Myocardial Ischemic Syndromes, Heart Failure Syndromes, Electrocardiographic Abnormalities, Arrhythmic Syndromes and Angiographic Diagnosis of Coronary Artery Spasm: Literature Review

In coronary artery spasm (CAS), an excess coronary vasoconstriction causing total or subtotal vessel occlusion could lead to syncope, heart failure syndromes, arrhythmic syndromes, and myocardial ischemic syndromes including asymptomatic myocardial ischemia, stable and unstable angina, acute myocardial infarction, and sudden cardiac death. Although the clinical significance of CAS has been underrated because of the frequent absence of symptoms, affected patients appear to be at higher risk of syncope, serious arrhythmias, and sudden death than those with classic Heberden's angina pectoris. Therefore, a prompt diagnosis has important therapeutic implications, and is needed to avoid CAS-related complications. While a definitive diagnosis is based mainly on coronary angiography and provocative testing, clinical features may help guide decision-making. We perform a literature review to assess the past and current state of knowledge regarding the clinical features, electrocardiographic abnormalities and angiographic diagnosis of CAS, while a discussion of mechanisms is beyond the scope of this review.


Introduction
Angina pectoris is caused by a transient imbalance between myocardial demand and supply [1,2], which results in 2 types of ischemia, non-exertional supply ischemia and exertional demand ischemia [3]. Furthermore, coronary lesions are dynamic [4]. As a result, non-obstructive coronary lesions might restrict increases in coronary blood supply if vascular tone is augmented [4], and hence myocardial ischemia is not always preceded by increased oxygen demand [5]. Among the mechanisms of angina pectoris, coronary artery spasm (CAS) had long been considered the chief one [6], albeit as yet unproved until 1940s when the recognition of angina-associated fixed atherosclerotic obstruction post mortem led to a revision of the theory that CAS may produce paroxysmal myocardial ischemia [7][8][9] (Table 1).
However, Dr. Myron Prinzmetal (1908Prinzmetal ( -1987 published his observations on "A variant form of angina pectoris" in 1959, which was the 1 st article [10] Ivyspring International Publisher distinguishing it as a distinct entity from the classic angina pectoris (pectoris dolor) described by Dr. William Heberden (1710-1801 based on 20 cases with this affliction in 1772 [11], which occurred when increased cardiac work or emotional disturbance provoked chest pain and was relieved by rest or the administration of nitroglycerin. Although some patients with non-exertional angina of Heberden's cases probably represents the 1 st reported variant form of angina pectoris, his description of non-exertional angina is vague. On the other hand, patients with Heberden's angina may also manifest CAS [12].
In Prinzmetal's 1 st report of 32 cases of variant angina, of which 20 were personally observed and 12 were from the literature, the pain associated with transient non-progressive ST-segment elevation appeared at rest or during ordinary activity but was not brought on by exercise or emotional disturbance. Among the 32 patients studied, 12 developed myocardial infarction during follow-up [10]. Because coronary atherosclerosis was a common finding in both forms of angina pectoris post mortem, and the attack usually occurred with the subject at rest, when vascular hypertonic activity is physiologically greatest [10], vascular hypertonus proposed by Prinzmetal et al. or CAS proposed by other researchers was the explanation for variant angina. Although CAS had never been proved [7,13] within a decade following the 1 st report of coronary angiography in 1959 [14], CAS was documented angiographically in early 1970s in patients of variant angina [13,15,16].
In the 1970s and 1980s, the diagnosis of CAS by coronary angiography in the catheterization laboratory was not rare. It then became clear that CAS could occur in patient with atherosclerotic obstructive coronary artery disease [10,11] or angiographically normal coronary arteries, which was referred to as "variant of the variant" [15] or "coronary vasospastic angina" [17]. Moreover, ST-segment depression rather than non-progressive elevation occurred more commonly in CAS [18,19]. Therefore, the term "variant angina" is used for CAS-related angina with transient non-progressive ST-segment elevation. Additionally, CAS and acute coronary events can be caused by allergic reactions, with mediators released during mast cell degranution such as histamine, chymase, leukotrienes, platelet activating factor acting on coronary vascular smooth muscle cells that constitute the pathophysiologic basis of Kounis syndrome [20,21]. Collectively, the presence of atherosclerotic obstructive coronary artery disease cannot be considered as the only determinant of angina pectoris [22]. There are long intervals of perfect health. Wine, and spirituous liquors, and opium afford considerable relief. It is increased by disturbance of the mind It continues many years without any other injury to the health. In the beginning it is not brought on by riding on horseback, as in a carriage, as is usual in diseases arising from scirrhus or inflammation. During the fit the pulse is not quickened Its attacks are often after the 1 st sleep, which is a circumstance common to many spasmodic disorders 1895 The 1 st practical electrocardiography is invented by Dr. Willem Einthoven [139]. 1940 Among the mechanisms of angina pectoris, although CAS has long been considered the chief one [6], the difficulty of visualizing CAS of the arteriosclerotic arteries in patients with angina pectoris is frequently pointed out [7]. 1941 While the theory that CAS may produce paroxysmal myocardial ischemia is as yet unproved, the recognition of angina-related fixed atherosclerotic obstruction post mortem in 1940s leads to a revised perception that atherosclerosis, rather than CAS, is the chef mechanism of angina pectoris. The 1 st provocative testing using intracoronary ergonovine is performed by Hackett et al. [104]. 1988 The 1st provocative testing using intracoronary acetylcholine is performed by Okumura et al. [106]. 1992 Risk factors for CAS were not known until a U.S. study in 1992 demonstrated that smoking was a risk factor for CAS in young women [140]. 1993 Smoking is a major risk factor for Japanese CAS patients [141].

2000
CAS-related regional wall motion abnormality, left ventricular dilation and reduced ejection fraction improve 6 months to >1 year after medical treatment, including calcium channel blockers and nitrate/nicorandil [50,53].

2005
C-reactive protein level is an independent risk factor of CAS in Taiwanese patients [142]. CAS = coronary artery spasm.

Prevalence
CAS-related angina and myocardial ischemia, regardless of symptoms, are common [10, 23], though not nearly as common as classic Heberden's angina pectoris. The prevalence of CAS and obstructive coronary artery disease in Taiwanese general population during a follow-up period of 12 years is 0.067% and 8.7%, respectively [24]. However, the prevalence of CAS in different general populations remains to be defined. On the other hand, the number of CAS patients would rise among angina patients when systematic rules for its detection are applied [23]. Therefore, undoubtedly the incidence of CAS-related myocardial ischemia could be significantly greater than is indicated by the demonstration of variant angina if one considers that (1) angina at rest with S-T segment depression and with pseudonormalization of T waves also appears to be caused by CAS; (2) that asymptomatic ischemic episodes are frequent [23,25]; and (3) that cold-induced angina may result from CAS [26].
There are wide differences in the CAS prevalence in different countries. The frequency of CAS in Japan is greater than that in western countries [27] and the diagnosis of variant angina with transient non-progressive ST-segment elevation among patients with angina referred to Japanese medical institutions is as high as 40% [17]. In addition, multiple spasms (≥2 spastic coronary arteries) induced by provocative testing in Japanese (24.3%) [28] and Taiwanese populations (19.3%) [29] occur more frequently than in Caucasians (7.5%) [30]. CAS is more prevalent among men than women in East Asia as well as Western countries [17,29]. Most CAS occur in patients between 40 and 70 years of age and the prevalence decreases after 70 years of age [10,17,29]. Previous Asian and German studies have shown that the prevalence of CAS is around 50% in patients with angina and 57% in Asian patients with acute coronary syndrome without obstructive coronary artery disease [31][32][33]. Among provocative vasomotor studies in patients with acute coronary syndrome without a culprit lesion, 79% of Japanese patients had a positive result [34], whereas 16% of French [35] and 49% of similar German [33] patients developed CAS after intracoronary acetylcholine. On the other hand, CAS can be difficult to diagnose owing to premedication with spasmolytic drugs such as nitroglycerin or calcium channel blockers, avoidance of coronary constrictors, and variation of disease activity. The prevalence of CAS tends currently to decrease, especially in Japan, for many reasons such as less performing vasoreactivity test (time consuming), or widespread use of statins and calcium channel blockers [36]. Taken together, these results suggest that while racial differences exist in coronary vasomotor response [27], CAS prevalence in different populations is as yet unknown.

Myocardial Ischemic Syndromes with or without Symptoms
Symptoms vary widely and may be silent (Table  2), among which the length (longer duration) of CAS is an essential determinant. The typical CAS-related angina at rest is a vague sensation of compression in the precordium or upper abdomen [17] with radiation to the neck, jaws, left shoulder, and elsewhere [17]. The angina may be accompanied by cold sweats and disturbance of consciousness including syncope [17]. During CAS attack, a lowering of blood pressure or decrease in pulse pressure may appear [10]. Although prolonged episodes of CAS can lead to angina and even myocardial infarction [37], brief episodes of CAS without any symptoms can result in silent myocardial ischemia, or cause life-threatening arrhythmias, resulting in sudden death [38][39]. The incidence of silent myocardial ischemia is more than 2 times higher than that of symptomatic ischemia [38]. Hence, there is a wide spectrum of CAS-related myocardial ischemic syndromes, including silent myocardial ischemia, stable angina, unstable angina, acute myocardial infarction and sudden death [23,37,38,40]. In addition, CAS has been reported to be associated with migraine syndrome [41], Raynaud's phenomenon [41] and spasm of digital arteries [42].
CAS occurs mostly at rest or at night, sometimes in association with awakening from sleep [43], especially from midnight to early morning [10,23,[38][39][40][44][45][46], during which 67% of CAS attacks are asymptomatic [17]. A previous report using intravenous methergine provocation tests showed that the frequency of CAS was 38% when angina occurred only at rest, compared with 13.8% when angina at rest and during exertion [30]. Moreover, CAS precipitated by variable threshold effort, particularly in the morning in some patients [39], can be associated with ST-segment depression or elevation, or pseudonormalization of T waves [18,23], suggesting that spastic arteries are abnormal because normal coronary arteries dilate during exercise.
The incidence of CAS shows daily, weekly, monthly, and circadian variations [47]. The complexity of the neural networks modulating the tone of the coronary arteries [48], and the association of the occurrence of CAS in the early morning with rapid eye movement [49], during which time there is a rapid elevation of sympathetic activity, suggest that changes in the activity of the autonomic nervous system may be involved in the circadian variation of CAS. With the use of coronary artery angiography in patients with CAS, Yasue at al. [46] found that in the early morning, the tone of the major coronary artery was increased and its diameter was smaller than normal, while in the afternoon, the major coronary artery was usually dilated. Therefore, most patients with CAS have a diurnal variation in the exercise capacity. Of note, as attacks of CAS may occur frequently, ie, several times every day, or may not occur for several months to several years [17], patients should be followed up closely. While the prevalence of hypertension and smoking was higher in CAS-related than non-CAS-related HFrEF in a previous study [55], further studies are needed to identify the risk factors of CAS-related HFrEF. The CAS-related regional wall motion abnormality, left ventricular dilation and reduced ejection fraction improve 6 months to >1 year after medical treatment for CAS, including calcium channel blockers and nitrate/nicorandil [50,53]. HFrEF, such as dilated cardiomyopathy in Syrian hamsters [51,58] and in German patients [59], with microcirculatory disorders which is possibly due to CAS, can be improved by treatment with verapamil and diltiazem, respectively, through vasodilator effect. Notably, while adjunctive diltiazem treatment in possibly CAS-related dilated cardiomyopathy has beneficial effects on mortality, hemodynamics and symptoms through reducing afterload, decreasing arrhythmias, and inhibiting catecholamines [59], diltiazem in patients with HFrEF due to infarction has a poor outcome [60]. On the other hand, the use of calcium channel blockers in patients with non-ischemic HFrEF is not a first-line therapy at the present time. Therefore, although 1st generation dihydropyridine and nondihydropyridine calcium channel blockers (except amlodipine and felodipine) should generally be avoided in patients with non-CAS-related HFrEF since they provide no functional or mortality benefit and may worsen outcomes [61], if patients with HFrEF have provoked CAS, the use of calcium channel blockers might be beneficial to improve CAS-related myocardial ischemia [50,54]. Future studies are required to elucidate the potential treatment role of calcium channel blockers in CAS-related HFrEF. On the contrary, the use of β-blockers in patients with CAS and HFrEF may result in the aggravation of CAS [56]. In addition, the prevalence of atrial fibrillation in the patients with dilated cardiomyopathy and CAS is greater than that in dilated cardiomyopathy without CAS [67% vs 8% (P<0.05)] [54]. Hence, dilated cardiomyopathy with atrial fibrillation may be a clue for identifying CAS [54]. Taken together, although there is no guideline addressing the role of calcium channel blockers in CAS-related heart failure [55], CAS should be considered in the differential diagnosis of dilated cardiomyopathy or HFrEF as calcium channel blockers may be a promising therapy [53,55], and provocative tests for CAS can be safely performed after the stabilization of heart failure [56].

Electrocardiographic Abnormalities and Arrhythmic Syndromes
All CAS-related electrocardiographic changes may occur without the subsequent angina [22] ( On the other hand, a normal electrocardiography does not rule out the presence of CAS [10], as it may be recorded when the CAS starts early or when the CAS is only mild [47]. CAS of a major coronary artery results in ST-segment elevation in the leads corresponding to the distribution of a large coronary artery and the subsequent locations of myocardial infarction [10]. Of note, thallium scintigraphy revealed a regional massive and localized reduction of myocardial perfusion during S-T segment elevation and pseudonormalization of T waves [23]. While a transmural ischemia and injury results in ST-segment elevation, peaking of T waves, or pseudonormalization of T wave changes, a less severe, non-transmural subendocardial myocardial ischemia results in ST-segment depression or T wave inversion [22]. Notably, CAS is associated more frequently with ST-segment depression rather than ST-segment elevation [18,19,63]. ST-segment depression appears when CAS of a major artery is less severe, when a major artery receiving collaterals is completely occluded, or when a small artery is completely occluded [64]. This condition may exist in unstable angina/non-ST-elevation myocardial infarction. About 45% of patients with angina at rest and ST-segment depression alone has CAS [30]. Moreover, ischemic episodes characterized by ST-segment elevation or depression or by T wave change (inversion, peaking, pseudonormalization of negative wave) may occur in the same patient with CAS within a few minutes [22,23]. In addition to ST-segment changes, a taller and broader R wave [10, 65], a decrease in magnitude of S wave, peak T wave and negative U wave may also appear [47]. Because the location of CAS may be fixed, or fluctuate from one vessel to another over time [66], ST-segment elevation and depression could occur alternatively in the same patient or even in the same lead within minutes or hours [23]. Furthermore, electrocardiographic changes may vary during repeated provocative tests and recurrent spontaneous attacks [67,68]. Hence, the appearance of ST-segment changes may differ over time.
The ST-segment and T wave changes of CAS are associated with the subsequent left ventricular dysfunction and practically every known form of arrhythmia [10,32,47,[69][70][71][72][73], sometimes life-threatening [22,58], which often occur in patients with acute coronary syndrome [32]. The high incidence of arrhythmia in CAS may be related to the usually severe ischemia or to the sudden massive reperfusion [69]. Among arrhythmias, ventricular premature complex was most common and high-grade atrioventricular block was next most common [11], and of special importance are sinus node arrest and ventricular fibrillation (VF) [69]. Bradycardia and supra-His conduction disorders tend to occur preferentially during inferior wall ischemia, usually indicating the most commonly CAS-involved right coronary artery, given the junctional location of the block due to ischemia of the branch supplying the sinoarterial and atrioventricular node [74], while an infra-His block may occur when CAS involves left coronary arteries [75]. As a result, sinus bradycardia occurs more frequently than sinus tachycardia, and when profound sinus bradycardia and periods of sinoarterial block or sinus arrest occur, it may cause an acute form of the sick sinus syndrome complicated by syncope [69]. In addition, right bundle branch block [76] and intermittent left bundle branch block [11,12,43,77] have been reported to be associated with CAS. CAS-related sudden death most frequently results from bradyarrhythmias, rather than from tachyarrhythmias [78,79]. Nitrates and calcium channel blockers may be effective in the control of CAS induced arrhythmia, but other traditional antiarrhythmic agents and pacemaker treatment may be required in some patients [69].
Arrhythmias, particularly ventricular, appear more frequently through unknown mechanisms during CAS attacks in >50% of cases than during attacks of classic Heberden's angina pectoris [10,43] ( Table 2). Ventricular arrhythmias are more common during anterior wall ischemia [74]. Sudden death with normal appearing coronary arteries on autopsy examination has been attributed to VF complicating CAS [80]. Although VF uisually needs to be terminated by cardioversion [30], CAS-related VF rarely reverts spontaneously [81][82][83]. In addition, VF was found to be asymptomatic in 43% and nonsustained in 40% episodes in a study of patients with implantable cardioverter defibrillators [84]. The incidence of syncope or pre-syncope is 25% when VF is <10 seconds, compared with 62% if VF is ≥10 seconds [84]. Therefore, CAS should be considered in the differential diagnosis of syncope.
On the other hand, severe CAS may cause fatal pulseless electrical activity or asystole without complications of ventricular tachycardia or VF [85][86][87][88]. Triple-vessel severe CAS can cause the heart to suddenly stop beating due to pulseless electrical activity and flash-freeze the entire myocardium in an instant, resulting in unrecognized coronary flow [88]. Consequently, contrast medium may stay in the coronary arteries for a prolonged period of time despite intracoronary administration of nitroglycerine. Prolonged continuous cardiac massage has been effective for resolving CAS-related pulseless electrical activity [88]. However, cardiac pacing or implantable cardioverter defibrillator might not restore frozen myocardium to viable muscle during pulseless electrical activity arrest, and may lead to unexplained death after the implantation [85,88]. Furthermore, CAS-related ischemia of the sinus node artery or atrioventricular node artery can influence the occurrence of pulseless electrical activity or asystole [88]. Collectively, CAS may cause pulseless electrical activity or asystole without ventricular arrhythmias.

Differential Diagnosis
For patients presenting with transient typical chest pain [89] with exertion or at rest, regardless of electrocardiographic ischemic changes, the diagnostic approach should include obstructive coronary artery disease (Figure 1). Other diagnosis that should be considered include gastroesophageal reflux disease with esophageal spasm [90] and microvascular angina, which has largely replaced cardiac syndrome X [91].   (Figure 1). Patients with acute ST-elevation myocardial infarction usually present with pain and ST-elevation for >15 minutes, which are not resolved by acute therapy with nitroglycerin or calcium channel blockers [96]. Acute pericarditis [97] and takotsubo syndrome [93] are characterized by repetitive episodes of chest pain for hours or days over a period of weeks or months. The chest pain in acute pericarditis is generally worse when lying supine and relieved by sitting, and might radiate to the neck, arms, or left shoulder, making differentiation from myocardial ischemia difficult [97].

Diagnostic Coronary Angiography
Although the key to the clinical diagnosis in medicine is the taking of a history, CAS may present with or without symptoms [38] A recently developed clinical diagnostic score for prediction of CAS in patients with acute chest pain consists of 6 factors, including allergies, asthma, angina attack at rest, ST-segment elevation, myocardial bridge, and hyperventilation test [99]. However, myocardial bridge is present anatomically in approximately 25% of patients based on autopsy and computed tomography, but only results in angiographically detectable systolic compression in less than 10% of patients [100]. Therefore, a larger scale of clinical data is needed to examine its predictive accuracy and specificity.
Coronary angiography with provocative testing, initially described in 1972 [101], is the only certain method of diagnosing CAS [102]. Although an occasional angiographic documentation of CAS in a patient with angina and normal electrocardiography at rest was reported by Gensini et al. in 1962 [103], it was not until the early 1970s that the hypothesis of CAS was provided by serial reports. While the 1 st CAS, probably catheter-or contrast-related, with reproduced chest pain was demonstrated angiographically in a patient with Prinzmetal angina in 1972 [83], spontaneously occurring CAS was not proved until 1973 when Prinzmetal angina of a non-smoking woman was demonstrated by coronary angiography [13]. The 1 st provocative testing using intravenous and intracoronary ergonovine were performed by the Cleveland Clinic in 1972 [101] and Hackett et al. in 1987 [104], respectively. Interestingly, Yasue et al. reported that the use of subcutaneous injection of methacholine induced CAS in 1974 [105], and the usefulness of intracoronary acetylcholine in 1988 [106].
In patients with ST-segment elevation during episodes of angina and a normal coronary angiography, provocative tests usually are not necessary for diagnosis of CAS [102]. Provoked CAS is defined as a reduction of >50% [102] The diagnostic criteria of positive provocative testing for CAS was initially described by Chahine et al. according to [12,30]: (1) appearance of 100% occlusion of a segment of coronary artery; (2) appearance of significant narrowing (≥75%) of a segment of coronary artery; (3) the disappearance, either spontaneous or by administration of nitroglycerin, of the ≥75% narrowing or total occlusion. In humans with one-vessel obstructive coronary artery disease, basal resting myocardial blood flow remains constant regardless of the severity of coronary artery obstruction [110]. During hyperemia as in exertion, the ability to increase myocardial blood flow becomes impaired with obstruction >50% and is virtually abolished at >70% [111]. In patients with one-vessel obstructive coronary artery disease, a percent diameter stenosis of ≥50% and a percent area stenosis of ≥75% correspond to haemodynamically significant stenosis as evaluated by perfusion images [111]. Animal experiments indicate that only in the presence of a ≥90% acute lumen reduction does flow through the stenosis decrease below resting level [112]. CAS has been observed in obstructive coronary artery stenosis varying from 50% to subocclusive [22]; it is possible that a small reduction in luminal diasmeter, not easily detectable angiographically, may suffice to reduce the flow in these cases [22]. Therefore, Yasue et al. [47] suggested no limits on the reduction in luminal diameter for CAS diagnosis since myocardial ischemia results from the changes of vessel size. Individual patients have their own specific clinical features; hence, decisions regarding diagnosis of CAS should be based on the specific conditions of patients [17]. Collectively, because CAS can occur with variable threshold exertional angina and rarely with exertional angina only, a reduction of >50% to 100% in luminal diameter with or without symptoms and/or ischemic ST-segment changes compared with postintracoronary nitroglycerin should be considered a positive test for CAS.
The severity and location of CAS and the associated electrocardiographic abnormalities have been variable in different episodes of CAS [13,22,63]. However, among the spasm-provoked arteries, the right coronary artery and left circumflex artery are the most and least frequently involved, respectively [12]. The susceptibility of the right coronary artery to spasm is demonstrated by the common occurrence of proximal spasm induced by the catheter tip during angiography [43].
During provocative tests, the occurrence of severe chest pain with ST-segment depression but without epicardial CAS has been termed microvascular CAS [108]. While a substantial proportion of CAS patients with angina involving the epicardial coronary arteries also have microvascular CAS [113], coronary microvascular dysfunction is a common finding in invasively managed angina patients with non-obstructive [114] or obstructive epicardial coronary artery disease [115]. The current gold standard for clinically invasive assessment of microvascular function in response to metabolic demands has been coronary flow reserve, which remains normal until diameter stenosis of epicardial large artery is >50% [116,117]. In addition, microvascular CAS can be inferred when coronary slow phenomenon, defined as TIMI frame count >25, appears [114]. Hence, in patients with non-obstructive or obstructive epicardial coronary artery disease, microvascular CAS may be considered one of the contributing factors for ischemia-like symptoms and myocardial ischemia. The involvement of the microvascular CAS adds a new diagnostic and therapeutic dimension to the problem, which needs to be considered in future studies, as coronary microvessels do not necessarily respond to currently used vasodilator agents in an identical fashion as epicardial coronary arteries.
The provocative testing at present involves the use of ergonovine or acetylcholine [102]. Ergonovine, an ergot alkaloid used to control postpartum uterine bleeding, was found in 1949 to provoke angina, and was proposed in 1963 as a diagnostic test for coronary disease [118]. Although methylergonovine, structurally similar to norepinephrine, and acetylcholine stimulate endothelial nitric oxide generation [119], they cause smooth muscle cell contraction in the setting of endothelial dysfunction [120][121][122][123]. In normal coronary arteries, only mild generalized vasoconstriction (<20% diameter reduction) would be induced [115,124]. Ergonovine testing in the catheterization laboratory was used in the late1970s and early 1980s to help identify the mechanism of chest pain when non-obstructive coronary artery disease was found by angiography. In early studies, however, patients receiving very high doses of intravenous ergonovine frequently had severe angina and a reported death in a small series caused the intravenous route to be abandoned [125]. The frequency of provoked CAS by the intracoronary administration is about 2.5-fold higher than that by the intravenous administration of ergonovine and acetylcholine [28,30]; however, there is no difference concerning the incidence of provoked CAS between ergonovine and acetylcholine [126]. While provoked CAS by ergonovine tends to be proximal and focal, CAS provoked by acetylcholine is distal and diffuse [127][128][129]. Although the intracoronary injection of ergonovine and acetylcholine provoked CAS in 65% and 80% in a previous study [128], respectively, no differences existed regarding the provoked CAS between intracoronary ergonovine and acetylcholine in a later study [129]. Further studies are needed to evaluate the coronary response between the ergonovine and acetylcholine examinations.
To ensure a valid diagnosis, vasodilators (calcium antagonists and nitrates) must be withdrawn for ≥24 hours except for sublingual nitroglycerin if necessary [17,102,130]. Prophylactic administration of coronary vasodilators at the beginning of coronary angiography should be avoided [12]. On the other hand, the nitroglycerin or atropine [131] solution for intracoronary administration must be well prepared before starting provocative testing to abolish documented CAS immediately. The intracoronary administration of methylergonovine affords the opportunity to evaluate the left and right coronary arteries separately with small dosing increments of 5 to 10 μg and a total dose not to exceed 50 μg [102]. The effectiveness of intracoronary administration of acetylcholine in doses of 10 to 100 μg is comparable to methylergonovine [102,132,133]. Cautious administration of increasing doses of intracoronary ergonovine was given, with angiography several minutes after each dose or until whenever chest pain or electrocardiographic changes occurred. During coronary angiography, 2 sets of coronary cineangiograms are performed before and after the administration of nitroglycerin [12].
About one-third of patients with dilated cardiomyopathy has CAS and multiple episodes and locations of CAS may lead to HFrEF [50]. To help determine the causes of HFrEF for patients with no fixed coronary artery obstruction, the spasm provocative testing should be performed with careful attention [126,134] as it has a potential to cause angina, hypotension and various arrhythmias. For intracoronary acetylcholine provocative testing, 100 μg acetylcholine is injected directly into the left and right coronary arteries separately [53]. To provoke CAS by ergonovine (methylergometrine maleate), ergonovine was injected in incremental doses of 1, 5, 10, and 30 μg into the left and 1, 5, and 10 μg into the right coronary artery over 1 minute with a 3-minute interval between each injection [54]. In previous Japanese studies [50,55], acetylcholine was injected in incremental doses of 20, 50, and 100 μg in 5-10 ml 0.9% saline solution into the left and of 20, 50 [50,56], and 80 [55] μg into the right coronary arteries over 20 seconds, On the other hand, ergonovinie in 0.9% saline solution was injected in total doses of 40 μg/40ml into the RCA and of 64 μg/64ml into the LCA over 4 min each [50]. Although severe HFrEF was previously considered an absolute contraindication [102], CAS provocative testing has been safely performed recently [50,[53][54][55].
While the complications of intracoronary provocative testing include angina, hypotension, dyspnea, flushing, nausea, vomiting and various arrhythmias [47,135], systemic effects, such as hypertension, are avoided [136]. No procedurerelated mortality, myocardial infarction or irreversible complications have been reported during intracoronary provocative testing [28,123]. Because VF is a possible complication following intracoronary provocative testing, its use inside the cardiac catheterization laboratory is highly recommended. The absolute contraindications to methylergonovine include high-grade left main coronary artery disease, severe left ventricular dysfunction, moderate to severe aortic stenosis, severe hypertension and pregnancy [102]. A multicenter, retrospective study showed that the rates of serious cardiac complications were <1% in patients undergoing a pharmacological provocative testing [137]. However, acetylcholine provocative testing were associated with a higher rate of serious cardiac complications than ergonovine tests (odds ratio: 1.75, 95% confidence interval: 1.13-2.69, P = 0.011) [137].

Conclusion
The management of angina should not be oversimplified as CAS not only induces angina but also causes HFrEF. Patients with HFrEF and CAS may have associated atrial fibrillation. In addition, asymptomatic CAS patients could die suddenly of VF, pulseless electrical activity or asystole. Awareness of CAS is important for clinicians for appropriate management, and preventing progression to more severe atrioventricular block necessitating permanent pacemaker implant. Furthermore, since the coronary vasoconstriction is nonspecific and the angina of CAS is not relieved by rest, CAS-related angina in the same patient may occur under different conditions. As a result, it is important to identify patients with CAS because treatment strategies are different between obstructive coronary artery disease and CAS, and the administration of calcium channel blockers is necessary to improve left ventricular function for CAS-relarted HFrEF.