JCS/CVIT/JCC 2023 guideline focused update on diagnosis and treatment of vasospastic angina (coronary spastic angina) and coronary microvascular dysfunction

Seiji Hokimoto, Koichi Kaikita, Satoshi Yasuda, Kenichi Tsujita, Masaharu Ishihara, Tetsuya Matoba, Yasushi Matsuzawa, Yoshiaki Mitsutake, Yoshihide Mitani, Toyoaki Murohara, Takashi Noda, Koichi Node, Teruo Noguchi, Hiroshi Suzuki, Jun Takahashi, Yasuhiko Tanabe, Atsushi Tanaka, Nobuhiro Tanaka, Hiroki Teragawa, Takanori Yasu, Michihiro Yoshimura, Yasuhide Asaumi, Shigeo Godo, Hiroki Ikenaga, Takahiro Imanaka, Kohei Ishibashi, Masanobu Ishii, Takayuki Ishihara, Yunosuke Matsuura, Hiroyuki Miura, Yasuhiro Nakano, Takayuki Ogawa, Takashi Shiroto, Hirofumi Soejima, Ryu Takagi, Akihito Tanaka, Atsushi Tanaka, Akira Taruya, Etsuko Tsuda, Kohei Wakabayashi, Kensuke Yokoi, Toru Minamino, Yoshihisa Nakagawa, Shozo Sueda, Hiroaki Shimokawa, Hisao Ogawa on behalf of the Japanese Circulation Society and Japanese Association of Cardiovascular Intervention and Therapeutics and Japanese College of Cardiology Joint Working Group. Guideline | Volume 82, ISSUE 4, P293-341, October 2023. DOI: https://doi.org/10.1016/j.jjcc.2023.06.009


In 2008, the Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) were developed by the Japanese Circulation Society, and the revised version was published in 2013. Since then, new findings from various fields such as coronary microvascular dysfunction (CMD), biomarkers, imaging, physiological functions, and genes have accumulated. Furthermore, together with the spread of emergency coronary angiography (CAG) for acute coronary syndrome (ACS) and the development of diagnostic techniques using high-sensitive troponin, the new concepts of myocardial infarction with non-obstructive coronary arteries (MINOCA) and ischemia with non-obstructive coronary artery disease (INOCA) have been proposed. The term “angina pectoris”, named in the mid-18th century, was extended to include variant forms in the 20th century, and as a result of advances in both invasive and noninvasive diagnostic techniques and pharmaco- or catheter therapy, the European Society of Cardiology (ESC) proposed the concept of chronic coronary syndrome (CCS), taking into account the need for ongoing risk management in the 21st century.

Coronary spasm, for which regional and racial differences have been noted, is not rare in Europe and the USA. The Coronary Vasomotion Disorders International Study (COVADIS) group, an international research group on coronary artery dysfunction, published criteria on vasospastic angina (VSA) in 2017, and microvascular angina (MVA) in 2018. In the case of MINOCA or INOCA, the importance of recognizing and considering functional abnormalities in the absence of organic lesions and without seeking noncardiac causes of chest symptoms is challenged.

This focused update is based on the Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (2013 revision), JCS 2018 Guideline on diagnosis and treatment of acute coronary syndrome, and JCS 2018 Guideline on diagnosis of chronic coronary heart diseases, while considering the position of coronary spasm, CMD, coronary microvascular spasm (MVS), and non-obstructive coronary artery disease (CAD) in the field of ischemic heart disease (IHD). Updates on the following topics have been provided.

  1. MINOCA and INOCA are described as new disease concepts related to coronary spasm.
  2. New findings on the pathophysiology, diagnosis, and treatment of coronary spasm have been added since the 2013 revision.
    1. For pathophysiology: aldehyde dehydrogenase 2 (ALDH2) gene polymorphism, coronary MVS, spasm after implantation of drug-eluting stents (DES), and pediatric diseases.
    2. For diagnosis: a review of the criteria, intravascular imaging such as intravascular ultrasound (IVUS), optical coherence tomography (OCT), and angioscopy, imaging such as computed tomography-derived fractional flow reserve (FFRCT) and magnetic resonance imaging (MRI), physiologic examinations such as coronary flow reserve (CFR), and index of microcirculatory resistance (IMR), and endothelial function tests.
    3. For treatment: pharmacotherapy, nonpharmacotherapy, and cardiovascular rehabilitation.
  3. The diagnostic criteria for diffuse coronary spasm as well as focal coronary spasm during coronary angiography (CAG) are added.
  4. The diagrams are designed to help the reader understand the relationship among epicardial coronary spasm, coronary MVS and MVA related to CMD (Fig. 4, Fig. 5).

Classes of recommendation and levels of evidence

In this focused update, recommendations and levels of evidence are classified in accordance with the updated JCS statement, encompassing the estimated benefit in proportion to risk (Table 1, Table 2).

Table 1: Classes of recommendation.

Class IThere is evidence and/or general agreement that a given procedure or treatment is effective and/or useful
Class IIaThere is a high probability of efficacy/usefulness based on evidence and opinion
Class IIbEffectiveness/usefulness is not well established based on evidence and opinion
Class III (No benefit)There is evidence and/or general agreement that the procedure or treatment is not effective and/or useful
Class III (Harm)There is evidence and/or general agreement that the procedure or treatment is harmful

Table 2: Levels of evidence.

Level ADemonstrated by multiple randomized clinical trials and/or meta-analyses
Level BDemonstrated by a single randomized clinical trial or large nonrandomized studies
Level CConsensus from expert opinion and/or small clinical trials (including retrospective studies and case series)

This focused update version was developed with the participation of 8 academic societies: The Japanese Circulation Society, Japanese College of Cardiology, Japanese Association of Cardiovascular Intervention and Therapeutics, Japanese Society of Pediatric Cardiology and Cardiac Surgery, Japanese Heart Rhythm Society, The Japanese Association of Cardiac Rehabilitation, The Japanese Coronary Association, and Japanese Association of Cardioangioscopy. Please note that the basic information is as in the 2013 revised edition, and that this is a focused update.

New disease concepts related to coronary spasm


Pathophysiology of MINOCA

Cases of acute myocardial infarction (AMI) without acute coronary occlusion or obstructive CAD have been reported, and in 2012, the term “MINOCA” was proposed to describe AMI without significant fixed stenosis (≥50%) in the epicardial coronary arteries on CAG. It became widely accepted, together with the technical innovation of medical treatment for myocardial infarction (MI) with CAD (MI-CAD). The establishment of a measurement system for highly sensitive myocardial troponin, capable of detecting even minute myocardial injury, the proposal of a Universal Definition of AMI based on myocardial troponin variation, the availability of routine emergency CAG for AMI and the widespread use of reperfusion therapy for ST-elevation MI have improved the prognosis of AMI patients. On the other hand, there are a certain number of cases of MI “without obstructive coronary arteries”, and cardiologists have faced more than a few cases of difficulty in diagnosing and treating them, and the challenging problem has become apparent.

The Fourth Universal Definition of Myocardial Infarction clearly stated that MI, which is based on acute myocardial ischemia such as atherosclerosis, thrombosis, or imbalance between oxygen demand and supply, is distinguished from myocardial injury, although both present an elevation of myocardial troponin above the 99th percentile of healthy individuals. Therefore, in diagnosing MINOCA, it is necessary to exclude myocardial injury of noncardiac cause (e.g., sepsis or renal dysfunction) or myocardial injury from cardiac causes other than CAD (e.g., myocarditis or cardiomyopathy) that present similar symptoms to ACS. However, because MINOCA is a “working diagnosis”, tentatively diagnosed by the absence of significant stenosis at the time of CAG, it is not always practical to exclude all myocardial injury due to nonischemic causes at the time of performing CAG. Thus, attention should be paid to whether MINOCA is being used as a “working diagnosis” or a final diagnosis. To avoid confusion, the term “troponin-positive non-obstructive coronary arteries” (TP-NOCA) has been proposed as a term for conditions presenting with elevated myocardial troponin, including myocardial injury of cardiac or noncardiac cause (Fig. 1). Importantly, MINOCA is considered as a “working diagnosis” at the time of CAG, as in the differential diagnosis of the cause of heart failure (HF), and differential diagnosis of the causes should be performed by using various modalities, as described in Chapter I.1.3.

Fig. 1 Relationship between TP-NOCA and MINOCA. ACh, acetylcholine; AMI, acute myocardial infarction; GTN, glyceryl trinitrate; MINOCA, myocardial infarction with non-obstructive coronary arteries; TP-NOCA, troponin-positive non-obstructive coronary arteries.

Potential causes of MINOCA are shown in Fig. 2. Main causes due to CAD include plaque rupture/erosion, coronary artery spasm, CMD, coronary MVS, coronary artery dissection, and coronary artery embolism. Main causes due to non-CAD include myocarditis, takotsubo syndrome, cardiomyopathy, congenital coagulation abnormalities, pulmonary thromboembolism, and sepsis. Initially, MINOCA is a “working diagnosis”, then non-coronary causes and differentiation of causes due to CAD, such as coronary spasm, are excluded. However, in daily practice, these might not be clearly distinguished and overlap with some other pathological conditions. The etiology of coronary embolism, one of the causes of MINOCA, is mainly atrial fibrillation (AF), but septic emboli due to infective endocarditis or paradoxical embolism due to deep vein thrombosis may also occur. The possibility of concurrent non-CAD should be considered. In addition, it has been reported that in some cases are coronary spasm induced by pharmacological provocation testing in patients presenting with transient left ventricular dysfunction such as takotsubo syndrome. Therefore, in the clinical practice for MINOCA management, cardiologists and physicians should scrutinize for overlapping single or multiple etiologies and consider treatment according to the etiology.

Fig. 2 Plausible causes of MINOCA. MINOCA, myocardial infarction with non-obstructive coronary arteries; TP-NOCA, troponin-positive non-obstructive coronary arteries. (Adapted from Pasupathy S, et al. 2016, 2017.)


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Authors: Seiji Hokimoto,Koichi Kaikita,Satoshi Yasuda,Kenichi Tsujita,Masaharu Ishihara,Tetsuya Matoba,Yasushi Matsuzawa,Yoshiaki Mitsutake,Yoshihide Mitani,Toyoaki Murohara,Takashi Noda,Koichi Node,Teruo Noguchi,Hiroshi Suzuki,Jun Takahashi,Yasuhiko Tanabe et al.

Publication: Journal of Cardiology

Publisher: Elsevier

Date published: October 2023


Copyright © 2023, Japanese College of Cardiology. Published by Elsevier Ltd.

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