August 23, 2017

Dan Shen, a Powerful Cardiovascular Chinese Herb

Heart Health

by Aaron Mello, CNTP, MNT

Dan Shen is a cardioprotective herb that has been used in Traditional Chinese Medicine for 2000 years or more. Also known as salvia miltiorrhiza, this perennial plant in the mint family has a long history of use in the treatment of cardiovascular disease (CVD), atheroscleroris, thrombosis and angina pectoris, as well as related disorders like hypertension. Despite its long history of use, Dan Shen has only recently been studied in formal clinical trials. This article will review what modern clinical trials and animal models have revealed about the efficacy and safety of Dan Shen in the treatment of cardiovascular disease.

Worldwide cardiovascular disease burden

Cardiovascular disease is a class of disorders that involve the heart and blood vessels and includes coronary heart disease, rheumatic heart disease, peripheral vascular disease, heart failure, congenital heart disease and cardiomyopathies. CVD is the number one cause of morbidity and mortality in the United States and worldwide (1). In the United States alone, about 610,000 people die from heart disease every year, accounting for one out of every four deaths (2). Because of its significant negative impact on health worldwide, effective treatments to reduce CVD mortality are in high demand.

History of dan shen

The roots of the Dan Shen plant are highly valued and their medicine properties were described in Shennong’s Herbal Classic of Materia Medica, a Chinese book believed to have been compiled from oral tradition between about 200 and 250 AD. Dan Shen was also well described in the classical TCM textbook, the Compendium of Materia Medica during the Ming dynasty in 1596 AD and was officially added to the Chinese pharmacopoeia in 1953. But like many Chinese herbs with a long history of use, randomized clinical trials have only begun to be performed in recent years. Keep reading to learn more about modern research on Dan Shen!

Dan shen in traditional Chinese medicine

The red roots of the Dan Shen plant, also called red sage, are usually harvested in spring and autumn every year. According to the Grand Compendium of Materia Medica, “S. miltiorrhiza matches the heart called Chi (Red) Shen.” The plant gets its name from the red color of the bitter roots. Chinese Pharmacopoeia asserts that Salvia Miltiorrhizae Radix and Rhizoma promotes blood circulation to remove blood stasis and alleviate pain, clears heart heat to relieve restlessness, and cools blood to remove carbuncle (3). From a TCM perspective, chest pain and heart failure are caused by obstruction of Qi and blood circulation, and Dan Shen works to relieve these obstructions.

Modern research on dan shen

In the last 20 years or so, more research has been performed to evaluate the benefits of Dan Shen and other traditional Chinese herbs on CVD. Although much of the research has demonstrated positive benefits, it’s important to note that not all of the research has been well-designed. More better designed clinical studies need to be performed to evaluate the efficacy and safety of Dan Shen more conclusively. With that in mind, I have focused here on well-designed studies and omitted research that is low quality. There were a number of studies which I intentionally omitted from this blog that I did not include because the quality of their research was poor. Let’s look next at what the available research has to say about the power of Dan Shen to improve cardiovascular health.

Phytochemistry of dan shen

Before we get to the actual clinical trials, let’s look briefly at the chemical constituents of Dan Shen that have been identified as possible active compounds. According to the Chinese Academy of Science Chemistry Database and the Chinese Herbal Drug Database, more than 200 compounds have been identified in Dan Shen. These constituents can be broadly classified into two major groups: water-soluble phenolic compounds and lipid-soluble diterpenoid compounds.

The water-soluble phenolic acids of Dan Shen are mostly composed of C6C3 units, which are usually isolated from the plant with water, methanol, ethanol or aqueous acetone. The resulting colorless or tan amorphous powders are very sensitive to light and head, and are easily oxidized when exposed to air. In contrast, the lipid-soluble diterpenoid tanshinones are red in color and usually stable in their solid state (4).

Mechanisms of action

The biological actions of these substances have been elucidated over the last several years, and several mechanisms have been proposed for the cardioprotective effects of this plant, including:

  • Anti-inflammatory (5)
  • Anti-oxidation (6) (7)
  • Anti-thrombosis (8)
  • Anti-proliferation of vascular smooth muscle cells
  • Inhibitory of the expression of adhesion molecules in vascular endothelium and leukocytes (9) (10)
  • Improvement of acute myocardial ishemia (11)

Next I’ll go into clinical trials of Dan Shen, in both animal and human models.

Dan Shen improves CHD markers

In one randomized, placebo-controlled human study, Dan Shen was able to improve a number of blood markers that pertain to cardiovascular disease in a group of participants with an active coronary heart disease (CHD) diagnosis. The active group of 63 participants received 270mg of Dan Shen three times per day over a three month period, whereas an equal number of subjects in the placebo group took placebo three times per day.

At the conclusion of the study, the active group experienced reductions in the following makers: triglycerides, total cholesterol, LDL, Lp(a), gamma-glutamyl transpeptidase (GGT), direct bilirubin, uric acid and homocysteine. Dan Shen also increased levels of HDL, ApoA, ApoB, ApoE, total bilirubin and indirect bilirubin. The authors conclude that Dan Shen is able to reduce the risk of coronary heart disease by improving markers related to CHD (12).

Myocardial infarction

A rat study evaluated the protective effects of Dan Shen in myocardial ishemia-induced rats. After administering Dan Shen, researchers measured the size of the myocardial infarction as well as inflammatory markers and the activity of anti-oxidative enzymes. They found that Dan Shen reduced the infarction and several inflammatory markers, including C-reactive protein, IL-6, tumor necrosis factor-alpha and malondialdehyde. It also increased the activities of superoxide dismutase and serum levels of glutathione. The authors conclude that Dan Shen provides significant cardioprotective benefits against acute ischemic myocardial injury in rats and speculate that the benefits may lie in its anti-inflammatory and anti-oxidant properties (13).

Stroke prevention

A human study evaluated the ability of Dan Shen dripping pills to protect against secondary stroke occurrence in a group of 106 participants who had suffered from ischemic stroke or a transient ischemic attack (TIA) within the last 20 days. The patients were divided roughly in half into active and placebo groups and monitored over the course of one year. During that time period, incidence of recurrent stroke and TIA were lower in the active group  than in placebo (9.6% vs 24.1). In addition, blood C-reactive protein levels decreased significantly in the active group participants as compared to placebo. The authors conclude that Dan Shen treatment may reduce the risk of stroke and TIA recurrence, which they attribute to the anti-inflammatory effects of the herb (14).

HIF1α and VEGFA improved by Dan Shen

A study evaluated the effects and mechanism of action of Dan Shen in mice with myocardial infarction-induced cardiac damage. Dan Shen was injected into mice after left anterior descending coronary artery (LAD) ligation for four weeks, at which point cardiac function was evaluated by echocardiography. Researchers also evaluated protein and mRNA expression of hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor A (VEGFA). These two proteins are implicated in heart disease.

In the study, the mouse hearts were subjected to LAD ligation, at which point the hearts showed significantly impaired angiogenesis. After treating these hearts with Dan Shen, angiogenesis defect and heart failure were partially rescued. In addition, HIF1α and VEGFA mRNA levels and protein expression increased significantly, leading the authors to conclude that the cardioprotective effects of Dan Shen were at least partly due to increased HIF1α and VEGFA expression (15).

Dan shen + Gegen

This study evaluated the effects of a two-herb combination, Dan shen and Gegen as a cardioprotective formula in vitro and in vivo. Gegen is also known as Puerariae Lobatae Radix. In the in vitro investigation, the formula demonstrated anti-inflammatory and anti-oxidative properties, prevented foam cell formation on vascular endothelium, and promoted vasodilation. The formula also promoted expression of ApoD, lecithin cholesterol acyltransferase and intercellular adhesion molecule 1, which are well-known cardiac biomarkers. Expression of inducible nitric oxide synthase (iNos) was also upregulated by the formula. Expression of tumor necrosis factor-α (TNF-α) was also downregulated, both at the gene and protein expression levels.

Three randomized, double-blind, placebo-controlled clinical trials included in this study also found significant benefits with the formula in vivo. In two of the trials, researchers noted improvements in carotid intima media thickness and brachial flow-mediated dilation. In the third trial, postmenopausal women with early hypercholesterolemia also demonstrated a reduced carotid intima media thickness, as well as significantly reduced serum LDL and total cholesterol. The Dan Shen and Gegen formula was overall well tolerated in all three trials (16).

Dan Shen + Sanqi

Another two-herb combination formula was evaluated for its synergistic benefits on vascular disease via anti-inflammatory activities. In this study, Dan Shen was combined with Notoginseng Radix et Rhizoma, also known as Sanqi in TCM. The two herbs were combined in different ratios to determine the optimal ratio to each other. Nine combination ratios were screened in the RAW264.7 cell line and their anti-inflammatory effects were examined in lipopolysaccharide- (LPS-) induced nitric oxide (NO), tumor necrosis factor (TNF) and monocyte chemoattractant protein-1 (MCP-1) generation pathways. Researchers found that an 8:2 Dan Shen:Sanqi ratio was optimal and exerted a synergistic benefit in inhibiting NO, TNF, and MCP-1. The authors conclude that this herbal combination formula is effective for vascular disease, due to their synergistic anti-inflammatory effects (17).

Benefits of dan shen water-soluble extracts

This study evaluated the cardioprotective effects of water-soluble Dan Shen extracts (DEs) both in vitro and in vivo to identify the mechanisms of their antiatherogenic effects. For the in vitro arm of the study, rat vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) were treated with DE. The DE inhibited the production of reaction oxygen species and the migration and proliferation of platelet-derived growth factor-BB stimulated VSMCs. In addition, DE prevented inflammation and apoptosis in HUVECs.

Researchers also confirmed both of these benefits in vivo and ex vivo, in rat and rabbit models. DE treatment reduced platelet aggregation and pretreatment prevented κ-carrageenan injection-induced tail vein thrombosis. In addition, ED-treated rabbits showed decreased in-stent restenosis of stented iliac arteries. The authors conclude that their findings suggest water-soluble DE modulates key atherogenic events in VSMCs, endothelial cells and platelets, in both in vitro and in vivo models (18).

Dan Shen benefits in summary

From the research, the primary benefits of Dan Shen appear to stem from its anti-inflammatory and antioxidant properties. These qualities have been shown to be a main source of cardioprotection for other natural remedies as well. For example, I wrote about the cardioprotective effects of pomegranate a few weeks ago. Many of the benefits of pomegranate stem from its anti-inflammatory and anti-oxidant qualities as well. Hopefully more well-designed research will be performed in the coming years to confirm and further elucidate the benefits of Dan Shen.

Using Dan shen clinically

The primary human study I found which specified a dosage used 270mg three times per day, which researchers found to be an effective dose. In that trial, participants took Dan Shen for three months, which suggests that this duration is a reasonable period of time to deliver results.

References

  1. Dyakova, Mariana, et al. “Systematic versus Opportunistic Risk Assessment for the Primary Prevention of Cardiovascular Disease.” Cochrane Database of Systematic Reviews, 2016, doi:10.1002/14651858.cd010411.pub2.
  2. CDC, NCHS. Underlying Cause of Death 1999-2013 on CDC WONDER Online Database, released 2015. Data are from the Multiple Cause of Death Files, 1999-2013, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. Accessed Feb. 3, 2015.
  3. Pharmacopoeia of the People’s Republic of China, Vol. 1. Beijing Chemical Industry Press: Beijing, China.
  4. Wang L, Ma R, Liu C, et al. Salvia miltiorrhiza: A Potential Red Light to the Development of Cardiovascular 
Diseases. Current Pharmaceutical Design. 2017;23(7):1077-1097. doi:10.2174/1381612822666161010105242.
  5. Fang, Zhi-Yuan, et al. “Tanshinone IIA Downregulates the CD40 Expression and Decreases MMP-2 Activity on Atherosclerosis Induced by High Fatty Diet in Rabbit.” Journal of Ethnopharmacology, vol. 115, no. 2, 2008, pp. 217–222., doi:10.1016/j.jep.2007.09.025.
  6. Hur, Kyu Yeon, et al. “Therapeutic Effect of Magnesium Lithospermate B on Neointimal Formation after Balloon-Induced Vascular Injury.” European Journal of Pharmacology, vol. 586, no. 1-3, 2008, pp. 226–233., doi:10.1016/j.ejphar.2008.02.072.
  7. Zhao, Guang-Rong, et al. “Characterization of the Radical Scavenging and Antioxidant Activities of Danshensu and Salvianolic Acid B.” Food and Chemical Toxicology, vol. 46, no. 1, 2008, pp. 73–81., doi:10.1016/j.fct.2007.06.034.
  8. Lu, Jun, et al. “Screening of Direct Thrombin Inhibitors from Radix Salviae Miltiorrhizae by a Peak Fractionation Approach.” Journal of Pharmaceutical and Biomedical Analysis, vol. 109, 2015, pp. 85–90., doi:10.1016/j.jpba.2015.02.020.
  9. Ho, Jennifer, and Chuang-Ye Hong. “Salvianolic Acids: Small Compounds with Multiple Mechanisms for Cardiovascular Protection.” Journal of Biomedical Science, vol. 18, no. 1, 2011, p. 30., doi:10.1186/1423-0127-18-30.
  10. Han, Jing-Yan, et al. “Ameliorating Effects of Compounds Derived from Salvia Miltiorrhiza Root Extract on Microcirculatory Disturbance and Target Organ Injury by Ischemia and Reperfusion.” Pharmacology & Therapeutics, vol. 117, no. 2, 2008, pp. 280–295., doi:10.1016/j.pharmthera.2007.09.008.
  11. Xia, Hongrui, et al. “Conversion of Salvianolic Acid B into Salvianolic Acid A in Tissues of Radix Salviae Miltiorrhizae Using High Temperature, High Pressure and High Humidity.”Phytomedicine, vol. 21, no. 6, 2014, pp. 906–911., doi:10.1016/j.phymed.2014.01.005.
  12. Liu B, Du Y, Cong L, Jia X, Yang G. Danshen (Salvia miltiorrhiza) Compounds Improve the Biochemical Indices of the Patients with Coronary Heart Disease. Evidence-based Complementary and Alternative Medicine : eCAM. 2016;2016:9781715. doi:10.1155/2016/9781715.
  13. YAN K-P, GUO Y, XING Z, et al. Dan-Shen-Yin protects the heart against inflammation and oxidative stress induced by acute ischemic myocardial injury in rats. Experimental and Therapeutic Medicine. 2012;3(2):314-318. doi:10.3892/etm.2011.404.
  14. Xu, G., Zhao, W., Zhou, Z., Zhang, R., Zhu, W. and Liu, X. (2009), Danshen extracts decrease blood c reactive protein and prevent ischemic stroke recurrence: a controlled pilot study. Phytother. Res., 23: 1721–1725. doi:10.1002/ptr.2819
  15. Ai F, Chen M, Li W, et al. Danshen improves damaged cardiac angiogenesis and cardiac function induced by myocardial infarction by modulating HIF1α/VEGFA signaling pathway. International Journal of Clinical and Experimental Medicine. 2015;8(10):18311-18318.
  16. Leung P-C, Koon C-M, Lau CB-S, et al. Ten Years’ Research on a Cardiovascular Tonic: A Comprehensive Approach—From Quality Control and Mechanisms of Action to Clinical Trial. Evidence-based Complementary and Alternative Medicine : eCAM. 2013;2013:319703. doi:10.1155/2013/319703.
  17. Zhou X, Razmovski-Naumovski V, Chang D, et al. Synergistic Effects of Danshen (Salvia Miltiorrhiza Radix et Rhizoma) and Sanqi (Notoginseng Radix et Rhizoma) Combination in Inhibiting Inflammation Mediators in RAW264.7 Cells. BioMed Research International. 2016;2016:5758195. doi:10.1155/2016/5758195.
  18. Cho YH, Ku CR, Hong Z-Y, et al. Therapeutic Effects of Water Soluble Danshen Extracts on Atherosclerosis. Evidence-based Complementary and Alternative Medicine : eCAM. 2013;2013:623639. doi:10.1155/2013/623639.
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