key: cord-0031854-2qhi64p4
authors: Wang, Baofu; Teng, Yu; Li, Yang; Lai, Sijia; Wu, Yang; Chen, Shiqi; Li, Tong; Han, Xiaowan; Zhou, Hufang; Wang, Yu; Lu, Ziwen; Li, Haiyan; Ding, Yukun; Ma, Liang; Zhao, Mingjing; Wang, Xian
title: Evidence and Characteristics of Traditional Chinese Medicine for Coronary Heart Disease Patients With Anxiety or Depression: A Meta-Analysis and Systematic Review
date: 2022-05-05
journal: Front Pharmacol
DOI: 10.3389/fphar.2022.854292
sha: fc311013c7531d2fa9341532ec456dc06de53f91
doc_id: 31854
cord_uid: 2qhi64p4

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, I(2) = 0%; depression: OR = 3.27, 95% CI (1.67, 6.40), p = 0.0005, I(2) = 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, I(2) = 67%; depression: OR = 1.97, 95%CI (0.73, 5.28), p = 0.18, I(2) = 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, I(2) = 0%; depression: p = 0.004] and WM groups [anxiety: SMD = 1.14, 95%CI (0.80, 1.47), p < 0.00001, I(2) = 0%; depression: SMD = 12.15, 95%CI (6.07, 18.23), p < 0.0001, I(2) = 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.

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, I 2 = 0%; depression: OR = 3.27, 95% CI (1.67, 6.40) , p = 0.0005, I 2 = 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, I 2 = 67%; depression: OR = 1.97, 95%CI (0.73, 5.28), p = 0.18, I 2 = 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, I 2 = 0%; depression: p = 0.004] and WM groups [anxiety: SMD = 1.14, 95%CI (0.80, 1.47), p < 0.00001, I 2 = 0%; depression: SMD = 12.15, 95%CI (6.07, 18 .23), p < 0.0001, I 2 = 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

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. information was regarded as unclear risk, and no related information was regarded as high risk.

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 (I 2 < 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.

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.

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 .

Thirty-two studies included 15 studies on CHD with anxiety ( For control groups of CHD with anxiety, four studies used flupentixol and melitracen tablets (Qi and Song, 2017; Qin, 2018) , diazepam , and lorazepam , 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; 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.

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) .

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.

In Supplementary Figure S1 , the HAMA score displayed significant heterogeneity due to scoring bias in different studies. Therefore, the (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, I 2 = 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, I 2 = 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.

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, I 2 = 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, I 2 = 0%] and WM groups [OR = 2.95, 95% CI (1.47, 5.90) , p = 0.002, I 2 = 0%] ( Figure 3 ). 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, I 2 = 45%; AF: SMD = 0.71, 95%CI (0.38, 1.03), p < 0.0001, I 2 = 64%] (Figures 4, 5) , blank groups [AS: SMD = 0.55, 95%CI (0.32, 0.79), p < 0.00001, I 2 = 0%; AF: SMD = 0.87, 95%CI (0.47, 1.28), p < 0.0001, I 2 = 62%], and WM groups [AS: SMD = 1.14, 95%CI (0.80, 1.47), p < 0.00001, I 2 = 0%; AF: SMD = 0.39, 95%CI (0.08, 0.71), p = 0.01, I 2 = 0%] (Figures 4, 5) .

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 Note: A1, antiplatelets; A2, ACEI/ARB; A3, nitrate esters drugs; A4, anticoagulants; AMI, acute myocardial infarction; B, β-blocker; C1, statins; C2, Ca antagonists; CABG, coronary artery bypass grafting; CHD, coronary heart disease; E, regulate emotion; IHD, ischemic heart disease; N, without intervention; NSTEMI, non-ST, segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SA, stable angina; TCMS, traditional Chinese medicine syndrome; UA, unstable angina a The evaluation criteria refer to the guiding principles for clinical research of Chinese medicine from China. b The evaluation criteria refer to other acceptable evaluation methods.

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 , 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.

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, I 2 = 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, I 2 = 0%] but was the same as WM groups [OR = 1.97, 95%CI (0.73, 5.28) , p = 0.18, I 2 = 33%] ( Figure 6 ). (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, I 2 = 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, I 2 = 0%] (Figure 7) .

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, I 2 = 0%; AF: SMD = 11.13, 95%CI (7.46, 14.80) , p < 0.00001, I 2 = 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, I 2 = 0%; AF: SMD = 10.34, 95%CI (5.26, 15.41) , p < 0.0001, I 2 = 48%] (Figures 8, 9 ).

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. Table S2 ). Also, the CHM with a frequency not 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.

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.

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 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 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 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 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, antiinflammation, 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.

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.

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.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors. 

Bupleuri radix], Cyperus rotundus L

Cyperi rhizoma], Ziziphus jujuba Mill

Carthamus tinctorius L

Glycyrrhiza uralensis Fisch. ex DC

Astragali radix] CHD: MI rat TNF-α-HUVEC 1. Anti damage/apoptosis (LDH, CK-MB, cTnI, Bax

Anti-inflammation (TNF-α, IL-6, VCAM-1, ICAM-1, E-selectin

Antioxidative stress

JAK-STAT3) Anxiety: LPSanxiety rat mTBI mouse SIA mouse 1. Anti-inflammation (IL-1β/6, cyclooxygenase-2, iNOS⍗)

Antioxidative stress (MDA⍗; CAT, GSH-Px, SOD⍐)

Maintaining neurotransmitters homeostasis (ACTH, Cort⍗; 5-HT, BDNF, ACh⍐) 4. Signal pathways (NF-κB) Depression: CUMS mouse/rat 1. Anti-inflammation

Antioxidative stress

Cyperus rotundus L

Glycyrrhiza uralensis Fisch. ex DC

Astragali radix], Carthamus tinctorius L

CHD: I/R DM rat ox-LDL-HUVECs 1. Anti-damage/apoptosis (Bax, cleaved-caspase-3, TUNEL

Anti-inflammation (IL-1β/6, TNF-α⍗)

Antioxidative stress (ROS, MDA⍗; SOD⍐)

CS 1 +US rat 1. Regulating endocannabinoid system

Depression: CSDS mouse 1. Anti-inflammation (IL-1β

Antioxidative stress

Luteolin Codonopsis pilosula (Franch.) Nannf. [Campanulaceae

Cyperus rotundus L

Salviae miltiorrhizae radix et rhizoma], Platycodon grandiflorus (Jacq.) A.DC

CHD: I/R-rats/ mouse H 2 O 2 -H9C2 H/R-H9C2

Anti-inflammation (IL-1β/6, TNFα, ASC⍗)

Antioxidative stress

Regulating autophagy (Mst1

Improving mitochondria function (ATP, CS 3 , complexes I/II/III/IV/V activities⍐)

Signal pathways (Sirt1/NLRP3/NF-κB

Anxiety: male Swiss mouse 1. Maintaining neurotransmitters homeostasis (luteolin's metabolites might show a higher affinity for the BDZ-R, and the anxiolytic-like effects through a GABAergic mechanism)

Anti-inflammation

Antioxidative stress (MDA⍗; SOD⍐)

Signal pathways (AKT/STAT3, SIRT1/ NF-κB) References stigmasterol Bupleurum chinense DC

Angelica sinensis (Oliv.) Diels [Apiaceae

Wurfbainia villosa

Amomi fructus], Cyperus rotundus L

Cyperi rhizoma], Ziziphus jujuba Mill

Gardeniae fructus], Paeonia lactiflora Pall

Carthamus tinctorius L

Anti-inflammation (iNOS, IL-1β/6, COX2, microglial activation marker⍗)

Regulating autophagy (NLRP3inflammasome, ASC, caspase-1 p20⍗; LC3-II

ACh: acetylcholine; ACTH: adrenocorticotropic hormone; AGE: advanced glycation end product; AKT: protein kinase B; AMPAR: AMPA-type glutamate receptor

AP-1: activator protein 1; ASC: apoptosis-associated speck-like protein; ATP: adenosine triphosphate; Bax: Bcl-2 associated X protein; Bcl-2: B-cell lymphoma/leukemis-2; BDNF: brain-derived neurotrophic factor; Bim: Bcl-2-interacting mediator of cell death; BMP: bone morphogenetic protein; CaMK-II: members of the Ca(2+)/calmodulin-dependent protein kinase II; CAT: catalase; CFs: cardiac fibroblasts; CHOP: C/EBP homologous protein

Cox-2: cyclooxygenase-2; CREB: cAMP response element-binding protein; CRH: corticotropin-releasing hormone

CS3: citrate synthase; CSDS: chronic social defeat stress; CSRS: chronic spatial restraint stress; cTnI: cardiac troponin I; CUMS: chronic unpredictable mild stress; DA: dopamine; DM: diabetes mellitus; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal-regulated kinase; FAAH: fattyacid amide hydrolase; FGF-2: fibroblast growth factor 2; FGFR: fibroblast growth factor receptor; FXR: frnesoid X receptor; GABA: gamma-aminobutyric acid; GRP78: Glucose-Regulated Protein 78; GSH: glutathione; GSH-Px: glutathione peroxidase; GSK-3β: glycogen synthase kinase-3β

HO-1: heme oxygenase-1; 5-HT: 5-hydroxytryptamine; HUVEC: human umbilical vein endothelial cells; ICAM-1: intercellular adhesion molecule-1; IFN: interferon; IL: interleukin; iNOS: inducible nitric oxide synthase

light chain 3; LDH: lactate dehydrogenase; Lp-PLA2: lipoprotein-associated Phospholipase A2; LVEDVi: left ventricular end-diastolic volumes index; LVEF: left ventricular ejection fraction; LVESVi: left ventricular end-systolic volume index; MAO: monoamine oxidase; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemoattractant protein-1; MDA: malondialdehyde

MPO: myeloperoxidase; Mst1:macrophage stimulating 1; mTBI: mild traumatic brain injury; mTOR: mammalian target of rapamycin; mtPTP: mitochondrial permeability transition pore; NE: noradrenaline; NF: neurofilaments; NF-κB: Nuclear factor-kappaB; NLRP3: NACHT, LRR, and PYD domains-containing protein 3; Nox4: NADPH oxidase 4; Nrf2: Nuclear factor E2-related factor 2; NRVM: neonatal rat ventricular myocyte; OGD: oxygen-glucose deprivation model; OID: ovariectomy-induced depression primary

PDRD: Parkinson's disease-related depression; PGC1α: peroxisome proliferator-activated receptor-γ co-activator-1α; PI3K: phosphatidylinositol 3-kinase; PMAT: plasma membrane monoamine transporter; PPAR: peroxisome proliferator-activated receptor; PRX: Peroxiredoxins; PSD95: postsynaptic density 95; RAGE: receptor for AGE; ROS: reactive oxygen species; RRSD: repeated restraint stress-induced depression-like behavior; SIA: stress-induced anxiety; SERCA2a:sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a; SOD: superoxide dismutase; Sp1: specificity protein 1; STAT3: signal transducers and activators of transcription3

TNF-α: tumor necrosis factor-α; TrkB: tropomycin receptor kinase B; TUNEL: terminal dUTP nick-end labeling; US: unconditioned stimulus; VCAM-1: vascular cell adhesion molecule-1; α-SMA: α-smooth muscle actin. Frontiers in Pharmacology | www

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Kaempferol Facilitated Extinction Learning in Contextual Fear Conditioned Rats via Inhibition of Fatty-Acid Amide Hydrolase

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Quercetin Inhibits TNF-α Induced HUVECs Apoptosis and Inflammation via Downregulating NF-kB and AP-1 Signaling Pathway In Vitro

Protective Effects of Isorhamnetin on Apoptosis and Inflammation in TNF-α-Induced HUVECs Injury

Clinical Observation of Chaihu Jieyu Decoction in the Treatment of Coronary Heart Disease Stable Angina Pectoris (Qi Stagnation

FGF-2 Signaling Activation in the hippocampus Contributes to the Behavioral and Cellular Responses to Puerarin

The Prevalence of Anxiety and Associated Factors in a Multiracial Sample of Older Adults

Prevalence of Anxiety and Depression Symptoms in Patients with Myocardial Infarction with Non-obstructive Coronary Arteries

Treatment of Anxiety and Depressive Disorders in Patients with Cardiovascular Disease

Involvement of GABAergic Non-benzodiazepine Sites in the Anxiolytic-like and Sedative Effects of the Flavonoid Baicalein in Mice

Luteolin Mediates the Antidepressant-like Effects of Cirsium Japonicum in Mice, Possibly through Modulation of the GABAA Receptor

Effects of Quercetin Supplementation on Inflammatory Factors and Quality of Life in post-myocardial Infarction Patients: A Double Blind, Placebo-Controlled, Randomized Clinical Trial

Clinical Observation of Danqi Anshen Decoction in Treating Coronary Heart Disease Stable Angina Pectoris (Qi Deficiency and Blood Stasis Type) with Anxiety

Stress and Inflammation in Coronary Artery Disease: A Review Psychoneuroendocrineimmunology-Based. Front Immunol

Effects of the Combination of Tanshinone IIA and Puerarin on Cardiac Function and Inflammatory Response in Myocardial Ischemia Mice

Antidepressive Effects of Kaempferol Mediated by Reduction of Oxidative Stress, Proinflammatory Cytokines and Up-Regulation of AKT/β-catenin cascade

Susceptibility to Chronic Social Stress Increases Plaque Progression, Vulnerability and Platelet Activation

Increased Prevalence of Anxiety and Depression Symptoms in Patients with Coronary Artery Disease before and after Percutaneous Coronary Intervention Treatment

Clinical Study of Shugan Jieyu Decoction on Coronary Heart Disease Complicated with Depression

Effects of Quercetin on the Alterations of Serum Elements in Chronic Unpredictable Mild Stress-Induced Depressed Rats

Quercetin Reverses Chronic Unpredictable Mild Stress-Induced Depression-like Behavior In Vivo by Involving Nuclear Factor-E2-Related Factor 2

Clinical Observation of Shenchai Shuxin Decoction on Angina Pectoris Complicated with Anxiety of Coronary Heart Disease

Luteolin Alleviates post-infarction Cardiac Dysfunction by Up-Regulating Autophagy through Mst1 Inhibition

Luteolin Modulates SERCA2a via Sp1 Upregulation to Attenuate Myocardial Ischemia/ reperfusion

Activity Dependent Mammalian Target of Rapamycin Pathway and Brain Derived Neurotrophic Factor Release Is Required for the Rapid Antidepressant Effects of Puerarin

Clinical Study on Guanxinning Tablets for Coronary Heart Disease Complicated with Depression

Pharmacological Mechanism and Apoptosis Effect of Baicalein in Protecting Myocardial Ischemia Reperfusion Injury in Rats

Clinical Effect of Shuxin Decoction on Angina Pectoris Complicated with

Stigmasterol Can Be New Steroidal Drug for Neurological Disorders: Evidence of the GABAergic Mechanism via Receptor Modulation

Subsyndromal Depression and Anxiety in Older Adults: Health Related, Functional, Cognitive and Diagnostic Implications

Flavonoids as Therapeutic Candidates for Emotional Disorders Such as Anxiety and Depression

Quercetin Mitigates Anxiety-like Behavior and Normalizes Hypothalamus-Pituitary-Adrenal axis Function in a Mouse Model of Mild Traumatic Brain Injury

Baicalein Protects Isoproterenol Induced Myocardial Ischemic Injury in Male Wistar Rats by Mitigating Oxidative Stress and Inflammation

Nutritional and Herbal Supplements for Anxiety and Anxiety-Related Disorders: Systematic Review

Chronic Administration of Baicalein Decreases Depression-like Behavior Induced by Repeated Restraint Stress in Rats

Protective Effects of Quercetin on Anxiety-like Symptoms and Neuroinflammation Induced by Lipopolysaccharide in Rats

Cardioprotection of CAPE-oNO2 against Myocardial Ischemia/reperfusion Induced ROS Generation via Regulating the SIRT1/eNOS/NF-Κb Pathway In Vivo and In Vitro

Clinical Observation of 40 Cases of Coronary Heart Disease with Depression after PCI Treated by Liu Yujie with Modified Wendan Decoction

Clinical Observation of Tiaogan Jianpi Tongyang Prescription in the Treatment of Anxiety State after PCI for Coronary Heart Disease

Kaempferol Alleviates Human Endothelial Cell Injury through circNOL12/miR-6873-3p/ FRS2 axis

Xiaoyaowan on Coronary Heart Disease with Major Depression Patients Qua Lity of Life

β-Sitosterol Protects against Myocardial Ischemia/Reperfusion Injury via Targeting PPARγ/NF-Κb Signalling

Herbal Medicine for Anxiety, Depression and Insomnia

Clinical Efficacy and Safety of the Shugan Jieyu Capsule in Patients with Acute Myocardial Infarction and Depression

Nobiletin Ameliorates Cardiac Impairment and Alleviates Cardiac Remodeling after Acute Myocardial Infarction in Rats via JNK Regulation

Tanshinone IIA Improves Depression-like Behavior in Mice by Activating the ERK-CREB-BDNF Signaling Pathway

Observation on Curative Effect of Jieyu Shugan Tongmai Decoction in Treating Depression after PCI (Syndrome of Liver Stagnation and Qi Stagnation)

The Effect of Xinkeshu Tablets on Depression and Anxiety Symptoms in Patients with Coronary Artery Disease: Results from a Double-Blind, Randomized, Placebo-Controlled Study

Quercetin Alleviates Chronic Unpredictable Mild Stress-Induced Depressive-like Behaviors by Promoting Adult Hippocampal Neurogenesis via FoxG1/ CREB/BDNF Signaling Pathway

Sodium Tanshinone IIA Sulfonate Prevents the Adverse Left Ventricular Remodelling: Focus on Polymorphonuclear Neutrophil-Derived Granule Components

Clinical Study on Anxiety State of Patients after Percutaneous Coronary Intervention

Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA Statement

The Clinical Research of YangXinJieYu Soup to Treat Mild Depression Disorder in the Elderly after Percutaneous Coronary Intervention

A Clinical Study on Treating Anxiety Disorder after Coronary Heart Disease Intervention with the Jieyu Tongmai Granule

Observation on the Curative Effect of Invigorating Qi and Activating Blood to Relieve Stagnation in the Treatment of Depression Related to Coronary Heart Disease

The Clinical Research Based on the Principle of "ZhiQi" in the Treatment of Anxiety Disorder with Coronary Heart Disease after Percutaneous Coronary Intervention

Puerarin Ameliorated the Behavioral Deficits Induced by Chronic Stress in Rats

The Anxiolytic-like Effects of Puerarin Are Associated with the Changes of Monoaminergic Neurotransmitters and Biosynthesis of Allopregnanolone in the Brain

What Is in a Name? the Need for Accurate Scientific Nomenclature for Plants

Anxiety and Risk of Incident Coronary Heart Disease: a Meta-Analysis

Oxidative Stress and the Central Nervous System

Quercetin Protects against Stress-Induced Anxiety-and Depression-like Behavior and Improves Memory in Male Mice

Clinical Observation on 30 Cases of Depression after PCI Treated with Bupleurum Plus Longgu Oyster Decoction

Clinical Study of Tongmai Sanyu Decoction on Unstable Angina Pectoris (Blood Stasis Type) with Depression

Clinical Observation of Jieyu Tongmai Decoction on 68 Cases of Depression after Coronary Stenting

Inhibition of 12/15 Lipoxygenase by Baicalein Reduces Myocardial Ischemia/reperfusion Injury via Modulation of Multiple Signaling Pathways

Clinical Observation of Jiaweisuanzaoren Decoction in the Treatment of Revascularization in

Molecular Pathways Involved in the Amelioration of Myocardial Injury in Diabetic Rats by Kaempferol

Clinical Study of Jieyuhuoxue Anshen Method in Treatment of CHD with Depression

Puerarin Attenuates Locomotor and Cognitive Deficits as Well as Hippocampal Neuronal Injury through the PI3K/Akt1/GSK-3β Signaling Pathway in an In Vivo Model of Cerebral Ischemia

Associations of Low Grade Inflammation and Endothelial Dysfunction with Depression -the Maastricht Study

Double Heart Effect and Partial Mechanism of Bupleurum Plus Longguoyasu Decoction in Treating Coronary Heart Disease Complicated with Anxiety

Clinical Study of Jiawei Dachaihu Decoction on Stable Angina Pectoris of Coronary Heart Disease with Depression

Nobiletin Ameliorates NLRP3 Inflammasome-Mediated Inflammation through Promoting Autophagy via the AMPK Pathway

Clinical Efficacy of Shuxin Oral Liquid Combined with Conventional Western Medicine in the Treatment of Stable Coronary Heart Disease with Anxiety Based on "Psycho-cardiology Disease

Microglial Activation Mediates Chronic Mild Stress-Induced Depressive-and Anxiety-like Behavior in Adult Rats

A Chinese Herbal Formula Shows Beneficial Effects on Comorbid Depression and Coronary Heart Disease Based on the Philosophy of Psycho-Cardiology

Puerarin Protects against Myocardial Ischemia/reperfusion Injury by Inhibiting Inflammation and the NLRP3 Inflammasome: The Role of the SIRT1/NF-Κb Pathway

Luteolin Ameliorates Rat Myocardial Ischaemia-Reperfusion Injury through Activation of Peroxiredoxin II

Nobiletin Attenuates Adverse Cardiac Remodeling after Acute Myocardial Infarction in Rats via Restoring Autophagy Flux

Isorhamnetin, A Flavonol Aglycone from Ginkgo Biloba L., Induces Neuronal Differentiation of Cultured PC12 Cells: Potentiating the Effect of Nerve Growth Factor

Cardioprotective Effect of Isorhamnetin against Myocardial Ischemia Reperfusion (I/R) Injury in Isolated Rat Heart through Attenuation of

Clinical Intervention Effect of Chaihu Plus Longgu Oyster Decoction on Coronary Heart Disease Complicated with Anxiety

The Role of Traditional Chinese Medicine in the Regulation of Oxidative Stress in Treating Coronary Heart Disease

Involvement of Monoaminergic Systems in the Antidepressant-like Effect of Nobiletin

The Effect of Beta-Sitosterol and its Derivatives on Depression by the Modification of 5-HT, DA and GABA-Ergic Systems in Mice

Luteolin Inhibits ROS-Activated MAPK Pathway in Myocardial Ischemia/reperfusion Injury

Nobiletin Ameliorates Myocardial Ischemia and Reperfusion Injury by Attenuating Endoplasmic Reticulum Stress-Associated Apoptosis through Regulation of the PI3K/AKT Signal Pathway

Effect of Jiangqi Dayu Decoction on Unstable Angina Pectoris Complicated with Anxiety

Clinical Effect of Xuefu Zhuyu Decoction Combined with Yueju Pill on Coronary Heart Disease with Stable Angina Pectoris Due to Qi Stagnation and Blood Stasis Type

Clinical Observation on the Treatment of Coronary Heart Disease Complicated with Depression by Removing Phlegm and Stasis

Traditional Chinese Medicine for Coronary Heart Disease: Clinical Evidence and Possible Mechanisms

Clinical Effect of Dual Heart Mode on Angina Pectoris with Anxiety of Coronary Heart Disease

Effects of Puerarin on Clinical Parameters, Vascular Endothelial Function, and Inflammatory Factors in Patients with Coronary Artery Disease

Structural Features and Potent Antidepressant Effects of Total Sterols and β-sitosterol Extracted from Sargassum Horneri

Puerarin Alleviates Coronary Heart Disease via Suppressing Inflammation in a Rat Model

Luteolin Alleviates Myocardial Ischemia Reperfusion Injury in Rats via Siti1/NLRP3/NF-Κb Pathway

Isorhamnetin Protects against Hypoxia/reoxygenation-Induced Injure by Attenuating Apoptosis and Oxidative Stress in H9c2 Cardiomyocytes

Baicalein Alleviates Depression-like Behavior in Rotenone-Induced Parkinson's Disease Model in Mice through Activating the BDNF/TrkB/CREB Pathway

Clinical Observation of Xinling Pills in the Teatment of Coronary Heart Disease after PCI Complicated with Anxiety Based on Dual Heart Therapy

Nobiletin Attenuates Pathological Cardiac Remodeling after Myocardial Infarction via Frontiers in Pharmacology | www

Activating PPARγ and PGC1α

The Clinical Research of Jieyu Particle in Treatment of Unstable Angina Patients with Depression Status

Luteolin Shows Antidepressant-like Effect by Inhibiting and Downregulating Plasma Membrane Monoamine Transporter (PMAT, Slc29a4)

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.Copyright © 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.Frontiers in Pharmacology | www.frontiersin.org