Traditional Chinese medicine composition for treating heart failure and application thereof

Abstract

The invention relates to a traditional Chinese medicine composition for treating heart failure. The traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 1-7 parts of astragalus membranaceus, 1-5 parts of ginseng, 1-5 parts of angelica sinensis, 1-5 parts of ligusticum wallichii, 1-6 parts of salvia miltiorrhiza, 1-5 parts of peach kernel, 1-5 parts of fructus aurantii and 1-5 parts of honey-fried licorice root. The invention further provides application of the traditional Chinese medicine composition in preparation of a medicine for treating heart failure. The heart failure is caused by qi deficiency and blood stasis, and the heart function of the heart failure is grade II to grade III. After the traditional Chinese medicine composition is combined with standard treatment, in cardiac function grading, the proportion of an observation group in the I-level cardiac function is remarkably increased. After the traditional Chinese medicine composition is combined with standard treatment, the exercise tolerance of a subject is remarkably improved compared with that of a control group. After being combined with standard treatment, the traditional Chinese medicine composition has significant differences in improvement of chest distress, shortness of breath, palpitation and fatigue and weakness. All patients completing follow-up visit do not have adverse reactions such as muscular soreness and urinary tract infection.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine, and specifically, to a traditional Chinese medicine composition for treating heart failure and its application. Background Art

[0002] Heart failure refers to a group of syndromes caused by various diseases that lead to abnormal heart structure or function, resulting in impaired ventricular filling or (and) ejection function, and the heart's pumping volume being unable to meet the metabolic needs of body tissues, manifested as pulmonary congestion and insufficient blood supply to organ tissues. The main symptoms are dyspnea, inability to perform physical activities, edema due to fluid retention, pulmonary congestion, etc. Heart failure caused by qi deficiency and blood stasis is characterized by palpitations, shortness of breath, dyspnea and fatigue, spontaneous sweating, less lustrous complexion, dark or ecchymotic tongue, and deep or string-like pulse.

[0003] Chinese Patent Document CN 116549560A discloses a traditional Chinese medicine composition for treating chronic heart failure, which is prepared from raw medicinal materials in the following proportions: 45 - 55 parts of Astragalus membranaceus, 10 - 18 parts of Epimedium brevicornu, 10 - 18 parts of Lepidium apetalum, 10 - 18 parts of Poria cocos, 10 - 18 parts of Atractylodes macrocephala stir-fried, 10 - 18 parts of Acanthopanax senticosus, 10 - 18 parts of Salvia miltiorrhiza, 9 - 12 parts of Ophiopogon japonicus, and 9 - 12 parts of Cinnamomum cassia. The present invention also discloses a preparation method of the above traditional Chinese medicine composition, and the application of the above traditional Chinese medicine composition in the preparation of drugs for treating chronic heart failure. The traditional Chinese medicine composition of the present invention can inhibit and delay the development of myocardial remodeling, block the vicious cycle, and reduce the mortality rate of heart failure patients.

[0004] Chinese Patent Document CN 1810277A discloses a traditional Chinese medicine composition for treating heart failure, which is mainly prepared from Codonopsis pilosula, Astragalus membranaceus, Paeonia lactiflora, Aconitum carmichaelii (processed), Ilex pubescens, Plantago asiatica, Lepidium apetalum, Cinnamomum cassia, Ligustrum lucidum, and Cinnamomum cassia in certain weight ratios. It can be prepared into any common oral dosage form. The present invention has obvious curative effects on heart failure and no obvious toxic and side effects were found during the clinical trial period. The present invention also discloses a preparation method of the above traditional Chinese medicine composition.

[0005] There are many such traditional Chinese medicine compositions for treating heart failure, but they all have more or less disadvantages. For example, there are too many medicinal flavors, it is difficult to obtain raw materials, and the price is expensive; the medicinal effect is not obvious, and the treatment effect is poor, etc. Therefore, there is an urgent need for a traditional Chinese medicine composition with obvious curative effect on heart failure, few medicinal flavors, practical operability, high compliance, safety and effectiveness. Summary of the Invention

[0006] The purpose of the present invention is to provide a traditional Chinese medicine composition for treating heart failure and its application in view of the deficiencies in the prior art.

[0007] In a first aspect, the present invention provides a traditional Chinese medicine composition for treating heart failure, which is prepared from the following raw materials by weight: 1-7 parts of Astragalus membranaceus, 1-5 parts of Panax ginseng, 1-5 parts of Angelica sinensis, 1-5 parts of Ligusticum chuanxiong, 1-6 parts of Salvia miltiorrhiza, 1-5 parts of Prunus persica, 1-5 parts of Aurantii Fructus Immaturus, and 1-5 parts of Radix Glycyrrhizae Preparata.

[0008] As a preferred example, the traditional Chinese medicine composition is prepared from the following raw materials by weight: 1-5 parts of Astragalus membranaceus, 1-3 parts of Panax ginseng, 1-3 parts of Angelica sinensis, 1-3 parts of Ligusticum chuanxiong, 1-4 parts of Salvia miltiorrhiza, 1-3 parts of Prunus persica, 1-3 parts of Aurantii Fructus Immaturus, and 1-3 parts of Radix Glycyrrhizae Preparata.

[0009] As another preferred example, the traditional Chinese medicine composition is prepared from the following raw materials by weight: 3 parts of Astragalus membranaceus, 1 part of Panax ginseng, 1 part of Angelica sinensis, 1 part of Ligusticum chuanxiong, 2 parts of Salvia miltiorrhiza, 1 part of Prunus persica, 1 part of Aurantii Fructus Immaturus, and 1 part of Radix Glycyrrhizae Preparata.

[0010] In a second aspect, the present invention provides the use of the traditional Chinese medicine composition in the preparation of a drug for treating heart failure.

[0011] As a preferred example, the heart failure is heart failure caused by qi deficiency and blood stasis.

[0012] As another preferred example, the heart function of the heart failure is grade II to III.

[0013] The advantages of the present invention are as follows:

[0014] 1. There was no difference in the levels of NT-proBNP between the two groups of subjects before treatment. Compared with the control group, the decrease in NT-proBNP was more significant in the observation group (P < 0.01). The effective rate of the observation group in improving the decrease rate of NT-proBNP ≥ 30% (88.1%) was higher than that of the control group (68.29%), and there was a statistical difference (P = 0.026).

[0015] 2. Compared with the control group, taking the Yiqi Huayu formula (the present invention) for 12 weeks can effectively improve the symptom burden of HFpEF patients, improve the quality of life of patients, and effectively increase the total score of the KCCQ myocardial scoring scale (P < 0.01).

[0016] 3. There was no significant difference in the proportion of NYHA classification between the two groups before treatment, P = 0.70. After 12 weeks of treatment with the Yiqi Huayu formula (the present invention) combined with standard treatment, in the cardiac function classification, the proportion of the observation group (47.6%) in grade I cardiac function was significantly increased compared with that of the control group (17.1%), and the difference was statistically significant, P = 0.012.

[0017] 4; There was no significant difference in the 6MWT between the two groups before treatment, P = 0.37. After 12 weeks of treatment with the Yiqi Huayu formula (the present invention) combined with standard treatment, the exercise tolerance of the subjects was significantly improved compared with the control group, and the difference was statistically significant, P = 0.01.

[0018] 5; There was no significant difference in the echocardiogram between the two groups of subjects before treatment. After 12 weeks of treatment with the Yiqi Huayu formula (the present invention) combined with standard treatment, there was no significant difference in improving LVEF and reducing the LA inner diameter between the observation group and the control group (P > 0.05), and there was no significant change in the two groups compared with before treatment. However, it could effectively reduce LAVI and E / e' compared with the control group (P < 0.05)

[0019] 6; After 12 weeks of treatment with the Yiqi Huayu formula (the present invention) combined with standard treatment, there was a significant difference in improving ST2 and Cr between the observation group and the control group (P < 0.05).

[0020] 7; There was no significant difference in the TCM syndrome scores and total scores between the two groups of subjects before treatment. After 12 weeks of treatment with the Yiqi Huayu formula (the present invention) combined with standard treatment, there was a significant difference in improving chest tightness, shortness of breath, palpitations and fatigue between the observation group and the control group (P < 0.01).

[0021] 8; The safety evaluation indicators of the two groups of patients were examined at the time of enrollment and the 12th week: alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatine kinase, etc. No adverse reactions such as muscle soreness and urinary tract infection occurred in all patients who completed the follow-up in this study. Description of the Drawings

[0022] Figure 1 Comparison chart of the KCCQ score scale of the two groups of subjects before and after treatment

[0023] PL: Physical Limitation, SB: Symptom Burden, SS: Symptom Stability, QoL: Quality of Life, SL: Social Limitation, SE: Self-Efficacy.

[0024] Figure 2 Statistical analysis of phenotypic data of each group of mice (n = 5)

[0025] A: Ratio of heart mass to tibia length (HW / TL) B: Ratio of lung wet weight to body weight (LW / BW)

[0026] C: Ratio of wet weight to dry weight of the lung (WL / DL) D: Content of plasma NT-proBNP.

[0027] Figure 3 Echocardiograms of each group of mice

[0028] M-Mode: Measure the LVEF graph, PW-Mode: Measure the E / A graph, Tissue-Mode: Measure the e' graph.

[0029] Figure 4 HE and Masson staining of the long axis of the heart of each group of mice (n = 5)

[0030] A: HE staining *1 magnification, B: HE staining *20 magnifications, C: Masson staining *1 magnification, D: Masson staining *20 magnifications.

[0031] Figure 5 Bar graph of the exercise fatigue test of each group of mice

[0032] Figure 6 Oral glucose tolerance test (OGTT) of each group of mice

[0033] A: Blood glucose levels at each time point of OGTT, B: Statistical graph of the area under the glucose tolerance curve. Specific implementation mode

[0034] The present invention will be further described below in conjunction with specific implementation modes. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content recorded in the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0035] Example 1 A traditional Chinese medicine composition for treating heart failure (I)

[0036] Astragalus membranaceus 3 parts, Panax ginseng 1 part, Angelica sinensis 1 part, Ligusticum chuanxiong 1 part, Salvia miltiorrhiza 2 parts, Prunus persica 1 part, Aurantii Fructus Immaturus 1 part, Radix Glycyrrhizae Preparata 1 part.

[0037] Functions and indications of the present invention: Tonifying qi and nourishing the heart, promoting blood circulation and dredging collaterals. Used for heart failure caused by qi deficiency and blood stasis. Symptoms include palpitations, shortness of breath, dyspnea, fatigue, spontaneous sweating, sallow complexion, dark or ecchymotic tongue, deep or stringy pulse; those with HFpEF (heart function: grade II - III) presenting the above syndromes. Dosage and administration: Take half an hour after meals. One bag each time, twice a day. 8 weeks is a course of treatment or follow the doctor's advice. Combined medication: When used in combination with other traditional Chinese medicines or Chinese patent medicines, the principle of syndrome differentiation and treatment should be noted.

[0038] Example 2 A traditional Chinese medicine composition for treating heart failure (II)

[0039] Astragalus membranaceus 3 parts, Panax ginseng 1 part, Angelica sinensis 5 parts, Ligusticum chuanxiong 1 part, Salvia miltiorrhiza 4 parts, Prunus persica 1 part, Aurantii Fructus Immaturus 1 part, Radix Glycyrrhizae Preparata 5 parts.

[0040] Example 3 A Traditional Chinese Medicine Composition for Treating Heart Failure (III)

[0041] Astragalus membranaceus 1 part, Panax ginseng 5 parts, Angelica sinensis 1 part, Ligusticum chuanxiong 3 parts, Salvia miltiorrhiza 2 parts, Prunus persica 1 part, Aurantii Fructus Immaturus 5 parts, Honey-fried Licorice Root 1 part.

[0042] Example 4 A Traditional Chinese Medicine Composition for Treating Heart Failure (IV)

[0043] Astragalus membranaceus 7 parts, Panax ginseng 1 part, Angelica sinensis 3 parts, Ligusticum chuanxiong 1 part, Salvia miltiorrhiza 1 part, Prunus persica 5 parts, Aurantii Fructus Immaturus 1 part, Honey-fried Licorice Root 3 parts.

[0044] Example 5 A Traditional Chinese Medicine Composition for Treating Heart Failure (V)

[0045] Astragalus membranaceus 1 part, Panax ginseng 3 parts, Angelica sinensis 1 part, Ligusticum chuanxiong 1 part, Salvia miltiorrhiza 6 parts, Prunus persica 1 part, Aurantii Fructus Immaturus 3 parts, Honey-fried Licorice Root 1 part.

[0046] Example 6 A Traditional Chinese Medicine Composition for Treating Heart Failure (VI)

[0047] Astragalus membranaceus 5 parts, Panax ginseng 1 part, Angelica sinensis 1 part, Ligusticum chuanxiong 5 parts, Salvia miltiorrhiza 1 part, Prunus persica 3 parts, Aurantii Fructus Immaturus 1 part, Honey-fried Licorice Root 1 part.

[0048] Example 7 A Traditional Chinese Medicine Composition for Treating Heart Failure (VII)

[0049] Astragalus membranaceus 3 parts, Panax ginseng 5 parts, Angelica sinensis 1 part, Ligusticum chuanxiong 3 parts, Salvia miltiorrhiza 2 parts, Prunus persica 1 part, Aurantii Fructus Immaturus 5 parts, Honey-fried Licorice Root 1 part.

[0050] Example 8 A Traditional Chinese Medicine Composition for Treating Heart Failure (VIII)

[0051] Astragalus membranaceus 1 part, Panax ginseng 1 part, Angelica sinensis 3 parts, Ligusticum chuanxiong 1 part, Salvia miltiorrhiza 1 part, Prunus persica 5 parts, Aurantii Fructus Immaturus 1 part, Honey-fried Licorice Root 3 parts.

[0052] Example 9 A Traditional Chinese Medicine Composition for Treating Heart Failure (IX)

[0053] Astragalus membranaceus 7 parts, Panax ginseng 3 parts, Angelica sinensis 1 part, Ligusticum chuanxiong 1 part, Salvia miltiorrhiza 6 parts, Prunus persica 1 part, Aurantii Fructus Immaturus 3 parts, Honey-fried Licorice Root 1 part.

[0054] Example 10 A Traditional Chinese Medicine Composition for Treating Heart Failure (X)

[0055] Astragalus membranaceus 1 part, Panax ginseng 1 part, Angelica sinensis 1 part, Ligusticum chuanxiong 5 parts, Salvia miltiorrhiza 1 part, Prunus persica 3 parts, Aurantii Fructus Immaturus 1 part, Honey-fried Licorice Root 1 part.

[0056] Example 11 A Traditional Chinese Medicine Composition for Treating Heart Failure (XI)

[0057] Astragalus membranaceus 5 parts, Panax ginseng 1 part, Angelica sinensis 5 parts, Ligusticum wallichii 1 part, Salvia miltiorrhiza 4 parts, Prunus persica 1 part, Aurantii Fructus Immaturus 1 part, Honey-fried Licorice Root 5 parts.

[0058] Example 12 Clinical Research

[0059] 1 Research Protocol

[0060] 1.1 Clinical Data

[0061] 1.1.1 Case Source

[0062] Taking HFpEF patients as the research objects, all of whom meet the traditional Chinese medicine syndrome of qi deficiency and blood stasis. The cases of the Department of Cardiology of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from August 2023 to December 2024 were collected. The research was approved by the Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Ethics number: 2023-1345-112).

[0063] 1.2 Diagnostic Criteria

[0064] Western medicine diagnostic criteria: Based on the guidelines of the European Society of Cardiology in 2021, based on typical symptoms (dyspnea, fatigue, peripheral edema), signs (jugular venous distension, pulmonary rales, lower extremity edema), and laboratory and imaging examinations. According to the left ventricular ejection fraction (LVEF), for HFpEF (LVEF≥50%), laboratory tests include natriuretic peptide (NT-proBNP>125 pg / mL), and echocardiography is used to evaluate LVEF, ventricular size, myocardial thickness, and valve function.

[0065] In addition to LVEF≥50% in HFpEF, it is also necessary to meet echocardiography with structural heart disease (such as left ventricular hypertrophy or left atrial (LA) enlargement). The definition of structural heart disease is as follows: LA width (diameter)≥3.8 cm, or LA length≥5.0 cm, or LA area≥20 cm 2 or LA volume≥55 mL, or LA volume index≥29 mL / m 2 .

[0066] Traditional Chinese medicine syndrome criteria: Conform to the "Guiding Principles for Clinical Research of New Chinese Medicines (2002)" edited by Zheng Xiaoyu

[18] in the chapter of heart failure and the "Guidelines for the Diagnosis and Treatment of Traditional Chinese Medicine in Chronic Heart Failure (2022)"

[19] , combined with the previous clinical research results of the research group, the diagnostic criteria for qi deficiency and blood stasis in HFpEF were summarized. Main symptoms: palpitations, shortness of breath, fatigue and weakness in breathing, especially worse with movement, pale complexion and listlessness. Secondary symptoms: cyanosis of the lips and nails, even prominent neck veins, masses under the hypochondrium, purple and dark tongue or ecchymosis, deep, thready, unsmooth or intermittent pulse. If the above symptoms meet ≥2 main symptoms and 1 symptom of each syndrome type accompanied by tongue and pulse manifestations, they are classified into their respective syndrome types. The symptom grading and quantification table is divided into four stages: none (0 points), mild (2 points), moderate (4 points), and severe (6 points). The symptom grading and quantification table was improved in combination with the results of epidemiological investigations.

[0067] 1.3 Inclusion criteria

[0068] 1. Simultaneously meet the western medicine diagnostic criteria and traditional Chinese medicine diagnostic criteria for heart failure with preserved ejection fraction;

[0069] 2. Aged 40 - 80 years old;

[0070] 3. The patient's basic information is complete, able to adhere to taking medicine, and has the conditions for follow-up;

[0071] 4. The purpose of this study needs to be understood by the patient and their family members, and an informed consent form is signed, voluntarily participating in this study.

[0072] 1.4 Exclusion criteria

[0073] 1. Patients with restrictive (infiltrative) cardiomyopathy or congenital heart disease.

[0074] 2. Acute coronary syndrome.

[0075] 3. History of stent implantation, coronary artery bypass grafting, or permanent pacemaker implantation within 90 days before enrollment (calculated from the admission time).

[0076] 4. Estimated glomerular filtration rate (eGFR) ≤ 20 ml / min / 1.73m 2 or severe liver insufficiency.

[0077] 5. Patients with malignant tumors, hematological diseases, or acute infectious diseases.

[0078] 6. Patients with mental diseases or infectious diseases

[0079] If it is found after the start of the trial that the patient's selection violates the inclusion or exclusion criteria, or the compliance is poor: defined as the medication compliance < 80% or > 120%. The patient took prohibited medications specified in the research protocol during the observation period.

[0080] 1.5 Exclusion criteria

[0081] 1. Decided by the researcher to withdraw.

[0082] 2. During the trial, the patient's condition deteriorated, which may lead to dangerous events. The researcher may decide to terminate the clinical trial for the safety of the patient. The patient may receive other treatments, and this case is regarded as invalid.

[0083] 3. Complications, co-morbidities or significant physiological changes occur, making it inappropriate to continue the trial.

[0084] 4. An adverse event or a serious adverse event occurs.

[0085] 5. The patient voluntarily decides to withdraw from the trial.

[0086] 6. The patient withdraws from the clinical trial without any reason.

[0087] 7. The patient does not clearly withdraw but stops taking medicine or being followed up, resulting in loss of contact.

[0088] In all cases, every effort should be made to understand and record the reasons for withdrawal. If the patient believes that the treatment is ineffective, intolerable side effects occur, or they cannot continue due to personal problems, it should be recorded.

[0089] 1.6 Intervention measures

[0090] Both the observation group and the control group should provide guidance on diet and exercise to the patients. Instruct the patients to quit smoking and drinking, control their weight, and ensure a low-salt, low-fat, and light diet. Patients with hypertension or diabetes also need to actively monitor their blood pressure and blood sugar. The patient must receive all appropriate heart failure treatments (when available and tolerable), including SGLT2 inhibitors, diuretics, renin-angiotensin system inhibitors, neprilysin, beta-blockers, and mineralocorticoid receptor antagonists; the doses of these drugs must be stable for at least 1 week before screening until randomization. Observation group: Yiqi Huayu Prescription (Example 1 of the present invention) (twice a day, one bag each time, orally) + basic treatment, continuous medication for 12 weeks.

[0091] 1.7 Main efficacy evaluation indicators

[0092] Evaluate the proportion of subjects with a ≥30% decrease in serum NT-proBNP level compared to the baseline. Serum samples are collected at baseline (week 0) and week 12 respectively to detect the NT-proBNP level. A ≥30% decrease in NT-proBNP level after treatment compared to the baseline is defined as effective, and those who do not reach this threshold are defined as ineffective.

[0093] 1.8 Secondary efficacy evaluation indicators

[0094] 1.8.1 Kansas City Cardiomyopathy Questionnaire (KCCQ)

[0095] The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to evaluate the cardiac function status and quality of life of the patients. This questionnaire covers multiple dimensions such as symptom frequency, symptom stability, physical function, social function, quality of life, and self-efficacy. The total score ranges from 0 to 100 points, and the higher the score, the better the cardiac function status and quality of life of the patients. In this study, the KCCQ score was used as one of the secondary endpoint indicators and was evaluated at week 0 and week 12 respectively to quantify the improvement in the cardiac function and quality of life of the patients.

[0096] 1.8.2 NYHA (New York Heart Association Functional Classification) Cardiac Function Classification

[0097] The New York Heart Association (NYHA) functional classification was used to evaluate the cardiac function status of the patients. The NYHA classification divides cardiac function into four grades: Grade I (no limitation in daily activities, and ordinary physical activities do not cause symptoms), Grade II (mild limitation in physical activities, no symptoms at rest, but ordinary physical activities can cause fatigue, palpitations or dyspnea), Grade III (obvious limitation in physical activities, no symptoms at rest, but mild activities can cause symptoms), and Grade IV (any physical activity will cause discomfort, and symptoms can also occur at rest). The higher the grade, the more severe the cardiac function impairment. Evaluations were conducted at week 0 and week 12 respectively to quantify the improvement in the cardiac function of the patients.

[0098] 1.8.3 6-Minute Walk Test (6MWT)

[0099] The 6MWT was used to evaluate the exercise endurance and functional status of the patients. The subjects walked in a 50-meter corridor in the Department of Cardiology at their maximum tolerated speed for 6 minutes, and their walking distance was recorded. The longer the walking distance, the better the exercise endurance and cardiac function status of the patients. Evaluations were conducted at week 0 and week 12 respectively to quantify the improvement in the exercise endurance and functional status of the patients.

[0100] 1.8.4 Doppler Echocardiogram

[0101] Doppler Echocardiography was used to evaluate the cardiac structure and functional status of the patients. All echocardiography examinations were performed and interpreted by professional echocardiography physicians with the title of deputy chief physician or above to ensure the accuracy and reliability of the data. The detection indexes included left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left atrial diameter (LAD), left atrial volume index (LAVI), mitral valve blood flow spectrum (E / A ratio), and the ratio of early mitral valve blood flow velocity to early diastolic velocity of the mitral annulus (E / e'). The above indexes were used to comprehensively evaluate the cardiac systolic function, diastolic function and cardiac remodeling of the patients, among which E / e' and LAVI were important indexes for evaluating left ventricular diastolic function and left atrial load. Evaluations were performed at week 0 and week 12 respectively to evaluate the improvement of the basic cardiac structure and function of the patients.

[0102] 1.8.5 Laboratory indexes

[0103] Laboratory index detection included serum soluble growth stimulation expressed gene 2 protein (sST2), glycated hemoglobin (HbA1c), and low-density lipoprotein cholesterol (LDL-C). Venous blood samples were collected from all subjects in a fasting state to ensure the accuracy and comparability of the test results. sST2 was used to evaluate the prognosis of myocardial fibrosis and heart failure; HbA1c reflected the long-term blood glucose control of the patients; LDL-C was used to evaluate the lipid metabolism status. Evaluations were performed at week 0 and week 12 respectively.

[0104] 1.8.6 Traditional Chinese medicine syndrome score

[0105] According to the case inclusion situation, the symptoms and signs of the patients were recorded in detail, filled in the traditional Chinese medicine syndrome scoring form truthfully, and the symptom scores before and after treatment were statistically calculated respectively. Evaluations were performed at weeks 0, 6, and 12 respectively.

[0106] 1.8.7 Safety indexes

[0107] Safety indexes included the incidence rates related to adverse events and serious adverse events, vital signs (blood pressure, heart rate, respiratory rate, body temperature), laboratory safety indexes (blood routine, liver function AST / ALT, renal function: creatinine), and electrocardiogram (ECG) examination results. All subjects were closely monitored for the above indexes during the study period to evaluate the safety of the treatment. Vital signs and laboratory indexes were evaluated at week 0 and week 12, and electrocardiograms were examined at baseline and at the end of the study.

[0108] 1.9 Statistical methods

[0109] IBM SPSS Statistics 25.0 was used for the statistical analysis of clinical and demographic data. Measurement data were subjected to normality test and homogeneity of variance test. Data with normal distribution were expressed as mean ± standard deviation, and data with non-normal distribution were expressed as interquartile range. One-way ANOVA was used for between-group comparison, and Shapiro-Wilk test was used for non-normal distribution. Paired t-test was used for within-group comparison of data with normal distribution, and Wilcoxon signed-rank test was used for non-normal distribution. Independent sample t-test was used for comparison before and after treatment, and P < 0.05 was considered statistically significant.

[0110] 2 Research results

[0111] 2.1 General conditions of the two groups of subjects completed

[0112] In this study, 122 patients were evaluated for eligibility. After screening, 32 patients were excluded. Ninety eligible subjects were randomly divided into the observation group (n = 45) of Yiqi Huayu Decoction (Example 1 of the present invention) and the western medicine control group (n = 45) using SPSS software by the random number method. During the study, in the observation group, a total of 42 patients completed the follow-up, but 3 patients dropped out during the treatment. The specific reasons are as follows: 1 subject dropped out due to boredom with the follow-up. 1 patient reported skin itching and maculopapular rash, and another patient withdrew from this study due to cough and epistaxis discomfort symptoms. At the same time, 41 cases of follow-up were completed in the control group, and 4 subjects dropped out during the treatment. Among them, 3 patients withdrew from this study due to gastrointestinal symptoms such as nausea and vomiting, and 1 patient withdrew from this study due to poor control of atrial fibrillation and undergoing radiofrequency ablation. Finally, a total of 83 eligible cases were obtained in this study. During the follow-up period, the dropout rate in the observation group was 6.7%, and the dropout rate in the control group was 8.9%.

[0113] 2.2 Comparison of general clinical data of the two groups of subjects

[0114] There were no significant differences in the demographic characteristics and clinical manifestations between the two groups statistically. The average age of the observation group was 70.29 ± 5.83 years old, the proportion of females was 53.7%, and the level of BMI was: 26.12 ± 3.52. Relatively speaking, the average age of the control group was 69.9 ± 6.39 years old, the proportion of females was 53.66%, and the BMI level was: 26.12 ± 3.52. The underlying diseases of the two groups of subjects all included hypertension, diabetes, coronary heart disease, atrial fibrillation and other diseases, and there was no significant difference in the proportion of the number of people. In terms of concomitant medications, there was no significant difference in the proportion of the number of people using angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors, β-blockers, and diuretics between the two groups (P > 0.05). (Table 1-1).

[0115] Table 1-1 Baseline comparison of general clinical data of the two groups of subjects (Mean±s)

[0116]

[0117] 2.3 Serum NT-proBNP

[0118] There was no difference in the levels of NT-proBNP between the two groups of subjects before treatment. Compared with the control group, the decrease in NT-proBNP was more significant in the observation group (P < 0.01). The effective rate (88.1%) of the improvement in the decrease rate of NT-proBNP ≥ 30% in the observation group was higher than that in the control group (68.29%), and there was a statistical difference (P = 0.026). See Tables (1-2, 1-3).

[0119] Table 1-2 Levels of serum NT-proBNP before and after treatment (Mean±s)

[0120]

[0121] Table 1-3 Number and proportion of people with a decrease rate of serum NT-proBNP ≥ 30% before and after treatment n(%)

[0122]

[0123] 2.4 KCCQ scoring scale

[0124] Compared with the control group, taking the Yiqi Huayu formula (Example 1 of the present invention) for 12 weeks can effectively improve the symptom burden of HFpEF patients, improve the quality of life of patients, and can effectively increase the total score of the KCCQ myocardial scoring scale (P < 0.01), see Figure 1 , Table 1-4.

[0125] Table 1-4 Levels of the total KCCQ scores of the two groups before and after treatment (Mean±s)

[0126]

[0127] 2.5 NYHA cardiac function classification

[0128] There was no significant difference in the proportion of NYHA classification between the two groups before treatment, P = 0.70. After 12 weeks of combined treatment with the Yiqi Huayu formula (Example 1 of the present invention) and standard treatment, in the cardiac function classification, the proportion of the observation group (47.6%) in grade I cardiac function was significantly increased compared with that of the control group (17.1%), and the difference was statistically significant, P = 0.012. See Table 1-5.

[0129] Table 1-5 Levels of NYHA cardiac function classification of the two groups of subjects before and after treatment n(%)

[0130]

[0131] 2.66MWT and Grading

[0132] There was no significant difference in the 6MWT between the two groups before treatment, P = 0.37. After 12 weeks of treatment with the Yiqi Huayu formula (Example 1 of the present invention) combined with standard treatment, the exercise tolerance of the subjects was significantly improved compared with the control group, and the difference was statistically significant, P = 0.01. See Table 1-6.

[0133] Table 1-6 Levels of 6MWT in the two groups of subjects before and after treatment (Mean±s)

[0134]

[0135] 2.7 Doppler Echocardiogram

[0136] There was no significant difference in the echocardiogram between the two groups of subjects before treatment. After 12 weeks of treatment with the Yiqi Huayu formula (Example 1 of the present invention) combined with standard treatment, there was no significant difference in improving LVEF and reducing the LA diameter between the observation group and the control group (P>0.05), and there was no significant change in the two groups compared with before treatment. However, it could effectively reduce LAVI and E / e' compared with the control group (P<0.05). See Tables 1-7, 1-8, 1-9, and 1-10.

[0137] Table 1-7 Levels of LVEF in the two groups of subjects before and after treatment % (Mean±s)

[0138]

[0139] Table 1-8 Levels of LA diameter in the two groups of subjects before and after treatment mm (Mean±s)

[0140]

[0141] Table 1-9 Levels of LAVI in the two groups of subjects before and after treatment (Mean±s)

[0142]

[0143] Table 1-10 Levels of E / e′ in the two groups of subjects before and after treatment (Mean±s)

[0144]

[0145] 2.8 Laboratory Indexes

[0146] After 12 weeks of treatment with the Yiqi Huayu formula (Example 1 of the present invention) combined with standard treatment, there were significant differences in improving ST2 and Cr between the observation group and the control group (P<0.05).

[0147] Table 1-11 Levels of laboratory indexes in the two groups of subjects before and after treatment (Mean±s)

[0148]

[0149] Note: When comparing between the two groups after treatment, * P < 0.05; when comparing the treatment group before and after treatment, # P < 0.05; when comparing the control group before and after, & P < 0.05.

[0150] 2.9 TCM syndrome score

[0151] There was no significant difference in the TCM syndrome scores and total scores of the two groups of subjects before treatment. After 12 weeks of combined treatment with the Yiqi Huayu formula (Example 1 of the present invention) and standard treatment, compared with the control group, there were significant differences in improving chest tightness, shortness of breath, palpitations, and fatigue and weakness in the observation group (P < 0.01).

[0152] Table 1-12 Levels of TCM syndrome scores of two groups of subjects before and after treatment M(P25, P75)

[0153]

[0154] Note: When comparing between the two groups after treatment, * P < 0.05; when comparing the treatment group before and after treatment, # P < 0.05; when comparing the control group before and after, & P < 0.05.

[0155] 2.10 Safety indicators

[0156] The safety evaluation indicators of the two groups of patients were examined at the time of enrollment and the 12th week: alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatine kinase, etc. No adverse reactions such as muscle soreness and urinary tract infection occurred in all patients who completed the follow-up in this study.

[0157] Example 13 Basic experiment

[0158] 1 Experimental method

[0159] 1.1 Experimental modeling and grouping

[0160] Ninety C57BL / 6N mice were adaptively fed under standard rodent feed and sterile water conditions for 1 week, and then were randomly divided into a blank group (15 mice) and an HFpEF model group (75 mice) by the completely randomized method. The HFpEF model was established by a 10-week intervention with a high-fat diet (60% of energy from fat, fresh feed was replaced every 3 days) combined with sterile water containing Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME, 0.5 g / L) (replaced once every 3 days, and the L-NAME solution was stored in the dark). After 10 weeks, echocardiography (specific equipment model) was used to detect the cardiac function of the mice. If E / A < 1.5 or E / A > 2, and E / e’ > 30

[20] , it was determined that the HFpEF model was successfully established. The 75 mice with successful modeling were randomly divided into a model group (gavage with sterile water), a low-dose group of Yiqi Huayu formula (1.95 g / kg / d), a middle-dose group (3.90 g / kg / d), a high-dose group (7.8 g / kg / d, which were equivalent to 0.5, 1, and 2 times the clinical dose according to body surface area conversion), and an empagliflozin group (1.89 mg / kg / d, calculated according to the active ingredient of the drug), with 15 mice in each group.

[0161] 1.2 Specimen collection

[0162] Four weeks after administration, echocardiography was used to detect the cardiac function of the mice to evaluate the drug efficacy. Since no significant changes were observed, the gavage administration was continued for another 2 weeks and then detected again. The second detection results showed that significant differences appeared in the echocardiogram parameters of E / A ratio and E / e' ratio among the mice in each group. Subsequently, the mice were fasted but given water (without L-NAME) for 12 hours, and their body weights were weighed and recorded before blood collection. Blood was collected by the method of removing the eyeball and placed in a 1.5 ml EDTA anticoagulation tube. After standing at room temperature for 2 hours, the plasma was separated by centrifugation at 3000 rpm for 15 minutes. After the plasma was aliquoted, it was quickly frozen in liquid nitrogen and stored in a -80°C refrigerator for later use. The chest and abdomen were opened, the heart was taken out and weighed. The hearts of 5 randomly selected mice in each group were washed with PBS and then fixed in 4% paraformaldehyde fixative for 24 hours. The remaining 10 mice in each group were quickly frozen in liquid nitrogen and stored in a -80°C refrigerator for later use. The lungs were taken out and weighed for wet weight, and then placed in a 12-well plate and put into an oven at 37°C until dried to a constant weight, and then the dry weight was weighed and the wet-to-dry weight ratio of the lungs was calculated. The bilateral lower limbs of the mice were taken, the skin and muscle were stripped in turn, and the tibia was separated after removing the joints. The tibia length was recorded for the calculation of the heart mass index.

[0163] 1.3 Plasma NT-proBNP level in mice

[0164] Take out the required strip. The experimental design follows the requirements in the instruction manual with standard wells, zero wells, blank wells, and sample wells: Add 50 μL of NT-proBNP standards with gradient concentrations (1200, 600, 300, 150, 75, 37.5 pg / mL) to the standard wells, add 50 μL of the sample diluent to the zero wells, and the blank wells are without adding any reagents; the total volume of the sample wells is 50 μL, which is 10 μL of the sample to be tested and 40 μL of the sample diluent. Except for the blank wells, 100 μL of the HRP-labeled detection antibody needs to be added to the remaining wells. After sealing the plate, incubate in the dark at 37 °C for one hour. After the incubation ends, discard the liquid in each well one by one, pat dry on the absorbent paper, fill each measurement well with the washing solution in sequence, discard it after standing for 20 seconds, and repeat the washing 5 times. After the washing is completed, the strip should be patted dry thoroughly. Subsequently, add 100 μL of the freshly prepared substrate mixture (substrate A and substrate B are mixed at a volume ratio of 1:1) to each well again. After sealing the plate, continue to incubate in the dark at 37 °C for 15 min. Then add 50 μL of the termination solution to each well, adjust the microplate reader to measure the absorbance (OD value) of each well at a wavelength of 450 nm in sequence, draw the standard curve, and calculate the concentration of NT-proBNP in the sample.

[0165] 1.4 Cardiac Doppler ultrasound

[0166] After successful modeling, anesthesia: Use 1.5%-2% isoflurane inhalation anesthesia to ensure that the heart rate of the mice is maintained at 400-500 beats per minute. Use a high-resolution small animal ultrasound device equipped with an MX400 high-frequency probe. Position: Fix the mice in the supine position on the heating plate to maintain the body temperature at 37 °C. Shave the chest hair and apply ultrasonic coupling agent. Place the probe at 135 degrees to the horizontal line beside the left sternum of the mice to obtain the long-axis view of the left ventricle. Directly measure the ejection fraction of two consecutive cardiac cycles on the echocardiograph, measure each mouse 3 times, and take the average value. Switch to the pulsed Doppler mode, adjust the sampling frame and the blood flow direction to the mitral valve part to obtain the mitral valve blood flow. The early filling peak (E peak) and the late filling peak (A peak) will be displayed on the screen. Take screenshots for at least three consecutive measurements, take the average value, and use it for calculating the E / A ratio later. Switch to the tissue Doppler mode, adjust the sampling frame to the mitral annulus, record the early diastolic velocity (e') of the mitral annulus, and calculate the E / e' ratio.

[0167] 1.5 HE and Mosson staining of the cardiac long-axis section

[0168] Mouse heart tissues were collected, washed with PBS, fixed in 4% paraformaldehyde at room temperature for 24 hours, dehydrated with gradient ethanol, embedded in paraffin, soaked in an ice-water mixture, and cut into wax sections with a thickness of (5 μm). HE staining: After dewaxing, hydration was performed, hematoxylin was selected for staining for 8 minutes, differentiated with hydrochloric acid ethanol, followed by eosin staining for 2 minutes, dehydration again, and coverslipping. Masson staining: Dewaxing and hydration were the same as in HE staining, stained with Weigert iron hematoxylin for 8 minutes, stained with ponceau acid fuchsin solution for 5 minutes, differentiated with phosphomolybdic acid for 5 minutes, stained with aniline blue for 5 minutes, dehydrated, and coverslipped. HE staining showed cell nuclei (blue) and cytoplasm (pink), and Masson staining showed collagen fibers (blue) and muscle fibers (red), which were used to evaluate myocardial morphology and fibrosis degree.

[0169] 1.6 Exercise fatigue test

[0170] The mice were placed on a small animal treadmill, with the initial speed set at 10 - 15 m / min, increasing by 5 m / min every 2 minutes until the mice could no longer run, and could not recover even with electric shock. The exhaustion time and running distance of the mice were recorded to evaluate their exercise endurance. The mice were allowed to adapt to the treadmill for 1 - 2 days before the experiment, 10 - 15 minutes each time, to reduce stress.

[0171] 1.7 Glucose tolerance test

[0172] The mice were fasted for 12 hours (water not restricted) before the experiment, the tail was clipped to measure the basal blood glucose (0 minute), and then a 20% glucose solution was orally administered at a dose of 2 g / kg body weight. The tail tip blood glucose levels of the mice were measured at 30, 60, 90, and 120 minutes after glucose administration, and the blood glucose values at each time point were recorded for subsequent plotting of the blood glucose-time curve. The evaluation of glucose tolerance was related to the area under the curve (AUC).

[0173] 1.8 Statistical analysis

[0174] GraphPad Prism (Version 10.1.2) was used for statistical analysis and plotting in this study. All data were expressed as mean ± standard deviation, and one-way analysis of variance (ANOVA) was used for comparison among multiple groups. The statistical significance level was set at P < 0.05.

[0175] 2 Experimental results

[0176] 2.1 Animal functional phenotype data are shown in Figure 2

[0177] Compared with the Normal group, the HW / TL, LW / BW, WT / DL, and plasma NT-proBNP levels of the mice in the Model group were significantly increased, and the differences were statistically significant (p < 0.001). Compared with the Model group, the HW / TL, LW / BW, WT / DL, and plasma NT-proBNP levels of each dose group of the Yiqi Huayu formula and the positive drug group decreased to varying degrees, but were still higher than those of the Normal group, and the differences were statistically significant (p <

[0178] 0.01), and the YQHY-M group had the best effect.

[0179] 2.2 Doppler echocardiogram

[0180] Compared with the Normal group, the LVEF (%) and LVFS (%) of the mice in the Model group decreased, while E / A and E / e’

[0181] increased significantly, and the differences were statistically significant (p < 0.001). Although the LVEF of the mice in the Model group decreased, it was still > 50%. Combined with other relevant indicators, it was suggested that the Model mice had left ventricular diastolic dysfunction. Compared with the Model group, the cardiac function of each dose group of the Yiqi Huayu formula and the positive drug group increased significantly, but was still lower than that of the Normal group, manifested as an increase in LVEF (%) and LVFS (%) and a decrease in E / A and E / e’, and the differences were statistically significant (p < 0.01). Among them, the YQHY-M group had the best effect on improving E / A and E / e’. See Figure 3 , Table 2-1.

[0182] Table 2-1 Comparison of Doppler ultrasound data of each group (Mean ± s)

[0183]

[0184] Note: Compared with the normal group, *P < 0.05, **P < 0.01; compared with the model group, #P < 0.05, ##P < 0.01.

[0185] 3.3 HE and Mosson staining of the long axis section of the heart

[0186] HE staining results showed that the myocardial fibers in the Normal group were arranged neatly, the nuclear morphology was regular, the cross striations were clear, and the interstitial structure was normal; the disordered arrangement of myocardial fibers was more significant in the Model group, the nuclei were irregular, inflammatory cell infiltration and myocardial cell necrosis were visible in local areas, and the cross striations were blurred; while in the drug intervention groups with different doses of Yiqi Huayu formula, the arrangement of myocardial fibers was significantly improved compared with the Model group, the nuclear morphology tended to be regular, the inflammatory cell infiltration decreased, the necrotic area of myocardial cells shrank, and the cross striation structure was partially restored. The empagliflozin drug group was closer to the normal group. Masson staining results showed that the myocardial fibers in the Normal group still showed red, and no collagen fibers (blue) were seen in the interstitium, without obvious fibrosis; a large amount of blue collagen fiber deposition could be found in the Model group, the myocardial fibers were arranged disorderly, and interstitial fibrosis was significant; in the drug intervention groups with different doses of Yiqi Huayu formula, the collagen fiber deposition was significantly reduced compared with the Model group, the myocardial fibers were arranged more orderly, and the degree of interstitial fibrosis was alleviated. These results indicate that different doses of Yiqi Huayu formula can effectively improve the myocardial structural damage and fibrosis degree of HFpEF, and have a certain therapeutic effect. (See Figure 4 )。

[0187] 2.4 Exercise fatigue test

[0188] The exhaustion time of the mice in the Normal group during treadmill exercise was longer, and the exercise endurance was better, manifested as the continuous exercise distance being significantly higher than that in the Model group; the exercise distance of the mice in the Model group decreased significantly, suggesting that the decrease in exercise ability might be caused by impaired cardiac function; while the exercise endurance of the mice in the drug intervention groups with different doses of Yiqi Huayu formula was significantly prolonged compared with the model group (see Figure 5 )。

[0189] 2.5 Glucose tolerance test

[0190] The glucose metabolism ability of the mice in each group was evaluated by the oral glucose tolerance test (OGTT). See Figure 6 , and the results showed that the blood glucose of the mice in the Normal group increased rapidly and gradually recovered after oral glucose, and the AUC-OGTT value was lower, indicating normal glucose metabolism ability; the blood glucose of the mice in the Model group increased significantly and recovered slowly, and the AUC-OGTT value was significantly higher than that of the blank group, suggesting abnormal glucose tolerance; the increase amplitude of the blood glucose of the mice in the drug intervention groups with different doses of Yiqi Huayu formula was significantly lower than that in the Model group, the recovery speed was accelerated, and the AUC-OGTT value was significantly decreased, indicating that the intervention of Yiqi Huayu formula can effectively improve the glucose metabolism ability and relieve abnormal glucose tolerance.

[0191] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the method of the present invention, several improvements and supplements can still be made, and these improvements and supplements should also be regarded as the protection scope of the present invention.

Claims

1. A traditional Chinese medicine composition for treating heart failure, characterized in that, The traditional Chinese medicine composition is prepared from the following raw medicinal materials in parts by weight: 1-7 parts of Astragalus membranaceus, 1-5 parts of Panax ginseng, 1-5 parts of Angelica sinensis, 1-5 parts of Ligusticum chuanxiong, 1-6 parts of Salvia miltiorrhiza, 1-5 parts of Prunus persica, 1-5 parts of Aurantii Fructus Immaturus, 1-5 parts of Radix Glycyrrhizae Preparata.

2. The traditional Chinese medicine composition according to claim 1, wherein The traditional Chinese medicine composition is prepared from the following raw medicinal materials in parts by weight: 1-5 parts of Astragalus membranaceus, 1-3 parts of Panax ginseng, 1-3 parts of Angelica sinensis, 1-3 parts of Ligusticum chuanxiong, 1-4 parts of Salvia miltiorrhiza, 1-3 parts of Prunus persica, 1-3 parts of Aurantii Fructus Immaturus, 1-3 parts of Radix Glycyrrhizae Preparata.

3. The traditional Chinese medicine composition according to claim 1, wherein The traditional Chinese medicine composition is prepared from the following raw medicinal materials in parts by weight: 3 parts of Astragalus membranaceus, 1 part of Panax ginseng, 1 part of Angelica sinensis, 1 part of Ligusticum chuanxiong, 2 parts of Salvia miltiorrhiza, 1 part of Prunus persica, 1 part of Aurantii Fructus Immaturus, 1 part of Radix Glycyrrhizae Preparata.

4. Use of the traditional Chinese medicine composition according to any one of claims 1-3 in the preparation of a drug for treating heart failure.

5. The application according to claim 4, characterized in that The heart failure is heart failure caused by qi deficiency and blood stasis.

6. The application according to claim 5, characterized in that, The cardiac function of the heart failure is grade II-III.

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