Baofu Wang1†
Yu Teng1†
Yang Li1†Sijia Lai1Yang Wu1
Shiqi Chen1
Tong Li1Xiaowan Han1
Hufang Zhou1Yu Wang2Ziwen Lu1
Haiyan Li1Yukun Ding1Liang Ma1
Mingjing Zhao1,3*Xian Wang1,3*- 1Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- 2The First Hospital of Hebei Medical University, Shijiazhuang, China
- 3Institute of Cardiovascular Diseases, Beijing University of Chinese Medicine, Beijing, China
Aims: The objective of this study was to assess the efficacy and potential mechanisms of Chinese herbal medicine (CHM) for treating coronary heart disease (CHD) patients with anxiety or depression.
Methods: A systematic literature search was performed. Screening studies, extracting data, and assessing article quality were carried out independently by two researchers. The active ingredients of CHM for the treatment of CHD with anxiety or depression were analyzed by the network pharmacology, and the main potential mechanisms were summarized by the database of Web of Science.
Results: A total of 32 studies were included. The results showed that compared with the blank control groups, CHM was more beneficial in treating anxiety or depression in patients with CHD [anxiety: OR = 3.22, 95% CI (1.94, 5.35), p < 0.00001, I2 = 0%; depression: OR = 3.27, 95% CI (1.67, 6.40), p = 0.0005, I2 = 0%], and the efficacy of CHM was not inferior to that of Western medicine (WM) [anxiety: OR = 1.58, 95%CI (0.39, 6.35), p = 0.52, I2 = 67%; depression: OR = 1.97, 95%CI (0.73, 5.28), p = 0.18, I2 = 33%,]. Additionally, CHM also showed a significant advantage in improving angina stability (AS) in CHD patients with anxiety or depression compared with blank groups [anxiety: SMD = 0.55, 95%CI (0.32, 0.79), p < 0.00001, I2 = 0%; depression: p = 0.004] and WM groups [anxiety: SMD = 1.14, 95%CI (0.80, 1.47), p < 0.00001, I2 = 0%; depression: SMD = 12.15, 95%CI (6.07, 18.23), p < 0.0001, I2 = 0%]. Angina frequency (AF) and electrocardiogram (ECG) analysis after using CHM demonstrated similar trends. Based on the network pharmacology, quercetin, kaempferol, luteolin, beta-sitosterol, puerarin, stigmasterol, isorhamnetin, baicalein, tanshinone IIa, and nobiletin were most closely and simultaneously related to the pathological targets of CHD, anxiety, and depression. The main underlying mechanisms might involve anti-damage/apoptosis, anti-inflammation, antioxidative stress, and maintaining neurotransmitter homeostasis.
Conclusion: CHM exhibited an obvious efficacy in treating CHD patients with anxiety or depression, especially for improving the symptom of angina pectoris. The most active compounds of CHM could simultaneously act on the pathological targets of CHD, anxiety, and depression. Multiple effective components and multiple targets were the advantages of CHM compared with WM.
Introduction
Anxiety and depression are commonly found in patients with coronary heart disease (CHD), and the prevalence of CHD complicated with anxiety or depression is 21 and 13%, respectively (Daniel et al., 2018). Percutaneous coronary intervention (PCI) treatment increases the prevalence of anxiety and depression symptoms in CHD patients (Gu et al., 2016). Accumulating evidence has demonstrated that anxiety and depression are associated with the increased risk of CHD (Roest et al., 2010; Lederbogen and Ströhle, 2012; Giannarelli et al., 2017), and the use of anxiolytics or antidepressants is necessary for CHD patients with anxiety or depression. However, current drugs for emotional disorders, such as serotonin-specific reuptake inhibitors (SSRIs) and benzodiazepines, usually exert their effects after several weeks of treatment, with some unwanted side effects (Lakhan and Vieira, 2010; Ko et al., 2020). Thus, a more optimized treatment option is needed.
As an important treatment strategy, Chinese herbal medicine (CHM) is characterized by multiple components, multiple targets, and multiple channels. It has been verified that CHM had a satisfactory efficacy and fewer adverse effects on CHD with anxiety or depression (Liu and Qin, 2016; Ma et al., 2019). However, due to poor methodological quality and limited sample size, the evidence to support the effect of CHM on CHD with anxiety or depression is still weak. Moreover, the possible underlying mechanisms via which CHM treats CHD patients with anxiety or depression is still needed to be clarified. Therefore, by comprehensively analyzing published studies, a meta-analysis and systematic review were performed to assess the efficacy of CHM and the underlying mechanisms in the treatment of CHD patients with anxiety or depression, which might provide an essential clinical value for the disease management in the future.
Methods
This meta-analysis and systematic review were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (Moher et al., 2009).
Information Source and Search Strategy
Published articles were searched comprehensively in electronic databases (PubMed, Web of Science, Embase, Cochrane, China National Knowledge Infrastructure, WanFang Data, VIP Database, and SinoMed) up to October 2021. “Coronary disease OR coronary artery disease OR myocardial infarction OR acute coronary syndrome” AND “anxiety OR depression OR depressive disorder” AND “traditional Chinese medicine OR herbal medicine” AND “randomized controlled trial” and their common synonyms were used for the searching strategy. The detailed searching strategy was shown in supplementary material.
Inclusion and Exclusion Criteria
The inclusion criteria of the articles were as follows: 1) all participants met the diagnostic criteria of CHD with anxiety or depression; 2) the number of subjects in each group was not less than 30; 3) CHD patients in control and trial groups received basic treatments, with antianxiety or antidepressant Western medicine (WM) used (WM groups) or not (blank control groups) in control groups, and oral CHM was used in trial groups; 4) Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) were used to evaluate patients’ anxiety and depression, respectively; and 5) the efficacy index of CHD included one of the following: ① electrocardiogram (ECG); ② angina stability (AS) and angina frequency (AF) come from Seattle Angina Questionnaire; and ③ traditional Chinese medicine syndrome (TCMS) score.
The exclusion criteria of the studies were as follows: 1) Nonclinical study and irrelevant research; 2) CHM was used in control groups, antianxiety or antidepressant WM was used in trial groups; 3) articles with incomplete data; 4) articles more than one high-risk item; and 5) review, meta-analysis, and conference abstracts.
Study Selection and Data Extraction
Retrieved articles were assessed independently by two researchers (YT and SL) according to the inclusion and exclusion criteria. Data, including first authors’ name, year of publication, sample size, age, gender, diseases, therapeutic regimen, final duration of treatment, dosage form and compositions of TCM, and the outcome index, were extracted from the included studies. The CHM was reported in scientific name, not the Latin name in pharmacopeia to avoid confusion (Table 1) (Rivera et al., 2014). Any disagreements were resolved by discussing and consulting with corresponding authors (MZ and XW).
TABLE 1. Compositions of formulation and patented drugs.
Study Quality Assessment
Two authors (YL and YT) independently assessed the methodological quality according to the Cochrane risk-of-bias tool (Zhang K. J. et al., 2019). Sufficient domain information in relevant studies was considered as low risk, inadequate information was regarded as unclear risk, and no related information was regarded as high risk.
Data Analysis and Synthesis
RevMan 5.3 software provided by the Cochrane Collaboration was used for meta-analysis. The odds ratio (OR) and standard mean difference (SMD) were used to analyze the pooled effects of dichotomous outcomes and continuous variable, respectively. When the heterogeneity of included studies was low (I2 < 50%), the fixed effect model was selected to analyze the data; otherwise, a random-effects model was applied. The subgroups analysis was based on whether control groups used WM or not. Sensitivity analysis was performed to explore potential effect modification. Also, funnel plots were used to assess publication bias. p < 0.05 was considered statistically significant.
Chinese Herbal Medicine Compositions and Potential Mechanisms
The frequency statistics of single CHM was performed to identify the commonly used drugs, and CHM with frequency not less than three were selected for network pharmacology to find the primary active ingredients and the disease targets. The targets of the active ingredient of CHM were extracted from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, while the targets of CHD, anxiety, and depression were collected from the GeneCards database. The networks of active ingredients-disease targets were acquired according to the Cytoscape 3.6.1. The active ingredients that most related with CHD, anxiety, and depression simultaneously were acquired by matching ingredients-disease targets. Also, the main potential mechanisms of the primary active compounds (top 10) were summarized by the database of Web of Science.
Results
Literature Search Results
A total of 2,102 records were identified from eight electronic databases. Thirty-two studies met the inclusion criteria, and 2070 studies were excluded due to 1) irrelevant studies; 2) nonclinical studies; 3) review, meta-analysis, and conference abstracts; 4) sample size was less than 30; 5) using WM in trial groups; 6) non-HAMA or HAMD for evaluating the efficacy of anxiety or depression; 7) non-ECG or AS or AF or TCMS score for evaluating the efficacy of CHD; and 8) articles with incomplete data or more than one high-risk item. The specific screening process is illustrated in Figure 1.
FIGURE 1. Flow diagram of literature search.
Study and Patient Characteristics
Thirty-two studies included 15 studies on CHD with anxiety (Mo et al., 2016; Li G. Y. et al., 2017; Guo, 2017; Qi and Song, 2017; Zhang et al., 2017; Qin, 2018; Wang C., 2018; Chen, 2019; Dong, 2019; Yang, 2019; Zhang, 2019; Zhao et al., 2019; Jin et al., 2021; Wang et al., 2021; Zhang and Jin, 2021) and 17 studies on CHD with depression (Sun, 2011; Lin, 2012; Zhang et al., 2012; Qin and Liu, 2013; Zhu, 2013; Gu et al., 2014; Shang et al., 2014; Mu, 2015; Shi et al., 2016; Li F. E. et al., 2017; Su, 2017; Shi, 2018; Wang Y. et al., 2018; Wang D. D., 2018; Lu, 2019; Huang et al., 2020; Zhang et al., 2020). All studies accounted for baseline comparability, and the patients’ overall characteristics are summarized in Tables 2A,B. Subjects of CHD who were diagnosed as stable angina (SA), unstable angina (UA), acute myocardial infarction (AMI), non-ST segment elevation myocardial infarction (NSTEMI), or post-percutaneous coronary intervention (post-PCI) were also evaluated by HAMA (Mo et al., 2016; Li G. Y. et al., 2017; Guo, 2017; Qi and Song, 2017; Zhang et al., 2017; Qin, 2018; Wang C., 2018; Chen, 2019; Dong, 2019; Yang, 2019; Zhang, 2019; Zhao et al., 2019; Jin et al., 2021; Wang et al., 2021; Zhang and Jin, 2021) and HAMD (Sun, 2011; Lin, 2012; Zhang et al., 2012; Qin and Liu, 2013; Zhu, 2013; Gu et al., 2014; Shang et al., 2014; Mu, 2015; Shi et al., 2016; Li F. E. et al., 2017; Su, 2017; Shi, 2018; Wang Y. et al., 2018; Wang D. D., 2018; Lu, 2019; Huang et al., 2020; Zhang et al., 2020). Secondary prevention drugs for CHD were used in all studies.
TABLE 2A. Research characteristics of the CHD with anxiety.
TABLE 2B. Research characteristics of the CHD with depression.
For control groups of CHD with anxiety, four studies used flupentixol and melitracen tablets (Qi and Song, 2017; Qin, 2018), diazepam (Jin et al., 2021), and lorazepam (Zhang and Jin, 2021), while nine studies used fluoxetine hydrochloride (Zhang et al., 2012; Qin and Liu, 2013; Shang et al., 2014), flupentixol and melitracen tablets (Zhu, 2013; Li F. E. et al., 2017; Wang D. D., 2018; Lu, 2019), and escitalopram (Shi et al., 2016; Wang Y. et al., 2018) in the CHD with depression. No WM were used in control groups in the remaining researches except for the study by Lin et al. who used a placebo (Lin, 2012). CHM was used in trial groups and the details are shown in Table 1. The treatment course in all studies varied from 2 weeks to 3 months. The primary efficacy endpoints, including the score and efficacy of HAMA and HAMD, ECG efficacy, AS score, and AF score, were extracted for this meta-analysis and systematic review. The score and efficacy of TCMS were also extracted for the evaluation as the secondary efficacy endpoint.
Quality Assessment of Included Studies
The study methodological quality is concluded in Supplementary Table S1. Random allocation was used in all included studies. Five studies performed blind method (Lin, 2012; Mo et al., 2016; Li G. Y. et al., 2017; Wang C., 2018; Su, 2017), and blinded outcome assessment was conducted in two studies (Qi and Song, 2017; Zhang and Jin, 2021). Additionally, allocation concealment was used in three studies (Sun, 2011; Mo et al., 2016; Wang C., 2018).
Efficacy of Chinese Herbal Medicine in Coronary Heart Disease With Anxiety
As shown in Table 2A, the score and efficacy of HAMA, ECG, AS, AF, and TCMS in trial groups in most studies possessed a significant improvement. However, there were also some different results. Two studies showed that there was no significant difference in the score or efficacy of HAMA between trial groups and flupentixol and melitracen tablet-treated groups (Qi and Song, 2017; Qin, 2018). Three studies reported that the efficacy of ECG in trial groups was not significantly different compared with blank control groups (Mo et al., 2016; Chen, 2019; Zhang, 2019). Thus, the primary endpoint results were pooled to further confirm the efficacy of CHM.
Efficacy of Chinese Herbal Medicine in Anxiety
In Supplementary Figure S1, the HAMA score displayed significant heterogeneity due to scoring bias in different studies. Therefore, the efficacy of CHM for treating anxiety was further analyzed. Meta-analysis of nine studies showed a significant efficiency of CHM for improving anxiety [OR = 2.73, 95%CI (1.78, 4.18), p < 0.00001, I2 = 0%] (Figure 2), and the subgroup analysis based on whether the control group used WM or not was also performed. As shown in Figure 2, the results of subgroup analysis showed a favor for CHM in curing anxiety in CHD patients compared with blank control groups [OR = 3.22, 95%CI (1.94, 5.35), p < 0.00001, I2 = 0%], whereas the efficacy of CHM in treating anxiety was not inferior to that of WM [OR = 1.58, 95%CI (0.39, 6.35), p = 0.52, I2 = 67%]. Moreover, a repetitive meta-analysis by consecutively excluding each study in WM groups was performed. The study by Qi et al. was the main source of heterogeneous, but it was not removed because of reasonable research design.
FIGURE 2. Forest plot: CHM improved HAMA efficacy in CHD with anxiety compared with control groups.
Efficacy of Chinese Herbal Medicine in Coronary Heart Disease
Meta-analysis of eight studies showed that the improvement of ECG in CHD patients was significantly associated with CHM treatment [OR = 1.99, 95%CI (1.39, 2.85), p = 0.0002, I2 = 0%] (Figure 3). In addition, subgroup analysis showed a consistent result favoring CHM in improving CHD compared with blank [OR = 1.72, 95%CI (1.12, 2.62), p = 0.01, I2 = 0%] and WM groups [OR = 2.95, 95%CI (1.47, 5.90), p = 0.002, I2 = 0%] (Figure 3).
FIGURE 3. Forest plot: CHM improved ECG in CHD with anxiety compared with control groups.
In terms of improving AS and AF, CHM also showed a significant advantage in trial groups compared with control groups [AS: SMD = 0.75, 95%CI (0.56, 0.94), p < 0.00001, I2 = 45%; AF: SMD = 0.71, 95%CI (0.38, 1.03), p < 0.0001, I2 = 64%] (Figures 4, 5), blank groups [AS: SMD = 0.55, 95%CI (0.32, 0.79), p < 0.00001, I2 = 0%; AF: SMD = 0.87, 95%CI (0.47, 1.28), p < 0.0001, I2 = 62%], and WM groups [AS: SMD = 1.14, 95%CI (0.80, 1.47), p < 0.00001, I2 = 0%; AF: SMD = 0.39, 95%CI (0.08, 0.71), p = 0.01, I2 = 0%] (Figures 4, 5).
FIGURE 4. Forest plot: CHM for improved AS of CHD with anxiety compared with control groups.
FIGURE 5. Forest plot: CHM for improved AF in CHD with anxiety compared with control groups.
Efficacy of Traditional Chinese Medicine in Coronary Heart Disease With Depression
As shown in Table 2B, most included studies showed a significant improvement in the score and efficacy of HAMD, ECG, AS, AF, and TCMS in treatment groups. However, some studies showed different results. Three studies reported that the score or efficacy of HAMD in CHM groups was no statistical difference between treatment and control groups using antidepressants (Zhu, 2013; Shi et al., 2016; Lu, 2019). Similarly, for the score or efficacy of ECG, angina, and TCMS, there were also no statistical differences between treatment and control groups (Zhu, 2013; Gu et al., 2014; Shang et al., 2014; Li F. E. et al., 2017; Zhang et al., 2020). Additionally, the study by Lin et al. was the only study that used placebo (Lin, 2012). The scores of AS and AF were not significantly different between the CHM and placebo group, but the result of the 36-item short form survey showed a superior benefit of CHM compared with placebo. In the study by Wang Y. et al. (2018), antidepressants and CHM both possessed obvious efficacy for treating CHD with depression, and antidepressants exhibited even more efficiency. Therefore, the primary endpoint results were pooled to further confirm the efficacy of CHM.
Efficacy of Chinese Herbal Medicine in Depression
Meta-analysis of seven studies showed that CHM had a significant effect on treating depression compared with control groups [OR = 2.79, 95%CI (1.61, 4.86), p = 0.0003, I2 = 0%] (Figure 6). The results of subgroup analysis also revealed that the antidepressive effect was improved significantly compared with blank control groups [OR = 3.27, 95%CI (1.67, 6.40), p = 0.0005, I2 = 0%] but was the same as WM groups [OR = 1.97, 95%CI (0.73, 5.28), p = 0.18, I2 = 33%] (Figure 6).
FIGURE 6. Forest plot: CHM improved HAMD efficacy in CHD with depression compared with control groups.
Efficacy of Chinese Herbal Medicine in Coronary Heart Disease
Eight studies reported that CHM significantly improved ECG in CHD patients [OR = 1.89, 95%CI (1.23, 2.89), p = 0.004, I2 = 0%] (Figure 7). In addition, subgroup analysis showed a similar result favoring CHM in improving CHD compared with blank groups [OR = 1.96, 95%CI (1.14, 3.37), p = 0.02, I2 = 0%], but no statistical difference was found when comparing CHM with WM groups [OR = 1.78, 95%CI (0.89, 3.55), p = 0.10, I2 = 0%] (Figure 7).
FIGURE 7. Forest plot: CHM improved ECG in CHD with depression compared with control groups.
Regarding the efficacy of CHM in AS and AF, CHM also provided a more significant advantage compared with control groups [AS: SMD = 11.62, 95%CI (6.92, 16.33), p < 0.00001, I2 = 0%; AF: SMD = 11.13, 95%CI (7.46, 14.80), p < 0.00001, I2 = 6%] (Figures 8, 9), blank groups [AS: p = 0.004; AF: p < 0.00001], and WM [AS: SMD = 12.15, 95%CI (6.07, 18.23), p < 0.0001, I2 = 0%; AF: SMD = 10.34, 95%CI (5.26, 15.41), p < 0.0001, I2 = 48%] (Figures 8, 9).
FIGURE 8. Forest plot: CHM for improved AS in CHD with depression compared with control groups.
FIGURE 9. Forest plot: CHM improved AF in CHD with depression compared with control groups.
Comparisons of the Characteristics of Chinese Herbal Medicine in Coronary Heart Disease With Anxiety or Depression
Due to the promising results of CHM treatment observed in most included studies, the frequency statistics of CHM was analyzed to identify the commonly used drugs among different groups. The results showed that Bupleurum chinense DC. [Apiaceae; Bupleuri radix], Glycyrrhiza uralensis Fisch. ex DC. [Fabaceae; Glycyrrhizae radix et rhizoma], Ligusticum chuanxiong Hort. [Apiaceae; Chuanxiong rhizoma], Salvia miltiorrhiza Bunge [Lamiaceae; Salviae miltiorrhizae radix et rhizoma], Angelica sinensis (Oliv.) Diels [Apiaceae; Angelicae sinensis radix], Paeonia lactiflora Pall. [Paeoniaceae; Paeoniae radix alba], Pinellia ternata (Thunb.) Makino [Araceae; Pinelliae rhizoma], Curcuma aromatica Salisb. [Zingiberaceae; Curcumae radix], and Citrus×aurantium L. [Rutaceae; Aurantii fructus] were commonly used for treating CHD with anxiety or depression (Supplementary Table S2). Also, the CHM with a frequency not less than three were selected for the networks of active ingredients-disease targets, and the results demonstrated the efficacy of CHM for CHD with anxiety or depression (Supplementary Figure S2). Furthermore, the primary active ingredients of these CHM that could act on the targets of CHD, anxiety, and depression simultaneously were analyzed by matching ingredients disease targets. The results showed the active ingredients including quercetin, kaempferol, luteolin, beta-sitosterol, puerarin, stigmasterol, isorhamnetin, baicalein, tanshinone IIa, and nobiletin were most closely related to the targets of CHD, anxiety, and depression based on degree centrality, and the top 10 ingredients are shown in Table 3. These active compounds could either act on the targets of CHD, anxiety, and depression simultaneously or be extracted from varieties CHM.
TABLE 3. Mechanisms of main active components of CHM on CHD with anxiety or depression.
Potential Relevant Mechanisms
The effects and mechanisms of the primary active compounds (top 10) were searched in the Web of Science database. As shown in Table 3, the experimental research of quercetin, kaempferol, luteolin, beta-sitosterol, puerarin, and baicalein covered CHD, anxiety, and depression. Models of myocardial infarction or ischemia reperfusion were commonly used in the study of CHD, while the ICR mice and multiple stress-stimulated rats were selected for anxiety and depression research.
The related mechanisms of these top 10 active ingredients in CHD, anxiety, and depression are summarized in Table 3, which mainly includes anti damage/apoptosis, anti-inflammation, antioxidative stress, antifibrosis, maintaining neurotransmitters homeostasis, and regulating autophagy. In addition, myocardial injure biomarkers (lactate dehydrogenase, creatine kinase MB, cardiac troponin I) and the damage/apoptosis biomarkers (Bcl-2 associated X protein, cleaved caspase-3, p53, B-cell lymphoma/leukemis-2) could be regulated by quercetin, kaempferol, luteolin, beta-sitosterol, puerarin, isorhamnetin, baicalein, tanshinone IIa, and nobiletin. These phytochemicals were also reported to exert an anti-inflammatory effect by reducing the levels of interleukin (IL) -1β/6, tumor necrosis factor-α, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, or elevating the IL-10 level in CHD patients. The anti-inflammatory role of quercetin, puerarin, or nobiletin was reported in anxiety or depression. Additionally, almost all active ingredients except stigmasterol and nobiletin possessed the functions of antioxidative stress and balancing level of reactive oxygen species, malondialdehyde, myeloperoxidase, and catalase, superoxide dismutase, glutathione. Quercetin, tanshinone IIa, and nobiletin were reported to reduce the levels of α-smooth muscle actin, angiotensin II, collagen I/III, matrix metalloproteinases 2/9, transforming growth factor (TGF)-β, and Smad7 to prevent myocardial fibrosis, which was one of the complications associated with myocardial infarction. Besides, the imbalance of adrenocorticotropic hormone, 5-hydroxytryptamine, brain-derived neurotrophic factor (BDNF), acetylcholine, noradrenaline, dopamine, and gamma-aminobutyric acid, which caused anxiety or depression, could be regulated by quercetin, kaempferol, luteolin, beta-sitosterol, puerarin, stigmasterol, baicalein, tanshinone IIa, or nobiletin. Isorhamnetin and baicalein could improve the depression by inducing neuronal differentiation and protecting synaptic plasticity, respectively. The roles of active compounds in regulating autophagy and improving mitochondria were also reported. Overall, the related mechanisms of TCM-active compounds in treating CHD with anxiety or depression contained a variety of signaling pathways, such as nuclear factor-kappa B, mitogen-activated protein kinase, Jun N-terminal kinase, extracellular signal-regulated kinase1/2, signal transducers and activators of transcription3, TGF-β1/Smad3, phosphatidylinositol 3-kinase/protein kinase B, and BDNF.
Discussion
There is accumulating evidence showing high prevalence of anxiety and depression comorbidities in patients with CHD. SSRIs and benzodiazepines are frequently used for treating depression or anxiety disorders, and the effectiveness of these drugs on psychiatric disorders has also been acknowledged (Davies et al., 2004). However, the side effects, such as suicidal ideation, sexual dysfunction, and dependency, have not been resolved (Lakhan and Vieira, 2010; Ko et al., 2020). In addition, it is a common clinical phenomenon that CHD patients show subsyndromal anxiety or depression-like symptoms that do not meet the diagnostic criteria of anxiety or depression (Cohen et al., 2006; Kasckow et al., 2013). The issue of treatment for these patients still deserves much attention.
TCM has been reported to be effective in treating CHD, anxiety, and depression with a less adverse effect, and might be a potential therapeutic option for patients with subsyndromal anxiety or depression. However, the efficacy and benefit of CHM in treating CHD with anxiety or depression still need to be further verified due to poor methodological quality and potential confounding factors. This meta-analysis and systematic review was performed to provide the evidence for the application of CHM in CHD patients with anxiety or depression. Thirty-two studies (15 CHD with anxiety, and 17 CHD with depression) were included for the evaluation of the efficacy of CHM. The results showed that CHM had a significant benefit on anxiety and depression in CHD patients, and its efficacy was not inferior to that of WM. Importantly, CHM also had a significant advantage to alleviate the angina symptom compared with blank control and WM groups. Besides that, there were no obvious adverse effects of CHM in the included studies (Zhang et al., 2012; Qin and Liu, 2013; Zhu, 2013; Mo et al., 2016; Shi et al., 2016; Guo, 2017; Wang Y. et al., 2018; Wang C., 2018; Wang D. D., 2018; Chen, 2019; Lu, 2019; Yang, 2019; Huang et al., 2020).
Furthermore, the frequency of CHM used in the included studies was analyzed, and the commonly used drugs were analyzed by network pharmacology. The results concluded that the CHM regulating Qi and promoting blood circulation, including Bupleurum chinense DC. [Apiaceae; Bupleuri radix], Glycyrrhiza uralensis Fisch. ex DC. [Fabaceae; Glycyrrhizae radix et rhizoma], Ligusticum chuanxiong Hort. [Apiaceae; Chuanxiong rhizoma], Salvia miltiorrhiza Bunge [Lamiaceae; Salviae miltiorrhizae radix et rhizoma], Angelica sinensis (Oliv.) Diels [Apiaceae; Angelicae sinensis radix], Paeonia lactiflora Pall. [Paeoniaceae; Paeoniae radix alba], Pinellia ternata (Thunb.) Makino [Araceae; Pinelliae rhizoma], Curcuma aromatica Salisb. [Zingiberaceae; Curcumae radix], and Citrus×aurantium L. [Rutaceae; Aurantii fructus] were commonly used for CHD with anxiety and depression. The phytochemicals identified in the CHM could act on the pathological targets of CHD, anxiety, and depression simultaneously.
Inflammatory response to vascular injury participates in the pathological processes of the atherosclerosis and CHD, and is associated with the increased risk of cardiovascular events and recurrent myocardial infarction (Fioranelli et al., 2018; Zhang K. J. et al., 2019). Oxidative stress is also an important factor involved in myocardial cell injury and apoptosis caused by ischemia reperfusion, which is followed by heart failure and myocardial fibrosis (Li et al., 2018; Yang et al., 2019). The effectiveness of CHM ingredients including quercetin, kaempferol, luteolin, beta-sitosterol, puerarin, and baicalein was reported in the experimental research on CHD. Puerarin, quercetin, and tanshinone IIa were also shown to have a satisfactory efficacy in improving clinical prognosis (Mao et al., 2019; Zhang S. et al., 2019; Dehghani et al., 2021). Additionally, inflammation and oxidative stress could cause neuron damage and neurotransmitter disorder, leading to anxiety and depression (Bankier et al., 2009; Liu et al., 2015; van Dooren et al., 2016; Salim, 2017; Wang Y. L. et al., 2018). Quercetin, kaempferol, luteolin, and puerarin also showed a positive effect in curing anxiety and depression.
Overall, these findings reveal that the CHM has a satisfactory efficacy for CHD with anxiety and depression, especially for improving the symptom of angina pectoris. Of importance, CHM itself contains multiple components that play critical functions in a large number of signaling pathways involved in distinct biological processes of CHD with anxiety or depression mainly including anti-damage/apoptosis, anti-inflammation, antioxidative stress, and maintaining neurotransmitters homeostasis. Compared with WM’s single effect on the nervous system, CHM may extert its functions in multiple places and systems by targeting distinct factors in CHD with anxiety or depression to improve both CHD and anxiety/depression syndromes.
Limitations
First, the sample size in each group of included studies was not more than 50, except the study by Wang Y. L. et al. (2018), and the sample size needs to be expanded in future studies. Second, it is difficult to perform double blind due to the special smell and taste of TCM decoction. Also, the characteristics of TCM treatment affect the implementation of double blind. Additionally, the blinding of outcome assessment was conducted in 2 of 32 studies (Qi and Song, 2017; Zhang and Jin, 2021). Therefore, the strict trial design is also necessary to further verify the efficacy of CHM.
Conclusion
CHM had a significant efficacy for the treatment of CHD patients with anxiety or depression. Particularly, CHM could improve the symptoms of angina pectoris while alleviating anxiety and depression. The main mechanisms underlying the functions of these CHM-active ingredients might involve anti-damage/apoptosis, anti-inflammation, antioxidative stress, antifibrosis, maintaining neurotransmitters homeostasis, and regulating autophagy.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
Author Contributions
BW, YT, and YL are co-first authors. Theme and design of the research: BW, YT, and YL. Extract data: YL, YT, and SL. Network pharmacology: YW. Statistical analysis: SC, YL, and XH. Data handling of mechanisms: HZ, YW, ZL, HL, YD, and LM. Writing of the manuscript: BW, YT, and YL. Critical revision of the manuscript for intellectual content: MZ and XW. Obtaining funding: MZ and XW.
Funding
This study was supported by the National Natural Science Foundation of China (81973787) and the key research projects of Beijing University of Chinese Medicine (2020-JYB-ZDGG-113).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2022.854292/full#supplementary-material
Abbreviations
AF, angina frequency; AS, angina stability; CHD, coronary heart disease; CHM, Chinese herbal medicine; ECG, electrocardiogram; HAMA, Hamilton anxiety scale; HAMD, Hamilton depression scale; TCM, traditional Chinese medicine; WM, Western medicine.
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Keywords: coronary heart disease, anxiety, depression, Chinese herbal medicine, efficacy
Citation: Wang B, Teng Y, Li Y, Lai S, Wu Y, Chen S, Li T, Han X, Zhou H, Wang Y, Lu Z, Li H, Ding Y, Ma L, Zhao M and Wang X (2022) Evidence and Characteristics of Traditional Chinese Medicine for Coronary Heart Disease Patients With Anxiety or Depression: A Meta-Analysis and Systematic Review. Front. Pharmacol. 13:854292. doi: 10.3389/fphar.2022.854292
Received: 13 January 2022; Accepted: 29 March 2022;
Published: 05 May 2022.
Edited by:
Yusof Kamisah, Universiti Kebangaan Malaysia, MalaysiaCopyright © 2022 Wang, Teng, Li, Lai, Wu, Chen, Li, Han, Zhou, Wang, Lu, Li, Ding, Ma, Zhao and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mingjing Zhao, bWpneDIwMDRAMTYzLmNvbQ==; Xian Wang, d3g2NTA1MTVAMTYzLmNvbQ==
†These authors shares co-first authorship