Current Concepts in Coronary Artery Spasm - European Medical Journal
×

Browse

Current Concepts in Coronary Artery Spasm

| Cardiology Download as | PDF
Authors:
*†Ozan M. Demir,1 †Jonathan Hudson,2 William Wallis1
Disclosure:

The authors have declared no conflicts of interest.

Received:
09.03.16
Accepted:
23.08.16
Citation
EMJ Cardiol. ;4[1]:96-102.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Abstract

Coronary artery spasm is an abnormality of coronary vascular smooth muscle contraction that is associated with significant morbidity and mortality. The underlying pathophysiological process has remained unclear since Myron Prinzmetal described it in 1959. This article reviews current literature of the pathogenesis and outlines clinical features, diagnosis, and treatment options.

INTRODUCTION

Coronary artery spasm (CAS) is caused by abnormal coronary artery vascular smooth muscle (VSM) contraction.1 The pathophysiological process underlying CAS remains uncertain, leading to numerous incongruous descriptions of this disease. In 1959, Prinzmetal et al.2 first realised variant angina as being a separate entity from classical angina pectoris, described by Heberden.3 Prinzmetal et al. described a syndrome independent of physical exertion, during which ST-segments are transiently and often remarkably elevated but almost always terminate spontaneously. It was thought that this transient myocardial ischaemia was brought on by temporary occlusion of a large diseased artery due to an increase in vascular wall tone.3

The advent of coronary angiography has allowed for direct visualisation of the coronary arteries during episodes of CAS. This demonstrated patients with angiographically unobstructed coronary arteries,4,5 leading to the idea that variant angina represented focal spasm of coronary arteries in otherwise disease-free vessels.6 More recently there has been discussion that CAS occurs at the site of atherosclerotic plaque lesions.7

EPIDEMIOLOGY

The prevalence of CAS is difficult to characterise due to variation within different populations, variable use of provocative testing, and differing diagnostic criteria. CAS is more prevalent in males, with most patients aged between 40–70 years, but this prevalence tends to decrease after the age of 70 years.8,9 Japanese populations have a greater frequency of CAS10 (thought to be secondary to hyperreactive coronary arteries) when compared with their Caucasian counterparts.11 Western studies have demonstrated, in selected population groups, the prevalence of CAS amongst patients with angiographically unobstructed coronary arteries (no focal obstruction >50%) undergoing provocative testing at 49% and 33.4%, respectively.12 In addition, the frequencies of multiple regions of spasm during provocation testing in Japanese (24.3%) and Taiwanese (19.3%) populations are higher than those of Caucasian populations (7.5%).13

Although not supported by robust epidemiological data, the incidence of CAS is thought to be declining.14 The decreased incidence of smoking is thought to be a major contributing factor, along with the increased use of calcium channel blockers (CCBs)15 for hypertension, and statins for primary and secondary prevention of ischaemic heart disease. There is also thought to be a reduced interest in performing time-consuming provocative testing in the cardiac catheterisation laboratory14 and a presumed diagnosis of CAS is normally managed with a trial of CCBs.

CLINICAL FEATURES

CAS can manifest clinically as a wide spectrum of coronary syndromes, which can make diagnosis challenging. It is suspected in the presence of severe chest pain at rest, with concurrent electrocardiogram (ECG) changes showing transient ST-segment elevation. Although chest pain remains the most common symptom of CAS, it is worth noting that many attacks of CAS can be asymptomatic or silent.16 Syncope may occur during these silent ischaemic episodes.17 A distinguishing feature of CAS is that angina is thought to occur predominantly at rest and not during exercise; this has preponderance for occurring late at night or early in the morning, with a peak frequency reported as 5 am.18,19 Interestingly, light exercise, when performed early in the morning, has been shown to induce episodes of spasm, whereas strenuous exercise in the afternoon did not provoke the same episodes.20 Therefore, CAS is thought to follow diurnal circadian variations possibly related to the contributions of the autonomic nervous system (ANS).

DIAGNOSIS

Electrocardiogram

Although Prinzmetal’s angina is most commonly associated with ST-elevation, the ECG findings of CAS are extremely varied and may in fact be absent. Traditionally, a total or subtotal spasm of a major coronary artery will lead to ST-elevation in the corresponding distribution of that artery. CAS is also frequently associated with ST-segment depression rather than ST-elevation.21 There are a number of associated arrhythmias including sinus bradycardia, sinus arrest, atrioventricular block, paroxysmal atrial fibrillation, ventricular tachycardia, ventricular fibrillation, and asystole, lending further credence to the argument that CAS encompasses a spectrum of diseases and can present in a wide variety of ways. Sudden death may also result from CAS, with bradyarrhythmia rather than tachyarrhythmia being the most common terminal event.22,23

CORONARY ANGIOGRAPHY

Yasue et al.16 suggested that CAS can be diagnosed clinically if the anginal attacks disappear quickly upon administration of nitroglycerin and any one of five specific criteria are met: attacks appearing at rest in the morning, diurnal variation in exercise tolerance, presence of transient ST-elevation, attacks induced by hyperventilation, or ability of CCBs to suppress the attacks.

Angiography may reveal normal, or near normal, coronary arteries.24,25 The presence of angiographically normal coronary arteries in CAS has been widely documented in studies from Japan.16 This may be due to environmental and genetic factors that have been suggested to give a higher prevalence of CAS in the Japanese population.1,10 More recently it has been suggested that the presence of normal coronary arteries is actually overstated and that atherosclerotic disease, in the form of focal irregularities along the coronary vasculature, contributes to almost all focal CAS.14 This is supported by evidence of focal irregularities detected by intravascular ultrasound in angiographically ‘normal’ coronary arteries.26,27 Therefore, the higher proportion of normal coronary arteries seen in the Japanese population may be a result of a lower threshold for describing a coronary artery as ‘normal’ on angiography.

PROVOCATIVE TESTING

The diagnosis of CAS should ideally be made by witnessing a CAS angiographically during an attack, however this is often not possible. Provocative testing allows for the induction of CAS by certain physiological processes or pharmacological agents in order to demonstrate the vasculature’s abnormal predisposition to contraction. Hyperventilation,28 exercise testing,29 and cold pressor tests have all been used to physiologically induce CAS, however these are limited by modest sensitivity. Ergonovine and acetylcholine are the most commonly used agents for this purpose and cause contraction of smooth muscle cells that are more sensitive to these agents due to the presence of endothelial dysfunction.30-33 Although provocative testing with ergonovine or acetylcholine has good sensitivity for the detection of CAS,34 associated complications have resulted in a decline in utilisation, especially in Europe and North America.35 However, a recent study demonstrated that when performed in controlled environments, the use of acetylcholine provocation testing can be safe and effective at demonstrating diffuse CAS in patients with unobstructed coronary arteries (<50% obstruction).35,36

PATHOPHYSIOLOGY

The causes of CAS are multifactorial and remain poorly defined. Much has been made of the potential role of the ANS in the development of spasm, yet the relationship remains complex and not fully explained. The parasympathetic system was initially thought to be central to CAS as it has preponderance for occurring at night when vagal tone is highest,37,38 and acetylcholine is known to induce CAS.16 However, alpha adrenergic vasoconstriction by the sympathetic nervous system has also been suggested as a possible trigger for CAS.39,40 Propranolol has been shown to exacerbate spasm, presumably because of the resultant unopposed alpha adrenergic vasoconstriction.41 Despite the above evidence, therapies aimed at manipulating the effects of the ANS have failed to translate into effective treatments.42,43

Endothelial dysfunction, although not always present in patients with CAS,44 is thought to be central to the hyperreactive vasomotor response of coronary arteries. In ‘normal’, healthy individuals, acetylcholine causes arterial vasodilatation,45 however in vessels prone to spasm it causes abnormal constriction and hence is used in provocation testing.35 Ergonovine and acetylcholine both cause vasodilatation in normal vessels via the release of nitric oxide, therefore dysfunctional endothelial nitric oxide synthase has been suggested as a possible contributor to CAS.46 Underlying atherosclerotic lesions are often the substrate on which these changes in the endothelium take place. Statins and vitamin E have both been shown to improve endothelial function and reduce symptoms of CAS.47,48 Smoking is a known risk factor for CAS and may contribute to the development of endothelial dysfunction through chronic low-grade inflammation.49 High levels of circulating inflammatory cytokines have been shown to be independently associated with a diagnosis of CAS,50 and chronic inflammation of the vascular endothelium is thought to predispose arteries to abnormal spasm.51

The effectiveness of CCBs at reducing the frequency of symptoms of CAS may be directly linked to the hypercontractility of VSM in affected arteries. Animal models have suggested a role for increased Rho kinase activity which can directly increase the sensitivity of myosin light-chain to calcium, augmenting its phosphorylation and thus favouring contraction of the smooth muscle cell.52 Other animal models have suggested a number of pathways through which hypercontractility in smooth muscle cells may be induced, however their relevance remains to be clarified.53,54

TREATMENT

In the acute setting, early treatment of CAS is important to the prevention of significant complications such as myocardial infarction, arrhythmias, and sudden cardiac death. Sublingual, intravenous, or intracoronary nitroglycerin in the acute phase has been shown to be effective for relieving attacks (Figure 1).55

Figure 1: Coronary angiogram.
A) Left coronary system demonstrating significant obstructive proximal LAD artery stenosis secondary to coronary spasm; B) Left coronary system after intracoronary nitrate demonstrating resolution of proximal LAD artery stenosis.
LAD: left anterior descending.

Cessation of smoking is the most effective non-medical intervention for the prevention of further attacks of CAS. As CAS is likely to occur in the context of existing atherosclerotic disease, controlling risk factors for ischaemic heart disease must also be undertaken to try and control recurrent episodes of spasm.49 Other non-medical treatments include avoiding drugs which induce spasm, reducing alcohol intake,56 avoiding emotional stress, and replacing any magnesium deficiency.1,57,58

CCBs have demonstrated efficacy at reducing the frequency of attacks of CAS by inhibiting the contraction of VSM.59 The use of CCBs has been shown to be an independent predictor of survival and can successfully reverse provocative testing, allowing for the safe discontinuation of medical treatment if necessary.60 Interestingly, complications of CAS such as atrioventricular block have been terminated with CCB therapy.61 High-dose long-acting CCBs are used as the initial treatment and are uptitrated according to symptomatic response, with the occasional requirement of using two agents to control symptoms. Given the preponderance for attacks of CAS to take place at night and in the early hours of the morning, CCBs should be taken at night before bed to be most effective.1

Long-acting nitrates, despite not having any prognostic benefit, also act at the level of the VSM to promote relaxation and prevent episodes of spasm. They have not been shown to be as effective as CCBs and their use is limited by their side effect profile62 and the development of tolerance.63 Despite this, they can be used safely in combination with CCBs to try and suppress recurrent episodes of spasm. Nicorandil, a potassium channel activator, may also be used in the management of recurrent episodes of spasm refractory to CCBs or nitrates.64 Other agents, including magnesium, antioxidants, Rho kinase inhibitors, statins, and pioglitazone65 have all been suggested as possible treatments for CAS due to their effects on vascular endothelial function, however their integration into clinical practice remains to be seen.

Non-medical treatment of CAS has included attempts at using angioplasty and coronary artery bypass grafting to try and prevent further episodes of spasm. The reports of cases treated with coronary artery bypass grafts (CABG) have given variable results.66 The success of this operation in the treatment of CAS is most likely dependent on the degree of atherosclerosis present and to what extent that disease is contributing to the spasm. If there is a focal site of spasm caused by atherosclerotic disease, then it could be effectively bypassed. However, if the spasm is multivessel and diffuse, CABG would be less efficacious. In order to address this problem, one approach considered was to perform a sympathectomy to prevent diffuse spasm. This seems to improve the outcome. Sympathectomy has recently been used in the treatment setting of acute CAS causing life-threatening complications.67

Primary percutaneous coronary intervention (PCI) has been presented as another possible treatment for refractory CAS.68 PCI may provide a rapid and effective treatment for focal spasm that presents as a life-threatening complication. Unfortunately, the long-term outcomes following PCI remain variable.69 Once again this most likely represents the wide spectrum of underlying pathology in CAS. Some cases demonstrate the diffuse spasm of multiple arteries, which are clearly not suitable for a targeted intervention such as PCI. Each case must be considered individually and the appropriate non-medical treatment applied depending on the nature of the spasm (diffuse or fixed), the possible underlying atherosclerotic disease, and the acuteness of the presentation. More research is required and a randomised controlled trial should be performed, investigating the possibility of PCI as a treatment for CAS. (Table 1)59,60,69-76

Table 1: Treatment for coronary spasm.
CCBs: calcium channel blockers; ISMN: isosorbide-5 mononitrate; PCI: percutaneous coronary intervention.

PROGNOSIS

Major adverse cardiovascular events (including death and myocardial infarction) for CAS are difficult to quantify due to the lack of consensus in diagnostic criteria. Initial studies reported 3-year major adverse cardiovascular events rates between 5% and 37%. However, more recent studies have described rates of ≤1%. Of note, the period of highest major adverse cardiovascular event rates is within 3 months from onset of symptoms. This highlights the importance of early recognition and diagnosis, especially in patients presenting with acute coronary syndromes without culprit lesion, unexplained syncope, or aborted sudden cardiac death.7 The Japanese Coronary Spasm Association (JCSA) risk score can be utilised for risk assessment and prognostic stratification of CAS patients.77

CONCLUSION

CAS is caused by abnormal coronary artery VSM contraction and can manifest clinically as a wide spectrum of coronary syndromes, which can make diagnosis challenging. The prevalence of CAS is difficult to characterise due to variations within different populations. CAS is more prevalent in males, with most patients aged 40–70 years. The Japanese Coronary Spasm Association risk score can be utilised for risk assessment and prognostic stratification of CAS patients. CAS is suspected in the presence of severe chest pain at rest, with concurrent ECG changes showing transient ST-segment elevation. Chest pain remains the most common symptom of CAS, although silent attacks can occur, for example with syncope.

The causes of CAS are multifactorial and remain poorly defined. The ANS and endothelial dysfunction are thought to play an integral role in the pathophysiology of CAS. Treatment of CAS includes sublingual or intravenous nitroglycerin in the acute phase. In addition, long-acting nitrates, CCBs, and nicorandil all have a role in the treatment of CAS. There is limited evidence of invasive therapy with PCI or CABG, which should be considered in refractory cases.

References
Yasue H et al. Coronary artery spasm—clinical features, diagnosis, pathogenesis, and treatment. J Cardiol. 2008;51(1):2-17. Prinzmetal M et al. Angina pectoris. I. A variant form of angina pectoris; preliminary report. Am J Med. 1959;27:375-88. Prinzmetal M et al. Variant form of angina pectoris: previously undelineated syndrome. JAMA. 1960;174:1794-800. Oliva PB et al. Coronary arterial spasm in Prinzmetal angina: documentation by coronary arteriography. N Engl J Med. 1973;288(15):745-51. Hanazono N et al. Prinzmetal’s Angina Pectoris with Normal Coronary Arteriograms. Jpn Heart J. 1976;17(1):43-53. MacAlpin RN. Coronary arterial spasm: a historical perspective. J Hist Med Allied Sci. 1980;35(3):288-311. Beltrame et al. The Who, What, Why, When, How and Where of Vasospastic Angina. Circ J. 2016;80(2):289-98. JCS Joint Working Group. Japanese Circulation Society of Guidelines for Diagnosis and Treatment of Patients with Vasospastic Angina (Coronary Spastic Angina) (JCS 2008): digest version. Cir J. 2010;74(8):1745-62. Hung MY et al. Interactions among gender, age, hypertension and C-reactive protein in coronary vasospasm. Eur J Clin Invest. 2010;40(12):1094-103. Beltrame JF et al. Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients. J Am Coll Cardiol. 1999;33(6):1442-52. Pristipino C et al. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction. Circulation. 2000;101(10):1102-8. Ong P et al. Clinical usefulness, angiographic characteristics and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive Caucasian patients with unobstructed coronary arteries. Circulation. 2014;129(17):1723-30. Hung MJ et al. Coronary Artery Spasm: Review and Update. Int J Med Sci. 2014;11(11):1161-71. MacAlpin RN. Some observations on and controversies about coronary arterial spasm. Int J Cardiol. 2015;181:389-98. Sueda S et al. Did the widespread use of long-acting calcium antagonists decrease the occurrence of variant angina? Chest. 2003;124(6):2074-8. Yasue H, Kugiyama K. Coronary spasm: clinical features and pathogenesis. Intern Med. 1997;36(11):760-5. Liu Q et al. Diffuse triple-vessel coronary spasm as a cause of asystole and syncope. Am J Emerg Med. 2015;33(10):1546. Araki H et al. Diurnal distribution of ST-segment elevation and related arrhythmias in patients with variant angina: a study by ambulatory ECG monitoring. Circulation. 1983;67(5):995-1000. Kusama Y et al. Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology, and management. J Nippon Med Sch. 2011;78(1):4-12. Yasue H et al. Circadian variation of exercise capacity in patients with Prinzmetal’s variant angina: role of exercise-induced coronary arterial spasm. Circulation. 1979;59(5):938-48. Nakagawa H et al. Coronary Spasm Preferentially Occurs at Branch Points An Angiographic Comparison With Atherosclerotic Plaque. Circ Cardiovasc Interv. 2009;2(2):97-104. Romagnoli E, Lanza GA. Acute myocardial infarction with normal coronary arteries: role of coronary artery spasm and arrhythmic complications. Int J Cardiol. 2007;117(1):3-5. Hung MJ et al. Coronary vasospasm-induced acute coronary syndrome complicated by life-threatening cardiac arrhythmias in patients without hemodynamically significant coronary artery disease. Int J Cardiol. 2007;117(1):37-44. Bory M et al. Coronary artery spasm in patients with normal or near normal coronary arteries. Eur Heart J. 1996;17(7):1015-21. Castelló R et al. Syndrome of coronary artery spasm of normal coronary arteries. Clinical and angiographic features. Angiology. 1988;39(1 Pt 1):8-15. Yamagishi Matake K et al. Intravascular ultrasound detection of atherosclerosis at the site of focal vasospasm in angiographically normal or minimally narrowed coronary segments. J Am Coll Cardiol. 1994;23(2):352-7. Hong MK et al. Intravascular ultrasound findings of negative arterial remodeling at sites of focal coronary spasm in patients with vasospastic angina. Am Heart J. 2000;140(3):395-401. Crea F et al. Different susceptibility to myocardial ischemia provoked by hyperventilation and cold pressor test in exertional and variant angina pectoris. Am J Cardiol. 1985;56(1):18-22. Waters DD et al. Comparative sensitivity of exercise, cold pressor and ergonovine testing in provoking attacks of variant angina in patients with active disease. Circulation. 1983;67(2):310-5. Heupler FA Jr et al. Ergonovine maleate provocative test for coronary arterial spasm. Am J Cardiol. 1978;41(4):631-40. Harding MB et al. Ergonovine maleate testing during cardiac catheterization: a 10-year perspective in 3,447 patients without significant coronary artery disease or Prinzmetal’s variant angina. J Am Coll Cardiol. 1992;20(1):107-11. Okumura K et al. Multivessel coronary spasm in patients with variant angina: a study with intracoronary injection of acetylcholine. Circulation. 1988;77(3):535-42. Okumura K et al. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm. J Am Coll Cardiol. 1988;12(4):883-8. Sueda S et al. Frequency of provoked coronary spasms in patients undergoing coronary arteriography using a spasm provocation test via intracoronary administration of ergonovine. Angiology. 2004;55(4):403-11. Bertrand ME et al. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation. 1982;65(7):1299-306. Waters DD et al. Circadian variation in variant angina. Am J Cardiol. 1984;54(1):61-4. Yasue H et al. Role of autonomic nervous system in the pathogenesis of Prinzmetal’s variant form of angina. Circulation. 1974;50(3):534-9. Kaski JC et al. Spontaneous coronary artery spasm in variant angina is caused by a local hyperreactivity to a generalized constrictor stimulus. J Am Coll Cardiol. 1989;14(6):1456-63. King MJ et al. Variant angina associated with angiographically demonstrated coronary artery spasm and REM sleep. Am J Med Sci. 1973;265(5):419-22. Tilmant PY et al. Detrimental effect of propranolol in patients with coronary arterial spasm countered by combination with diltiazem. Am J Cardiol. 1983;52(3):230-3. Kern MJ et al. Attenuation of coronary vascular resistance by selective alpha1,-adrenergic blockade in patients with coronary artery disease. J Am Coll Cardiol. 1985;5(4):840-6. Winniford MD et al. Alpha-adrenergic blockade for variant angina: a long-term, double-blind, randomized trial. Circulation. 1983;67(6):1185-8. Yasue H et al. Pathogenesis and treatment of angina pectoris at rest as seen from its response to various drugs. Jpn Circ J. 1978;42(1):1-10. Egashira K et al. Preserved endothelium-dependent vasodilation at the vasospastic site in patients with variant angina. J Clin Invest. 1992;89(3):1047-52. Rubanyi GM. The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol. 1993;22 Suppl 4:S1-14. Nakayama M et al. T− 786à C mutation in the 5’-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation. 1999;99(22):2864-70. Yasue H et al. Effects of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin, on coronary spasm after withdrawal of calcium-channel blockers. J Am Coll Cardiol. 2008;51(18):1742-8. Motoyama T et al. Vitamin E administration improves impairment of endothelium-dependent vasodilation in patients with coronary spastic angina. J Am Coll Cardiol. 1998;32(6):1672-9. Takaoka K et al. Comparison of the risk factors for coronary artery spasm with those for organic stenosis in a Japanese population: role of cigarette smoking. Int J Cardiol. 2000;72(2):121-6. Hung MJ et al. Comparison of serum levels of inflammatory markers in patients with coronary vasospasm without significant fixed coronary artery disease versus patients with stable angina pectoris and acute coronary syndromes with significant fixed coronary artery disease. Am J Cardiol. 2006;97(10):1429-34. Shimokawa H. Cellular and molecular mechanisms of coronary artery spasm. Jpn Circ J. 2000;64(1):1-12. Kandabashi T et al. Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioscler Thromb Vasc Biol. 2003;23(12):2209-14. Kakkar R et al. Spontaneous Coronary Vasospasm in KATP Mutant Mice Arises From a Smooth Muscle–Extrinsic Process. Circ Res. 2006;98(5):682-9. Chen CC et al. Abnormal coronary function in mice deficient in a1H T-type Ca2+ channels. Science. 2003;302(5649):1416-8. JCS Joint Working Group. Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013). Circ J. 2014;78(11):2779-801. Takizawa A et al. Variant angina induced by alcohol ingestion. Am Heart J. 1984;107(1):25-7. Goto K et al. Magnesium deficiency detected by intravenous loading test in variant angina pectoris. Am J Cardiol. 1990;65(11):709-12. Miyagi H et al. Effect of magnesium on anginal attack induced by hyperventilation in patients with variant angina. Circulation. 1989;79(3):597-602. Chahine RA et al. Randomized placebo-controlled trial of amlodipine in vasospastic angina. J Am Coll Cardiol. 1993;21(6):1365-70. Waters DD. Ergonovine testing to detect spontaneous remissions of variant angina during long-term treatment with calcium antagonist drugs. Am J Cardiol. 1981;47(1):179-84. Gao B et al. The Use of Calcium Channel Blockers in the Treatment of Coronary Spasm and Atrioventricular Block. Cell Biochem Biophys. 2015;72(2):527-31. Hill JA et al. Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm. Am J Cardiol. 1982;49(2):431-8. Münzel T et al. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005;97(7):618-28. Kaski JC. Management of vasospastic angina—role of nicorandil. Cardiovasc Drugs Ther. 1995;9 Suppl 2:221-7. Morita S et al. Pioglitazone, a peroxisome proliferator-activated receptor g activator, suppresses coronary spasm. Coron Artery Dis. 2014;25(8): 671-7. Pasternak RC et al. Variant angina. Clinical spectrum and results of medical and surgical therapy. J Thorac Cardiovasc Surg. 1979;78(4):614-22. Cardona-Guarache R et al. Thoracic Sympathectomy for Severe Refractory Multivessel Coronary Artery Spasm. Am J Cardiol. 2016;117(1):159-61. Demir OM et al. Recurrent coronary spasm necessitating primary percutaneous coronary intervention. Br J Hosp Med (Lond). 2016;77(2):112-3. Gaspardone A et al. Coronary artery stent placement in patients with variant angina refractory to medical treatment. Am J Cardiol. 1999;84(1):96-8. Yasue H et al. Long-term prognosis for patients with variant angina and influential factors. Circulation. 1988;78(1):1-9. Kimura E, Kishida H. Treatment of variant angina with drugs: a survey of 11 cardiology institutes in Japan. Circulation. 1981;63(4):844-8. Tanabe Y et al. Limited role of coronary angioplasty and stenting in coronary spastic angina with organic stenosis. J Am Coll Cardiol. 2002;39(7):1120-6. Lombardi M et al. Efficacy of isosorbide-5-mononitrate versus nifedipine in preventing spontaneous and ergonovine-induced myocardial ischaemia. A double-blind, placebo-controlled study. Eur Heart J. 1993;14(6):845-51. Takahashi J et al. Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association. Eur Heart J. 2015;36(4):228-37. Lablanche JM et al. Prevention of coronary spasm by nicorandil: comparison with nifedipine. J Cardiovasc Pharmacol. 1992;20 Suppl 3:S82-5. Kishida H, Murao S. Effect of a new coronary vasodilator, nicorandil, on variant angina pectoris. Clin Pharmacol Ther. 1987;42(2):166-74. Takagi Y et al. Prognostic stratification of patients with vasospastic angina: a comprehensive clinical risk score developed by the Japanese Coronary Spasm Association. J Am Coll Cardiol. 2013;62(13):1144-53.