Silent myocardial ischemia and its Chinese medicine treatment

Tiejun Tang

Silent myocardial ischemia (SMI), also called asymptomatic myocardial ischemia, is the most common manifestation of coronary heart disease. SMI patients do not seek medical attention as often as angina pectoris patients because SMI does not necessarily cause severe chest pains. Hence the necessary diagnostic procedures such as blood tests, ECG and heart scan are left undone. This places SMI patients under a higher risk of experiencing a sudden and possibly fatal cardiac event. Some cases have been diagnosed as myocardial infarction after been sent to hospital, some cause sudden death. If the myocardial ischemic is emerged in the heart, no matter patient felt pain or not, the potential risk is the same. I would like to remind people, SMI is a silent killer!

Asymptomatic mean no symptom literally. But it does not mean patients didn’t have any symptoms at all. Actually it only means no chest pain. Some SMI patients might experience chest tightness, palpitation and short of breath sometimes, especially after exercise. A person experiencing any of the above symptoms should contact their GP.

Traditional Chinese medicine believes most chest pain and palpitation might due to Qi stagnation and/or blood stasis in heart meridian, or heart yang deficiency. From Han dynasty, Zhang Zhong Jing (AD150-219) applied Gualou Xiebai Tang to treat chest pain due to heart yang deficiency. In Qing dynasty, Wang Qingren (1768-1831) used the herbal formula Xuefu Zhuyu Tang or Buyang Huanwu Tang to treat the chest pain and stroke. Scientific research has approved many Chinese herbs and formulas can improve myocardial ischemia through different methods of action in the body (Refer next paper in this blog).

Kaixin capsule is a patent medicine, combining several herbs, especially developed for treating SMI. The formula was developed from one of my tutor Professor Chen Jinghe. In the 1990s’ I spent three years investigating anti-myocardial ischemia mechanism of the Kaixin capsule through laboratory and clinical research. My research results showed that Kaixin capsule can effectively reduce the risk of myocardial ischemia as well as lower the blood lipid levels.   

Wholism is the characteristic of traditional Chinese medicine, thus one herbal formula consists of several herbs in order to address all aspects of each individuals health condition. Each herbal ingredient plays a unique role, and the choice of herbs and dosage is determined on an individual basis.   

Recently I received a question in the internet could a patient with an elevated ST segment in their ECG reading benefit from Chinese herbs. Elevation of a ST segment indicates myocardial infarction. I replied that even though this is an emergency and requires hospital care, Chinese herbs can be used to improve the insufficient coronary artery circulation, and release the tightness or pain in the chest. Chinese herbs can also be used to reduce high blood pressure and to regulate blood lipid levels.

Sometimes ECG still shows ischemic changes after a coronary bypass operation, PTCA or coronary stents accompanied with chest tightness and shortness of breath. This is believed to be related to re-narrowing of a coronary artery. Also these conditions can be treated like SMI in Chinese medicine.

Apart from Chinese herbal medicine acupuncture also shewed a good effect in MI. (Refer: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0094604 )

Be aware of the risks of SMI, take care of your heart, take care your life.

The latest research review on Chinese herbs of anti myocardial ischemia

Tiejun Tang, Louise Helen Booker

Coronary heart disease (CHD) is the UK's biggest killer. Although western medicine has achieved a lot progress in treating CHD, it is still causing around 82,000 deaths each year. About one in five men and one in eight women die from the disease. In traditional Chinese medicine many herbal remedies have showed a good effect on treating angina. Many laboratory studies have been done to investigate the mechanism of treating myocardial ischemia (MI). I published a research review on this topic many years ago (Tang, T. 2003). Many progressive new reports have been published in the last 5 years. For a clinical practitioner these research updates will provide a helpful reference in treatment of CHD. For researchers and students it can provide a useful reference for future research projects. As for the general public, it has displayed some scientific evidence for Chinese herbs in treating ischemic heart disease.

1. Research on individual herb and plant monomer  

 Danshen (Salvia miltiorrhiza) is a very commonly used traditional Chinese herb in treating heart disease. It contains many sub fractions, which are mainly TanshinoneⅠ, ⅡA, ⅡB, Salvianolic acid A (SAA), and Salvianolic acid B (SAB). In an in vivo study, rat MI model was induced by permanent left anterior descending coronary artery ligation. The results showed Tanshinone IIA attenuates the MI pathological changes and improves heart function, and reduces expression of MCP-1, TGF-β₁ and macrophage infiltration. It could also decrease the expression of TNF-α and activation of nuclear transcription factor-kappa B (Z.H.Ren, 2010).        Researchers applied a myocardial infarct rats model. The rats were given different concentrations of SAA. Immunohistological analysis was performed to measure vascular endothelial growth factor and vascular endothelial growth factor receptor-2 expressions. The secretion of matrix metalloproteinase type X was evaluated in serum of post-ischemic rats. The result showed SAA potentiated the ischemia induced neovascularization. These findings show that SAA has potent proangiogenic properties by promoting the expression of proangiogenic factors (Yujuan Li, 2014).  Another study shows SAB also can markedly and dose-dependently reduce fibrinogen and malonaldehyde levels, increase the HDL level, improve blood viscosity and plasma viscosity in MI rabbits (Qian Yang, 2010). A study applied an RT-PCR and Western blot method to detect p38 MAPK gene expression. The result suggests that Tanshinone IIA play a role in protection cardiomyocytes from ischemic and hypoxic injury. The effect is based on inhibiting miR-1 expression through p38 MAPK signal pathway (Zhang, Y. 2010).

 Asperosaponin VI is a saponin from Chinese herb Xuduan (Dipsacus asper). A study investigated the anti-MI effects of Asperosaponin VI both in vivo and in vitro. The results suggested that it could provide significant cardioprotective effects against acute MI in rats. These mechanisms might be attributed to scavenging lipid peroxidation products and reactive oxygen species, increasing antioxidant defence enzymes and preventing mitochondrial damage (Chunmei Li, 2010).

Angelica sinensis polysaccharides are an active ingredient extracted from Danggui (Angelica sinensis). The cardioprotective effects were evaluated by using MI/reperfusion rats.  A.sinensis polysaccharides treatment significantly reduced myocardial infarction size, enhanced CT-1 and antioxidant enzymes activity, down regulated caspase-12 mRNA expression in rats (Song Zhang, 2010).

Juemingzi (Semen Cassiae) was proved to reduce blood lipid levels. A study investigated whether it can reduce MI and reperfusion injury. The results showed Juemingzi extract can not only significantly reduce the plasma lipid level, but it can also improve the instantaneous first derivation of left ventricle pressure and reduce infarct size (Feng Fu, 2014).

 Gegen (Lobed Kudzuvine Root) has been widely used in the treatment of myocardial and cerebral ischemia. Puerarin is a major active ingredient extracted from Gegen. A study was designed to observe the effects of puerarin on the signalling transmission mediated by P2X₃ receptor in stellate ganglia and cervical dorsal root ganglia after MI damage. The results suggested that Puerarin could reduce systolic blood pressure and heart rate, relieved pain and decreased up-regulated expression of P2X₃ mRNA and protein after MI. Puerarin was shown to inhibit the up-regulated ATP-activated currents after MI. This suggested that puerarin can relieve MI through blocking the P2X₃ signalling transmission (Shuangmei Liu, 2014).

Rougui (Cinnamomum cassia) is widely used for the treatment of ischemic heart disease. The active components, cinnamic aldehyde and cinnamic acid, can be isolated from Rougui. A study has investigated the effects of anti MI of Cinnamic aldehyde and cinnamic acid. The results showed these two extracts can decrease the ST elevation induced by acute MI, decreased serum levels of CK-MB, LDH, TNF-α and IL-6, and increased serum NO activity, increased SOD activity and decreased MDA content in myocardial tissue (Fan Song,2013).

Shanzha (hawthorn) is commonly used Chinese medicine. A study was designed to investigate the effects and mechanisms of hawthorn leaf flavonoids on acute MI/reperfusion in anesthetized dogs. The results indicated that this flavonoid can significantly decrease the degree and scope of MI, markedly inhibit the increase of myeloperoxidase activity, and IL-1 and TNF-α content induced by MI/infarction. It can also increase G protein-coupled receptor kinase 2 expression and inhibited NF-κB expression (Jianhua Fu, 2013).

Tetramethylpyrazine, sodium ferulate and puerarin are extracts from Chinese herbs Chuangxiong, Danggui and Gegen respectively. Some research has shown that these three extracts can antagonize the nociceptive or pain transmission mediated by P2X₃ and/or P2X_2/3 receptors in primary afferent neurons. They could therefore be considered as new methods for treating MI injury and cardiac arrhythmia (Shangdong Liang, 2010).

Dracocephalum moldavica L is an extract from Chinese herb Xiang Qing Lan. A study evaluates antioxidative and cardioprotective effects of total flavonoids extracted from Xiang Qing Lan. It showed remarkable scavenging effects against 1, 1-diphenyl-2-picrylhydrazyl, hydroxyl and superoxide anion radicals in vitro. It can improve the heart rate and coronary flow, raise left ventricular developed pressure and decrease creatine kinase, lactate dehydrogenase levels in coronary flow. It can also reduce the infarct size in ischemic area of heart. (Jiangtao Jian, 2014).

2. Research on compound formulas

Apart from individual herb and plant monomers, some studies have focused on compound formulas. Many traditional and modern formulas have been shown to be effective in treating MI.

Compound Danshen Tablets (CDT) are formulated from a compound remedy. The ingredients are Danshen, Sanqi, and Borneol. A study investigated therapeutic mechanisms of CDT by using a metabolomic approach. Plasma extracts from sham, MI model, CDT and western medicines were used in treating rats. Plasma was analyzed by ultra-performance liquid chromatography/quadruple. The orthogonal partial least square model was built, and found that metabolites were expressed in significantly different amounts between MI and sham groups of rats. The results showed that CDT presented protective effects on MI by reversing potential biomarkers to sham levels, especially for the four metabolites in the pathway of purine metabolism. (Yonghai Lv, 2010).

Tanshinone IIA, SAB and ginsenoside Rb1 are the three major active ingredients of CDT. A report has found that the combination of these three ingredients brings nearly equal therapeutic effects on MI as CDT and it plays more stable regulated action on those 22 identified metabolites than single compound (Yonghai Lu, 2011). Another report uses an in vivo myocardial infarction model mice; endothelial nitric oxide syntheses (eNOS)/nitric oxide (NO) pathway were detected. The results showed that both Tanshinone IIA and salvianolic acid B have cardio protective function in certain levels through multiple targets related with NO production, such as eNOS phosphorylation, L-arginine uptake (Chunshui Pan, 2011).

Another study applied an ischemia-reperfusion injury rat model to examine coronary blood flow, vascular diameter, velocity of red blood cells, and albumin leakage in vivo after reperfusion. The result showed pre-treatment with CPT significantly attenuated myocardial microcirculatory disturbance, including decreased coronary blood flow and red blood cell velocity in arterioles, increased expression of CD18 on neutrophils and intercellular adhesion molecule 1 on endothelial cells, and albumin leakage from venules. It was also shown that it could significantly ameliorate the myocardial damage and apoptosis, inhibitor-κBα degradation, and expression of Bcl-2, Bax, and caspase-3 in myocardial tissues (Na Zhao, 2010).  A metabonomic study was conducted to assess the effect of Danshen, Sanqi and their compound formula for myocardial infarction in rats.  As a result, the compound was shown to exert synergistic therapeutic efficacies to exhibit a better effect on MI when compared to singular herbs (Xiaoping Liang, 2011).

Gualou Xiebai Tang is composed of Gualou (fructus trichosanthis) and Xiebai (macrostem onion). It was first recorded in JinGui YaoLue, and is one of the main formulae to treat chest pain, used since the Han Dynasty (A.D 206). A study aimed to investigate the effect of Gualou Xiebai Tang ethanol extract on myocardial fibrosis. The mRNA levels of Collagen I and Collagen III were detected by real-time PCR. The results showed that Gualou Xiebai Tang could significantly reduce the heart weight/body weight ratio as well as the left ventricle weight/body weight ratio. It also significantly alleviated the degree of inflammation, decreased myocardial collagen volume fraction, and markedly prevented the up-regulations of Collagen I and Collagen III, down regulated expressions of TGF-β1, TGFβRI, TGFβRII in the rats with myocardial fibrosis (Yongfang Ding, 2013).

 Buyang Huanwu Tang is a commonly used formula to treat ischemic heart disease. A study investigated the potential mechanism of this formula in alleviating MI in rats. The expression of the cluster of differentiation 40 (CD40) in the mononuclear cells was measured using flow cytometry, and the expressions of CD40 and its ligand (CD40L) in myocardial tissues were determined by western blotting. The results showed that Buyang Huanwu Tang could decrease the expression of CD40 in the mononuclear cells and the CD40 and CD40L expressions in myocardial tissues (Yu Liu, 2011).     

Sini Tang is has been used to treat MI for many years. A lot of research has been done in the past two decades. A recent study applied a urinary metabonomic method based on nuclear magnetic resonance and ultra high-performance liquid chromatography coupled to mass spectrometry in order to characterize MI related metabolic profiles and delineate the effect of Sini Tang on MI. Nineteen potential biomarkers in rat urine were screened out, primarily related to myocardial energy metabolism, including the glycolysis, citrate cycle, amino acid metabolism, purine metabolism and pyrimidine metabolism. The results demonstrated that Sini Tang could provide satisfactory effect on MI through partially regulating the perturbed myocardial energy metabolism (Guangguo Tan, 2012).

 Guanxin II is a relatively new formula, currently used to treat coronary heart disease. It contains 5 traditional herbs. Akt is a key protein kinase in the processes of inhibition of apoptosis in cardiomyocytes. The results of a study found that Guanxin II can significantly activate Akt kinase, increase the Bcl-2/Bax ratio, inhibit cytochrome c release, reduced caspase-9 activation, and attenuated subsequent caspase-3 activation. These results therefore suggest that Guanxin II ensures the survival of myocardium by enhancing the Akt-mediated antiapoptosis pathway (Xi Huang, 2010).

 Shen-fu injection is a modern formulation composed by Renshen (Ginseng) and Fuzi (Aconite). A study found that this formula can significantly decrease infarct size, apoptosis, caspase-3 protein expression in myocardial tissues, and increase p-Akt, p-eNOS, bcl-2 protein expression, compared to the control group (Yang Wu, 2011). 

In this field a large number of reports have been published within the past 5 years. I have included some of the major ones here. From this review we can sum up a number of points. Firstly, research methods have been updated. A large number of studies have applied the latest biomedical techniques, such as metabolomics, apoptosis, cellular signal transduction etc. These new molecular biology techniques have been widely applied in the research of Chinese herbs. Secondly, Danshen and its sub fractions have become a hot point in this field. There have been approximately 4000-5000 reports conducted annually within the past 3 years. Thirdly, most reports are conducted as laboratory research, and relatively few are clinical reports. Finally, although all the papers are published on formal academic journals, there is still an unfortunate lack of papers from the core journals. As there is a lot of research in Chinese medicine still to be done, I believe there will be much progress in the future of this field.

Reference

1. Chunmei Li. Protective roles of Asperosaponin VI, a triterpene saponin isolated from Dipsacus asper wall on acute myocardial infarction in rats. European Journal of Pharmacology. 2010; 627(1-3): 235-241.
2. Chunshui Pan. Salvianolic acid B and Tanshinone IIA attenuate myocardial ischemia injury in mice by NO production through multiple pathways. Ther. Adv.Cardiovasc.Dis. 2011; 5(2): 99-111.
3. Fan Song. Protective effects of cinnamic acid and cinnamic aldehyde on isoproterenol-induced acute myocardial ischemia in rats. Journal of Ethnopharmacology. 2013; 150(1): 125-130.
4. Feng Fu. Semen Cassiae Attenuates Myocardial Ischemia and Reperfusion Injury in High-Fat Diet Streptozotocin-Induced Type 2 Diabetic Rats. Am. J. Chin. Med.2014; 42(1): 95
5. Guangguo Tan. Metabonomic Profiles Delineate the Effect of Traditional Chinese Medicine Sini Decoction on Myocardial Infarction in Rats. PLoS ONE 2012; 7(4): 34157.
6. Jianhua Fu. Hawthorn leaves flavonoids decreases inflammation related to acute myocardial ischemia/reperfusion in anesthetized dogs. Chinese Journal of Integrative Medicine. 2013; 19(8): 582-588.
7. Jiangtao Jiang. Ant oxidative and Cardioprotective Effects of Total Flavonoids Extracted from Dracocephalum moldavica L. Against Acute Ischemia/Reperfusion-Induced Myocardial Injury in Isolated Rat Heart. Cardiovascular Toxicology 2014.
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