Skip to main content
SpringerLink
Log in

Vasotonic Angina as a Cause of Myocardial Ischemia in Women

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

The frequency, presentation, prognosis, and treatment of myocardial ischemia differ in men and women. A large proportion of women who have “normal” coronary arteries on angiography without any significant evidence of flow-limiting disease also have biochemical or imaging evidence of myocardial ischemia. In these women it is believed to be a dysfunction of coronary microcirculation and/or macrocirculation, or vasotonic angina (VA), that leads to abnormal vasoconstriction, and potentially to myocardial infarction, ventricular arrhythmias, and sudden death. Despite having a “normal” or near normal coronary angiography, these women should therefore undergo additional testing with acetylcholine to assess endothelial function. Long-term survival is believed to be relatively good. Predictors of poorer prognosis include documentation of severe endothelial dysfunction and presence of concurrent angiographycally visible coronary atherosclerosis. Because atherosclerosis is common in patients with VA, medical and lifestyle interventions for preventing or treating atherosclerosis should be implemented when appropriate. Angiotensin converting enzyme inhibitors are the mainstays of medical therapy for VA. Other agents have been tried with variable success, including beta-blockers. There are no available data on any specific treatment of VA in women (versus men).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012;33:734–44.

    Article  PubMed  Google Scholar 

  2. Bugiardini R, Bairey Merz CN. Angina with “normal” coronary arteries: a changing philosophy. JAMA. 2005;293:477–84.

    Article  CAS  PubMed  Google Scholar 

  3. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2015 update: a report from the american heart association. Circulation. 2015;131:e29–322.

    Article  PubMed  Google Scholar 

  4. Hulten E, Pickett C, Bittencourt MS, et al. Outcomes after coronary computed tomography angiography in the emergency department: a systematic review and meta-analysis of randomized, controlled trials. J Am Coll Cardiol. 2013;61:880–92.

    Article  PubMed  Google Scholar 

  5. Truong QA, Hayden D, Woodard PK, et al. Sex differences in the effectiveness of early coronary computed tomographic angiography compared with standard emergency department evaluation for acute chest pain: the rule-out myocardial infarction with computer-assisted tomography (ROMICAT)-II trial. Circulation. 2013;127:2494–502.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Dolor RJ, Patel MR, Melloni C et al. Noninvasive technologies for the diagnosis of coronary artery disease in women. agency for healthcare research and quality (US); 2012. Report No.: 12-EHC034-EF.

  7. Sanders GD, Patel MR, Chatterjee R, et al. Noninvasive technologies for the diagnosis of coronary artery disease in women: future research needs. agency for healthcare research and quality (US); 2013. Report No.: 13-EHC072-EF.

  8. Johnson BD, Shaw LJ, Buchthal SD, et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the national institutes of health-national heart, lung, and blood institute-sponsored women’s ischemia syndrome evaluation (WISE). Circulation. 2004;109:2993–9.

    Article  PubMed  Google Scholar 

  9. Bugiardini R, Badimon L, Collins P, et al. Angina, “normal” coronary angiography, and vascular dysfunction: risk assessment strategies. PLoS Med. 2007;4:e12.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Vaccarino V, Badimon L, Corti R, et al. Presentation, management, and outcomes of ischaemic heart disease in women. Nat Rev Cardiol. 2013;10:508–18.

    Article  PubMed  Google Scholar 

  11. Bugiardini R. Women, ‘non-specific’ chest pain, and normal or near-normal coronary angiograms are not synonymous with favourable outcome. Eur Heart J. 2006;27:1387–9.

    Article  PubMed  Google Scholar 

  12. Johnson BD, Shaw LJ, Pepine CJ, 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.

    Article  PubMed  Google Scholar 

  13. Sullivan AK, Holdright DR, Wright CA, Sparrow JL, Cunningham D, Fox KM. Chest pain in women: clinical, investigative, and prognostic features. BMJ. 1994;308:883–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. von Mering GO, Arant CB, Wessel TR, et al. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the national heart, lung, and blood institute-sponsored women’s ischemia syndrome evaluation (WISE). Circulation. 2004;109:722–5.

    Article  Google Scholar 

  15. Sharaf B, Wood T, Shaw L, et al. Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) angiographic core laboratory. Am Heart J. 2013;166:134–41.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Bugiardini R, Manfrini O, De Ferrari GM. Unanswered questions for management of acute coronary syndrome: risk stratification of patients with minimal disease or normal findings on coronary angiography. Arch Intern Med. 2006;166:1391–5.

    Article  PubMed  Google Scholar 

  17. Hemingway H, McCallum A, Shipley M, Manderbacka K, Martikainen P, Keskimäki I. Incidence and prognostic implications of stable angina pectoris among women and men. JAMA. 2006;295:1404–11.

    Article  CAS  PubMed  Google Scholar 

  18. Shaw LJ, Merz CN, Pepine CJ, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the national institutes of health–national heart, lung, and blood institute–sponsored women’s ischemia syndrome evaluation. Circulation. 2006;114:894–904.

    Article  PubMed  Google Scholar 

  19. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol. 2009;54:1561–75.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Gulati M, Cooper-DeHoff RM, McClure C, et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the women’s ischemia syndrome evaluation study and the St James women take heart project. Arch Intern Med. 2009;169:843–50.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Anderson HV, Stokes MJ, Leon M, Abu-Halawa SA, Stuart Y, Kirkeeide RL. Coronary artery flow velocity is related to lumen area and regional left ventricular mass. Circulation. 2000;102:48–54.

    Article  CAS  PubMed  Google Scholar 

  22. Buchthal SD, den Hollander JA, Merz CN, et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med. 2000;342:829–35.

    Article  CAS  PubMed  Google Scholar 

  23. Arbogast R, Bourassa MG. Myocardial function during atrial pacing in patients with angina pectoris and normal coronary arteriograms. Comparison with patients having significant coronary artery disease. Am J Cardiol. 1973;32:257–63.

    Article  CAS  PubMed  Google Scholar 

  24. Kemp Jr HG. Left ventricular function in patients with the anginal syndrome and normal coronary arteriograms. Am J Cardiol. 1973;32:375–6.

    Article  PubMed  Google Scholar 

  25. Temkin LP, Marcus FI. Nonatherosclerotic myocardial ischemia. J Am Coll Cardiol. 1983;1:1534–5.

    Article  CAS  PubMed  Google Scholar 

  26. Yasue H, Omote S, Takizawa A, Nagao M, Miwa K, Tanaka S. Circadian variation of exercise capacity in patients with Prinzmetal’s variant angina: role of exercise-induced coronary arterial spasm. Circulation. 1979;59:938–48.

    Article  CAS  PubMed  Google Scholar 

  27. Bugiardini R, Pozzati A, Ottani F, Morgagni GL, Puddu P. Vasotonic angina: a spectrum of ischemic syndromes involving functional abnormalities of the epicardial and microvascular coronary circulation. J Am Coll Cardiol. 1993;22:417–25.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  PubMed  Google Scholar 

  29. Diver DJ, Bier JD, Ferreira PE, et al. Clinical and arteriographic characterization of patients with unstable angina without critical coronary arterial narrowing (from the TIMI-IIIA Trial). Am J Cardiol. 1994;74:531–7.

    Article  CAS  PubMed  Google Scholar 

  30. Gehrie ER, Reynolds HR, Chen AY, et al. Characterization and outcomes of women and men with non-ST-segment elevation myocardial infarction and nonobstructive coronary artery disease: results from the can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA guidelines (CRUSADE) quality improvement initiative. Am Heart J. 2009;158:688–94.

    Article  PubMed  Google Scholar 

  31. Bourque JM, Beller GA. Stress myocardial perfusion imaging for assessing prognosis: an update. JACC Cardiovasc Imaging. 2011;4:1305–19.

    Article  PubMed  Google Scholar 

  32. Khuddus MA, Pepine CJ, Handberg EM, et al. An intravascular ultrasound analysis in women experiencing chest pain in the absence of obstructive coronary artery disease: a substudy from the national heart, lung and blood institute-sponsored women’s ischemia syndrome evaluation (WISE). J Interv Cardiol. 2010;23:511–9.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation. 2004;109:2518–23.

    Article  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. Bugiardini R, Chierchia S, Davies G, Crea F, Lenzi S, Maseri A. Differential transmyocardial platelet behavior in response to pacing and ergonovine-induced myocardial ischemia. Am Heart J. 1986;112:255–62.

    Article  CAS  PubMed  Google Scholar 

  36. 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;35:1850–6.

    Article  CAS  PubMed  Google Scholar 

  37. Morita H, Ohmori K, Matsuyama T, Mizushige K, Matsuo H. A new noninvasive method of diagnosing vasospastic angina based on dilation response of the left main coronary artery to nitroglycerin as measured by echocardiography. J Am Coll Cardiol. 1996;27:1450–7.

    Article  CAS  PubMed  Google Scholar 

  38. Maseri A, Severi S, Nes MD, et al. “Variant” angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Pathogenetic mechanisms, estimated incidence and clinical and coronary arteriographic findings in 138 patients. Am J Cardiol. 1978;42:1019–35.

    Article  CAS  PubMed  Google Scholar 

  39. Kaski JC, Maseri A, Vejar M, Crea F, Hackett D. Spontaneous coronary artery spasm in variant angina is caused by a local hyperreactivity to a generalized constrictor stimulus. J Am Coll Cardiol. 1989;14:1456–63.

    Article  CAS  PubMed  Google Scholar 

  40. Selzer A, Langston M, Ruggeroli C, Cohn K. Clinical syndrome of variant angina with normal coronary arteriogram. N Engl J Med. 1976;295:1343–7.

    Article  CAS  PubMed  Google Scholar 

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. 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.

    Article  CAS  PubMed  Google Scholar 

  43. Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106:653–8.

    Article  PubMed  Google Scholar 

  44. Nabel EG, Ganz P, Gordon JB, Alexander RW, Selwyn AP. Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test. Circulation. 1988;77:43–52.

    Article  CAS  PubMed  Google Scholar 

  45. Xhyheri B, Manfrini O, Mazzolini M, Pizzi C, Bugiardini R. Heart rate variability today. Prog Cardiovasc Dis. 2012;55:321–31.

    Article  PubMed  Google Scholar 

  46. Manfrini O, Pizzi C, Viecca M, Bugiardini R. Abnormalities of cardiac autonomic nervous activity correlate with expansive coronary artery remodeling. Atherosclerosis. 2008;197:183–9.

    Article  CAS  PubMed  Google Scholar 

  47. Bugiardini R, Galvani M, Ferrini D, et al. Myocardial ischemia induced by prostacyclin and iloprost. Clin Pharmacol Ther. 1985;38:101–8.

    Article  CAS  PubMed  Google Scholar 

  48. Bugiardini R, Galvani M, Ferrini D, et al. Myocardial ischemia during intravenous prostacyclin administration: hemodynamic findings and precautionary measures. Am Heart J. 1987;113:234–40.

    Article  CAS  PubMed  Google Scholar 

  49. Dagres N, Haude M, Baumgart D, Sack S, Erbel R. Assessment of coronary morphology and flow in a patient with Guillain-Barré syndrome and ST-segment elevation. Clin Cardiol. 2001;24:260–3.

    Article  CAS  PubMed  Google Scholar 

  50. Manfrini O, Cenko E, Verna E, Salerno Uriarte JA, Bugiardini R. Endothelial dysfunction versus early atherosclerosis: a study with high resolution imaging. Int J Cardiol. 2013;168:1714–6.

    Article  PubMed  Google Scholar 

  51. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115:1285–95.

    PubMed  Google Scholar 

  52. Vaccarino V, Badimon L, Corti R, et al. Ischaemic heart disease in women: are there sex differences in pathophysiology and risk factors? Position paper from the working group on coronary pathophysiology and microcirculation of the European society of cardiology. Cardiovasc Res. 2011;90:9–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation. 2011;124:1414–25.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med. 1999;340:115–26.

    Article  CAS  PubMed  Google Scholar 

  55. Maddox TM, Stanislawski MA, Grunwald GK, et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA. 2014;312:1754–63.

    Article  CAS  PubMed  Google Scholar 

  56. Montalescot G, Sechtem U, Achenbach S, 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;34:2949–3003.

    Article  PubMed  Google Scholar 

  57. Bugiardini R, Borghi A, Biagetti L, Puddu P. Comparison of verapamil versus propranolol therapy in syndrome X. Am J Cardiol. 1989;63:286–90.

    Article  CAS  PubMed  Google Scholar 

  58. Lanza GA, Colonna G, Pasceri V, Maseri A. Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X. Am J Cardiol. 1999;84:854–6.

    Article  CAS  PubMed  Google Scholar 

  59. Cannon 3rd RO, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med. 1994;330:1411–7.

    Article  PubMed  Google Scholar 

  60. Manfrini O, Bazzocchi G, Luati A, Borghi A, Monari P, Bugiardini R. Coronary spasm reflects inputs from adjacent esophageal system. Am J Physiol Heart Circ Physiol. 2006;290:H2085–91.

    Article  CAS  PubMed  Google Scholar 

  61. Lerman A, Burnett Jr JC, Higano ST, McKinley LJ, Holmes Jr DR. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation. 1998;97:2123–8.

    Article  CAS  PubMed  Google Scholar 

  62. Pizzi C, Manfrini O, Fontana F, Bugiardini R. Angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme a reductase in cardiac syndrome X: role of superoxide dismutase activity. Circulation. 2004;109:53–8.

    Article  CAS  PubMed  Google Scholar 

  63. Pauly DF, Johnson BD, Anderson RD, 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Manfrini O, Morrell C, Das R, et al. Effects of angiotensin-converting enzyme inhibitors and beta blockers on clinical outcomes in patients with and without coronary artery obstructions at angiography (from a register-based cohort study on acute coronary syndromes). Am J Cardiol. 2014;113:1628–33.

    Article  CAS  PubMed  Google Scholar 

  65. Mehta PK, Goykhman P, Thomson LE, 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.

    Article  PubMed  Google Scholar 

  66. Bugiardini R, Borghi A, Pozzati A, Ottani F, Morgagni GL, Puddu P. The paradox of nitrates in patients with angina pectoris and angiographically normal coronary arteries. Am J Cardiol. 1993;72:343–7.

    Article  CAS  PubMed  Google Scholar 

  67. Rubinshtein R, Yang EH, Rihal CS, et al. Coronary microcirculatory vasodilator function in relation to risk factors among patients without obstructive coronary disease and low to intermediate Framingham score. Eur Heart J. 2010;31:936–42.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Conflict of Interest

None

Author information

Authors and Affiliations

  1. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, c/o Policlinico Sant’Orsola Malpighi (Padiglione 11), Via Massarenti 9, 40138, Bologna, Italy

    Edina Cenko & Raffaele Bugiardini

Authors
  1. Edina Cenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raffaele Bugiardini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raffaele Bugiardini.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cenko, E., Bugiardini, R. Vasotonic Angina as a Cause of Myocardial Ischemia in Women. Cardiovasc Drugs Ther 29, 339–345 (2015). https://doi.org/10.1007/s10557-015-6595-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-015-6595-4

Keywords

Search

Navigation