Atheroprotective Effects and Mechanisms of Postmarketing Chinese Patent Formulas in Atherosclerosis Models: A Systematic Review

Background Some postmarketing Chinese patent formulas have been widely used to treat atherosclerosis (AS) and play critical roles in Chinese healthcare. However, the usage of these herbs is yet controversial due to unclear effects and lack of understanding of the mechanism of action. With the modernization of traditional Chinese formulas, we are to elucidate the atheroprotective properties of these remedies from successful postmarketing experiments in vivo. Methods In this systematic review, we critically searched the databases, applied stringent criteria, assessed the methodological quality, and examined the current evidence in vivo. Results Consequently, 60 studies were included in the present qualitative synthesis. Data on models, high-fat diet, intervention time, outcome measures, efficacy, and mechanisms were collected. Finally, 23 formulas that could alleviate AS were correlated to the amelioration of plaques, improvement of plaque stability, modification of lipid level and lipid metabolism, and the effects of anti-inflammation and antioxidant stress with multiple components and targets. However, the methodological quality was low and incomplete among the included literature. Conclusions Thus, taken together, the studies on postmarketing Chinese patent formulas would provide a novel approach to improve the treatment of AS, and rigorously designed studies would provide high-quality evidence.


Introduction
Cardiovascular diseases (CVDs) are the leading causes of death worldwide, with an estimated 17.9 million deaths each year and 32% of all deaths globally [1,2]. Compared with the high-income countries (HICs), the death rate of low-and middle-income countries is about three times higher, causing a heavy economic burden to the society [3]. Coronary heart disease (CHD) is one of the CVDs caused by atherosclerosis (AS) in blood vessels and a significant cause of death in both developing and developed countries [4][5][6]. AS is a multifaceted disorder involving the core mechanisms of endothelium dysfunction, lipid deposition, vascular inflammation, oxidative stress, foam cell formation, and smooth muscle cell migration [7]. In addition, AS can also be identified as an inflammatory disease characterized by immune responses [8]. Modern therapies have made significant progress in the treatment of AS; for example, the Western medicine of statins and the surgeries of percutaneous transluminal coronary intervention (PCI) or coronary artery bypass grafting (CABG). However, interventional therapy can only improve local vascular problems, and statins have been identified to cause side effects of liver damage, muscle dissolution, and new-onset type 2 diabetes mellitus [9]. erefore, other remedies for improving the efficacy and the adverse reactions are urgent requirements.
Traditional Chinese medicine (TCM) has a history of over 2000 years and has been widely used in Chinese healthcare [10]. Unlike Western medicines, traditional Chinese herbs usually consist of various compounds and provide multiple targets for the prevention and treatment of AS [11]. With widespread clinical applications and adequate tolerance, some TCMs have been deemed as an effective approach for treating ASCVD and restoring the balance of the human body [12].
Hitherto, many Chinese patent formulas produced by pharmaceutical companies have emerged and been approved in China. Several postmarketing studies in vivo have been identified to understand the effects and mechanisms of Chinese patent formulas with antiatherosclerotic properties, and some reviews reported the use of Chinese patent formulas in AS [3,13,14]. However, most of these reviews were focused on a single formula. In this study, we critically evaluated the effects and summarized the mechanisms of all the postmarketing Chinese patent formulas in treating AS. A systematic review method was implemented by searching the databases, applying strict criteria, assessing the methodological quality, and evaluating outcomes. In this review, we focused on the formulas in the field of AS and the animal models and mechanisms in atheroprotective effects.

Information Sources and Search Strategy.
e search was applied to three databases, including PubMed, Embase, and Web of Science (publication duration was from the inception through March 29, 2021). e search strategy used the following general terms as mesh terms or free terms: "Medicine, Chinese Traditional", "Herbal Medicine", "Drugs, Chinese Herbal", "Atherosclerosis", "Chinese patent medicine", "Chinese patent drug", "Chinese traditional patent medicine", "traditional Chinese medicine or Chinese medicine", "TCM", "Chinese herb medicine", "Chinese herbal medicine", "atherosclerosis", "arteriosclerosis", "atherosis". For instance, the detailed search strategy of PubMed is as follows: (((Medicine, Chinese Traditional) OR (Herbal Medicine) OR (Drugs, Chinese Herbal)) AND (Atherosclerosis)) OR (((Chinese patent medicine or Chinese patent drug or Chinese traditional patent medicine) OR (traditional Chinese medicine or Chinese medicine or TCM or Chinese herb medicine or Chinese herbal medicine)) AND (atherosclerosis or arteriosclerosis or atherosis)). Also, we used a search filter previously developed for PubMed in order to identify all the publications on animal studies [15].

Inclusion and Exclusion Criteria.
Considering the objective of our review, the inclusion criteria were listed as follows: (1) original studies were mainly related to the postmarketing Chinese patent formulas in vivo; (2) the patent drugs that were approved to treat the related AS diseases could be searched on the website (http://app1. nmpa.gov.cn/data_nmpa/face3/base.jsp?tableId�25&table Name�TABLE25&title�%E5%9B%BD%E4%BA%A7%E8% 8D%AF%E5%93%81&bcId�15290471376121329632279580 6604&CbSlDlH0�qGqJcGqBhnZBhnZBhCJzH3eKIwCWYj 2zliOBDl.Z9naqqcZ) of the National Medical Products Administration (NMPA) of the Chinese government; (3) any validated AS model could be applied in this review, including ApoE −/− mice, LDLR −/− mice, New Zealand white rabbits, Japanese white rabbits, Wistar rats, Sprague-Dawley (SD) rats, and C57BL/6 mice with or without a high-fat diet (HFD), balloon injury, and ligation or silastic collar implantation around a specific artery [16,17]; and (4) language was not restricted, but the literature should have been published in official journals. e studies were excluded if they were (1) only in vitro or clinical research; (2) mainly Chinese medicine monomers or other unlisted formulas; or (3) AS models combined with models of other diseases.

Study Selection and Data Extraction.
Two investigators (SQC and XXW) individually conducted the literature search using the predetermined criteria in Endnote X8 software. First, duplicates were identified in various databases and removed from the initial search results. Second, the obviously irrelevant studies were eliminated after reading the titles and abstracts. ird, the full texts were screened to identify the relevant studies, and the unqualified studies were removed. e study selection was independently cross-checked by two researchers. Any disagreement was resolved by discussion in a consensus meeting with the corresponding authors (YHW and MJZ).
Subsequently, two authors (TL and YL) independently extracted data from the included literature employing a standardized sheet prepared for this review, which was further checked by BFW. e extracted data included study title, year of the research publication, drug name, approval number by NMPA, pharmaceutical company, main Chinese herbs, experimental models, HFD feeding time, drug intervention time, outcome measures, efficacy, and mechanisms.

Assessment of Risk of Bias (ROB) in Individual Studies.
Two authors (WTC and YT) independently assessed the ROB using SYRCLE's ROB tool [18] for animal studies to evaluate the methodological quality of the included studies with respect to sequence generation (i.e., selection bias), baseline characteristics (i.e., selection bias), allocation concealment (i.e., selection bias), random housing (i.e., performance bias), blinding (i.e., performance bias), random outcome assessment (i.e., detection bias), blinding (i.e., detection bias), incomplete outcomes data (i.e., attrition bias), selective outcome reporting (i.e., reporting bias), and other sources of bias; it was further checked by JJY. e disagreements were resolved by consensus with the corresponding authors (YHW and MJZ).

Summary Measures and Analysis.
Regarding the high heterogeneity of the various formulas and the different methodologies, all the outcome measures, which compared the experimental groups with the model groups, were recorded as a significant uptrend marker "↑" or a significant downtrend marker "↓". e summary analysis was presented using a qualitative synthesis.

Models of AS.
A total of 15 primary AS models were utilized in these studies, including HFD ApoE −/− mice, HFD LDLR −/− mice, HFD New Zealand or Japanese rabbits, HFD SD rats, HFD SD or Wistar rats with vitamin D3 injection, HFD Wistar rats with vitamin D3 injection and balloon injury in aorta, SD rats with the carotid artery balloon injury, HFD New Zealand rabbits or Japanese rabbits with balloon injury in aorta, HFD ApoE −/− mice with silastic collar implantation, Wistar rats with the silicone collar around the carotid artery, HFD Japanese rabbits or New Zealand rabbits with the silastic collar implantation around the carotid artery, C57BL/6 mice with the common carotid artery ligation, ApoE −/− mice combined partial ligation of the left common carotid artery and left renal artery, HFD New Zealand rabbits with balloon injury and plaques triggering by Chinese Russell viper venom (RVV), and HFD New Zealand rabbits with balloon injury, transfected with adenovirus-containing p53 and plaques triggered by RVV.
Among these, mice and rabbits were common animal species that accounted for 70% of the included studies. e HFD ApoE −/− mice model constituted 45% (27/60) of the studies, and rabbits made up 25% (15/60) of the studies. e models established by extra injection of adenovirus-containing p53 or triggered with RVV aimed to aggravate local inflammation and led to vulnerable plaques in rabbits [71,72]. Despite the varied content of fat feeding, HFD was fed in most (93.3%, 56/60) of the animal models to promote the formation of AS. Furthermore, studies using only male animals constituted 81.7% (49/60) of the series.
Furthermore, Danhong injection significantly suppressed the serum total triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels, upregulated the serum high-density lipoprotein cholesterol (HDL-C) level of HFD ApoE −/− mice [19], and downregulated the serum total cholesterol (TC), TG, and LDL-C levels of HFD New Zealand rabbits [63]. Zhixiong capsule administration showed a significant plasma lipid-lowering effect of the decreased TC level, LDL level, TC/HDL-C ratio, and log(TG/HDL-C) value and elevated HDL-C content [20,78]. Danlou tablet also significantly reduced the TC, TG, and LDL-C levels in HFD ApoE −/− mice [77] and HFD Wistar rats with vitamin D3 injection [42] and increased the HDL-C levels in HFD ApoE −/− mice [24]. Longxuetongluo capsule decreased the serum TC, TG, and LDL-C levels and increased HDL-C levels in HFD male SD rats [26]. Naoxintong inhibited the serum LDL-C and TC in HFD New Zealand rabbits [57], reduced TC and TG in HFD LDLR −/− mice [58], and promoted the HDL-C level in HFD ApoE −/− mice [32]. Qishenyiqi pill decreased the level of blood LDL-C in HFD ApoE −/− mice [34]. Angong Niuhuang pill significantly reduced the serum content of TC, LDL-C, and the ratio of LDL-C to HDL-C in HFD male SD rats with vitamin D3 injection [35]. Ginkgo biloba tablet treatment significantly reduced serum levels of TC, TG, and LDL-C in HFD Wistar male rats with vitamin D3 injection and balloon injury in the aorta [37]. Xuefu Zhuyu granule reduced the serum level of TC in HFD Wistar male rats with vitamin D3 injection [40]. Yindanxinnaotong capsule also decreased the levels of blood TC, TG, and LDL-C in HFD SD male rats with vitamin D3 injection [48]. Longhu Rendan, Di'ao Xinxuekang capsule, or compound Chuanxiong capsule treatment ameliorated AS by significantly reducing serum levels of TC, TG, and LDL-C in HFD ApoE −/− mice [28,30,47]. Tongxinluo, Shexiang Tongxin dropping pill, Fufang Danshen dropping pill, Xuezhikang, Suxiaojiuxin pill, Guanxinshutong capsule, or Xuezhitong capsule treatment reduced serum levels of TC, TG, and LDL-C and increased HDL-C in different models [44,52,54,66,68,72,74,76]. In addition, Danhong injection and compound Chuanxiong capsule decreased the atherosclerotic index (AI) [19,47], which could be calculated as the ratio of non-HDL-C and HDL-C.
Longshengzhi capsule maintained the integrity of the arterial wall and enhanced plaque stability by decreasing necrotic core areas (NCAs); increasing collagen-positive areas (CPAs), smooth muscle cell (SMC) content, and fibrous cap areas (FCAs); and inhibiting cell apoptosis in the lesion areas [21]. Tongxinluo capsule treatment increased the stability of plaques by increasing the intraplaque contents of SMC, CPA, and fibrous cap thickness (FCT) and reducing that of macrophages and lipids [22,41]. e vulnerability index (VI) was calculated as follows: (lipids staining% + macrophages (MOMA-2) staining%)/(SMCs staining% + collagen staining%). Tongxinluo capsule treatment also stabilized atherosclerotic plaques by significantly attenuating VI and macrophage apoptosis and enhancing Beclin-1-induced autophagy [31]. In the plaque rupture models, Tongxinluo capsule treatment prevented vulnerable plaques from rupture by downregulating VI, reducing macrophages and lipids, increasing CPA and SMC, lowering the levels of matrix metalloproteinase-1 (MMP-1), MMP-3, and MMP-12, and upregulating tissue inhibitor of metalloproteinase-1 (TIMP-1) protein in plaques [71,72]. Furthermore, Tongxinluo capsule treatment downregulated MMP-9 [64] and MMP-2 in plaques [22]. Naoxintong treatment enhanced plaque stability by increasing CPA, FCT, FCA, and SMC content and reducing the MMP-2 level, macrophage accumulation, and calcification events in lesion areas [32,39]. Danhong injection maintained the content of CPA in the arterial wall and reduced the expression of MMP-2 and MMP-9 [53]. Xuezhikang treatment also increased CPA and SMC and decreased NCA, MMP-8, and MMP-13, thereby stabilizing the atherosclerotic plaques and Evidence-Based Complementary and Alternative Medicine rupture by the suppression of macrophage endoplasmic reticulum (ER) stress-mediated apoptosis and the NF-κB pathway [33]. Compound Chuanxiong capsule increased collagen proportion in plaques [47]. Suxiaojiuxin pill enhanced atherosclerotic plaque stability by increasing SMC, TIMP-1, and TIMP-2 proteins while decreasing MMP-2 and MMP-9 proteins, which might be associated with the mechanism of modulating the MMPs/TIMPs balance [50]. Both Zhixiong and Guanxinshutong capsules enhanced plaque stability by increasing the content of CPA [76,78]. In addition, Zhixiong capsule decreased vascular mineralization [78] and Guanxinshutong reduced the accumulation of macrophages in aortic root sections [76].

Amelioration of Lipid Metabolism and Lipid
Accumulation.
e disorder of hepatic lipid metabolism induced fatty liver and increased the risk of AS. Excessive accumulation of lipid in aortas and oxidative low-density lipoprotein (ox-LDL) taken in by macrophages could also lead to AS. A total of 14 formulas involving Longshengzhi capsule, Naoxintong, Shexiang Baoxin pill, Danlou tablet, Longhu Rendan, ginkgo biloba tablet, Di'ao Xinxuekang capsule, Xuezhitong capsule, Qishenyiqi pill, Danhong injection, Tongxinluo capsule, Shexiang Tongxin dropping pill, Zhixiong capsule, and Suxiaojiuxin pill described the related mechanisms.
Longshengzhi capsule ameliorated hepatic lipid metabolism by activating the sterol regulatory element binding protein (SREBP) 2 pathway and regulating the expression of SREBP1c protein, low-density lipoprotein receptor (LDLR), hydroxymethylglutaryl coenzyme A synthase (HMGCS), diacylglycerol acyltransferase-1 (DGAT1), adipose triglyceride lipase (ATGL), microsomal triglyceride transporter protein (MTTP), and apolipoprotein C II (APOC2) related to lipogenesis, cholesterol, and TG metabolism in the liver. Longshengzhi capsule also reduced AS lesions associated with the reduction of macrophage and foam cell accumulation by triggering the expression of ATP binding cassette transporter A1 (ABCA1) and ATP binding cassette transporter G1 (ABCG1) [21]. Naoxintong capsule reduced hepatic TG levels by the inhibition of TG synthesis and the activation of TG hydrolysis, including downregulation of DGAT1 while activating AMPKα, ATGL, and comparative gene identification-58 (CGI-58) expression in the liver [32]; Naoxintong treatment also significantly reduced foam cell accumulation in atherosclerotic plaques [29,32]. Shexiang Baoxin pill treatment inhibited lipid accumulation by elevating the levels of liver X receptor α (LXRα), ABCA1, and ABCG1 and reducing the content of scavenger receptor class A (SR-A) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the arterial wall [23]. e mechanism of Danlou tablet in accelerating cholesterol efflux was to activate the peroxisome proliferator-activated receptor α (PPARα)/ABCA1 signaling pathway by upregulating the expression of PPARα, PGC-1α, and ABCA1 [24]. Longhu Rendan ameliorated AS via downregulating the protein expression of LOX-1 in the aortic root, subsequently attenuating AS and lipid deposition [28]. Ginkgo biloba tablet decreased the content of SR-A in the arterial wall [37]. Di'ao Xinxuekang capsule treatment demonstrated lipid-lowering and antiatherosclerotic mechanisms via the downregulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) and upregulation of the LDLR signaling pathway in the liver tissue [30]. It also facilitated reverse cholesterol transport (RCT) via enhanced cholesterol efflux through ABCA1 and ABCG1 in aortas, the upregulation of HDL synthesis modulated by the PPARc-LXRα-ABCA1 pathway, the modification of HDL maturation by increasing serum lecithin-cholesterol acyltransferase (LCAT) activity, and the promotion of scavenger receptor class B type 1 (SR-B1)mediated HDL-cholesteryl ester uptake [33]. Xuezhitong capsule improved blood lipid dysfunction via the activation of RCT and the accompanying increase in the HDL levels, as characterized by improved ABCA1, SR-B1, LCAT, apolipoprotein A I (ApoA1), and apolipoprotein B (ApoB) [74]. Qishenyiqi pill treatment removed blood cholesterol by promoting the LDLR-LXR-α-ABCG5 pathway in the liver, and it also blocked phagocytosis of ox-LDL by macrophages by inhibiting the expression of CD36 in the aorta [34]. Danhong injection treatment reduced the AS by inhibiting HMG-CoA reductase (HMGCR), activating the LDLR in the liver, and reducing macrophage accumulation while increasing ABCA1 expression in the aortic root in various AS models [55]. Tongxinluo capsule administration promoted the antiatherosclerotic effects by increasing the level of PPARc in aortas [64] and lowering the expression of macrophages and LOX-1 in vascular walls [65,67,72]. Zhixiong capsule blocked the proliferation of macrophages and monocytes, thereby reducing the formation of foam cells by upregulating p53 expression and decreasing MAPK14 expression [78]. Moreover, all these formulas, including Danlou tablet, Shexiang Tongxin dropping pill, Suxiaojiuxin pill, Tongxinluo capsule, and Xuezhitong capsule treatment, led to a significant reduction in the serum level of ox-LDL [42,44,61,72,74].
Tongxinluo inhibited oxidative stress injury by downregulating serum malondialdehyde (MDA), while upregulating the levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and NADPH quinone oxidoreductase-1 (NQO1) in the arterial wall and increasing the serum levels of superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) [27]. Shexiang Baoxin pill enhanced the antioxidative abilities by increasing SOD, catalase (CAT), and glutathione (GSH) in the circulation of ApoE −/− mice and improved the oxidative injury by reducing serum MDA, hydrogen peroxide (H 2 O 2 ), and myeloperoxidase (MPO) content [23]. Angong Niuhuang pill also exerted the antioxidant effect of decreasing the serum MDA level [35]. Xuezhikang regulated the blood levels of MDA, SOD, CRP, and T-AOC [56,59,66]. Shexiang Tongxin dropping pill increased the serum levels of GSH and SOD and decreased MDA, which also reduced reactive oxygen species (ROS) generation in the aortic root lesions [43,44]. Yindanxinnaotong capsule enhanced the antioxidative effect by regulating SOD, MDA, GSH, and glutathione peroxidase (GSH-PX) [48]. Guanxinshutong capsule improved serum SOD, MDA, and GSH and upregulated the expression of heme oxygenase-1 (HO-1) and Nrf2 in the aortic sinus [76]. Both Dahuang Zhechong and Suxiaojiuxin pills attenuated AS via the regulation of SOD and MDA levels in the serum [60,61] and inhibited MPO in the arterial wall [60].

Other Effects and Mechanisms.
Other mechanisms were mainly related to improved endothelial dysfunction, the inhibition of angiogenic factors, the regulation of VSMCs proliferation, and apoptosis.

Discussion
In this review, we have summarized 60 studies, including 23 Chinese patent formulas in treating AS. e animal models, effects, and mechanisms were listed via a critical systematic review. Opposite to Western medicine, traditional Chinese herbs are aimed at multiple targets for various pharmaceutical ingredients. TCM also has the potential to increase the therapeutic efficacy of AS.

Choice of AS Models.
Herein, we presented well-established animal models related to AS. e HFD ApoE−/− mice pattern might be a long-desired AS model owing to its high plasma TC level, foam cell-rich depositions in the proximal aortas, and easy breeding and handling procedures [79,80]. Rabbits are also commonly used in AS models; both ApoE −/− mice and rabbits are suitable models for the studies of plaque stability and lipid accumulation in vascular walls. Despite the sensitivity to dietary cholesterol induction, the locations of AS lesions in rabbits are different from those of humans [81], and prolonged cholesterol feeding in rabbits may result in hepatic toxicity [82]. e major limitation of ApoE −/− mice is the rare occurrence of thrombosis and plaque rupture, which is common in humans [16]. Owing to the studies of vulnerable plaques, the rabbit model is successfully established through the overexpression of p53 in local plaques and triggered by RVV [83]. Rats and C57BL/6 mice are used in the included studies; these animals are naturally resistant to atherogenesis and lack plasma cholesteryl ester transfer protein (CETP) activity [79,84]. In addition, the rat and mouse models established by HFD, vitamin D3 injection, balloon injury, and artery ligation may be valuable methods to promote AS; however, the fibrous plaques in the vascular wall lack lipid depositions and are different from those of ApoE −/− mice and rabbits [79]. Typically, there is no perfect model for any experimental condition, and an appropriate animal model should be considered based on the sample size, docility, feeding and housing, specific genetic profile, aims of the pathological aspects, costs, and analogy with humans [85].

Methodological
Quality of the Results. We also assessed the methodological quality of the included studies and evaluated all of them as generally low. Although many entries were judged as unclear risk of bias, the reporting of essential details still needs to be emphasized. Sequence generation, baseline characteristics, and random outcome assessment are necessary to be reported in an animal experiment in order to make the results adequately comparable. Regarding random housing conditions, the pharmacological agents could be influenced because of inconsistent temperature, lighting, humidity, and nonrandomized shelves or different rooms for animals [18]. For the judgment of attrition bias, the incomplete outcome data should be noticed and addressed adequately. SYRCLE's ROB is an adapted tool based on the Cochrane ROB tool that facilitates critical appraisal in a systematic review and improves the reporting quality of animal experiments. However, during the actual animal experiment, random methods should be considered with respect to animal weight, modeling parameters, and high-fat intake that would impact grouping. Although it is an effective method to improve internal validity and avoid subjectivity in interpreting the results, the blinding of caregivers, investigators, and outcome assessors in animal studies is often hard to achieve. Considering the practical difficulties in some items, we propose that SYRCLE's ROB could be further updated to better evaluate the animal experiments.

Effects and Mechanisms in All
Formulas. Based on the outcome analysis, we summarized the effects and mechanisms involved in plaque formation and stability, the changes in the lipid level, lipid metabolism and accumulation, anti-inflammation, and antioxidative stress in vivo. Interestingly, most of the included drugs in different models reduce the areas of plaques, which are directly related to AS procession. Regarding the stability of plaques, the relevant factors are the areas of plaque necrotic core and fibrous cap, the content of collagen and SMCs, macrophage accumulation and apoptosis, and the synthesis and balance of MMPs/ TIMPs in lesion areas. In addition, hyperlipidemia is the independent risk in AS, and over three-quarters of the drugs have reported the lipid-lowing property related to the downregulation of TC, TG, and LDL-C and upregulation of HDL-C in the serum level. e in-depth studies further found the mechanisms in the modification of hepatic lipid disorders and promoted lipid efflux from macrophages, which reduce the lipid deposition and indirectly inhibit AS development. Excessive phagocytosis of ox-LDL into macrophages depends on the scavenger receptors, such as SR-A, CD36, and LOX-1, and ultimately leads to foam cell formation and AS procession. In the current review, some formulas have also been identified for the property of reducing the scavenger receptors. In addition, chronic inflammation and oxidative stress are the major contributors throughout the whole AS progression [86,87]; some formulas have been verified to suppress the proinflammatory and pro-oxidative stress while activating the anti-inflammation and antioxidative stress, including the NF-κB signaling pathway and the related cytokines, chemokines, cell adhesion molecules, and oxidant enzymes. Moreover, some studies have listed other atheroprotective mechanisms in protecting endothelial injury and inhibiting VSMCs proliferation and migration.

Multiple Components and Targets in Chinese Patent
Formulas. Statins are the first choice for AS that can reduce plasma cholesterol levels due to their effects on the synthesis, reuptake, and intestinal absorption of cholesterol [88]. Different from statins, Chinese patent formulas contain many active components with multiple targets and functions in AS. In this review, 16 studies of Tongxinluo capsules elucidated the effects and mechanisms of ameliorating APA, recovering the serum lipid level, inhibiting macrophage accumulation, stabilizing atherosclerotic plaques, reducing inflammation, and antioxidant stress, and protecting endothelial dysfunction in ApoE −/− mice and rabbit models. Especially in the vulnerable plaque rabbit model, Tongxinluo capsule treatment exerts protective effects in plaque rupture, and the mechanisms in the amelioration of MMPs and TIMPs were explored [31]. e bioactive ingredients from Tongxinluo also supported the evidence in the prevention and treatment of AS. According to the major extracts, ginsenoside Rb1 has anti-AS effects in reducing inflammation and oxidative stress responses, stabilizing plaques and attenuating the plaque formation. Additionally, it prevents endothelial dysfunction by upregulating the eNOS expression and improves the balance between apoptosis and autophagy; ginsenoside Rg1 has also been reported to inhibit AS by activating the AMPK/mTOR signaling pathway in the macrophages [89,90]. Paeoniflorin is one of the aqueous extracts of Tongxinluo that could ameliorate AS by inhibiting the inflammation of the TLR4/MyD88/NF-κB pathway [91]. e combination of bioactive ingredients in a formula has a synergistic role in treating AS and is beneficial to the balance of the whole body.
Unlike other formulas, Xuezhikang extract from red yeast Chinese rice containing lovastatin, unsaturated fatty acids, essential amino acids, and ergosterol [59] naturally. In addition to the lipid-lowering and anti-inflammatory effects of lovastatin, Xuezhikang has also been investigated with respect to stabilizing atherosclerotic plaques and improving endothelial dysfunction, which might be related to other useful substances [33,56]. In our study, other formulas like Danhong injection, Danlou tablet, and Naoxintong capsule were also significant. Besides the mechanisms in reducing APA and blood lipids, inhibiting plaque inflammation, and regulating the level of oxidative stress, Danhong injection can maintain the collagen content in the arterial wall and reduce the expression of MCP-1, MMP-2, and MMP-9 mRNAs in the aortic wall [53]; ethanol extracts of Danlou tablet plays a key role in anti-inflammation and preventing lipid deposition in macrophages of AS via suppressing the NF-κB signaling pathway and triggering the PPARα/ABCA1 signaling pathway [24]; Naoxintong has shown its ability in inhibiting dendritic cells maturation, improving endothelial function, and enhancing plaque stability [29,32,39,57,58]. In summary, multiple components with multiple targets in Chinese patent formulas are beneficial in AS and may surpass single Western therapies.

4.5.
Limitations. Nevertheless, the present study has several limitations. Firstly, we used the qualitative synthesis rather than the quantitative method due to the varied models and inconsistent interventions, and hence, we could not draw specific conclusions from the meta-analysis. Owing to the stringent inclusion and exclusion criteria in the systematic review, relevant cell experiments were excluded, necessitating further investigation of the mechanisms in vitro. In addition, to elucidate the effects and mechanisms of action, HPLC/MS analysis for compound identification should be employed.

Conclusions
In summary, our analysis revealed the atheroprotective effects and mechanisms of 23 postmarketing Chinese patent formulas in vivo. In this systematic review, we first summarized the roles of the amelioration of plaques, the improvement of plaque stability, the modification of lipid level and metabolisms, and the anti-inflammation and antioxidant stress in alleviating AS lesions. Also, the methodological quality was found to be low in the included literature.
us, additional high-quality evidence is essential through a broad perspective of postmarketing Chinese patent formulas in treating AS. Heme oxygenase-1 hs-CRP: High-sensitivity C-reactive protein ICAM-1: Intercellular adhesion molecules-1 IL-6:

Data Availability
All the data generated or analyzed during this study are included in this published article and its additional files.

Disclosure
Shiqi Chen and Xiaoxiao Wu are co-first authors. Yahong Wang and Mingjing Zhao are the corresponding authors.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this article.

Authors' Contributions
YHW and MJZ designed the research and supervised the whole process. SQC and XXW conducted the literature searching and selection. TL, YL, and BFW extracted and analyzed the outcomes. WTC, YT, and JJY assessed the risk of bias. SQC drafted the manuscript with the help of HM, LW, ZWL, and YYJ. YHW and MJZ detected any mistakes in the entire process. All the authors have approved the final manuscript for submission.