heart failure, and improving the quality of life in patients.Recent studies have shown that[4], some inflammatory factors such as high-sensitivity C-reactive protein (CRP), interleukin-6(IL-6), tumor necrosis factor (TNF-α), endothelin-1 (ET-1) and nitric oxide (NO) are vital in the pathogenesis of CHF.The purpose of this study was to observe the clinical efficacy of Jiawei Xiaoshui Shengyu Decoction combined with western medicine in the treatment of CHF (yang deficiency and water stasis syndrome) and the effect on the levels of NO and inflammatory factors.Eighty patients were included in this study, to provide certain clinical guiding value for the treatment of CHF using integrative Chinese and western medicine.The report is as follows.

Materials and Methods

General information

Eighty CHF patients (yang deficiency and water stasis syndrome) hospitalized in the Cardiovascular Department of the First Affiliated Hospital of Shaanxi University of Chinese Medicine from September 2017 to January 2019 were included in this study, and they were randomly divided into control group and treatment group, with 40 cases in each group.There were 23 males and 17 females in the treatment group; their mean age was (62.78±2.90)years; the course of heart failure was 2.2-5.4 years, with an average of (3.32±0.86) years; 11 cases had a previous history of ischemic cardiomyopathy, 3 cases of type 2 diabetes, and 7 cases of hypertension.There were 20 males and 20 females in the control group; their mean age was(60.02±3.90) years; the course of heart failure was 2.3-5.5 years, with an average of (3.30±0.61) years; 8 cases had a previous history of ischemic cardiomyopathy, 4 cases of type 2 diabetes, and 8 cases of hypertension.The general data of patients in two groups were comparable.

Diagnostic criteria

Diagnostic criteria of western medicine refer to the“Guidelines for the Diagnosis and Treatment of Heart Failure in China 2018”[5]; Diagnostic criteria of TCM refer to the symptom differentiation standard of yang deficiency and water stasis syndrome in “Guiding Principles for Clinical Research of New Drugs in Traditional Chinese Medicine”[6].

Case enrollment criteria

Inclusion criteria

Complying with the diagnostic criteria of western medicine for heart failure, and the grade of cardiac function is grade II-III; The syndrome differentiation of TCM syndromes belongs to yang deficiency and water stasis syndrome; Patients aged 45-75 years and did not take other proprietary Chinese medicines and Chinese herbal decoctions within 1 week before the trial; All patients were reviewed by the hospital ethics committee and voluntarily signed informed consent.

Exclusion criteria

Those who do not meet the inclusion criteria; Those with other diseases that cause heart failure, with severe liver and kidney dysfunction, tumors, hematopoietic system diseases; Those who were not informed of this study;Pregnant and lactating women, patients with mental illness and those who are allergic to this drug; Anyone who meets the exclusion criteria will be excluded immediately.

Treatment methods

All patients were treated with comprehensive medical treatment of CHF in western medicine, including removal of predisposing factors, restriction of sodium intake, control of blood pressure, treatment of primary disease, and attention to rest.(1) Control group: Benazepril Hydrochloride Tablets(Beijing Novartis Pharmaceutical Co., Ltd., State Drugs Administration License No.: H20030514) at initial dosage of 5 mg, and then 10 mg to avoiding the first hypotension,once a day; Metoprolol Tartrate Tablets (AstraZeneca Pharmaceutical Co., Ltd., State Drugs Administration License No.: H32025391) at 12.5 mg, once a day, adjusted according to heart rate; Spironolactone Tablets (Guangzhou Kanghe Pharmaceutical Co., Ltd., State Drugs Administration License No.: H44023416) at 20 mg, once a day; Furosemide Tablets (Jiangsu Epson Pharmaceutical Co., Ltd., State Drugs Administration License No.: H32021428) at 20 mg, once a day, diuretic dosage adjusted according to the degree of edema, regular review of electrolytes; Digoxin(Shanghai Wanxiang Pharmaceutical Co., Ltd., State Drugs Administration License No.: H31020678) at 0.125 mg,once a day.The total course of treatment was 4 weeks.If the patient was discharged from the hospital within 4 weeks, the discharging medication, contact via telephone and outpatient follow-up were required.(2) Treatment group: In addition to the treatment in control group, patients were given Jiawei Xiaoshui Shengyu Decoction, the prescription is as follows:Ramulus Cinnamomi 9 g, Radix Aconiti Lateralis Preparata 9 g, Herba Ephedrae Preparata 6 g, Radix Astragali 18 g,Herba Asari 3 g, Poria 15 g, Saviae Miltiorrhizae Radix 15 g,Rhizoma Anemarrhenae 9 g, Rhizoma Ligustici Chuanxiong 9 g, Semen Armeniacae Amarum 9 g, Fructus Jujubae 5 pcs, Radix Glycyrrhizae Preparata 3 g, Rhizoma Zingiberis Recens 6 g.All decoctions were prepared by the Pharmacy Department of our hospital, one dose per day, taking in morning and evening, the total course of treatment was 4 weeks.If the patient was discharged from the hospital within 4 weeks, the discharging medication, contact via telephone and outpatient follow-up were required.

Outcome measures

The clinical efficacy, TCM symptom scores, Minnesota Quality of Life scale scores, and cardiac function indicators including NYHA grading score, left ventricular ejection fraction (LVEF), stroke volume (SV), and N-terminal pro B-type natriuretic peptide (NT-proBNP) were observed before and after treatment.Serum inflammatory cytokines such as interleukin-6 (IL-6), TNF-α, high-sensitivity C-reactive protein (hs-CRP), endothelin-1 (ET-1) and NO levels were also detected.Adverse reactions caused by Jiawei Xiaoshui Shengyu Decoction were recorded.

Efficacy criteria

The criteria of efficacy assessment was formulated according to the “Handbook of Integrated Traditional Chinese and Western Medicine in Cardiology”[7].①M(fèi)arkedly effective: NYHA grading increases by 2, TCM syndrome score reduction rate is greater than or equal to 70%; ② Effective: NYHA grading increases by 2, TCM syndrome score reduction rate is 40%-70%; ③ Invalid:below the above standard.

Statistical analysis

Data were analyzed using SPSS 19.0 statistical package.The measurement data were expressed as (±s), usingttest or variance test, and the count data were analyzed byx2test.AP＜0.05 value indicated a difference between the two groups is statistically significant.

Results

Case drop-out

A total of 3 cases were detached in this study, including 1 case in the treatment group, who was basically cured and voluntarily terminated the medication on the 13thday of treatment; and 2 cases in the control group, one case was transferred to intensive care unit on the 5thday of admission due to the deterioration, and the other case was automatically discharged without cause on the 7thday and the medication was terminated.Drop-outs were not included in the 4-week clinical efficacy and statistical analysis.

Comparison of clinical effects between the two groups after treatment

Compared with before treatment, the total effective rate was 87.17% in the treatment group and 68.42% in the control group after treatment.The clinical efficacy of the treatment group was significantly better than that of the control group (P＜0.05) (Table 1).

Table 1 Comparison of clinical effects between two groups (n)

Comparison of TCM syndrome scores and Minnesota Quality of Life scale scores before and after treatment in two groups

There was no significant difference in the scores of TCM syndrome and quality of life between the two groups before treatment (P＞0.05); The TCM syndrome scores and quality of life scale scores in the two groups were significantly decreased after treatment, especially in the treatment group, and the difference was statistically significant (P＜0.05) (Table 2).

Table 2 Comparison of TCM syndrome scores and Minnesota Quality of Life scale scores before and after treatment in two groups(points, ±s)

Note: △P＜0.05, vs.before treatment in this group; ＊P＜0.05, vs.control group after treatment.

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Comparison of various indexes of cardiac function before and after treatment in two groups

There was no significant difference in the indexes of cardiac function between the two groups before treatment(P＞0.05); The NYHA grading scores, LVEF, SV and NT-proBNP levels in the two groups were significantly improved after treatment compared with those before treatment, and the improvement in the treatment group was significantly better than that in the control group(P＜0.05) (Table 3).

Table 3 Comparison of various indexes of cardiac function before and after treatment in two groups (±s)

Table 3 Comparison of various indexes of cardiac function before and after treatment in two groups (±s)

Note: △P＜0.05, vs.before treatment in this group; ＊P＜0.05, vs.control group after treatment.

Group Time NYHA grading score LVEF (%) NT-ProBNP (μg/L) SV (ml)Treatment group (n=39) Before treatment 3.69±0.76 45.22±4.31 1036.85±131.53 55.98±5.76 After treatment 1.70±0.24＊△ 55.04±5.76 ＊△ 827.56±37.65＊△ 71.02±5.31＊△Control group (n=38) Before treatment 3.64±0.71 45.67±4.08 1036.09±128.25 55.97±5.38 After treatment 2.40±0.52 △ 48.76±5.13 △ 986.24±51.87△ 67.14±5.07△

Comparison of inflammatory factors levels before and after treatment in two groups

There was no significant difference in the levels of inflammatory factors between the two groups (P＞0.05);The levels of hs-CRP, IL-6, TNF-α were significantly decreased in the two groups after treatment compared with those before treatment, and the decrease in the treatment group was more significant, and the difference was statistically significant (P＜0.05) (Table 4).

Table 4 Comparison of serum inflammatory factors levels before and after treatment in two groups (mg/L, ±s)

Table 4 Comparison of serum inflammatory factors levels before and after treatment in two groups (mg/L, ±s)

Note: △P＜0.05, vs.before treatment in this group; ＊P＜0.05, vs.control group after treatment.

Group Time hs-CRP IL-6 TNF-α Treatment group (n=39) Before treatment 15.14±2.56 36.14±3.08 28.98±6.53 After treatment 6.65±2.02＊△ 14.75±3.01＊△ 16.84±4.01＊△Control group (n=38) Before treatment 15.24±3.36 36.16±4.05 28.99±6.75 After treatment 10.31±2.98△ 25.12±3.84△ 23.76±4.36△

Comparison of NO and ET-1 levels before and after treatment in two groups

There was no significant difference in NO and ET-1 between the two groups before treatment (P＞0.05); After treatment, the levels of NO and ET-1 were significantly improved compared with those before treatment, and the improvement of the treatment group was significantly better than that of the control group (P＜0.05) (Table 5).

Table 5 Comparison of NO and ET-1 levels before and after treatment in two groups ( ±s)

Table 5 Comparison of NO and ET-1 levels before and after treatment in two groups ( ±s)

Note: △P＜0.05, vs.before treatment in this group; ＊P＜0.05, vs.control group after treatment.

Group Time NO (μmol/L) ET-1 (ng/L)Treatment group (n=39) Before treatment 45.98±6.45 86.85±18.26 After treatment 63.37±8.49 ＊△ 59.03±12.09 ＊△Control group (n=38) Before treatment 46.21±4.95 86.79±16.81 After treatment 55.96±6.87 △ 71.92±12.94 △

Adverse reactions

One patient in the treatment group had a faster heart rate,and decreased to normal after adjusting the dose of beta blocker; In the control group, 3 patients had high blood pressure, after adjusting the ACEI dose, the blood pressure dropped to normal, and the remaining patients had no obvious adverse reactions.

Discussion

CHF is caused by a variety of circulatory diseases such as coronary heart disease, pulmonary heart disease,cardiomyopathy and hypertension, which induces changes in cardiac function and/or structure and increases cardiac load, thus leading to a group of clinical syndromes such as decreased ventricular filling and pumping function,and decreased cardiac output, systemic circulation or pulmonary circulation congestion.A large number of studies have confirmed that the mechanism of heart failure is mostly associated with ventricular remodeling after myocardial injury, so the key link in the treatment of CHF is to effectively block and delay ventricular remodeling.Studies have shown that[8], among the factors involved in ventricular remodeling associated with CHF, abnormal levels of some inflammatory factors and endothelial growth factors play an important role in damaging the myocardium and aggravating ventricular remodeling,in addition to the renin-angiotensin-aldosterone system(RAAS) system, activation of the neurohumoral system,and increased excitability of the sympathetic nervous system.A large number of related studies have shown that CHF is associated with inflammatory response[9],when heart failure occurs, damaged myocardial tissue may promote the release of inflammatory factors such as IL-6, TNF-α, hs-CRP, from macrophages, activate the RAAS system, elevate the level of norepinephrine(NA), increase the levels of interleukin-6 in smooth muscle cells and vascular endothelial cells, inhibit the excitement-contraction coupling mechanism of myocardial cells, aggravate ventricular remodeling and participate in the occurrence of heart failure[10].Among them, TNF-α is a systemic inflammatory response factor, which can cause inflammatory cytokines to migrate to the infected site, promote the release of platelet activating factor, cause pulmonary hypertension, aggravate myocardial ischemia and hypoxia, and further participate in the infiltration and activation of inflammatory factors[11].Through a series of inflammatory cytokines produced by infiltration, direct and indirect aggregation, hs-CRP contributes to damage vascular endothelial cells, induce activation of the coagulation system and complement to cause myocardial cell damage, and aggravates heart failure[12].In addition, when cardiac function declines in patients with heart failure, the body’s self-stress response is enhanced, the vascular endothelium is damaged,resulting in decreased NO secretion, increased synthesis of endothelin-1 (ET-1), and imbalance between the two levels can induce vasospasm contraction, resulting in the aggravation of local renal tissue ischemia and hypoxia and the microcirculatory disorder, which ultimately aggravate renal impairment[13].Therefore, in addition to blocking and antagonizing the factors leading to ventricular remodeling in CHF, attention should be paid to the regulation of serum inflammatory factors, endothelin-1 and NO levels that promote cardiac function deterioration in clinical treatment.

In the theory of traditional Chinese medicine, heart failure is classified as “edema, asthma syndrome” and other fields.This disease is located in the heart and can affect the kidney, lung, spleen and other organs.Ancient medical doctors have a solid theoretical foundation for the treatment of heart failure from yang deficiency and water stasis syndrome.For example, “Su Wen·Reverse Tune”says that, if the person can not lie or appears syndrome characterized by dyspnea when lying, his body is invaded by water and wetness, which pointed out that the cause of heart failure is closely related to the stagnation of water and wetness in the body.In the “Synopsis of Prescriptions of the Golden Chamber·Treatment of Pulse Syndrome of Water-Qi Disease”, blood is unfavorable for water,indicating that blood stasis and excessive water are the important pathogenesis of heart failure.For the treatment of heart failure, “Blood Syndrome” has proposed that water and blood are dependent on each other, water disease does not leave the blood, blood disease does not leave the water, water treatment is effective to cure blood, and blood treatment is effective to control water.In the “Su Wen”,the treatment is based on the principles of opening pores,inducing diuresis, dissipating stagnation, which is equal to three methods for arresting massive water (sweating,alleviating water retention, and promoting blood circulation).Professor Li Lianshe summed up more than 30 years of clinical experience and combined with the new guidelines on the treatment of heart failure, he proposed that the pathogenesis of this disease is associated with asthenia in origin and sthenia in superficiality, the asthenia is characterized by the heart-kidney yang deficiency, and the sthenia is characterized by the blood stasis blocking,water-wetness stagnation.The patient suffers from yin and yang dysfunction in heart and kidney, and the water transpiration and weakness.When the qi is difficult to promote water circulation for a long time, the water is stopped and the blood is slowed down, ultimately causing the disease.Treatment shall emphasize on the heartkidney yang deficiency, blood stasis and water stagnation,comply with the principle of warming the kidney to help the yang, circulating blood and water.Jiawei Xiaoshui Shengyu Decoction is a potential approach.Xiaoshui Shengyu Decoction comes from Chen Xiuyuan’s “Shi Fang Miao Yong”, and it is composed of Guizhi Decoction,eliminating Chinese herbaceous peony, combined with Mahuang Fuzi Xixin Tang and Anemarrhena asphodeloides in “Synopsis of the Golden Chamber,Syndrome of Dampness and Pulse Disease”.Its functions include warming the kidney, promoting yang, promoting blood circulation, inducing diuresis, dispelling cold and dredging channels.The tutor adds and subtracts the drug composition of the prescription, and has achieved good efficacy in clinical treatment of CHF patients with yang deficiency and water stasis syndrome.The prescription consists of Ramulus Cinnamomi, Radix Aconiti Lateralis Preparata, Herba Ephedrae Preparata, Herba Asari,Rhizoma Anemarrhenae, Radix astragali, Poria, Saviae Miltiorrhizae Radix, Atractylodis Rhizoma, Semen Armeniacae Amarum, Rhizoma Ligustici Chuanxiong,Fructus Jujubae, Radix Glycyrrhizae Preparata, Rhizoma Zingiberis Recens, etc.In the prescription, Radix Aconiti Lateralis Preparata and Ramulus Cinnamomi are taken as the monarch, Radix Aconiti Lateralis Preparata is pungent and sweet in nature and is used for warming the kidney and yang, the spleen and soil, as well as the water and dampness.Ramulus Cinnamomi is sweet and warm, it enters the heart meridian, which can warm the meridian and unblock the pulse, and help yang to transform qi.Both are combined to play the effects of warming kidney and yang, transforming qi and moving water.Herba Ephedrae Preparata and Herba Asari can remove pathogenic cold in the body, warm the lung and generate water, and enhance the yang warming and water promoting effects of Rhizoma Zingiberis Recens.Saviae Miltiorrhizae Radix and Rhizoma Ligustici Chuanxiong have effects in promoting blood circulation, removing blood stasis, dredging channels and relieving pain; The compatibility of Atractylodis Rhizoma and Poria cocos may strengthening the spleen, nourish the kidney, and eliminate dampness, and they are all ministerial drugs.Rhizoma Anemarrhenae can nourish yin, clear fire and promote urination, and prevent pungent and heat drugs from burning fluid and damage fluid, it acts as a counteradjuvant.Radix astragali can invigorate spleen-stomach and replenish qi, raise yang and consolidate superficiality,promote blood circulation and inducing diuresis.Semen Armeniacae Amarum opens the heart and dispels lung qi.Rhizoma Zingiberis Recens warms and disperses water and dampness, and helps Radix Aconiti Lateralis Preparata to warm yang and dispel cold.The above drugs are all adjuvant drugs.Radix Glycyrrhizae Preparata warms the yang and regulates the middle warmer, and also regulates the toxicity of Radix Aconiti Lateralis Preparata.Fructus Jujubae supplements qi deficiency, benefits spleen and stomach, and helps to support the injured qi.These two drugs are conductant drugs.The compatibility of various drugs contributes to exert the effects of warming the kidney and helping the yang, promoting blood circulation and inducing diuresis.Modern pharmacological study confirmed that,Ramulus Cinnamomi[14]extract can increase NO activity and reduce TNF-α secretion, reduce the release of inflammatory factors such as hs-CRP and IL-6, and improve cardiac function and vascular endothelial function; Radix Aconiti Lateralis Preparata extract aconitine can increase the level of cyclic adenosine monophosphate in cardiomyocytes, enhance myocardial contractility, reduce cardiac load, improve peripheral and coronary circulation, thereby protecting myocardial cells and delaying ventricular remodeling[15];Both ephedrine in ephedra and asarum extracts can excite adrenergic nerves, increase myocardial contractility, reduce ventricular filling, and reduce cardiac load[16]; Rhizoma Anemarrhenae has the effect of protecting the vascular endothelium and improving the synthesis of NO[17]; Radix astragali’s effective monomer, astragaloside IV, protects damaged mitochondria of cardiomyocytes, significantly improves left ventricular contractility, and increases cardiac output[18]; Poria cocos has diuretic, promoting myocardial contraction, bacteriostasis, anti-inflammatory, lipid-lowering effects[19]; Saviae Miltiorrhizae Radix has anti-atherosclerosis,protects the myocardium, resists myocardial fibrosis,improves heart function, regulates lipids[20]; Organic acids and alkaloids in Rhizoma Ligustici Chuanxiong have effects such as anti-oxidation, scavenging superoxide free radicals,anti-platelet aggregation, protection of vascular endothelium and anti-oxidative damage[21].

In this study, compared with before treatment, the overall effective rate of the treatment group was 87.17%, and that of the control group was 68.42% after treatment,the clinical effect of the treatment group was significantly better than that of the control group; in the treatment group,TCM syndrome scores, quality of life score, NYHA grading score, LVEF, SV, and NT-proBNP levels were significantly better than those of the control group after treatment;The improvement of ET-1, NO and IL-6, TNF-α and hs-CRP levels in the treatment group were significantly better than those in the control group.It has been proved that the Chinese herbal drugs for warming kidney and supporting yang, activating blood and promoting diuresis in this decoction can help to regulate the levels of ET-1 and NO, antagonize the release of inflammatory factors,and improve the inflammatory state.This may be the mechanism of its therapeutic effect on CHF.

In summary, Jiawei Xiaoshui Shengyu Decoction combined with western medicine for the treatment of CHF (yang deficiency and water stasis syndrome) can significantly alleviate the relevant clinical symptoms, and has important significance for the long-term prognosis of patients and the reduction of rehospitalization rate.