Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Vasospastic angina

Duane S Pinto, MD, MPH
Filippo Crea, MD
Section Editor
Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA
Deputy Editor
Gordon M Saperia, MD, FACC


Vasospastic angina, which was previously referred to as Prinzmetal or variant angina, is a clinical entity characterized by episodes of rest angina that promptly respond to short-acting nitrates and are attributable to coronary artery vasospasm. Prinzmetal, et al [1] initially described a clinical syndrome that manifested as rest angina associated with ST-segment elevation that promptly responded to sublingual nitrates. Since this differed to the classical angina described by Heberden (effort angina associated with ST depression) [2], he referred to it as “variant angina.” With the advent of coronary angiography, subsequent studies confirmed Prinzmetal’s original suspicion that variant angina was attributable to coronary artery spasm but also demonstrated that episodes could be associated with ST-segment depression. Consequently, the term "vasospastic angina" evolved. This topic will discuss all aspects of vasospastic angina; other forms of (cardiac) angina are discussed in separate topic reviews. (See "Stable ischemic heart disease: Overview of care" and "Classification of unstable angina and non-ST elevation myocardial infarction", section on 'Classification of unstable angina' and "Cardiac syndrome X: Angina pectoris with normal coronary arteries".)


Within the literature, there have been a variety of definitions for vasospastic angina, leading to confusion. Consequently, the Coronary Vasomotion Disorders International Study group (COVADIS) has published diagnostic criteria for vasospastic angina (table 1) [3]. There are three core elements establishing the diagnosis of vasospastic angina, including nitrate-responsive angina, transient ischemic electrocardiographic (ECG) changes, and angiographic evidence of coronary artery spasm. In patients with a documented spontaneous episode, the diagnosis can be made on the basis of nitrate-responsive angina with associated transient ECG changes. Occasionally, a spontaneous episode may occur during diagnostic angiography so that all three elements may be documented. However, when typical spontaneous episodes cannot often be documented, provocative testing is undertaken to make the diagnosis. During provocation testing, the diagnosis of vasospastic angina is confirmed if the provocative stimulus induced chest pain, transient ECG changes, and a >90 percent constrictor response.


Vasospastic angina is caused by focal or diffuse spasm (of the smooth muscle layer of the arterial wall) of an epicardial coronary artery [4,5], resulting in a high-grade obstruction. Transient myocardial ischemia causes angina in many patients; myocardial infarction may develop in some if spasm is persistent [1,6]. Vascular smooth muscle hyper-reactivity is thought to be central to the pathogenesis of vasospastic angina [1,4,5].

Spasm may occur in the absence of any preceding increase in myocardial oxygen demand (eg, exercise) and in normal or diseased vessels. Original descriptions reported anatomically focal spasm sites but increasingly diffuse spasm is being described [7]. Spasm can occur in angiographically normal coronary vessels but more commonly at the site of atherosclerotic plaques of variable severity.

Vascular smooth muscle hyper-reactivity — Animal and clinical studies have implicated coronary vascular smooth muscle hyper-reactivity as a key factor in the pathogenesis of coronary artery spasm. Important observations include:

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Feb 06, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. PRINZMETAL M, KENNAMER R, MERLISS R, et al. Angina pectoris. I. A variant form of angina pectoris; preliminary report. Am J Med 1959; 27:375.
  2. Silverman ME. William Heberden and Some Account of a Disorder of the Breast. Clin Cardiol 1987; 10:211.
  3. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2015.
  4. Kaski JC, Crea F, Meran D, et al. Local coronary supersensitivity to diverse vasoconstrictive stimuli in patients with variant angina. Circulation 1986; 74:1255.
  5. Kaski JC, Maseri A, Vejar M, 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; 14:1456.
  6. PRINZMETAL M, EKMEKCI A, KENNAMER R, et al. Variantform of angina pectoris, previously undelineated syndrome. JAMA 1960; 174:1794.
  7. Okumura K, Yasue H, Matsuyama K, et al. Diffuse disorder of coronary artery vasomotility in patients with coronary spastic angina. Hyperreactivity to the constrictor effects of acetylcholine and the dilator effects of nitroglycerin. J Am Coll Cardiol 1996; 27:45.
  8. De Caterina R, Carpeggiani C, L'Abbate A. A double-blind, placebo-controlled study of ketanserin in patients with Prinzmetal's angina. Evidence against a role for serotonin in the genesis of coronary vasospasm. Circulation 1984; 69:889.
  9. Winniford MD, Filipchuk N, Hillis LD. Alpha-adrenergic blockade for variant angina: a long-term, double-blind, randomized trial. Circulation 1983; 67:1185.
  10. Shimokawa H, Seto M, Katsumata N, et al. Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc Res 1999; 43:1029.
  11. Kandabashi T, Shimokawa H, Miyata K, et al. Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation 2000; 101:1319.
  12. Masumoto A, Mohri M, Shimokawa H, et al. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation 2002; 105:1545.
  13. Nakano T, Osanai T, Tomita H, et al. Enhanced activity of variant phospholipase C-delta1 protein (R257H) detected in patients with coronary artery spasm. Circulation 2002; 105:2024.
  14. Yasue H, Touyama M, Shimamoto M, et al. Role of autonomic nervous system in the pathogenesis of Prinzmetal's variant form of angina. Circulation 1974; 50:534.
  15. Sueda S, Ochi N, Kawada H, et al. Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine. Am J Cardiol 1999; 83:1186.
  16. Yasue H, Touyama M, Kato H, et al. Prinzmetal's variant form of angina as a manifestation of alpha-adrenergic receptor-mediated coronary artery spasm: documentation by coronary arteriography. Am Heart J 1976; 91:148.
  17. Ricci DR, Orlick AE, Cipriano PR, et al. Altered adrenergic activity in coronary arterial spasm: insight into mechanism based on study of coronary hemodynamics and the electrocardiogram. Am J Cardiol 1979; 43:1073.
  18. Yasue H, Horio Y, Nakamura N, et al. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation 1986; 74:955.
  19. Bertrand ME, Lablanche JM, Tilmant PY, et al. Complete denervation of the heart (autotransplantation) for treatment of severe, refractory coronary spasm. Am J Cardiol 1981; 47:1375.
  20. Lanza GA, Pedrotti P, Pasceri V, et al. Autonomic changes associated with spontaneous coronary spasm in patients with variant angina. J Am Coll Cardiol 1996; 28:1249.
  21. Stern S, Bayes de Luna A. Coronary artery spasm: a 2009 update. Circulation 2009; 119:2531.
  22. Saitoh T, Kishida H, Hanashi A, et al. Coronary hyperreactivity to adrenergic stimulation and increased nocturnal vagal tone trigger coronary vasospasm. Jpn Circ J 1998; 62:721.
  23. Bertrand ME, Lablanche JM, Tilmant PY. Treatment of Prinzmetal's variant angina. Role of medical treatment with nifedipine and surgical coronary revascularization combined with plexectomy. Am J Cardiol 1981; 47:174.
  24. Kugiyama K, Yasue H, Okumura K, et al. Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina. Circulation 1996; 94:266.
  25. Kugiyama K, Ohgushi M, Motoyama T, et al. Nitric oxide-mediated flow-dependent dilation is impaired in coronary arteries in patients with coronary spastic angina. J Am Coll Cardiol 1997; 30:920.
  26. Nakayama M, Yasue H, Yoshimura M, et al. T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999; 99:2864.
  27. Levin ER. Endothelins. N Engl J Med 1995; 333:356.
  28. Cox ID, Bøtker HE, Bagger JP, et al. Elevated endothelin concentrations are associated with reduced coronary vasomotor responses in patients with chest pain and normal coronary arteriograms. J Am Coll Cardiol 1999; 34:455.
  29. Figueras J, Domingo E, Cortadellas J, et al. Comparison of plasma serotonin levels in patients with variant angina pectoris versus healed myocardial infarction. Am J Cardiol 2005; 96:204.
  30. Motoyama T, Kawano H, Kugiyama K, et al. Vitamin E administration improves impairment of endothelium-dependent vasodilation in patients with coronary spastic angina. J Am Coll Cardiol 1998; 32:1672.
  31. Hirashima O, Kawano H, Motoyama T, et al. Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: possible role of reactive oxygen species. J Am Coll Cardiol 2000; 35:1860.
  32. Miyao Y, Kugiyama K, Kawano H, et al. Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina. J Am Coll Cardiol 2000; 36:432.
  33. Suzuki H, Kawai S, Aizawa T, et al. Histological evaluation of coronary plaque in patients with variant angina: relationship between vasospasm and neointimal hyperplasia in primary coronary lesions. J Am Coll Cardiol 1999; 33:198.
  34. Hung MJ, Cherng WJ, Yang NI, et al. Relation of high-sensitivity C-reactive protein level with coronary vasospastic angina pectoris in patients without hemodynamically significant coronary artery disease. Am J Cardiol 2005; 96:1484.
  35. Sun H, Mohri M, Shimokawa H, et al. Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina. J Am Coll Cardiol 2002; 39:847.
  36. Nobuyoshi M, Abe M, Nosaka H, et al. Statistical analysis of clinical risk factors for coronary artery spasm: identification of the most important determinant. Am Heart J 1992; 124:32.
  37. Takaoka K, Yoshimura M, Ogawa H, 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; 72:121.
  38. Suzuki S, Yoshimura M, Nakayama M, et al. A novel genetic marker for coronary spasm in women from a genome-wide single nucleotide polymorphism analysis. Pharmacogenet Genomics 2007; 17:919.
  39. Murase Y, Yamada Y, Hirashiki A, et al. Genetic risk and gene-environment interaction in coronary artery spasm in Japanese men and women. Eur Heart J 2004; 25:970.
  40. Shinozaki K, Suzuki M, Ikebuchi M, et al. Insulin resistance associated with compensatory hyperinsulinemia as an independent risk factor for vasospastic angina. Circulation 1995; 92:1749.
  41. Stricker BH. Coronary vasospasm and sumatriptan. BMJ 1992; 305:118.
  42. Lange RA, Cigarroa RG, Yancy CW Jr, et al. Cocaine-induced coronary-artery vasoconstriction. N Engl J Med 1989; 321:1557.
  43. Forman MB, Blass M, Jackson EK. Variant angina in the setting of food-borne botulism. Clin Infect Dis 2011; 53:1300.
  44. Satake K, Lee JD, Shimizu H, et al. Relation between severity of magnesium deficiency and frequency of anginal attacks in men with variant angina. J Am Coll Cardiol 1996; 28:897.
  45. Shimokawa H, Tomoike H, Nabeyama S, et al. Coronary artery spasm induced in atherosclerotic miniature swine. Science 1983; 221:560.
  46. Ginsburg R, Bristow MR, Kantrowitz N, et al. Histamine provocation of clinical coronary artery spasm: implications concerning pathogenesis of variant angina pectoris. Am Heart J 1981; 102:819.
  47. Forman MB, Oates JA, Robertson D, et al. Increased adventitial mast cells in a patient with coronary spasm. N Engl J Med 1985; 313:1138.
  48. Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract 1991; 45:121.
  49. Kounis NG, Hahalis G, Theoharides TC. Coronary stents, hypersensitivity reactions, and the Kounis syndrome. J Interv Cardiol 2007; 20:314.
  50. Kusama Y, Kodani E, Nakagomi A, et al. Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology, and management. J Nippon Med Sch 2011; 78:4.
  51. Ogawa H, Yasue H, Oshima S, et al. Circadian variation of plasma fibrinopeptide A level in patients with variant angina. Circulation 1989; 80:1617.
  52. Heart Disease: A Textbook of Cardiovascular Medicine, 9th ed, Braunwald E (Ed), Elsevier Saunders, Philadelphia 2011.
  53. Sugiishi M, Takatsu F. Cigarette smoking is a major risk factor for coronary spasm. Circulation 1993; 87:76.
  54. Rosamond W. Are migraine and coronary heart disease associated? An epidemiologic review. Headache 2004; 44 Suppl 1:S5.
  55. Nakamura Y, Shinozaki N, Hirasawa M, et al. Prevalence of migraine and Raynaud's phenomenon in Japanese patients with vasospastic angina. Jpn Circ J 2000; 64:239.
  56. Koh KK, Roe IH, Lee MM, et al. Variant angina complicating ergot therapy of migraine. Chest 1994; 105:1259.
  57. Previtali M, Ardissino D, Barberis P, et al. Hyperventilation and ergonovine tests in Prinzmetal's variant angina pectoris in men. Am J Cardiol 1989; 63:17.
  58. Matsuda Y, Ozaki M, Ogawa H, et al. Coronary arteriography and left ventriculography during spontaneous and exercise-induced ST segment elevation in patients with variant angina. Am Heart J 1983; 106:509.
  59. Minoda K, Yasue H, Kugiyama K, et al. Comparison of the distribution of myocardial blood flow between exercise-induced and hyperventilation-induced attacks of coronary spasm: a study with thallium-201 myocardial scintigraphy. Am Heart J 1994; 127:1474.
  60. Kishida H, Tada Y, Fukuma N, et al. Significant characteristics of variant angina patients with associated syncope. Jpn Heart J 1996; 37:317.
  61. Ahn JM, Lee KH, Yoo SY, et al. Prognosis of Variant Angina Manifesting as Aborted Sudden Cardiac Death. J Am Coll Cardiol 2016; 68:137.
  62. Enseleit F, Duru F. Long-term continuous external electrocardiographic recording: a review. Europace 2006; 8:255.
  63. Araki H, Koiwaya Y, Nakagaki O, Nakamura M. Diurnal distribution of ST-segment elevation and related arrhythmias in patients with variant angina: a study by ambulatory ECG monitoring. Circulation 1983; 67:995.
  64. Lahiri A, Subramanian B, Millar-Craig M, et al. Exercise-induced S-T segment elevation in variant angina. Am J Cardiol 1980; 45:887.
  65. Song JK, Park SW, Kang DH, et al. Safety and clinical impact of ergonovine stress echocardiography for diagnosis of coronary vasospasm. J Am Coll Cardiol 2000; 35:1850.
  66. Hamilton KK, Pepine CJ. A renaissance of provocative testing for coronary spasm? J Am Coll Cardiol 2000; 35:1857.
  67. Yamada T, Okamoto M, Sueda T, et al. Ergonovine-induced alterations in coronary flow velocity preceding onset of occlusive spasm in patients without significant coronary artery stenoses. Am J Cardiol 1998; 81:688.
  68. Pepine CJ, Feldman RL, Conti CR. Action of intracoronary nitroglycerin in refractory coronary artery spasm. Circulation 1982; 65:411.
  69. Bertrand ME, LaBlanche JM, Tilmant PY, et al. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation 1982; 65:1299.
  70. Sueda S, Saeki H, Otani T, et al. Major complications during spasm provocation tests with an intracoronary injection of acetylcholine. Am J Cardiol 2000; 85:391.
  71. Ong P, Athanasiadis A, Borgulya G, et al. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation 2014; 129:1723.
  72. Nakao K, Ohgushi M, Yoshimura M, et al. Hyperventilation as a specific test for diagnosis of coronary artery spasm. Am J Cardiol 1997; 80:545.
  73. Task Force Members, Montalescot G, Sechtem U, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34:2949.
  74. JCS Joint Working Group. Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013). Circ J 2014; 78:2779.
  75. Miwa K, Fujita M, Miyagi Y. Beneficial effects of smoking cessation on the short-term prognosis for variant angina--validation of the smoking status by urinary cotinine measurements. Int J Cardiol 1994; 44:151.
  76. Drugs for the Heart, 4th ed, Opie LH (Ed), WB Saunders, Philadelphia 1995. p.31.
  77. Yasue H, Takizawa A, Nagao M, et al. Long-term prognosis for patients with variant angina and influential factors. Circulation 1988; 78:1.
  78. Kimura E, Kishida H. Treatment of variant angina with drugs: a survey of 11 cardiology institutes in Japan. Circulation 1981; 63:844.
  79. Lanza GA, Maseri A. Coronary Artery Spasm. Curr Treat Options Cardiovasc Med 2000; 2:83.
  80. Lombardi M, Morales MA, Michelassi C, 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; 14:845.
  81. Takahashi J, Nihei T, Takagi Y, 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; 36:228.
  82. Shin ES, Lee JH, Yoo SY, et al. A randomised, multicentre, double blind, placebo controlled trial to evaluate the efficacy and safety of cilostazol in patients with vasospastic angina. Heart 2014; 100:1531.
  83. Frenneaux M, Kaski JC, Brown M, Maseri A. Refractory variant angina relieved by guanethidine and clonidine. Am J Cardiol 1988; 62:832.
  84. Yasue H, Mizuno Y, Harada E, 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; 51:1742.
  85. Teragawa H, Kato M, Yamagata T, et al. The preventive effect of magnesium on coronary spasm in patients with vasospastic angina. Chest 2000; 118:1690.
  86. Corcos T, David PR, Bourassa MG, et al. Percutaneous transluminal coronary angioplasty for the treatment of variant angina. J Am Coll Cardiol 1985; 5:1046.
  87. Gaspardone A, Tomai F, Versaci F, et al. Coronary artery stent placement in patients with variant angina refractory to medical treatment. Am J Cardiol 1999; 84:96.
  88. Tanabe Y, Itoh E, Suzuki K, et al. Limited role of coronary angioplasty and stenting in coronary spastic angina with organic stenosis. J Am Coll Cardiol 2002; 39:1120.
  89. Robertson RM, Wood AJ, Vaughn WK, Robertson D. Exacerbation of vasotonic angina pectoris by propranolol. Circulation 1982; 65:281.
  90. Miwa K, Kambara H, Kawai C. Effect of aspirin in large doses on attacks of variant angina. Am Heart J 1983; 105:351.
  91. Wasson S, Jayam VK. Coronary vasospasm and myocardial infarction induced by oral sumatriptan. Clin Neuropharmacol 2004; 27:198.
  92. Maseri A, Lanza G. Fluorouracil-induced coronary artery spasm. Am J Med 2001; 111:326.
  93. Kishida H, Tada Y, Tetsuoh Y, et al. A new strategy for the reduction of acute myocardial infarction in variant angina. Am Heart J 1991; 122:1554.
  94. Bory M, Pierron F, Panagides D, et al. Coronary artery spasm in patients with normal or near normal coronary arteries. Long-term follow-up of 277 patients. Eur Heart J 1996; 17:1015.
  95. Walling A, Waters DD, Miller DD, et al. Long-term prognosis of patients with variant angina. Circulation 1987; 76:990.
  96. Miwa K, Nakagawa K, Yoshida N, et al. Lipoprotein(a) is a risk factor for occurrence of acute myocardial infarction in patients with coronary vasospasm. J Am Coll Cardiol 2000; 35:1200.
  97. Myerburg RJ, Kessler KM, Mallon SM, et al. Life-threatening ventricular arrhythmias in patients with silent myocardial ischemia due to coronary-artery spasm. N Engl J Med 1992; 326:1451.
  98. Matsue Y, Suzuki M, Nishizaki M, et al. Clinical implications of an implantable cardioverter-defibrillator in patients with vasospastic angina and lethal ventricular arrhythmia. J Am Coll Cardiol 2012; 60:908.
  99. Yasue H, Nakagawa H, Itoh T, et al. Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment. J Cardiol 2008; 51:2.
  100. Ong P, Athanasiadis A, Borgulya G, et al. 3-year follow-up of patients with coronary artery spasm as cause of acute coronary syndrome: the CASPAR (coronary artery spasm in patients with acute coronary syndrome) study follow-up. J Am Coll Cardiol 2011; 57:147.
  101. Onaka H, Hirota Y, Shimada S, et al. Prognostic significance of the pattern of multivessel spasm in patients with variant angina. Jpn Circ J 1999; 63:509.
  102. Ishii M, Kaikita K, Sato K, et al. Acetylcholine-Provoked Coronary Spasm at Site of Significant Organic Stenosis Predicts Poor Prognosis in Patients With Coronary Vasospastic Angina. J Am Coll Cardiol 2015; 66:1105.
  103. Chevalier P, Dacosta A, Defaye P, et al. Arrhythmic cardiac arrest due to isolated coronary artery spasm: long-term outcome of seven resuscitated patients. J Am Coll Cardiol 1998; 31:57.
  104. Meisel SR, Mazur A, Chetboun I, et al. Usefulness of implantable cardioverter-defibrillators in refractory variant angina pectoris complicated by ventricular fibrillation in patients with angiographically normal coronary arteries. Am J Cardiol 2002; 89:1114.
  105. Takagi Y, Takahashi J, Yasuda S, 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; 62:1144.