Objective There are no comparative studies on provoked coronary microvascular spasm (CMS) in patients undergoing both acetylcholine (ACh) and ergonovine (EM) vasoreactivity testing. We investigated the incidence of provoked CMS in patients with ischemia with nonobstructive coronary artery disease (INOCA) undergoing ACh and EM vasoreactivity testing. Methods We recruited 494 INOCA patients who underwent both ACh and EM vasoreactivity testing. ACh was injected at incremental doses of 20/50/100/200 μg into the left coronary artery (LCA) and 20/50/80 μg into the right coronary artery (RCA), whereas 40 μg of EM was administered into the RCA and 64 μg into the LCA. Positive CMS was defined as <75% transient coronary constriction, accompanied by typical chest symptoms or ischemic ECG changes. Results Among the 494 patients, CMS was observed in 23 (4.7%) patients. Eighteen patients had CMS alone, and 5 patients had coexisting epicardial spasm. The ACh test alone, EM test alone, and both tests provoked CMSs in 12 patients, 7 patients, and 4 patients, respectively. There were no marked differences in incidence between ACh- and EM-induced CMS (70% vs. 48%, p=0.2307). Conclusion Differences were observed between ACh-induced CMS and EM-induced CMS. The complementary use of vasoreactivity testing is essential for accurately documenting the presence of CMS in real-world settings.

The Japanese Circulation Society guidelines recommend a class I vasoreactivity test to diagnose patients with vasospastic angina (VSA). However, the acetylcholine or ergonovine test has been established as the gold standard for variant angina (VA). The sensitivity and specificity of intracoronary vasoreactivity testing in patients with VA were acceptable. Cardiologists have employed these vasoreactivity tests to conveniently diagnose the presence of coronary spasms in patients with all VSA. The majority of VSAs may have lower disease activity than VA cases. We have summarized the usefulness of spasm provocation tests in patients with VA and VSA. A positive-provoked spasm diagnosed by standard vasoreactivity testing may indicate a disease state similar to that of VA, whereas a negative-provoked spasm after standard vasoreactivity testing may indicate a lower disease state than that of VA. Cardiologists should reconsider the limited usefulness of vasoreactivity testing when diagnosing the presence of coronary spasms in all VSAs, but not VA.

BACKGROUND:Vasoreactivity testing, such as intracoronary acetylcholine (ACh) or ergometrine (EM), is defined as Class I for the diagnosis of patients with vasospastic angina (VSA) according to recommendations from the Coronary Vasomotion Disorders International Study (COVADIS) group and guidelines from the Japanese Circulation Society (JCS). HYPOTHESIS:Although vasoreactivity testing is a clinically useful tool, it carries some risks and limitations in diagnosing coronary artery spasm. METHODS:Previous reports on vasoreactivity testing for diagnosing the presence of coronary spasm are summarized from the perspective of Class I. RESULTS:There are several problems such as reproducibility, underestimation, overestimation, and inconclusive/nonspecific results associated with daily spasm. Because provoked spasm caused by intracoronary ACh is not always similar to that caused by intracoronary EM, possibly due to different mediators, supplementary use of these vasoreactivity tests is necessary for cardiologists to diagnose VSA when a provoked spasm is not revealed by each vasoactive agent. CONCLUSIONS:Cardiologists should understand the imperfection of these vasoreactivity tests when diagnosing patients with VSA.

Intracoronary acetylcholine (ACH) testing is clinically useful to diagnose the presence of the coronary vasomotor disorders coronary endothelial dysfunction and coronary epicardial/microvascular spasm. In Western countries, continuous intracoronary injection of ACH for 2–3 minutes without a pacemaker is the usual method, while rapid injection of ACH for 20–30 seconds with a pacemaker is the traditional procedure in Japan. Coronary microvascular spasm is often observed in Western populations, whereas coronary epicardial spasm is frequently seen in Japanese subjects. Methodological differences between Western and Japanese protocols may lead to the opposite prevalence of coronary vasomotor disorders. This article discusses the optimal method for diagnosing endothelial dysfunction and epicardial/microvascular spasm based on previous reports, and compares intracoronary ACH testing performed by Western cardiologists with that by Japanese physicians.

OBJECTIVES:We retrospectively analyzed the usefulness and safety of intracoronary acetylcholine (ACh) 200 μg into the left coronary artery (LCA) as vasoreactivity testing compared with intracoronary ACh 100 μg. METHODS:We recruited 1433 patients who had angina-like chest pain and intracoronary ACh testing in the LCA, including 1234 patients with a maximum ACh 100 μg and 199 patients with a maximum ACh 200 μg. ACh was injected in incremental doses of 20/50/100/200 μg into the LCA. Positive spasm was defined as ≥ 90% stenosis, usual chest pain, and ischemic electrocardiogram (ECG) changes. RESULTS:The incidence of coronary constriction ≥ 90%, usual chest pain, and ischemic ECG changes with a maximum ACh of 100 μg was markedly higher than that with a maximum ACh of 200 μg. The frequency of unusual chest pain in patients with a maximum ACh of 200 μg was higher than that in those with a maximum ACh of 100 μg (13% vs. 3%, p < 0.001). In patients with rest angina, positive spasm of maximum ACh 100 μg was significantly higher than that of maximum ACh 200 μg, whereas there was no difference regarding positive spasm in patients with atypical chest pain between the two ACh doses. Major complications (1.38% vs. 1.51%, p = 0.8565) and the occurrence of paroxysmal atrial fibrillation (1.81% vs. 2.63%, p = 0.6307) during ACh testing in the LCA were not different between the two maximum ACH doses. CONCLUSIONS:Intracoronary ACh 200 μg into the LCA is clinically useful and safe for vasoreactivity testing when intracoronary ACh 100 μg dose not provoke spasms.

Coronary artery epicardial spasm is involved in the pathogenesis of many cardiac disorders. Vasoreactivity testing, such as intracoronary injection of acetylcholine (ACH) or ergonovine (ER), is the gold standard method for the diagnosis of vasospastic angina. Provoked epicardial spasm phenotypes are classified as focal spasm and diffuse spasm. Multiple factors, including sex, ethnicity, and use of coronary vasoactive stimulators, are related to the provoked phenotypes of epicardial spasm. Diffuse-provoked spasm is often observed in females, where focal-provoked spasm is markedly more common in males. ACH provokes more diffuse and distal spasms, whereas ER induces more focal and proximal spasms. Yellow plaque and coronary thrombi are often observed in lesions with focal spasms, and intimal thickness with a sonolucent zone is significantly more common in lesions with focal spasm. Furthermore, clinical outcomes in patients with focal spasm are unsatisfactory compared with those in patients with diffuse spasm. However, the reproducibility and eternality of provoked spasm phenotypes by vasoreactivity testing is uncertain. Coronary atherosclerosis or endothelial damage may affect coronary vasomotor tone. Although coronary artery spasm may persist in the same coronary artery, provoked coronary spasm phenotypes may exhibit a momentary coronary reaction by intracoronary ACH or ER testing.

Objectives There are few reports regarding the prognosis in patients with obstructive coronary artery disease (OCAD) and vasospastic angina (VSA). This study investigated the clinical characteristics and clinical outcomes in patients with VSA and OCAD, especially regarding provoked spasm phenotypes and sites. Methods This was a retrospective, observational, single-center study of 403 patients with typical or atypical angina-like chest pain undergoing acetylcholine (ACH) spasm provocation testing and OCAD. An obstructed coronary artery was defined as ≥50% luminal narrowing. We defined positive epicardial spasm as ≥90% transient stenosis and usual chest symptoms or ischemic ECG changes. Results Among these 403 patients with OCAD, positive spasm by intracoronary ACH testing was observed in 196 patients (49%), whereas negative spasm was found in the remaining 207 patients (51%). The clinical outcomes in the patients with OCAD and provoked spasm were not different according to the provoked-spasm phenotypes. Furthermore, the clinical outcomes were unsatisfactory in the patients with spasm at the site of nonobstructive lesion alone compared with those with spasm at the site of obstructive and nonobstructive lesions. Conclusion We should precisely diagnose patients with OCAD who have provoked spasm by using intracoronary ACH testing and medicate the nonobstructive vessels in patients with OCAD and VSA under optimal coronary vasodilators.

Vasoreactivity testing is used by cardiologists in the diagnosis of coronary spasm endotypes, such as epicardial and microvascular spasm. Intracoronary injection of acetylcholine and ergonovine is defined as a standard class I method according to the Coronary Vasomotion Disorder (COVADIS) Group. Because single vasoreactivity testing may have some clinical limitations in detecting the presence of coronary spasm, supplementary or sequential vasoreactivity testing should be reconsidered. The majority of cardiologists do not consider pseudonegative results when performing these vasoreactivity tests. Vasoreactivity testing may have some limitations when it comes to documenting clinical spasm. In the future, cardiologists around the world should use multiple vasoreactivity tests to verify the presence or absence of epicardial and microvascular spasms in the cardiac catheterisation laboratory.

In 2008, the Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) [[1]JCS Joint Working Group Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008): digest version.Circ J. 2010; 74: 1745-1762Crossref PubMed Scopus (231) Google Scholar] were developed by the Japanese Circulation Society, and the revised version was published in 2013 [[2]JCS Joint Working Group Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2013): digest version.Circ J. 2014; 78: 2779-2801Crossref PubMed Google Scholar]. 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 [[3]Bairey Merz C.N. Pepine C.J. Walsh M.N. Fleg J.L. Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing evidence-based therapies and research agenda for the next decade.Circulation. 2017; 135: 1075-1092Crossref PubMed Scopus (438) Google Scholar,[4]Beltrame J.F. Assessing patients with myocardial infarction and nonobstructed coronary arteries (MINOCA).J Intern Med. 2013; 273: 182-185Crossref PubMed Scopus (87) Google Scholar]. The term “angina pectoris”, named in the mid-18th century, was extended to include variant forms [[5]Prinzmetal M. Kennamer R. Merliss R. Wada T. Bor N. Angina pectoris. I. A variant form of angina pectoris: preliminary report.Am J Med. 1959; 27: 375-388Abstract Full Text PDF PubMed Google Scholar] 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 [[6]Knuuti J. Wijns W. Saraste A. Capodanno D. Barbato E. Funck-Brentano C. et al.2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes: the task force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC).Eur Heart J. 2020; 41: 407-477Crossref PubMed Scopus (3299) Google Scholar]. Coronary spasm, for which regional and racial differences have been noted, is not rare in Europe and the USA [[7]Yasue H. Nakagawa H. Itoh T. Harada E. Mizuno Y. 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This focused update is based on the Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (2013 revision) [[2]JCS Joint Working Group Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2013): digest version.Circ J. 2014; 78: 2779-2801Crossref PubMed Google Scholar], JCS 2018 Guideline on diagnosis and treatment of acute coronary syndrome [[17]JCS Joint Working Group JCS 2018 guideline on diagnosis and treatment of acute coronary syndrome.Circ J. 2019; 83: 1085-1196Google Scholar], and JCS 2018 Guideline on diagnosis of chronic coronary heart diseases [[18]JCS Working Group JCS 2018 guideline on diagnosis of chronic coronary heart diseases.Circ J. 2021; 85: 402-572Google Scholar], 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). 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 1Classes of recommendation.Class IThere is evidence and/or general agreement that a given procedure or treatment is effective and/or usefulClass IIaThere is a high probability of efficacy/usefulness based on evidence and opinionClass IIbEffectiveness/usefulness is not well established based on evidence and opinionClass III (No benefit)There is evidence and/or general agreement that the procedure or treatment is not effective and/or usefulClass III (Harm)There is evidence and/or general agreement that the procedure or treatment is harmful Open table in a new tab Table 2Levels of evidence.Level ADemonstrated by multiple randomized clinical trials and/or meta-analysesLevel BDemonstrated by a single randomized clinical trial or large nonrandomized studiesLevel CConsensus from expert opinion and/or small clinical trials (including retrospective studies and case series) Open table in a new tab 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. Cases of acute myocardial infarction (AMI) without acute coronary occlusion or obstructive CAD have been reported [[19]Gross H. Steinberg W.H. Myocardial infarction without significant lesions of coronary arteries.Arch Intern Med (Chic). 1939; 64: 249-267Crossref Google Scholar,[20]Miller R.D. Burchell H.B. Edwards J.E. Myocardial infarction with and without acute coronary occlusion: a pathologic study.AMA Arch Intern Med. 1951; 88: 597-604Crossref PubMed Scopus (0) Google Scholar], and in 2012, the term “MINOCA” was proposed to describe AMI without significant fixed stenosis (≥50%) in the epicardial coronary arteries on CAG [[4]Beltrame J.F. Assessing patients with myocardial infarction and nonobstructed coronary arteries (MINOCA).J Intern Med. 2013; 273: 182-185Crossref PubMed Scopus (87) Google Scholar]. 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 [[21]Thygesen K. Alpert J.S. Jaffe A.S. Chaitman B.R. Bax J.J. Morrow D.A. et al.Fourth universal definition of myocardial infarction (2018).Circulation. 2018; 138: e618-e651Crossref PubMed Scopus (1426) Google Scholar], 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 [[21]Thygesen K. Alpert J.S. Jaffe A.S. Chaitman B.R. Bax J.J. Morrow D.A. et al.Fourth universal definition of myocardial infarction (2018).Circulation. 2018; 138: e618-e651Crossref PubMed Scopus (1426) Google Scholar]. 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 [22Pasupathy S. Tavella R. Beltrame J.F. The what, when, who, why, how and where of myocardial infarction with non-obstructive coronary arteries (MINOCA).Circ J. 2016; 80: 11-16Crossref PubMed Scopus (56) Google Scholar, 23Agewall S. Beltrame J.F. Reynolds H.R. Niessner A. Rosano G. Caforio A.L. et al.Working Group on Cardiovascular Pharmacotherapy. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries.Eur Heart J. 2017; 38: 143-153PubMed Google Scholar, 24Tamis-Holland J.E. Jneid H. Reynolds H.R. Agewall S. Brilakis E.S. Brown T.M. et al.Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association.Circulation. 2019; 139: e891-e908Crossref PubMed Scopus (443) Google Scholar], 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 [[25]Pasupathy S. Tavella R. Beltrame J.F. Myocardial infarction with nonobstructive coronary arteries (MINOCA): the past, present, and future management.Circulation. 2017; 135: 1490-1493Crossref PubMed Scopus (124) Google Scholar] (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. Potential causes of MINOCA are shown in Fig. 2 [[22]Pasupathy S. Tavella R. Beltrame J.F. The what, when, who, why, how and where of myocardial infarction with non-obstructive coronary arteries (MINOCA).Circ J. 2016; 80: 11-16Crossref PubMed Scopus (56) Google Scholar,[25]Pasupathy S. Tavella R. Beltrame J.F. Myocardial infarction with nonobstructive coronary arteries (MINOCA): the past, present, and future management.Circulation. 2017; 135: 1490-1493Crossref PubMed Scopus (124) Google Scholar]. Main causes due to CAD include plaque rupture/erosion, coronary artery spasm, CMD, coronary MVS, coronary artery dissection, and coronary artery embolism [[22]Pasupathy S. Tavella R. Beltrame J.F. The what, when, who, why, how and where of myocardial infarction with non-obstructive coronary arteries (MINOCA).Circ J. 2016; 80: 11-16Crossref PubMed Scopus (56) Google Scholar,24Tamis-Holland J.E. Jneid H. Reynolds H.R. Agewall S. Brilakis E.S. Brown T.M. et al.Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association.Circulation. 2019; 139: e891-e908Crossref PubMed Scopus (443) Google Scholar, 25Pasupathy S. Tavella R. Beltrame J.F. Myocardial infarction with nonobstructive coronary arteries (MINOCA): the past, present, and future management.Circulation. 2017; 135: 1490-1493Crossref PubMed Scopus (124) Google Scholar, 26Shibata T. Kawakami S. Noguchi T. Tanaka T. Asaumi Y. Kanaya T. et al.Prevalence, clinical features, and prognosis of acute myocardial infarction attributable to coronary artery embolism.Circulation. 2015; 132: 241-250Crossref PubMed Scopus (196) Google Scholar]. 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 [[27]Lindahl B. Baron T. Albertucci M. Prati F. Myocardial infarction with non-obstructive coronary artery disease.EuroIntervention. 2021; 17: e875-e887Crossref PubMed Scopus (6) Google Scholar]. 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 [[26]Shibata T. Kawakami S. Noguchi T. Tanaka T. Asaumi Y. Kanaya T. et al.Prevalence, clinical features, and prognosis of acute myocardial infarction attributable to coronary artery embolism.Circulation. 2015; 132: 241-250Crossref PubMed Scopus (196) Google Scholar]. 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 [[28]Dote K. Sato H. Tateishi H. Uchida T. Ishihara M. Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. [in Japanese].J Cardiol. 1991; 21: 203-214PubMed Google Scholar,[29]Tsuchihashi K. Ueshima K. Uchida T. Oh-mura N. Kimura K. Owa M. et al.Angina Pectoris-Myocardial Infarction Investigations in Japan. Transient left ventricular apical ballooning without coronary artery stenosis: A novel heart syndrome mimicking acute myocardial infarction: Angina Pectoris-Myocardial Infarction Investigations in Japan.J Am Coll Cardiol. 2001; 38: 11-18Crossref PubMed Scopus (0) Google Scholar]. 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. Coronary spasm involves hypercontraction based on a hyperactivity of the Rho-kinase pathway in vascular smooth muscle cells (VSMCs) [[30]Shimokawa H. Seto M. Katsumata N. Amano M. Kozai T. Yamawaki T. et al.Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm.Cardiovasc Res. 1999; 43: 1029-1039Crossref PubMed Scopus (282) Google Scholar], endothelial dysfunction due to decreased production of nitric oxide (NO) by the vascular endothelium [[31]Kugiyama K. Yasue H. Okumura K. Ogawa H. Fujimoto K. Nakao K. et al.Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina.Circulation. 1996; 94: 266-271Crossref PubMed Google Scholar], inflammation of the vascular adventitia and perivascular adipose tissue [[32]Ohyama K. Matsumoto Y. Takanami K. Ota H. Nishimiya K. Sugisawa J. et al.Coronary adventitial and perivascular adipose tissue inflammation in patients with vasospastic angina.J Am Coll Cardiol. 2018; 71: 414-425Crossref PubMed Scopus (116) Google Scholar], and increases in localized contraction of coronary arteries, resulting in decreased coronary blood flow and subsequent myocardial ischemia. Coronary spasm also leads to increases in coagulation [[33]Oshima S. Yasue H. Ogawa H. Okumura K. Matsuyama K. Fibrinopeptide A is released into the coronary circulation after coronary spasm.Circulation. 1990; 82: 2222-2225Crossref PubMed Scopus (66) Google Scholar], decreases in fibrinolytic activity [[34]Misumi I. Ogawa H. Masuda T. Sakamoto T. Okumura K. Yasue H. Increased plasma plasminogen activator inhibitor activity after coronary spasm.Int J Cardiol. 1993; 41: 21-29Abstract Full Text PDF PubMed Scopus (13) Google Scholar], and promotion of platelet activation and release of adhesion molecules [[35]Kaikita K. Ogawa H. Yasue H. Sakamoto T. Suefuji H. Sumida H. et al.Soluble P-selectin is released into the coronary circulation after coronary spasm.Circulation. 1995; 92: 1726-1730Crossref PubMed Scopus (88) Google Scholar], resulting in a thrombogenic state. A previous study using intravascular imaging investigated thrombus formation due to coronary spasm; the researchers observed the site of coronary spasm with OCT and found thrombus in 28% of coronary spasm sites or their proximal lesion, and plaque erosion with thrombus in 26% [[36]Shin E.S. Ann S.H. Singh G.B. Lim K.H. Yoon H.J. Hur S.H. et al.OCT-defined morphological characteristics of coronary artery spasm sites in vasospastic angina.JACC Cardiovasc Imaging. 2015; 8: 1059-1067Crossref PubMed Scopus (71) Google Scholar]. Another prospective observational study comparing OCT findings in vessels responsible for ACS due to coronary spasm and coronary spastic angina (CSA) reported that coronary spasm-induced ACS had more frequency of plaque erosion (69% vs. 27%), intimal tears (46% vs. 7%), and thrombus formation (28% vs. 5%) than CSA [[37]Park H.C. Shin J.H. Jeong W.K. Choi S.I. Kim S.G. Comparison of morphologic findings obtained by optical coherence tomography in acute coronary syndrome caused by vasospasm and chronic stable variant angina.Int J Cardiovasc Imaging. 2015; 31: 229-237Crossref PubMed Scopus (23) Google Scholar]. Based on these OCT studies and autopsy studies [[38]Lin C.S. Penha P.D. Zak F.G. Lin J.C. Morphodynamic interpretation of acute coronary thrombosis, with special reference to volcano-like eruption of atheromatous plaque caused by coronary artery spasm.Angiology. 1988; 39: 535-547Crossref PubMed Google Scholar], it is assumed that one of the mechanisms of vulnerable plaque rupture in ACS might be rupture of the fibrous capsule at the plaque surface and the protrusion of plaque contents into the vessel due to mechanical stress caused by coronary spasm, resulting in thrombus formation. In spontaneous coronary artery dissection (SCAD), another cause of MINOCA, the involvement of coronary spasm in the pathogenesis of coronary artery dissection has been reported [[39]Tsujita K. Miyazaki T. Kaikita K. Chitose T. Takaoka N. Soejima H. et al.Premenopausal woman with acute myocardial infarction caused by spontaneous coronary artery dissection and potential association with coronary vasospasm.Cardiovasc Interv Ther. 2012; 27: 121-126Crossref PubMed Scopus (6) Google Scholar,[40]Mori R. Macaya F. Escaned J. Mejía-Rentería H. Endothelial dysfunction and epicardial coronary spasm in a woman with previous spontaneous coronary artery dissection.JACC Cardiovasc Interv. 2020; 13: e219-e220Google Scholar]. On the other hand, a retrospective study comparing 10 patients with SCAD with a control group after performing an acetylcholine (ACh) provocation testing and measurement of CFR showed no involvement of coronary spasm or CMD in coronary artery dissection [[41]Waterbury T.M. Tweet M.S. Hayes S.N. Prasad A. Lerman A. Gulati R. Coronary endothelial function and spontaneous coronary artery dissection.Eur Heart J Acute Cardiovasc Care. 2020; 9: 90-95Crossref PubMed Google Scholar]. The association between coronary artery dissection and coronary spasm in MINOCA should be investigated in future large, prospective studies. Another single-center prospective observational study investigating the association between myocardial bridging, coronary spasm, and MINOCA reported that ACh-induced coronary spasm was a high risk for MINOCA in patients with myocardial bridge [[42]Montone R.A. Gurgoglione F.L. Del Buono M.G. Rinaldi R. Meucci M.C. Iannaccone G. et al.Interplay between myocardial bridging and coronary spasm in patients with myocardial ischemia and non-obstructive coronary arteries: pathogenic and prognostic implications.J Am Heart Assoc. 2021; 10e020535Crossref PubMed Scopus (35) Google Scholar], but not in patients without it, suggesting that myocardial bridge may be a cause of MINOCA and that coronary spasm may be involved in the pathogenesis of MINOCA due to myocardial bridge. We summarized previous reports from Japan and abroad regarding the epidemiology of coronary spasm and MINOCA [43Pasupathy S. Air T. Dreyer R.P. Tavella R. Beltrame J.F. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.Circulation. 2015; 131: 861-870Crossref PubMed Google Scholar, 44Smilowitz N.R. Mahajan A.M. Roe M.T. Hellkamp A.S. Chiswell K. Gulati M. et al.Mortality of myocardial infarction by sex, age, and obstructive coronary artery disease status in the ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines).Circ Cardiovasc Qual Outcomes. 2017; 10e003443Crossref PubMed Scopus (194) Google Scholar, 45Lindahl B. Baron T. Erlinge D. Hadziosmanovic N. Nordenskjöld A. Gard A. et al.Medical therapy for secondary prevention and long-term outcome in patients with myocardial infarction with nonobstructive coronary artery disease.Circulation. 2017; 135: 1481-1489Crossref PubMed Scopus (273) Google Scholar, 46Montone R.A. Niccoli G. Fracassi F. Russo M. Gurgoglione F. Cammà G. et al.Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests.Eur Heart J. 2018; 39: 91-98PubMed Google Scholar, 47Safdar B. Spatz E.S. Dreyer R.P. Beltrame J.F. Lichtman J.H. Spertus J.A. et al.Presentation, clinical profile, and prognosis of young patients with Myocardial Infarction With Nonobstructive Coronary Arteries (MINOCA): results from the VIRGO Study.J Am Heart Assoc. 2018; 7e009174Crossref PubMed Scopus (223) Google Scholar, 48Choo E.H. Chang K. Lee K.Y. Lee D. Kim J.G. Ahn Y. et al.KAMIR - NIH Investigators. Prognosis and predictors of mortality in patients suffering myocardial infarction with non-obstructive coronary arteries.J Am Heart Assoc. 2019; 8e011990Google Scholar, 49Eggers K.M. Hjort M. Baron T. Jernberg T. Nordenskjöld A.M. Tornvall P. et al.Morbidity and cause-specific mortality in first-time myocardial infarction with nonobstructive coronary arteries.J Intern Med. 2019; 285: 419-428Crossref PubMed Scopus (39) Google Scholar, 50Dreyer R.P. Tavella R. Curtis J.P. Wang Y. Pauspathy S. Messenger J. et al.Myocardial infarction with non-obstructive coronary arteries as compared with myocardial infarction and obstructive coronary disease: outcomes in a Medicare population.Eur Heart J. 2020; 41: 870-878Crossref PubMed Scopus (59) Google Scholar, 51Ishii M. Kaikita K. Sakamoto K. Seki T. Kawakami K. Nakai M. et al.JROAD Investigators. Characteristics and in-hospital mortality of patients with myocardial infarction in the absence of obstructive coronary artery disease in super-aging society.Int J Cardiol. 2020; 301: 108-113Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 52Pasupathy S. Lindahl B. Litwin P. Tavella R. Williams M.J.A. Air T. et al.Survival in patients with suspected myocardial infarction with nonobstructive coronary arteries: a comprehensive systematic review and meta-analysis from the MINOCA Global Collaboration.Circ Cardiovasc Qual Outcomes. 2021; 14e007880Crossref PubMed Scopus (26) Google Scholar, 53Sueda S. Sakaue T. Coronary artery spasm-induced acute myocardial infarction in patients with myocardial infarction with non-obstructive coronary arteries.Heart Vessels. 2021; 36: 1804-1810Google Scholar] (Table 3). The frequency of MINOCA in AMI ranged from approximately 3.5% to 11.1%, with no significant differences between reports, and the frequency of coronary spasm in MINOCA ranged from 3.7% to 72.6%, with a wide variation between reports. Because the frequency of provoked coronary spasm after AMI has been reported to be higher in Asians, including Japanese, than in Caucasians [[8]Pristipino C. Beltrame J.F. Finocchiaro M.L. Hattori R. Fujita M. Mongiardo R. et al.Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction.Circulation. 2000; 101: 1102-1108Crossref PubMed Google Scholar,[54]Beltrame J.F. Sasayama S. Maseri A. Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients.J Am Coll Cardiol. 1999; 33: 1442-1452Crossref PubMed Scopus (291) Google Scholar], racial differences may be a factor in the difference in the frequency of coronary spasm. On the other hand, the ACOVA study [[55]Ong P. Athanasiadis A. Borgulya G. Mahrholdt H. Kaski J.C. Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries: the ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries).J Am Coll Cardiol. 2012; 59: 655-662Crossref PubMed Scopus (301) Google Scholar] and an international study of Japanese and German patients reported that the frequency of ACh-induced coronary spasm was also high in Westerners [[56]Suda A. Seitz A. Odaka Y. Athanasiadis A. Pirozzolo G. Sato K. et al.Assessment of coronary vasomotor responses to acetylcholine in German and Japanese patients with epicardial coronary spasm: more similarities than differences?.Heart Vessels. 2021; 36: 337-344Crossref PubMed Scopus (0) Google Scholar]. Thus, there is a common understanding that there are no racial differences in the frequency of coronary spasm. The ESC and the American Heart Association have issued recommendations regarding the diagnostic protocol for MINOCA [[23]Agewall S. Beltrame J.F. Reynolds H.R. Niessner A. Rosano G. Caforio A.L. et al.Working Group on Cardiovascular Pharmacotherapy. ESC working group position paper on myocardial infarction with non-obstruc

Sex-related differences in the prevalence of cardiac disorders have been elucidated beyond races. Angina/ischemia with nonobstructive coronary artery disease (AINOCA) is often observed in females. Coronary microvascular dysfunction (CMD) and coronary epicardial spasm (CES) are the principal cause of AINOCA. The clinical outcomes of Western patients with CMD were less satisfactory than expected, while the prognosis of Japanese patients with CES treated with medications including calcium channel blockers was favorable. However, the incidence and clinical features of coronary spasm endotypes were different between Western and Japanese populations. Furthermore, sex-related differences in the clinical manifestations and outcomes of patients with different spasm endotypes remain uncertain beyond race. In this article, we will review the sex differences in Japanese AINOCA patients with coronary vasomotor disorders, including CMD and CES, and compare them with those of Western patients.

Statin treatment improves endothelial dysfunction and decreases plaque volume in patients with obstructive coronary artery disease (OCAD) as a pleiotropic mechanism. Clinical outcomes in patients with OCAD under statin therapy are favorable compared with those outcomes for patients without statins. However, the effect of statins may be uncertain in patients with vasospastic angina and nonobstructive coronary artery disease (VSA-NOCAD). Several researchers in South Korea and Japan have reported on the effectiveness of statin therapy in patients with VSA-NOCAD. Flow-mediated dilatation was shown to be improved in VSA patients with statins compared with patients without statins. However, statin treatment was shown to not be effective in reducing the major cardiovascular events (MACEs) in patients with VSA-NOCAD, although after propensity score matching, the prognosis was better in patients with VSA-NOCAD. Furthermore, high-intensity statin therapy showed no clinical utility for mitigating MACEs in patients with VSA-NOCAD.

Background: Some cardiologists perform vasoreactivity testing on the left coronary artery (LCA) or the right coronary artery (RCA) alone.Objectives: We retrospectively analyzed the incidence of epicardial spasm (ES) and coronary microvascular spasm (CMS) in Japanese patients with unobstructed coronary artery disease on both coronary artery testing. Methods: A total of 716 consecutive patients (241 women, mean age 64.3 ± 10.6 years old) who underwent first diagnostic angiography for suspected myocardial ischemia and who had unobstructed coronary arteries (< 50%) were enrolled. For all 716 patients, complete acetylcholine (ACh) testing was performed on both coronary arteries without the administration of nitroglycerine to relieve any provoked spasm in the first artery tested. ES was defined as ≥ 90% stenosis, usual chest symptoms, and ischemic electrocardiogram (ECG) changes, while CMS was defined as < 75% stenosis, usual chest symptoms, and ischemic ECG changes.Results: Negative spasms for ACh tests were diagnosed in 370 patients (51.7%), whereas the ACh test revealed positive spasms in 346 patients (48.3%), including 314 ESs and 36 CMSs. We obtained positive ES results in 67 patients (9.4%) with only their LCAs, while we obtained positive ES results in 110 patients (15.4%) with only their RCAs. Both the RCA and LCA showed negative ES results in 402 patients (56.1%), whereas both showed positive ES results in 137 patients (19.1%). In contrast, 10 patients (1.4%) had CMS in just their RCA, while 22 patients (3.1%) had CMS in just their LCA. Both the RCA and LCA showed negative CMS results in 680 patients (94.9%), whereas both showed positive CMS results in 4 patients (0.6%).Conclusions: We found heterogeneity in ACh testing results in the clinic because some cases were positive for the LCA while some were positive for the RCA alone.

Aims Although nitrates are widely used as a concomitant therapy with calcium channel blockers (CCBs) for vasospastic angina (VSA), their prognostic contribution remains unclear. The present study aimed to examine the prognostic impact of chronic nitrate therapy in patients with VSA.Methods and results A total of 1429 VSA patients (median 66 years; male/female, 1090/ 339) were enrolled. The primary endpoint was defined as major adverse cardiac events (MACE). The propensity score matching and multivariable Cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. Among the study patients, 695 (49%) were treated with nitrates, including conventional nitrates [e.g. nitroglycerin (GTN), isosorbide mono-and dinitrate] in 551 and nicorandil in 306. Calcium channel blockers were used in >90% of patients. During the median follow-up period of 32 months, 85 patients (5.9%) reached the primary endpoint. Propensity score-matched analysis demonstrated that the cumulative incidence of MACE was comparable between the patients with and those without nitrates [11 vs. 8% at 5 years; hazard ratio (HR): 1.28; 95% confidence interval (CI): 0.72-2.28, P = 0.40]. Although nicorandil itself had a neutral prognostic effect on VSA (HR: 0.80; 95% CI: 0.28-2.27, P = 0.67), multivariable Cox model revealed the potential harm of concomitant use of conventional nitrates and nicorandil (HR: 2.14; 95% CI: 1.02-4.47; P = 0.044), particularly when GTN and nicorandil were simultaneously administered.Conclusions Chronic nitrate therapy did not improve the long-term prognosis of VSA patients when combined with CCBs. Furthermore, the VSA patients with multiple nitrates would have increased risk for cardiac events.

Abstract Aims  Intracoronary acetylcholine (ACh) testing is useful for the detection of epicardial spasm (ES) and coronary microvascular spasm (CMS). We retrospectively analysed the incidence of ES and CMS in consecutive Japanese patients with unobstructed coronary artery disease. Methods and results From January 1991 to February 2019, we performed intracoronary ACh testing of 1864 patients. Among these patients, a total of 746 consecutive patients (254 women, mean age 64 ± 11 years) who underwent first diagnostic angiography for suspected myocardial ischaemia and had unobstructed coronary arteries (<50%) were enrolled. Epicardial spasm was defined as ≥90% stenosis and usual chest symptoms and ischaemic ECG changes, while CMS was defined as <75% stenosis and usual chest symptoms and ischaemic ECG changes. We performed intracoronary ACh testing on both coronary arteries in 96% (716/746) of all subjects. Overall, ES was found in 329 patients (44%), whereas CMS was revealed in 40 patients (5%) including 4 patients with coexisting ES. In patients with ES, women made up 22%, and approximately three-quarters of the patients had resting chest pain. In contrast, women composed 65% (26/40) of those with CMS, and 15 patients with CMS had another chest symptom. Coronary microvascular spasm was frequently observed in the left coronary artery (LCA) but not the right coronary artery. Electrical cardioversion was necessary for two patients. Conclusions  Coronary microvascular spasm was recognized in only 5% of consecutive Japanese patients with unobstructed coronary artery disease, whereas ES was revealed in 44% of those patients. Coronary microvascular spasm was often observed in women and in the LCA.

Intracoronary ergonovine (ER) testing is useful for the detection of epicardial spasm (ES) and coronary microvascular spasm (CMS). We retrospectively analyzed the incidence of ES and CMS in consecutive Japanese patients with unobstructed coronary artery disease. From January 1991 to February 2019, we performed intracoronary ER testing of 1196 patients. Among these patients, a total of 505 consecutive patients (207 women, mean age 64 ± 11 years) who underwent first diagnostic angiography for suspected myocardial ischemia and had unobstructed coronary arteries (< 50%) were enrolled. Resting chest pain was reported by 229 patients, exertional chest pain was reported by 62 patients, exertional and resting chest pain was reported by 61 patients, and another chest symptom (not typical chest pain but suspected to be myocardial ischemia) was reported by 153 patients. ES was defined as ≥ 90% stenosis and usual chest symptoms and ischemic ECG changes, while CMS was defined as < 75% stenosis (no epicardial spasm) and usual chest symptoms and ischemic ECG changes. We performed intracoronary ER testing on both coronary arteries in 86% (432/505) of all subjects. Overall, ES was found in 82 patients (16%), whereas CMS was revealed in 12 patients (2%). In patients with ES, women made up 9%, and 70% of the patients had resting chest pain. In contrast, women composed 67% (8/12) of those with CMS, and 5 patients with CMS had another chest symptom. Ventricular fibrillation was observed in two patients who had sinus rhythm after thump version or cardiac resuscitation. However, we observed no irreversible complications during ER testing. CMS was recognized in only 2% of consecutive Japanese patients with unobstructed coronary artery disease by intracoronary ER testing, whereas ES was revealed in 16% of those patients. CMS was often observed in women.

Background: Epicardial spasm (ES) phenotypes may be related to the prognosis in patients with coronary spastic angina. Objectives: The purpose of this study was to elucidate the relationship between angiographic coronary vasomotor responses to intracoronary acetylcholine (ACh) injection and prognosis in patients with angina and nonobstructive coronary artery disease (ANOCAD). Methods: This was a retrospective, observational, single-center study of 680 patients with ANOCAD. ACh spasm provocation tests on both coronary arteries were performed without administering nitroglycerine to relieve provoked spasm in a first-attempt artery. ACh was injected in incremental doses of 20/50/100/200 μg into the left coronary artery and 20/50/80 μg into the right coronary artery. Positive ES was defined as ≥90% stenosis and usual chest pain and ischemic ECG changes. Results: Provoked positive ES was observed in 310 patients (46%), including 85 patients (13%) with focal spasm, 150 patients (22%) with diffuse spasm, and 75 patients (11%) with combined spasm (diffuse spasm and focal spasm), whereas the remaining 370 patients (54%) had no provoked spasm. An unclassified ACh test was observed in 186 patients (27%), while 184 patients (27%) had a complete negative ACh test. The clinical outcomes in patients with complete negative ES were satisfactory compared with those with positive ES and unclassified ACh test results. The prognosis in patients with an unclassified ACh test was not different from those with a positive ES. Furthermore, prognosis in patients with ES phenotypes was not different among the three groups. Conclusions: There was no correlation between provoked ES phenotypes via intracoronary ACh testing and prognosis in patients with ANOCAD; however, clinical outcomes in patients with positive ES and unclassified ACh tests were worse compared to those with complete negative ACh tests. We should focus on the treatments in patients with unclassified ACh tests as well as those with ESs.

Japanese physicians have made major contributions in this fi eld of coronary epicardial spasm 13, 14) . Compared with Caucasian variant angina, Japanese variant angina affect fewer female patients and exhibits less organic stenosis, less poor left ventricular function, less prior myocardial infarction, and good prognosis as shown in Table 1 13 - 18) . Under the optimal medications, Japanese variant angina had favorable clinical outcomes, whereas Caucasian variant angina did not have a benign prognosis in the clinic. The incidence of death without organic stenosis in Japanese variant angina is higher than that in Caucasian variant angina. We rarely experi-Review Racial differences regarding coronary vasomotion disorders between Caucasian and Japanese populations are controversial. In the past, coronary epicardial spasm was more often recognized in Japanese people than in Caucasian populations. In contrast, coronary microvascular dysfunction is typically observed in Caucasian patients. Japanese cardiologists perform spasm provocation testing actively in patients with unobstructive coronary artery disease, whereas Caucasian cardiologists except for those in some special institutions may skip coronary reactivity testing in the cardiac catheterization laboratory if they encounter patients with unobstructive coronary artery disease. In this review, we present the racial and ethnic disparities in the incidence and clinical characteristics between Caucasian and Japanese populations with coronary vasomotion disorders.

Objective A pathological acetylcholine (ACh) test was observed at lower ACh doses in females compared with males in European populations. We retrospectively analyzed the sex-related differences in Japanese patients with provoked positive spasm by ACh spasm provocation testing. Methods We performed the ACh spasm provocation tests in 1,854 patients from Jan 1991 until Mar 2019. ACh was injected in incremental doses of 20/50/100/200 μg into the left coronary artery and 20/50/80 μg into the right coronary artery. Positive spasm was defined as >90% stenosis and usual chest pain or ischemic ECG changes. We compared the clinical characteristics, angiographical findings during ACh testing, and clinical outcomes between female and male patients with and without provoked positive spasm. Results Positive provoked spasm was diagnosed in 917 patients including 737 (80.4%) males and 180 (19.6%) females. The incidence of provoked positive spasm in females was significantly lower than that in males (33.5% vs. 56.0%, p<0.001). Female patients with provoked positive spasm tended to be older, have less history of smoking, less provoked spasm in the left circumflex artery, or less focal type spasm than male patients with provoked positive spasm. The incidence of ST elevation during ACh testing in male patients was significantly higher than that in female patients, whereas the frequency of ST depression in females was remarkably higher than that in males. The mean maximum used ACh dose for provoked positive spasm on both coronary arteries in female patients was significantly higher than that in male patients. The observed major complications during ACh testing did not differ substantially between the sexes. In addition, the prognosis in females with provoked positive spasm was not different from males. Conclusion Provoked positive spasm by ACh test was obtained at lower mean maximum ACh doses in males compared with females in Japanese patients.