Assessment of Coronary Vasomotor Responses: Clinical Usefulness

  • Peter Ong
  • Anastasios Athanasiadis
  • Udo Sechtem


Assessment of coronary vasomotor responses can be a helpful tool to detect coronary vasomotor abnormalities as the underlying cause for chest pain in patients with normal or unobstructed coronary arteries. Testing can be performed using intravenous or intracoronary administration of vasoactive substances such as ergonovine or acetylcholine. Intracoronary provocation testing for the assessment of coronary vasomotor responses is an integral part of coronary angiography in Asia. However, in the US and Europe it is only performed in few centres as part of daily clinical routine. This book chapter gives a detailed explanation on how to perform assessment of coronary vasomotor responses and how to interpret the test results. In addition, frequent pitfalls and limitations are described. Moreover, the different clinical scenarios where abnormal coronary vasomotion can explain angina symptoms in patients with normal or unobstructed coronary arteries, such as ACS, stable angina, etc. are highlighted. If vasomotor abnormalities have been demonstrated calcium channel blockers and nitrates are often the drugs of choice. In addition, patients should receive drugs to improve endothelial function or to reduce inflammation such as ACE-inhibitors and statins. The results of intracoronary provocation tests can serve as a basis to estimate prognosis. Patients with a pathologic test result have an increased morbidity and risk for cardiovascular events during follow-up. Patients with proof of epicardial spasm have been shown to be at an elevated risk for cardiac death and myocardial infarction (approx. 1–1.5 % per year). In patients with microvascular spasm/dysfunction prognosis regarding major cardiovascular events is generally good (0 % for cardiac death, ∼0.5 % for myocardial infarction per year). However, persistent or ongoing angina represents a major problem.


Acetylcholine Ergonovine Coronary spasm Microvascular dysfunction Coronary microcirculation Myocardial ischemia 


  1. 1.
    Puri R, Liew GY, Nicholls SJ, Nelson AJ, Leong DP, Carbone A, et al. Coronary {beta}2-adrenoreceptors mediate endothelium-dependent vasoreactivity in humans: novel insights from an in vivo intravascular ultrasound study. Eur Heart J. 2012;33:495–504.PubMedCrossRefGoogle Scholar
  2. 2.
    Tio RA, Monnink SH, Amoroso G, Jessurun GA, Veeger N, Volkers C, et al. Safety evaluation of routine intracoronary acetylcholine infusion in patients undergoing a first diagnostic coronary angiogram. J Investig Med. 2002;50:133–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Sechtem U. Clinical usefulness and safety evaluation of intracoronary provocation testing among 1000 consecutive caucasian patients with anginal symptoms and unobstructed coronary arteries. J Am Coll Cardiol. 2012;59:E1487–7. doi: 10.1016/S0735-1097(12)61488-0.CrossRefGoogle Scholar
  4. 4.
    Noto Jr TJ, Johnson LW, Krone R, Weaver WF, Clark DA, Kramer Jr JR, et al. Cardiac catheterization 1990: a report of the Registry of the Society for Cardiac Angiography and Interventions (SCA&I). Cathet Cardiovasc Diagn. 1991;24:75–83.PubMedCrossRefGoogle Scholar
  5. 5.
    Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, et al. Guidelines on the management of stable angina pectoris: executive summary: the task force on the management of stable angina pectoris of the European Society of Cardiology. Eur Heart J. 2006;27:1341–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. ACC/AHA 2002 guideline update for the ­management of patients with chronic stable angina – summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 2003;41:159–68.PubMedCrossRefGoogle Scholar
  7. 7.
    JCS Joint Working Group. Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina). Circ J. 2010;74:1745–62.CrossRefGoogle Scholar
  8. 8.
    Karagianni A, Schaeufele T, Athanasiadis A, Yilmaz A, Sechtem U. Feasibility of transradial approach without radial artery spasm prophylaxis for intracoronary spasm provocation test. Eur Heart J. 2011;32(Abstract Suppl):859–60.Google Scholar
  9. 9.
    Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Egashira K, Inou T, Yamada A, Hirooka Y, Takeshita A. Preserved endothelium-dependent vasodilation at the vasospastic site in patients with variant angina. J Clin Invest. 1992;89:1047–52.PubMedCrossRefGoogle Scholar
  11. 11.
    Shimizu H, Lee JD, Ogawa K, Hara A, Nakamura T. Coronary artery vasoreactivity to intracoronary acetylcholine infusion test in patients with chest pain syndrome. Intern Med. 1992;31:22–7.PubMedCrossRefGoogle Scholar
  12. 12.
    ENCORE Investigators. Effect of nifedipine and cerivastatin on coronary endothelial function in patients with coronary artery ­disease: the ENCORE I study (Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function). Circulation. 2003;107:422–8.CrossRefGoogle Scholar
  13. 13.
    Sueda S, Izoe Y, Kohno H, Fukuda H, Uraoka T. Need for documentation of guidelines for coronary artery spasm: an investigation by questionnaire in Japan. Circ J. 2005;69:1333–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol. 2012;59:655–62.PubMedCrossRefGoogle Scholar
  15. 15.
    Sueda S, Kohno H, Fukuda H, Ochi N, Kawada H, Hayashi Y, et al. Frequency of provoked coronary spasms in patients undergoing coronary arteriography using a spasm provocation test via ­intracoronary administration of ergonovine. Angiology. 2004;55:403–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Wang CH, Kuo LT, Hung MJ, Cherng WJ. Coronary vasospasm as a possible cause of elevated cardiac troponin I in patients with acute coronary syndrome and insignificant coronary artery disease. Am Heart J. 2002;144:275–81.PubMedGoogle Scholar
  17. 17.
    Harding MB, Leithe ME, Mark DB, Nelson CL, Harrison JK, Hermiller JB, 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;20:107–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Bertrand ME, LaBlanche JM, Tilmant PY, Thieuleux FA, Delforge MR, Carre AG, et al. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation. 1982;65:1299–306.PubMedCrossRefGoogle Scholar
  19. 19.
    Song JK, Lee SJ, Kang DH, Cheong SS, Hong MK, Kim JJ, et al. Ergonovine echocardiography as a screening test for diagnosis of vasospastic angina before coronary angiography. J Am Coll Cardiol. 1996;27:1156–61.PubMedCrossRefGoogle Scholar
  20. 20.
    Mohri M, Koyanagi M, Egashira K, Tagawa H, Ichiki T, Shimokawa H, et al. Angina pectoris caused by coronary microvascular spasm. Lancet. 1998;351:1165–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Waters DD, Miller DD, Bouchard A, Bosch X, Theroux P. Circadian variation in variant angina. Am J Cardiol. 1984;54:61–4.PubMedCrossRefGoogle Scholar
  22. 22.
    Sueda S, Ochi T, Yano K, Mineoi K, Kondou T, Ochi N, et al. New combined spasm provocation test in patients with rest angina: ­intracoronary injection of acetylcholine after intracoronary adminis­tration of ergonovine. Jpn Circ J. 2000;64:559–65.PubMedCrossRefGoogle Scholar
  23. 23.
    Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coll Cardiol. 1991;17:499–506.PubMedCrossRefGoogle Scholar
  24. 24.
    Summers MR, Lerman A, Lennon RJ, Rihal CS, Prasad A. Myocardial ischaemia in patients with coronary endothelial ­dysfunction: insights from body surface ECG mapping and implications for invasive evaluation of chronic chest pain. Eur Heart J. 2011;32:2758–65.PubMedCrossRefGoogle Scholar
  25. 25.
    Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve ­versus angiography in multivessel evaluation. J Am Coll Cardiol. 2010;55(25):2816–21.PubMedCrossRefGoogle Scholar
  26. 26.
    Okumura K, Yasue H, Matsuyuma K, et al. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary arterial spasm. J Am Coll Cardiol. 1988;12:833.CrossRefGoogle Scholar
  27. 27.
    Cayley WE. Diagnosing the cause of chest pain. Am Fam Physician. 2005;72:2012–21.PubMedGoogle Scholar
  28. 28.
    Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M, Sechtem U. Coronary artery spasm as a frequent cause of acute coronary syndrome: The CASPAR (Coronary Artery Spasm in Patients With Acute Coronary Syndrome) Study. J Am Coll Cardiol. 2008;52:523–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Niccoli G, Renda G, Cianflone D, Crea F. Transient microvascular vasoconstriction: a possible cause of unstable angina. Ital Heart J. 2000;1:365–7.PubMedGoogle Scholar
  30. 30.
    Athanasiadis A, Vogelsberg H, Hauer B, Meinhardt G, Hill S, Sechtem U. Transient left ventricular dysfunction with apical ballooning (tako-tsubo cardiomyopathy) in Germany. Clin Res Cardiol. 2006;95:321–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Bielecka-Dabrowa A, Mikhailidis DP, Hannam S, Rysz J, Michalska M, Akashi YJ, et al. Takotsubo cardiomyopathy – the current state of knowledge. Int J Cardiol. 2010;142:120–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Haghi D, Suselbeck T, Wolpert C. Severe multivessel coronary vasospasm and left ventricular ballooning syndrome. Circ Cardiovasc Interv. 2009;2:268–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Yilmaz A, Mahrholdt H, Athanasiadis A, Vogelsberg H, Meinhardt G, Voehringer M, et al. Coronary vasospasm as the underlying cause for chest pain in patients with PVB19 ­myocarditis. Heart. 2008;94:1456–63.PubMedCrossRefGoogle Scholar
  34. 34.
    Ong P, Athanasiadis A, Alscher MD, Fritz P, Mahrholdt H, Sechtem U, et al. Coronary artery spasm as a cause for myocardial infarction in patients with systemic inflammatory disease. Int J Cardiol. 2011;151:e32–4.PubMedCrossRefGoogle Scholar
  35. 35.
    Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Angina pectoris. I. A variant form of angina pectoris; preliminary report. Am J Med. 1959;27:375–88.PubMedCrossRefGoogle Scholar
  36. 36.
    Cheng TO, Bashour T, Kelser Jr GA, Weiss L, Bacos J. Variant angina of Prinzmetal with normal coronary arteriograms. A variant of the variant. Circulation. 1973;47:476–85.PubMedCrossRefGoogle Scholar
  37. 37.
    Higgins CB, Wexler L, Silverman J, Schroeder JS. Clinical and arteriographic features of Prinzmetal variant angina: documentation of arterial spasm. Am J Cardiol. 1976;37:831–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Yilmaz A, Hill S, Schäufele T, Vöhringer M, Geissler A, Sechtem U. Exercise-induced spastic coronary artery occlusion at the site of a moderate stenosis: neither Prinzmetal’s angina nor cardiac ­syndrome X but “Prinzmetal X”. Circulation. 2010;122:e570–4.PubMedCrossRefGoogle Scholar
  39. 39.
    Sun H, Mohri M, Shimokawa H, Usui M, Urakami L, Takeshita A. Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina. J Am Coll Cardiol. 2002;39:847–51.PubMedCrossRefGoogle Scholar
  40. 40.
    Vermeltfoort IA, Raijmakers PG, Riphagen II, Odekerken DA, Kuijper AF, Zwijnenburg A, et al. Definitions and incidence of cardiac syndrome X: review and analysis of clinical data. Clin Res Cardiol. 2010;99:475–81.PubMedCrossRefGoogle Scholar
  41. 41.
    Lanza GA. Cardiac syndrome X: a critical overview and future perspectives. Heart. 2007;93:159–66.PubMedCrossRefGoogle Scholar
  42. 42.
    Cannon 3rd RO, Epstein SE. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol. 1988;61:1338–43.PubMedCrossRefGoogle Scholar
  43. 43.
    Ong P, Athanasiadis A, Mahrholdt H, Borgulya G, Sechtem U, Kaski JC. Increased coronary vasoconstrictor response to acetylcholine in women with chest pain and normal coronary ­arteriograms (cardiac syndrome X). Clin Res Cardiol. 2012;101:673–81.PubMedCrossRefGoogle Scholar
  44. 44.
    Lanza GA, Crea F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation. 2010;121:2317–25.PubMedCrossRefGoogle Scholar
  45. 45.
    Monnink S, Tio R, Veeger N, Amoroso G, van Boven A, van Gilst W. Exercise-induced ischemia after successful percutaneous coronary intervention is related to distal coronary endo­thelial dysfunction. J Invest Med. 2003;51:221–6.CrossRefGoogle Scholar
  46. 46.
    Ito S, Nakasuka K, Morimoto K, Inomata M, Yoshida T, Tamai N, et al. Angiographic and clinical characteristics of patients with acetylcholine-induced coronary vasospasm on follow-up coronary angiography following drug-eluting stent implantation. J Invasive Cardiol. 2011;23:57–64.PubMedGoogle Scholar
  47. 47.
    Shah BR, Cowper PA, O’Brien SM, Jensen N, Drawz M, Patel MR, et al. Patterns of cardiac stress testing after revascularization in community practice. J Am Coll Cardiol. 2010;56:1328–34.PubMedCrossRefGoogle Scholar
  48. 48.
    Mohri M, Takeshita A. Coronary microvascular disease in humans. Jpn Heart J. 1999;40:97–108.PubMedCrossRefGoogle Scholar
  49. 49.
    Canetti M, Akhter MW, Lerman A, Karaalp IS, Zell JA, Singh H, et al. Evaluation of myocardial blood flow reserve in patients with chronic congestive heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol. 2003;92:1246–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Stolen KQ, Kemppainen J, Kalliokoski KK, Karanko H, Toikka J, Janatuinen T, et al. Myocardial perfusion reserve and peripheral endothelial function in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2004;93:64–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Mathier MA, Rose GA, Fifer MA, Miyamoto MI, Dinsmore RE, Castaño HH, et al. Coronary endothelial dysfunction in patients with acute-onset idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1998;32:216–24.PubMedCrossRefGoogle Scholar
  52. 52.
    Inami T, Kataoka M, Shimura N, Ishiguro H, Kohshoh H, Taguchi H, et al. Left ventricular dysfunction due to diffuse multiple vessel coronary artery spasm can be concealed in dilated cardio­myopathy. Eur J Heart Fail. 2012;14:1130–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Sakata K, Nawada R, Ohbayashi K, Tamekiyo H, Yoshida H. Diffuse and severe left ventricular dysfunction induced by epicardial coronary artery spasm. Angiology. 2000;51:837–47.PubMedCrossRefGoogle Scholar
  54. 54.
    Pauly DF, Johnson BD, Anderson RD, Handberg EM, Smith KM, Cooper-DeHoff RM, et al. In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: A double-blind randomized study from the National Heart, Lung and Blood Institute Women’s Ischemia Syndrome Evaluation (WISE). Am Heart J. 2011;162:678–84.PubMedCrossRefGoogle Scholar
  55. 55.
    Yasue H, Mizuno Y, Harada E, Itoh T, Nakagawa H, Nakayama M, 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;51:1742–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Miwa Y, Masai H, Shimizu M. Differential effects of calcium-­channel blockers on vascular endothelial function in patients with coronary spastic angina. Circ J. 2009;73:713–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Schnorbus B, Schiewe R, Ostad MA, Medler C, Wachtlin D, Wenzel P, et al. Effects of pentaerythritol tetranitrate on endothelial function in coronary artery disease: results of the PENTA study. Clin Res Cardiol. 2010;99:115–24.PubMedCrossRefGoogle Scholar
  58. 58.
    Aizawa T, Ogasawara K, Nakamura F, Hirosaka A, Sakuma T, Nagashima K, et al. Effect of nicorandil on coronary spasm. Am J Cardiol. 1989;63:75J–979.PubMedCrossRefGoogle Scholar
  59. 59.
    Nielsen H, Egeblad H, Mortensen SA, Sandøe E. Observations on increased susceptibility to coronary artery vasospasm during beta blockade. Am Heart J. 1987;114:192–4.PubMedCrossRefGoogle Scholar
  60. 60.
    Kaski JC, Valenzuela Garcia LF. Therapeutic options for the management of patients with cardiac syndrome X. Eur Heart J. 2001;22:283–93.PubMedCrossRefGoogle Scholar
  61. 61.
    Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y, et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging. 2011;4:514–22.PubMedCrossRefGoogle Scholar
  62. 62.
    Reriani M, Raichlin E, Prasad A, Mathew V, Pumper GM, Nelson RE, et al. Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis. Circulation. 2010;122:958–66.PubMedCrossRefGoogle Scholar
  63. 63.
    Yamagishi M, Ito K, Tsutsui H, Miyazaki S, Goto Y, Nagaya N, et al. Lesion severity and hypercholesterolemia determine long-term prognosis of vasospastic angina treated with calcium channel antagonists. Circ J. 2003;67:1029–35.PubMedCrossRefGoogle Scholar
  64. 64.
    Bory M, Pierron F, Panagides D, Bonnet JL, Yvorra S, Desfossez L. Coronary artery spasm in patients with normal or near normal ­coronary arteries. Long-term follow-up of 277 patients. Eur Heart J. 1996;17:1015–21.PubMedCrossRefGoogle Scholar
  65. 65.
    Ong P, Athanasiadis A, Borgulya G, Voehringer M, Sechtem U. 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;57:147–52.PubMedCrossRefGoogle Scholar
  66. 66.
    Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106(6):653–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Takagi Y, Yasuda S, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, et al. Clinical characteristics and long-term prognosis of vasos­pastic angina patients who survived out-of-hospital cardiac arrest: multicenter registry study of the Japanese Coronary Spasm Association. Circ Arrhythm Electrophysiol. 2011;4:295–302.PubMedCrossRefGoogle Scholar
  68. 68.
    Myerburg RJ, Kessler KM, Mallon SM, Cox MM, de Marchena E, Interian Jr A, et al. Life-threatening ventricular arrhythmias in patients with silent myocardial ischemia due to coronary-artery spasm. N Engl J Med. 1992;326:1451–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Noda T, Shimizu W, Taguchi A, Satomi K, Suyama K, Kurita T, et al. ST-segment elevation and ventricular fibrillation without ­coronary spasm by intracoronary injection of acetylcholine and/or ergonovine maleate in patients with Brugada syndrome. J Am Coll Cardiol. 2002;40:1841–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Masumoto A, Mohri M, Takeshita A. Three-year follow-up of the Japanese patients with microvascular angina attributable to ­coronary microvascular spasm. Int J Cardiol. 2001;81:151–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. J Am Coll Cardiol. 1995;25:807–14.PubMedCrossRefGoogle Scholar
  72. 72.
    Johnson BD, Shaw LJ, Pepine CJ, Reis SE, Kelsey SF, Sopko G, et al. Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the ­NIH-NHLBI-sponsored Women’s Ischaemia Syndrome Evaluation (WISE) study. Eur Heart J. 2006;27:1408–15.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  • Peter Ong
    • 1
  • Anastasios Athanasiadis
    • 1
  • Udo Sechtem
    • 1
  1. 1.Department of CardiologyRobert-Bosch-KrankenhausStuttgartGermany

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