A Chinese medicine composition for treating chronic heart failure, and its preparation method and application

Abstract

The present invention discloses a Chinese medicine composition for treating chronic heart failure, and its preparation method and application. The Chinese medicine composition comprises the following raw materials: 9-50 parts of raw astragalus, 1-5 parts of cinnamon, 5-30 parts of ginseng, 5-30 parts of prepared rehmannia, 5-30 parts of angelica, 1-20 parts of notoginseng, 3-15 parts of processed aconite, 5-30 parts of tuckahoe, 5-30 parts of atractylodes macrocephala, and 5-20 parts of liquorice. The present invention also discloses a preparation method of the above-mentioned Chinese medicine composition and its application in the preparation of a drug for treating chronic heart failure. The Chinese medicine composition of the present invention can effectively improve the clinical symptoms of patients with chronic heart failure, has no obvious adverse effects, and is clinically safe and effective.

Description

Technical Field

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

[0002] Chronic heart failure (CHF, referred to as chronic heart failure or heart failure) belongs to the category of "asthma", "edema", "palpitations", "heart water" and so on in traditional Chinese medicine. Looking at the medical practitioners of all dynasties, the understanding of the etiology and pathogenesis of CHF is basically consistent, that is, this disease is a syndrome of deficiency of the root and excess of the symptoms. The deficiency of the root is mainly qi and yang deficiency, but also yin deficiency, and the excess of the symptoms is mainly blood stasis and water retention, but also phlegm obstruction. In the early stage, it is mostly deficiency syndrome, and in the late stage, it manifests as a mixture of deficiency and excess due to the production of pathological products. Deficiency of heart qi is the pathological basis, blood stasis is the central link, and phlegm and dampness are the main pathological products. The disease site mainly involves the heart, spleen and kidney, with the heart and kidney as the main ones. Regarding the treatment principles of CHF, the treatment principles summarized by various doctors mainly include: (1) Qi-invigorating and blood-activating method: It is the most commonly used treatment method for CHF. The Qi-invigorating method and the blood-activating method have a synergistic effect. The Qi-invigorating method can enhance myocardial contractility and cardiac pump function; the blood-activating method can improve blood rheology, thereby reducing preload. The two methods can be used together to synergistically improve cardiac function. (2) The method of warming yang, purging the lungs and expelling water: This is a method of treating the symptoms in an emergency. Among them, Trichosanthes kirilowii, Morus alba bark, and Stephania tetrandra are the most commonly used drugs. Most of these drugs have strong efficacy and are often used in combination with other treatments, and are rarely used alone. At the same time, in the prior art, drugs for the treatment of heart failure are mostly formulated according to the above-mentioned treatment principles, and satisfactory clinical results have been achieved. However, the treatment of heart failure should not be limited to traditional etiology and pathogenesis, but also requires breakthroughs to better play the important role of traditional Chinese medicine in the treatment of chronic heart failure. Summary of the invention

[0003] In view of the above technical problems, an object of the present invention is to provide a new Chinese medicine composition, which takes tonifying the kidney and promoting yang, promoting blood circulation and promoting diuresis as the treatment principles, and emphasizes the treatment of heart failure with both the heart and the kidney.

[0004] Another object of the present invention is to provide a method for preparing the above-mentioned Chinese medicine composition.

[0005] Another object of the present invention is to provide a Chinese medicine preparation made using the above-mentioned Chinese medicine composition.

[0006] Another object of the present invention is to provide the use of the above-mentioned Chinese medicine composition and Chinese medicine preparation in the preparation of drugs for treating chronic heart failure.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a traditional Chinese medicine composition for treating chronic heart failure. The raw materials of the traditional Chinese medicine composition include, by weight: 9-50 parts of raw astragalus, 1-5 parts of cinnamon, 5-30 parts of ginseng, 5-30 parts of prepared rehmannia, 5-30 parts of angelica, 1-20 parts of Panax notoginseng, 3-15 parts of processed aconite, 5-30 parts of Poria, 5-30 parts of Atractylodes, and 5-20 parts of licorice.

[0009] The inventor team has rich clinical experience in treating chronic heart failure. They believe that heart failure is mostly based on heart and kidney yang deficiency, blood stasis and yang depression as the key pathogenesis, and water vapor overflow as the final result, which is a syndrome of deficiency in the root and excess in the superficial. Based on this, the treatment principle of tonifying the kidney and promoting yang, promoting blood circulation and promoting water excretion is proposed, emphasizing the academic idea of ​​treating heart failure with both heart and kidney. Therefore, after years of continuous adjustment and optimization of the prescription, and after verification by clinical trials, the above-mentioned Chinese medicine formula was finally determined, and the clinical efficacy is satisfactory.

[0010] In the prescription of the present invention, raw astragalus, cinnamon and ginseng are the main drugs. Raw astragalus is sweet in taste and slightly warm in nature, and has the functions of invigorating qi, tonifying kidney and promoting diuresis; cinnamon is pungent and sweet in taste and hot in nature, and has the functions of invigorating fire and strengthening yang, and guiding fire back to the origin. When combined with astragalus, it can warm the yang of the heart and kidney, transform qi and promote diuresis; ginseng is sweet in taste and warm in nature, and returns to the spleen, lung meridian and heart meridian, greatly invigorates the vital energy, restores the pulse and consolidates the body, and when combined with astragalus, strengthens the function of invigorating qi. The three are used together as the main drugs, which can help the heart yang to open the meridians, transport the kidney yang to benefit the fire, and help the spleen and earth to strengthen the transportation, so as to replenish the yang of the whole body.

[0011] Rehmannia root, Chinese angelica root and Panax notoginseng are assistant drugs. Rehmannia root nourishes kidney yin, which means "seeking yang in yin". At the same time, it can prevent yang-tonifying drugs such as ginseng and cinnamon from damaging yin and causing dryness. Chinese angelica root and Panax notoginseng promote blood circulation and nourish blood. When used together with ginseng and cinnamon, they can increase their power of circulation, so that they can nourish without obstruction, thereby promoting yang and activating blood circulation.

[0012] Processed aconite, Poria cocos and Atractylodes macrocephala are adjuvants. Processed aconite tastes pungent and sweet, and is very hot in nature. It enters the heart, kidney and spleen meridians. It can help heart yang to dredge the meridians, replenish kidney yang to benefit fire, and strengthen the function of the main medicine in warming and nourishing the heart and kidney yang. Poria cocos and Atractylodes macrocephala can strengthen the spleen and eliminate dampness, and combined with cinnamon, they can enhance the function of warming yang, promoting diuresis and reducing swelling.

[0013] Licorice is a guiding drug, which mainly replenishes Qi, tonifies the middle and harmonizes to reach the site of disease.

[0014] The whole prescription is refined and ingenious, and the medicines are combined, taking into account both deficiency and excess, nourishing the heart and kidney, warming and unblocking, warming yang without the risk of pungent dryness, activating blood circulation without the disadvantage of bleeding, nourishing the five internal organs and filling the heart. The whole prescription adopts the meaning of Shenfu Decoction, Sijunzi Decoction, Renshen Guipi Decoction, Baoyuan Decoction, Lingguishugan Decoction, etc., starting from "treating the heart and kidney together", and playing the role of nourishing the kidney and unblocking yang, strengthening the heart and promoting water, and is used to treat patients with heart and kidney yang deficiency, blood stasis and water retention type heart failure, with reliable clinical efficacy and good safety.

[0015] Exemplarily, the Chinese medicine composition for treating chronic heart failure, in terms of weight parts, includes the following raw medicines: 25 parts of raw astragalus, 5 parts of cinnamon, 9 parts of ginseng, 10 parts of prepared rehmannia, 10 parts of angelica, 2 parts of Panax notoginseng, 6 parts of processed aconite, 10 parts of Poria, 10 parts of Atractylodes, and 6 parts of licorice.

[0016] Exemplarily, the Chinese medicine composition for treating chronic heart failure, in terms of weight parts, includes the following raw medicines: 30 parts of raw astragalus, 3 parts of cinnamon, 9 parts of ginseng, 10 parts of prepared rehmannia, 6 parts of angelica, 3 parts of Panax notoginseng, 6 parts of processed aconite, 10 parts of Poria, 10 parts of Atractylodes, and 6 parts of licorice.

[0017] Exemplarily, the Chinese medicine composition for treating chronic heart failure, in terms of weight parts, includes the following raw materials: 20 parts of raw astragalus, 5 parts of cinnamon, 6 parts of ginseng, 15 parts of prepared rehmannia, 12 parts of angelica, 2 parts of Panax notoginseng, 9 parts of processed aconite, 15 parts of Poria, 15 parts of Atractylodes, and 6 parts of licorice.

[0018] The basic formula of each raw material medicine of the above-mentioned Chinese medicine composition of the present invention can be adjusted according to clinical symptoms on the basis of the above-mentioned Chinese medicine composition in a specific embodiment to achieve the purpose of treating chronic heart failure and improving certain special clinical symptoms, further enhance the adaptability of the composition of the present invention, and improve the therapeutic effect. These adjustments made based on the basic formula of the present invention are also within the protection scope of this application.

[0019] For example, for patients with obvious spleen and kidney yang deficiency, add dried ginger to warm the middle and dispel cold, warm the lungs and transform phlegm. The recommended dosage of dried ginger is 5-15 servings.

[0020] For example, for those with obvious water retention, add large belly peel to enhance the effect of promoting diuresis and reducing swelling. The recommended dosage of large belly peel is 5-15 servings.

[0021] For example, for patients with obvious chest tightness caused by insufficient heart yang, Xiebai can be added to promote yang and disperse nodules. The recommended dosage of Xiebai is 5-15 servings.

[0022] In a second aspect, the present invention provides a method for preparing a Chinese medicine composition for treating chronic heart failure, the preparation method comprising the following steps:

[0023] Take raw astragalus, cinnamon bark, ginseng, cooked rehmannia root, angelica root, processed aconite root, poria, atractylodes macrocephala, and liquorice according to the formula, add water and boil twice, filter, and combine the filtrate; optionally, add dried ginger, or add dried tangerine peel, or add trichosanthes root and Allium macrostemon;

[0024] The filtrate is concentrated into a clear paste, and dried to obtain a dry paste powder;

[0025] Mix dry paste powder and Panax notoginseng powder and you will get it.

[0026] In a third aspect, the present invention provides a traditional Chinese medicine preparation for treating chronic heart failure, which comprises the above-mentioned traditional Chinese medicine composition.

[0027] According to actual needs, the Chinese medicine preparation may also include pharmaceutically acceptable excipients. According to conventional preparation processes, various preparations such as decoctions, granules, pills, capsules, tablets, powders, oral liquids and the like may be prepared.

[0028] The present invention also provides the use of the above-mentioned Chinese medicine composition or the above-mentioned Chinese medicine preparation in preparing medicine for treating chronic heart failure.

[0029] In addition, unless otherwise specified, the raw materials of the Chinese medicine composition of the present invention can be obtained commercially, and any range recorded in the present invention, including the end values ​​and any numerical value between the end values, and any sub-range of the Chinese medicine composition composed of the end values ​​or any numerical value between the end values, can achieve the purpose of treating chronic heart failure.

[0030] The beneficial effects of the present invention are as follows:

[0031] Clinical research results show that the Chinese medicine composition of the present invention can significantly improve the clinical symptoms of patients with chronic heart failure, significantly reduce the TCM syndrome score of patients with heart and kidney yang deficiency and blood stasis and water retention type heart failure; improve cardiac function, reduce NYHA heart failure classification, Lee's heart failure score, BNP level, prolong 6-minute walking distance, and increase cardiac ultrasound EF% and FS% values. During the study, no serious adverse events occurred in the Chinese medicine composition of the present invention, and it is clinically safe and effective. There is no obvious effect on blood pressure, blood routine, liver and kidney function, blood electrolytes, urine and stool routine, etc., and the safety is good.

[0032] In addition, basic research shows that the Chinese medicine composition of the present invention can improve the EF value of rats with heart failure, reduce the level of NT-proBNP, upregulate the expression of SERCA2a and NCX1.1 in damaged myocardial tissue, downregulate the expression of RyR2, CaMKII, and PKA, and regulate the calcium homeostasis of damaged myocardial cells. It also reduces ventricular tachycardia and ventricular fibrillation induced by intraperitoneal injection of isoproterenol in rats with heart failure, and inhibits the occurrence of malignant arrhythmias in heart failure.

[0033] In summary, the Chinese medicine composition of the present invention is safe and effective for treating chronic heart failure, improving the symptoms of heart failure patients, improving the quality of life, and has good safety. A series of basic studies have been conducted to prove the mechanism of action of the prescription. It is also found that the prescription has the effect of reducing the occurrence of malignant arrhythmias in heart failure and reducing the risk of sudden death, which is also the advantage of the Chinese medicine composition of the present invention.

[0034] Therefore, the Chinese medicine composition of the present invention has great value for promotion and application in the field of treating heart failure. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Echocardiography of rats in each group;

[0036] Figure 2 Expression of calcium transporter in myocardial tissue of each group;

[0037] Figure 3 The occurrence of arrhythmia in rats in each group;

[0038] Figure 4 Action potential of myocardial cells of rats in each group (A Action potential of myocardial cells of rats in each group B Triggering activity recorded in the model group);

[0039] Figure 5 Changes of action potential-related parameters of myocardial cells in each group of rats. DETAILED DESCRIPTION

[0040] In order to explain the present invention more clearly, the present invention is further described below in conjunction with preferred embodiments. It should be understood by those skilled in the art that the following specific description is illustrative rather than restrictive, and should not be used to limit the scope of protection of the present invention.

[0041] Example 1 A Chinese medicine composition for treating chronic heart failure

[0042] Raw material drug formula: 30g raw astragalus, 3g cinnamon, 9g ginseng, 10g cooked rehmannia, 6g angelica, 3g Panax notoginseng powder, 6g processed aconite, 10g Poria, 10g Atractylodes, and 6g licorice.

[0043] Extraction: First decoction, (except for the slices of Panax notoginseng powder) add water to decoct, heat to boiling, keep slightly boiling for 1 to 2 hours, filter (200 mesh); second decoction, add water to decoct, heat to boiling, keep slightly boiling for 0.5 to 1 hour, filter (200 mesh), and combine the filtrate. Concentration: The filtrate is concentrated under reduced pressure to a clear paste with a certain specific gravity. Spray drying: The inlet air temperature is 165-195℃, and the outlet air temperature is 80-105℃. Collect the powder in time. Sieve and mix: Sieve the obtained dry paste powder, mix the dry paste powder with Panax notoginseng powder evenly, and you have it.

[0044] Example 2 A Chinese medicine composition for treating chronic heart failure

[0045] Raw material formula: raw astragalus 20g, cinnamon 5g, ginseng 6g, cooked rehmannia glutinosa 15g, angelica 12g, Panax notoginseng powder 2g, processed aconite 9g, Poria 15g, Atractylodes macrocephala 15g, and licorice 6g.

[0046] The preparation method is the same as Example 1.

[0047] Example 3 A Chinese medicine preparation (granules) for treating chronic heart failure

[0048] Raw material drug formula: raw astragalus 25g, cinnamon 5g, ginseng 9g, cooked rehmannia 10g, angelica 10g, Panax notoginseng powder 2g, processed aconite 6g, Poria 10g, Atractylodes 10g, and licorice 6g.

[0049] Extraction: First decoction, (except for the slices of Panax notoginseng powder) add water to decoct, heat to boiling, keep slightly boiling for 1 to 2 hours, and filter (200 mesh); second decoction, add water to decoct, heat to boiling, keep slightly boiling for 0.5 to 1 hour, filter (200 mesh), and combine the filtrate. Concentration: The filtrate is decompressed and concentrated into a clear paste with a certain specific gravity. Spray drying: The inlet air temperature is 165-195℃, and the outlet air temperature is 80-105℃. Collect the powder in time. Sieve and mix: Sieve to get the dry paste powder, and mix the extracted dry paste powder and Panax notoginseng powder (pass through an 80-mesh sieve) evenly. Granulation: Use dry granulation to make 12-40 mesh particles. Inkjet printing: Use blank aluminum foil bags for printing and packaging. Inner packaging: Pack the particles into small aluminum foil bags according to specifications.

[0050] Example 4 Clinical Study

[0051] Research plan: A randomized, controlled research method was adopted to clinically observe 60 patients with chronic heart failure of the type of deficiency of heart and kidney yang, blood stasis and water retention, with 30 cases in the treatment group and 30 cases in the control group. The treatment group was given the Chinese medicine preparation (Bu Shen Qiang Xin Granule) prepared in Example 3 of the present invention, 2 bags (8g) / time, 2 times / day, dissolved in hot water and taken. The control group was given conventional treatment of Western medicine such as furosemide and spironolactone, and the course of treatment was 4 weeks. The effective rate of TCM syndrome, NYHA cardiac function classification effective rate, cardiac ultrasound (EF%, FS%), TCM syndrome score, Lee score, 6-minute walking distance, BNP and other changes of the drug of the present invention were observed, and compared with the conventional treatment of Western medicine in the control group, and the effectiveness and safety of the drug of the present invention in treating chronic heart failure were evaluated.

[0052] Research results: Comparison of the total effective rate of TCM syndrome: After 4 weeks of treatment, the total effective rate of TCM syndrome in the treatment group was 90%, and the total effective rate in the control group was 66.7%. Compared with the two groups, the total effective rate of the treatment group was better than that of the control group (p<0.05), with statistically significant differences, as shown in Table 1.

[0053] Table 1 Comparison of the total effective rate of TCM syndromes between the two groups of patients (n, %)

[0054]

[0055] Comparison of total effective rate of NYHA heart function classification: After 4 weeks of treatment, the total effective rate of NYHA heart function classification in the treatment group was 93.3%, and the total effective rate of NYHA heart function classification in the control group was 70%. The treatment group was superior to the control group (p<0.05). This shows that the treatment group significantly improved the NYHA heart function classification of patients with heart failure, as shown in Table 2.

[0056] Table 2 Comparison of NYHA cardiac function between the two groups of patients (n, %)

[0057]

[0058] Comparison of total TCM syndrome scores: before treatment, the score in the treatment group was 31.99±12.05, and after treatment, it was 9.19±6.98; before treatment, the score in the control group was 32.63±11.701, and after treatment, it was 18.72±8.343. Compared with before treatment, the TCM syndromes of both groups of patients were significantly improved after treatment. Inter-group comparison showed that the degree of reduction in TCM syndrome scores in the treatment group after treatment was better than that in the control group (p<0.05), and the difference was statistically significant, as shown in Table 3.

[0059] Table 3 Comparison of total scores of TCM syndromes (points, )

[0060]

[0061] Comparison of single score of TCM syndrome: The scores of TCM in both groups of patients decreased to varying degrees compared with those before treatment. The treatment group had significant improvement in chest tightness, palpitations, chills and cold limbs, shortness of breath, fatigue and weakness (p<0.05), while the control group had improvement in chest tightness and palpitations (p<0.05), but no significant improvement in chills and cold limbs, facial limb edema, spontaneous sweating, night sweats, and expectoration (p>0.05). Compared with the control group, the treatment group had better improvement in chest tightness, palpitations, chills and cold limbs, shortness of breath, fatigue, facial limb edema, spontaneous sweating, night sweats, asthma, and expectoration than the control group (p<0.05). However, there was no significant difference between the two groups in dry mouth, cough, oliguria, irritability, and abdominal distension (p>0.05), as shown in Table 4.

[0062] Table 4 Comparison of individual scores of TCM syndromes (points, )

[0063]

[0064]

[0065] Comparison of Lee's heart failure scores: After 4 weeks of treatment, the Lee's heart failure scores of both groups of patients decreased significantly. Compared with the control group, the improvement of the treatment group after treatment was better than that of the control group (p<0.05), indicating that the treatment group had better efficacy than the control group, see Table 5.

[0066] Table 5 Comparison of Lee's heart failure scores between the two groups of patients (points, )

[0067]

[0068] Comparison of 6-minute walking distance: After 4 weeks of treatment, the 6-minute walking distance of both groups of patients increased significantly. Compared with the control group, the improvement of the treatment group after treatment was better than that of the control group (p<0.05), indicating that the treatment group had better therapeutic effect than the control group, see Table 6.

[0069] Table 6 Comparison of 6-minute walking distance between the two groups of patients (m, )

[0070]

[0071] Comparison of echocardiographic EF%: After 4 weeks of treatment, the EF% of both groups of patients increased (p<0.05), but there was no statistical difference between the groups.

[0072] Comparison of FS% in echocardiography: After 4 weeks of treatment, the FS% in the treatment group was significantly improved (p<0.05), while there was no significant change in the control group after treatment. However, there was no statistical difference between the two groups. See Table 7.

[0073] Table 7 Comparison of echocardiogram between the two groups of patients (%, )

[0074]

[0075]

[0076] Comparison of serum BNP: After 4 weeks of treatment, BNP decreased in both groups. Compared with the control group, the improvement of BNP in the treatment group was better than that in the control group (p<0.05), indicating that the treatment group had better efficacy than the control group, see Table 8.

[0077] Table 8 Comparison of BNP between the two groups of patients (pg / ml, )

[0078]

[0079] The above clinical research results prove that Bushen Qiangxin Granule can significantly improve the clinical symptoms of patients with chronic heart failure, improve the quality of life of patients, significantly reduce the TCM syndrome score of patients with heart and kidney yang deficiency, blood stasis and water retention type heart failure; improve cardiac function, reduce NYHA heart failure classification, Lee's heart failure score, BNP level, prolong 6-minute walking distance, and increase cardiac ultrasound EF% and FS% values. During the study, no serious adverse events occurred in the Chinese medicine composition of the present invention, and it is clinically safe and effective. There is no obvious effect on blood pressure, blood routine, liver and kidney function, blood electrolytes and urine and stool routine, and the safety is good.

[0080] Example 5 Basic Research

[0081] 1. Experimental Protocol

[0082] 65 clean grade healthy SD rats, of either sex, weighing about 250 g, were purchased from Weitonglihua Animal Company and randomly divided into 5 groups: 10 normal group, 10 sham operation group, 15 model group, 15 Chinese medicine group, and 15 positive control group (bisoprolol fumarate tablets).

[0083] A rat model of chronic heart failure was prepared with reference to relevant literature (Suetomi T, Willeford A, Brand CS, Cho Y, Ross RS, Miyamoto S, Brown JH. Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca / Calmodulin-Dependent Protein Kinase IIδSignalingin Cardiomyocytes Are Essential for Adverse Cardiac Remodeling[J]. Circulation, 2018, 138(22): 2530-2544.). The heart failure model was prepared by abdominal aorta ligation. The specific method is as follows: Preoperative preparation: healthy SD rats were taken, fasted before surgery, free drinking water, and weighed. Anesthesia: 1% pentobarbital solution was prepared and anesthetized by intraperitoneal injection at a dose of 40 mg / kg. Skin preparation: After successful anesthesia, the rat was placed in the left lateral position, the hair was trimmed, the skin was sterilely operated, and the lateral abdomen was disinfected with iodine tincture. Surgical incision: Make a 1-2cm long longitudinal incision at the midpoint of the right kidney's projection on the right iliac lumbar region, separate layer by layer, and enter the abdominal cavity. Exposure and separation: Use cotton balls to absorb the peritoneal blood, and use gauze to push the intestine to the left side of the abdominal cavity and isolate it, exposing the retroperitoneum and the right kidney. Find the right renal artery branch, peel off the abdominal aortic vascular sheath 2mm above the renal artery branch, and separate the abdominal aorta. Ligation: Insert No. 4 surgical suture between the abdominal aortic sheath and the abdominal aorta, place the No. 7 syringe needle with the tip worn off parallel to the abdominal aorta, use the surgical thread to ligate the abdominal aorta and the syringe needle together, and then slowly withdraw the needle to reduce the diameter of the rat's abdominal aorta by 70%. Note that the operation must be gentle, otherwise the aorta will be ruptured and cause heavy bleeding. Anti-infection: After surgery, before closing the abdominal cavity, an appropriate amount of penicillin (400,000 IU / ml) was injected into the abdominal cavity, and then the muscles and skin were sutured layer by layer and the abdomen was closed. Penicillin was injected intramuscularly every day for 4 consecutive days after surgery to prevent infection. Preparation of the sham operation group: After laparotomy, only the abdominal aorta was threaded without ligation, and the other steps were the same as the surgical group. After surgery, all groups were fed routinely and the animal reactions were closely observed. The ultrasound EF value of the model group after 16 weeks of modeling was reduced by more than 15% compared with the normal group as the standard for judging the successful preparation of the heart failure model.

[0084] After adaptive feeding for 1 week after modeling, oral administration began, and until 8 weeks after modeling, once a day, the Chinese medicine group was given the Chinese medicine preparation of Example 3 of the present invention (Bu Shen Qiang Xin Granule, provided by the Pharmacy Department of Guang'anmen Hospital, China Academy of Chinese Medical Sciences), and the positive control group was given bisoprolol fumarate tablets. The normal group, sham operation group and model group: an equal amount of distilled water was administered daily.

[0085] 16 weeks after modeling, 7 rats were randomly selected from each group for echocardiography. The EF of rats in each group was measured using a small animal multimode high-frequency acoustic imaging system (FUJIFILM Visual Sonics Vevo 3100) to confirm that the heart failure model was successfully established. Except for the normal group, the other groups underwent surface electrocardiography to record the occurrence of arrhythmias, the serum NT-proBNP level was measured by Elisa method, and the Ca level of each group was measured by RT-PCR and Western Blot technology. 2+ The mRNA and protein expressions of transport molecules (RyR2, SERCA2a, NCX1.1, CaMKII, PKA) and the action potential and calcium current of each group were measured by whole-cell patch clamp technique.

[0086] 2. Experimental results

[0087] 2.1 Changes of echocardiography in rats in each group

[0088] After 16 weeks of modeling, the EF value of the normal group rats was (80.54±3.33)%, and the sham operation group was (78.88±2.51)%. There was no statistical difference between the two groups (P>0.05); the EF value of the model group was (62.69±2.57)%, which was significantly decreased compared with the sham operation group (P<0.01), which was statistically significant. At the same time, the EF value of the model group was lower than that of the normal group and the sham operation group by more than 15%, which indicated that the heart failure model was successfully prepared. The EF value of the Chinese medicine group was (71.46±8.17)%, and the EF value of the positive control group was (69.56±9.71)%. Compared with the model group, the EF values ​​of each drug group were increased (P<0.05), indicating that Chinese medicine has the effect of improving the contractile function of rats with heart failure, and the efficacy is equivalent to that of the bisoprolol fumarate group, as shown in Table 9 and Figure 1 .

[0089] Table 9 EF values ​​of rats in each group (%, )

[0090]

[0091] Note: Compared with the normal group, ★P>0.05; compared with the sham operation group, *P<0.05; compared with the model group, Δ P<0.05; compared with the positive control group, ▲P>0.05.

[0092] 2.2 Serum NT-pro BNP levels in rats of each group

[0093] ELISA was used to detect the serum NT-pro BNP level of rats in each group. The results showed that the expression of NT-proBNP in the model group was significantly higher than that in the sham operation group, and both the Chinese medicine group and the positive control group could significantly reduce the level of NT-proBNP. The above results indicate that the Chinese medicine can reduce the level of NT-proBNP, an indicator of heart failure in the serum of rats with heart failure, as shown in Table 10.

[0094] Table 10 NT-proBNP levels of rats in each group (pg / ml, )

[0095]

[0096] Note: Compared with the sham operation group, *P<0.05, **P<0.01; compared with the model group, Δ P<0.05, ΔΔ P<0.01; compared with the positive control group, ▲ P<0.05, ▲▲ P<0.01.

[0097] 2.3 Effects of the Chinese medicine group on the protein and mRNA expression of calcium transport molecules RyR2, SERCA2a, NCX1.1, CaMKII, and PKA

[0098] The results showed that compared with the sham operation group, the expression of SERCA2a and NCX1.1 proteins in the model group decreased, and the expression of RyR2, CaMKII, and PKA proteins increased. Compared with the model group, the Chinese medicine group could up-regulate the expression of SERCA2a and NCX1.1, and down-regulate the expression of RyR2, CaMKII, and PKA, indicating that Chinese medicine can regulate the calcium homeostasis of damaged myocardial cells by regulating the expression of RyR2, SERCA2a, and NCX1.1. Figure 2 and Table 11-1 and Table 11-2.

[0099] RT-PCR results showed that compared with the sham operation group, the expression of SERCA2a and NCX1.1 in the model group decreased, and the expression of RyR2 increased (P < 0.05); compared with the model group, the Bushen Qiangxin prescription group could upregulate SERCA2a, downregulate RyR2 and CaMKII, while there was no statistically significant difference in NCX1.1. In addition to the statistically significant effect on NCX1.1, the positive control group had no statistically significant effect on RyR2 and SERCA2a. The above results indicate that the Bushen Qiangxin prescription can regulate the calcium homeostasis of damaged myocardial cells by regulating the expression of RyR2 and SERCA2a, thereby inhibiting the occurrence of malignant arrhythmias in heart failure.

[0100] Table 11-1 Relative mRNA expression of calcium channels and transporters in myocardial tissues of each group

[0101]

[0102] Table 11-2 Relative mRNA expression of calcium channels and transporters in myocardial tissue of each group

[0103]

[0104]

[0105] Note: Compared with the sham operation group, *P<0.05, **P<0.01; compared with the model group, Δ P<0.05, ΔΔ P<0.01; compared with the positive control group, ▲ P<0.05, ▲▲ P<0.01.

[0106] 2.4 Occurrence of induced arrhythmias in rats with heart failure in each group

[0107] The surface electrocardiogram monitoring of rats in each group showed that, before intraperitoneal injection of isoproterenol, except for occasional ventricular premature beats in the model group, no arrhythmia occurred in the other groups. After intraperitoneal injection of isoproterenol (ISO), the incidence of arrhythmia in the model group increased significantly, and ventricular tachycardia and ventricular fibrillation occurred in severe cases. The incidence of ventricular tachycardia in the sham operation group, the Chinese medicine group and the positive control group was significantly lower than that in the model group, and no ventricular fibrillation occurred, indicating that Chinese medicine can reduce the occurrence of ventricular arrhythmias in rats with heart failure, and the efficacy is equivalent to that of the positive control group, see Table 12.

[0108] Table 12 Arrhythmia occurrence in rats in each group

[0109]

[0110] Note: Compared with the sham operation group, **P<0.01; compared with the model group, ΔΔ P<0.01; compared with the sham operation group, ▲ P<0.05. PVB: premature ventricular beat; VT: ventricular tachycardia; VF: ventricular fibrillation.

[0111] 2.5 Study on the electrophysiological mechanism of Chinese medicine on ventricular myocytes in rats with heart failure

[0112] 2.5.1 Effects of Chinese medicine on TA and AP in rat cardiomyocytes

[0113] As Figure 4As shown, there were three cells in the model group with triggered activity, with an incidence of 50%, and no triggered activity (TA) was recorded in the other groups. Figure 5 As shown, the changes of APD90 were as follows: model group>positive control group>TCM group>sham operation group; the changes of APD50 were as follows: model group>positive control group>TCM group>sham operation group; the changes of APD30 were as follows: model group>positive control group>TCM group>sham operation group, and the differences of APD90 were statistically significant, while there were no statistical differences in APD30 and APD50 between the TCM group and the positive control group. There was no significant difference in action potential amplitude (APA) between the drug administration group and the model group, and the resting potential (RP) in the model group was significantly elevated, which was statistically significant, and the resting potential of the positive control group and the TCM group was lower than that of the model group, which was statistically significant; the maximum depolarization rate (dv / dt Max) in the model group was significantly slowed down, while the positive control group and the TCM group were faster than the model group, which was statistically significant. The above results indicate that TCM reduces the occurrence of triggered activity of ventricular myocytes in rats with heart failure by restoring the action potential duration of damaged myocardial cells.

[0114] The above basic research shows that Bushen Qiangxin Granule can improve the EF value of rats with heart failure, reduce the level of NT-proBNP, upregulate the expression of SERCA2a and NCX1.1 in damaged myocardial tissue, downregulate the expression of RyR2, CaMKII, and PKA, and regulate the calcium homeostasis of damaged myocardial cells. It can also reduce ventricular tachycardia and ventricular fibrillation induced by intraperitoneal injection of isoproterenol in rats with heart failure, inhibit the occurrence of malignant arrhythmias in heart failure, and reduce the risk of possible sudden death.

[0115] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not limitations on the implementation methods of the present invention. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made based on the above description. It is impossible to list all the implementation methods here. All obvious changes or modifications derived from the technical solution of the present invention are still within the protection scope of the present invention.

Claims

1. A Chinese medicine composition for treating chronic heart failure, characterized in that: The traditional Chinese medicine composition is prepared from the following raw materials by weight: 9-50 parts of raw astragalus, 1-5 parts of cinnamon, 5-30 parts of ginseng, 5-30 parts of prepared rehmannia, 5-30 parts of angelica, 1-20 parts of notoginseng, 3-15 parts of processed aconite, 5-30 parts of poria, 5-30 parts of atractylodes, and 5-20 parts of licorice.

2. The Chinese medicine composition according to claim 1, characterized in that: In parts by weight, the Chinese medicine composition is prepared from the following raw materials: 25 parts of raw astragalus, 5 parts of cinnamon, 9 parts of ginseng, 10 parts of prepared rehmannia, 10 parts of angelica, 2 parts of notoginseng, 6 parts of processed aconite, 10 parts of tuckahoe, 10 parts of atractylodes, and 6 parts of liquorice; or, 30 parts of raw astragalus, 3 parts of cinnamon bark, 9 parts of ginseng, 10 parts of prepared rehmannia root, 6 parts of angelica, 3 parts of notoginseng, 6 parts of processed aconite root, 10 parts of tuckahoe, 10 parts of atractylodes macrocephala, 6 parts of liquorice; or, 20 parts of raw astragalus, 5 parts of cinnamon bark, 6 parts of ginseng, 15 parts of prepared rehmannia, 12 parts of angelica, 2 parts of notoginseng, 9 parts of processed aconite, 15 parts of poria, 15 parts of atractylodes, and 6 parts of liquorice.

3. A Chinese medicine composition for treating chronic heart failure, characterized in that: The traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 9-50 parts of raw astragalus, 1-5 parts of cinnamon, 5-30 parts of ginseng, 5-30 parts of prepared rehmannia, 5-30 parts of angelica, 1-20 parts of notoginseng, 3-15 parts of processed aconite, 5-30 parts of poria, 5-30 parts of atractylodes, 5-20 parts of licorice, and 5-15 parts of dried ginger.

4. A Chinese medicine composition for treating chronic heart failure, characterized in that: The traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 9-50 parts of raw astragalus, 1-5 parts of cinnamon, 5-30 parts of ginseng, 5-30 parts of prepared rehmannia, 5-30 parts of angelica, 1-20 parts of notoginseng, 3-15 parts of processed aconite, 5-30 parts of poria, 5-30 parts of atractylodes, 5-20 parts of licorice, and 5-15 parts of dried tangerine peel.

5. A Chinese medicine composition for treating chronic heart failure, characterized in that: The traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 9-50 parts of raw astragalus, 1-5 parts of cinnamon, 5-30 parts of ginseng, 5-30 parts of prepared rehmannia, 5-30 parts of angelica, 1-20 parts of notoginseng, 3-15 parts of processed aconite, 5-30 parts of poria, 5-30 parts of atractylodes, 5-20 parts of licorice, and 5-15 parts of allium macrostemon.

6. The method for preparing the Chinese medicine composition for treating chronic heart failure according to claim 1 or 2, characterized in that: The preparation method comprises the following steps: Take raw astragalus, cinnamon bark, ginseng, cooked rehmannia root, angelica root, processed aconite root, poria, atractylodes macrocephala, and liquorice according to the formula, add water and boil twice, filter, and combine the filtrate; The filtrate is concentrated into a clear paste, and dried to obtain a dry paste powder; Mix the dry paste powder and Panax notoginseng powder to get the product.

7. The method for preparing the Chinese medicine composition for treating chronic heart failure according to claim 3, characterized in that: The preparation method comprises the following steps: Take raw astragalus, cinnamon bark, ginseng, cooked rehmannia root, angelica root, processed aconite root, tuckahoe, atractylodes macrocephala, licorice root and dried ginger according to the formula, add water and boil twice, filter and combine the filtrate; The filtrate is concentrated into a clear paste, and dried to obtain a dry paste powder; Mix the dry paste powder and Panax notoginseng powder to get the product.

8. The method for preparing the Chinese medicine composition for treating chronic heart failure according to claim 4, characterized in that: The preparation method comprises the following steps: Take raw astragalus, cinnamon bark, ginseng, cooked rehmannia root, angelica root, processed aconite root, tuckahoe, atractylodes macrocephala, licorice, and dried tangerine peel according to the formula, add water and boil twice, filter, and combine the filtrate; The filtrate is concentrated into a clear paste, and dried to obtain a dry paste powder; Mix the dry paste powder and Panax notoginseng powder to get the product.

9. The method for preparing the Chinese medicine composition for treating chronic heart failure according to claim 5, characterized in that: The preparation method comprises the following steps: Take raw astragalus, cinnamon bark, ginseng, cooked rehmannia root, angelica root, processed aconite root, poria, atractylodes macrocephala, liquorice and scallion according to the formula, add water and boil twice, filter and combine the filtrate; The filtrate is concentrated into a clear paste, and dried to obtain a dry paste powder; Mix the dry paste powder and Panax notoginseng powder to get the product.

10. A Chinese medicine preparation for treating chronic heart failure, characterized in that: The Chinese medicine preparation comprises the Chinese medicine composition according to any one of claims 1-5.

11. The Chinese medicine preparation according to claim 10, characterized in that: The traditional Chinese medicine preparation also includes pharmaceutically acceptable excipients.

12. The Chinese medicine preparation according to claim 10 or 11, characterized in that: The dosage form of the traditional Chinese medicine preparation includes decoction, granules, pills, capsules, tablets, powders or oral liquids.

13. Use of the Chinese medicine composition according to any one of claims 1 to 5 or the Chinese medicine preparation according to claims 10 to 12 in the preparation of a medicament for treating chronic heart failure.

14. Use of the Chinese medicine composition according to any one of claims 1 to 5 or the Chinese medicine preparation according to claims 10 to 12 in the preparation of a medicament for treating chronic heart failure of the heart-kidney yang deficiency, blood stasis and water retention type.

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