Convergent Points Volume 4 Issue 2

Herbal Modulation of the Gut–Brain Axis in IBS-D: A Case Report

By Erica Yang, MS, MTOM, LAc, Joshua Park, DSOM, LAc, and Timothy Ross, DAOM, LAc

Introduction

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain associated with loose or watery stools. Defined by Rome IV criteria, IBS-D occurs when more than 25% of bowel movements are classified as Bristol Stool Scale types 6-7 (Stanford Medicine, n.d.). This disorder involves complex interactions between the gut-brain axis, including altered gastrointestinal motility, visceral hypersensitivity, and intestinal microbiota dysbiosis(Altomare et al., 2021; Hadjivasilis et al., 2019).

IBS-D affects approximately 11.2% of the global population, representing 40% of all IBS cases. The condition exhibits a female predominance, particularly in women under 50, and significantly impacts quality of life and productivity (Endo, 2015; Sperber, 2017).

The pathogenesis of IBS-D involves multiple mechanisms, including visceral hypersensitivity, characterized by an increased perception of normal intestinal stimuli (Bai et al., 2024; Huang et al., 2023). Increased bile acid synthesis and subsequent malabsorption occur in approximately 30% of patients, which stimulates colonic motility and secretion (Min et al., 2022). Furthermore, IBS-D is also associated with altered serotonin signalling and gut microbiota dysbiosis, including a reduction in beneficial bacteria such as Bifidobacterium, which can lead to inflammation (Reference). These higher levels of inflammation in IBS have correlated with increased gut permeability (“leaky gut"), which can further aggravate and perpetuate IBS-D symptoms (Raskov et al., 2016).

Biomedical treatment options for IBS-D include loperamide and eluxadoline for motility, antispasmodics for pain relief, rifaximin for inflammation and dysbiosis, and alosetron for visceral hypersensitivity (Cangemi et al., 2019; Lacy et al., 2021). Each of these medications comes with significant potential side effects. Loperamide, for example, is linked to chronic constipation, toxic megacolon, and cardiac side effects (Sahi et al., 2024). With eluxadoline, there is risk for constipation, nausea, abdominal pain, and pancreatitis (Lembo et al., 2016), and alosetron may be associated with ischemic colitis (Butt et al., 2024). Medical researchers admit that personalized biomedical treatments for IBS-D are a work in progress (Kurin, M., & Cooper, G., 2020).

In TEAM, IBS-D falls under the disease categories of "abdominal pain" (腹痛) and "diarrhea" (泄瀉). Liver depression and Spleen deficiency are the most common patterns noted in the literature (Guo, J., & Yao, X., 2024). A prevalent type of Liver-Spleen disharmony is known as "Wood Overacting on Earth" (木乘土), describing a pathophysiology of the Five Phases' controlling cycle. Nanjing Chapter 50 refers to this as "robber evil" (賊邪), from "what cannot be overcome" (從所不勝來者為賊邪), signifying a distortion of typical physiological control. Neijing Suwen Chapter 67 states: "When qi is excessive, it overacts on what it normally controls and insults what it is not able to control." (氣有餘，則制己所勝而侮不所勝).

This tendency of pathology to move through the controlling cycle is emphasized in the Jin Gui Yao Lue, which notes that: "a doctor who treats disease before it manifests, sees a disease in the Liver [Wood] and knows the Liver will transmit to the Spleen [Earth], therefore first supplement the Spleen..." (夫治未病者，見肝之病，知肝傳脾，當先實脾)."

TEAM recognizes the mind-body interdependence, particularly the emotional impact on digestive health. Huangdi Neijing Suwen Chapter 39 notes: "anger causes the qi to rise, in severe cases there may be vomiting of blood or diarrhea with undigested food" (怒則氣逆，甚則嘔血及飱泄). This passage can be read as a description of brain-gut axis dysregulation leading to chronic diarrhea, which in a modern biomedical context could indicate IBS-D. This possible correlation suggests avenues for further research.

Case Description

A 32-year-old male who worked as a financial analyst presented with a chief complaint of recurrent abdominal pain and diarrhea persisting for three years, with symptom exacerbation over the preceding six months. The patient experienced loose, watery stools four to six times daily. His often post-prandial urgency, cramping, and lower abdominal pain was relieved after defecation, as was abdominal distension with flatulence.

Symptoms began during a period of prolonged work stress, shortly after returning from a trip to Thailand where he had experienced traveller's diarrhea. Previous biomedical treatments, including antibiotics, loperamide, and probiotics, provided only transient relief while causing constipation.

The patient avoided social activities due to fear of sudden bowel urgency. Stress, fatty foods, and dairy products exacerbated the patient's condition, while fasting and applying heat improved it.

The patient's tongue body was pale with a thin white coating and red lateral borders. On the left, the cun and guan pulse positions were both wiry. On the right, the cun position was rapid, slippery, and superficial; the right guan was weak, and the proper chi position was notably deep and weak.

Abdominal palpation revealed tenderness at ST25 on deep palpation. There was also subcostal congestion, which was particularly pronounced on the left side. The patient also exhibited frequent sighing and clenched fists when describing occupational stress throughout the initial consultation.

Diagnosis and Treatment Strategy

This case suggests Liver qi stagnation induced by chronic stress, which impairs the Spleen transportation function, resulting in dampness accumulation and diarrhea. Tongue and pulse findings confirmed Spleen deficiency (pale tongue, weak pulse) and Liver excess (red lateral tongue borders, wiry pulse, sighing, clenched fists, subcostal tension). Additionally, frequent lower back pain, pale urine, and a weak chi pulse position indicated Kidney deficiency. At the same time, mucus in the stool and a slippery right cun pulse at a superficial level, with deep palpation tenderness at ST-25, suggested residual damp heat in the Large Intestine.

In this particular case, the patient's high-stress lifestyle and visible manifestations of irritability show how "anger damages the Liver" (怒傷肝) as stated in Suwen Chapter 5 (Huang Di Nei Jing《黃帝內經》). This pre-existing tendency toward Liver excess likely made the patient more susceptible to lasting complications from traveller's diarrhea, which is likely the origin of the IBS-D, given the signs of lingering damp heat in the Large Intestine.

The development of Kidney yang deficiency illustrates the interdependence of the Spleen as the source of post-natal transformation and the Kidney as the prenatal source of warmth. Over a long enough period, weakness in the Spleen will begin to draw on the Kidney. It also illustrates a continuous movement of pathology through the controlling cycle of the Five Phases, from the Liver to the Spleen and then from the Spleen to the Kidneys. According to Chapter 1 of the Jin Gui Yao Lue, the next phase of the cycle will involve the Kidneys drawing upon the Heart (脾能傷腎，腎氣微弱則水不行，水不行則心火氣盛) (Jin Gui Yao Lue《金匱要略》).

The treatment strategy in this case focused primarily on harmonising the Liver and Spleen, both emolliating and dredging Liver qi while tonifying the Spleen and reducing dampness. The base formula chosen to achieve this result was  Tong Xie Yao Fang (TXYF). To address the patient's specific presentation, the formula was modified.

Herbal Formula and Modifications

In modern times, TXYF is one of the most researched formulas for IBS-D. It was first mentioned in Chapter 2 of "Essential Teachings of Zhu Danxi" 《丹溪心法》in the Ming Dynasty. At that time, however, the formula was described without an explicit name. The prescription was given for "painful diarrhea" (治痛泄), and subsequently was referred to as "Important Formula for Treating Painful Diarrhea" (TXYF). It was also mentioned in the late Ming Dynasty text "Systematic Great Compendium of Medicine Past and Present" 《古今醫統大全》by Xu Chunfu, where it was called "Bai Zhu Shao Yao San" (白術芍藥散) and noted that in cases of chronic diarrhea, six qian (30 g) of sheng ma should be added (久瀉者加升麻六錢).

The formula was given its definitive, current name in Chapter 2 of Wu Kun's "Investigations of Medical Formulas" 醫方考. This text described the pathophysiology of the formula: "The Spleen is responsible for diarrhea and the Liver is responsible for pain; the Liver is responsible for repletion and the Spleen is responsible for vacuity. Spleen vacuity and Liver repletion cause painful diarrhea, and this is the prescription." (瀉責之脾，痛責之肝；肝責之實，脾責之虛。脾虛肝實，故令痛瀉，是方也).

As the clinical picture increasingly indicated Liver qi constraint as the primary aggravating factor, the formula was modified to both nourish and soften the Liver with bai shao, to dredge and regulate Liver qi with chai hu, and to alleviate tension with gan cao. The addition of chai hu incorporates the classical formula Si Ni San, which can effectively treat constraint-pattern abdominal pain and diarrhea. Adding an equal amount of gan cao to bai shao incorporates Shao Yao Gan Cao Tang for antispasmodic effects, exemplifying the principle of using a sweet flavour to relax the Liver.

Secondarily, the patterns of Kidney yang deficiency and residual damp heat in the large intestine were addressed with further modifications. Firstly, the Kidney yang deficiency was managed with the inclusion of tu su zei, which astringes the intestines while also tonifying the Kidney yang and stopping diarrhea. Residual damp-heat was addressed via the addition of ge gen, which can gently clear heat, generate fluids, and raise yang to stop diarrhea.

Outcomes

The patient was provided with a two-week supply of the herbs in granule form. Abdominal pain was reduced by more than 50% after two days on the formula, with bowel movements progressing from daily loose stools to every other day. Ultimately, complete resolution of both abdominal pain and loose stools was achieved by the end of the two-week course of treatment.

As reported at a follow-up one month later, the patient had been passing one to two well-formed bowel movements per day, with no pain or other symptoms. He was advised on stress management, including qigong exercises, to ensure no further recurrence.

Discussion

IBS-D is a complex condition involving the brain-gut axis, neuro-immune crosstalk, and gut microbiota. TXYF offers multi-target therapeutic effects by regulating the gut-brain axis, modulating gut microbiota, providing anti-inflammatory action, and repairing the gut barrier, addressing key etiological factors.

Regarding the gut-brain axis, TXYF's baishao reduces nNOS overexpression, soothing spasms and regulating motility (Han, et al., 2021; Tan, et al., 2020) TXYF also inhibits CHRM3 expression, alleviating smooth muscle contraction and spasms (Feng, et al., 2024) Furthermore, it lowers colonic serotonin (5-HT) and substance P, regulating 5-HT via microbiome modulation to dampen visceral hypersensitivity (Li, et al., 2018; Yin, et al., 2015).

For microbiota restoration, modified TXYF increases Akkermansia and beneficial species, such as Bifidobacterium and Lactobacillus, via bai zhu and fang feng, while reducing Clostridium sensu stricto 1 (Li et al., 2018; Qi et al., 2015; Yan et al., 2011). The microbiome modulation of TXYF also upregulates intestinal Fgf15, a feedback signal controlling bile acid synthesis, which links to the TEAM concept of Liver overacting on Spleen with bile acid diarrhea. (Jia et al., 2024)

TXYF also exhibits both anti-inflammatory properties and is capable of helping to repair the gut barrier. It has been shown to downregulate the NF-κB/Notch pathway, reducing inflammatory cytokines (IL-6, TNF-α), modulating goblet cell secretion, and protecting the gut barrier by decreasing intestinal permeability. (Feng, et al., 2024; Hou, et al., 2019)

The additional herbs, chai hu, ge gen, tu su zi, and gan cao, synergise with TXYF. Chai hu exhibits anti-inflammatory and antidepressant effects by modulating the NF-κB/MAPK pathways, as well as neurotransmitters. (Ashor & Wink, et al., 2014; Ran, et al., 2024) Ge gen modulates GI motility with antidiarrheal, antispasmodic, and anti-inflammatory properties. (Zhou, et al 2014; Choi, et al., 2016). Tu su zi exhibits anti-inflammatory, mucosal protective, and antioxidant effects. (Yang, et al., 2024) Bai shao and gan cao together decrease visceral hypersensitivity by downregulating TRPV1 and 5-HT. (Shao et al., 2020) These additions strengthen the overall effect of TXYF on stress, motility, hypersensitivity, and barrier dysfunction.

This case study suggests several avenues for future research. One promising area is metabolomic analysis. Metabolomics analysis is the comprehensive study of small molecules, known as metabolites, in cells, tissues, or organisms. Using technologies such as gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS), researchers can identify specific metabolites linked to biomarkers, diseases, or drug responses. This enables a greater understanding of how various factors impact health.

Metabolomics studies of TXYF and other TEAM herbal formulations consistently reveal complex, multi-target mechanisms of action (Wang et al., 2019). Such studies can help advance our understanding of crosstalk between the gut microbiome, brain, and immune system, illuminating our understanding of pathophysiology and providing novel therapeutic targets for IBS and other complex, multi-factorial diseases (Sharma & Yadav, 2022).

Personalized medicine has been the standard in TEAM for over two thousand years. Tailoring treatments and prescriptions is achieved through pattern differentiation (bian zheng lun zhi 辯證論治). Case reports such as this one, which combine a classical understanding of symptom patterns and formula architecture with data-driven analysis of biochemical mechanisms, indicate the possibility of a future pattern-based precision medicine that draws equally from ancient and modern perspectives, as well as eastern and western traditions.

Conclusion

The patient had suffered from IBS-D for years, which had severely diminished his quality of life, impacting his ability to participate in work as well as social events. After only two weeks of treatment, his symptoms had resolved, and he was able to return to his previous level of activity. TEAM was able to provide a relatively rapid solution in this case, where conventional measures had failed due to its whole-systems approach to treatment.

This case demonstrates the effectiveness of TEAM pattern differentiation in treating IBS-D. The successful resolution of chronic symptoms through modified TXYF illustrates the importance of precise pattern differentiation and how the flow of the Five Phases enabled the tracking of the pathology's trajectory.

The integration of classical TEAM theory with modern science provides a framework for understanding and treating IBS-D. Further research investigating the mechanisms of action and clinical efficacy of traditional formulas, such as TXYF, in treating IBS-D would be valuable for the evidence-based integration of TEAM therapeutics.

Informed Consent

The patient provided written informed consent for the publication of this case report, and a copy is on file with the authors.

Safety

No adverse events were anticipated or reported.

Resources

Altomare, A., Di Rosa, C., Imperia, E., Emerenziani, S., Cicala, M., & Guarino, M. P. L. (2021). Diarrhea predominant-irritable bowel syndrome (IBS-D): Effects of different nutritional patterns on intestinal dysbiosis and symptoms. Nutrients, 13(5), 1506. https://doi.org/10.3390/nu13051506

Ashour, M. L., & Wink, M. (2011). Genus Bupleurum: A review of its phytochemistry, pharmacology and modes of action. Journal of Pharmacy and Pharmacology, 63(3), 305–321. https://doi.org/10.1111/j.2042-7158.2010.01170.x

Bai, C., Wang, J., Wang, Y., et al. (2024). Exploration of the mechanism of traditional Chinese medicine for anxiety and depression in patients with diarrheal irritable bowel syndrome based on network pharmacology and meta-analysis. Frontiers in Pharmacology, 15, 1404738. https://doi.org/10.3389/fphar.2024.1404738

Cangemi, D. J., & Lacy, B. E. (2019). Management of irritable bowel syndrome with diarrhea: A review of nonpharmacological and pharmacological interventions. Therapeutic Advances in Gastroenterology, 12, 1756284819878950. https://doi.org/10.1177/1756284819878950

Choi, S., Woo, J. K., Jang, Y. S., Kang, J. H., Jang, J. E., Yi, T. H., Park, S. Y., Kim, S. Y., Yoon, Y. S., & Oh, S. H. (2016). Fermented Pueraria lobata extract ameliorates dextran sulfate sodium-induced colitis by reducing pro-inflammatory cytokines and recovering intestinal barrier function. Laboratory Animal Research, 32(3), 151–159. https://doi.org/10.5625/lar.2016.32.3.151

Dudzińska, E., Grabrucker, A. M., Kwiatkowski, P., Sitarz, R., & Sienkiewicz, M. (2023). The importance of visceral hypersensitivity in irritable bowel syndrome—Plant metabolites in IBS treatment. Pharmaceuticals, 16(10), 1405. https://doi.org/10.3390/ph16101405

Endo, Y., Shoji, T., & Fukudo, S. (2015). Epidemiology of irritable bowel syndrome. Annals of Gastroenterology, 28(2), 158–159.

Feng, T., Zhou, Y., Lv, B., & Cai, L. (2024). Tongxieyaofang decoction alleviates IBS by modulating CHRM3 and gut barrier. Drug Design, Development and Therapy, 18, 3191–3208. https://doi.org/10.2147/DDDT.S455497

Guo, J., & Yao, X. (2024). 腹泻型肠易激综合征的中医病因病机认识 [Understanding the etiology and pathogenesis of diarrhea-type irritable bowel syndrome in traditional Chinese medicine]. Journal of Clinical Personalized Medicine, 3(4), 1934–1940. https://doi.org/10.12677/jcpm.2024.34272

Hadjivasilis, A., Tsioutis, C., Michalinos, A., Ntourakis, D., Christodoulou, D. K., & Agouridis, A. P. (2019). New insights into irritable bowel syndrome: From pathophysiology to treatment. Annals of Gastroenterology, 32(6), 554–564. https://doi.org/10.20524/aog.2019.0428

Han, J. P., Lee, J. H., Lee, G. S., Koo, O. J., & Yeom, S. C. (2021). Positive correlation between nNOS and stress-activated bowel motility is confirmed by in vivo HiBiT system. Cells, 10(5), 1028. https://doi.org/10.3390/cells10051028

Hou, Q., Huang, Y., Zhu, Z., Liao, L., Chen, X., Han, Q., & Liu, F. (2019). Tong-Xie-Yao-Fang improves intestinal permeability in diarrhoea-predominant irritable bowel syndrome rats by inhibiting the NF-κB and Notch signalling pathways. BMC Complementary and Alternative Medicine, 19(1), 337. https://doi.org/10.1186/s12906-019-2749-4

Huang, K. Y., Wang, F. Y., Lv, M., Ma, X. X., Tang, X. D., & Lv, L. (2023). Irritable bowel syndrome: Epidemiology, overlap disorders, pathophysiology and treatment. World Journal of Gastroenterology, 29(26), 4120–4135. https://doi.org/10.3748/wjg.v29.i26.4120

Huang Di 黃帝 (206 BCE–220 CE). Huang Di Nei Jing 《黃帝內經》 [Inner Canon of the Yellow Emperor].

Huang Di 黃帝 (206 BCE–220 CE). Huang Di Ba Shi Yi Nan Jing 《黃帝八十一難經》 [The Yellow Emperor’s Canon of 81 Difficult Issues].

Jia, F., Du, L., He, J., Zhang, Z., Hou, X., Dong, Q., Bian, Z., & Zhao, L. (2024). Tong-Xie-Yao-Fang strengthens intestinal feedback control of bile acid synthesis to ameliorate irritable bowel syndrome by enhancing bile salt hydrolase-expressing microbiota. Journal of Ethnopharmacology, 331, 118256. https://doi.org/10.1016/j.jep.2024.118256

Kurin, M., & Cooper, G. (2020). Irritable bowel syndrome with diarrhea: Treatment is a work in progress. Cleveland Clinic Journal of Medicine, 87(8), 501–511. https://doi.org/10.3949/ccjm.87a.19011

Lacy, B. E., Pimentel, M., Brenner, D. M., et al. (2021). ACG clinical guideline: Management of irritable bowel syndrome. American Journal of Gastroenterology, 116(1), 17–44. https://doi.org/10.14309/ajg.0000000000001036

Li, J., Cui, H., Cai, Y., et al. (2018). Tong-Xie-Yao-Fang regulates 5-HT level in diarrhea predominant irritable bowel syndrome through gut microbiota modulation. Frontiers in Pharmacology, 9, 1110. https://doi.org/10.3389/fphar.2018.01110

Min, Y. W., Rezaie, A., & Pimentel, M. (2022). Bile acid and gut microbiota in irritable bowel syndrome. Journal of Neurogastroenterology and Motility, 28(4), 549–561. https://doi.org/10.5056/jnm22129

Qi, S. Y., Cai, J. Y., Zhou, L. Y., Yang, T., Tan, X., Li, M., Hu, X., et al. (2015). Effect of Radix saposhnikoviae on intestinal flora and serine protease signal in rats with postinfection irritable bowel syndrome. Traditional Chinese Drug Research and Clinical Pharmacology, 6, 790–796.

Ran, S., Peng, R., Guo, Q., Cui, J., Chen, G., & Wang, Z. (2024). Bupleurum in treatment of depression disorder: A comprehensive review. Pharmaceuticals, 17(4), 512. https://doi.org/10.3390/ph17040512

Raskov, H., Burcharth, J., Pommergaard, H. C., & Rosenberg, J. (2016). Irritable bowel syndrome, the microbiota and the gut-brain axis. Gut Microbes, 7(5), 365–383. https://doi.org/10.1080/19490976.2016.1218585

Shao, Y. Y., Guo, Y. T., Gao, J. P., Liu, J. J., Chang, Z. P., Feng, X. J., Xu, D., Deng, G. F., & Hou, R. G. (2020). Shaoyao-Gancao decoction relieves visceral hyperalgesia in TNBS-induced postinflammatory irritable bowel syndrome via inactivating transient receptor potential vanilloid type 1 and reducing serotonin synthesis. Evidence-Based Complementary and Alternative Medicine, 2020, 7830280. https://doi.org/10.1155/2020/7830280

Sharma, B., & Yadav, D. (2022). Metabolomics and network pharmacology in the exploration of the multi-targeted therapeutic approach of traditional medicinal plants. Plants, 11, 233243. https://doi.org/10.3390/plants11233243

Sperber, A. D., Dumitrascu, D., Fukudo, S., Gerson, C., Ghoshal, U. C., Gwee, K. A., Hungin, A. P. S., Kang, J. Y., Minhu, C., Schmulson, M., Bolotin, A., Friger, M., Freud, T., & Whitehead, W. (2017). The global prevalence of IBS in adults remains elusive due to the heterogeneity of studies: A Rome Foundation working team literature review. Gut, 66(6), 1075–1082. https://doi.org/10.1136/gutjnl-2015-311240

Stanford Medicine. (n.d.). Bristol stool – simple. Stanford Primary Care. https://med.stanford.edu/content/dam/sm/ppc/documents/General_Primary_Care/Bristol-stool---simple.pdf

Tan, Y. Q., Chen, H. W., Li, J., & Wu, Q. J. (2020). Efficacy, chemical constituents and pharmacological actions of Radix Paeoniae Rubra and Radix Paeoniae Alba. Frontiers in Pharmacology, 11, 1054. https://doi.org/10.3389/fphar.2020.01054

Wang, X., Ren, J., Zhang, A., Sun, H., Yan, G., Han, Y., & Liu, L. (2019). Novel applications of mass spectrometry-based metabolomics in herbal medicines and its active ingredients: Current evidence. Mass Spectrometry Reviews. https://doi.org/10.1002/mas.21589

Wu, K. 吳昆 (1368–1644 CE). Yi Fang Kao 《醫方考》 [Study of Medical Prescriptions].

Xu, C. 徐春甫 (1368–1644 CE). Gu Jin Yi Tong Da Quan 《古今醫統大全》 [Complete Collection of Medical Knowledge, Ancient and Modern].

Yan, W. L., Wang, S. S., & Ren, X. (2011). Modulatory effects of Rhizoma Atractylodis Macrocephalae on mouse gut microbiota. Journal of Traditional Chinese Medicine (Shandong), 30, 417–419.

Yang, S., Liu, H., Li, K., Chen, B., Tang, Y., Li, J., Wang, D., & Zhang, X. (2024). Research in revealing the effects on Cuscuta chinensis to diarrhea-type irritable bowel syndrome based on network pharmacology and molecular docking potential mechanism. Medicine, 103(19), e38113. https://doi.org/10.1097/MD.0000000000038113

Yin, Y., Zhong, L., Wang, J. W., Zhao, X. Y., Zhao, W. J., & Kuang, H. X. (2015). Tong Xie Yao Fang relieves irritable bowel syndrome in rats via mechanisms involving regulation of 5-hydroxytryptamine and substance P. World Journal of Gastroenterology, 21(15), 4536–4546. https://doi.org/10.3748/wjg.v21.i15.4536

Zhang, Z. 張仲景 (206 BCE–220 CE).  Jin Gui Yao Lue《金匱要略》 [Essential Prescriptions of the Golden Casket].

Zhou, Y. X., Zhang, H., & Peng, C. (2014). Puerarin: A review of pharmacological effects. Phytotherapy Research, 28(7), 961–975. https://doi.org/10.1002/ptr.5083

Zhu, D. 朱丹溪 (1271–1368 CE). Dan Xi Xin Fa 《丹溪心法》 [Danxi’s Heart Method].