Traditional Chinese Medicine Syndrome Types, Medication Patterns, and Related Pharmacological Analysis of Chronic Heart Failure Based on Data Mining and Network Pharmacology
Chronic heart failure (CHF), as the terminal stage of various cardiovascular diseases, has caused serious impacts worldwide. A study has found that there are over 64.3 million heart failure patients worldwide, and their average age of onset is decreasing. It is estimated that by 2030, over 8 million people in the United States will suffer from heart failure, with each patient spending nearly $30000 annually. In China, there are currently over 8.9 million heart failure patients, and the number of patients is still increasing. At present, the conventional treatment drugs for heart failure include beta blockers, angiotensin-converting enzyme inhibitors, aldosterone antagonists, etc., which have the disadvantages of large side effects and high recurrence rate in the long term. Traditional Chinese medicine has a long history of treating chronic heart failure, and has certain advantages in improving myocardial fibrosis, antioxidant and anti-inflammatory reactions, regulating mitochondrial energy metabolism, inhibiting cell apoptosis, etc. It also has the characteristics of safety, reliability, few side effects, simplicity and affordability. Its effectiveness in preventing and treating CHF is increasingly valued. Core journals are an important component of China’s academic evaluation system and are recognized as journals with high academic standards, making them more informative. Therefore, based on data mining and network pharmacology techniques, this article summarizes and analyzes the traditional Chinese medicine treatment formulas for chronic heart failure published in core journals in the past 20 years, and explores in depth the TCM syndrome types, medication rules, and characteristics of CHF, as well as the mechanism of action of high-frequency drug groups in the treatment of CHF, in order to provide reference for further clinical and scientific research.

 

There is no specific record of chronic heart failure in ancient Chinese medicine books. Due to its main symptoms such as palpitations, wheezing, and limb edema, it can be classified under the categories of “palpitations”, “wheezing syndrome”, “edema” and other diseases in traditional Chinese medicine. The description of it in traditional Chinese medicine can be traced back to the Yellow Emperor’s Inner Canon. For example, the Ling Shu states: “Those with heart distension are troubled by short qi and restless lying down.” Similarly, the Su Wen states: “Those with heart obstruction have blocked meridians, while those with restlessness have bulging hearts and shortness of breath. Throughout history, medical experts have extensively discussed it, accumulating valuable experience for the treatment of chronic heart failure with traditional Chinese medicine. Nowadays, contemporary medical practitioners have basically reached a consensus on its treatment, such as tonifying qi and warming yang, promoting blood circulation and diuresis, and treating the same symptoms and root causes. At present, although Western medicine has certain therapeutic effects on CHF, there are many adverse reactions, while traditional Chinese medicine is safe and effective in treating CHF, with certain advantages in improving symptoms and enhancing quality of life. Traditional Chinese medicine therapy has become one of the important means of treating CHF.

Through data mining, it was found that the main TCM syndromes of CHF are Yang deficiency and water flooding syndrome, as well as Qi deficiency and blood stasis syndrome. The most frequently used TCM classifications are tonifying deficiency drugs, promoting blood circulation and removing blood stasis drugs, and diuresis and dampness dispelling drugs, which are consistent with the characteristics of the main TCM syndromes of CHF. The medicinal properties are mainly warm, calm, and slightly cold, and the medicinal flavors are mostly sweet, spicy, and bitter, mainly affecting the lungs, spleen, and heart meridians. Among them, Huangqi, Danshen, Fuling, Licorice, Fuzi, and Tengzi have the highest frequency of use. Huangqi has a warm medicinal property and a sweet taste. It can replenish qi, absorb blood, promote diuresis, and reduce swelling. Modern pharmacological research has shown that it can reduce cardiac load and improve blood absorption ability. Danshen is beneficial for regulating the heart and liver meridians, promoting blood circulation, removing blood stasis, and generating new energy. Research has found that it can improve coronary circulation and resist myocardial ischemia. Fuling Ganping has the effects of invigorating the spleen, promoting diuresis, calming the heart, and calming the mind. Pharmacological studies have shown that it can promote diuresis and enhance myocardial contractility. Licorice can nourish the heart qi, invigorate qi and restore pulse, and has anti arrhythmic effects. Fuzi, as a warming herb, can nourish fire and promote yang, and has a significant effect on strengthening the heart. Tingpuzi can reduce swelling and promote diuresis. According to “Chinese Materia Medica”, it is good at “wheezing and swelling in heart failure”, which can increase cardiac output, reduce cardiac load, and promote diuresis. Traditional Chinese Medicine believes that the pathogenesis of CHF is based on the deficiency of the root and the excess of the excess, which is mainly caused by the pathogenic factors of blood stasis and water dampness. Therefore, it is commonly used to supplement deficiency, promote blood circulation and remove blood stasis, and promote diuresis and dampness to achieve the goal of supplementing deficiency, resolving blood stasis, and promoting diuresis. Its location is in the heart and closely related to the lungs and spleen. The heart is a fire organ that relies on the fire nature to promote blood circulation. The heart and lungs coexist in the upper burner, and the heart controls blood circulation and the lungs affect each other’s breathing. When heart failure occurs, the fire qi is weak and cannot promote circulation. If the heart meridian is blocked, the lungs will lose convergence, and if the lung’s circulation is abnormal, it will not be able to help the heart flow blood normally. The heart and spleen are both involved in the transformation of blood. The essence of water and grain in the spleen runs through the heart meridian and turns red to produce blood. The heart controls the blood, while the spleen controls the blood. Fire is the mother of earth. When heart failure occurs, the mother is weak and the child is weak, and the fire does not warm the earth. The spleen’s soil transport and transformation are lost, making it difficult for qi and blood to be generated. Blood does not follow the meridians, and phlegm and fluid are concentrated, further exacerbating heart failure. The lungs control the qi of the body, and the spleen is the source of qi and blood. Supplementing the lungs and spleen promotes biochemical activity and restores qi and blood. Therefore, using warm and pungent substances to promote circulation in the lungs, sweet and calm substances to promote circulation in the spleen, and bitter and slightly cold medicines to promote the heart meridian, strengthens the heart and qi, promotes the circulation of fire and qi, and facilitates blood circulation. When the Ming Dynasty returns to its original position, blood stasis and dampness are eliminated, and heart failure is stopped.

Cluster analysis can group high-frequency traditional Chinese medicines for treating CHF into four categories. Class I includes Ophiopogon japonicus, Schisandra chinensis, Salvia miltiorrhiza, and Panax ginseng. This is a modified formula of Shengmai San and Salvia miltiorrhiza. In the early stage of chronic heart failure, the main symptoms are heart and lung qi deficiency. If qi deficiency persists for a long time, blood stasis persists, and the heart fails to produce enough blood, it can lead to a deficiency of both qi and yin. The prescription uses Shengmai San to nourish qi and yin, and modified Danshen can enhance the ability to promote blood circulation and remove blood stasis. Modern research has shown that Shengmai San can have anti heart failure effects by anti-inflammatory, improving mitochondrial function, and enhancing ventricular remodeling. Class II includes safflower, peach kernel, Chuanxiong, angelica, and red peony, which are modified formulas for Taohong Siwu Tang. In the formula, Taohong promotes blood circulation and removes blood stasis, and is combined with Siwu to supplement blood and blood. Research has found that Taohong Siwu Tang can reduce the expression of matrix metalloproteinase-2 (MMP-2) in the myocardium of heart failure rats, inhibit myocardial remodeling, improve heart function, and alleviate heart failure. Class III includes Codonopsis pilosula, Panax notoginseng, Leonurus heterophyllus, Zelan, Scutellaria baicalensis, Scutellaria baicalensis, Atractylodes macrocephala, Alisma vulgaris, Astragalus membranaceus, and Poria cocos, which have the functions of nourishing qi, activating blood circulation, promoting lung function, and promoting diuresis. They mainly focus on promoting diuresis and are suitable for heart failure with edema as the main symptom. Class V includes Poria cocos, Atractylodes macrocephala, Paeonia lactiflora, Ginger, Aconitum, Licorice, Cinnamomum cassia, and Dried Ginger. This is a modified formula of Zhenwu Tang and Cinnamomum cassia Licorice Tang. If chronic heart failure persists and both the heart and kidney yang qi are deficient, with water and dampness overflowing, then the combination of Zhenwu Tang and Guizhi Gancao Tang can be used to warm up the heart yang and lower the kidney yang, achieving the effect of warming yang and promoting water circulation. Studies have shown that the combination of the two can significantly improve cardiac function, alleviate clinical symptoms, and promote ventricular remodeling.

Association rule analysis resulted in 11 drug groups: Huangqi Danshen, Huangqi Tingpuzi, Fuling Baizhu, Huangqi Chuanxiong, Huangqi Ophiopogon, Huangqi Fuling Danshen, Huangqi Tingpuzi Danshen, Huangqi Licorice Danshen, Fuling Baizhu Huangqi, Huangqi Tingpuzi Fuling, Huangqi Guizhi Fuling. Among them, the combination of Huangqi and Danshen has the highest degree of support. Huangqi is a qi tonifying medicine with a good nature to nourish qi and invigorate qi, while Danshen is a blood activating medicine with a long function to promote blood circulation and remove blood stasis. When the two medicines are used together, qi flows through blood, blood stasis is eliminated, and new life is formed, greatly benefiting the heart muscle. Modern research has shown that Huangqi Danshen can improve myocardial contractility and reverse myocardial hypertrophy. The combination of Huangqi and Tengzi can both strengthen the heart and enter the lung meridian. Huangqi benefits lung qi and helps Tengzi enhance the function of promoting diuresis and reducing swelling. Pharmacological studies have found that Astragalus membranaceus can regulate mitochondrial dynamics in myocardial tissue of heart failure rats, thereby exerting anti heart failure effects. The combination of Poria cocos and Atractylodes macrocephala is necessary. Poria cocos promotes diuresis and dampness, while Atractylodes macrocephala strengthens the spleen and dries dampness. The combination of the two medicines promotes dryness and dampness, and the combination of good fortune and good fortune can treat various syndromes caused by spleen deficiency and internal stagnation of water intake. Studies have shown that the method of strengthening the spleen and promoting diuresis is an important treatment for cardiovascular diseases, and the use of the “heart spleen simultaneous treatment” approach to regulate heart failure also has good effects. Huangqi combined with Chuanxiong, Huangqi promotes qi and blood production. Chuanxiong is a blood medicine in the qi, which can maintain the blood concentration of the main component of Chuanxiong, ligustilide, in rats with myocardial ischemia, and prolong myocardial protection. Huangqi combined with Ophiopogon japonicus can nourish qi and blood. Ophiopogon japonicus can not only replenish qi, but also nourish yin. Huangqi can help Ophiopogon japonicus play a role in replenishing qi. Based on the combination of the above medicine groups, it mainly emphasizes the combination of functions such as tonifying qi, strengthening spleen, promoting blood circulation, and promoting diuresis.

Network pharmacology analysis was conducted on Huangqi Danshen, which has the highest frequency of use. The results showed that quercetin, 6-O-syringin-8-O-acetylshanzhizhi glycoside methyl ester, luteolin, kaempferol, and salvianolic acid B can simultaneously act on multiple CHF targets with high correlation, indicating that they may be the main efficacy substances of Huangqi Danshen in treating CHF. Research has found that quercetin has antihypertensive, anti-inflammatory, and antioxidant effects. It can alleviate the degree of myocardial fibrosis in spontaneously hypertensive rats and improve ventricular remodeling. Osmanthus extract can improve cardiac dysfunction in rats with heart failure by regulating the expression of SERCA2a. Kaempferol can alleviate Ang II induced cardiac fibrosis and dysfunction in mice by inhibiting inflammatory response and oxidative stress. Danshensu B can inhibit Ang II induced proliferation and collagen synthesis of cardiac fibroblasts, as well as suppress the expression of TGF – β/Smad pathway. Through the construction of protein interaction network and further screening of core targets, it was found that IL1B, ALB, AKT1, TNF, CASP3, IL6, EGFR, SRC, TP53, and VEGFA were at the core of the network and were significantly enriched in many pathways, of which IL1B was enriched in lipid and arteriosclerosis, ErbB signaling pathways; ALB is enriched in serum synapses and thyroid hormone synthesis pathways; AKT1 is enriched in lipid and atherosclerosis, relaxin signaling pathway, FoxO signaling pathway, HIF-1 signaling pathway, VEGF signaling pathway, ErbB signaling pathway; TNF is enriched in lipid and atherosclerosis, FoxO signaling pathway, ErbB signaling pathway; CASP3 is enriched in lipid and atherosclerosis signaling pathways; IL6 is enriched in lipids and atherosclerosis, FoxO signaling pathway, HIF-1 signaling pathway; EGFR is enriched in lipid and atherosclerosis, relaxin signaling pathway, FoxO signaling pathway, HIF-1 signaling pathway, VEGF signaling pathway, ErbB signaling pathway; SRC is enriched in lipid and atherosclerosis, relaxin signaling pathway, VEGF signaling pathway, ErbB signaling pathway; TP53 is enriched in lipid and atherosclerosis, VEGF signaling pathway, ErbB signaling pathway; VEGFA is enriched in lipid and atherosclerosis, relaxin signaling pathway, HIF-1 signaling pathway, and VEGF signaling pathway. Therefore, it is speculated that they are the core targets regulated by Huangqi Danshen in the treatment of CHF. The key pathways of enrichment mainly include VEGF signaling pathway, lipid and atherosclerosis signaling pathway, relaxin signaling pathway, HIF-1 signaling pathway, ErbB signaling pathway, FoxO signaling pathway, etc. The VEGF signaling pathway can maintain the activity of endothelial cells, promote the generation of cardiac lymphatic vessels, and play a protective role in the progression of cardiac hypertrophy and heart failure. Lipid deposition is one of the main pathological characteristics of atherosclerosis, and coronary atherosclerosis is closely related to the occurrence and development of heart failure. Relaxin, as a multi acting hormone, can regulate inflammation, fibrosis, and arrhythmia, and has been shown to have cardioprotective effects in animal models of ischemic heart failure. The HIF-1 signaling pathway is an important pathway for hypoxia regulation, which has functions such as promoting angiogenesis, anti hypoxia, and improving metabolism, and is beneficial for alleviating the ischemic and hypoxic state of heart failure myocardium. The ErbB signaling pathway can participate in the development of the embryonic heart and maintain the normal structure and function of the heart in adulthood. The FoxO signaling pathway is an important antioxidant signaling pathway in the body, and regulating it can improve oxidative stress in heart failure rats.

In summary, this study found through data mining and network pharmacology that the traditional Chinese medicine (TCM) syndrome types of clinical research cases related to chronic heart failure in the past 20 years are mainly Yang deficiency, water flooding syndrome, and Qi deficiency and blood stasis syndrome. TCM treatment mainly includes tonifying deficiency drugs, promoting blood circulation and removing blood stasis drugs, and promoting diuresis and dampness. They are often used in combination with drugs with warm, calm, and slightly cold properties, sweet, spicy, and bitter flavors, and are suitable for the lungs, spleen, and heart meridians. Among them, high frequency medicine group astragalus salvia miltiorrhiza may play an anti heart failure mechanism through VEGF signaling pathway, lipid and atherosclerosis signaling pathway, relaxin signaling pathway, HIF-1 signaling pathway, ErbB signaling pathway, FoxO signaling pathway, etc., which provides a reference for further clinical medication and mechanism research of traditional Chinese medicine in treating CHF.