A pharmaceutical composition for the prevention or treatment of atrial fibrillation and its application.

Abstract

This invention provides a pharmaceutical composition for the prevention or treatment of atrial fibrillation and its application. Composed of herbs such as Astragalus membranaceus and Angelica sinensis, this invention is based on the theory of collaterals and the principle of invigorating qi and lifting sunken qi, guided by the theory of collaterals. It uses warming and dispersing wind-dispelling herbs as adjuvants, supplemented with herbs that promote blood circulation and remove blood stasis, and regulate qi flow. The entire formula has the effects of tonifying and lifting, nourishing the collaterals, and extinguishing internal and external wind.

Description

Technical Field

[0001] This invention relates to a traditional Chinese medicine composition for the prevention or treatment of atrial fibrillation and its application, belonging to the field of traditional Chinese medicine application. For patients with atrial fibrillation, it establishes the treatment principle of "tonifying and nourishing the collaterals, extinguishing wind and calming palpitations" and formulates a prescription. The whole prescription has the effects of nourishing the collaterals and calming wind and palpitations, providing a new treatment idea for the clinical treatment of atrial fibrillation. Background Technology

[0002] Atrial fibrillation (AF) is the most common cardiovascular disease among middle-aged and elderly people, with a global prevalence of approximately 1%-2%. Paroxysmal atrial fibrillation (PAF) accounts for about one-third of AF cases, defined as atrial fibrillation lasting ≤7 days and terminating spontaneously. Studies show that PAF easily leads to serious complications such as thromboembolism, stroke, cognitive impairment, and heart failure. PAF patients have a 5 times increased risk of stroke compared to normal individuals, demonstrating that PAF has become one of the most serious cardiovascular diseases threatening human health.

[0003] The pathogenesis of PAF is complex. Atrial remodeling is an important basis for the occurrence and maintenance of PAF, mainly including electrical remodeling, structural remodeling and autonomic remodeling.

[0004] Currently, the main treatments for cardiopulmonary bypass (PAF) are oral antiarrhythmic drugs and radiofrequency ablation. While both treatments are effective, long-term use of antiarrhythmic drugs can easily lead to side effects such as drug-induced arrhythmias, pulmonary fibrosis, cirrhosis, and hyperthyroidism. Radiofrequency ablation is a first-line treatment for PAF, but it carries operational risks and postoperative recurrence risks, reducing patient compliance. Therefore, there is an urgent need to develop safe, effective, and long-term medications for treating PAF. Traditional Chinese medicine has advantages in systemic intervention and comprehensive regulation, with fewer toxic side effects and high medication safety. Summary of the Invention

[0005] This invention's pharmaceutical composition is an innovative traditional Chinese medicine formula developed by Professor Jia Zhenhua based on the theory of collaterals and the pathogenesis of PAF (atrial fibrillation) characterized by "deficiency of ancestral qi, stagnation of deficient qi, and internal wind disturbing the collaterals." The formula comprehensively tonifies and lifts the collaterals, nourishes them, and extinguishes internal and external wind, exerting the effects of "tonifying and clearing the collaterals, extinguishing wind, and calming palpitations." This formula utilizes the light and mild nature of wind-dispelling herbs to enhance the effects of dispersing wind pathogens, regulating qi, and promoting blood circulation and unblocking the collaterals, thus eliminating pathogens and restoring balance, nourishing the mind and spirit. This study aims to explore the therapeutic effect of this pharmaceutical composition on PAF by examining its effects on susceptibility to atrial fibrillation, atrial conduction dispersion, neural distribution density, and atrial electrical remodeling, structural remodeling, and neural remodeling in Ach-CaCl2-induced PAF rats, in order to provide a new and effective intervention approach for PAF.

[0006] This invention relates to a traditional Chinese medicine composition, consisting of Astragalus membranaceus, Angelica sinensis, and other herbs. It possesses the effects of "tonifying and clearing the meridians, calming wind and relieving palpitations," and is suitable for paroxysmal atrial fibrillation (Qi deficiency type). Compared with similar traditional Chinese medicine products, this invention's composition is innovative in its formulation principles and herbal composition. Unlike previous studies that primarily used warming and tonifying kidney-yang herbs to treat atrial fibrillation, this composition targets the underlying pathological condition of Qi deficiency, tonifying and lifting Qi, calming wind and relieving palpitations. In this formula, Astragalus membranaceus, Pueraria lobata, Cimicifuga foetida, and Bupleurum chinense tonify Qi, raise Yang and lift prolapse. With Qi replenished, lung Qi is astringed, and heart Qi is replenished. Sufficient Qi leads to a regular pulse. Nardostachys chinensis regulates Qi and strengthens the spleen, smoothing the meridians and ensuring that tonification is not stagnant, achieving a balance of tonification and unblocking. Ziziphus jujuba var. spinosa, Platycladus orientalis seed, and Angelica sinensis nourish blood and calm the mind, thus relieving palpitations. Cornus officinalis nourishes Yin and extinguishes wind, while oyster shell subdues Yang and extinguishes wind. Combined with Notopterygium incisum to dispel external wind, they work together to calm palpitations and relieve wind. The wind-dispelling herbs are warm and dispersing, moving without stagnation or blockage, thus regulating Qi, unblocking blood vessels, and restoring a regular pulse, thereby stopping palpitations. Blood is the mother of Qi; blood stasis leads to Qi stagnation. Corydalis yanhusuo and Ligusticum chuanxiong are used to promote Qi circulation, remove stagnation, and invigorate blood, thus relieving palpitations, anxiety, chest tightness, shortness of breath, and fatigue caused by blood stasis. Coptis chinensis clears heart fire and stops irritability, thus moderating the warming and tonifying properties of the herbs in this formula. The combination of these two herbs clears heat without harming Yin and nourishes Yin without retaining pathogens. This prescription addresses paroxysmal atrial fibrillation caused by deficiency of vital energy, stagnation of deficient qi, and internal wind disturbing the collaterals. The fundamental pathogenesis of this condition is deficiency of vital energy, stagnation of deficient qi, and internal wind disturbing the collaterals. It aims to tonify and lift the vital energy, nourish the collaterals, extinguish wind, and calm palpitations, thereby improving patients' clinical symptoms and quality of life. Simultaneously, it also shows significant efficacy in treating systemic symptoms caused by deficiency of vital energy, such as shortness of breath, fatigue, dizziness, tinnitus, chest tightness, insomnia, and excessive dreaming. The prescription is simple yet highly effective, demonstrating its unique characteristics and innovation.

[0007] The pharmaceutical composition for preventing or treating atrial fibrillation according to the present invention comprises the following components in parts by weight: Astragalus membranaceus 20-40 parts, Cimicifuga foetida 5-15 parts, Bupleurum chinense 5-15 parts, Pueraria lobata 20-40 parts, Ziziphus jujuba var. spinosa 10-20 parts, Platycladus orientalis var. 10-20 parts, Angelica sinensis 10-20 parts, Ostrea gigas 20-40 parts, Ligusticum chuanxiong 10-20 parts, Corydalis yanhusuo 10-20 parts, Notopterygium incisum 5-15 parts, Coptis chinensis 5-15 parts, Nardostachys jatamansi 10-20 parts, and Cornus officinalis 20-40 parts.

[0008] The preferred composition comprises the following components in parts by weight: 30 parts Astragalus membranaceus, 10 parts Cimicifuga foetida, 10 parts Bupleurum chinense, 30 parts Pueraria lobata, 15 parts Ziziphus jujuba var. spinosa, 15 parts Platycladus orientalis, 15 parts Angelica sinensis, 30 parts Ostrea gigas, 15 parts Ligusticum chuanxiong, 15 parts Corydalis yanhusuo, 10 parts Notopterygium incisum, 10 parts Coptis chinensis, 15 parts Nardostachys jatamansi, and 30 parts Cornus officinalis.

[0009] The composition may also preferably include the following components in parts by weight: 20 parts Astragalus membranaceus, 15 parts Cimicifuga foetida, 5 parts Bupleurum chinense, 40 parts Pueraria lobata, 10 parts Ziziphus jujuba var. spinosa, 20 parts Platycladus orientalis, 10 parts Angelica sinensis, 40 parts Ostrea gigas, 10 parts Ligusticum chuanxiong, 20 parts Corydalis yanhusuo, 5 parts Notopterygium incisum, 15 parts Coptis chinensis, 10 parts Nardostachys jatamansi, and 40 parts Cornus officinalis.

[0010] The composition may also preferably include the following components in parts by weight: 40 parts Astragalus membranaceus, 5 parts Cimicifuga foetida, 15 parts Bupleurum chinense, 20 parts Pueraria lobata, 20 parts Ziziphus jujuba var. spinosa, 10 parts Platycladus orientalis, 20 parts Angelica sinensis, 20 parts Ostrea gigas, 20 parts Ligusticum chuanxiong, 10 parts Corydalis yanhusuo, 15 parts Notopterygium incisum, 5 parts Coptis chinensis, 20 parts Nardostachys jatamansi, and 20 parts Cornus officinalis.

[0011] The composition may also preferably include the following components in parts by weight: Astragalus membranaceus 35 parts, Cimicifuga foetida 12 parts, Bupleurum chinense 12 parts, Pueraria lobata 30 parts, Ziziphus jujuba var. spinosa 12 parts, Platycladus orientalis var. cylindrica 12 parts, Angelica sinensis 12 parts, Ostrea gigas 35 parts, Ligusticum chuanxiong 15 parts, Corydalis yanhusuo 15 parts, Notopterygium incisum 10 parts, Coptis chinensis 10 parts, Nardostachys jatamansi 15 parts, and Cornus officinalis 30 parts.

[0012] In this composition, Astragalus membranaceus is preferably raw Astragalus membranaceus, oyster shell is preferably raw oyster shell, and Ziziphus jujuba var. spinosa is preferably roasted Ziziphus jujuba var. spinosa.

[0013] The composition can be used to prepare pharmaceutical dosage forms including capsules, tablets, pills, oral liquids, granules, injections, or powders.

[0014] The present invention also provides the use of this pharmaceutical composition in the preparation of atrial structural remodeling drugs.

[0015] This invention also provides the use of this pharmaceutical composition in the preparation of drugs that improve atrial electrical conduction and cardiac electrical remodeling.

[0016] The present invention also provides the use of this pharmaceutical composition in the preparation of drugs that improve sympathetic remodeling.

[0017] The pharmaceutical composition of the present invention has been experimentally proven to reduce susceptibility to atrial fibrillation, conduction dispersion, decrease the distribution density and uniformity of TH protein, and downregulate TH protein expression.

[0018] The present invention also provides the use of the pharmaceutical composition in the preparation of drugs that improve the distribution of connexion43 (Cx43) and upregulate the expression of connexion43.

[0019] This invention's pharmaceutical composition is guided by the theory of collaterals in Traditional Chinese Medicine, proposing the pathogenesis of paroxysmal atrial fibrillation as "deficiency of ancestral qi, stagnation of deficient qi, and internal wind disturbing the collaterals." Ancestral qi travels through the respiratory tract to regulate respiration and circulates through the heart vessels to circulate qi and blood. When ancestral qi is deficient, qi fails to return to its source, floating upwards and shaking the chest, causing palpitations and easy startling, even to the point of loss of self-control. Qi deficiency weakens the body's ability to circulate blood, resulting in shortness of breath, lethargy, fatigue, and inability to nourish the head and face, thus causing dizziness and tinnitus. The heart stores the spirit, and malnourishment of the heart spirit leads to palpitations, restlessness, and mental unease. Deficiency of heart blood and qi allows internal wind to rise and disturb the body, causing palpitations and insomnia. Qi deficiency hinders blood circulation, resulting in insufficient blood supply to the vessels, sluggish blood flow, blood stasis obstructing the vessels, and disharmony of qi and blood circulation, leading to anxiety, chest tightness, and discomfort.

[0020] Based on the main pathogenesis of paroxysmal atrial fibrillation, namely "deficiency of vital energy, stagnation of deficient energy, and internal wind disturbing the collaterals," the treatment principle of "tonifying and unblocking the collaterals, extinguishing wind and calming palpitations" was proposed. A formula for tonifying and unblocking to prevent atrial fibrillation was developed, and the inventors established the formula of the drug composition of this invention:

[0021] The principal ingredient is Astragalus membranaceus; the assistant ingredients are Ziziphus jujuba var. spinosa, Cornus officinalis, and Corydalis yanhusuo; the adjuvant ingredients are Platycladus orientalis seed, Angelica sinensis, raw oyster shell, Ligusticum chuanxiong, Nardostachys chinensis, Pueraria lobata, Coptis chinensis, and Notopterygium incisum; the guiding ingredients

[0022] The formula heavily utilizes raw Astragalus membranaceus to replenish vital energy, raise yang, and lift sunken qi. Astragalus membranaceus is considered the "best among qi-tonifying herbs," excelling at tonifying lung and spleen qi and effectively treating qi sinking in the chest. Astragalus membranaceus is the chief herb, ensuring that vital energy has a root, qi and blood return to their source, vital energy flows smoothly through the respiratory tract, circulates through the heart vessels, and qi and blood circulate. When the heart vessels are warmed and nourished by qi and blood, the pulse rhythm becomes normal. Ziziphus jujuba seed nourishes heart yin, calms the mind and relieves palpitations, and treats restlessness and insomnia. When the mind is calmed, the spirit is at peace, palpitations are relieved, and sleep improves. Cornus officinalis tonifies the kidneys and replenishes essence, nourishes yin and extinguishes wind, promotes blood circulation, regulates the pulse rhythm, and relieves tinnitus. Corydalis yanhusuo invigorates blood, relieves pain, promotes qi circulation and disperses blood stasis, and promotes the flow of qi and blood, thus eliminating chest tightness. These three herbs work together as assistant herbs, ensuring that tonification is not stagnant, and that tonification is combined with unblocking, achieving the effects of nourishing the heart and calming the mind, promoting qi circulation and dispersing blood stasis, extinguishing wind and relieving palpitations. The formula is supplemented with cypress seed to nourish the heart and calm the mind, relieving restlessness and palpitations; angelica is known as the "holy medicine of blood," replenishing qi and essence, nourishing blood and promoting blood circulation, benefiting the mind and spirit without causing stagnation. Cypress seed and angelica complement each other, combined with jujube seed to astringe yin, nourish blood, and calm the mind, thus alleviating palpitations and promoting restful sleep. Raw oyster shell astringes yin and subdues yang, heavily calming the mind, containing floating yang qi and restraining turbulent yin qi, assisting cornus officinalis in nourishing yin and extinguishing wind, thus calming the mind and alleviating palpitations. Chuanxiong (Ligusticum striatum) invigorates blood and qi, dispels wind and relieves pain. As a qi-regulating herb in the blood, it invigorates blood without causing stagnation, and regulates qi without harming the body's vital energy. It unblocks the flow of qi and blood, and resolves blood stasis without harming the body's vital energy. It assists Yuanhu (Corydalis yanhusuo) in regulating qi and clearing blood stasis, improving patients' anxiety, chest tightness and discomfort caused by blood stasis. Gansong (Nardostachys chinensis) regulates qi and strengthens the spleen, smoothing the flow of qi in the meridians, ensuring that tonification is not stagnant, and that tonification is combined with unblocking. Gegen (Pueraria lobata) raises yang qi, assisting Huangqi (Astragalus membranaceus) in tonifying the ancestral qi. Huanglian (Coptis chinensis) clears heat and dries dampness, drains fire and detoxifies, effectively draining heart fire and relieving irritability, and assisting Huangqi in warming and dispersing the tonifying properties. The two herbs work together, one clearing and one tonifying, draining fire without harming yin, and nourishing yin without retaining pathogens. Qianghuo (Notopterygium incisum) dispels wind and relieves pain, regulates the limbs, and unblocks blood vessels. This formula takes advantage of its function of dispelling external wind. The above eight herbs are used as adjuvant herbs. Using Cimicifuga and Bupleurum as guiding herbs can carry the medicine upward, lift the vital energy, and help Astragalus and Pueraria to enhance the effect of raising yang and lifting prolapse. When the vital energy rises, the qi and blood flow smoothly, the heart vessels are unblocked, and chest tightness is relieved.

[0023] In summary, this formula uses Astragalus membranaceus, Pueraria lobata, Cimicifuga foetida, and Bupleurum chinense to replenish the ancestral qi, raise yang and lift prolapse. With the ancestral qi replenished, the lung qi is astringed, and the heart qi is replenished. When the qi is sufficient, the pulse rhythm is regular. Nardostachys chinensis regulates qi and strengthens the spleen, smoothing the flow of qi in the meridians, ensuring that the replenishment is not stagnant, and that replenishment is combined with unblocking. Ziziphus jujuba var. spinosa, Platycladus orientalis seed, and Angelica sinensis nourish blood and calm the mind, soothing the heart and calming palpitations. Cornus officinalis nourishes yin and extinguishes wind, while Ostrea gigas subdues yang and extinguishes wind. It is supplemented with Notopterygium incisum to dispel external wind, working together to extinguish wind and calm palpitations. Wind-dispelling herbs are warm and dispersing, moving without stagnation, dispersing without depression, regulating qi, unblocking blood vessels, and regulating the pulse rhythm, thus stopping palpitations. Blood is the mother of qi, and blood stasis leads to qi stagnation. Corydalis yanhusuo and Ligusticum chuanxiong are used to promote qi circulation, remove blood stasis, and ensure the smooth flow of qi and blood. Symptoms such as anxiety, chest tightness, shortness of breath, and fatigue caused by blood stasis are relieved. Coptis chinensis clears heart fire and relieves restlessness, while also counteracting the warming and tonifying properties of the other herbs in this formula. The combination of these two herbs clears heat without harming Yin, and nourishes Yin without retaining pathogens. When all the herbs are used together, one's Qi is sufficient, sleep is restful, the pulse is regular, and palpitations cease. Attached Figure Description

[0024] Figure 1 Normal electrocardiogram and atrial fibrillation electrocardiogram in rats.

[0025] Figure 2 The effects of the pharmaceutical composition of the present invention on the atrial fibrillation induction time (A) and duration of atrial fibrillation (B) in rats with paroxysmal atrial fibrillation.

[0026] Figure 3 The effect of the pharmaceutical composition of the present invention on cardiac electrical conduction in atrial fibrillation rats.

[0027] Figure 4 The effect of the pharmaceutical composition of the present invention on the diameter and area of ​​the left atrium in rats with paroxysmal atrial fibrillation.

[0028] Figure 5 The effect of the pharmaceutical composition of the present invention on collagen fibers in the atrial myocardial tissue of rats with paroxysmal atrial fibrillation was detected by Masson staining (×200).

[0029] Figure 6 The effect of the drug composition of the present invention on the expression of TH protein in rats with paroxysmal atrial fibrillation by immunohistochemistry (×400).

[0030] Figure 7 The effects of the pharmaceutical composition of this invention on the expression of TH and Cx43 proteins in rats with paroxysmal atrial fibrillation were detected by Western blot method.

[0031] Figure 8 The effect of the drug composition of the present invention on the expression of Cx43 protein in the atrial tissue of rats in each group by immunofluorescence detection (×400). Detailed Implementation

[0032] Functional testing

[0033] To illustrate the efficacy of the pharmaceutical composition of the present invention, functional tests were conducted on the samples of Example 1, Example 2, and Example 3 prepared in the examples.

[0034] 1. Materials and methods

[0035] 1.1 Animals

[0036] SPF-grade male SD rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., license number: SCXK (Beijing) 2016-0011, 5-6 weeks old, body weight (160-200) g. The experimental animals were housed in the State Key Laboratory of Collateral Disease Research and Innovative Traditional Chinese Medicine. The temperature was 20°C - 25°C, and the relative humidity was 40% - 70%. The animals had free access to water and food. The animal experiments conformed to the relevant regulations of the animal ethics of the State Key Laboratory of Collateral Disease Research and Innovative Traditional Chinese Medicine (Animal Experiment Ethical Review Form number: N2021073).

[0037] 1.2 Drugs and reagents

[0038] Example 1, Example 2, and Example 3 of the pharmaceutical composition of the present invention (provided by Yiling Pharmaceutical Research Institute); Amiodarone Hydrochloride Tablets (batch number: AHG0717, purchased from Sanofi Pharmaceuticals); Urethane (batch number: DC08BA0021, purchased from BBILife Sciences); Acetylcholine Chloride (batch number: BCBX5660, purchased from SIGMA-ALDRICH); Anhydrous Calcium Chloride (batch number: YD20190102, Tianjin Yongda Chemical Reagent Co., Ltd.); Rabbit SP Kit kit (batch number: 2122B0701, purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.); Recombinant Anti-GAPDH antibody (batch number: GR3219790-17, purchased from Abcam); Goat Anti-Rabbit IgG H&L pre-adsorbed secondary antibody (batch number: GR3361088-5, purchased from Abcam); Tyrosine Hydroxylase (TH, batch number: GR*******-10, ab137869, purchased from Abcam); Acetylcholine Transferase (purchased from Abcam); Connexin 43 (purchased from Abcam); DAPI (Beijing Solarbio Science & Technology Co., Ltd.).

[0039] 1.3 Instruments

[0040] PowerLab physiological recorder, Ed Instruments International Trading (Shanghai) Co., Ltd.; Vevo small animal ultrasound imaging system, Fujifilm (China) Investment Co., Ltd.; 3K15 high-speed refrigerated centrifuge, SIGMA GmbH, Germany; small animal isolated heart perfusion system (Langendorff), HSE GmbH, Germany; multi-channel matrix electrical signal mapping system (MappingLab), MappingLab Ltd., UK; 221BR semi-dry transfer apparatus (Bio-Rad, Japan); ERS301 electrophoresis apparatus (CE, USA); DYY-Ⅲ bridge electrophoresis tank, Beijing Liuyi Instrument Factory; Odyssey dual-color infrared laser imaging system, LI-Cor, USA.

[0041] 2. Methods

[0042] 2.1 Grouping and Dosing

[0043] Rats were divided into 6 groups, with 15 rats in each group: a blank control group (Control group), a model group (Model group), the drug composition of the present invention Example 1 (TBL group), the drug composition of the present invention Example 2 (TBM group), the drug composition of the present invention Example 3 (TBH group), and an amiodarone group (AMD group). Control group: Rats were administered 1 mL / 100 g / day of pure water by gavage for 30 days; starting on day 24, 0.1 mL / 100 g / day of physiological saline was injected via tail vein for 7 consecutive days.

[0044] Model group: 1 mL / 100 g / d of pure water was administered by gavage for 30 days. On day 24, 0.1 mL / 100 g / d of a mixture of Ach-CaCl2 (containing 60 μg / mL Ach and 10 mg / mL CaCl2) was injected via tail vein for 7 consecutive days.

[0045] The TBL group, TBM group, and TBH group were administered the extracts obtained from Examples 1, 2, and 3 of the present invention by gavage at a dose of 8 g / kg / d for 30 days. Starting on day 24, the Ach-CaCl2 mixed solution was injected via tail vein at a dose of 0.1 mL / 100 g / d for 7 consecutive days.

[0046] AMD group: Administered by gavage at 80 mg / kg / day for 7 days, followed by intravenous injection of 0.1 mL / 100 g / day of Ach-CaCl2 mixture starting on day 24 for 7 consecutive days.

[0047] 2.2 Indicator Testing

[0048] Before specimen collection, rats were fasted for 12 hours and then anesthetized with an intraperitoneal injection of 0.5 mL / 100 g of 25% maltodextrin. An electrocardiogram was then used to detect the susceptibility to atrial fibrillation in each group (calculation of atrial fibrillation induction time and duration). Three rats were randomly selected from each group, and the atrial conduction dispersion was detected using an isolated heart perfusion method and an electro-mapping system. The remaining rats underwent skin preparation and disinfection, and the diameter and area of ​​the left atrium were recorded using a small animal ultrasound. After blood was drawn from the abdominal aorta, the heart was exposed, and the pericardium was carefully dissected with ophthalmic forceps. The aorta was slowly separated upwards along the aortic segment, and the heart was quickly removed. The peripheral thymus and pericardial tissue were removed, and the tissue was washed with physiological saline. A portion of the heart tissue was fixed in 4% paraformaldehyde solution, dehydrated, and embedded in paraffin to prepare sections approximately 4 μm thick for Masson staining and immunohistochemical detection. Another portion of the heart tissue was cryopreserved in liquid nitrogen for subsequent Western blot analysis.

[0049] 2.3 Evaluation of PAF Model

[0050] After anesthetizing rats with 0.5 mL / 100 g of 25% ursodeoxycholic acid via intraperitoneal injection, the rats were connected to the limb leads of an electronic electrocardiograph, and Ach-CaCl2 mixture was injected into the tail vein to induce atrial fibrillation (PAF). The electrocardiogram was recorded immediately. The appearance of f waves and the disappearance of P waves were used as markers of the onset of atrial fibrillation, and the disappearance of f waves and the appearance of P waves were used as markers of the termination of atrial fibrillation. The preparation of the PAF rat model was evaluated.

[0051] 2.4 Electrocardiogram (ECG) Detection of Susceptibility to Atrial Fibrillation

[0052] After the PAF model was successfully established, LabChart software was used to record the time points of tail vein injection of Ach-CaCl2 mixture and the start and end times of atrial fibrillation after modeling in each group of rats. The induction time and duration of atrial fibrillation were calculated to evaluate the susceptibility of each group of animals to atrial fibrillation.

[0053] 2.5 Detection of atrial conduction changes using an electrical mapping system

[0054] Prepare KH solution in advance and oxygenate (95% O2 + 5% CO2) for at least 30 minutes; the pH value should be 7.4. Pour the prepared solution into the constant temperature storage tank of the perfusion device and preheat to 37°C. Randomly select 3 rats per group, anesthetize them after injection of 100 IU / mL heparin (1mL / 100g), open the chest through a midline sternal incision to expose the heart, and quickly remove the heart along with the aortic arch. Wash with pre-cooled KH solution; use forceps to open the severed end of the aortic arch and connect it to the Langendorff perfusion system. Measure the pressure value at 80 mmHg and use the MappingLab mapping system for detection. Keep the electrode positions of the heart of each rat as consistent as possible. After the atrial electrical conduction is stable, select the atrial wave to measure the atrial conduction dispersion, and use EMapScope 5.0 software to analyze the differences between groups.

[0055] 2.6 Echocardiography to detect left atrial diameter and left atrial area

[0056] After disinfection and preparation of the chest and abdomen of rats, echocardiography was performed using a small animal ultrasound machine. Animated images of the rat heart were captured using two-dimensional ultrasound mode, and the diameter and area of ​​the left atrium were measured to assess atrial structural remodeling in each group of rats.

[0057] 2.7 Masson staining to examine collagen fibers in atrial myocardial tissue

[0058] After routine dewaxing, Masson staining was performed, followed by Weigert iron hematoxylin for 5 min, differentiation with acidic ethanol for 5-15 s, washing with distilled water, staining with Ponceau S and fuchsin for 5-10 min, washing with a weak acid solution for 1 min, phosphomolybdic acid solution for 1-2 min, washing with a weak acid solution for 1 min, staining with aniline blue solution for 1-2 min, washing with a weak acid solution for 1 min, dehydration, clearing with xylene, mounting with neutral resin, and observation of atrial myocardial collagen fibers in randomly selected fields of view under an optical microscope.

[0059] 2.8 Immunohistochemical detection of TH protein expression in atrial tissue

[0060] Paraffin sections in each group were routinely dewaxed to water, antigen retrieval was performed, incubated with 3% H2O2, blocked with serum, and primary and secondary antibodies were added. PBS was used as a negative control. DAB staining was then performed, and the sections were mounted. The appearance of brownish-yellow granules under the microscope was considered a positive criterion. A computer-aided morphometric analysis system (Image-Pro plus 6.0) was used to automatically identify sympathetic nerves after immunohistochemical staining and calculate their pixel area. Six random regions were selected from each section. The average distribution density of nerves was represented by the ratio of nerve area to total detected area (µm² / mm²). The mean difference between the average nerve density in the field of view with the highest nerve density and the average nerve density in the field of view with the lowest nerve density was used as the degree of heterogeneity in nerve distribution. The average distribution density and degree of heterogeneity of TH were detected.

[0061] 2.9 Immunofluorescence detection of Cx43 protein distribution in atrial tissue

[0062] Dewax each set of paraffin sections, then place them in a retrieval container containing sodium citrate-EDTA antigen retrieval solution. Heat in a microwave oven, allow to cool naturally, then place the sections in PBS (pH 7.4) and wash three times (5 min each) on a shaker. Quickly spin-dry the sections, drop 3% hydrogen peroxide solution onto the tissue, and incubate at 37°C in the dark for 10 min. Then place the sections in PBS (pH 7.4) and wash three times (5 min each) on a shaker. Spin-dry the sections, add 5% BSA, and block at room temperature for 30 min for serum blocking. Then place the sections in PBS (pH 7.4) and wash three times (5 min each) on a shaker. Add diluted primary antibody (Cx43, 1:100) to completely cover the tissue and incubate overnight at 4°C. After washing with PBS following primary antibody incubation, the cells were labeled with diluted secondary antibody (Alexa Fluor 594, 1:500) and incubated at room temperature for 50 min. Finally, the cells were mounted with mounting medium containing DAPI and observed using a laser confocal microscope. The cell nuclei stained with DAPI turned blue under ultraviolet excitation, and the corresponding fluorescently labeled red light was used as a positive reaction to detect the distribution of Cx43 protein.

[0063] 2.10 Western blot analysis of TH and Cx43 protein expression levels in atrial tissue

[0064] The liquid nitrogen-frozen specimen was removed, and 100 mg of the specimen was cut using ophthalmic scissors. After washing away residual blood from the heart with physiological saline, lysis buffer was added, and after complete lysis, protein quantification was performed. SDS-polyacrylamide gel electrophoresis was performed, and after completion, the semi-dry gel was transferred to a PVDF membrane. After blocking with blocking buffer, the membrane was incubated overnight at 4°C with primary antibody (TH 1:1000, GAPDH 1:5000). After washing at room temperature, the membrane was incubated with goat anti-rabbit IgG H&L pre-adsorbed secondary antibody (1:25000) at room temperature for 1 hour. After washing, the membrane was scanned using an Odyssey dual-color infrared laser imaging system. GAPDH was used as an internal control, and the gray value ratio of the target protein was calculated. The expression levels of TH and Cx43 proteins were analyzed and statistically analyzed.

[0065] 2.11 Statistical Methods

[0066] The experimental results were analyzed and processed using SPSS 20.0 statistical software. The data results are presented as follows: The results indicate that one-way ANOVA was used for testing. Before comparing the data from each group, normality and homogeneity of variance were tested. For pairwise comparisons of homogeneity of variance, the least significant difference (LSD) test was used, and for analysis of unequal variances, nonparametric tests were performed.

[0067] 3. Results

[0068] 3.1 Preparation of a paroxysmal atrial fibrillation model

[0069] like Figure 1 As shown, the Control group has a normal electrocardiogram of rats, with normal P waves and regular RR intervals; the Model group has P waves that disappear and are replaced by irregular f waves, and the RR intervals are absolutely irregular, indicating that the paroxysmal atrial fibrillation model has been successfully established.

[0070] 3.2 Effect of the pharmaceutical composition of the present invention on susceptibility to atrial fibrillation in PAF rats

[0071] Electrocardiography was used to detect the induction time and duration of atrial fibrillation in each group of rats to assess the susceptibility of PAF rats to atrial fibrillation. (See Table 1 and...) Figure 2 As shown in -A and 2-B, compared with the Model group, the atrial fibrillation induction time and duration were significantly prolonged and shortened in the TBL, TBM, TBH, and AMD groups (P<0.01, 0.001). Compared with the AMD group, there was no statistically significant difference in the atrial fibrillation induction time in the TBM and TBH groups (P>0.05), and no statistically significant difference in the atrial fibrillation duration in the TBL, TBM, and TBH groups (P>0.05). In summary, all embodiments of the pharmaceutical composition of the present invention can significantly prolong the atrial fibrillation induction time and shorten the atrial fibrillation duration, suggesting that the pharmaceutical composition of the present invention can reduce the susceptibility to atrial fibrillation in PAF rats.

[0072]

[0073] 3.3 Effects of the pharmaceutical composition of the present invention on atrial electrical conduction in PAF rats

[0074] The MappingLab mapping system was used to monitor changes in atrial conduction dispersion in each group of rats to assess atrial electrical conduction in PAF rats, as shown in Table 2. Figure 3 As shown, compared with the Control group, the conduction dispersion in the Model group was increased (P<0.05). Compared with the Model group, the conduction dispersion in the TBL group, TBM group, TBH group, and AMD group was significantly decreased (P<0.05). There were no statistically significant differences among the treatment groups (P>0.05). In summary, all embodiments of the pharmaceutical composition of the present invention can reduce atrial conduction dispersion in atrial fibrillation, suggesting that the pharmaceutical composition of the present invention can improve atrial electrical conduction in PAF rats.

[0075]

[0076] 3.4 Effects of the pharmaceutical composition of the present invention on the left atrial diameter and left atrial area in PAF rats

[0077] Small animal ultrasound was used to measure the atrial diameter and atrial area of ​​rats in each group to assess the atrial structural remodeling in PAF rats. Figure 4 As shown, compared with the Control group, the LAD and LA area in the Model group were significantly enlarged (P<0.001). Compared with the Model group, the LAD and LA area in the TBL, TBM, TBH, and AMD groups were significantly reduced (P<0.05, 0.01, 0.001, respectively). Compared with the AMD group, there was no statistically significant difference in atrial diameter between the TBM and TBH groups (P>0.05), and no statistically significant difference in atrial area between the TBL, TBM, and TBH groups (P>0.05). In summary, all embodiments of the pharmaceutical composition of the present invention can significantly reduce the diameter and area of ​​the left atrium, suggesting that the pharmaceutical composition of the present invention can improve atrial structural remodeling in PAF rats.

[0078]

[0079] 3.5 Effects of the pharmaceutical composition of the present invention on collagen fibers in the atrial myocardial tissue of PAF rats

[0080] Masson staining was used to detect fibrosis in the atrial myocardial tissue of rats in each group to assess atrial structural remodeling in PAF rats. (See attached image) Figure 5 As shown, no collagen fiber deposition was observed in the atrial myocardium tissue of the Control group; compared with the Control group, the deposition of collagen fibers around blood vessels in the atrial myocardium tissue of the Model group was significantly increased; compared with the Model group, the deposition of collagen fibers around blood vessels in the atrial myocardium tissue of the TBL group, TBM group, TBH group and AMD group was significantly reduced. In summary, this indicates that Tongbu Fangchan Fang significantly reduced collagen fibers in the atrial myocardium tissue of PAF rats, suggesting that Tongbu Fangchan Fang can improve atrial structural remodeling in PAF rats.

[0081] 3.6 Effect of the pharmaceutical composition of the present invention on TH protein expression in PAF rats

[0082] 3.6.1 Immunohistochemical detection of the effect of the pharmaceutical composition of the present invention on TH protein expression in PAF rats

[0083] Immunohistochemistry was used to detect TH protein expression in rats of each group to assess sympathetic remodeling in PAF rats. (See Table 4 for details.) Figure 6As shown, compared with the Control group, the Model group showed a significantly increased average distribution density and uneven distribution of TH protein, with a coarse and disordered morphology and clustered bundles, confirming the remodeling of the cardiac sympathetic nervous system in atrial fibrillation model rats (P<0.001). Compared with the Model group, the TBL, TBM, TBH, and AMD groups showed significantly decreased average distribution density and uneven distribution of TH protein (P<0.01, 0.001). Compared with the AMD group, the TBH group showed a significantly decreased uneven distribution of TH protein (P<0.001). There were no statistically significant differences among the treatment groups (P>0.05). In summary, the drug composition of the present invention significantly reduces the distribution density and uneven distribution of TH in PAF rats, suggesting that the drug composition of the present invention can improve the sympathetic nervous system remodeling in PAF rats.

[0084]

[0085] 3.6.2 Western blot analysis of the effect of the pharmaceutical composition of the present invention on TH protein expression in PAF rats

[0086] The expression of TH protein in the atrial tissue of rats in each group was detected by Western blot to assess the sympathetic remodeling in PAF rats. (See Table 5). Figure 7 (A represents TH protein; B represents Cx43 protein) As shown, compared with the Control group, the expression level of TH protein in the Model group was significantly upregulated (P<0.001). Compared with the Model group, the expression level of TH protein in the TBL group, TBM group, TBH group, and AMD group was significantly downregulated (P<0.001). There were no statistically significant differences among the treatment groups (P>0.05). In summary, the pharmaceutical composition of the present invention significantly downregulated the expression of TH protein in PAF rats, suggesting that the pharmaceutical composition of the present invention can improve the sympathetic remodeling of PAF rats.

[0087]

[0088] 3.7 Effect of the pharmaceutical composition of the present invention on Cx43 protein expression in PAF rats

[0089] 3.7.1 Immunofluorescence assay was used to detect the effect of the pharmaceutical composition of the present invention on the expression of Cx43 protein in PAF rats.

[0090] The expression and distribution of Cx43 protein in rats of each group were detected by immunofluorescence. Figure 8As shown, Cx43 protein expression was clear in the Control group, mainly exhibiting intermittent strip-like distribution, with a few scattered punctate distributions; Cx43 protein expression was significantly reduced in the Model group, showing scattered punctate distributions; Cx43 protein expression was significantly increased in the TBL, TBM, TBH, and AMD groups, with some Cx43 cells showing strip-like distributions. In summary, this demonstrates that the pharmaceutical composition of the present invention can upregulate Cx43 protein expression and improve Cx43 protein distribution in rats.

[0091] 3.7.2 Western blot analysis of the effect of the pharmaceutical composition of the present invention on Cx43 protein expression in PAF rats

[0092] The expression of Cx43 protein in the atrial tissue of rats in each group was detected by Western blot, as shown in Table 5. Figure 7 (A represents TH protein; B represents Cx43 protein) As shown, compared with the Control group, the expression level of Cx43 protein in the Model group was significantly downregulated (P<0.01); compared with the Model group, the expression level of Cx43 protein in the TBL group, TBM group, and TBH group was significantly upregulated (P<0.05); the expression level of Cx43 protein in the AMD group was upregulated, but there was no statistically significant difference (P>0.05). In summary, this indicates that the pharmaceutical composition of the present invention significantly upregulates the expression of Cx43 protein in rats.

[0093] 4. Discussion

[0094] The pathogenesis of peripheral atrial fibrillation (PAF) includes triggering and maintenance mechanisms. Previous studies have found that the maintenance mechanism, such as the "multiple wavelet" hypothesis, re-entrant excitation, and focal drive with fibrillation-like conduction, can lead to PAF. Atrial remodeling is the basis for its development, leading to changes in atrial function and structure. Ach and CaCl2 play important roles in atrial electrical remodeling. The combined use of Ach and CaCl2 can cause partial conduction block and inconsistent pulse diffusion, reducing the inhibitory effect of the sinoatrial node on ectopic excitation points, similar to the reentry mechanism of atrial fibrillation. Therefore, this study established a PAF animal model by injecting a mixture of Ach and CaCl2 into the tail vein of rats, aiming to explore the preventive and therapeutic effects of a traditional Chinese medicine formula on Ach-CaCl2-induced PAF. The results of this experiment showed that the P wave disappeared on the electrocardiogram of the model group rats and was replaced by a fully formed f wave with an absolutely irregular RR interval, indicating that the PAF rat model was successfully established, consistent with the results of previous studies.

[0095] The occurrence and maintenance of atrial fibrillation (PAF) are closely related to atrial remodeling, which mainly includes electrical remodeling, structural remodeling, and neural remodeling. Atrial electrical conduction is regulated by ion channels, pumps, and exchangers, and atrial conduction disturbances lead to atrial electrical remodeling, promoting the occurrence and maintenance of PAF. Its main characteristics include a shortened atrial effective refractory period and increased dispersion, cardiac conduction delay, and a decrease in adaptive frequency. In the early stages of atrial fibrillation, the stability of atrial myocardial cell membranes decreases, causing intracellular calcium... 2+ Increased influx leads to calcium overload, resulting in a shortened effective refractory period and action potential duration, lowering the atrial fibrillation threshold and increasing susceptibility to atrial fibrillation. The results of this study show that the pharmaceutical composition of this invention can significantly reduce atrial fibrillation susceptibility in PAF rats and decrease atrial conduction dispersion, suggesting that the pharmaceutical composition of this invention can improve atrial electrical remodeling in PAF rats. Atrial structural remodeling is a core link in the development of PAF. Atrial enlargement leads to changes in atrial structure, promoting anisotropic conduction of impulses, reducing electrical coupling between some cells, strengthening focal driving activity at ectopic excitation points, increasing conduction heterogeneity and delay, and forming reentry, thus promoting atrial fibrillation. Left atrial diameter and atrial area are both important predictors of atrial fibrillation structural remodeling. Atrial diameter and area values ​​are positively correlated with the recurrence rate of atrial fibrillation; therefore, left atrial diameter and left atrial area are the main methods for evaluating the degree of atrial enlargement. The results of this study show that the pharmaceutical composition of this invention can reduce the left atrial diameter and atrial area in PAF rats and reduce fiber deposition, suggesting that the pharmaceutical composition of this invention can improve atrial structural remodeling in PAF rats. Prolonged rapid atrial pacing can alter the density, morphology, and even spatial distribution of atrial autonomic nerve fibers, leading to neural remodeling and increasing the likelihood of atrial fibrillation triggering and maintenance. TH is the rate-limiting enzyme in norepinephrine synthesis and a marker of sympathetic nerve localization and activity. The results of this study show that the pharmaceutical composition of this invention can reduce the density of sympathetic nerve distribution and downregulate the expression of related proteins, suggesting that the pharmaceutical composition of this invention can improve atrial neural remodeling in PAF rats.

[0096] Fibrosis is the most prominent manifestation of structural remodeling. Atrial fibrosis mainly refers to the proliferation and differentiation of atrial fibroblasts into myofibroblasts, causing extracellular matrix remodeling, accompanied by atrial myocyte hypertrophy or hyperplasia—a pathophysiological process. Atrial fibrosis can cause heterogeneous conduction in the atria, leading to unidirectional conduction block and reentry, triggering atrial fibrillation. Prolonged atrial fibrillation can worsen the degree of atrial fibrosis, further promoting the maintenance and development of atrial fibrillation. Cx43 is a major channel protein expressed in the heart, mainly present at junctions between adjacent cells and intercalated discs in a flag-like or ladder-like arrangement. Its normal expression and distribution play an important role in normal cardiac electrical activity and coordinated contraction and relaxation. Abnormal Cx43 protein can accelerate the formation of atrial myocardial fibrosis, causing abnormal electrical coupling between cells, thereby triggering arrhythmias. The results of this study show that the atrial diameter and area are enlarged in PAF rats, atrial myocardial fibrosis deposition is increased, and Cx43 protein distribution is abnormal and expression is reduced, suggesting that structural remodeling occurs in the atria of PAF rats. The pharmaceutical composition of the present invention can reduce the diameter and area of ​​the left atrium, reduce atrial fibrosis deposition, increase Cx43 protein expression, and improve Cx43 protein distribution to varying degrees, thereby improving the structural remodeling of PAF rats.

[0097] Based on the clinical manifestations of paroxysmal atrial fibrillation, it can be categorized under the traditional Chinese medicine terms of "palpitation," "anxiety," and "fright palpitation," with the disease location in the heart. Professor Jia Zhenhua, guided by the theory of collaterals in traditional Chinese medicine, proposed that the pathogenesis of paroxysmal atrial fibrillation is characterized by "deficiency of ancestral qi, stagnation of deficient qi, and internal wind disturbing the collaterals." Ancestral qi travels through the respiratory tract to regulate respiration and circulates through the heart vessels to circulate qi and blood. When ancestral qi is deficient, qi fails to return to its source, floating upwards and shaking the chest, resulting in palpitations and easy fright, sometimes even leading to loss of control, as described in the *Suwen* (Plain Questions) chapter "On the Phenomena of Normal Human Qi": "It originates below the left breast, and its movement is felt through clothing; this is the leakage of ancestral qi." Based on these pathogenesis characteristics, the treatment principle of "tonifying and clearing the collaterals, extinguishing wind, and calming palpitations" was established, along with a formula for tonifying and clearing to prevent palpitations. Paroxysmal atrial fibrillation has a sudden onset, characterized by easy induction, sudden onset and cessation, loss of control, and recurrent attacks. Its typical manifestation is a feeling of rapid, uncontrollable heartbeat. From a macroscopic perspective, the typical manifestations and episodic characteristics of paroxysmal atrial fibrillation (PAF) are similar to the "active" and "frequently changing" characteristics of wind-evil. From a microscopic perspective, the electrocardiogram of PAF shows the disappearance of sinus P waves, replaced by f waves with varying shapes, sizes, and intervals, which is similar to the "frequently changing" characteristics of wind-evil, indicating a close relationship between PAF pathogenesis and wind-evil. This formula utilizes the warming and dispersing properties of wind-evil herbs to disperse, invigorate Yang, promote blood circulation, and dredge the meridians, thus nourishing the heart and spirit and alleviating palpitations. In summary, different dosage groups of the Tongbu Fangchan formula can effectively improve cardiac electrical remodeling, structural remodeling, and neural remodeling. This further corroborates the theoretical value of the collaterals theory in guiding PAF pathogenesis and has potential development prospects in the prevention and treatment of PAF. This study preliminarily confirms at the animal whole-body level that the Tongbu Fangchan formula has the effect of improving PAF electrical remodeling, structural remodeling, and neural remodeling; its specific regulatory mechanism needs further in-depth research at the molecular level.

[0098] Example 1:

[0099] The raw material formula is as follows: Astragalus membranaceus 20g, Cimicifuga foetida 15g, Bupleurum chinense 5g, Pueraria lobata 40g, Ziziphus jujuba var. spinosa 10g, Platycladus orientalis 20g, Angelica sinensis 10g, Ostrea gigas 40g, Ligusticum chuanxiong 10g, Corydalis yanhusuo 20g, Notopterygium incisum 5g, Coptis chinensis 15g, Nardostachys jatamansi 10g, Cornus officinalis 40g.

[0100] The above-mentioned raw materials are extracted, concentrated, dried, and made into capsules according to conventional formulation methods.

[0101] Example 2:

[0102] The raw material formula is as follows: 30g of raw Astragalus membranaceus, 10g of Cimicifuga foetida, 10g of Bupleurum chinense, 30g of Pueraria lobata, 15g of stir-fried Ziziphus jujuba var. spinosa, 15g of Platycladus orientalis, 15g of Angelica sinensis, 30g of raw Ostrea gigas, 15g of Ligusticum chuanxiong, 15g of Corydalis yanhusuo, 10g of Notopterygium incisum, 10g of Coptis chinensis, 15g of Nardostachys jatamansi, and 30g of Cornus officinalis.

[0103] Tablets are obtained by extracting, concentrating, drying, granulating, sizing, and compressing using conventional processes.

[0104] Example 3:

[0105] The raw material formula is as follows: Astragalus membranaceus 35g, Cimicifuga foetida 12g, Bupleurum chinense 12g, Pueraria lobata 30g, stir-fried Ziziphus jujuba var. spinosa 12g, Platycladus orientalis var. cylindrica 12g, Angelica sinensis 12g, raw oyster shell 35g, Ligusticum chuanxiong 15g, Corydalis yanhusuo 15g, Notopterygium incisum 10g, Coptis chinensis 10g, Nardostachys jatamansi 15g, Cornus officinalis 30g.

[0106] The product is obtained by extraction, concentration, drying, granulation, sizing, and encapsulation using conventional processes.

[0107] Example 4:

[0108] The raw material formula is as follows: Astragalus membranaceus 40g, Cimicifuga foetida 5g, Bupleurum chinense 15g, Pueraria lobata 20g, Ziziphus jujuba var. spinosa 20g, Platycladus orientalis 10g, Angelica sinensis 20g, Ostrea gigas 20g, Ligusticum chuanxiong 20g, Corydalis yanhusuo 10g, Notopterygium incisum 15g, Coptis chinensis 5g, Nardostachys jatamansi 20g, Cornus officinalis 20g.

[0109] Granules are prepared by extraction, concentration, granulation, and sizing using conventional processes.

[0110] Example 5:

[0111] Astragalus membranaceus 30g, Cimicifuga foetida 10g, Bupleurum chinense 10g, Pueraria lobata 30g, Ziziphus jujuba var. spinosa 15g, Platycladus orientalis var. 15g, Angelica sinensis 15g, Ostrea gigas 30g, Ligusticum chuanxiong 15g, Corydalis yanhusuo 15g, Notopterygium incisum 10g, Coptis chinensis 10g, Nardostachys jatamansi 15g, Cornus officinalis 30g.

[0112] The oral liquid was prepared by extraction, filtration, and processing using conventional methods.

[0113] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition for the prevention or treatment of atrial fibrillation, characterized in that... The composition consists of the following components in parts by weight: Astragalus membranaceus 20-40 parts, Cimicifuga foetida 5-15 parts, Bupleurum chinense 5-15 parts, Pueraria lobata 20-40 parts, Ziziphus jujuba var. spinosa 10-20 parts, Platycladus orientalis var. 10-20 parts, Angelica sinensis 10-20 parts, Ostrea gigas 20-40 parts, Ligusticum chuanxiong 10-20 parts, Corydalis yanhusuo 10-20 parts, Notopterygium incisum 5-15 parts, Coptis chinensis 5-15 parts, Nardostachys jatamansi 10-20 parts, and Cornus officinalis 20-40 parts.

2. The composition according to claim 1, characterized in that... The composition consists of the following components in parts by weight: Astragalus membranaceus 30 parts, Cimicifuga foetida 10 parts, Bupleurum chinense 10 parts, Pueraria lobata 30 parts, Ziziphus jujuba var. spinosa 15 parts, Platycladus orientalis var. cylindrica 15 parts, Angelica sinensis 15 parts, Ostrea gigas 30 parts, Ligusticum chuanxiong 15 parts, Corydalis yanhusuo 15 parts, Notopterygium incisum 10 parts, Coptis chinensis 10 parts, Nardostachys jatamansi 15 parts, and Cornus officinalis 30 parts.

3. The composition according to claim 1, characterized in that... The composition consists of the following components in parts by weight: Astragalus membranaceus 20 parts, Cimicifuga foetida 15 parts, Bupleurum chinense 5 parts, Pueraria lobata 40 parts, Ziziphus jujuba var. spinosa 10 parts, Platycladus orientalis 20 parts, Angelica sinensis 10 parts, Ostrea gigas 40 parts, Ligusticum chuanxiong 10 parts, Corydalis yanhusuo 20 parts, Notopterygium incisum 5 parts, Coptis chinensis 15 parts, Nardostachys jatamansi 10 parts, and Cornus officinalis 40 parts.

4. The composition according to claim 1, characterized in that... The composition consists of the following components in parts by weight: Astragalus membranaceus 40 parts, Cimicifuga foetida 5 parts, Bupleurum chinense 15 parts, Pueraria lobata 20 parts, Ziziphus jujuba var. spinosa 20 parts, Platycladus orientalis 10 parts, Angelica sinensis 20 parts, Ostrea gigas 20 parts, Ligusticum chuanxiong 20 parts, Corydalis yanhusuo 10 parts, Notopterygium incisum 15 parts, Coptis chinensis 5 parts, Nardostachys jatamansi 20 parts, and Cornus officinalis 20 parts.

5. The composition according to claim 1, characterized in that... The composition consists of the following components in parts by weight: Astragalus membranaceus 35 parts, Cimicifuga foetida 12 parts, Bupleurum chinense 12 parts, Pueraria lobata 30 parts, Ziziphus jujuba var. spinosa 12 parts, Platycladus orientalis var. cylindrica 12 parts, Angelica sinensis 12 parts, Ostrea gigas 35 parts, Ligusticum chuanxiong 15 parts, Corydalis yanhusuo 15 parts, Notopterygium incisum 10 parts, Coptis chinensis 10 parts, Nardostachys jatamansi 15 parts, and Cornus officinalis 30 parts.

6. The composition according to any one of claims 1-5, characterized in that... In this composition, Astragalus membranaceus is preferably raw, oyster shell is preferably raw, and jujube seed is roasted.

7. The composition according to any one of claims 1-5, characterized in that... The formulation of this composition is in the form of capsules, tablets, pills, oral liquids, granules, injections, or powders.

8. The composition according to any one of claims 1-5, characterized in that... Application of this pharmaceutical composition in the preparation of drugs for atrial structural remodeling.

9. The composition according to any one of claims 1-5, characterized in that... The application of this pharmaceutical composition in the preparation of drugs that improve atrial electrical conduction and cardiac electrical remodeling.

10. The composition according to any one of claims 1-5, characterized in that... The application of this pharmaceutical composition in the preparation of drugs that improve sympathetic remodeling.

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