About this research group

Greetings from the representative organizer

Representative of the Japanese Society for Coronary Microcirculatory Disorders (J-CMD)
Professor Emeritus and Visiting Professor at Tohoku University
Specially Appointed Professor at International University of Health and Welfare
Hiroaki Shimokawa, MD, PhD.

On behalf of the Japanese Association of Coronary Microvascular Dysfunction (J-CMD), I would like to extend my greetings

Regarding the important coronary artery spasm, which is a key factor in the pathogenesis of ischemic heart disease in Japanese individuals, I have served as the representative and, from 2006 to 2021—totaling 15 years (five years × three terms)—conducted academic activities under the auspices of the Japan Heart Foundation as the leader of the "Coronary Spasm Study Group." This research group involved participation from 85 facilities nationwide, conducting large-scale registry studies, publishing numerous papers (references 1–8), and presenting at academic conferences, thereby engaging in active scholarly activities.

Internationally, in 2012, a group of ten researchers interested in coronary vasomotor disorders established the "Coronary Vasomotor Disorders International Study Group (COVADIS)" (URL: https://covadis.online/).I was one of the founding members and have been actively involved in its activities (references 9–18). Among these efforts was the proposal of diagnostic criteria for microvascular angina (MVA) (reference 15). Notably, among the ten founding members are Professor Filippo Crea, currently Editor-in-Chief of the European Heart Journal, and Professor Paolo Camici, Editor-in-Chief of the International Journal of Cardiology.

Ischemic heart disease is classified into acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). The mechanisms underlying CCS include: 1) stenosis or occlusion of large coronary arteries, 2) coronary artery spasm, and 3) coronary microvascular dysfunction (see Figures 1 and 2). The latter two are collectively referred to as Ischemia with No Obstructive Coronary Artery Disease (INOCA) (see Figure 3). An important point is that these three mechanisms often coexist in the same patient in varying proportions (see Figure 3). Furthermore, the pathogenesis of coronary microvascular dysfunction involves two mechanisms: increased vasoconstrictive ability and decreased vasodilatory capacity (see Figure 4). Our research has revealed that these two mechanisms also coexist in varying proportions within the same patient (see Figure 5). Importantly, the prognosis is poorest when both large coronary artery abnormalities and microvascular dysfunction are present simultaneously (see Figure 6).

From 2015 to 2019, primarily at COVADIS facilities, a total of 14 facilities across seven countries participated in a multicenter prospective registration study on microvascular angina (MVA), with myself serving as the principal investigator (Figure 7). As a result, it was revealed that patients registered based on COVADIS's strict diagnostic criteria for MVA experienced a significant rate of major cardiovascular events (MACE) at 7.7% per year, predominantly due to unstable angina. Additionally, long-term prognosis analyses, after adjusting for clinical background factors, showed no significant differences based on sex or race, indicating that MVA is an important pathological condition (References 1,10).
These findings were comparable to the annual MACE incidence rate of approximately 5% reported in the ISCHEMIA Study published in the New England Journal of Medicine in 2000 (Figure 8). In response, the European Society of Cardiology (ESC) issued a press release simultaneously with the publication of this paper, emphasizing that "coronary microvascular dysfunction is a significant global health issue" (Figure 9).

As mentioned above, the importance of coronary microcirculatory disorders is increasingly recognized worldwide. However, awareness in clinical practice remains insufficient, and in Japan, tests for coronary microcirculatory disorders are only conducted at limited facilities. Consequently, many patients across the country suffer without receiving an accurate diagnosis.

Based on these medical and social backgrounds, we aim to further develop the "Coronary Spasm Study Group" into the "Japan Coronary Microcirculatory Disorder Research Society." Our goal is to continue research and to enhance the understanding of this condition within the medical community and society at large.

Moving forward, this society will strive to disseminate information through our website and activities, and we plan to conduct prospective registration studies on microvascular angina to further accumulate evidence specific to the Japanese population.

We sincerely appreciate your understanding and support.

Research Paper Presented by the Coronary Spasm Research Group

1.Shimokawa H, Suda A, Takahashi J, Berry C, Camici PG, Crea F, Escaned J, Ford T, Yii E, Kaski JC, Kiyooka T, Mehta PK, Ong P, Ozaki Y, Pepine C, Rimoldi O, Safdar B, Sechtem U, Tsujita K, Yasuda S, Beltrame JF, Merz CNB; the Coronary Vasomotor Disorders International Study (COVADIS) Group. Clinical characteristics and prognosis of patients with microvascular angina -An international and prospective cohort study by the Coronary Vasomotor Disorders International Study (COVADIS) Group-　Eur Heart J. 2021;42: 4592-4600.

2.Mori H, Takahashi J, Sato K, Miyata S, Takagi Y, Tsunoda R, Sumiyoshi T, Matsui M, Tanabe Y, Sueda S, Momomura S, Kaikita K, Yasuda S, Ogawa H, Shimokawa H, Suzuki H; Japanese Coronary Spasm Association. The impact of antiplatelet therapy on patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association. Int J Cardiol Heart Vasc. 2020 Jun 9;29:100561. doi: 10.1016/j.ijcha.2020.100561.

3.Sato K, Takahashi J, Odaka Y, Suda A, Sueda S, Teragawa H, Ishii K, Kiyooka T, Hirayama A, Sumiyoshi T, Tanabe Y, Kimura K, Kaikita K, Ong P, Sechtem U, Camici PG, Kaski JC, Crea F, Beltrame JF, Shimokawa H; Japanese Coronary Spasm Association. Clinical characteristics and long-term prognosis of contemporary patients with vasospastic angina: Ethnic differences detected in an international comparative study. Int J Cardiol. 2019;291:13-18.

4.Takahashi J, Nihei T, Takagi Y, Miyata S, Odaka Y, Tsunoda R, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Momomura S, Yasuda S, Ogawa H, Shimokawa H; Japanese Coronary Spasm Association. Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicenter registry study of the Japanese coronary spasm association. Eur Heart J. 2015;36:228-37.

5.Takagi Y, Takahashi J, Yasuda S, Miyata S, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H; Japanese Coronary Spasm Association. Prognostic stratification of patients with vasospastic angina: a comprehensive clinical risk score developed by the Japanese Coronary Spasm Association. J Am Coll Cardiol. 2013;62:1144-53.

6.Kawana A, Takahashi J, Takagi Y, Yasuda S, Sakata Y, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Kubo N, Momomura S, Ogawa H, Shimokawa H; Japanese Coronary Spasm Association. Gender diff erences in the clinical characteristics and outcomes of patients with vasospastic angina. Circ J. 2013;77:1267-74.

7.Takagi Y, Yasuda S, Takahashi J, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H; Japanese Coronary Spasm Association. Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: Multicentre Registry Study of the Japanese Coronary Spasm Association. Eur Heart J 2013;34:258-67.

8.Takagi Y, Yasuda S, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H; Japanese Coronary Spasm Association. Clinical characteristics and long-term prognosis of vasospastic angina patients who survived out-of hospital cardiac arrest: multicenter registry study of the Japanese Coronary Spasm Association. Circ Arrhythm Electrophysiol 2011;4:295-302.

Research paper published by COVADIS

9.Bairey Merz CN, Beltrame JF, Berry C, Boden WE, Camici PE, Crea F, Hochman JS, Kaski JC, O’Gara PT, Ong P, Pepine CJ, Shimokawa H, Sechtem U, Stone GW.
Insights to advance our management of myocardial ischemia: From obstructive epicardial disease to functional coronary alterations Am Heart J Plus. Published Online 8 October 2021.

10.Shimokawa H, Suda A, Takahashi J, Berry C, Camici PG, Crea FE, Ford T, Yii E, Kaski JC, Kiyooka T, Mehta PK, Ong P, Ozaki Y, Pepine C, Rimoldi O, Safdar B, Sechtem U, Tsujita K, Beltrame JF, Bairey Merz CN. Clinical characteristics and prognosis of patients with microvascular angina: an international and prospective cohort study by the Coronary Vasomotor Disorders International Study (COVADIS) Group Eur Heart J. 2021;42: 4592-4600.

11.Suda A, Takahashi J, Beltrame JF, Berry C, Camici PG, Crea F, Escaned J, Ford T, Carlos Kaski J, Kiyooka T, Metha PK, Ong P, Ozaki Y, Pepine C, Rimoldi O, Safdar B, Sechtem U, Tsujita K, Yii E, Bairey Merz CN, Shimokawa H. International prospective cohort study of microvascular angina – Rationale and design Int J Cardiol Heart Vasc. 2020 31:100630.

12.Ford TJ, Ong P, Sechtem U, Beltrame J, Camici PG, Crea F, Kaski JC, Bairey Merz CN, Pepine CJ, Shimokawa H, Berry C. Assessment of Vascular Dysfunction in Patients Without Obstructive Coronary Artery Disease: Why, How, and When. JACC Cardiovasc Interv JACC Cardiovasc Interv. 2020;13(16):1847-1864.

13.Crea F, Bairey Merz CN, Beltrame JF, Berry C, Camici PG, Kaski JC, Ong P, Pepine CJ, Sechtem U, Shimokawa H. Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization Eur Heart J. 2019;40(29):2455-2462.

14.Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U, Kaski JC, Bairey Merz CN, Coronary Vasomotion Disorders International Study Group (COVADIS). Response to letter from Picichè: The microvascular network connecting extracardiac arteries to the heart. Int J Cardiol. 2018 15;259:56.

15.Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U, Kaski JC, Bairey Merz CN. Coronary Vasomotion Disorders International Study Group (COVADIS).
International standardization of diagnostic criteria for microvascular angina.
Int J Cardiol. 2018 250:16-20.

16.Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Bairey Merz CN. The Who, What, Why, When, How and Where of Vasospastic Angina
Circ J. 2016 80 (2): 289-298.

17.Crea F, Bairey Merz CN, Beltrame JF, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Camici PG. The parallel tales of microvascular angina and heart failure with preserved ejection fraction: a paradigm shift Eur Heart J. 2016;38 (7): 473–477.

18.Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Bairey Merz CN, On Behalf of the Coronary Vasomotion Disorders International Study Group (COVADIS). International standardization of diagnostic criteria for vasospastic angina Eur Heart J. 2015;38 (33): 2565–2568.