Dual-heart disease refers to the coexistence of cardiovascular disease and mental illness, which interact to form complex pathophysiological changes. Coronary heart disease (CHD) complicated by depression is the most common clinical type [1] . Statistics show that the incidence of depression in CHD patients is approximately 15% - 30%, and it increases to 30% - 60% after acute myocardial infarction. Moreover, CHD patients with depression have a significantly higher incidence of cardiovascular accidents [2] . With population aging and changes in work and living pressures, the morbidity and mortality of CHD complicated by depression have increased annually, imposing growing economic and life burdens on society, especially in underdeveloped ethnic regions, and have become a major public health concern. Therefore, analyzing the medication and prescription rules for this disease can provide theoretical support for subsequent diagnosis, treatment, and medication.

Traditional Chinese medicine (TCM) does not have a specific term for CHD complicated with depression, which falls under the categories of “心痛” (heart pain), “胸痹” (chest impediment), “胸痛” (chest pain) combined with “郁证” (depression syndrome), “百合病” (lily disease), and “脏躁” (hysteria). Symptoms include chest pain, chest tightness, palpitations, shortness of breath, sighing, lethargy, poor appetite and sleep, fatigue, a dark tongue with a white greasy coating, and a thready, string-like, or deep pulse. TCM physicians have long recognized the interaction between zang-fu organs, qi movement, and emotions. Su Wen·Ling Lan Mi Dian Lun states, “The heart is the monarch organ, from which spirit brilliance emanates.” Ling Shu·Ben Shen notes, “Grief, sorrow, worry, and anxiety disturb the heart; when the heart is disturbed, all zang-fu organs shake” and “Deficiency of heart qi leads to sadness, while excess leads to incessant laughter.” Su Wen·Ju Tong Lun describes, “Anger causes qi to rise; joy causes qi to relax; sorrow causes qi to dissipate; fear causes qi to sink; shock causes qi to become chaotic; overthinking causes qi to stagnate.” Jin Kui Yao Lue·Xiong Bi Xin Tong Duan Qi Bing Mai Zheng Zhi Jiu records, “Pulse examination should identify excess and deficiency; faint yang and tight yin pulses indicate chest impediment and pain, resulting from extreme deficiency. Yang deficiency in the upper jiao and tight yin pulses cause chest impediment and heart pain.” Lin Zheng Zhi Nan Yi An states, “Depressive disorders always start with qi disease; when qi flows smoothly, there is no depression.” Dan Xi Xin Fa·Liu Yu emphasizes, “Harmony of qi and blood prevents disease; depression gives rise to various illnesses.” With social and economic development, changes in lifestyle, and work pressure, TCM physicians vary in clinical medication based on regional environment, constitution, and personal experience.

All included prescriptions in this study clearly specified disease names, formula names, herb names, and dosages, with no forbidden herb combinations or highly toxic herbs, and no reported adverse reactions. Prescription composition and dosages were appropriate, with reasonable monarch-minister-assistant-guide 配伍, reflecting the rationality and safety of TCM in disease treatment. Formula categories mainly included qi-regulating, blood-regulating, phlegm-resolving, harmony-restoring, tonifying, and mind-calming formulas, aligning with the pathogenesis of deficiency, depression, phlegm, and stasis in CHD complicated with depression [3] . For syndromes of CHD complicated with depression, liver depression, qi stagnation, blood stasis, and phlegm turbidity are predominant. Za Bing Yuan Liu Xi Zhu·Xin Tong states, “Heart pain may be caused by cold pathogen, phlegm-fluid retention, or blood stasis, treated by warming and unblocking cold, promoting blood circulation and removing stasis.” Zheng Yin Mai Zhi·Xiong Bi notes, “Chest impediment presents with chest tightness, shortness of breath, wheezing, cough with saliva, chest and back pain, deep and slow pulse at cun position, and tight and rapid pulse at guan position, due to phlegm-fluid stagnation and failure of chest yang to circulate.” Additionally, Zheng Yin Mai Zhi·Yu Zheng states, “Depressive syndrome results from emotional discomfort and qi stagnation, treated by soothing the liver, relieving depression, regulating qi, and harmonizing the middle jiao.” Ling Shu·Ben Shen states, “Deficiency of heart qi leads to sadness,” indicating that insufficient qi and blood production or disordered qi and blood in the heart may cause spirit malnutrition and depression. Thus, spleen deficiency, qi stagnation, blood stasis, and phlegm turbidity are key pathogenic factors. The root cause of this disease lies in dysfunction of liver dispersion; liver depression impairs the spleen, and the spleen and stomach are the hub of qi movement. Qi disorder leads to zang-fu dysfunction: “Smooth liver qi ensures harmonious heart qi; stagnant liver qi causes heart qi deficiency.” The heart is the monarch of zang-fu organs, and liver qi interacts with heart qi; liver qi stagnation gives rise to various symptoms. Therefore, treatment should focus on soothing the liver and relieving depression, combined with nourishing the heart and calming the spirit, strengthening the spleen and resolving dampness, and promoting blood circulation and unblocking collaterals for optimal efficacy.

In terms of herb nature, flavor, and meridian tropism, herbs for CHD complicated with depression are mainly cold, warm, or neutral, with bitter and pungent flavors, primarily entering the liver, spleen, and heart meridians. Jing Yue Quan Shu·Za Zheng Mo·Yu Zheng states: “For anger injuring the liver with unresolved rebellious qi causing distension or pain, Jie Gan Jian is appropriate. For anger injuring the liver leading to fire, heat, flank pain, distension, or bleeding, Hua Gan Jian is suitable. For unresolved anger depression with phlegm formation, Wen Dan Tang is used. For liver and spleen injury after anger with fatigue and poor appetite, Wu Wei Yi Gong San is indicated.” CHD complicated with depression is a chronic disease; long-term stagnation generates internal heat, damaging yin and blood. Treatment follows “cooling heat syndromes” (for heat) and “tonifying deficiency syndromes” (for spleen and liver), using cold, warm, and neutral herbs. Bitter flavor drains and dries; pungent flavor circulates, disperses, opens orifices, and resolves dampness; sweet flavor tonifies, relieves pain, and harmonizes; sour flavor astringes, relieves pain, and softens the liver. Combined flavors achieve draining stagnant heat, pungent dispersion for blood circulation, sweet nourishment, and sour astringency for pain relief, reflecting TCM principles of combining tonification and draining, and balancing cold and heat. The liver is most closely related to this disease: “The liver is a hard organ needing free flow”; impaired dispersion affects the spleen (“Treating liver disease requires strengthening the spleen first”). Spleen deficiency reduces qi and blood production; the heart governs blood vessels and stores spirit, so insufficient vessel filling leads to spirit disturbance. The lung governs qi, disperses, descends, and regulates water passages, cooperating with liver dispersion to ensure smooth qi movement. Modern studies by Xu et al. [4] using data mining on medication rules for CHD complicated with depression identified Bupleurum chinense, Curcuma aromatica, Cyperus rotundus, Salvia miltiorrhiza, Ligusticum chuanxiong, Paeonia lactiflora, Poria cocos, and Glycyrrhiza uralensis as core herbs, with neutral, cold, and warm natures and sweet, bitter, and pungent flavors, entering the heart, liver, and spleen meridians, consistent with our findings.

Association rule analysis identified 21 high-support herb pairs (frequencies ≥ 50: Bupleurum chinense-Glycyrrhiza uralensis, Bupleurum chinense-Paeonia lactiflora, Bupleurum chinense-Ligusticum chuanxiong, etc.) and 27 high-confidence associations (confidence ≥ 0.90: Paeonia lactiflora-Curcuma aromatica→Bupleurum chinense, Ligusticum chuanxiong-Paeonia lactiflora→Bupleurum chinense, etc.). Nine core herbs were identified: Bupleurum chinense, Glycyrrhiza uralensis, Paeonia lactiflora, Ligusticum chuanxiong, Curcuma aromatica, Salvia miltiorrhiza, Poria cocos, Citrus aurantium, and Cyperus rotundus, with combined effects of soothing the liver, relieving depression, promoting blood circulation, regulating qi, strengthening the spleen, and softening the liver. This formulation is derived from Chai Hu Shu Gan San (Bupleurum Liver-Soothing Powder) by removing Citrus reticulata and adding Salvia miltiorrhiza, Poria cocos, and Citrus aurantium, thereby enhancing the effects of strengthening the spleen, resolving phlegm, and promoting blood circulation.

Cluster analysis yielded 5 core formulas as basic combinations for treatment: 1) Group 1 (Bupleurum chinense, Poria cocos, Glycyrrhiza uralensis, Ligusticum chuanxiong, Codonopsis pilosula, Atractylodes macrocephala) is derived from Xiao Yao San minus Angelica sinensis and Paeonia lactiflora, plus Ligusticum chuanxiong and Codonopsis pilosula to enhance qi circulation, pain relief, spleen strengthening, and qi replenishment, focusing on soothing the liver, relieving depression, strengthening the spleen, and replenishing qi. Zong et al. [5] used Xiao Yao San for 8 weeks in 60 patients, achieving a 90% total effective rate in improving angina and depression with few adverse reactions (P < 0.05 vs. control). Lyu [6] observed 39 patients treated with Xiao Yao San plus fluoxetine, showing a significantly higher effective rate and lower recurrence than control (P < 0.05). 2) Group 2 (Bupleurum chinense, Salvia miltiorrhiza, Curcuma aromatica, Glycyrrhiza uralensis, Paeonia lactiflora, Cyperus rotundus) is modified from Chai Hu Shu Gan San minus Citrus reticulata, Citrus aurantium, and Ligusticum chuanxiong, adding Salvia miltiorrhiza and Curcuma aromatica to enhance qi and blood circulation and liver-soothing depression relief, suitable for liver qi stagnation, blood stasis with internal heat. Hu [7] used modified Chai Hu Shu Gan San in 31 patients, showing superior TCM syndrome scores, anxiety-depression scores, and angina scores vs. control (P < 0.05). 3) Group 3 (Pinellia ternata, Glycyrrhiza uralensis, Bupleurum chinense, Poria cocos, Trichosanthes kirilowii, Ligusticum chuanxiong) is derived from Gua Lou Xie Bai Ban Xia Tang minus Allium macrostemon, adding Bupleurum chinense, Poria cocos, and Ligusticum chuanxiong to enhance phlegm resolving, liver soothing, blood circulation, and pain relief, suitable for phlegm-stasis binding and qi stagnation-blood stasis. Wang et al. [8] observed 64 patients treated with modified Gua Lou Xie Bai Ban Xia Tang for 2 months, with a 93.65% total effective rate significantly higher than control and reduced levels of inflammatory factors (IL-1β, IL-6, TNF-α; P < 0.01). Zhai et al. [9] identified common herbs for chest impediment as Allium macrostemon, Trichosanthes kirilowii, Poria cocos, Pinellia ternata, and Zingiber officinale through textual research. Additionally, the 2017 Expert Consensus on Integrative Chinese and Western Medicine Diagnosis and Treatment of Atherosclerosis [10] included modified Gua Lou Xie Bai Ban Xia Tang for phlegm-stasis syndrome of atherosclerosis. Group 3 formula adds Bupleurum chinense, Ligusticum chuanxiong, and Poria cocos to enhance liver-soothing depression relief and mind-calming, beneficial for CHD complicated with depression.

After deduplication and integration of core formulas with frequencies > 30, the core prescription for CHD complicated with depression was determined: Bupleurum chinense, Poria cocos, Ligusticum chuanxiong, Codonopsis pilosula, Atractylodes macrocephala, Salvia miltiorrhiza, Curcuma aromatica, Cyperus rotundus, Pinellia ternata, Trichosanthes kirilowii, and Glycyrrhiza uralensis. This prescription is modified from Chai Hu Shu Gan San as the base formula. Experimental studies [11] showed that modified Chai Hu Shu Gan San improved the depressive state and myocardial ischemia in CHD-complicated-depression rat models, and regulated serum lipid levels (TC, TG, LDL, HDL) and the contents of Apelin-13 and ERK1/2 (P < 0.01). Numerous clinical studies [12] - [14] confirmed that modified Chai Hu Shu Gan San combined with conventional Western medicine was more effective than the control in treating CHD complicated with depression (P < 0.05), demonstrating its solid clinical foundation. Targeted modification of classic formulas, based on modern constitution, symptoms, and signs, enhances efficacy.

Analysis of the core prescription’s compatibility showed that Bupleurum chinense combined with Cyperus rotundus and Curcuma aromatica forms a key herb group for soothing the liver, regulating qi, and relieving depression, strengthening both depression relief and blood circulation for pain relief. Poria cocos combined with Atractylodes macrocephala and Codonopsis pilosula enhances spleen strengthening, qi replenishment, mind calming, and spirit stabilizing, reflecting the principle of “strengthening the spleen first when treating liver disease.” Salvia miltiorrhiza combined with Ligusticum chuanxiong promotes blood circulation, removes stasis, and unblocks collaterals for pain relief. Pinellia ternata combined with Trichosanthes kirilowii resolves phlegm, dissipates masses, and regulates qi in the chest. Glycyrrhiza uralensis harmonizes all herbs and relieves spasm for pain relief. The entire prescription constructs a comprehensive treatment system of “co-regulating the liver, spleen, and heart; simultaneously treating deficiency, excess, phlegm, and stasis.” Through synergistic compatibility of tonification with qi regulation and collateral unblocking, it achieves “soothing the liver and regulating qi without consuming healthy qi, promoting blood circulation and unblocking collaterals without leaving stasis, strengthening the spleen and replenishing qi to consolidate the root without causing stagnation or assisting pathogens,” balancing regulation. Herb compatibility emphasizes both qi-blood co-regulation (nourishing blood to soften the liver, replenishing qi to promote blood circulation) and zang-fu synergy (soothing the liver and strengthening the spleen to calm the spirit, resolving phlegm and unblocking collaterals to stabilize the heart), forming a bidirectional regulation mechanism of “strengthening the root to consolidate the foundation” and “eliminating pathogens to unblock collaterals.” It ultimately integrates four-dimensional efficacies: “strengthening the spleen and nourishing blood, soothing the liver and relieving depression, promoting blood circulation and resolving phlegm, calming the mind and stabilizing the spirit,” fully embodying TCM characteristics of “treating both the root and branch, combining attack and tonification.”

This study analyzed TCM medications and prescription rules for CHD complicated with depression using literature data mining. The core treatment principles include soothing the liver and regulating qi, promoting blood circulation and unblocking collaterals, resolving phlegm and removing turbidity, relieving depression and stabilizing the mind, strengthening the spleen and replenishing qi, harmonizing the liver and spleen, and replenishing qi to stabilize the heart, emphasizing zang-fu function synergy and qi movement balance for treating both the root and branch. Herb compatibility coordinates “spleen strengthening, liver soothing, blood circulation promotion, and phlegm resolving.” Additionally, artificial intelligence models were used to assist in literature review, key data extraction, and statistical analysis, significantly reducing researchers’ workload in tedious data processing, improving efficiency, and providing new ideas for future literature data mining research.

Self-funded project of Guangxi Zhuang Autonomous Region Administration of Traditional Chinese Medicine (GXZYA20230181, GXZYA20230200); Scientific Research Project of Guangxi University of Chinese Medicine (General Fund) (2024MS017); Open Project of Guangxi Health Emergency Skills Training Center for the Year 2024 (HESTCG202403); Doctoral Research Start-up Fund of Guangxi University of Chinese Medicine.

Zheng Chuncheng conceived and designed the study, analyzed the data, and drafted the manuscript. Yang Liqiang and Zeng Qingqing contributed to data collection and manuscript revision. All authors read and approved the final manuscript.