Therapeutic Effects of Breviscapine in Cardiovascular Diseases: A Review

Protective Effect against Ischaemia/Reperfusion (I/R)

I/R injury often manifests as an aggravated endothelial impairment, leading to accelerated cardiomyocyte apoptosis or death, which can be measured by the size of MI (Kong et al., 2016; Yu et al., 2016). Studies have demonstrated that the protective effects of scutellarin alone on cardiovascular ischaemia are better than breviscapine with regards to the size of MI and myocardium cell apoptosis in MI rats, and its effects are dependent on the dose (Lin et al., 2007). The development of myocardial I/R injury has been shown to involve multiple mechanisms, including interference of specific pathways regulating the expression of some genes and activating relevant ATPase. One study suggested that breviscapine could provide significant protective effect against MI I/R injury, with the mechanism potentially involving the suppression of apoptosis of cardiomyocytes through the activation of the PI3K/Akt/eNOS signaling pathway (Wang J. et al., 2015). Moreover, as suggested by another study, breviscapine could inhibit the expression of IL-18 and ICAM-1 in protecting the lungs from inflammatory cascades (Wang Y. et al., 2013). In addition, the protective effects of breviscapine has been closely linked to the scavenging of oxygen free radicals, decreasing the expressions of ICAM-I protein in the myocardium and increasing the activities of Na(+)-K(+)-ATPase, Mg(2+)-ATPase, Ca(2+)-ATPase in the myocardial mitochondria (Jia et al., 2008).

Anti-inflammatory Effect

Inflammatory processes play an important role in the development of CVDs and their associated complications (Ruparelia et al., 2017). Atherosclerosis is considered as an inflammatory disease (Ross, 1999). Many biological factors such as inflammatory cytokines, enzymes, and other mediators have been shown to be related to the effects of atherosclerosis (Walsh, 2003). It has been demonstrated that breviscapine is able to treat coronary disease and reduce the associated inflammatory response. The observed anti-inflammatory effects of breviscapine were demonstrated by a study comparing ischemic preconditioning with breviscapine and ischemic preconditioning alone; the combination treatment had better effect on decreasing the expression of TNF-α and NF-κB and reducing the injury due to inflammation to achieve myocardial protection during myocardial I/R in New Zealand rabbits (Zhao, 2010). Similarly, it could also decrease the expression of TNF-α and IL-6 to reduce the injury of I/R in rats (Gong et al., 2013).

Anticoagulation Effect

The coagulation system and the anticoagulation and fibrinolytic systems interact dynamically, playing a major role in physiological haemostasis. On the other hand, this interaction might also be a common thread in a wide range of diseases, i.e., it might contribute to the pathology of various diseases, especially heart disease, cancer and inflammation (Marx, 1982). There is evidence that breviscapine can simulate fibrinolysis and anticoagulation of endothelial cells as indicated by the induction of thrombomodulin (TM) production and the downregulation of the expression of TM on the surface of the cells as well as the inhibition of TM release from the cells (Zhou et al., 1992). In addition, another study showed that the breviscapine extract influenced anticoagulation by significantly delaying the coagulation time (CT) and prothrombin time (PT), inhibiting the activity of platelet factor III (PF3) and decreasing the euglobulin lysis time (ELT); additionally, it could enhance the activity of fibrinolysis (Wang et al., 2003).

Antithrombotic Effect

Pathogenic thrombi are responsible for acute clinical atherothrombotic diseases, such as acute coronary syndromes and ischaemic stroke. The activated platelets play a crucial role in the formation of pathogenic thrombi. During the process of platelet activation, specific agonists including thromboxane A2 (TxA2), adenosine diphosphate (ADP) and thrombin are associated with their corresponding receptors on the surface of platelets. Patients who suffered from atherothrombosis benefitted from the use of oral antiplatelet agents targeting the TxA2 (aspirin) and ADP (P2Y12 inhibitors such as clopidogrel, ticlopidine) platelet activation pathways (Fintel, 2012). One research showed that the Erigeron breviscapus flavones could significantly inhibit ADP, arachidonic acid (AA) and platelet activating factor (PAF) from forming into a thrombus (Shen et al., 2000). Meanwhile, another study suggested that scutellarin could prevent thrombosis and platelet aggregation and improve the characteristics of haemorheology by restricting the ADP-induced platelet aggregation rate in rats in a dose-dependent manner (Song et al., 2011).

Endothelial Protective Effect

Vascular endothelial cells (VECs) are important for the endocrine system and target organs (Salles et al., 2016). Damage to VECs can cause various vascular dysfunctions, frequently accompanied by endothelial cell injury, production of oxygen free radicals and release of inflammatory cytokines. One study showed that Dengzhan Xixin injection (the main ingredient is breviscapine) could reduce the damage of TNF-α to cardiac micro VECs by inhibiting the inflammatory reaction (Zhang et al., 2009). Meanwhile, breviscapine was shown to have a protective role in ox-LDL-induced endothelial cell injury, which may be related to its antioxidant effects and inhibition of NF-κB activation (Chen et al., 2015). Vascular Endothelial Growth Factors (VEGFs), the most potent angiogenic factors in both physiological and pathological angiogenesis, play a crucial step in the process of repair after injuries. Similarly, another study suggested that scutellarin had a protective effect on VECs after ischaemia-reperfusion injury, and the mechanism may be related to the early increase of VEGF (Lin et al., 2011).

Myocardial Protective Effect

When myocardial cells become injured by pathological factors such as cardiac surgery, ischaemia-reperfusion injury, diabetic injury, hypoxia injury, the pathological process may evolve from the initial cellular edema, degeneration, and necrosis into cardiac hypertrophy and myocardial fibrosis. There are several studies elucidating the potential myocardial protective effect of breviscapine and its mechanism. One study indicated that breviscapine favored myocardial protection by significantly reducing the LDH leakage, intracellular free Ca²⁺ levels, apoptosis and necrosis in cardiomyocytes subjected to hypoxia (Li et al., 2004). In case of diabetic injury, breviscapine may have a protective effect on diabetic cardiomyopathy by decreasing the expression of protein kinase C (PKC) and phospholamban (PLB), as well as increasing the expression of protein phosphatase inhibitor-1 (PPI-1), Ca(2+)-ATPase (SERCA-2), and ryanodine receptor (RyR) (Wang et al., 2010). In conditions of cardiac hypertrophy induced by angiotensin II (Ang II), it was demonstrated that breviscapine may still have a protective potential against cardiac hypertrophy by disrupting PKC-alpha-dependent ERK1/2 and PI3K/AKT signaling both in cardiac myocytes in vitro and mice in vivo (Yan et al., 2010). Another study also suggested that scutellarin could prevent isoprenaline-induced myocardial fibrosis by the inhibition of cardiac endothelial-mesenchymal transition, which may be associated with the Notch pathway (Zhou et al., 2014).

Reduction of Smooth Muscle Cell Migration and Proliferation

Vascular smooth muscle cell (VSMC) migration and proliferation is a major pathophysiological step in the development of atherosclerosis. In addition, modulation VSMC proliferation might have therapeutic effects for vascular diseases (Ross, 1993). Thrombin has been shown to induce VSMC proliferation. Thrombin receptor is present in all the cell types that respond to thrombin, including platelets, endothelial cells and VSMC. In addition, thrombin receptor antagonists could be used as therapeutic agents that might have value by specific inhibition of cellular proliferation (Pakala et al., 2001). There was a research suggesting that breviscapine could significantly inhibit the proliferation of rat aortic smooth muscle cells to induce thrombin. And the possible mechanism is blocking the expression of thrombin receptor gene (Hou et al., 2009). In addition, breviscapine could obviously inhibit the proliferation of VSMC and may prevent atherosclerosis, and the mechanism may be realized partly by regulating NF-κB activity of VSMC (Pang et al., 2004). Furthermore, breviscapine could ameliorate high glucose-induced proliferation and migration of VSMCs via inhibiting ERK1/2 MAPK signaling (He et al., 2012).

Anticardiac Remodeling Effect

Ventricular remodeling is the process of pathological repair, ventricular compensation and a secondary pathophysiological response that is accompanied by a series of ventricular myocardial injury-associated changes in parameters including size, shape, wall thickness and tissue structure. One study suggested that breviscapine could regulate ventricular remodeling in heart failure animal by improving the myocardial systolic and diastolic function (Li, 2011).

Antiarrhythmic Effect

Breviscapine has been shown to advance certain kinds of specific antiarrhythmic effects on the rabbit heart and rat ventricular myocytes, even though the underlying mechanism behind the effects remains unclear, and is still under research. One study showed that breviscapine could diminish the transmural repolarization dispersion (TDR) and reduced the incidence of early after depolarization (EAD) and torsades de pointes (Tdp), which decreased the incidence of ventricular arrhythmias in hypertrophic rabbit hearts (Bo et al., 2011). It has been demonstrated that cardiac electrical activities depend on the ion channels on membranes of cardiac cells for their physiological function. Then, concerns have been raised about affecting the potassium and sodium currents in ventricular myocytes. It has been observed that breviscapine could inhibit potassium current (I_to) in a concentration- and voltage-dependent manner (Deng et al., 2008) and I_Na channel current in a concentration-dependent manner (Tang et al., 2009), which might be an important mechanism in its antiarrhythmic effect.

Lipid-Lowering Effect

Lipid-lowering is a routine treatment in CVDs. Some clinical studies have shown that breviscapine can reduce blood lipids. However, there have been different results in animal experiments. One study has shown that breviscapine could reduce blood lipid levels in diabetic rats (Wei et al., 2010). Another study suggested that it could inhibit the progress of intimal hyperplasia and atherosclerosis but could not reduce serum cholesterol levels (Lou and Liu, 2009). Additionally, there is no research explaining its mechanism of its lipid-lowering effect.

Coronary Heart Disease

Coronary heart disease is the most common type of CVD and one of the fatal diseases. The latest data showed that CHD led to 8.14 million deaths, which accounted for 16.8% of all deaths globally in 2013 (GBD 2013 Mortality and Causes of Death Collaborators, 2015). Currently, by changing lifestyle, such as exercising, having a healthy diet, treating hypertension, and medications, including anti-platelet drugs such as aspirin, nitro-glycerine, beta-blockers and statins, the morbidity of CHD has been reduced to some extent. However, these drugs also have some inevitable adverse effects. Breviscapine is a complementary medicine that has been used in combination with conventional medicine to prevent and treat CHD for decades in China. It provides many benefits; for example, it improves the therapeutic effectiveness compared to conventional treatment alone, and it helps to decrease the dosage of several drugs that may cause adverse effects (Wang C. et al., 2015). A large number of randomized, controlled trials have been carried out to explore the effects of breviscapine on CHD.

In one randomized controlled trial, 50 patients with stable angina pectoris were randomly allocated into two groups that received breviscapine (40 mg/250 ml 0.9% sodium chloride, iv drip, qd) combined with standard medication (n = 25) or standard medication alone (n = 25) for 14 days. The outcome showed that the symptoms of angina, the change of ST-T in ECG and the change time of ST-T in dynamic electrocardiogram improved more in the test group than in the control group. Additionally, the improvements in haemorheology, such as whole blood viscosity (WBV), plasma viscosity (PV), fibrinogen (FIB), and serum lipids in the test group were more remarkable than the control group (Zhang and Zhang, 2012). Similarly, another RCT was conducted to test the efficacy of breviscapine in patients with unstable angina pectoris, who were randomly assigned to receive 20 ml breviscapine daily in addition to conventional Western medicine (n = 53) or the conventional Western medicine alone (n = 51) for 2 weeks. The results demonstrated that the dosage of isosorbide dinitrate in the test group was lower than that in the control group and the curative effect on the ECG was better in the test group. In addition, the whole blood high viscosity (WBHV), PV, erythrocyte aggregation index, FIB and hs-CRP in the test group were also lower than that in the control group. Nevertheless, the researchers had not found a significant difference in the whole blood low shear viscosity and erythrocyte rigidity index between the two groups. In addition, this study reported 4 cases of nausea and 1 case of palpitation in the control group and 3 cases of nausea and 2 cases of abdominal distension in the test group (Shen et al., 2014).

Myocardial Infarction (MI)

MI, also known as acute myocardial infarction (AMI), is a heart attack caused by the blockage of blood flow to the heart due to a thrombus of a ruptured atherosclerotic plaque (Mendis et al., 2011). A study reported that the rate of MI has decreased globally between 1990 and 2010 (GBD 2013 Mortality and Causes of Death Collaborators, 2015). Although the morbidity and mortality of MI have been controlled to a large extent with early and effective preventive measures and interventions, there are still some problems in secondary prevention and rehabilitation of patients with MI. Chinese medicine (CM) shows some advantages in these aspects, such as improving the quality of life (QOL) and decreasing the rate of adverse events (Xu-Feng et al., 2010; Duan et al., 2012; Zhang Y.H., 2014). Several clinical studies with breviscapine have reported its effects on MI. A controlled clinical trial was designed to observe the efficacy of breviscapine in AMI patients who received either breviscapine (60 mg/d) with routine treatments (n = 25) or the routine treatments alone (n = 20) for a period of 10 days. The outcomes of left ventricular ejection fraction (LVEF), peripheral vascular resistance and incidence rate of post-angina pectoris were significantly different in the patients in the combination group compared to the patients in control group (Gu T.B. et al., 2002). Similarly, another RCT was conducted on 60 patients after percutaneous coronary intervention (PCI) who were treated with conventional medicine and breviscapine injection. The results showed that the proportion of cardiac function class ≤NYHA functional class II in the test group (88.3%) was higher than that in the control group (61.7%). In addition, the incidence of cardiac adverse events (MI, arrhythmia, death) was lower in test group (6.7%) compared to the control group (21.7%) (Yang and Chen, 2013). Another RCT was carried out to observe the effects of breviscapine on exercise tolerance in patients with AMI who have received a successful intravenous thrombolytic treatment. Ninety-eight patients were randomly assigned to receive breviscapine with conventional treatment or the conventional treatment alone for 14 days. The results of the treadmill exercise test showed a significant prolongation of the time of exercise-induced electrocardiographic ST-segment depression (≥0.1 mV) and shortening of the duration of ST-segment depression in the combination group than the control group on the 36th day. However, there was no significant difference on the 14th day. This implied that breviscapine might have sustained effects (Wang et al., 2009).

Hypertension

Hypertension results in 7.8 million deaths annually, accounting for 12.8% of the total deaths worldwide. The size of the population with uncontrolled blood pressure has grown from 6 million to nearly one billion between 1980 and 2008 (Mendis et al., 2011). Uncontrolled blood pressure is the major contributor not only to CHD and stroke but also to heart failure, chronic kidney disease, among others (Poulter et al., 2015). Herbal medicine combined with anti-hypertensive drugs are being increasingly used as an integrative therapy to control blood pressure and associated complications in both Eastern and Western countries (Ernst, 2005; Wang et al., 2012). A clinical trial studied the effects of erigeron injection on the renal function of elderly patients with essential hypertension. The result demonstrated that erigeron injection (the main ingredient is breviscapine) (40 ml, qd) had similar anti-hypertensive effect as enalapril (20 mg, qd). In addition, urinary NAG and β₂-MG significantly decreased in the breviscapine group, which indicated that breviscapine might improve the tubular function of these patients (Wang, 2000). Another RCT aimed to investigate the efficacy of breviscapine in acute hypertensive cerebral hemorrhage patients. The patients were treated either with breviscapine plus routine Western medicine (n = 39) or routine Western medicine alone (n = 39) for 2 weeks. Outcomes of the haematoma volume, edema area and Scandinavian stroke scale (SSS) in breviscapine group were statistically better than those in control group (Shi and Ding, 2009).

Arrhythmia

In the clinical practice, most of the therapies for arrhythmia are medically indicated. However, AF, a serious type of arrhythmia (Munger et al., 2014), is still not easy to address. AF is a major cause of sudden cardiac death, which accounts for half of the death due to CVDs worldwide (Mehra, 2007). Although the anti-arrhythmic effect of breviscapine has been investigated in several animal studies, there are a few clinical trials. One case series of 30 elderly patients with persistent AF who received erigeron injection (36 mg, iv drip, qd) for 2 weeks reported that the heart rate in the patients decreased from 115.4 ± 8.2 to 83.3 ± 7.6 after the treatment. The reported adverse events included three cases of dizziness, which were spontaneously resolved (Han, 1999).

Hyperlipoidaemia

Hyperlipidaemia is abnormal increase of lipids in the blood, usually referred to the elevation of serum cholesterol and TG. High amount of cholesterol and TGs would increase the risk of CVDs. Data show that the prevalence of heart disease will decrease by 50% in 40-year-old men within five years if the serum cholesterol was reduced by 10% (Mendis et al., 2011). Thus, it is necessary to control the level of serum cholesterol and TGs. Animal studies have found that breviscapine can help lower elevated serum lipids. A clinical study was also carried out to observe its effects on patients with hyperlipidaemia. The results showed that the level of total cholesterol (TC), LDL-c, and TG decreased after a daily treatment with 25 mg breviscapine for 2 weeks. In contrast, the level of HDL-c increased (Yu, 2011). Another trial studied 36 elderly patients with hyperlipidaemia who received erigeron injection (30 mg, qd) for 2 weeks. A similar result was obtained (Wen and Ruan, 2004). Another RCT was designed to investigate the effect of breviscapine in patients with unstable angina pectoris with hyperlipidaemia. Neither the test group nor the control group received statins. The outcome of the serum lipid, WBV and PV showed statistically significant differences in the test group. Moreover, the duration of angina also decreased in the test group (Peng and Ye, 2011).

Viral Myocarditis

Viral myocarditis is an inflammation in the cardiac muscle due to a viral infection. It contributes to the development of heart failure. Currently, symptomatic treatment is the major treatment of VMC and other therapies, such as intravenous immunoglobulin (IVIG) or herbal medicine have not shown any evidence-based benefits (Robinson et al., 2005; Liu et al., 2012). Several studies have demonstrated the effects of breviscapine on VMC. A randomized controlled trial was designed to study the effect of breviscapine injection on the deceleration capacity (DC, a technique to quantitatively detect autonomic nerve tension) of the heart rate in children with VMC with daily administration of 10 mg breviscapine (n = 30) or 100 U coenzyme A (CoA) and 40 mg adenosine triphosphate (ATP) (n = 30) for 2 week. The results showed that there was a significant elevation of the DC in the breviscapine group compared to the control group. The investigators also found a more marked decrease in CK-MB in the test group than in the control group (Gu et al., 2014). Another study reported similar results; the investigators demonstrated the TNF-α, a cytokine that can reflect the degree of inflammation in the myocardium (Lenzo et al., 2001), noticeably dropped in the breviscapine group (Wang and Wang, 2009).

Chronic Heart Failure

Chronic heart failure often occurs at the terminal stage of most CVDs. Epidemiological survey shows that the prevalence of CHF in adults in the developed countries is approximately 2%, and in China, it is 0.9% (Gu et al., 2002; Mcmurray and Pfeffer, 2005). Although 30–40% of the patients die within a year of CVD diagnosis, the mortality is less than 10% annually. The key problem that needs to be solved is the impact on the QOL, such as mood disorder (National Clinical Guideline Centre, 2010). In a randomized controlled trial, 100 stage NYHA III∼IV patients with heart failure with normal ejection fraction (HF-NEF) were instructed to take 40 mg/d breviscapine plus routine medication or the routine medication alone for 10 days. The outcome parameters demonstrated that the B-type natriuretic peptide (BNP) decreased more in the test group. However, there was no difference in the LVEF and left ventricular end-diastolic volume (LVEDV) between the test and control groups. In addition, the typical symptoms such as shortness of breath, chest tightness, fatigue, and weakness improved a lot in the test group than in the control group (Zhang F., 2014). One RCT was conducted in 126 stage NYHA II∼III patients who were randomly given breviscapine (50 mg, qd) with conventional medicine or the conventional medicine alone for 2 weeks. The results showed that the LVEF and 6-minute walk test (6 MWT) in the combination group was markedly better compared to the control group (Tian, 2010). Another clinical trial studied 46 stage NYHA III∼IV patients with severe heart failure and obtained similar results (Li, 2007).