Advances in research on the protective mechanisms of traditional Chinese medicine (TCM) in myocardial ischaemia-reperfusion injury

Abstract Context Developing effective drugs to treat myocardial ischaemia-reperfusion (MI/R) injury is imperative. Traditional Chinese medicines (TCMs) have had considerable success in the treatment of cardiovascular diseases. Elucidating the mechanisms by which TCMs improve MI/R injury can supplement the literature on MI/R prevention and treatment. Objective To summarise TCMs and their main protective mechanisms against MI/R injury reported over the past 40 years. Methods Relevant literature published between 1980 and 2020 in Chinese and English was retrieved from the Web of Science, PubMed, SpringerLink, PubMed Central, Scopus, and Chinese National Knowledge Infrastructure (CNKI) databases. Search terms included ‘medicinal plants’, ‘myocardial ischaemia reperfusion injury’, ‘Chinese medicine prescriptions’, ‘mechanisms’, ‘prevention’, ‘treatment’ and ‘protection’. For inclusion in the analysis, medicinal plants had to be searchable in the China Medical Information Platform and Plant Database. Results We found 71 medicinal species (from 40 families) that have been used to prevent MI/R injury, of which Compositae species (8 species) and Leguminosae species (7 species) made up the majority. Most of the effects associated with these plants are described as antioxidant and anti-inflammatory. Furthermore, we summarised 18 kinds of Chinese compound prescriptions, including the compound Danshen tablet and Baoxin pill, which mainly reduce oxidative stress and regulate mitochondrial energy metabolism. Discussion and conclusions We summarised TCMs that protect against MI/R injury and their pharmacological mechanisms. This in-depth explanation of the roles of TCMs in MI/R injury protection provides a theoretical basis for the research and development of TCM-based treatment drugs.


Introduction
Myocardial ischaemia-reperfusion (MI/R) injury refers to the progressive aggravation of damaged tissue after blood flow to the ischaemic myocardium, which may eventually lead to myocardial fibrosis, heart failure, and myocardial infarction (Neri et al. 2017;Bai et al. 2019). Jennings et al. (1960) first identified MI/R injury. Since then, MI/R injury mechanisms and treatment strategies have been popular research topics. Currently, reperfusion injury is considered the major complication of vascular reperfusion therapy for acute myocardial infarction (MI) and is estimated to occur in up to 60% of patients (Moon et al. 2020). Inhibition of reperfusion injury is key to the treatment of MI.
The pathophysiological changes caused by reperfusion include inflammation, oxidative stress, intracellular Ca 2þ overload, and impaired energy metabolism (Yellon and Hausenloy 2007) and ultimately can cause irreversible cell death (Heusch et al. 2010). The interrelationships of injury mechanisms often trigger or indirectly aggravate other injury factors (Garcia-Dorado et al. 2009;Yang et al. 2018). When reperfusion lasts for a few minutes, a large amount of oxygen suddenly enters the reperfused myocardium, and multiple mechanisms, such as neutrophil respiration burst and mitochondrial electron transport chain damage, lead to a sudden increase in reactive oxygen species (ROS) (Goldhaber and Weiss 1992). ROS can inhibit mitochondrial oxidative phosphorylation, resulting in insufficient energy synthesis (Laskey 2005) and mediating sarcoplasmic reticulum dysfunction (Hausenloy and Yellon 2013). Oxygen-free radicals also promote the formation of microthrombi . Another important mechanism is the inflammatory response, which accompanies the entire process (Marchant et al. 2012) and is the basis of myocardial structural and functional defects. Inflammation is related to the generation of ROS. Proteases and danger-associated molecular patterns (DAMPs) are released when ROS levels surge (Marchant et al. 2012), promoting inflammation by activating NF-jB (Vallabhapurapu and Karin 2009). ROS can also activate NLRP3 (Pellegrini et al. 2019) and further promote the production of inflammatory cytokines and other molecules such as IL-1b (Marchant et al. 2012), IL-6 (Legendre et al. 2005), IL-8 (Pawlinski et al. 2007), TNF-a (Saito et al. 2012), NO (Su et al. 2016) and HMGB1 (Xu et al. 2011;Herzog et al. 2014). In the acute ischaemic phase, the increase in intracellular Ca 2þ in cardiomyocytes may be related to Ca 2þ uptake disorders caused by Na þ -Ca 2þ exchange and sarcoplasmic reticulum injury . Furthermore, large amounts of Ca 2þ are deposited in the mitochondria (Hausenloy and Yellon 2013), which destroys excitation-contraction coupling (Xie and Weiss 2009) and mitochondrial function, producing energy barriers. During reperfusion, Ca 2þ and ROS activate the mitochondrial permeability transition pore (MPTP), a non-selective channel in the inner mitochondrial membrane that plays a key role in MI/R injury (Cheng et al. 2016); this activation prompts the MPTP to open, dephosphorylate (Kulek et al. 2020) and depolarise the mitochondrial membrane potential (Cheng et al. 2016), which further hinders the synthesis of ATP, causing a vicious cycle.
Nonetheless, the mechanisms of MI/R injury remain unclear, and the development of therapeutic approaches for reperfusion injury has been disappointing (Ib añez et al. 2015). Many clinical trials have failed to demonstrate the existence of specific therapies that can reduce reperfusion injury (Fern andez-Jim enez and Ibanez 2015;Jones et al. 2015). Although currently used drugs such as statins (Mensah et al. 2005) and ACE inhibitors (ACEIs) (Manning and Vehaskari 2005) have certain therapeutic effects on MI/R injury, synthetic drugs can cause side effects. The field of traditional Chinese medicine (TCM) has a history of more than 2000 years and features unique theories and abundant resources (Hao et al. 2015). Over the past several years, more than 100 TCM studies have been registered with ClinicalTrials.gov. Evidence from randomised controlled trials (Hao et al. 2017) and some other studies have indicated that TCMs can effectively relieve abnormal myocardial perfusion by acting on multiple pathways ) and controlling risk factors for cardiovascular disease. Moreover, the side effects of medicinal plants are usually mild (Sedighi et al. 2019). Therefore, it is feasible to treat MI/R injury with TCMs and their active compounds.
This review summarises both single Chinese herbs and TCM compound prescriptions that have therapeutic and protective effects against MI/R injury with a focus on the protective mechanisms. Potential medicinal plants with similar pharmacological effects are also summarised. Further research on the treatment of MI/R injury and the mechanisms of the effects of TCMs on MI/ R injury is warranted.

Methods
To carry out this review, articles in Chinese and English from 1980 to 2020 related to the treatment of MI/R injury with TCMs were retrieved from the Web of Science (WOS), PubMed, SpringerLink, PubMed Central, Scopus, and China National Knowledge Infrastructure (CNKI) databases. The search terms included 'medicinal plants', 'myocardial ischaemia reperfusion injury', 'Chinese medicine compounds ', 'mechanisms', 'prevention', 'treatment', and 'protection'. A total of 5285 articles were located. Other medicinal plants (such as Indian herbs) and Chinese medicines that have been studied repetitively were excluded. Only medicinal plants that could be retrieved from the China Medical Information Platform and Plant Database were included in the analysis. After screening, we identified articles that contained information on 18 TCM compound prescriptions and 71 species (from 40 families) of single Chinese herbs, including two plants with potential therapeutic effects.

Results and discussion
The mechanism of MI/R injury is complicated and involves inflammation, oxidative stress, intracellular Ca 2þ overload, impairment of energy metabolism and ultimately irreversible cell death, as described previously (Yellon and Hausenloy 2007;Heusch et al. 2010). We identified 71 species (from 40 families) of single Chinese herbs used in MI/R treatment and classified them according to their pharmacological mechanisms (Tables 1-5). Two potential plants with similar pathological effects (Table 6) and 18 types of TCM compound prescriptions (Table  7) were also summarised. An overview of the possible mechanisms underlying the effects of TCMs in the treatment of MI/R injury is shown in Figure 1. Next, we will review these TCMs in terms of their protective mechanisms against MI/R injury.

Chinese herbs considered to inhibit MI/R injury through antiinflammatory effects
Inflammation plays a key role in MI/R injury. Previous studies (Wang et al. 2006) have found that the levels of inflammatory cytokines are directly related to the amount of damage to heart function and the number of necrotic cells after ischaemia. Among the 71 species of Chinese herbs accepted for this review, 27 species were found to inhibit inflammation in MI/R injury (Table 1). Among them, Compositae plants accounted for the highest proportion (22.2%), followed by Leguminosae plants (11.1%).
Reductions in cytokine levels are major anti-inflammatory effects of TCMs in the treatment of MI/R injury (Nos. 2 and 3 in Figure 1). As shown in Table 1, 13 species of Chinese herbs exert cardioprotective effects by regulating the levels of intracellular cytokines, including Rosa rugosa Thunb. (Rosaceae) (Hou et al. 2016), Dioscorea zingiberensis C. H. Wright (Dioscoreaceae) (Ebrahimi et al. 2014) and others. Among them, plumbagin extracted from Plumbago zeylanica L. (Plumbaginaceae) was used to prevent heart diseases in ancient times (Luo et al. 2010;Sheeja et al. 2010). Plumbagin induces activation of Nrf2 and reduces the expression of cytokines (MCP-1, IL-6, IL-8, and TNF-a) to return inflammation markers to normal levels . Valerian extract from Valeriana officinalis L. (Valerianaceae) (Xue et al. 1988) causes central sedation, exerts anti-arrhythmia effects, increases coronary blood flow, and reduces the scope of MI. Valerian extract can inhibit TNF-a production by monocytes/macrophages, reducing the expression of neutrophil (polymorphonuclear neutrophil, PMN) adhesion molecules, and thereby reducing the accumulation of PMNs in ischaemic regions in rabbits (Yin et al. 2000).
Some TCMs exert important therapeutic effects on MI/R injury by inhibiting the NF-jB signalling pathway (No. 4 in Figure 1). The increased production of ROS and pro-inflammatory cytokines resulting from myocardial ischaemia and hypoxia activates NF-jB (Karin and Greten 2005), and continuous activation of NF-jB leads to the expression of inflammatory cytokines, finally leading to cell death (Hamid et al. 2011). Caffeoylquinic Acid Derivatives Extract (AE) from Erigeron multiradiatus (Lindl.) Benth. (Compositae) significantly inhibits MI/R-induced injury by decreasing myocardial infarct size, reducing CK and LDH activity, and preventing ST-segment depression in a dose- Through the PI3K/Akt and ERK 1/2 signal pathways.  Valerianaceae Valeriana officinalis L.

Roots and rhizomes
Valerian extract 100 mg/kg Big-eared white rabbits, 1 h of ischaemia and 1.5 h of reperfusion.
Reduce the production of TNF-a. (Yin et al. 2000) Zygophyllaceae Tribulus terrestris L.
Some pro-inflammatory genes and adhesion molecule-encoding genes such as ICAM-1, are downstream of the NF-jB pathway, and an inflammatory response occurs when they are triggered (downstream in No. 4 in Figure 1). Total flavone of Abelmoschus manihot L. (Malvaceae) (TFA) contains a total of 12 flavonoids, of which the chemical structures of 8 flavonoids have been identified (Li et al. 2001;Fan et al. 2003). TFA can downregulate the high expression of ICAM-1 and inhibit myocardial inflammation in vivo (Fan et al. 2006). The protective effect of TFA against MI/R injury is similar to that of ischaemic preconditioning (IPC), an endogenous protective mechanism in the body that is difficult to implement in the clinic. The therapeutic effect of TFA is better than that of the clinical medication verapamil (0.8 mg/kg), which suggests that TFA preconditioning is a promising strategy to effectively reduce the myocardial damage caused by MI/R (Fan et al. 2006).
Furthermore, inhibition of the NLRP3 inflammasome is an effective treatment means for MI/R injury. Reperfusion injury can trigger activation of the NLRP3 inflammasome; accelerate the secretion of IL-1b, IL-18 and caspase-1; and then induce an inflammatory response and pyroptosis (Bian et al. 2020). Hydroxysafflor yellow A (HSYA) of Carthamus tinctorius L. (Compositae) can inhibit the NLRP3 inflammasome by regulating the AMPK/mTOR signalling pathway (No.1 in Figure 1) in vitro ) and in vivo ). The therapeutic effect of HSYA on MI/R injury is comparable to that of diltiazem hydrochloride tablets (DTZ), a positive control. Studies have shown that HSYA may be a promising drug to prevent MI/ R injury; therefore, its pharmacokinetics and toxicity should be further explored in the future. Erigeron breviscapus (Vant.) Hand.-Mazz. (Compositae)  and Artemisia annua L. (Compositae) ) also exert myocardial protective effects by inhibiting the NLRP3 inflammasome.

Chinese herbs considered to inhibit MI/R injury by reducing oxidative stress
We have summarised 35 species of Chinese herbs that reduce the oxidative stress state of cardiomyocytes to exert myocardial protection in Table 2. The most represented families among these species are the Leguminosae family (14.3%), the Compositae family (11.4%), the Polygonaceae family (8.6%) and the Rutaceae family (5.7%).
During oxidative stress in myocardial cells, neutrophil inflammatory infiltration and protease secretion increase, and a large number of oxidative intermediates are produced (Yellon and Hausenloy 2007). Most antioxidant effects of herbs involve scavenging of free radicals and enhancement of the activity of antioxidant enzymes (Nos. 10 and 11 in Figure 1). Panax notoginseng (Burk.) F. H. Chen (Apiaceae) is commonly used in China and was used as early as the publication of the Compendium of Materia Medica, as its use is recorded by Shizhen Li (Li et al. 2009). Notoginsenoside R1 (NGR1) is a new saponin extracted from Panax notoginseng that can reduce ROS levels in MI/R injury, participate in antioxidative stress mechanisms and restrain endoplasmic reticulum stress (ERS) (No.18 in Figure 1). Latifolin, a new flavone extracted from Dalbergia odorifera T. Chen. (Leguminosae), has the functions of removing blood stasis, regulating qi and relieving pain ). An in vitro study has shown that latifolin significantly reduces the ROS content in H9c2 cells after hypoxia and reoxygenation (H/R), the mechanism of which may be related to activation of the Nrf2/HO-1 pathway (No. 9 in Figure  1). Cassia mimosoides L. (Leguminosae), is used as a food and tea (Yamamoto et al. 2000). In TCM, the whole plant is often used. An in vivo study (Lim and Lee 2012) has revealed that  Reduce the production of free radicals.  administration of the methanol extract of Cassia mimosoides reduces the infarct size in reperfusion injury-induced size of myocardial infarction MI by up to 28.3%. The methanol extract of Cassia mimosoides prevents MI/R injury mainly by scavenging ROS (No. 10 in Figure 1) and then blocking the apoptotic cascade. It is hoped that a new drug to prevent MI/R injury will be developed as a consequence of the identification of the active components of Cassia mimosoides. extract. Rutin, a natural flavonoid glycoside, is the main active ingredient of Sophora japonica L. (Leguminosae). In an antioxidant activity assay with 1, 1-diphenyl-2-picrylhydrazine (DPPH), 100 lM rutin was found to scavenge 82.62% ± 0.91 of radicals. In vivo and in vitro studies have shown that rutin can treat MI/R injury mainly by altering hemodynamic factors and enhancing the activity of the antioxidant enzymes superoxide dismutase (SOD) and DPPH (No. 11 in Figure 1) (Bhandary et al. 2012). A comparison of the therapeutic effects of five isoflavones on MI/R injury, including biochanin A, daidzein, genistein, quercetin and rutin, has suggested that rutin is the most protective isoflavone (Bhandary et al. 2012). In addition, herbs such as Arctium lappa L.  (Table 2).

Chinese herbs considered to inhibit MI/R injury by reducing Ca 21 overload
Application of drug antagonists targeting Ca 2þ channels, mitochondrial Ca 2þ single transmitters and Na þ -H þ exchange carriers to reduce the intracellular Ca 2þ concentration can effectively reduce the area of MI by more than 50% (Ussher and Lopaschuk 2009). However, there have been few relevant studies in this area, and only Mollugo pentaphylla L. (Aizoaceae) ) has been found to reduce intracellular calcium overload, as shown in No. 12 in Figure 1 and Table 3. The whole plant of the grass Mollugo pentaphylla is used as a medicine with heat-clearing and detoxifying effects.
Modern medical research has shown that Mollugo pentaphylla has anticancer, anti-arrhythmia, antihypertensive and other pharmacological effects (Liu KY 2009). Extract of Mollugo pentaphylla can effectively reduce the incidence of arrhythmia in rats, improve the activity of Ca 2þ -ATPase in myocardial tissue and maintain the levels at magnitudes comparable to those in sham-operated rats , suggesting that Mollugo pentaphylla extract has a certain protective effect against Ca 2þ overload in MI/R injury.

Chinese herbs considered to inhibit MI/R injury by regulating mitochondrial energy metabolism
Reperfusion leads to intracellular Ca 2þ overload, causing mitochondrial Ca 2þ overload, which in turn prompts the opening of   the MPTP and causes mitochondrial dysfunction (Hausenloy and Yellon 2013). We found eight kinds of Chinese herbs that reduce MI/R injury by regulating mitochondrial energy metabolism (Table 3). When reactive aldehydes are produced by oxidative stress due to sudden reperfusion of the damaged myocardium, aldehyde dehydrogenases (ALDHs) in mitochondria can convert the reactive aldehydes into harmless acids. Piperlonguminine (PPLG) is a kind of natural alkaloid extracted from Piper longum L. (Piperaceae). In a study in which a MI/R injury rat model was constructed and rat myocardial mitochondria were isolated (Yoval-S anchez et al. 2020), PPLG was proved to reduce the levels of lipid peroxidation products, activate ALDHs to maintain mitochondrial function (No. 15 in Figure 1), and protect cardiomyocytes and tissues during MI/R injury. Activation of mitoKATP channels can regulate Ca 2þ uptake disorder and prevent MPTP opening and ROS formation to resist myocardial ischaemia, which is an important way to improve myocardial injury with drugs (Testai et al. 2021). National herbal medicine assembly records the use of Dioscorea zingiberensis for 'the treatment of early boils ulcer, bee sting, appendicitis.' Diosgenin is extracted from the rhizomes of Dioscorea zingiberensis, and an ex-vivo MI/R injury model study found that preconditioning with diosgenin (0.001 lM) can not only reduce the production of inflammatory mediators but also possibly provide myocardial protection by activating mitoKATP channels (No. 13 in Figure 1) (Ebrahimi et al. 2014). Notably, excessive Dioscorea zingiberensis may cause dizziness and other toxic phenomena, so it is critical to study the toxicology of diosgenin before developing a new drug. In addition, naringin (Nari), a flavonoid obtained from the dry outer layer of Citrus maxima (Burm.) Merr. (Rutaceae), has been documented to dose-dependently activate KATPs, especially mitoKATP, to exert a protective effect on damaged myocardia (Meng et al. 2016).
The ATP content and mitochondrial membrane potential can reflect the level of cardiomyocyte energy metabolism (He et al. 2021). Some medicinal plants protect mitochondria directly by promoting mitochondrial ATP synthesis, improving mitochondrial membrane potential and increasing Na þ -K þ -ATPase and Ca 2þ -Mg 2þ -ATPase activity (Takahashi et al. 2021). In particular, apigenin-8-C-b-D-glucopyranoside (vitexin), a bioactive flavonoid compound, can be isolated from the dried leaves of Crataegus pinnatifida Bge. (Rosaceae) and has been well studied. In vivo and in vitro (Xue et al. 2020), transmission electron microscopy imaging and mitochondrial isolation have shown that vitexin can reduce ROS levels, increase ATP content (No. 14 in Figure 1) and promote the elevations in matrix metalloproteinase (MMP) levels in MI/R injury. Vitexin can alleviate mitochondrial damage, maintain the dynamic balance of mitochondria, reduce the area of MI, and improve the function of the damaged myocardium; thus, it has therapeutic potential for MI/R injury.

Chinese herbs considered to inhibit MI/R injury by reducing apoptosis, autophagy and necrosis
We found 19 species of Chinese herbs that have a regulatory effect on apoptosis (Table 4). Caspase-3, Bax, Bcl-2 and other apoptosis-related proteins can directly reflect apoptosis. Many herbs regulate these apoptosis-related proteins to inhibit apoptosis (No. 16 in Figure 1), such as Paeonia veitchii Lynch (Ranunculaceae) (Wang K and Hu 2020), Pueraria lobata (Willd.) Ohwi (Leguminosae) (Fan HX and Zhang et al. 2017), and Curcuma longa L. (Zingiberaceae) (Mohanty et al. 2006). The mitogen-activated protein kinase (MAPK) signalling Inhibiting the production of necrose-related proteins.  10, 20, 40 Activating the AKT/mTOR signalling pathway.  pathway is an important pathway causing myocardial cell injury and apoptosis   Figure 1). Furthermore, ERS is a relatively newly identified mechanism of apoptosis regulation (No. 18 in Figure 1). The endoplasmic reticulum plays irreplaceable roles in protein folding, transport and secretion (Xu et al. 2005). ERS is triggered by intracellular homeostasis imbalance, and continuous ERS induces cells to enter the apoptotic program, which hampers cell function .
The main active ingredient of Dracaena cochinchinensis (Lour.) S. C. Chen (Liliaceae) is resina draconis (RD), which is extracted from the dried trunk of the plant. Studies have shown that RD can serve as an antioxidant and preservative compound (Choy et al. 2008). In a MI/R injury model , RD (1 mg/mL) has been found to effectively increase SOD activity and reduce MDA content almost to normal levels and significantly reduce the levels of GPR78, CHOP and other apoptosis-related proteins. These findings suggest that RD inhibits ER-induced apoptosis in MI/R injury by regulating miR-423-3p and its target ERK. For protecting the myocardium from reperfusion injury by targeting ERS, Allium fistulosum L.
(Liliaceae) (Li 2019), Schisandra chinensis  and Paeonia lactiflora (Zheng YP and Liu et al. 2019) are also available. The process of autophagy has been conserved throughout cell evolution (Fujiwara et al. 2013); however, excessive autophagy caused by reperfusion exacerbates tissue damage . We screened three herbs [Coptis chinensis Franch. (Ranunculaceae) , Magnolia officinalis (Tan et al. 2019) and Gardenia jasminoides Ellis (Rubiaceae) ] that regulate autophagy in MI/R injury (Table 5 and No. 19 in Figure 1). Berberine (BBR), the main active ingredient of Coptis chinensis, can effectively reduce the autophagic flux of H9c2 cells subjected to H/R and improve mitochondrial function . Moreover, in vivo and in vitro studies have shown that geniposide, an organic compound extracted from the dried and ripe fruits of Gardenia jasminoides is, can effectively reduce the MI size and H/R-induced autophagosome formation. The possible mechanism may involve inhibition of autophagy through the AKT/mTOR signalling pathway .
During reperfusion, TNF-a and other inflammatory factors bind to their receptors to activate programmed necrosis. Eventually, necrosomes composed of RIP1, RIP3 and MLKL are formed to execute cell necrosis (Pasparakis and Vandenabeele 2015). We found that three species of Chinese herbs can regulate necrosis caused by MI/R injury (Table 5 and No. 20 in Figure  1), including Scutellaria baicalensis Ceorgi (Labiatae) , Bauhinia championii Benth. (Leguminosae)  and Arctium lappa. . In particular, arctiin, an extract of Arctium lappa, not only plays an antioxidant role in the treatment of MI/R injury but also has an inhibitory effect on necrosis in H9c2 cell subjected to H/R ). Detection of the protein levels of RIPK1/pRIPK1, RIPK3/ pRIPK3 and MLKL/pMLKL, has confirmed that arctiin inhibits cell necrosis by inhibiting the production of necrosis-related proteins. According to bioinformatics data, arctiin may also directly target RIPK1 and/or MLKL to prevent necrosis in MI/R injury.
Potential Chinese medicines considered to protect against MI/R injury Several Chinese plants have potential protective effects against MI/R injury (Table 6), including Camellia oleifera Abel (Theaceae) (Lai et al. 2004) and Rosmarinus officinalis L. (Labiatae) . Sasanquasaponin (SQS) is an effective extract of Camellia oleifera whose main structure is similar to that of some ginseng saponins (Liu CX and Xiao 1992;Attele et al. 1999). In vitro studies (Lai et al. 2004) have shown that SQS can inhibit arrhythmia during MI/R and may play a protective role in the myocardium by regulating intracellular Clhomeostasis. Rosmarinus officinalis is a traditional herb with abundant application value. Rosemary extract (MDX60) is derived from Rosmarinus officinalis; the main component is carnosic acid (60%). A study on MI/R model rats ) has shown that MDX60 can reduce the MI size. These potential medicinal plants have not yet been used in clinical practice, and more in vivo and in vitro studies are needed to support their use. Further exploration of their specific mechanisms may lead to new measures for the treatment and prevention of MI/R injury.

TCM compound prescriptions considered to have therapeutic effects on MI/R injury
The compatibility of TCMs with other therapeutics can often expand the range of treatments and enhance the efficacy of drugs, which may help maximise the impact on MI/R injury given its complicated mechanisms. Huoxue Huatan Decoction has been used for the treatment of cardiovascular diseases for over 20 years. It is composed of Salvia miltiorrhiza, Astragalus membranaceus, Panax notoginseng, Ginkgo biloba L., Trichosanthes kirilowii Maxim. (Cucurbitaceae), Allium macrostemon Bunge (Liliaceae). and Ziziphus jujuba Mill. (Rhamnaceae). In vivo studies ) have shown that Huoxue Huatan Decoction can regulate lipid metabolism in MI/R damaged hyperlipidaemia rats in a dose-dependent manner, improve mitochondrial energy disorder through the PGC-1a-PPARa signalling pathway, promote the expression of PGC-1a-NRF1-mtTFA and increase T-SOD levels to protect the heart. Compound Danshen tablet promotes blood circulation and removes stasis, regulating qi and relieving pain Liang et al. 2019;Zheng CM 2019). It is mainly used for the clinical treatment of cardiovascular and cerebrovascular diseases and has definitive curative effects (Liang et al. 2019). It has even been used as a positive control in efficacy studies on other TCMs (Fan HX and Zhang et al. 2017). The major components include Salvia miltiorrhiza, Panax notoginseng, and Dryobalanops aromatica Gaertn. f. (Dipterocarpaceae). Among them, Salvia miltiorrhiza plays a major role; this drug is also known as the "monarch drug" in TCM. An in vivo study ) has shown that  compound Danshen tablet can significantly reduce ST segment elevation; the myocardial ischaemia rate; and the levels of CK, LDH, AST and other myocardial enzymes in serum while increasing the levels of NO and eNOS (a kind of cardiovascular protective molecule) in MI/R injury model rats. Additionally, the therapeutic effect of compound Danshen tablet is better than that of the single medicines in improving myocardial ischaemia ). More information on Chinese compound prescriptions is listed in Table 7. All of the prescriptions have been proven to have therapeutic efficacy against MI/R injury. Among these prescriptions, Salvia miltiorrhiza and Astragalus membranaceus are the most commonly used monarch drug. Tanshinone IIA in Salvia miltiorrhiza and astragaloside IV in Astragalus membranaceus, which have anti-inflammatory and antioxidative effects Ren et al. 2019;Yuan et al. 2020), are promising agents for MI/R injury.

Conclusions and outlook
This article reviews advances in research on the use of TCMs in the treatment of MI/R injury from 1980 to 2020. We collected and summarised information on the families, Latin binomials, parts used, active compounds, doses, experimental animal models, pharmacological mechanisms and references in tables to provide theoretical support for screening and developing safe, efficient and low-toxicity drugs for MI/R injury. Among the 71 species (40 families) identified as Chinese herbs used to treat MI/R, Compositae herbs accounted for the largest proportion at 11.3%. The second most popular family was Leguminosae, accounting for 10% of species. Compositae plants mostly inhibit MI/R injury by exerting anti-inflammatory effects, while Leguminosae plants primarily exert myocardial protective effects by reducing oxidative stress. Among the TCMs whose active ingredients have been identified, we found that the myocardial protective effect is mainly attributed to flavonoids, such as baicalein in Scutellaria baicalensis , rutin in Sophora japonica (Bhandary et al. 2012) and silybin in Silybum marianum (Cao et al. 2017); anthraquinones are the second most important components for myocardial protection. Flavonoids can scavenge ROS such as superoxide and hydrogen peroxide free radicals to reduce oxidative stress; inhibit the pro-inflammatory cytokines production and restrict inflammatory mediator levels, enhance Na þ /K þ -ATPase activity and reduce intracellular Ca 2þ overload. These compounds, which have C6-C3-C6 structures, can exert effective vasodilatory, antioxidant, anti-inflammatory, and antiapoptotic effects in the damaged myocardium. Structural modification of flavonoids and anthraquinones is expected to lead to the development of new effective therapeutic drugs for MI/R injury. In addition, two species with potential therapeutic effects and 18 types of TCM compound prescriptions were included in the current review.
TCMs have the advantages of low toxicity, few side effects, stable curative effects, and the ability to act on multiple pathways. In addition to crude extracts and identified effective monomers, Chinese compound prescriptions have shown significant therapeutic potential in in vivo and/or in vitro basic research, suggesting that TCMs have potential treatment value for MI/R injury. TCMs are widely used globally, but the complexity of the chemical compositions of TCM compound formulas makes replication and pharmacological research difficult. Tremendous efforts need to be made to address this issue. More in-depth studies on the active ingredients, pharmacokinetics and drug   toxicity of TCMs can be conducted, and more effective drugs with fewer side effects can be screened. Additionally, structural modification of the main active monomers is a promising strategy to develop new efficient drugs for MI/R injury. Importantly, to demonstrate the clinical activity of TCMs in MI/R injury, large randomised trials are required.