I. New Disease Concepts Related to Coronary Spasm
1. MINOCA
1.1 Pathophysiology of MINOCA
Cases of acute myocardial infarction (AMI) without acute coronary occlusion or obstructive CAD have been reported,19,20 and in 2012, the term “MINOCA” was proposed to describe AMI without significant fixed stenosis (≥50%) in the epicardial coronary arteries on CAG.4 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 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 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,22–24 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 cause25 (Figure 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 Figure 2.22,25 Main causes due to CAD include plaque rupture/erosion, coronary artery spasm, CMD, coronary MVS, coronary artery dissection, and coronary artery embolism.22,24–26 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 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 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.28,29 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.
1.1.1 Involvement of Coronary Spasm in MINOCA
Coronary spasm involves hypercontraction based on a hyperactivity of the Rho-kinase pathway in vascular smooth muscle cells (VSMCs),30 endothelial dysfunction due to decreased production of nitric oxide (NO) by the vascular endothelium,31 inflammation of the vascular adventitia and perivascular adipose tissue,32 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 decreases in fibrinolytic activity,34 and promotion of platelet activation and release of adhesion molecules,35 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 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 Based on these OCT studies and autopsy studies,38 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.39,40 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 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 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.
1.2 Epidemiology of MINOCA
We summarized previous reports from Japan and abroad regarding the epidemiology of coronary spasm and MINOCA43–53 (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,8,54 racial differences may be a factor in the difference in the frequency of coronary spasm. On the other hand, the ACOVA study55 and an international study of Japanese and German patients reported that the frequency of ACh-induced coronary spasm was also high in Westerners.56 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.23,24 The COVADIS group in which Japan participates, has proposed standardization of diagnostic criteria for CSA.9 To clarify the epidemiology of coronary spasm and MINOCA, universal diagnostic criteria and protocols should be established not only in Japan but also worldwide.
Table 3. Frequency and Prognosis of Coronary Spasm in MINOCA
| Authors |
Year of
publication |
Study design |
Frequency
of MINOCA |
Frequency of
coronary
spasm |
Comparison of
in-hospital mortality
rate between
MINOCA and MI-CAD |
Comparison of long-term
mortality rate between
MINOCA and MI-CAD |
Pasupathy S
et al43 |
2015 |
Systematic review
Meta-analysis |
6%
(95% CI:
5–7%) |
28% |
MINOCA: 1.1%
(95% CI: −0.1–2.2%)
MI-CAD: 3.2%
(95% CI: 1.8–4.6%) |
All-cause mortality at 12
months
MINOCA: 3.5%
(95% CI: 2.2–4.7%)
MI-CAD: 6.7%
(95% CI: 4.3–9.0%) |
Smilowitz NR
et al44 |
2017 |
Multicenter Observational
Study: ACTION
Registry-GWTG |
5.9% |
– |
MINOCA: 1.1%
MI-CAD: 2.9% |
– |
Lindahl B
et al45 |
2017 |
Multicenter observational
study: SWEDEHEART
Registry |
8.0% |
– |
– |
– |
Montone RA
et al46 |
2018 |
Single-center
observational study |
– |
30% |
– |
– |
Safdar B
et al47 |
2018 |
Multicenter observational
study: VIRGO Study |
11.1% |
3.7% |
– |
– |
Choo EH
et al48 |
2019 |
Multicenter observational
study: KAMIR-NIH
Registry |
3.5% |
24% |
MINOCA: 2.8%
MI-CAD: 3.5% |
All-cause mortality at 24
months
MINOCA: 9.1%
MI-CAD: 8.8% |
Eggers KM
et al49 |
2019 |
Multicenter observational
study: TOTAL-AMI Study |
9.5% |
– |
– |
All-cause mortality (median
follow-up 3.8 years)
MINOCA: 12.1%
MI-CAD: 14.9% |
Dreyer RP
et al50 |
2020 |
Multicenter observational
study: National
Cardiovascular Data
Registry CathPCI Registry |
5.9% |
– |
MINOCA: 2.1%
MI-CAD: 4.1% |
All-cause mortality at 12
months
MINOCA: 12.3%
MI-CAD: 16.7% |
Ishii M
et al51 |
2020 |
Multicenter observational
study: JROAD-DPC
database |
9.5%
(10.2% for
working
diagnosis) |
11.7% |
MINOCA: 6.4%
MI-CAD: 6.2% |
– |
Pasupathy S
et al52 |
2021 |
Systematic review
Meta-analysis |
8.1%
(95% CI:
6.3–9.9 %) |
– |
MINOCA: 0.7%
(95% CI: 0.3–1.2%)
MI-CAD: 2.2%
(95% CI: 1.3–3.1%) |
All-cause mortality at 12
months
MINOCA: 3.3%
(95% CI: 2.5–4.1%)
MI-CAD: 5.6%
(95% CI: 4.1–7.0%) |
Sueda S
et al53 |
2021 |
Single-center
observational study |
6.3% |
72.6% |
– |
– |
MI-CAD, myocardial infarction with coronary artery disease; MINOCA, myocardial infarction with non-obstructive coronary arteries.
Previous reports show that MINOCA patients are younger, female, and have fewer coronary risk factors such as dyslipidemia, diabetes, hypertension, and a history of smoking, and more frequency of Killip class I/II compared withMI-CAD.43,44,48–52 In addition, they report that MINOCA has more frequency of a history of HF, AF and systemic comorbidity such as chronic lung disease, cerebrovascular disease, peripheral arterial disease, chronic liver disease, renal disease, and hemodialysis.44,48,49,51 Two reports investigating racial differences found that black patients were observed more frequently in MINOCA cases compared with MI-CAD.44,50 Although, as environmental factors, air pollutants such as fine particulate matter PM2.5 and Asian dust are known to be a risk factor for MI-CAD or death due to ischemic heart disease (IHD),57–59 short-term exposure to air pollutants has also been reported to be a risk factor in MINOCA.60,61 In addition, smoking is a coronary risk factor and widely recognized as a risk factor for coronary spasm.62,63 A single-center, retrospective observational study in Japan reported that patients with MINOCA due to coronary spasm had 91% prevalence of smoking history.53 As for genetic factors, a significant association between Glu298Asp mutation, one of the polymorphisms of the endothelial nitric oxide synthase (eNOS) gene, and CSA64 has been reported, and an association between this gene polymorphism and AMI has been also reported.65,66 In addition, an association between genetic polymorphisms of ALDH2, a member of the ALDH superfamily, and coronary angina67 and high creatinine kinase levels in patients with ST-elevation MI68 has been reported. Based on these findings, gene polymorphisms may be involved in pathogenesis of MINOCA due to coronary spasm. Further studies are needed to confirm the mechanistic role of gene polymorphism in MINOCA.
The short- and long-term prognoses for MINOCA compared with MI-CAD are summarized in Table 3. In a meta-analysis reported in 2015,43 the in-hospital mortality rate for MINOCA was 1.1% and 3.2% for MI-CAD, indicating a better in-hospital outcome for MINOCA (odds ratio [OR]: 0.37, 95% confidence interval [CI]: 0.2–0.67). At 12 months, the mortality rate for MINOCA was 3.5% and 6.7% for MI-CAD and MINOCA was also significantly associated with a lower risk for all-cause death at 12 months, compared with MI-CAD (OR: 0.59, 95% CI: 0.41–0.83). In a meta-analysis reported in 2021,52 the in-hospital mortality rate for MINOCA was 0.7% and 2.2% for MI-CAD, indicating that MINOCA had a favorable in-hospital prognosis. At 12 months, the mortality rate for MINOCA was 3.3% and 5.6% for MI-CAD, with a significantly lower OR for in-hospital death of MINOCA (OR: 0.60, 95% CI: 0.5–0.7). The OR for cardiovascular death and re-infarction at 12 months was also significantly lower for MINOCA than for MI-CAD (OR: 0.40, 95% CI: 0.2–0.7; OR: 0.48, 95% CI: 0.3–0.9), but not for worsening HF (OR: 0.71, 95% CI: 0.4–1.4).
Although there are many reports showing better prognosis of MINOCA,44,49,50,69 there are also reports showing almost no difference in prognosis48 or poor prognosis of MINOCA.51 Further epidemiological studies are needed to clarify the prognosis of MINOCA. In addition, although predictors of in-hospital death for MINOCA are common to those for MI-CAD, cardiogenic shock and ST-segment elevation on ECG were more strongly associated with in-hospital death in MINOCA than in MI-CAD.44 On the other hand, coronary spasm is not a significant predictor of in-hospital death,48 but rather a lower risk.51 It has been reported that poor long-term prognostic factors in MINOCA are age, male sex, atypical chest symptoms, smoking history, cardiogenic shock, diabetes, HF, prior stroke, peripheral artery disease, cancer, chronic lung disease, AF, and chronic kidney disease.48,49 Angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blockers (ARBs) and statins have been reported to reduce the risk of all-cause death and major cardiovascular events,45,48 and subgroup analyses showed an interaction between age and ACE inhibitors/ARBs, with a decreased risk of major cardiovascular events in MINOCA patients aged 70 years and older (<70 years: hazard ratio [HR]: 0.96, 95% CI: 0.80–1.15, ≥70 years: HR: 0.74, 95% CI: 0.63-0.87).45
1.3 Diagnosis
The diagnosis of coronary spasm in MINOCA consists of (1) the diagnosis of MINOCA and (2) of coronary spasm as the cause of MINOCA (Figure 3).
1.3.1 Diagnosis of MINOCA
MINOCA is MI without evidence of occlusive coronary artery lesions, and its diagnosis consists of a diagnosis of MI and evidence of non-obstructive coronary arteries.
The universal definition of MI was proposed by a joint task force of European and USA societies and the current 4th edition was published in 2018.21 The universal definition defines MI as the presence of acute myocardial injury detected by myocardial biomarkers on the basis of acute myocardial ischemia. Myocardial troponin is a myofibrillar protein that is expressed almost exclusively in the myocardium and is released into the blood upon myocardial injury. Myocardial troponin includes myocardial troponin T and myocardial troponin I, both of which have extremely high sensitivity and specificity compared with conventional myocardial biomarkers such as creatine kinase (CK) and CK-MB, and elevated myocardial troponin levels indicate the presence of myocardial injury. Myocardial troponin can be analyzed by multiple methods, and myocardial injury is defined as an increase in myocardial troponin levels above the 99th percentile of the upper reference limit in each assay. Acute myocardial injury is judged as a raise and a subsequent fall, or either of them. An elevated myocardial troponin level suggests myocardial injury, but does not reflect the cause of myocardial injury. The diagnosis of MI therefore requires evidence of myocardial ischemia as indicated by symptoms suggestive of ischemia, ECG changes, loss of new viable myocardium, or abnormal wall motion, in addition to a rise and/or fall in myocardial troponin. The diagnosis of MINOCA requires careful evaluation of the CAG findings by reviewing the images to ensure that side-branch occlusions are not overlooked.23,24
If the cause of elevated troponin cannot be identified as MINOCA at the time of emergency CAG, other causative diseases should be excluded under the working diagnosis of TP-NOCA.25 Diseases to be differentiated include those of cardiac origin, such as acute myocarditis and takotsubo syndrome, and those of noncardiac origin, such as sepsis and acute pulmonary thromboembolism. The distinction between acute myocardial injury from CAD and that of nonischemic origin is determined by comprehensive evaluation of medical history and imaging, among which cardiovascular magnetic resonance (CMR) images are particularly useful.70 In patients with MI, late gadolinium enhancement (LGE) is present in the subendocardial or transmural area that corresponds to the coronary artery territory, whereas the CMR patterns observed in myocardial injury due to nonischemic causes such as myocarditis, often include intramyocardial or subepicardial LGE. T2-weighted images show a similar distribution pattern of the high signals suggestive of myocardial edema, even in the absence of LGE.
1.3.2 Diagnosis of Coronary Spasm as the Cause of MINOCA
MINOCA is classified according to its underlying pathophysiological mechanisms into type 1 MI caused by atherosclerotic plaque disruption, or type 2 MI caused by a mismatch between oxygen supply and demand.21 The oxygen demand/supply mismatch can be divided into increased demand, such as sustained tachycardia or severely elevated blood pressure, and decreased supply. Decreased oxygen supply can be caused by coronary artery abnormalities such as coronary spasm, SCAD and coronary artery embolism, or non-CAD such as persistent bradycardia and high levels of anemia. The diagnosis of coronary spasm requires first ruling out other conditions that may cause MINOCA.
Plaque disruption may be seen on CAG as wall irregularities or haziness, but often requires evaluation with intravascular imaging modalities such as OCT. For patients with the findings of plaque disruption or intracoronary thrombus, antiplatelet therapy should be prescribed. However, the presence of these findings alone does not rule out the involvement of coronary spasm as the cause of MINOCA, because such findings are often seen in patients with VSA. SCAD is more common in women younger than 50 years of age. Intravascular imaging is also useful in the diagnosis of SCAD as the presence of a false lumen within the coronary artery wall. Coronary artery embolism is seen as an abrupt interruption of the coronary artery on CAG. It often occurs as systemic embolism based on AF, cardiomyopathy, or valvular disease, but may be a distal embolization of a mural thrombus in the coronary artery as it dissolves.
Although some patients with MINOCA caused by coronary spasm may already have a previous diagnosis of VSA, or a history of symptoms suggestive of VSA, MINOCA is often the first presentation. Diagnosis of coronary spasm is made according to the diagnostic criteria of this guideline (see Chapter III.1, III.2), but spontaneous attacks are rarely captured, requiring a coronary spasm provocation test in most cases. Regarding the timing of the coronary spasm provocation test, performing it during emergency CAG for ACS has been considered dangerous and was classified as Class III in the 2013 revised JCS guidelines, which recommended coronary spasm provocation test after stabilization.2 The COVADIS group, published their international standardization of the diagnosis of VSA in 2017, which similarly contraindicated coronary spasm provocation test in emergency situations.9 On the other hand, as the importance of MINOCA in ACS became increasingly recognized, studies of the safety and utility of coronary spasm provocation test during acute CAG began to be reported. In a study of 80 patients diagnosed with MINOCA who underwent immediate CAG followed by coronary spasm provocation test with ACh or ergonovine, 37 patients were diagnosed as having coronary spasm with no complications from the emergency coronary spasm provocation test.46 Patients with a positive coronary spasm provocation test are more likely to die or be rehospitalized for ACS after hospital discharge, suggesting the coronary spasm provocation test is useful for identifying high-risk patients. In a study comparing 84 patients who underwent coronary spasm provocation test with ACh at the time of emergency CAG with 445 patients who underwent the provocation test at the time of non-emergency CAG, the rate of serious complications was similar in both groups (1.2% vs. 1.3%, P=1.00), with no deaths.71 In a study comparing 80 patients who underwent coronary spasm provocation test with ACh following diagnostic CAG for MINOCA and 100 patients with INOCA, there were no irreversible complications, suggesting that the coronary spasm provocation test in the acute phase of MINOCA can be performed as safely as with INOCA.72 In light of these results, the coronary spasm provocation test may be considered for patients with MINOCA even during acute CAG under conditions in which other diseases such as plaque disruption and SCAD have been definitely excluded and adequate safety precautions are taken (Table 4). On the other hand, for patients in whom the diagnosis of coronary spasm has already been made with documentation of spontaneous attacks, such as spontaneous or nitroglycerin-induced remission of ST-segment elevation on ECG or remission of occlusion or severe stenosis on CAG, performing the coronary spasm provocation test during acute CAG has no benefit. In addition, the coronary spasm provocation test should not be performed during acute CAG for patients in whom drug-induced coronary spasm may cause severe complications, such as severely depressed cardiac function or congestive HF.
Table 4. Recommendations and Levels of Evidence for Coronary Spasm Provocation Test During Acute Coronary Angiography in MINOCA
| |
COR |
LOE |
Coronary spasm provocation test may be considered in the acute setting for patients in whom
alternative conditions, such as plaque disruption and SCAD, have been definitely ruled out, under
conditions in which adequate safety considerations have been taken into account46,71,72 |
IIb |
C |
Coronary spasm provocation test is not recommended in patients with documented attacks, such
as spontaneous or nitroglycerin-induced remission of ST-segment elevation on ECG or occlusive
or severely stenotic lesions on coronary angiography |
III (No
benefit) |
C |
Coronary spasm provocation test should not be performed in the acute phase in patients in whom
drug-induced coronary spasm is expected to cause severe complications (e.g., patients with
severely depressed cardiac function, congestive heart failure, etc.) |
III
(Harm) |
C |
COR, Class of Recommendation; LOE, Level of Evidence; MINOCA, myocardial infarction with non-obstructive coronary arteries; SCAD, spontaneous coronary artery dissection.
Coronary MVS can also produce MINOCA, but caution should be paid in assessing CMD in MINOCA because it can also occur as a result of myocardial ischemia/infarction.73
2. INOCA
2.1 Emerging Concept and Universal Definition of INOCA
Approximately half of patients undergoing CAG for suspected angina pectoris due to typical anginal pain, angina-equivalent symptoms, or noninvasive stress test results suggestive of myocardial ischemia do not have significant (≥50%) organic stenosis in the epicardial coronary arteries.74–83 Coronary vasomotion abnormalities such as coronary vasospasm and CMD have been shown to be more prevalent than previously thought in these patients of both sexes, with a predominance of women, associated with worse clinical outcomes,79,84–95 decreased quality of life (QOL),96 and increased medical cost due to hospitalization for unstable angina pectoris and repeat CAG.97–100 In 2017, the concept of ischemia with non-obstructive CAD (i.e., INOCA) was proposed as a chronic syndrome with symptoms, signs, and objective findings suggestive of myocardial ischemia but without significant organic stenosis in the epicardial coronary arteries.3 Subsequently in 2020, the European Association of Percutaneous Cardiovascular Interventions (EAPCI) published the first expert consensus document on INOCA, which proposed the universal definition, diagnosis, and management of INOCA and recommends performing interventional diagnostic procedure (IDP) or invasive functional CAG (FCA) including coronary vasospasm provocation testing in order to identify the endotype of INOCA.101 The consensus document published in the UK in 2022 also recommends endotyping of INOCA by IDP or FCA and providing individualized treatment based on the cause of INOCA.102
2.2 Definition of INOCA
INOCA is defined as (1) stable, chronic (> several weeks) chest symptoms (typical angina) or atypical symptoms (angina equivalent), (2) objective findings of myocardial ischemia detected by ECG, echocardiography, CMR imaging, or nuclear medicine imaging, and increased myocardial lactate production during coronary vasospasm provocation testing,103–110 and (3) no flow-limiting stenosis as defined by ≥50% organic stenosis (obstructive CAD) or a fractional flow reserve (FFR) ≤0.80 on CAG or CCTA.3,101 Although INOCA is by definition assumed to be symptomatic as mentioned above, the initial evaluation should rule out noncardiogenic and nonischemic conditions that may produce angina-like symptoms.101
2.3 Pathogenesis and Epidemiology of INOCA
2.3.1 Mechanisms of Myocardial Ischemia
The 2 major mechanisms of myocardial ischemia in INOCA are coronary vasospasm and CMD, both of which can cause myocardial ischemia due to an imbalance between myocardial oxygen demand and supply, either alone or in combination with varying degrees of CAD (Figure 4). The ESC guidelines for chronic coronary syndrome[s] (CCS) published in 2019 classify patients with angina pectoris associated with coronary vasospasm or CMD, which corresponds to INOCA, as CCS V, one of the most frequently encountered 6 clinical scenarios of CCS.6 As shown in Figure 5, ischemic mechanisms can be divided into functional or structural abnormalities of epicardial coronary arteries or coronary microvessels. Coronary vasospasm can cause myocardial ischemia by transient hypercontraction of the epicardial coronary arteries or coronary microvessels (i.e., supply ischemia/primary angina) (Figure 5).111 On the other hand, impaired metabolic vasodilatation of coronary microvessels due to functional or structural abnormalities as represented by decreased CFR or by increased IMR can cause myocardial ischemia when myocardial oxygen consumption is increased (i.e., demand ischemia/secondary angina), similar to effort angina pectoris in the presence of obstructive CAD (Figure 5). Although these mechanisms can contribute to myocardial ischemia in combination with obstructive CAD, it should be noted that patients with obstructive CAD are not included in the definition of INOCA (Figure 4).101
2.3.2 Coronary Vasospasm in INOCA
A growing body of evidence has shown the importance of endotyping/phenotyping of coronary vasospasm.42,106,112–116 A large retrospective study from Japan (n=1,877) showed that focal coronary vasospasm was associated with more major cardiovascular events than diffuse coronary vasospasm during a mean follow-up period of 49 months.106 A report from a large multicenter prospective Korean registry (n=2,960) also showed that focal coronary vasospasm was associated with worse clinical outcomes than diffuse coronary vasospasm during a median follow-up period of 30 months.116 Furthermore, a study from Japan enrolling patients with INOCA who underwent coronary vasospasm provocation testing and optical frequency domain imaging (n=329) showed that focal coronary vasospasm was associated with the highest incidence of major cardiovascular events during a median follow-up period of 3 years in association with intraplaque neovascularization.112 Patients with diffuse coronary vasospasm showed an intermediate prognosis, associated with increased vasa vasorum.112 These findings suggest that the combined assessment of function and morphology may be useful for prognostic stratification of patients with INOCA.112
2.3.3 CMD in INOCA
CMD has been attracting much attention in recent years because of its association with various cardiovascular diseases as well as its important role in the mechanisms of myocardial ischemia in INOCA.80,84,88,93,117–130 The mechanisms of CMD are multifactorial and result from functional or structural abnormalities of the coronary microvessels, including (1) increased vasoconstriction (e.g., coronary MVS), (2) impaired endothelium-dependent or -independent coronary vasodilator capacities (e.g., endothelial or vascular smooth muscle dysfunction), (3) structural alterations leading to increased coronary microvascular resistance (e.g., luminal narrowing, vascular remodeling, vascular rarefaction, and extramural compression), which may occur alone or in combination (Figure 6).131–136 Angina pectoris caused by CMD is referred to as MVA, and the international diagnostic criteria of MVA were proposed in 2018.10 The guidelines in Japan, the USA, and Europe recommend performing IDP or FCA for the diagnosis of CMD,2,6,24 which is based on the following criteria: decreased CFR, MVS, increased IMR, and decreased coronary blood flow velocity (e.g., increased contrast delay and Thrombolysis In Myocardial Infarction [TIMI] frame counts).2,10,137,138
2.3.4 Overlap and Coexistence of Mechanisms in INOCA
In a recent systematic review and meta-analysis of the prevalence of coronary vasomotion abnormalities in patients with INOCA (56 studies, 14,427 patients), coronary vasospasm was present in 40%, CMD in 41%, combination of both in 23%, and MVA in 24% of the patients.139 Women had 1.45-fold more CMD than men.139 It is important to note that these mechanisms of INOCA and organic coronary stenosis often overlap and coexist in varying degrees in individual patients and may affect prognosis and the treatment strategy (Figure 4).14,80,104,113,140–145 The EAPCI expert consensus document published in 2020 proposed classifying INOCA into 5 endotypes based on the results of coronary reactivity testing by IDP or FCA (Table 5).101
Table 5. Endotypes and Ischemic Mechanisms of INOCA
| Endotype |
Ischemic mechanism |
| MVA |
CMD |
| VSA |
Epicardial coronary vasospasm |
| MVA + VSA |
CMD + epicardial coronary vasospasm |
| Chest pain syndrome of non-cardiac origin |
None |
| No flow-limiting stenosis |
Diffuse, non-obstructive CAD |
CAD, coronary artery disease; CMD, coronary microvascular dysfunction; INOCA, ischemia with non-obstructive CAD; MVA, microvascular angina; VSA, vasospastic angina. (Adapted from Kunadian V, et al. 2020.101)
2.4 Knowledge Gaps and Perspectives
Many knowledge gaps still exist for INOCA.
2.4.1 INOCA and Obstructive CAD
Although INOCA by definition does not include patients with obstructive CAD (i.e., ≥50% organic stenosis), the ESC guidelines on CCS published in 2019 state that if a coronary stenosis is not physiologically significant, as defined by FFR >0.80, it is considered as non-obstructive CAD and may warrant close examination for coronary vasomotion abnormalities.6 Although patients with obstructive CAD are excluded from the definition of INOCA, those with INOCA may have varying degrees of coronary atherosclerosis.112,140,146–151 Indeed, VSA and CMD combined with organic stenosis can lead to increased myocardial ischemia and worse prognosis.14,79,91,142,146,148,149,152–154
2.4.2 Diagnostics of INOCA
For the diagnosis of coronary vasospasm and CMD, comprehensive evaluation of coronary artery function by invasive cardiac catheterization is recommended by the guidelines2,6,24 and consensus documents101,102 in Japan, the USA, and Europe, because it has been shown to be a safe46,114,155–160 and cost-effective strategy.161 However, there is no uniformity in the method used to evaluate coronary reactivity.162 Specifically, it remains to be elucidated which should be evaluated first, coronary vasospasm or CMD, in a single cardiac catheterization.
2.4.3 Treatment and Management of INOCA
The Coronary MICrovascular Angina (CorMicA) trial is the only randomized controlled trial addressing the treatment and management of INOCA, using therapeutic interventions stratified by the endotype of INOCA based on the results of IDP or FCA.11,81 Patients with VSA were treated with calcium-channel blockers (CCBs), nitrates, and nicorandil, and those with CMD with β-blockers, CCBs, and nicorandil. Although the CorMicA study showed a 27% improvement in anginal symptom scores as assessed by the Seattle Angina Questionnaire compared with controls, the study was limited to a comprehensive evaluation of coronary artery function in only 1 coronary artery, mainly the left anterior descending coronary artery, and thus further studies are needed. The efficacy of CCBs for the treatment of coronary vasospasm is well established.2,6,24 Several randomized controlled trials addressing the treatment and management of INOCA are currently underway, including the Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) study to evaluate the efficacy of an endothelin A receptor antagonist zibotentan in the treatment of MVA,163 Coronary Microvascular Function and CT Coronary Angiogram (CorCTCA) study to evaluate endotype-specific management of INOCA based on IDP results,164 and Women’s IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR) trial to evaluate the effect of high-intensity statins and ACE inhibitors/angiotensin II receptor blockers in women with INOCA.165
2.5 Diagnosis of INOCA
The endotypes of INOCA are broadly divided into VSA and MVA. Although these causes can coexist, it is important to identify the endotype in order to provide appropriate treatment.101
2.5.1 Diagnosis of VSA
Coronary spasms can be divided into those occurring in the epicardial coronary artery and those occurring in the coronary microvasculature, and examination methods for spasm in the epicardial coronary artery have been established as described in Chapter III.1. The details of coronary MVS are given in Chapter II.3,10 but during pharmacological provocation test not only chest symptoms and ECG changes but also biochemical ischemia evaluation based on blood lactate levels from the coronary sinus are recorded.166 However, the test sensitivity and specificity of ACh-induced testing for spasm in epicardial coronary arteries (VSA) have proven to be high,167 but those for spasm in coronary microvessels are still unclear.
2.5.2 Diagnosis of MVA (Table 6)
Table 6. Recommendations and Levels of Evidence for Various Tests in Diagnosing INOCA
| |
COR |
LOE |
In patients with angina pectoris and demonstrated myocardial ischemia but no significant stenosis
of the epicardial coronary arteries, a pharmacological coronary spasm provocation test should be
considered to confirm the presence of coronary microvascular spasm during coronary
angiography10 |
IIa |
C |
In patients with angina pectoris and demonstrated myocardial ischemia but no significant stenosis
in the epicardial coronary arteries, coronary flow reserve and index of microcirculatory resistance
evaluation using a guide wire should be considered3,11,90,169,170 |
IIa |
B |
In patients with angina pectoris and demonstrated myocardial ischemia but no significant stenosis
of the epicardial coronary arteries, Doppler blood flow in the left anterior descending branch by
transthoracic echocardiography may be considered for coronary flow reserve assessment183,184 |
IIb |
B |
COR, Class of Recommendation; INOCA, ischemia with non-obstructive coronary artery disease; LOE, Level of Evidence.
The diagnostic criteria of MVA are (1) symptoms due to myocardial ischemia, (2) absence of significant stenotic lesions in the epicardial coronary arteries, (3) proven myocardial ischemia on other examinations, and (4) presence of CMD.10,101 In addition to invasive evaluation of coronary microvascular function using guidewires in catheterization, noninvasive methods such as cardiac MRI, PET, and transthoracic Doppler echocardiography are also used to evaluate coronary microvascular function.
As an invasive evaluation method using a guidewire, it is currently possible in Japan to diagnose CMD by measuring the CFR and IMR using a pressure wire with a temperature sensor. Although details are given in Chapter III.7, optimal cutoff values for CMD diagnosis have been reported from Europe and the USA,6,101,168 and it has been suggested that the diagnosis of CMD using an invasive evaluation method with a guidewire during catheterization may lead to improved QOL through risk stratification of cardiovascular events and therapeutic intervention.3,11,90,169,170
As a noninvasive assessment method, CFR can be measured by cardiac MRI171,172 or PET.173 In recent years, assessment of myocardial perfusion reserve by CMR173–175 and PET176–182 has been shown to be associated with prediction of cardiovascular events. For details on noninvasive methods of evaluating coronary microvasculature by cardiac MRI and PET, please refer to Chapter III.5.
The association between CFR and the risk of cardiovascular events in the left anterior descending coronary branch on transthoracic Doppler echocardiography has also been reported. Because of the limited number of reports compared with CMR and PET183,184 and the limited measurement sites in the left anterior descending coronary artery, we recommend Class IIb in this focused update in consideration of consistency with the European and USA guidelines.6,168
2.5.3 Revealing the INOCA Endotype by Invasive Assessment (Figure 7)
INOCA is suspected in patients with angina pectoris and documented myocardial ischemia on other examinations without significant stenotic lesions in the epicardial coronary arteries on cardiac CT scan or CAG. If CAG is performed, the endotype is subsequently clarified by pharmacological coronary spasm provocation test and evaluation of coronary microvascular function using a guidewire.
Regarding which should be performed first, the coronary spasm induction test or coronary microvascular function evaluation, it is recommended in Europe and the USA that CFR and IMR measurements be performed first, followed by ACh-induced testing as a diagnostic procedure for INOCA.101,102 However, as described in Chaper II.4, the drugs used to maximally dilate resistance vessels when assessing coronary microvascular function may affect the subsequent induction of coronary spasm, so in Japan, the coronary spasm induction test is generally performed first.142 Continued research is needed to establish more optimal diagnostic methods and procedures (Table 6).
3. Oncocardiology
3.1 Cancer Therapy-Induced Vascular Toxicity and VSA
Survival rates and longevity of cancer patients have improved significantly due to advances in therapy, including new molecular targeted drugs and immune checkpoint inhibitors, in addition to conventional cytotoxic anticancer drugs. However, most anticancer drugs are toxic and may cause cardiovascular diseases; various cardiovascular complications have been reported, such as hypertension, arrhythmia, HF, valvular heart disease, IHD, and vein thrombosis. Cancer therapy-induced vascular toxicity can lead to various pathological conditions in IHD: VSA as a functional abnormality; atherosclerosis as a structural abnormality; and AMI due to coronary embolism. Anticancer drug-induced cardiotoxicity can be classified into 2 types: structural and functional impairment. Vascular toxicity can also be classified into 2 types: type 1 (e.g., nilotinib, ponatinib), which causes long-term structural impairment; and type 2 (e.g., 5-fluorouracil), which is transient and often results in functional impairment.185,186 The most common drugs that can cause VSA are 5-fluorouracil, an anticancer drug classified as an antimetabolite, and its oral prodrug, capecitabine. These drugs induce myocardial ischemia, and the frequency is 4.0–8.5% according to recent major prospective studies.187–189 5-Fluorouracil and capecitabine cause VSA by inducing hyperreactivity in vascular smooth muscle,190 and direct toxicity to vascular endothelial cells.191,192 Other anticancer drugs, such as molecular targeted drugs and immune checkpoint inhibitors, have also been reported to induce VSA.193,194
3.2 Evaluation and Management of Anticancer Drug-Induced VSA
The goals of treatment of VSA in cancer patients are to prevent adverse cardiac events and to continue cancer treatment. However, guidelines do not provide recommendations for the methods because there is currently a lack of evidence regarding the evaluation and treatment of chest pain in cancer patients. Previous studies have reported that 5-fluorouracil-induced VSA can be effectively controlled by discontinuing 5-fluorouracil or avoiding high doses. It has also been reported that re-administration of 5-fluorouracil is effective with pretreatment with CCBs or nitrates when treatment is once discontinued due to VSA.195–197 Anticancer drug-induced VSA often occurs during drug administration. Therefore, when these drugs are administered to patients with a history of anticancer drug-induced cardiovascular toxicity, it may be effective to detect myocardial ischemia and arrhythmias by 12-lead ECG before and after administration and ECG monitoring during and after administration. Further evidence is needed for screening, risk assessment, and treatment of cancer therapy-induced VSA.
II. New Insights Into Pathogenesis
1. Genetic Factors Pathogenesis
Because coronary artery disease often appears in families and some cases occur even in patients with no lifestyle-related problems, the involvement of “genetic factors” has been suggested. In recent years, many genes involved in the pathogenesis of coronary spasm have been cloned, and the 2013 Guidelines for the diagnosis and treatment of patients with VSA2 describe the relationship between coronary spasm and genetic polymorphisms. More recently, mutation in the -786T/C eNOS gene, female sex, and diabetes mellitus have been shown to correlate with ACh-provoked myocardial ischemia in patients with coronary spasm.107
The elucidation of genetic factors of diseases may contribute to primary prevention through tailor-made medicine based on individual genetic information.
2. ALDH2 Polymorphism and Alcohol Metabolism
Coronary spasm attacks are more common during the post-drinking sobering-up period, depending on the individual. Drinking alcohol is a risk factor for coronary spasms, and one of the mechanisms of alcohol’s toxic effects is that it increases urinary excretion of Mg, resulting in Mg deficiency in tissues.198,199
Acetaldehyde, which is synthesized during the metabolism of ethanol, has been associated with cancers of the oral cavity, pharynx, and esophagus, as well as colon, liver, and breast cancer,200 and in the cardiovascular system, it is particularly associated with coronary spasm.67,201
ALDH2 protein contributes to the oxidation and detoxification of acetaldehyde, a metabolite of ethanol, in various tissues and cells, but mainly in the human liver.202–205 Furthermore, ALDH2 gene polymorphism causes individual differences in the time course of acetaldehyde levels during alcohol metabolism.
In a genome-wide association study of Japanese cardiovascular disease cases, a locus (rs671) exhibiting a defective ALDH2 genotype (ALDH2*2) was identified as a strong predictor.206 An association between ALDH2*2 and CAD and MI has also been reported in an East Asian meta-analysis.207ALDH2*2 is common in East Asians (30–50%) and rare in other populations, and is associated with alcohol flushing syndrome, which is characterized by facial flushing, nausea, palpitations, sleepiness, and headache after drinking alcohol.205 On the other hand, because CSA is associated with alcohol flushing syndrome and positive ethanol patch test responses,208 a case–control study was conducted and revealed a significant relationship between ALDH2*2 and CSA. Together with other genetic factors, ALDH2*2 is also an important factor in coronary spasm.67 If CSA is suspected, the presence or absence of alcohol flushing or the results of an ethanol patch test can be helpful during the medical history interview, even if genetic testing is not available.
Furthermore, when ALDH2*2 is combined with smoking, the risk of coronary spasm is synergistically amplified.209 In addition, ALDH2*2 is common found in MI cases in Japan, and the involvement of coronary spasm is a factor.68
ALDH2 also affects the bioactivation of nitroglycerin.210 Continuous administration of nitroglycerin leads to its tolerance and even cardiac events through inactivation of ALDH2 and elevated reactive oxygen species (ROS) levels.205,211 Thus, carriers of ALDH2*2 are less responsive to nitroglycerin, more prone to nitroglycerin tolerance, and more susceptible to increased ROS.212,213
Although racial differences in the incidence of CSA have not yet been fully investigated, it is generally believed that it is more common in East Asians than in Westerners.8,201 The reason for this is unclear, but may be explained by the high prevalence of ALDH2*2 and high smoking rates among East Asians.
In general, alcohol abstinence should be advised in the presence of alcohol flushing, and even more so if CSA is suspected. On the other hand, even in the absence of alcohol flushing, moderation is necessary in patients with CSA, because heavy drinking increases the amount of acetaldehyde in the body and increases the likelihood of its effects (Figure 8).
3. Coronary Microvascular Spasm
3.1 Disease Concept of CMD and Coronary MVS
The coronary vascular bed consists of epicardial coronary arteries and coronary microvessels (pre-arterioles [500–100 μm], arterioles [<100 μm], pre-capillary arterioles [<20 μm], capillaries).133,214,215 The epicardial coronary arteries are responsible for only about 5% of the total coronary vascular resistance in the absence of significant stenotic lesions, which means that coronary microvessels play a central role in regulating myocardial blood flow (MBF), and failure of the regulatory mechanism can induce ischemia with or without abnormalities (stenosis or spasm) in the epicardial coronary arteries. CMD is a syndrome that includes a wide range of conditions in which structural and functional changes in coronary microvessels and extravascular factors cause impaired coronary blood flow, ultimately leading to myocardial ischemia and infarction.131,216
In the clinical classification of CMD based on clinical scenarios, there are 4 types: CMD in the absence of obstructive CAD or myocardial diseases (Type 1), CMD in cardiomyopathy or valvular disease (Type 2), CMD in obstructive CAD (Type 3), and iatrogenic CMD (Type 4) (Table 7).10,14,16,131,132 CMD is thought to play an important role not only as INOCA/MINOCA, but also as epicardial CAD, primary cardiomyopathy, takotsubo syndrome, HF (especially HF with preserved ejection fraction: HFpEF).
Table 7. Clinical Classification of CMD Based on Clinical Scenarios
| Group |
Clinical
presentation |
Syndrome |
Major pathogenic mechanisms |
Type 1
CMD without obstructive coronary artery
disease or myocardial disease |
Angina pectoris
equivalent |
INOCA
MINOCA
Takotsubo syndrome
Post-PCI/CABG |
Vascular smooth muscle dysfunction
Vascular remodeling
Vascular endothelial dysfunction |
Type 2
CMD in patients with cardiomyopathy or
valvular disease |
Dyspnea
Exercise intolerance |
Diabetic cardiomyopathy
Aortic stenosis
Cardiac amyloidosis
Fabry’s disease
Myocarditis
Hypertensive heart disease
Dilated cardiomyopathy |
Vascular smooth muscle dysfunction
Vascular remodeling
Microvascular rarefaction
Extramural compression |
Type 3
CMD in patients with obstructive
coronary artery disease |
Angina pectoris
equivalent |
Chronic coronary syndrome
Acute coronary syndrome |
Vascular smooth muscle dysfunction
Vascular remodeling
Vascular endothelial dysfunction |
Type 4
Iatrogenic CMD |
Often asymptomatic |
Post-elective PCI
Post-elective CABG
Cardiac allograft vasculopathy |
Lumen narrowing/obstruction
Autonomic dysfunction
Systemic inflammatory reactions |
CABG, coronary artery bypass grafting; CMD, coronary microvascular dysfunction; INOCA, ischemia with non-obstructive coronary artery disease; MINOCA, myocardial infarction with non-obstructive coronary arteries; PCI, percutaneous coronary intervention. (Adapted from Crea F, et al. 2014,132 2022.16)
It is known that among patients who complain of angina-like symptoms during exertion or at rest and undergo CAG, there are cases in which neither severe stenotic lesions that obstruct blood flow nor coronary spasm is found in the epicardial coronary arteries, and such cases are diagnosed as MVA, which is considered Type 1 CMD in the CMD clinical classification.
The COVADIS group has proposed diagnostic criteria for MVA (Type 1 CMD) (Table 8).10,16 The diagnostic criteria for MVA include anginal symptoms on exertion or at rest, absence of significant organic stenosis of the epicardial coronary arteries, evidence of ischemia, and of CMD, including (1) impaired coronary microvascular dilation as represented by an increased coronary perfusion response to adenosine, (2) coronary MVS, (3) increased IMR, and (4) decreased coronary blood flow velocity (slow-flow phenomenon)217 (Table 8).
Table 8. Diagnostic Criteria for Microvascular Angina
| 1. Symptoms of myocardial ischemia |
| • Exertional and/or resting angina pectoris |
| • Angina-like symptoms (e.g., shortness of breath) |
| 2. Non-obstructive coronary artery disease |
| • Evaluation by coronary CT |
| • Evaluation by invasive CAG |
| *No significant stenotic lesions in epicardial coronary arteries on the above examinations |
| 3. Proof of myocardial ischemia |
| • Ischemic ECG changes during chest pain attacks |
| • Chest pain and/or ischemic ECG changes associated with loading |
| 4. Coronary microvascular dysfunction |
| • Decreased coronary flow reserve |
• Coronary microvascular spasm (reproduction of symptoms and ischemic ECG changes on pharmacological provocation
testing, without epicardial coronary artery spasm) |
| • Increased index of microcirculatory resistance |
| • Coronary slow flow phenomenon (TIMI frame count >25) |
CAG, coronary angiography; CT, computed tomography; TIMI, thrombolysis in myocardial infarction. (Adapted from Crea F, et al. 2022.16)
In individual cases, both structural abnormalities (organic stenosis) and functional abnormalities in both the epicardial coronary arteries and coronary microvasculature can overlap causing myocardial ischemia (Figure 5, Chapter I.2.3). The condition that excludes stenosis of the epicardial coronary arteries constitutes INOCA.
Although the pathophysiology of CMD has not been fully elucidated, oxidative stress due to overproduction of intracellular ROS and associated inflammatory reactions have been reported to be the mechanism of CMD.218 In addition, activation of RhoA/Rho-kinase by ROS, inhibition of vasodilation by NO, and enhancement of vasoconstrictor activity by endothelin 1 (ET-1) have been reported to be involved in CMD.16,219 In patients with epicardial coronary artery spasm and high IMR, inhibition of Rho-kinase reduces IMR, suggesting that Rho-kinase is involved in the pathogenesis of CMD.138,142
3.2 Epidemiology of Coronary MVS
MVS was first reported in Japan in 1998.103,220 The diagnosis of MVS is based on the following findings; Intracoronary administration of ACh or ergonovine can cause myocardial ischemia (angina symptoms, ischemic changes on ECG, myocardial lactate production) and decreased coronary blood flow velocity (delayed contrast and increased TIMI frame counts) without significant epicardial coronary artery spasm.10,55,101,220,221
Coronary MVS is thought to cause supply ischemia without an increase in myocardial oxygen demand. In actual reports, MVS is more common in postmenopausal women, who often present with angina only at rest during the night or early morning, but also with exertional angina.220 Cases of ECG ST-segment elevation on exertion have also been reported.222 MVS is more common in women than in men in Europe and the USA, and is associated with chest pain both at rest and on exertion.157,223 MVS can cause angina pectoris by itself, but it has also been suggested that MVS contributes to myocardial ischemia in VSA caused by epicardial coronary artery spasm, when myocardial ischemia occurs without significant epicardial artery spasm in the coronary spasm provocation test.104 Epicardial coronary artery spasm combined with MVS is more common in women, and a history of chest pain lasting >30 min, in addition to typical angina symptoms, is more common in women.104 Although the prognosis of patients with MVS is not bad, some cases of MI have been reported.46,105,112,224
The prevalence of MVS in INOCA and MINOCA has been reported (Table 9). The rates of coronary sinus blood lactate measurement in coronary spasm provocation tests vary from study to study, but MVS has been reported to be present in 13–53% of patients diagnosed with INOCA,55,105,157,225–227 and in 16–54% of those diagnosed with MINOCA.16,46,226,228,229 MVS may also cause ischemia in unstable angina caused by organically stenotic lesions in the coronary arteries, and may modulate the pathogenesis of IHD in general.230
Table 9. Incidence of MVS in INOCA/MINOCA
| INOCA |
MVS |
MINOCA |
MVS |
| Ohba K, et al, 2012105 |
13% |
Montone RA, et al, 201846 |
35.1% |
| Ong P, et al, 2014157 |
24.2% |
Vidal-Perez R, et al, 2019228 |
25% |
| Ong P, et al, 2018225 |
30% |
Pirozzolo G, et al, 2020229 |
54% |
| Probst S, et al, 2021226 |
53% |
Probst S, et al, 2021226 |
29% |
| Suzuki S, et al, 2021227 |
32% |
Crea F, et al, 202216 |
16% |
INOCA, ischemia with non-obstructive coronary artery disease; MINOCA, myocardial infarction with non-obstructive coronary arteries; MVS, microvascular spasm.
3.3 Diagnosis of Coronary MVS
Patients suspected of coronary MVS have: (1) typical anginal pain or angina equivalent symptoms at rest or on exertion;55,117,221 (2) MI with no apparent causative lesion in the coronary artery;229,231 and (3) the epicardial coronary arteries presenting non-obstructive coronary arteries (<50% diameter) or FFR >0.80.81,224,232,233
Because coronary MVS cannot be confirmed by CAG234 it is not an absolute diagnosis but rather a presumption.55,221 Reports from Japan have shown that coronary spasm is induced not only by ACh but also by ergonovine,156,235 and both drugs can be used for the diagnosis of coronary MVS.
The diagnosis is made when patients with suspected coronary artery dysfunction undergo ACh or ergonovine provocation test and the reproduction of chest symptoms is accompanied by the appearance of transient ischemic ECG changes but without significant epicardial coronary artery spasm10,55,236 (Figure 9). Hence, the diagnosis cannot be made when there is (1) no reproduction of chest symptoms, (2) no appearance of transient ischemic ECG changes, and (3) significant epicardial coronary artery spasm. Coronary MVS is considered negative in the absence of significant epicardial coronary artery spasm and either chest symptoms or ischemic ECG changes. If significant epicardial coronary artery spasm is found, the diagnosis of coronary MVS is pending and the diagnostic criteria for CSA are followed.
It has been reported that the frequency of coronary MVS comorbid with epicardial coronary artery spasm is high and that re-administration of ACh in the setting of suppressed epicardial coronary artery spasm with nitroglycerin can diagnose coexisting coronary MVS.13 Although that report was from a multicenter study, it is not included in this guideline because it was based on 95 patients, and we await the results of future studies.
A change from lactate uptake to production in the coronary circulation is evidence of ischemia instead of ischemic ECG changes,10,105,221,224 and lactate measurement in the coronary sinus is likely to be recommended in the future for the diagnosis of coronary MVS. Recently, the COVADIS international criteria indicated abnormal coronary flow reserve, abnormal coronary microvascular resistance, and coronary artery slow flow as evidence of abnormal coronary microvascular function.10 Coronary flow reserve can be measured by Doppler-wire105,237 or thermodilution using a pressure wire.81,238,239 CFR and coronary microvascular resistance81,239,240 do not provide evidence of coronary MVS. The same is true for TIMI frame counts,10,221 which indicate coronary slow flow. Doppler-wire is not currently commercially available and cannot be used,105,144,241,242 but real-time measurement of blood flow velocity by Doppler-wire during ACh or ergonovine provocation test allows calculation of coronary blood flow during the provocation test, and thus coronary MVS can be estimated.105 However, there are no diagnostic criteria for coronary blood flow to diagnose coronary MVS by pharmacological provocation test.
The COVADIS group has advocated a protocol of coronary microvascular function testing prior to ACh-provocation test.81,239 On the other hand, as will be discussed in detail in Chapter III.7, in Japan it is common practice to refrain from administering drugs that affect coronary vascular function before the ACh-provocation test.
4. Coronary Spasm After Drug-Eluting Stent Implantation
4.1 Pathophysiology and Epidemiology
The pathophysiological mechanisms of persistent or recurrent angina after percutaneous coronary intervention (PCI) include (1) flow-limiting epicardial obstruction, such as in-stent restenosis, stent thrombosis, and progression of coronary atherosclerosis in coronary segments distinct from those treated with index PCI, and (2) coronary vasomotion abnormalities including epicardial or microvascular spasm, and CMD.243 Table 10 gives the recommendation and evidence for coronary spasm provocation testing in symptomatic post-PCI patients. Although the coronary hyperconstricting response to ACh occurs near the edges of the stent,244 the degree of this response is enhanced in segments implanted with 1st-generation DES, compared with those with bare-metal stents (BMS).245,246 The DES-induced coronary hyperconstricting response has been reported for both 1st- and 2nd-generation DES,247,248 which is an important clinical issue as some serious cases exist among these reports. According to a Japanese report, significant hyperconstricting response was observed in 30 (71.2%) of 42 patients implanted with a 1st-generation DES who underwent ACh-induced spasm provocation test at follow-up.249 In a report examining the relationship between the degree of neointimal coverage by coronary angioscopy and coronary endothelial function assessed by intracoronary ACh infusion, less neointimal coverage was associated with an enhanced hyperconstricting response distal to the stent after 1st-generation DES implantation.250 Mechanistically, both poor neointimal coverage and the presence of intrastent thrombus were identified as independent factors contributing to the hyperconstricting response, suggesting the importance of endothelial dysfunction.250
Table 10. Recommendation and Level of Evidence for Coronary Spasm Provocation Test in Symptomatic Post-PCI Patients
| |
COR |
LOE |
In patients with persistent or recurrent angina after PCI, performing a spasm provocation
test with acetylcholine or ergonovine should be considered if coronary angiography
excludes significant coronary stenosis |
IIa |
C |
COR, Class of Recommendation; LOE, Level of Evidence; PCI, percutaneous coronary intervention.
Subsequently, 2nd-generation DES, which were clinically implemented in Japan around 2010, showed a decrease in the DES-induced coronary hyperconstricting response compared with 1st-generation DES.251,252 A report comparing the hyperconstricting response to ACh in segments implanted with and without 2nd-generation DES in the same patients at 6–8 months after PCI showed that there was no significant difference between the two.253 Also, cardiovascular events related to coronary spasm after PCI have been reported to be the lowest with 2nd-generation DES compared with BMS and 1st-generation DES (BMS 2.9%, 1st-generation DES 3.2%, 2nd-generation DES 0.4%), and the use of 2nd-generation DES and statins have been identified as independent factors contributing to the avoidance of cardiovascular events.254 In addition, when PCI was performed in patients with VSA diagnosed with a previous spasm provocation test using ergonovine, 1st-generation DES significantly increased cardiovascular events in patients with comorbid VSA compared with those without, and both BMS and 2nd-generation DES showed no significant difference between patients with and without comorbid VSA.255 Moreover, a pathological study showed that 2nd-generation DES had a higher rate of stent coverage and less inflammation and fibrin deposition than 1st-generation DES,256 which may contribute to the reduced hyperconstricting response to 2nd-generation DES.
An important pathological mechanism of the DES-induced coronary hyperconstricting response is the activation of Rho-kinase,111 a molecular switch in vascular smooth muscle contraction, as well as endothelial dysfunction described earlier. Rho-kinase activation inhibits myosin light chain phosphatase in vascular smooth muscle, resulting in inhibition of myosin light chain dephosphorylation and subsequent smooth muscle hypercontraction.111 The involvement of Rho-kinase in the coronary hyperconstricting response after DES implantation has been demonstrated in a porcine model,257 and in patients with CAD.258 Intracoronary infusion of fasudil, a Rho-kinase inhibitor, attenuates the DES-induced coronary hyperconstricting response. In a porcine model exploring the effects of DES components (antiproliferative drugs, polymers, and metal stents) on the coronary hyperconstricting response, polymers induced the response via inflammatory changes at the stent edges and by Rho-kinase activation.259 In addition, DES implantation induced formation of adventitial vasa vasorum (VV), and histologically developed inflammatory changes and Rho-kinase activation, suggesting an association between adventitial VV and DES-induced coronary hyperconstricting response.260 Furthermore, increased inflammatory accumulation in perivascular adipose tissue (PVAT) was seen on18 F-fluorodeoxyglucose positron emission tomography/computed tomography after DES implantation in a porcine model.261 On the other hand, DES implantation induced lymphangiogenesis in a porcine model, and lymphatic ligation after DES implantation exacerbated the coronary hyperconstricting responses and histologically demonstrated prolonged adventitial inflammation, which were associated with Rho-kinase activation.262 Taken together, these findings suggest that inflammation is indeed important for Rho-kinase activation as a pathological mechanism of the DES-induced coronary hyperconstricting response.263 Regarding therapeutic intervention of Rho-kinase activity, long-term treatment with nifedipine, a long-acting CCB, suppressed the DES-induced coronary hyperconstricting response through inhibition of inflammatory responses, microthrombus formation, and Rho-kinase activity in a porcine model.264
4.2 Treatment
In the Nifedipine on Coronary Vascular Function after Drug-Eluting Stent Implantation (NOVEL) study,265 100 patients with stable CAD who underwent implantation of an everolimus-eluting stent (EES), a 2nd-generation DES, were randomly assigned to receive either conventional treatment alone or additional long-acting nifedipine, and the patients underwent ACh-induced spasm provocation test 8–10 months after DES implantation. The results of the NOVEL study showed a significant reduction in coronary hyperconstricting responses to ACh in the nifedipine group compared with the control group. In addition, nifedipine-treated patients showed a decrease in serum levels of high-sensitivity C-reactive protein and an increase in those of adiponectin at follow-up, suggesting a relationship between the anti-inflammatory effect and the benefit of long-term nifedipine treatment.
On the other hand, in another study, 52 patients who underwent EES implantation for a single-vessel lesion were assigned to the β-blocker (bisoprolol 73%) or CCB (amlodipine 77%) group, and the positive rates of ACh-induced spasm provocation test at 9 months and major adverse cardiac events (MACE: composite of all-cause death, nonfatal MI, unstable angina, cerebrovascular disease, and coronary revascularization) at 24 months were investigated. The positive rate was similar in both groups (26.9%), but the incidence of MACE was significantly lower in the β-blocker group than in the CCB group, although all MACE were coronary revascularization (3.8% vs. 19.2%, P=0.01).266 However, this study lacked statistical power due to the small sample size, so further study is warranted.
5. Pediatric Disease, Coronary Sequelae in Kawasaki Disease and Vasospastic Angina
5.1 VSA in Children
Pediatric VSA is a rare disorder and described only in case reports. A literature search from 1985 to 2021 revealed 31 cases, and the reports were increased from the 2000s (Table 11,267–279 Figure 10267–279). The age of onset ranged from 6 to 19 years, with a median age of 13 years, and boys were twice as likely to have the disease as girls. Symptoms occurred either at rest or with exercise, with the rest state accounting for more than 2/3 of cases. Symptoms included anterior chest pain, chest discomfort, and syncope, possibly accompanied by epigastric pain or nausea. This condition occurred rarely as toothache, AMI, or ventricular fibrillation.271–273 Background of the patients included concomitant moyamoya disease, NO-related genetic mutations, and decreased reactive vascular index, a measure of systemic vascular endothelial function.274–276 VSA or drug-induced coronary spasm was reported in patients with cardiomyopathies such as muscular dystrophy.280
Table 11. Summary of Case Reports of VSA in Children
| |
(1985–2021) |
| No. of reports |
31 |
| Sex* |
Male 20 Female 10 |
| Age of onset (years) |
13 (6–19) |
| Onset of chest pain |
|
| At rest |
22 (71%) |
| Exercise - at rest |
3 (10%) |
| Exercise |
6 (19%) |
| Syncope |
4 (13%) |
| Myocardial infarction |
4 (13%) |
| Ventricular fibrillation · Cardiopulmonary resuscitation |
7 (23%) |
| Death |
2 (6%) |
| Positive myocardial troponin |
9 (30%) |
| Positive acetylcholine-induced test |
18 (58%) |
| Family history (cardiac disease) |
5 (16%) |
*1 case of no information available. VSA, vasospastic angina. (Collated from references267–279)
Diagnosis is often based on symptoms, ECG changes during attacks (ST-segment elevation or ST depression in ≥2 leads), or improvement of symptoms with nitrate use. ST-segment elevation/depression coinciding with chest pain in Holter ECG may also be a clue to the diagnosis. Provocation testing with intracoronary ACh administration, hyperventilation, or exercise is used for the diagnosis (see Chapter III.2).277 Provocation testing should be performed in collaboration with a cardiologist. Blood tests may show positive myocardial troponin and elevated cardiac enzymes. Treatment with oral or intravenous nitrates and calcium antagonists often improves the condition.276,278,279 In cases of refractory VSA, symptoms may persist and require continuous intravenous administration of nitrates, calcium antagonists, or magnesium sulfate. The conditions of cardiogenic shock necessitate intensive management to maintain hemodynamics.281 An implantable cardioverter defibrillator (ICD) device was used to treat cases of ventricular fibrillation and cardiac arrest.282 Autopsy of refractory cases has revealed coronary artery occlusion due to thickening of the coronary artery wall in multivessel lesions.271,274
5.2 History of Kawasaki Disease and VSA
Kawasaki disease (KD) is an acute febrile illness of children under 5 years of age, and is a vasculitis of medium-sized vessels with unknown cause. Inflammation in the acute phase of the disease induces coronary artery damage, resulting in coronary artery aneurysms in approximately 20% of untreated patients. Recently, treatment with intravenous immunoglobulin reduced the incidence of coronary sequelae to 2–3%.283 The occurrence of VSA in patients with a history of KD is rare, although 1 case in KD patient at rest and 1 during exercise were included in reports of VSA.284–286 In reports of VSA during pregnancy and delivery, a patient with a history of KD was included.287 Endothelial dysfunction in the epicardial coronary arteries has been reported in patients with KD-related coronary sequelae, but it is unknown whether endothelial dysfunction causes VSA in KD.288–290 There are also reports showing reduced MBF in cases of regressed coronary aneurysms after KD, even in the absence of significant stenosis of the epicardial coronary arteries.291 CMD in patients with a history of KD is an issue that should be addressed in the future.
III. New Insights Into Diagnosis
1. Diagnostic Criteria
Until 2008, VSA was diagnosed in Japan according to diagnostic criteria independently adopted by each institution.292 The “Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008 and 2013)”1,2 unified the diagnostic criteria for VSA, referring to previous reports and other findings.1,2 Yasue et al. state that VSA can be diagnosed even without performing CAG, provided that the anginal attacks disappear quickly upon administration of nitroglycerin and that any 1 of the following 5 conditions is met: (1) attacks occur at rest, particularly in the night and early morning; (2) marked diurnal variation is observed in exercise tolerance (in particular, reduction of exercise capacity in the early morning); (3) attacks are accompanied by ST elevation on ECG; (4) attacks are induced by hyperventilation (hyperpnea); and (5) attacks are suppressed by CCBs but not by β-blockers.293 The 2013 revision of the Guideline was based on this statement,2 which is also reflected in the international standardization initiatives on the diagnostic criteria for VSA that have been developed since that revision.9,294 There was no change in the outline of the 2013 revised guideline, which established reference items within the diagnostic criteria and set 3 grades of diagnostic criteria; “Definite”, “Suspected”, and “Unlikely”.2 However, whether to include “diffuse coronary spasm” in the positive diagnostic criteria for the pharmacological coronary spasm provocation test has been debated since the 2013 revision, as further accumulation of relevant evidence is needed. This focused update applies “diffuse coronary spasm” as a positive diagnostic criterion for CAG based on domestic and international evidence. The diagnostic criteria for VSA are provided below, and the diagnostic algorithm is shown in Figure 11.17,167,295–297
1.1 Diagnostic Criteria for “Definite/Suspected” VSA
If any 1 of the following conditions and 1 of the following requirements are met, Definite/Suspected VSA is considered present. If none are met, the condition is judged Unlikely to be VSA. Clinically, both Definite and Suspected VSA are diagnosed as VSA.
1.1.1 Conditions
Any 1 of (1)–(3)
(1) Spontaneous attacks.
(2) Positive for nonpharmacological coronary spasm provocation test (e.g., hyperventilation test and exercise test).
(3) Positive for pharmacological coronary spasm provocation test (e.g., ACh and ergonovine).
1.1.2 Requirements
Definite VSA: The patient is considered to have Definite VSA when ischemic change is clearly observed on the ECG during attacks (*1), when the ECG findings are borderline but a clear finding of myocardial ischemia or coronary spasm is obtained in examinations (*2) and the patient has a history and symptoms during attacks that are consistent with VSA; or when, if there is no ECG change during attacks or if ECG examination has not been performed, ≥1 of the reference items is met, and examinations (*2) reveal a clear finding of myocardial ischemia or coronary spasm.
Suspected VSA: The patient is considered to have Suspected VSA when the ischemic change on ECG during attacks is borderline, and no clear finding of myocardial ischemia or coronary spasm is obtained in any examination; (*2), or when, if there is no change on the ECG during attacks or ECG examination has not been performed, ≥1 of the reference items apply, and a clear finding of myocardial ischemia or coronary spasm cannot be demonstrated on any examination.
*1: Ischemic change is defined as a transient ST elevation ≥0.1 mV, an ST depression ≥0.1 mV, or a new appearance of negative U waves, recorded in ≥2 contiguous leads on the 12-lead ECG. If the ischemic ECG change is prolonged, the patient should be treated as directed in the guidelines for management of acute coronary syndrome.17
*2: Examinations include the pharmacological coronary spasm provocation test during cardiac catheterization and hyperventilation test.
At the time of the 2013 guideline revision, whether to include diffuse coronary spasm in the positive diagnostic criteria for coronary spasm on CAG during pharmacological coronary spasm provocation testing using ACh or ergonovine was inconclusive. However, several domestic and international reports included diffuse coronary spasm as a positive diagnostic criterion.9,101,106,112,157 In this guideline focused update, the positive diagnostic criteria for coronary spasm were changed and defined as follows, together with the previous findings:167,295–298 “transient, total, or subtotal focal occlusion (>90% stenosis) of a coronary artery with signs/symptoms of myocardial ischemia (anginal pain and ischemic ECG change) or 90% diffuse vasoconstriction induced in ≥2 contiguous segments of a coronary artery”.
1.1.3 Reference Items
An angina-like attack that disappears quickly upon administration of nitrate, and that meets at least 1 of the following 4 items:
(1) Appears at rest, particularly between night and early morning.
(2) Marked diurnal variation in exercise tolerance (in particular, reduction of exercise capacity in the early morning).
(3) Induced by hyperventilation (hyperpnea).
(4) Attacks are suppressed by CCBs but not by β-blockers.
2. Pharmacological Coronary Spasm Provocation Test
2.1 Overview
The pharmacological coronary spasm provocation test during cardiac catheterization involves the selective intracoronary injection of ACh or ergonovine followed by CAG. The “Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2013)”2 and the “JCS 2018 guideline on diagnosis of chronic coronary heart diseases”18 already included an overview of this provocation test, and new findings since then are added here. The provocation test aims to prove coronary spasm in patients with rest angina or rule out coronary spasm in patients with chest pain but without significant coronary artery stenosis. The patients with indication for this provocation test also include some cases of exertional angina pectoris and myocardial infarction (see Chapter I.1.3). Both the sensitivity and specificity of the provocation test for detecting coronary spasm are high, ranging from 80% to 90%. The sensitivity is reduced in patients with low activity of VSA or patients treated with an antispastic drug before the provocation test. Patients with multivessel coronary spasm have a poor long-term prognosis. On August 25, 2017, an additional indication for “OVISOT®
FOR INJECTION 0.1 g” was approved, and the ACh provocation test was officially covered by Japanese health insurance in 2018. Rest angina is common in Japan, and CAG often proves the presence of coronary spasm.299,300 The representative pharmacological provocation tests for coronary spasm include ACh167 or ergonovine301 provocation tests. In addition, adequate informed consent must be given before any invasive provocation test is performed in indicated cases.
2.2 ACh Provocation Test
ACh has a vasodilating effect by releasing NO from the endothelium and simultaneously also strongly contracts the vascular smooth muscles. Clinical studies in patients with variant angina have shown that selective injection of intracoronary ACh provokes coronary spasm with high sensitivity and specificity.167,295,296 Because many institutions have reported similar results, especially in Japan,297 this test has been established as a provocation test to diagnose coronary spasm as a pathogenesis of angina pectoris. With this provocation test, it is important to note that, especially in patients with highly active coronary spasm or multivessel coronary spasm, the provoked coronary spasm may be severe and extensive, and prolonged, which may cause critical conditions such as hypotension, cardiogenic shock, severe arrhythmia, and cardiac arrest. In such cases, intracoronary infusion of nitrate (nitroglycerin or isosorbide dinitrate) is necessary to release the spasm. The administration of drugs to raise blood pressure (noradrenaline) is necessary for hypotension, and serious arrhythmias should be treated immediately.
a. Standard Method of the ACh Provocation Test167,295–297,302,303
① Control CAG of the Left and Right Coronary Arteries: Perform CAG with the appropriate projection that ensures the best separation of the branches of each coronary artery. After ACh injection, repeat CAG in the same projection.
② Insertion of Temporary Pacing Electrode Into the Right Ventricle: Perform backup pacing (40–50 beats/min) because ACh administration, especially into the right coronary artery, may cause transient severe bradycardia.
③ Injection of ACh Into the Left Coronary Artery: Inject 20, 50, and 100 μg of ACh dissolved in 37℃ saline (concentration adjusted to obtain 5 mL solution volume for each quantity of ACh) into the left coronary artery over 20 s. Perform CAG 1 min after the start of each injection. If ischemic changes appear on the ECG or chest pain, perform CAG at that time. Doses of ACh should be given at 5-min intervals.
④ Injection of ACh Into the Right Coronary Artery: Inject 20 or 50 μg (each in 5 mL solution) into the right coronary artery over 20 s. The timing of CAG is the same as for the left coronary artery.
⑤ Left and Right CAG After Nitrate Administration: Inject the nitrate into each coronary artery, and perform CAG while the coronary artery is maximally dilated.
No principle states in which coronary artery to start the provocation test, the left or the right coronary artery, but the left coronary artery is often the first from the viewpoint of the number of coronary branches to be evaluated for the provoked spasm because the contralateral coronary spasm provocation test cannot be performed after nitrates administration for the release of provoked coronary spasm.
A small dose (20 μg) of ACh often provokes coronary spasm in patients with a high number of spontaneous attacks and high disease activity. In cases in which the incidence of hypotension or severe bradycardia during spontaneous attacks and extensive and severe ischemia is expected, starting with a smaller dose (10 μg) is recommended.
Because the half-life of ACh is extremely short, unlike spasm induced by ergonovine, the provoked coronary spasm spontaneously relieves in many cases. In other words, coronary spasm provoked by intracoronary infusion of ACh often does not require nitrate administration and does not affect the provocation test on the contralateral coronary artery, making it useful in the diagnosis of multivessel coronary spasm.296 Because multivessel coronary spasm attacks are often severe and are one of the prognostic factors in cases of variant angina,296,304 accurate diagnosis and treatment are important to improve the prognosis of these patients.
b. Sensitivity and Specificity of ACh Provocation Test167,297,305,306
Investigations in patients with atypical angina pectoris167,303 showed that ACh-provoked spasm was observed in 112 of 121 patients (93%) and in 144 (89%) of 162 coronary arteries (sensitivity, 89–93%) which coronary spasm was predicted to occur based on ECG at the time of the attack. ST-segment elevation was observed in 66% of the induced attacks, ST depression in 31%, and negative U waves in 3%. In more than 2/3 of patients, >50 μg of ACh was required to provoke coronary spasm in both the left and right coronary arteries. On the other hand, a study of patients with atypical chest pain without significant coronary artery stenosis167 demonstrated no provoked coronary spasm by ACh in 86 patients (specificity, 100%), and mild to moderate vasoconstriction and vasodilation was observed in some cases. A study in patients with severe coronary artery stenosis >90% showed that 4 of 16 patients with stable effort angina and 11 of 16 patients with a history of MI presented total or subtotal occlusion after provocation, consistent with the site of the stenosis.305 The diagnostic significance of this provocation test was high in patients without significant stenosis, but the specificity was low in patients with severe stenosis, suggesting that diagnostic significance was reduced. Investigations have shown that in Japanese patients, diffuse as well as focal coronary spasm is often prevalent. Whether or not to include diffuse coronary spasm as a positive diagnostic criterion for the spasm provocation test was inconclusive because of the lack of evidence accumulation at the time of formulation of the ‘‘Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2013)’’.2 Considering the current status of reports from Japan and overseas, this focused update includes diffuse coronary spasm as a diagnostic criterion.
2.3 Ergonovine Provocation Test
Ergonovine has a potent contractile effect on vascular smooth muscle by stimulating serotonin and α receptors. An investigation found that intravenous ergonovine-induced coronary spasm was almost the same as spontaneous attacks in patients with variant angina,307 and the clinical use of ergonovine was initiated, but a death with a high dose of intravenous ergonovine was reported.308 Later, the usefulness of the intracoronary ergonovine provocation test was confirmed, and the selective, lower-dose intracoronary ergonovine provocation test became a popular alternative to the conventional intravenous ergonovine provocation test.309,310 Many institutions in Japan reported data on the ergonovine provocation test, resulting in it being established as a pharmacological coronary spasm provocation test, as with the ACh-provocation test. The frequency of coronary spasm provoked by intravenous administration of ergonovine in variant angina ranges from 48% to 85%, but there are few reports on the diagnostic accuracy of intracoronary injection of ergonovine in variant angina. As with ACh, it is essential to note that this provocation test can induce severe coronary spasm in patients with high disease activity or with multivessel coronary spasm and that the provoked coronary spasm can be prolonged, resulting in critical conditions such as hypotension, cardiogenic shock, severe arrhythmias, and cardiac arrest. In such cases, it is necessary to quickly relieve the coronary spasm by intracoronary injection of nitrate (nitroglycerin or isosorbide dinitrate). Drugs to raise blood pressure (noradrenaline) should also be administered for hypotension. Severe arrhythmia should be treated immediately. However, ergonovine is not currently covered by Japanese health insurance.
a. Standard Method of the Ergonovine Provocation Test307–313
① Control CAG of the Left and Right Coronary Arteries: Perform CAG in the appropriate projection that ensures the best separation of the branches of each coronary artery. After the ergonovine injection, perform CAG in the same projection again.
② Injection of Ergonovine Into the Left Coronary Artery: Inject 20–60 μg of ergonovine dissolved in saline into the left coronary artery over a few minutes (≈2–5 min). Perform CAG 1–2 min after the start of each injection. If ischemic changes appear on the ECG or chest pain, perform CAG at that time. If the provocation test is negative, perform the provocation test in the right coronary artery 5 min later.
③ Injection of Ergonovine Into the Right Coronary Artery: Inject 20–60 μg of ergonovine dissolved in saline into the right coronary artery over a few minutes (≈2–5 min). The timing of CAG is the same as for the left coronary artery.
④ Left and Right CAG After Nitrate Administration: Inject the nitrate into each coronary artery, and perform CAG while the coronary artery is maximally dilated.
The provocation test can be started from either the left or right coronary artery. Coronary spasm provoked by ergonovine is less likely to release spontaneously than spasm provoked by ACh and often requires nitrates to relieve the spasm.314
In some cases, multivessel coronary spasm can be diagnosed by performing a contralateral provocation test after release of the provoked coronary spasm with nitrate, and the ergonovine provocation test can be performed in the contralateral coronary artery if the patient is hemodynamically stable.304 Multivessel coronary spasm is one of the prognostic factors in patients with VSA, and accurate diagnosis of multivessel coronary spasm is essential to improve the prognosis. In cases of continuous administration of ergonovine, CAG is performed during drug administration to confirm whether coronary spasm occurs.
The dose of ergonovine used for intracoronary administration differs among institutions, and there is currently no standardized dosage for this method.303 Based on previous reports, most institutions use a dosage of at least 20–60 μg for both right and left coronary arteries, and the continuous ergonovine administration method is recommended to avoid single administration for safety reasons. Continuous ergonovine administration requires a smaller dose and may further reduce complications. A small dose should be started when the ergonovine provocation test is performed to evaluate the severity of variant angina.
Investigations on the pharmacological coronary spasm provocation tests using ergonovine, serotonin, and ACh in patients with VSA suggest that each drug may provoke coronary spasm at a different site.314,315 Therefore, a negative result for a coronary spasm provocation test cannot entirely exclude the presence of coronary spasm. Considering the period of drug discontinuation before the provocation test or the activity of angina pectoris, treatment, including CCBs, should be initiated if there is a strong suspicion of VSA based on the clinical symptoms, even if the provocation test for coronary spasm is negative.
2.4 Indication Criteria
Table 12 shows the indication criteria for pharmacological coronary spasm provocation testing, which is summarized in reference to the ‘‘Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2013)’’,2 ‘‘JCS 2018 guideline on diagnosis of chronic coronary heart disease’’18 and other reports.106,148,149,156,157,167,295–297,301,307,310–312,316–318
Table 12. Recommendations and Levels of Evidence for Pharmacological Coronary Spasm Provocation Tests
2,18,106,148,149,156,157,167,295–297,301,307,310–312,316–318
| |
COR |
LOE |
It is recommended to perform pharmacological coronary spasm provocation tests for patients
with suspected vasospastic angina based on symptoms but not diagnosed with coronary spasm
by noninvasive evaluation |
I |
B |
Pharmacological coronary spasm provocation tests should be considered for patients diagnosed
with coronary spasm by noninvasive evaluation and for whom the effect of medical therapy is
inconclusive or inadequate |
IIa |
B |
Pharmacological coronary spasm provocation tests may be considered for patients who have
been diagnosed with coronary spasm by noninvasive evaluation and in whom medical treatment
has been effective |
IIb |
B |
It is not recommended to perform pharmacological coronary spasm provocation tests for patients
without symptoms suggestive of vasospastic angina |
III (No
benefit) |
C |
Pharmacological coronary spasm provocation tests should not be performed for patients with
acute coronary syndrome for which coronary angiography is performed and in whom serious
complications from induced coronary spasm are expected (e.g., severe cardiac dysfunction,
congestive heart failure) |
III
(Harm) |
C |
COR, Class of Recommendation; LOE, Level of Evidence. (Adapted from JCS 2018 guideline on diagnosis of chronic coronary heart diseases.18)
2.5 Diagnostic Significance
2.5.1 Objectives of Testing
The objectives of provocation testing are to (1) prove coronary spasm in patients with rest angina and in some patients with effort angina, (2) determine the severity of rest angina, and (3) rule out coronary spasm in patients without significant stenosis in the coronary arteries.
2.5.2 Diagnostic Performance
The sensitivity and specificity of coronary spasm provocation testing are generally quite high, being in the 80–90% range.167,301,310,317–319 However, coronary spasm may not be provoked in patients who have received drug therapy before provocation testing or in patients with infrequent spasm, even if ST elevation was confirmed by Holter ECG. Also, there are diurnal variations in the frequency of coronary spasm, and attacks only occur in the early morning in some patients.319 Therefore, to increase the diagnostic accuracy of pharmacological coronary spasm provocation testing, it should be performed in the morning whenever possible, and drugs, such as calcium antagonists and long-acting nitrates, should be discontinued for at least 2 days before testing if possible.
On the other hand, coronary spasm associated with ECG changes may be induced even in patients without a history of chest pain, but the pathological significance of such spasm is challenging to judge. Furthermore, with pharmacological coronary spasm provocation testing, it is challenging to assess the pathological relevance of coronary spasm that shows no change on ECG and does not meet the positive diagnostic criteria, although certain changes are seen on CAG. Recent reports from Europe and Japan indicate that 200 μg in the left and 80 μg in the right coronary artery improves diagnostic performance; however, the accumulation of evidence is still insufficient.157,320
2.5.3 Results and Diagnostic Significance
Proof of coronary spasm in patients with rest angina and in some with effort angina justifies long-term administration of nitrates and calcium antagonists as a treatment for angina pectoris. It also provides information to guide treatment with other drugs, such as whether β-blockers (which can induce coronary spasm) should be administered. Regarding the severity of rest angina, patients with multivessel coronary spasm have a poor long-term prognosis.296 An association between subclinical atherosclerotic lesions and prognosis has also been shown.146 In such cases, the results of provocation testing may be used to guide decisions about drug doses and the duration of treatment. Excluding coronary spasm in patients with chest pain showing no significant stenosis in the coronary arteries is crucial, especially in the Japanese population, because angina stemming from coronary spasm is more frequent in Japan.318 Coronary computed tomographic angiography (CCTA) has become popular recently and has a very high negative predictive value; therefore, excluding coronary stenosis in patients with chest pain is possible without performing CAG. However, the absence of coronary stenosis does not directly exclude a diagnosis of angina pectoris. It is also problematic to keep patients on long-term treatment with nitrates or calcium antagonists for chest pain without a definitive diagnosis of angina pectoris. It is crucial to perform coronary spasm provocation testing in patients with chest pain to determine the appropriate therapeutic strategy.
2.6 Contraindications
Pharmacological coronary spasm provocation testing is invasive, and extreme caution should be exercised when deciding the indications for this test. As listed in Table 12, (1) It is not recommended to perform pharmacological coronary spasm provocation tests for patients without symptoms suggestive of vasospastic angina, and (2) Pharmacological coronary spasm provocation tests should not be performed for patients with acute coronary syndrome for which coronary angiography is performed and in whom serious complications from induced coronary spasm are expected (e.g., severe cardiac dysfunction, congestive heart failure). If performing the pharmacological coronary spasm provocation test in the acute setting, ruling out other pathologies such as plaque rupture and SCAD with certainty and adequate consideration of safety are required. In addition, the use of ACh requires confirmation of the presence of contraindicated comorbidities (see ‘‘OVISOT®
FOR INJECTION 0.1 g’’ package insert). Although there is a retrospective study examining the safety of ACh use in patients with bronchial asthma, the evidence is limited.321
2.7 Complications
When coronary spasm provocation testing is performed, severe and extensive coronary spasm may be induced, and the induced vasospasm may be prolonged, especially in patients with frequent attacks or multivessel coronary spasm. As a result, hypotension, cardiogenic shock, severe arrhythmia, and cardiac arrest may occur. In such cases, an immediate alleviation of the coronary spasm by intracoronary infusion of nitrate, administration of vasopressors to maintain blood pressure, and immediate countermeasures for serious arrhythmia may be necessary. A recent investigation of complications in 17,700 patients undergoing coronary spasm provocation testing by intracoronary administration of ACh or ergonovine showed that serious procedural complications had a frequency of 0.89%, including 1 death (0.006%) and 2 cases of acute MI (0.01%).322
3. IVUS, OCT
CAG has been widely used in the study of VSA. Advances in in vivo imaging, such as IVUS and OCT, have allowed observation of the coronary artery wall itself in vivo and determination of the pathophysiology and etiology of VSA based on its morphological characteristics. Approximately 10 years have passed since the publication of the “Guidelines for diagnosis and treatment of patients with vasospastic angina” (2013 revision),2 and many findings on morphological features have been reported using in vivo imaging.
3.1 IVUS
IVUS has revealed that coronary arteries with spasm do not display significant stenotic lesions on CAG, but mild atherosclerosis is present.323,324 In addition, spasm sites frequently show negative remodeling with a reduced diameter compared with peripheral control vessel diameters.325–327 There are 2 morphological types of coronary spasm: focal and diffuse. The intima–media complex of the former is significantly thicker than that of the latter, suggesting that focal coronary spasm can be induced under relatively advanced atherosclerosis.328,329
Patients with focal spasms had fewer calcified lesions than those without spasms, although there were no significant differences in atherosclerotic lesion indices, such as plaque area and plaque angle.325,328 A study using virtual histology-IVUS, which uses signal processing of IVUS images to classify the histological characteristics of plaques into 4 colors, reported no difference in histological characteristics between patients with and without coronary spasm in a provocation test.330
3.2 OCT
OCT can discriminate 3 layers of the coronary artery wall and identify the change in each arterial wall layer before and after a provocation test. Since 2010, when OCT became available in Japanese clinical settings, many findings on the detailed morphological features of coronary spasm have been reported. Exploration of the spasm site in patients with VSA without significant stenosis on CAG via OCT revealed organic lesions in more than half of the cases.36 The morphology of the lesions varies widely, including layered plaque,331–333 intimal tears,36 thrombi,37,334 coronary artery dissection,335,336 macrophage accumulation,337 and vasa vasorum/intraplaque neovessels338 (Table 13, Figure 12). Therefore, in institutions skilled in the operation and reading of OCT, it should be considered when the involvement of organic lesions in the intima and tunica media of the vessel is suspected. Thickening of the tunica media,339,340 associated intimal bumps, and distorted lumen morphology have been observed even in patients without organic lesions341,342 (Figure 13). Furthermore, an attempt has been made to determine the complexity of the lumen caused by an intimal bump, using the shoreline development index to find the site of the spasm without a provocation test.341
Table 13. Recommendations and Levels of Evidence for IVUS/OCT in Patients With Suspected Coronary Spasm
| |
COR |
LOE |
Observation for the presence of atherosclerotic lesions in the coronary spasm site may be
considered using IVUS323–325,328,330/OCT36,37,331–338 |
IIb |
C |
| Searching for mechanisms of coronary spasm using IVUS325–329/OCT339–343 may be considered |
IIb |
C |
COR, Class of Recommendation; IVUS, intravascular ultrasound; LOE, Level of Evidence; OCT, optical coherence tomography.
3.2.1 Mechanisms of Coronary Spasm From OCT
Although no change in the intimal area occurs before or after coronary spasm, a significant increase in the area and thickness of the tunica media has been reported.339,340 Moreover, vasoconstriction occurs in asymptomatic patients with VSA, resulting in changes in intimal morphology.341 This finding suggests that hypercontraction of the tunica media, which is composed of vascular smooth muscle, plays an important role in the vascular structural changes of coronary spasm.343 Animal studies have shown that inflammation in the tunica media and hypercontraction of smooth muscle in the tunica media can be explained by a molecular mechanism centered on Rho-kinase,344 and that VSA cases also show inflammation consistent with the site of coronary spasm,32 which is consistent with this observation.
3.2.2 Involvement of Vasa Vasorum
The VV is a network of blood vessels, 30–200 μm in diameter, that surround larger blood vessels and can be evaluated in vivo using OCT.345 The VV is mainly responsible for supplying oxygen and nutrients to the vessel wall and is classified as adventitial (AVV), which runs in the adventitia, and intraplaque neovessels (IPNVs), which run within plaque.346 VVs are reported to proliferate in VSA, with AVVs increasing in diffusely spastic VSA, and IPNVs increasing in focally spastic VSA.112 Moreover, VSA with myocardial bridging (myocardial bridge) results in a loss of AVV at the site of myocardial bridging.347 However, the relationship between VVs and the phenotype of VSA remains unclear, and future studies are warranted.
3.2.3 Involvement of Layered Plaque
Organic abnormalities are found in more than half of cases of VSA.36 Of these, many cases have been reported to have layered plaque.331 Such stratified plaques are considered to be healed after asymptomatic rupture or erosion and are thought to form as a result of the fibrous component replacing the initial thrombus that was generated during the healing process.348,349 Thus, the main constituent components of layered plaques are the fibrous and flat thrombus components. One hypothesis for why layered plaques are more common in VSA is that thrombi develop and heal from intimal tears induced by coronary spasm, resulting in the formation of layered plaques,331 but this theory has not yet been fully elucidated.
4. Coronary Angioscopy
Coronary angioscopy (CAS) is an intravascular imaging modality that allows direct visualization of the vascular luminal surface in full-color, real-time images through a lens. Although evaluation of cross-sectional vessel images, as with IVUS and OCT, is not available with CAS, CAS enables detailed observation of the color tone, irregularities, and mobility of the luminal surface, which helps to evaluate intimal injuries, thrombus, etc.350,351
Because coronary spasm is diagnosed by CAG, CAS is not essential for clinical diagnosis of VSA and is instead mainly used for research purposes to clarify the pathophysiological mechanism.
The number of CAS reports on VSA is limited because CAS is approved for clinical use only in Japan. In this section, the CAS findings in VSA are summarized.
When coronary spasm sites are observed by CAS, intimal irregularities, thrombus, and yellow plaques are found at a frequency of ≈40%.352 In a recent report, thrombi were observed in coronary spasm-induced sites with about 30% frequency, whereas thrombus adherence was not seen in non-induced sites.353
Three mechanisms for the presence of thrombus in spasm sites have been proposed: (1) plaque rupture caused by external forces from coronary spasm,38,354 (2) intimal erosion due to hyperconstriction or hyperextension of the intima by severe or repeated coronary spasm,339 and (3) coronary spasm itself promotes thrombus formation by increasing platelet aggregation and activation of blood coagulation.33,355
Another study demonstrated that a strong vasoconstrictive response to intracoronary ACh infusion occurs distal to 1st-generation DES with poor neointimal coverage and in-stent thrombi.250 However, 2nd-generation everolimus-eluting stents demonstrated less thrombus adhesion and less vasoconstriction response to ACh than 1st-generation DES, and the degree of neointimal coverage was comparable.356 These reports suggest that there is an association between intracoronary thrombus and an endothelium-dependent vasoconstrictive response.
Although thrombi are often found in the early stages of vascular healing after stenting,357 thrombi in the chronic phase could be a predictor of future cardiovascular events.358 Because the presence of thrombus suggests endothelial dysfunction at the site, endothelial dysfunction may play a significant role in coronary spasm.
A previous study has investigated the CAS and OCT findings of the 2 coronary spasm types; focal spasm, which shows localized transient vessel narrowing, and diffuse spasm, which is diffuse vasoconstriction in >2 adjacent AHA coronary segments.359 In that study, yellow plaques and mural thrombi were more frequently observed at the focal spasm site than at the diffuse spasm site, and in addition the plaque volume and lipid content were larger at the focal spasm site.359
These results indicate that focal spasm could be related to a local hypersensitivity reaction due to atherosclerotic changes,323,339,360,361 whereas diffuse spasm could be attributed to disturbances of vasomotion.359 Therefore, in patients with focal coronary spasm, administration of aspirin or statins in addition to CCBs and nitrites may be considered to prevent future cardiovascular events.146,359,362 It has been reported that patients with yellow plaques in the chronic phase after DES implantation have a poorer prognosis.363 Thus, careful attention to patients presenting focal coronary spasm with yellow plaques may be required. Because differences in the features and the progression of arteriosclerosis have been found between focal and diffuse spasm, the mechanism may also differ between these two types of spasm. These have not yet been fully elucidated, and further research is warranted.
5. CT, MRI, Nuclear Medicine Examinations
5.1 Significance of Noninvasive Imaging in the Diagnosis of VSA
Recommendations for noninvasive imaging in patients with suspected VSA are shown in Table 14.364
Table 14. Recommendations and Levels of Evidence for Noninvasive Imaging in Patients With Suspected Vasospastic Angina
| |
COR |
LOE |
CCTA should be considered to rule out obstructive coronary artery disease in patients
with suspected vasospastic angina. |
IIa |
C |
123I-BMIPP myocardial scintigraphy may be considered in patients with suspected
vasospastic angina364 |
IIb |
C |
123I-BMIPP, 123I-β-methyl-p-iodophenyl-pentadecanoic acid; CCTA, coronary computed tomography angiography; COR, Class of Recommendation; LOE, Level of Evidence.
5.1.1 Coronary Computed Tomography Angiography (CCTA)
Even when a patient has symptoms suspicious of VSA, it may be difficult to exclude obstructive CAD by symptoms and ECG. CCTA has a high negative predictive value for obstructive CAD and is useful for ruling it out.365 The ESC guidelines recommend invasive angiography or CCTA to evaluate underlying CAD in patients with characteristic episodic resting anginal symptoms and ST-segment changes that are relieved by nitrates or CCBs.6 Therefore, it is reasonable to consider CCTA to rule out obstructive CAD in cases of suspected VSA.
On the other hand, it is difficult to diagnose VSA with CCTA, considering the impracticality of CCTA imaging during an attack of coronary spasm and the fact that coronary arteries are usually dilated with nitroglycerin during CCTA imaging to improve coronary artery visualization. In the absence of obstructive CAD on CCTA, the need for evaluation of INOCA, including VSA, should be carefully considered. It should also be noted that obstructive CAD may be accompanied by VSA, so the presence of obstructive CAD on CCTA does not exclude VSA.
In addition, β-blockers are sometimes used during CCTA to improve coronary artery visualization by controlling the patient’s heart rate, but, in general, there is concern that β-blockers may exacerbate coronary spasm.366 Caution should be exercised in the use of β-blockers when testing patients whose history is highly suggestive of VSA and whose risk is considered high, such as patients with a history of syncope or frequent resting anginal symptoms. Because calcium antagonists such as verapamil and diltiazem, which are used to treat VSA, can also be expected to decrease heart rate, consideration may be given to take these medications instead of β-blocker administration during CCTA.
5.1.2 Myocardial Scintigraphy
In the “Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina)” (JCS 2013),2 123I-MIBG (123I-metaiodobenzylguanidine) myocardial scintigraphy, 201Tl (201thallium) myocardial scintigraphy combined with hyperventilation stress test or exercise stress test, and 123I-BMIPP (123I-β-methyl-p-iodophenyl-pentadecanoic acid) myocardial scintigraphy were all Class IIb recommendations and may be considered in patients with suspected VSA.2 Reports from 1980 to 2018 on the diagnostic performance of these tests for VSA have been summarized.364 123I-BMIPP myocardial scintigraphy is reported to have a relatively high diagnostic performance with sensitivity of 72.5% and specificity of 82.7%, whereas 123I-MIBG myocardial scintigraphy (sensitivity 61.9%, specificity 79%) and 201Tl myocardial scintigraphy (exercise stress: sensitivity 56.6%, specificity no data; hyperventilation stress: sensitivity 64.9%, specificity 54.5%) had relatively insufficient diagnostic performance.364 Although VSA was diagnosed as coronary spasm provoked by the intracoronary administration of ACh or ergonovine in these reports on diagnostic performance, it should be noted that the diagnostic criteria for VSA have not been standardized, the sample size of these studies were small, and biases were not fully eliminated.364 Considering that little research has been conducted on these testing methods in recent years, we have not included in this focused update version of the Guideline the recommendations for 123I-MIBG myocardial scintigraphy and 201Tl myocardial scintigraphy combined with hyperventilation stress test or exercise stress test. The following outlines 123I-BMIPP myocardial scintigraphy.
5.1.3 123I-BMIPP Myocardial Scintigraphy
123I-BMIPP myocardial scintigraphy is a procedure to image myocardial fatty acid metabolism. The administered 123I-BMIPP, as with free fatty acids in the blood, is taken up by cardiac myocytes and becomes 123I-BMIPP-CoA, which is mainly incorporated into the intracellular lipid pool and partly translocated into mitochondria. 123I-BMIPP is a branched-chain fatty acid with a methyl group at the β position of the carboxyl group, and it accumulates temporarily in the myocardium, which produce images reflecting fatty acid metabolism.
Beta-oxidation of fatty acids accounts for almost two-thirds of myocardial energy metabolism. However, in the presence of myocardial ischemia, the substrate for energy metabolism shifts from fatty acids to glucose. In addition, the impairment of myocardial fatty acid metabolism associated with ischemia persists for a while after coronary reperfusion (ischemic memory).367–369 By performing 123I-BMIPP myocardial scintigraphy during this period, the myocardial fatty acid metabolic impairment associated with myocardial ischemia can be detected without a stress test. Therefore, 123I-BMIPP myocardial scintigraphy may be useful in the diagnosis of VSA, but it should be noted that it is difficult to differentiate it from ischemia due to obstructive CAD. The diagnostic sensitivity is not high (72.5%) enough to rule out VSA with negative results. In addition, the degree of accumulation of 123I-BMIPP is influenced by the severity of ischemia and the time between the ischemic attack and imaging; thus care must be taken in the interpretation.
123I-BMIPP myocardial scintigraphy can play a role in the follow-up of therapy. Previous reports have shown that in 75.5% of patients with VSA, the course of symptoms and the result of 123I-BMIPP myocardial scintigraphy are consistent, but in the remaining 24.4% of patients there is a discrepancy;364 thus further evidence should be accumulated regarding the prognostic impact of follow-up strategies using 123I-BMIPP myocardial scintigraphy.
5.2 Significance of Noninvasive Imaging in the Diagnosis of Microvascular Angina
Recommendations for noninvasive imaging in the diagnosis of MVA are shown in Table 15.88,173,370–372
Table 15. Recommendations and Levels of Evidence for Noninvasive Imaging in the Diagnosis of Microvascular Angina
| |
COR |
LOE |
Evaluation of myocardial perfusion with 13N-ammonia PET should be considered in
patients with stable chronic chest pain but no significant stenosis in the epicardial coronary
arteries88,173 |
IIa |
B |
Evaluation of myocardial perfusion with stress myocardial perfusion MRI may be considered
in patients with stable chronic chest pain but no significant stenosis in the epicardial
coronary arteries370–372 |
IIb |
B |
COR, Class of Recommendation; LOE, Level of Evidence; MRI, magnetic resonance imaging; PET, positron emission tomography.
5.2.1 13N-Ammonia Positron Emission Tomography (13N-Ammonia PET)
PET allows quantitative evaluation of MBF using tracers such as 15O-water, 13N-ammonia, and 82rubidium (82Rb). These are the most widely studied noninvasive quantitative methods of MBF to date and are considered the gold standard.373
Imaging in list mode is performed at the same time as or slightly before tracer injection, dynamic data are collected, and MBF is calculated using mathematical models such as compartment analysis. Pharmacological stress such as adenosine injection increases MBF due to endothelium-independent intramyocardial vasodilation. MBF reserve (MFR) is obtained by dividing MBF at pharmacologic stress by MBF at rest. MFR can be impaired in both epicardial coronary stenosis and CMD, but it can be used to evaluate coronary microvascular function in patients without significant stenosis of the epicardial coronary arteries. A reduction in MFR assessed by myocardial perfusion PET has been shown to be associated with cardiovascular events independent of the severity of coronary artery stenosis.173 In addition, studies using myocardial perfusion PET to assess the severity of CMD have shown that patients with an MFR <2.0 have a higher 3-year incidence of cardiac events compared with patients with preserved MFR.88
In Japan, only the 13N-ammonia PET scan is covered by health insurance for the diagnosis of IHD that cannot be diagnosed by other tests. However, 13N-ammonia requires in-center synthesis using a small cyclotron, which limits the number of facilities where it can be performed.
5.2.2 Stress Myocardial Perfusion MRI
Stress myocardial perfusion MRI can provide a visual or semiquantitative assessment of reduced myocardial perfusion. Stress myocardial perfusion MRI has a high diagnostic performance for ischemia, and a meta-analysis using CAG with FFR as the standard has reported a diagnostic performance exceeding that of single-photon emission computed tomography (SPECT) and is comparable to PET (PET: sensitivity 84%, specificity 87%. MRI: sensitivity 89%, specificity 87%. SPECT: sensitivity 74%, specificity 79%).374 Myocardial perfusion MRI is dynamic imaging of the myocardium with an intravenous bolus injection of gadolinium contrast agent to evaluate the dynamics of the first pass of the gadolinium. To assess myocardial ischemia, it needs to be combined with pharmacological stress using coronary vasodilators such as adenosine or adenosine triphosphate (ATP). In myocardium with preserved blood flow, the gadolinium contrast agent generates a high signal as it perfuses the myocardium, whereas myocardium with reduced blood flow has a slower onset of signal intensity and relatively low signal intensity. Typically, myocardial perfusion MRI scanned during coronary vasodilator stress shows a lower signal in the endocardial compared with the epicardial myocardium in patients with myocardial ischemia. When such findings suggestive of myocardial ischemia are obtained in patients without significant stenosis of the epicardial coronary arteries, the involvement of CMD is suspected.375,376 The myocardial perfusion reserve index (MPRI), a semiquantitative measure of myocardial perfusion reserve, can be calculated from the time-signal intensity curves of resting and stress myocardial perfusion MRI. It has also been reported that the MPRI can be used to detect patients with CMD diagnosed by catheterization,371 and has been shown to be associated with prognosis.370,372
A quantitative evaluation method for MBF using stress myocardial perfusion MRI has also been developed. It has been reported that MBF quantitatively evaluated by stress myocardial perfusion MRI correlates well with MBF evaluated by PET, and is a promising method for evaluating CMD.377 However, it requires a dual bolus approach of contrast agents or dual sequence and dedicated software, and is not yet widely used in clinical practice. Further accumulation of evidence is expected in the future.
Coronary vasodilators such as adenosine and ATP, which are used for pharmacological stress, are not covered by health insurance in Japan as drugs for stress myocardial perfusion MRI examinations, which is an obstacle to the widespread use of this testing method. In addition, arrhythmias such as AF are likely to worsen the image quality, and the gadolinium contrast agent cannot be used in patients with renal dysfunction (endstage renal disease with long-term dialysis, nondialysis cases with estimated glomerular filtration rate <30 mL/min/1.73 m2, acute renal failure, etc.378). These are drawbacks to stress myocardial perfusion MRI. However, unlike PET, there is no radiation exposure, and when combined with myocardial delayed enhancement imaging, MI and other cardiomyopathies can also be evaluated in a single examination.
5.2.3 CCTA
CCTA has a high negative predictive value in the diagnosis of obstructive CAD and is performed mainly to rule it out in cases of suspected CAD.365,379 Even in patients without obstructive CAD, if symptoms suggest myocardial ischemia, further evaluation is warranted because of the possibility of INOCA. On the other hand, one of the weaknesses of CCTA is that its positive predictive value for the diagnosis of obstructive CAD is not high enough.365,380 Even if CCTA shows >50% stenosis, invasive CAG often does not show it. It is also difficult to evaluate whether the coronary artery stenosis detected by conventional CCTA alone is a functionally significant stenosis or not. Recently, FFRCT has emerged as an attractive method that can overcome these weaknesses. In addition, myocardial perfusion CT has made it possible to diagnose myocardial ischemia and to quantitatively evaluate MBF.
a. FFRCT (Fractional Flow Reserve-Computed Tomography)
FFRCT is a method of noninvasively estimating the FFR from conventional CCTA by post-hoc analysis. Based on 3D anatomical and physiological models of the coronary arteries created from conventional CCTA, fluid dynamics analysis is applied to simulate blood flow dynamics, and the estimated FFR values at each coronary artery segment are calculated as FFRCT values. The NXT study has shown improved specificity and positive predictive value with FFRCT compared with conventional CCTA when ischemia demonstrated by invasive FFR is used as the standard (CCTA: sensitivity 94%, specificity 34%, positive predictive value 40%, negative predictive value 92%. FFRCT: sensitivity 86%, specificity 79%, positive predictive value 65%, negative predictive value 93%).381 When the quality of CCTA images is sufficient enough to analyze FFRCT, it has high diagnostic performance compared with SPECT and PET.175
In Japan, the HeartFlow FFRCT
(HeartFlow, Inc., Mountain View, California) was covered by health insurance in December 2018, but the number of facilities where it can be performed is limited.
b. Stress Myocardial Perfusion CT
CT perfusion (CTP) is a method of evaluating myocardial ischemia by observing the effect of intravenously injected iodine contrast medium on the myocardium, combined with pharmacological stress with coronary vasodilators such as adenosine and ATP. A meta-analysis using CAG with FFR as the standard reported that the diagnostic performance of stress CTP for ischemia is high (sensitivity 88%, specificity 80%), exceeding that of SPECT and comparable to PET and stress myocardial perfusion MRI.374
There are 2 types of CTP: static CTP, in which evaluation is based on image data from a single cardiac phase, and dynamic CTP, in which the first pass of contrast agent to the myocardium is imaged over time. A meta-analysis using CAG with FFR as the standard reported that both imaging methods have high diagnostic performance (static CTP: sensitivity 72%, specificity 90%; dynamic CTP: sensitivity 85%, specificity 81%).382 Static CTP allows a relative reduction in radiation dose, whereas dynamic CTP is characterized by its ability to quantify MBF. Stress CTP is characterized by its ability to simultaneously evaluate CCTA for the presence of occlusive CAD, and its usefulness in the diagnosis of INOCA has been reported.383 However, as with the stress myocardial perfusion MRI, coronary vasodilators such as adenosine and ATP, which are used for pharmacological stress, are not covered by health insurance in Japan as drugs for stress CTP.
5.3 Significance of Noninvasive Imaging in the Diagnosis of MINOCA
5.3.1 Cardiac MRI
CMR is useful to explore the underlying etiology of TP-NOCA (Table 16384,385). LGE imaging requires the administration of gadolinium contrast agent, whereas cine MRI and T2-weighted imaging are performed without contrast agents.
Table 16. Recommendation and Level of Evidence for Cardiac MRI in the Diagnosis of MINOCA
| |
COR |
LOE |
Cardiac MRI with gadolinium contrast should be considered to explore the underlying
etiology of TP-NOCA384,385 |
IIa |
B |
COR, Class of Recommendation; LOE, Level of Evidence; MINOCA, myocardial infarction with non-obstructive coronary arteries; MRI, magnetic resonance imaging; TP-NOCA, troponin-positive non-obstructive coronary arteries.
Cine MRI can obtain cine images with high spatial resolution and can detect regional wall motion abnormalities. It is possible to set an arbitrary imaging cross-section, and evaluation of the right ventricle, which is difficult to evaluate with echocardiography, is also possible.
On T2-weighted images, edematous tissue can be detected with high signal. Myocardium damaged by AMI, acute myocarditis, or takotsubo syndrome can all be depicted with high signal on T2-weighted images.
There are various LGE patterns depending on the etiology of myocardial injury. Usually, MI shows subendocardial or transmural LGE in a particular coronary artery territory.386 Myocarditis, on the other hand, often shows mid-wall or epicardial LGE.386 LGE is usually absent in takotsubo syndrome,387 but has been reported as present in some cases in the acute phase.388,389
CMR with gadolinium contrast has been reported to distinguish the etiology in 87% of patients with TP-NOCA (acute myocarditis: 37%, takotsubo syndrome: 27%, AMI: 21%).385 In a meta-analysis including 556 TP-NOCA patients, CMR with gadolinium contrast was reported to determine MI in 21% of patients and myocarditis in 33% of patients.384
6. Vascular Endothelial Function Test and Vascular Reactivity
6.1 Significance and Usefulness of Vascular Endothelial Function Tests in the Pathogenesis and Diagnosis of INOCA
Impaired production and release of NO due to vascular endothelial dysfunction plays an important role in the pathogenesis of coronary artery vasospasm. However, although vascular endothelial dysfunction is frequently observed in atherosclerosis, not all atherosclerosis results in coronary artery vasospasm. This is thought to be because the pathophysiology of coronary artery vasospasm involves multiple factors, such as genetic predisposition (e.g., eNOS gene polymorphisms), that directly contribute to endothelial dysfunction and abnormal increase in vascular smooth muscle tone. As discussed in detail in other chapters, INOCA includes epicardial coronary spasm as well as CMD. The primary pathogenesis of CMD is either (1) structural remodeling of the microvasculature or (2) microvascular functional abnormality, or a combination of both.390 Typical features of structural remodeling are wall thickening in the lumen of arterioles and capillary rarefaction,391 which reduces the vasodilatory ability of the microvasculature and limits maximum blood flow and oxygen supply. The following parameters are used to evaluate structural remodeling: decrease in CFR, assessed by coronary artery reactivity to endothelium-independent vasodilators such as adenosine; and increase in the IMR. Microvascular dysfunction is primarily an abnormality of arterioles with relatively larger diameters that act as resistance vessels.390 The physiological effect of microvascular function is an endothelium-dependent vasodilatory response in resistance vessels that occurs with increased oxygen demand in tissues. Vascular endothelial dysfunction causes impaired vasodilation and, in some cases vasoconstriction.392 Coronary endothelial function is invasively assessed by increasing coronary blood flow through the administration of ACh to coronary arteries. ACh acts as both vasoconstrictor and vasodilator.393–395 As a vasoconstrictor, it binds to the muscarinic type-3 receptor (M3 receptor) on VSMCs and stimulates the intracellular release of calcium ions, inducing vasoconstriction. As a vasodilator, it binds to the M3 receptor on vascular endothelial cells, stimulates the release of calcium ions, and activates NO synthase, which results in calmodulin-dependent NO release; NO stimulates soluble guanylate cyclase (sGC) in vascular smooth muscle to increase cyclic guanosine monophosphate (cGMP), causing vasodilation. Thus, ACh predominantly induces either the vasoconstriction of vascular smooth muscle or vasodilation mediated by vascular endothelial cells. It has been reported that myocardial ischemia during exercise stress myocardial perfusion scintigraphy or at rest in INOCA patients correlates with endothelial dysfunction of the left anterior descending coronary artery as assessed by an intracoronary ACh test.396,397 Microangiopathy due to structural remodeling of the microvasculature is often complicated by coronary endothelial dysfunction.80
There are 2 major noninvasive tests of peripheral vascular endothelial function currently used in clinical practice: flow-mediated endothelium-dependent vasodilation (FMD), and reactive hyperemia peripheral arterial tonometry (RH-PAT). The peripheral vascular endothelial function assessed by these tests is useful in prediction because it correlates positively with coronary endothelial function.398,399 Other reports have shown that endothelial dysfunction in INOCA involves not only coronary arteries but also systemic arteries.400–402 Coronary endothelial dysfunction in INOCA is associated with the urinary albumin/creatinine ratio, a marker of the renal microcirculation.403 Additionally, a recent study reported on the response of resistance vessels to drugs using gluteal subcutaneous fat biopsies from patients with INOCA, including CMD, MVS, and VSA; the results showed decreased endothelium-dependent vasodilatory responses in peripheral arteries and increased responses to vasopressor substances.404 Therefore, coronary artery disorder in INOCA is considered part of a systemic vascular disorder, and noninvasive tests of peripheral vascular endothelial function may predict INOCA. As an illustration, it has been reported that vascular endothelial dysfunction assessed by FMD or RH-PAT correlates with INOCA,398,405,406 and that vascular endothelial dysfunction in patients with INOCA assessed by FMD and RH-PAT is a strong predictor before catheterization.398,407 Likewise, previous studies have reported concomitant CMD and peripheral vascular endothelial dysfunction assessed by RH-PAT or FMD in patients with VSA.143,408,409 In contrast, other studies have reported that RH-PAT and FMD do not correlate with CMD,410,411 so further studies are required.
6.2 Usefulness of Assessing Peripheral Vascular Endothelial Function for Prognostication in INOCA Patients
Patients with CMD or VSA have a 4–5-fold risk of cardiovascular death and MI compared with patients without cardiac disease but similar conventional cardiovascular risk.412 Among these patients, complications of CMD with coronary endothelial dysfunction have been reported to have a particularly poor prognosis;412 therefore, risk assessment is important. Vascular endothelial function plays an important role not only in the regulation of vascular tonus, but also in vascular permeability, platelet function, the coagulation/fibrinolytic system, and smooth muscle proliferation. Thus, it involves INOCA as well as atherosclerosis development and acute coronary events. Coronary endothelial dysfunction has also been associated with the development of subsequent cardiovascular events in INOCA patients.413,414 Furthermore, the assessment of peripheral vascular endothelial dysfunction in INOCA patients by noninvasive RH-PAT could also predict subsequent cardiovascular events.415 Of the 2 available tests for peripheral vascular endothelial function in clinical practice, RH-PAT and FMD, a meta-analysis reported that their prognostic value was comparable, with a 1 SD (standard deviation) deterioration in measurements for either test doubling the risk of subsequent cardiovascular events.416
In summary, noninvasive assessment of vascular endothelial function is useful for predicting INOCA and the prognosis of INOCA patients. Additionally, the noninvasive nature of the tests allows for repeated testing and can be used for patient-specific monitoring (Table 17).
Table 17. Recommendations and Levels of Evidence for Noninvasive Endothelial Function Tests
| |
COR |
LOE |
Vascular endothelial function testing may be considered for patients with suspected INOCA,
including VSA and CMD |
IIb |
C |
Vascular endothelial function tests may be considered for patients with INOCA to predict
prognosis |
IIb |
C |
CMD, coronary microvascular dysfunction; COR, Class of Recommendation; INOCA, ischemia and non-obstructive coronary artery disease; LOE, Level of Evidence; VSA, vasospastic angina.
6.3 Significance of Vascular Endothelial Function in MINOCA
MINOCA encompasses the following pathological conditions: plaque disruption or erosion, coronary artery vasospasm, SCAD, CMD, and other type 2 MI that cause an imbalance of the oxygen demand–supply without obstructive CAD. As described above, endothelial dysfunction plays an important role in plaque disruption or erosion, coronary artery vasospasm, and microangiopathy, and these conditions are associated with peripheral vascular endothelial dysfunction as assessed by RH-PAT and FMD. Studies examining the association between SCAD and endothelial dysfunction have not yielded consistent results;41,417,418 however, coronary endothelial dysfunction may be involved in the pathogenesis of MINOCA. Further studies are needed to determine whether tests of vascular endothelial function are useful in predicting the development of MINOCA and the prognosis of patients with MINOCA.
6.4 Reference Values in the Testing of Peripheral Vascular Endothelial Function
There is ample evidence that vascular endothelial dysfunction plays a central role in various pathophysiologies, such as early and advanced atherosclerosis, coronary artery vasospasm, and microangiopathy; it has been proven to be predictive of cardiovascular events.416 On the other hand, guidelines for reference values and diagnostic criteria of peripheral endothelial dysfunction have not been established because of differences in subjects, study designs, and measurement methods. In 2021, the Japanese Circulation Society and the Japan Society for Vascular Failure published diagnostic guidelines for the application of tests of vascular endothelial function in daily clinical practice, disease management, and treatment.419 Figure 14419 shows the reference values for the 2 noninvasive vascular endothelial function tests that can be used in clinical practice: FMD, by placing a tourniquet around the forearm, and RH-PAT, which measures finger arterial pulse waves. The reference values shown here are not those determined by studies to predict coronary artery vasospasm or INOCA, but those reviewed from reports examining vascular endothelial function and prognosis. The validity of these reference values needs to be studied further in the future.
7.1 Vasospasm and CMD in INOCA
INOCA is a concept that encompasses several different pathophysiologies, including VSA and CMD. Although active vasoconstriction is diagnosed by imaging to confirm the response to drugs (ACh, ergonovine), physiological testing is required to evaluate the dilatation function of coronary arteries, especially coronary microvessels. Currently, CFR and IMR are used to evaluate the coronary microvascular dilation response. A low CFR and high IMR are the diagnostic criteria for MVA.139
7.2 Coronary Flow Reserve (CFR)
CFR is a measure of the reserve capacity of how much maximal hyperemic blood flow can increase relative to resting blood flow. It represents the ability of coronary blood flow to increase in response to increased myocardial oxygen demand. It is mainly regulated by resistance vessels (pre-arterioles, arterioles, pre-capillaries, and capillaries) that are <500 μm in diameter.
CFR is an indicator of abnormalities in both the epicardial arteries and coronary microvasculature, and can be used as an indicator of the coronary microcirculation if there is no significant stenosis in the epicardial arteries. However, its interpretation requires caution because it is sensitive to many other influences besides coronary stenosis, including myocardial status, cardiac (pressure and volume) load status, blood pressure, and heart rate at the time of measurement.
Invasive measurement of CFR includes a Doppler method using a Doppler guidewire, and a thermodilution method using a guidewire with a temperature sensor, and noninvasive tests include transthoracic echocardiography, myocardial scintigraphy, and PET, etc. In INOCA evaluation, no difference in the detection rate of CMD by CFR has been found between studies using invasive and noninvasive tests.139 Among the noninvasive tests, the detection rates have been reported to be higher in PET studies.
7.2.1 Standard for CFR Measurement by Thermodilution Method
By using a 0.014-inch guidewire with a pressure sensor and a temperature sensor, it is possible to measure CFR as well as FFR using the thermodilution method. The mean transit time (Tmn) is measured from the thermodilution curve in the guiding catheter and the thermodilution curve by the temperature sensor near the tip of the wire when room temperature saline is administered into the coronary artery. The Tmn is then measured again after maximum hyperemia is induced by administering a drug (adenosine, ATP, papaverine hydrochloride, nicorandil, etc.) that dilates the resistance vessels maximally.
According to the indicator dilution theory:
F = V / Tmn
where F indicates blood flow; V is vascular volume between the injection site and the measuring site; and Tmn, the mean transit time travelling from the injection site to the distal sensor.
Because CFR is the ratio of resting blood flow F-rest to maximal hyperemic blood flow F-hyperemia:
CFR = F-hyperemia / F-res = (vessel volume V / Tmn-hyperemia) / (vessel volume V / Tmn-rest)
Assuming the epicardial vascular volume V remains unchanged, CFR can be calculated as:
CFR = Tmn-rest / Tmn-hyperemia
7.2.2 Standard for CFR Measurement by the Doppler Method
The Doppler guidewire comprises a 0.014-inch guidewire with an ultrasound transducer onto its tip to measure coronary flow velocity using Doppler. To accurately measure coronary flow velocity, the transducer is placed in a straight section of an epicardial coronary artery, at a sufficient distance from either stenosis or vessel curve to avoid the influence of them, and the ultrasound beam direction is set as parallel as possible to the direction of coronary flow. Intracoronary nitrate is administered to maintain constant vessel area at the measurement site, and after confirming that a good flow velocity profile has been obtained, the time-averaged peak velocity (APV) at rest is measured. The APV is measured again during maximal hyperemia. Assuming the vessel area at the measurement site is constant, the ratio of APV represents the ratio of coronary blood volume. CFR can be calculated as:
CFR = APV at maximum hyperemia / APV at rest
7.3 Index of Microcirculatory Resistance (IMR)
By measuring intracoronary pressure and coronary flow at the distal coronary artery, just before the myocardial perforator branch, blood vessel resistance distal to the measurement site can be obtained. There are 2 resistance indices: IMR, obtained by thermodilution method using a pressure and a temperature sensor,420–423 and HMR (hyperemic microvascular resistance), obtained by a wire with a pressure and Doppler sensor.144,424 IMR and HMR are used as specific indices of coronary microcirculatory resistance compared with CFR (Figure 15).
7.3.1 Standard for IMR Measurement
A pressure guidewire with a temperature sensor is used to calculate IMR by simultaneously measuring distal coronary pressure (Pd) and distal Tmn. The pressure and temperature sensors are placed at least 6 cm distal to the catheter tip. The recommended location in each coronary artery is the mid to distal two-thirds of the left anterior descending artery, just before the 4PD-4AV bifurcation in the right coronary artery, and the branch with the largest perfusion area in the left circumflex artery.
TMR (true microcirculatory resistance) = Pd / F = Pd · Tmn / V
Assuming that vascular volume V is constant, TMR can be approximated by IMR as follows:
IMR = Pd · Tmn
7.4 Comprehensive Diagnostic Procedures for VSA and CMD in INOCA (Figure 16)
Both a low CFR and high IMR are used to diagnose CMD. In a report of CFR and IMR measurements following an ACh-provocation test as an evaluation for INOCA,142 a positive ACh-provocation was found in 68%, low CFR (<2.0) in 35%, and high IMR (≥18) in 40%. Many of these coexisted: VSA complicated by low CFR in 37%, high IMR in 48%, and VSA, low CFR and high IMR in 22%. On the other hand, in Europe and the USA, the recommended diagnostic procedure for INOCA is to measure CFR and IMR first, followed by ACh-provocation.101,102 In this diagnostic procedure, 52% of INOCA cases were diagnosed as MVA alone (CFR <2.0, IMR ≥25), 17% as VSA alone, and 21% as a combination of both. In cases excluding VSA (epicardial artery spasm and MVS), 25% had high IMR (≥25), 24% had low CFR (<2.0), and 9% had a combination of both.141
The different diagnostic procedures (CFR/IMR first, or ACh-provocation test first) resulted in a similar number of negative (noncardiac) determinations (11–16%), but the CFR/IMR first strategy resulted in a lower ACh-provocation positive rate (diagnosed as VSA) (37% vs. 68%) and more cases being diagnosed as MVA alone (52% vs. 16%). Differences in diagnostic procedures may affect the diagnosis of INOCA endotypes and should be noted (Figure 16).
7.5 Physiological Indices and Prognosis
Stratification of pathophysiology by physiological indices has been shown to be useful in predicting subsequent prognosis in INOCA. The COVADIS group, defined the diagnostic criteria for MVA as myocardial ischemia in the absence of obstructive CAD associated with low CFR (<2.0 by invasive measurement or <2.5 by noninvasive measurement), MVS, high IMR (>25), and presence of slow flow (TIMI frame count >25). It was reported that events occurred in 7.7%/year during observation, but no sex or racial differences were observed.14
In a report measuring CFR and IMR following an ACh-provocation test, VSA with high IMR (≥18) was high risk for events.142
The CorMicA study, which examined the effect of incorporating of IDPs into the INOCA comprehensive diagnosis and subsequent treatment strategy in a prospective, randomized fashion, showed IDP contributed to improvement in angina symptoms and QOL.11,81 However, the CorMicA study focused mainly on measurements in the left anterior descending coronary artery, and further research is needed.
In a retrospective study measuring FFR, CFR, and IMR for the evaluation of FFR-negative intermediate stenosis, the group with low CFR (≤2.0) and high IMR (≥23) had the worst prognosis.425 CFR and IMR are often reported to be a prognostic factor independent of FFR86,426–428 (Table 18).
Table 18. Recommendations and Levels of Evidence for Physiological Evaluation in INOCA Patients
| |
COR |
LOE |
If INOCA is suspected, physiological evaluation by measuring CFR and IMR
should be considered11,14,81,101,102,141,142 |
IIa |
B |
| CFR and IMR to predict prognosis in INOCA cases should be considered86,425–428 |
IIa |
B |
CFR, coronary flow reserve; COR, Class of Recommendation; IMR, index of microcirculatory resistance, INOCA, ischemia and non-obstructive coronary artery disease; LOE, Level of Evidence.
IV. New Insights Into Treatment
1. Daily Life Management
1.1 Cardiac Rehabilitation, etc.
1.1.1 Importance of Comprehensive Cardiac Rehabilitation in INOCA
Among patients with symptoms corresponding to angina pectoris, 50% have no significant fixed stenosis on CAG. The underlying mechanism for INOCA is epicardial or coronary MVS or CMD.6,14,139 Coronary endothelial damage is one of the etiologies of VSA and CMD, and because IVUS often shows the presence of plaque coinciding with the site of spasm, the risk factors for INOCA are considered to be similar to those for atherosclerotic diseases14,139 such as hypertension, diabetes, smoking, dyslipidemia, obesity, and lack of exercise. Comprehensive cardiac rehabilitation is recommended as Class 1 for INOCA as for IHD if there are no contraindications.6,429,430 For both VSA and CMD, moderate to vigorous aerobic exercise at an anaerobic metabolic threshold level for at least 30 min should be performed at least 3 times each week (preferably daily).6,429 Continuous full-body aerobic exercise such as brisk walking, jogging, or swimming for 140–180 min/week is recommended. Anginal attacks may occur during or immediately after exercise, with 2 possible mechanisms. One is coronary spasm due to exercise-induced hyperventilation and the other is due to CMD. In such cases, it is advisable to reduce the intensity of exercise and prolong the cool-down time to prevent hyperventilation. In CMD, β-blockers may be effective for exertional angina. Prominent risk factors of INOCA are smoking431 and heavy alcohol consumption, and stress or cold.
In INOCA, the most important aspects of daily life management are smoking cessation, continuation of medical treatment, exercise, blood pressure control, weight control, dyslipidemia control, blood glucose control if diabetes mellitus is present (be careful of hypoglycemia during exercise), and moderation of alcohol consumption (Table 19).
Table 19. Recommendations and Levels of Evidence for Comprehensive Cardiac Rehabilitation in INOCA
| |
COR |
LOE |
Comprehensive cardiac rehabilitation is recommended if there are no
contraindications6,429,430 |
I |
A |
Moderate to vigorous aerobic exercise is recommended (≥30 min, at least 3 times per
week)6,429,430 |
I |
B |
| Smoking cessation is recommended431 |
I |
A |
COR, Class of Recommendation; INOCA, ischemia and non-obstructive coronary artery disease; LOE, Level of Evidence.
2.1 Fasudil (Rho-Kinase Inhibitor)
Coronary artery spasm is a local hyperreactivity mainly caused by an increase in contractility of vascular smooth muscle.111 Phosphorylation of myosin light chain (MLC), which plays a central role in the regulation of vascular smooth muscle contraction and relaxation, is regulated by MLC kinase (MLCK) and phosphatase (MLCPh) activities (Figure 17).432,433 In VSMCs, inositol triphosphate (IP3) generated by phospholipase C (PLC) in response to vasoactive substances triggers Ca2+
release from the intracellular sarcoplasmic reticulum. Simultaneously, the L-type Ca2+
channel on the VSMC plasma membrane opens and causes Ca2+
influx from outside the cell. Eventual increase in intracellular Ca2+
forms a complex with calmodulin, which activates MLCK. Phosphorylated MLCK then cross-reacts with actin, causing VSCMs to contract. When the intracellular Ca2+
levels decrease, Ca2+
dissociates from calmodulin, MLCK is inactivated, and MLCPh becomes dominant. Rho-kinase regulates VSMC contraction and relaxation in a Ca2+
concentration-independent manner. Stimulation by vasoconstrictive agents activates small GTPase Rho, which regulates MLC phosphorylation through its target, Rho-kinase. Activated Rho-kinase inactivates MLCPh by phosphorylating its myosin-binding subunit. Accordingly, the balance of MLCK/MLCPh activities becomes MLCK-dominant and MLC phosphorylation is promoted, resulting in hypercontraction of VSMCs.434,435
Thus, Rho-kinase is an important molecular switch that regulates the contraction and dilatation of vascular smooth muscle in an intracellular Ca2+
concentration-independent manner.436 Fasudil, a Rho-kinase inhibitor, specifically and potently inhibits the Rho-kinase of VSMCs and releases coronary spasm.437 Because the mechanism of vasodilatation by fasudil is completely different from that by nitrates, additional administration of fasudil after nitrates could promote an additive effect in coronary vasodilatation.438 Although many case reports strongly suggest the usefulness of intracoronary administration of fasudil in patients with multidrug-resistant or refractory coronary spasms,142,439–444 no randomized controlled trials or observational studies have objectively demonstrated that fasudil is superior to conventionally used vasodilators such as nitrates and nicorandil in the relief of coronary spasm. Meanwhile, in a retrospective observational study445 that investigated the effect of fasudil on the slow-flow phenomenon, transient hypotension was observed in 22% of patients who received intracoronary fasudil (median dose of 18 mg, maximum dose of 30 mg) over 1–5 min under ECG monitoring. However, no serious complications such as death or MI occurred, indicating the safety of intracoronary administration of fasudil. Intracoronary administration of fasudil is being investigated as a therapeutic option for refractory coronary spasm that is intractable to conventional coronary vasodilators such as nitrates (Table 20).
Table 20. Recommendation and Level of Evidence for Intracoronary Administration of Fasudil for Release of Refractory Coronary Spasm
| |
COR |
LOE |
Intracoronary administration of fasudil should be considered to release refractory coronary
spasm |
IIa |
B |
COR, Class of Recommendation; LOE, Level of Evidence.
2.2 Denopamine (Table 21)
Table 21. Recommendation and Level of Evidence for Denopamine in Patients With VSA
| |
COR |
LOE |
| Denopamine may be considered for VSA450–452 (This is not covered by health insurance) |
IIb |
C |
(This guideline is not intended to recommend off-label use) COR, Class of Recommendation; LOE, Level of Evidence; VSA, vasospastic angina.
CCBs and nitrates are useful treatment for VSA, but approximately 20% of patients are reported to be refractory to these drugs,446 so other drugs have to be considered. In this context, adrenergic receptor agonists are an option, because autonomic nervous system involvement has been reported to be involved in the exacerbation and development of VSA.447
Denopamine, an oral adrenergic β1
receptor selective stimulator developed in Japan for the treatment of chronic HF, is known to have a different mechanism of action from catecholamine preparations such as noradrenaline and dopamine because it does not have a catecholamine structure and has less excessive effects on pulse rate and blood pressure.448 In addition, it has been reported that denopamine increases coronary blood flow through β1-receptor stimulation and increases renal and femoral blood flow through α-receptor blockade.448,449
In clinical cases, the usefulness of denopamine for VSA without significant stenosis of the coronary arteries in which coronary spasm has been proven by spontaneous attacks or induction studies has been reported.450–452 In 10 patients with VSA, administration of 40 mg of denopamine resulted in complete resolution of attacks in 7 cases, a significant decrease in the number of attacks and the use of nitroglycerin, and no exacerbations of attacks.451 The usefulness of a low dose of 15 mg/day in the treatment of refractory VSA in combination with multiple drugs has also been reported.452
However, although denopamine has been effective in many case reports, it is possible that only effective cases have been reported, and there are no recent reports or reports on a large number of cases. Although denopamine may be effective in some cases, further studies, including dosage, are needed, and at this point, there is insufficient evidence of prophylactic efficacy.
2.3 Aspirin (Table 22)
Table 22. Recommendation and Level of Evidence for Aspirin in Patients With VSA
| |
COR |
LOE |
| Aspirin is not recommended for patients with VSA without significant organic stenosis454–460 |
III (No
benefit) |
B |
COR, Class of Recommendation; LOE, Level of Evidence; VSA, vasospastic angina.
Low-dose aspirin is recommended for secondary prevention of not only ACS but also CCS because of its inhibitory effect on thromboxane A2 production by suppressing cyclooxygenase-1, thereby reducing thrombus formation.17 On the other hand, it is a well-known fact that aspirin increases the risk of bleeding in primary prevention, even if cardiovascular events are prevented by aspirin, and the true benefit of low-dose aspirin is determined by its balance.453
High-dose aspirin has been reported to exacerbate symptoms of VSA,454 and low-dose aspirin has been reported, including in meta-analyses.455–459 An analysis of patients with VSA without significant coronary artery stenosis divided into aspirin-treated and non-aspirin-treated groups found that the incidence of MACE was similar in both groups.455–458 A systematic review and meta-analysis459 included 4 propensity-matched studies, 1 retrospective study, and 1 prospective multicenter study. A total of 3,661 patients with VSA without significant coronary artery stenosis were included in the meta-analysis, with and without aspirin. After 1–5 years of observation, no correlation was show between aspirin use and occurrence of MACE, nor MI or cardiac death. On the other hand, in a retrospective study of patients who developed ACS due to coronary spasm, the incidence of AMI and recurrent chest pain was significantly lower in the aspirin-treated group than in the non-treated group.460 In addition, OCT has revealed thrombus-associated coronary plaque erosion at almost 25% of coronary spasm-inducing sites,36 and the association between coronary spasm and coronary plaque erosion has also attracted attention. It has also been reported that coronary artery plaque erosion and subsequent thrombus formation may be induced by coronary spasm, leading to ACS.461
Antiplatelet therapy for VSA may be effective in preventing platelet activation after a coronary spasm attack and intracoronary thrombus caused by increased coagulability, and may be especially useful in patients with unstable angina due to coronary spasm or those with a history of ACS. However, the efficacy of antiplatelet agents has not been established at this time. On the other hand, VSA complicated by significant organic stenosis should be treated according to antiplatelet therapy in stable exertional angina.
2.4 Kampo Medicines (Table 23)
Table 23. Recommendation and Level of Evidence for Kampo Medicines in Patients Wtih VSA
| |
COR |
LOE |
Kampo medicines may be considered for VSA463,466–468
(This is not covered by health insurance) |
IIb |
C |
(These guidelines are not intended to recommend off-label use) COR, Class of Recommendation; LOE, Level of Evidence; VSA, vasospastic angina.
The association between CAD and anxiety and depression is well known. Accordingly, it has been reported that more patients with VSA have anxiety and depression than those with organic CAD.462 The usefulness of kampo medicines used for anxiety and depression in VSA has been noted.
Shigyakusan has been reported as effective in the treatment of VSA associated with psychogenic symptoms including autonomic imbalance.463 In that study, 2 patients with VSA and severe anxiety whose chest pain was not controlled by benidipine, isosorbide nitrate, or nicorandil were treated with shigyakusan and keishibukuryogan in small doses and their chest pain attacks completely disappeared, taking side effects into consideration.463
Keishibukuryogan has an action to improve peripheral circulation by dilating small arteries, resulting in improvement of blood flow and red blood cell stasis.464,465 In addition, by producing endothelium-derived NO, it may improve vascular endothelial function and coronary spasm.465 There is a case report of a patient with VSA refractory to efonidipine and unable to use nicorandil due to its side effects, who was completely prevented from chest pain for a long period of time with the use of keishibukuryogan.466
Other kampo medicines used for VSA include saibokuto for patients receiving nitrate medications, which may also improve symptoms.467,468 Three cases have been reported in which a significant decrease in chest pain attacks and improvement in QOL were observed after additional administration of saibokuto to a patient with refractory VSA that was difficult to control with ≥2 coronary dilator drugs.467
Although kampo medicines including shigyakusan, keishibukuryogan, and saibokuto have been effective in many case reports, it is possible that only effective cases have been reported. There are no recent reports or studies of a large number of cases with comparator groups. Although it may be effective as an adjunctive therapy to standard drugs in some cases, further studies, including dosages, are needed.
3. Nonpharmacotherapy
3.1 ICD Implantation
3.1.1 Mechanism of Lethal Arrhythmias in VSA
The mechanism of lethal arrhythmias (ventricular tachycardia: VT/ventricular fibrillation: VF) in VSA is not well understood. It is thought that ischemia due to coronary spasm causes repolarization abnormalities,469 and that myocardial scar formation due to ischemia in coronary spasm470 is involved. In coronary artery ligation models, different mechanisms have been reported in the early acute phase (within 30 min of ischemia) and the late acute phase (within 12–48 h of ischemia).471 The early acute phase mechanism is thought to be reentry associated with injured myocardium generated by ischemia,472 while that of the late acute phase is assumed to be triggered activity via delayed afterdepolarization or early afterdepolarization.473
3.1.2 Frequency of Lethal Arrhythmias and Appropriate ICD Therapy in VSA
It has been reported that sudden cardiac death (SCD) may occur in patients with VSA, and is more frequent in cases refractory to medical therapy or with a history of out-of-hospital cardiac arrest.148 In a questionnaire survey completed by 34 centers in Japan, 5,726 SCDs occurred over a 5-year period from 2014 to 2018, with 808 (14%) due to VSA.474 Among SCDs due to VSA, 169 (21%) were resuscitated cardiac arrests (aborted SCD: ASCD), of which 117 (69%) had an ICD.
Although there are not many reports on prognosis and ICD availability in VSA (Table 24),475–479 a recent systematic review480 found that at a mean follow-up of 4.2 years, 6% of patients with VSA died, and the mortality rate was higher in patients with ASCD compared to patients without a history of cardiac arrest (9% vs. 5%). Among the ASCD patients, those who underwent an ICD implantation, had a lower mortality rate than those who did not (3% vs. 14%), and appropriate ICD therapy was observed in 17% of patients. It has been reported that death due to pulseless electrical activity can occur even in patients with an ICD, although this is not limited to patients with refractory VSA.474
Table 24. Mortality Rate and Frequency of Appropriate ICD Therapy in VSA
Study
(Author, Year) |
Mean (median)
observation
period (years) |
Mortality rate during the observation period |
Frequency of
appropriate ICD
therapy |
| Total |
No history of
cardiac arrest |
History of cardiac arrest |
| Total |
Without ICD |
With ICD |
| Ahn JM, et al, 2016475 |
(7.5) |
8% |
8% |
13% |
14% |
4% |
21% |
Rodríguez-Mañero M,
et al, 2018476 |
(4.9) |
10% |
NA |
10% |
40% |
7% |
27% |
| Vlastra W, et al, 2018477 |
7.5 |
3% |
0% |
9% |
0% |
13% |
25% |
| Ogino Y, et al, 2021478 |
(4.2) |
9% |
NA |
3% |
NA |
3% |
20% |
| Tateishi K, et al, 2021479 |
3.2 |
15% |
NA |
11% |
0% |
20% |
60% |
ICD, implantable cardioverter defibrillator; NA, not available; VSA, vasospastic angina.
Based on these considerations, it is reasonable to assign Class IIa to patients with pre-existing VT/VF, including ASCD, if they are refractory to medical therapy, and Class IIb even if medical therapy is effective (Table 25). In patients with a history of ASCD, the use of a wearable cardioverter defibrillator in the acute phase may also be considered.481
Table 25. Recommendations and Levels of Evidence for ICD Indication in VSA
| |
COR |
LOE |
ICD implantation should be considered in cases of pre-existing VT/VF, including out-of-
hospital cardiac arrest associated with coronary spasm, when refractory to medical
therapy148,474–480 |
IIa |
B |
ICD implantation may be considered in cases of pre-existing VT/VF, including out-of-hospital
cardiac arrest associated with coronary spasm, when medical therapy is effective148,474–480 |
IIb |
C |
COR, Class of Recommendation; ICD, implantable cardioverter defibrillator; LOE, Level of Evidence; VF, ventricular fibrillation; VSA, vasospastic angina; VT, ventricular tachycardia.
3.1.3 Risk Factors for Lethal Arrhythmias in VSA
Long-term survival in patients with VSA has been reported to be high with smoking cessation and calcium antagonist therapy, unless the patient has multivessel coronary spasm or organic coronary artery lesions.482 On the other hand, in a study of 2,032 VSA patients, including 188 ASCD cases, younger age, hypertension, dyslipidemia, family history of SCD, multivessel coronary spasm, and coronary spasm in the left anterior descending branch were risk factors for ASCD.475 The early repolarization (ER) pattern on ECG is also considered a risk factor for VT/VF; 64 (24%) of 265 patients with VSA showed the ER pattern, and the ER pattern was significantly more common in patients with pre-existing VF. Recurrence of VF was significantly more common in patients with pre-existing VF and the ER pattern.483 A recent systematic review found that the risk of VF is approximately 5-fold higher in the presence of the ER pattern.484 Conversely, in a report of 34 ER patients with a history of VF, 13 patients (38%) had VSA, and caution should be exercised with the combination of both diseases.485 Furthermore, Brugada syndrome can be associated with VSA, and it has been reported that coronary spasm can induce VF by acting additively or synergistically on the arrhythmogenic component of Brugada syndrome.486,487 Thus, ASCD cases among VSA patients should be thoroughly evaluated for coexistence of Brugada syndrome.
3.1.4 Method for Assessing the Risk of Developing Lethal Arrhythmias in VSA
Electrophysiologic studies (EPS) are used to assess the risk of VT/VF; the frequency of VT/VF induced by EPS has been reported to be significantly higher in patients with VSA.488 It has also been reported that VT/VF is often induced by EPS in patients with a history of out-of-hospital cardiac arrest.489 Although an arrhythmic substrate may be present in patients with VSA, especially in those with a history of out-of-hospital cardiac arrest, the significance of EPS for considering ICD indication has not been established.
Other tests, such as QT dispersion and T wave alternans (TWA), have been reported to be related to the occurrence of VT/VF. QT dispersion was reported to be greater in patients with VSA, with significantly greater QT dispersion in those with VT/VF than in those without VT/VF.490 The same was reported for TWA, with a higher incidence of TWA in patients with VSA and significantly greater variability in those with VT/VF compared to those without VT/VF.491 Thus, QT dispersion and TWA may be related to VT/VF in patients with VSA, but there is not enough evidence to determine ICD indication.
3.2 Stellate Ganglion Block, Thoracic Sympathectomy
Autonomic dysfunction is thought to be involved in the pathogenesis of coronary spasm,492 which occurs when vagal activity is high, such as late at night or at rest, and is induced by ACh, supporting the involvement of parasympathetic nerves.295,361 In contrast, the increase in blood catecholamine levels during coronary spasm and the appearance of coronary spasm during nocturnal REM sleep indicate a decrease in vagal tone and an increase in adrenaline via the sympathetic nervous system, suggesting sympathetic involvement.493,494 An imbalance between the sympathetic and parasympathetic nervous systems was believed to cause a predominance of sympathetic nervous system activity, which in turn affected coronary spasm.495 Platelet aggregation via the sympathetic nervous system was thought to induce coronary spasm.496,497 When anginal attacks occur during exertion or stress, increased myocardial oxygen demand may be involved in the coronary spasm.
Stellate ganglion block and thoracic sympathectomy have the following effects: (1) blocking noradrenaline binding to adrenergic α1-receptors that constrict vascular smooth muscle, (2) blocking the release of serotonin caused by platelet aggregation via α2-receptors, (3) decreasing myocardial oxygen demand by lowering heart rate and systolic blood pressure during thoracic sympathectomy, and (4) relieving pain by partially blocking the pain-sensing nerve pathway caused by ischemia (Figure 18). In addition, the antiarrhythmic effects through sympathetic nerve suppression and improvement of heart rate variability and QT time variability can potentially treat refractory or severe VSA.498–500
To date, most studies have demonstrated the benefit of stellate ganglion block and thoracic sympathectomy in refractory or severe VSA,501–505 and randomized trials have been limited to a few single-center studies.506 In the only prospective randomized study of the effect of thoracic sympathectomy on coronary spasm,506 the study evaluated the effect of thoracoscopic thoracic sympathectomy on MACE for 24 months in 79 patients with drug-refractory VSA randomized to thoracoscopic thoracic sympathectomy or medical therapy. The rate of MACE at 24 months was significantly lower in the thoracic sympathectomy group than in the medical therapy group (16.22% vs. 61.90%, P=0.0001). The overall mortality rates were 0% and 14.29% in the thoracic sympathectomy group and medical therapy group, respectively (P=0.0001). The study included high-risk patients, among whom 60% and 50% had ST-segment elevation and fatal arrhythmia, respectively.
One problem with stellate ganglion block and thoracic sympathectomy is the possibility that the therapeutic effect may include a placebo effect.507 Although controlled studies using a sham group are necessary to solve this problem, it is difficult to conduct such studies in patients with severe VSA who have a history of refractory or fatal cardiac accidents. Other issues include the dosage of anesthetic for stellate ganglion block,507 whether thoracic sympathectomy should be performed bilaterally, and how long the effect lasts.508
Currently, despite strict lifestyle management such as smoking cessation and removal of mental stress as well as administration of multiple different types of coronary dilators, for cases of (1) fatal major vasospastic attacks, including frequent ICD shock therapy, or (2) frequent episodes of angina pectoris associated with increased sympathetic tone (frequently during the day and induced by stress or physical activity), a stellate ganglion block and/or thoracic sympathectomy may be considered one of the nonpharmacologic treatments (Table 26, Figure 18).
Table 26. Recommendation and Level of Evidence for Stellate Ganglion Block and Thoracic Sympathectomy for Refractory or Severe VSA
| |
COR |
LOE |
Stellate ganglion block and/or thoracic sympathectomy may be considered for
refractory or severe VSA501,503,506
(This is not covered by health insurance) |
IIb |
C |
COR, Class of Recommendation; LOE, Level of Evidence; VSA, vasospastic angina.
Appendix 1. Details of Members
Chair:
• Seiji Hokimoto, Kumamoto City Ueki Hospital
Vice Chair:
• Koichi Kaikita, Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki
Members:
• Masaharu Ishihara, Department of Cardiovascular and Renal Medicine, School of Medicine, Hyogo Medical University
• Tetsuya Matoba, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences
• Yasushi Matsuzawa, Division of Cardiology, Yokohama City University Medical Center
• Yoshihide Mitani, Department of Pediatrics, Mie University Graduate School of Medicine
• Yoshiaki Mitsutake, Division of Cardiovascular Medicine, Kurume University School of Medicine
• Toyoaki Murohara, Department of Cardiology, Nagoya University Graduate School of Medicine
• Takashi Noda, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
• Koichi Node, Department of Cardiovascular Medicine, Saga University
• Teruo Noguchi, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
• Hiroshi Suzuki, Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital
• Jun Takahashi, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
• Yasuhiko Tanabe, Department of Cardiology, Niigata Prefectural Shibata Hospital
• Atsushi Tanaka*, Department of Cardiovascular Medicine, Wakayama Medical University
• Nobuhiro Tanaka, Division of Cardiology, Tokyo Medical University Hachioji Medical Center
• Hiroki Teragawa, Department of Cardiovascular Medicine, JR Hiroshima Hospital
• Kenichi Tsujita, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
• Takanori Yasu, Department of Cardiovascular Medicine and Nephrology, Dokkyo Medical University Nikko Medical Center
• Satoshi Yasuda, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
• Michihiro Yoshimura, Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine
Collaborators:
• Yasuhide Asaumi, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
• Shigeo Godo, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
• Hiroki Ikenaga, Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences
• Takahiro Imanaka, Department of Cardiovascular and Renal Medicine, School of Medicine, Hyogo Medical University
• Kohei Ishibashi, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
• Takayuki Ishihara, Kansai Rosai Hospital Cardiovascular Center
• Masanobu Ishii, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
• Yunosuke Matsuura, Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki
• Hiroyuki Miura, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
• Yasuhiro Nakano, Department of Cardiovascular Medicine, Kyushu University
• Takayuki Ogawa, Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine
• Takashi Shiroto, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
• Hirofumi Soejima, Health Care Center, Kumamoto University
• Ryu Takagi, Division of Cardiology, Tokyo Medical University Hachioji Medical Center
• Akihito Tanaka, Department of Cardiology, Nagoya University Graduate School of Medicine
• Atsushi Tanaka#, Department of Cardiovascular Medicine, Saga University
• Akira Taruya, Department of Cardiovascular Medicine, Wakayama Medical University
• Etsuko Tsuda, Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center
• Kohei Wakabayashi, Division of Cardiology, Cardiovascular Center, Showa University Koto-Toyosu Hospital
• Kensuke Yokoi, Department of Cardiovascular Medicine, Saga University
Independent Assessment Committee:
• Tohru Minamino, Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine
• Yoshihisa Nakagawa, Department of Cardiovascular Medicine, Shiga University of Medical Science
• Hisao Ogawa, Kumamoto University
• Hiroaki Shimokawa, Graduate School, International University of Health and Welfare
• Shozo Sueda, Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine
(Listed in alphabetical order; affiliations as of March 2023)
(*,#Separate individuals.)
