Tongxinluo: Heart of Healing

This is a poignant time, in healthcare and the world.

The US spends more per capita on medical care than any other developed nation. The number one and two causes of mortality, cardiovascular disease and cancer, are 90% and 30-50% preventable respectively (1,2). Via a 2016 British Medical Journal review, the third leading US cause of death is attributed to iatrogenic causes. In other words, medical error (3).

Granted, the season shows signs of turning.

Just a few weeks ago, the philanthropist couple Andrew and Peggy Cherng granted City of Hope 100 million dollars to pioneer an integrative oncology program in state-of-the-art facilities, with the explicit goal of articulating and implementing, at the national level, integrative solutions to managing chronic disease.

One may ask, “Why now?”

As Asian medical experts, we are undoubtedly aware, with likely adroitness, how to manage and ameliorate chronic conditions, with a focus on prevention. We may expel pathogenic factors, soften what is hard, firm what is leaking, disperse what is stagnant, and soothe what is unsettled. East Asian medicine, acupuncture and herbal therapeutics are phenomenally equipped to harmonize the inherent of the human organism (zhèngqì/正氣).

The approaches and interventions within this comprehensive medical system have been refined and optimized through careful, systematic observation and employment. There is an ever-growing body of research and evidence for the use of acupuncture in a variety of contexts. Chinese herbal medicine is following suit.

A study published last month in the main publication of JAMA sounds a clear bell.

Across 124 hospitals in China—with affiliation at the Departments of Medicine, Neurology and Population and Data Science, University of Texas Southwestern Medical Center, Dallas—researchers randomized 3,777 patients with acute ST-segment elevated myocardial infarction (STEMI), a very serious and often fatal variety of heart attack.

Within 24-hours of symptoms, the patient-population received a Chinese medicine patent formula tongxinluo, or a placebo which was engineered to look, smell, and taste identical to the active therapy. The patients maintained the herbal therapy for 12 months post-STEMI. All patients maintained STEMI guideline-directed western medical treatment throughout the trial.

Tongxinluo acts via a complex treatment principle: supporting the heart qi, moving blood, breaking stasis, opening orifices, and subduing wind, focusing on the luo-vessels of the heart.

Its composition includes Radix ginseng (ren shen), Scorpio (quan xie), Hirudo (shui zhi), Eupolyphaga seu steleophage (tu bie chong), Scolopendra (wu gong), Periostracum cicadae (chan tui), Radix paeoniae rubra (chi chao), and Borneolum syntheticum (bing pian).

The following are the study’s findings:

If we extrapolate the relative risk reduction from this data, the results are astounding:

30-Day MACCEs: The relative risk reduction for major adverse cardiac and cerebrovascular events (MACCEs) at 30 days is approximately 34.62%.

30-Day Cardiac Death: The relative risk reduction for cardiac death at 30 days is approximately 28.57%.

1-Year MACCEs: The relative risk reduction for MACCEs at 1 year is approximately 36.14%.

1-Year Cardiac Death: The relative risk reduction for cardiac death at 1 year is approximately 26.23%.

In sum, this air-tight study demonstrates a Chinese medicine formula, with no known singular mechanism-of-action (MOA) and an incredible safety profile, to significantly lower the rate of cardiac death at 30 days and 1 year post heart attack.

It’s worth mentioning that Kan Herb Company doesn't currently source the potent (and eclectic) ingredients which constitute tongxinluo. No scorpion, leech, centipede, cicada-molting, borneol, or cockroach is found in our facilities. That being said, a formula which complements the treatment approach guiding the formulation of tongxinluo, is Xue Fu Zhu Yu Tang (Dispel Stasis in the Mansion of Blood).

Xue Fu Zhu Yu Tang (血府逐瘀汤) was first introduced in the Qing Dynasty by Wang Qing-Ren in Yi Lin Gai Cuo (医林改错). This formula is primarily employed to address conditions arising from blood stasis, a core concept characterized by hindered blood flow leading to various health issues, specific to the upper jiao and chest region.

The formula includes numerous herbs, each with a specific role in invigorating blood circulation and alleviating pain:

Tao Ren (桃仁, Prunus persica) - Peach Kernel: Acts as a key herb for invigorating blood circulation and dispelling blood stasis. It's particularly effective in addressing conditions related to blood stagnation, such as menstrual pain or injuries.

Hong Hua (红花, Carthamus tinctorius) - Safflower: Works synergistically with Tao Ren to enhance the blood invigorating and stasis-dispelling effects. Hong Hua is known for its ability to promote circulation and reduce clotting.

Chuan Xiong (川芎, Ligusticum wallichii) - Ligusticum Wallichii: This herb activates the blood and promotes the flow of qi, helping to alleviate pain. It's particularly helpful for headaches and other pain due to blood stasis.

Dang Gui (当归, Angelica sinensis) - Angelica Sinensis: Known for its nourishing properties, Dang Gui both invigorates and harmonizes the blood. It's often used for challenges related to anemia or irregular menstruation.

Chi Shao (赤芍, Paeonia lactiflora) - Red Peony Root: Chi Shao cools the blood and dispels stasis, making it useful in reducing inflammation and pain, especially in patterns where heat signs are present.

Niu Xi (牛膝, Achyranthes bidentata) - Achyranthes Root: It directs the actions of the other herbs downwards, helping to relieve upward-rushing symptoms like headaches. Niu Xi also strengthens the sinews and bones and benefits the joints.

Jie Geng (桔梗, Platycodon grandiflorus) - Platycodon Root: Aids in dispersing lung qi and expelling phlegm. It's often used for respiratory issues but in this formula, it helps to guide the actions of other herbs to the upper parts of the body.

Zhi Ke (枳壳, Citrus aurantium) - Bitter Orange: Works to break up qi stagnation and reduce distension and bloating. It's particularly useful in this formula for alleviating chest and abdominal discomfort.

Gan Cao (甘草, Glycyrrhiza uralensis) - Licorice Root: Harmonizes the properties of the other herbs and mitigates potential side effects. Gan Cao has a soothing effect and can moderate harsh properties of other ingredients.

Shu Di Huang (熟地黄, Prepared Rehmannia glutinosa) - Rehmannia: Nourishes the yin and blood, and it's particularly effective in cooling the blood. It's useful in conditions where there's heat or inflammation accompanying the blood stasis.

Yu Jin (郁金, Curcuma aromatica) - Turmeric Tuber: Yu Jin is known for its ability to invigorate blood, promote the movement of Qi, and clear heat from the heart and liver. In a formula like Xue Fu Zhu Yu Tang, it can help in addressing conditions related to emotional distress, such as irritability or restlessness, as well as alleviating pain due to blood stasis.

Chai Hu (柴胡, Bupleurum chinense) - Bupleurum: Chai Hu is primarily used to regulate and harmonize the liver-spleen axis. It's effective in relieving liver Qi stagnation symptoms like tension, irritability, and flank pain. In the context of a blood-invigorating formula, it can help in ensuring the smooth flow of Qi, which is essential for the proper movement of blood.

Dan Shen (丹参, Salvia miltiorrhiza) - Salvia Root: Dan Shen is a potent herb for blood circulation. It's particularly known for its ability to dissolve blood stasis and cool blood heat. In a formula like Xue Fu Zhu Yu Tang, Dan Shen enhances the blood-invigorating properties, making the formula more effective in addressing conditions like chest pain, menstrual pain, or any other pain related to blood stasis. Additionally, it has a calming effect on the mind, making it beneficial for stress-related symptoms.

A suggested use of Xue Fu Zhu Yu Tang, is in cases of prevention, especially (and necessarily) when there are signs of blood stasis. These symptoms may include severe dry skin on the heel or foot, dark lips or complexion, dark spots on the sides of the tongue, piercing and difficult to treat headaches, and a choppy pulse.

A low, maintenance-dose is excellent for individuals at risk of developing complications from long-term blood stasis, especially in the chest area. Sometimes, blood stasis in the chest manifests as disturbances in the shen, or mind-spirit.

For individuals with mixed excess and deficiency, this formula can be modified to meet their specific needs. The Kan Single Chinese Red Ginseng Root is an excellent consideration for addressing any qi deficiency associated with the blood and qi stasis which warrant the use of Xue Fu Zhu Yu Tang (Dispel Stasis in the Mansion of Blood). Kan’s formulation includes qi-mobilizing herbs, supporting the addition of qi-tonics as deemed necessary.

Pregnant women and individuals with bleeding disorders or on anticoagulant therapy are advised to avoid this formula as it is strictly contraindicated.

Broadening Horizons

Now, there are notable obstacles to widespread integration of Chinese herbal medicine into the greater medical model. One is the need for rigorous trial(s) to demonstrate efficacy, using the gold standard of double-blind randomization with placebo control. The aforementioned JAMA study fulfills this requirement, although it is likely one of a cadre of future research. Repeats of this study in more varied populations are necessary for widespread consideration outside of China. Additionally, funding for these resource-intensive, highly-powered studies is difficult to secure. Without large pharmaceutical companies backing the research, it is generally left to governments to provide for the expensive endeavor. With that said, pharmaceutical corporations are certainly interested in such a robust therapeutic effect, as demonstrated by the recent JAMA trial. The caveat?

Messaging centers around the position that pharmaceutical development is predicated on developing patentable, highly-refined drug products with an exact mechanism-of-action (keep in mind that aspirin, acetaminophen, ibuprofen, lithium, and tricyclic-antidepressants, all ubiquitous medications, exert their effects in ways incompletely understood). Therefore, discovering the MOA of Tongxinluo is, in the eyes of the Western healthcare market, paramount.

A recent publication in the journal Science Advances explores a fascinating perspective on this precise question:

How does Chinese herbal medicine work within the framework of scientific understanding of biological mechanisms?

Hang tight.

Figure 3 (6).

Building on recent advances in network medicine and network pharmacology, researchers leveraged a library of protein-protein interactions (>300,000 of them) into 18,505 herb-symptom nodes associated with 174 symptoms, and >100,000 gene associations. Herb-symptom pairs were mapped and found to be most efficacious when the proximity of the herb to the target symptom module was nearest. The further away the herb-protein targets were to the symptom-network module, the less effective the herb.

Let's break this down a bit.

Network medicine is a growing field evolving away from single-target mechanisms and relatively straightforward disease processes. It involves critical assessment of huge datasets, primarily the relationships amongst proteins throughout the human protein-protein interactome (PPI). These protein interactions characterize disease states, as well as symptoms. Protein processes are most often the targets of pharmaceuticals. For example, ibuprofen, a type of non-steroidal anti-inflammatory agent, while having an unknown exact MOA, exerts an effect by targeting the enzyme cyclooxygenase (a protein), which it inhibits, leading to disruption of prostaglandin synthesis.

By defining multifactorial targets and relationships within the frame of health and illness, therapies can be researched and designed to exert effect across a wide swath of protein-related processes. This method of research and data analysis, for the first time, has been fundamentally applied to Chinese herbal medicine.

Figure 1 (7).

The findings? Let’s read the authors' discussion of their research.

The study has immediate practical implications. For example, we can identify single-herbs which were found to be significantly efficacious using the author’s classification and module formations for certain symptoms.

Let’s focus on abdominal complaints.

For reference, the first column is the pinyin spelling of the herb. The second column is the Latin name of the herb. The third is the symptom target. The fourth is the proximity score (how near the herb-chemical targets are to the protein-gene interactome complex associated with the symptom). The fifth column is the number of patients validated using medical charts from hospital admissions. The sixth column is the percentage of patients who recovered post-prescription. The seventh is the recovery rate after a patient was prescribed a different herb, or no herb for that same symptom.

Figure 2

If we add shén qū (Massa medicata fermentata), we compose the formula yuè jū wán (Release Restraint). Yuè jū wán is a classic formula used for the six depressions (liù yù/六鬱), as articulated by the 14th century physician Zhu Danxi. According to canon, this formulation is especially effective for middle-burner stagnation (of the spleen and stomach), resolving damp, phlegm, qi, blood, fire, and food-related constraint.

Elegantly, we may notice that the significantly efficacious single-herbs involved in the author’s analysis paint a similar image, with stagnation related to the middle-burner a clear diagnostic output.

The Way Forward

In my experience, being research-fluent improves patient care. Patients appreciate the confidence and currency of understanding. This isn’t to say that we must begin wielding the medicine in a fundamentally different way. Providing care based on classical, traditional, and integrative principles is not only scientifically valid, it is, in many contexts, the optimal tool for producing palpable and lasting results. There is a reason the theory of Asian medicine has the form it does, aspects of which have been bedrock for centuries. One new conceptual framework involves the understanding that herb-symptom pattern recognition is a therapeutic intervention at the level of the protein interactome.

There is pervasive misinformation and general unknowing of efficacy, strengths, and weaknesses within the medical marketplace, especially when it comes to adjunctive and complementary treatments. As TCM practitioners, we are inherently responsible for promulgating the medicine we represent. If we ignore its valid, epistemological roots, or contrarily, the state of the field within the scientific domain, we miss an opportunity to respectfully honor and embody the role we occupy within the healthcare system.

Healthcare needs all the help possible, and I hope we all take time to feel our strength: root, trunk, and foliage as it expands into the blue sky.

01. Cleveland Clinic Newsroom. (2021, September 29). 90 Percent of Heart Disease Is Preventable Through Healthier Diet, Regular Exercise and Not Smoking. Retrieved 2024, January 05, from https://newsroom.clevelandclinic.org/2021/09/29/90-percent-of-heart-disease-is-preventable-through-healthier-diet-regular-exercise-and-not-smoking/ ​

02. World Health Organization. (n.d.). Preventing cancer. Retrieved January 5, 2024, from https://www.who.int/activities/preventing-cancer

03. Makary M A, Daniel M. Medical error—the third leading cause of death in the US BMJ 2016; 353 :i2139 doi:10.1136/bmj.i2139

04. City of Hope. (n.d.). Cherng Center for Integrative Medicine. Retrieved 2024, January 05, from https://www.cityofhope.org/patients/departments-and-services/supportive-care-medicine/cherng-center

05. Yang Y, Li X, Chen G, et al. Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction: The CTS-AMI Randomized Clinical Trial. JAMA. 2023;330(16):1534–1545. doi:10.1001/jama.2023.19524

06. Zhang, J., Li, L. Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Radix Astragali against hypopharyngeal carcinoma. Sci Rep 14, 516 (2024). https://doi.org/10.1038/s41598...

07. Xiao Gan et al., Network medicine framework reveals generic herb-symptom effectiveness of traditional Chinese medicine.Sci. Adv.9,eadh0215(2023).DOI:10.1126/sciadv.adh0215