Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Presentation, management, and outcomes of ischaemic heart disease in women

Abstract

Scientific interest in ischaemic heart disease (IHD) in women has grown considerably over the past 2 decades. A substantial amount of the literature on this subject is centred on sex differences in clinical aspects of IHD. Many reports have documented sex-related differences in presentation, risk profiles, and outcomes among patients with IHD, particularly acute myocardial infarction. Such differences have often been attributed to inequalities between men and women in the referral and treatment of IHD, but data are insufficient to support this assessment. The determinants of sex differences in presentation are unclear, and few clues are available as to why young, premenopausal women paradoxically have a greater incidence of adverse outcomes after acute myocardial infarction than men, despite having less-severe coronary artery disease. Although differential treatment on the basis of patient sex continues to be described, the extent to which such inequalities persist and whether they reflect true disparity is unclear. Additionally, much uncertainty surrounds possible sex-related differences in response to cardiovascular therapies, partly because of a persistent lack of female-specific data from cardiovascular clinical trials. In this Review, we assess the evidence for sex-related differences in the clinical presentation, treatment, and outcome of IHD, and identify gaps in the literature that need to be addressed in future research efforts.

Key Points

  • Important differences exist between women and men in clinical presentation, recognition of symptoms by patients and physicians, outcome, and response to treatment for ischaemic heart disease (IHD)

  • Among patients with IHD, environmental or behavioural causes of sex-related differences in outcomes might be more important than biological factors

  • Onset of IHD in women, manifesting as an acute myocardial infarction before the age of 65 years, is associated with adverse outcomes compared with men of a similar age

  • A traditional diagnostic strategy, focusing on detection of severe coronary stenoses, is likely to be inadequate in women

  • Additional invasive testing aimed at determining endothelial coronary dysfunction might be useful to risk-stratify women with chest pain and minimal or no obstructive coronary artery disease

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Differences in presentation of AMI among 1,143,513 patients (481,581 of whom were women) in the National Registry of Myocardial Infarction (1994–2006).
Figure 2: Underestimation of stenosis by angiography in a woman aged 65 years.
Figure 3: Intracoronary imaging with optical coherence tomography in a woman aged 55 years.
Figure 4: Acetylcholine testing in a woman aged 55 years.
Figure 5: Temporal trends in hospital mortality by sex and age.

References

  1. 1

    Go, A. S. et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127, e6–e245 (2013).

    Google Scholar 

  2. 2

    Poon, S. et al. Bridging the gender gap: insights from a contemporary analysis of sex-related differences in the treatment and outcomes of patients with acute coronary syndromes. Am. Heart J. 163, 66–73 (2012).

    PubMed  Article  Google Scholar 

  3. 3

    Rajadurai, J. et al. Women's cardiovascular health: perspectives from South-East Asia. Nat. Rev. Cardiol. 9, 464–477 (2012).

    PubMed  Article  Google Scholar 

  4. 4

    Vaccarino, V. Ischemic heart disease in women: many questions, few facts. Circ. Cardiovasc. Qual. Outcomes 3, 111–115 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Murabito, J. M., Evans, J. C., Larson, M. G. & Levy, D. Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation. Circulation 88, 2548–2555 (1993).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Lerner, D. J. & Kannel, W. B. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am. Heart J. 111, 383–390 (1986).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Hemingway, H. et al. Prevalence of angina in women versus men: a systematic review and meta-analysis of international variations across 31 countries. Circulation 117, 1526–1536 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Hochman, J. S. et al. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. N. Engl. J. Med. 341, 226–232 (1999).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Berger, J. S. et al. Sex differences in mortality following acute coronary syndromes. JAMA 302, 874–882 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Genders, T. S. et al. A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension. Eur. Heart J. 32, 1316–1330 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  11. 11

    Milner, K. A., Funk, M., Arnold, A. & Vaccarino, V. Typical symptoms are predictive of acute coronary syndromes in women. Am. Heart J. 143, 283–288 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  12. 12

    Canto, J. G. et al. Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA 307, 813–822 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Milner, K. A. et al. Gender differences in symptom presentation associated with coronary heart disease. Am. J. Cardiol. 84, 396–399 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14

    Bugiardini, R. Women, 'nonspecific' chest pain, and normal or near-normal coronary angiograms are not synonymous with favourable outcome. Eur. Heart J. 27, 1387–1389 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  15. 15

    Kreatsoulas, C., Shannon, H. S., Giacomini, M., Velianou, J. L. & Anand, S. S. Reconstructing angina: cardiac symptoms are the same in women and men. JAMA Intern. Med. 173, 829–833 (2013).

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16

    Mackay, M. H., Ratner, P. A., Johnson, J. L., Humphries, K. H. & Buller, C. E. Gender differences in symptoms of myocardial ischaemia. Eur. Heart J. 32, 3107–3114 (2011).

    PubMed  Article  Google Scholar 

  17. 17

    Bugiardini, R. & Bairey Merz, C. N. Angina with “normal” coronary arteries: a changing philosophy. JAMA 293, 477–484 (2005).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Bugiardini, R. et al. Angina, “normal” coronary angiography, and vascular dysfunction: risk assessment strategies. PLoS Med. 4, e12 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Shaw, L. J., Bugiardini, R. & Merz, C. N. Women and ischemic heart disease: evolving knowledge. J. Am. Coll. Cardiol. 54, 1561–1575 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Mosca, L., Mochari-Greenberger, H., Dolor, R. J., Newby, L. K. & Robb, K. J. Twelve-year follow-up of American women's awareness of cardiovascular disease risk and barriers to heart health. Circ. Cardiovasc. Qual. Outcomes 3, 120–127 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Mosca, L. et al. Fifteen-year trends in awareness of heart disease in women: results of a 2012 American Heart Association national survey. Circulation 127, 1254–1263 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    Fukuoka, Y. et al. Is severity of chest pain a cue for women and men to recognize acute myocardial infarction symptoms as cardiac in origin? Prog. Cardiovasc. Nurs. 22, 132–137 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

  23. 23

    Rosengren, A. et al. Sex, age, and clinical presentation of acute coronary syndromes. Eur. Heart J. 25, 663–670 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  24. 24

    Mulvagh, S. L. et al. Contrast echocardiography: current and future applications. J. Am. Soc. Echocardiogr. 13, 331–342 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25

    Nandalur, K. R., Dwamena, B. A., Choudhri, A. F., Nandalur, M. R. & Carlos, R. C. Diagnostic performance of stress cardiac magnetic resonance imaging in the detection of coronary artery disease: a meta-analysis. J. Am. Coll. Cardiol. 50, 1343–1353 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26

    Centers for Disease Control and Prevention (CDC). Prevalence of heart disease—United States, 2006–2010. MMWR Morb. Mortal. Wkly Rep. 60, 1377–1381 (2011).

  27. 27

    Gibbons, R. J. et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation 106, 1883–1892 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  28. 28

    Shaw, L. J. et al. The value of estimated functional capacity in estimating outcome: results from the NHBLI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study. J. Am. Coll. Cardiol. 47, S36–S43 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  29. 29

    Mieres, J. H. et al. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation 111, 682–696 (2005).

    Article  Google Scholar 

  30. 30

    Grzybowski, A. et al. How to improve noninvasive coronary artery disease diagnostics in premenopausal women? The influence of menstrual cycle on ST depression, left ventricle contractility, and chest pain observed during exercise echocardiography in women with angina and normal coronary angiogram. Am. Heart J. 156, 964.e1–964.e5 (2008).

    Article  Google Scholar 

  31. 31

    Shaw, L. J. et al. Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) study: part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J. Am. Coll. Cardiol. 47 (Suppl.), S4–S20 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Lanza, G. A. & Crea, F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation 121, 2317–2325 (2010).

    PubMed  Article  Google Scholar 

  33. 33

    Maseri, A., Crea, F., Kaski, J. C. & Crake, T. Mechanisms of angina pectoris in syndrome X. J. Am. Coll. Cardiol. 17, 499–506 (1991).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Bugiardini, R., Pozzati, A., Ottani, F., Morgagni, G. L. & Puddu, P. Vasotonic angina: a spectrum of ischemic syndromes involving functional abnormalities of the epicardial and microvascular coronary circulation. J. Am. Coll. Cardiol. 22, 417–425 (1993).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Gan, S. C. et al. Treatment of acute myocardial infarction and 30-day mortality among women and men. N. Engl. J. Med. 343, 8–15 (2000).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Bugiardini, R., Manfrini, O. & De Ferrari, G. M. Unanswered questions for management of acute coronary syndrome: risk stratification of patients with minimal disease or normal findings on coronary angiography. Arch. Intern. Med. 166, 1391–1395 (2006).

    Article  Google Scholar 

  37. 37

    Scanlon, P. J. et al. ACC/AHA guidelines for coronary angiography: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Coronary Angiography) developed in collaboration with the Society for Cardiac Angiography and Interventions. Circulation 99, 2345–2357 (1999).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Ong, P. et al. 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. 59, 655–662 (2012).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Budoff, M. J. et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicentre ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J. Am. Coll. Cardiol. 52, 1724–1732 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Beigel, R. et al. Prognostic implications of nonobstructive coronary artery disease in patients undergoing coronary computed tomographic angiography for acute chest pain. Am. J. Cardiol. 111, 941–945 (2013).

    PubMed  Article  Google Scholar 

  41. 41

    Lin, F. Y. et al. Mortality risk in symptomatic patients with nonobstructive coronary artery disease: a prospective 2-centre study of 2,583 patients undergoing 64-detector row coronary computed tomographic angiography. J. Am. Coll. Cardiol. 58, 510–519 (2011).

    PubMed  Article  Google Scholar 

  42. 42

    Min, J. K. et al. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicentre CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicentre Registry) of 23,854 patients without known coronary artery disease. J. Am. Coll. Cardiol. 58, 849–860 (2011).

    PubMed  Article  Google Scholar 

  43. 43

    Martinez, M. W. et al. Myocardial infarction with normal coronary arteries: a role for MRI? Clin. Chem. 53, 995–996 (2007).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Steg, P. G. et al. Impact of collateral flow to the occluded infarct-related artery on clinical outcomes in patients with recent myocardial infarction: a report from the randomized occluded artery trial. Circulation 121, 2724–2730 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Wolff, S. D. et al. Myocardial first-pass perfusion magnetic resonance imaging: a multicentre dose-ranging study. Circulation 110, 732–737 (2004).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Schwitter, J. et al. MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial. Eur. Heart J. 29, 480–489 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Panting, J. R. et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N. Engl. J. Med. 346, 1948–1953 (2002).

    PubMed  Article  Google Scholar 

  48. 48

    Schwitter, J. Extending the frontiers of cardiac magnetic resonance. Circulation 118, 109–112 (2008).

    PubMed  Article  Google Scholar 

  49. 49

    Reynolds, H. R. et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation 124, 1414–1425 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Mieres, J. H. et al. American Society of Nuclear Cardiology consensus statement: Task Force on Women and Coronary Artery Disease—the role of myocardial perfusion imaging in the clinical evaluation of coronary artery disease in women [correction]. J. Nucl. Cardiol. 10, 95–101 (2003).

    PubMed  Article  Google Scholar 

  51. 51

    Klocke, F. J. et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to revise the 1995 guidelines for the clinical use of cardiac radionuclide imaging). Circulation 108, 1404–1418 (2003).

    Article  Google Scholar 

  52. 52

    Matsunari, I. et al. Attenuation-corrected rest thallium-201/stress technetium 99m sestamibi myocardial SPECT in normals. J. Nucl. Cardiol. 5, 48–55 (1998).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Hemingway, H. et al. Incidence and prognostic implications of stable angina pectoris among women and men. JAMA 295, 1404–1411 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Daly, C. et al. Gender differences in the management and clinical outcome of stable angina. Circulation 113, 490–498 (2006).

    Article  Google Scholar 

  55. 55

    Fox, K. 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. 27, 1341–1381 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Crilly, M., Bundred, P., Hu, X., Leckey, L. & Johnstone, F. Gender differences in the clinical management of patients with angina pectoris: a cross-sectional survey in primary care. BMC Health Serv. Res. 7, 142 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Johnston, N., Schenck-Gustafsson, K. & Lagerqvist, B. Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain? Eur. Heart J. 32, 1331–1336 (2011).

    PubMed  Article  Google Scholar 

  58. 58

    Vaccarino, V., Krumholz, H. M., Berkman, L. F. & Horwitz, R. I. Sex differences in mortality after myocardial infarction. Is there evidence for an increased risk for women? Circulation 91, 1861–1871 (1995).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Wenger, N. K., Shaw, L. J. & Vaccarino, V. Coronary heart disease in women: update 2008. Clin. Pharmacol. Ther. 83, 37–51 (2008).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Champney, K. P. et al. The joint contribution of sex, age and type of myocardial infarction on hospital mortality following acute myocardial infarction. Heart 95, 895–899 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Jneid, H. et al. Sex differences in medical care and early death after acute myocardial infarction. Circulation 118, 2803–2810 (2008).

    PubMed  Article  Google Scholar 

  62. 62

    Capewell, S. et al. Short-term and long-term outcomes in 133,429 emergency patients admitted with angina or myocardial infarction in Scotland, 1990–2000: population-based cohort study. Heart 92, 1563–1570 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63

    Fuster, V. Elucidation of the role of plaque instability and rupture in acute coronary events. Am. J. Cardiol. 76, 24C–33C (1995).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1,000 patients. Lancet 343, 311–322 (1994).

  65. 65

    Tamis-Holland, J. E. et al. Benefits of direct angioplasty for women and men with acute myocardial infarction: results of the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes Angioplasty (GUSTO II-B) angioplasty substudy. Am. Heart J. 147, 133–139 (2004).

    PubMed  Article  Google Scholar 

  66. 66

    Kim, E. S. & Menon, V. Status of women in cardiovascular clinical trials. Arterioscler. Thromb. Vac. Biol. 29, 279–283 (2009).

    CAS  Article  Google Scholar 

  67. 67

    Bavry, A. A. et al. Invasive therapy along with glycoprotein IIb/IIIa inhibitors and intracoronary stents improves survival in non-ST-segment elevation acute coronary syndromes: a meta-analysis and review of the literature. Am. J. Cardiol. 93, 830–835 (2004).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Glaser, R. et al. Benefit of an early invasive management strategy in women with acute coronary syndromes. JAMA 288, 3124–3129 (2002).

    PubMed  Article  Google Scholar 

  69. 69

    Lansky, A. J. et al. Percutaneous coronary intervention and adjunctive pharmacotherapy in women: a statement for healthcare professionals from the American Heart Association. Circulation 111, 940–953 (2005).

    PubMed  Article  Google Scholar 

  70. 70

    Cho, L. et al. Clinical benefit of glycoprotein IIb/IIIa blockade with abciximab is independent of gender: pooled analysis from EPIC, EPILOG and EPISTENT trials. Evaluation of 7E3 for the prevention of ischemic complications. Evaluation in percutaneous transluminal coronary angioplasty to improve long-term outcome with abciximab GP IIb/IIIa blockade. Evaluation of platelet IIb/IIIa inhibitor for stent. J. Am. Coll. Cardiol. 36, 381–386 (2000).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Boersma, E. et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 359, 189–198 (2002).

    CAS  Article  Google Scholar 

  72. 72

    Healy, B. The Yentl syndrome. N. Engl. J. Med. 325, 274–276 (1991).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Bugiardini, R., Oestrada, J. L., Nikus, K., Hall, A. S. & Manfrini, O. Gender bias in acute coronary syndromes. Curr. Vasc. Pharmacol. 8, 276–284 (2010).

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Blomkalns, A. L. et al. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) national quality improvement initiative. J. Am. Coll. Cardiol. 45, 832–837 (2005).

    PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Anand, S. S. et al. Differences in the management and prognosis of women and men who suffer from acute coronary syndromes. J. Am. Coll. Cardiol. 46, 1845–1851 (2005).

    PubMed  Article  Google Scholar 

  76. 76

    Dey, S. et al. Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events. Heart 95, 20–26 (2009).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Vaccarino, V. et al. Sex and racial differences in the management of acute myocardial infarction, 1994 through 2002. N. Engl. J. Med. 353, 671–682 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78

    Karp, I., Chen, S. F. & Pilote, L. Sex differences in the effectiveness of statins after myocardial infarction. CMAJ 176, 333–338 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Walsh, J. M. & Pignone, M. Drug treatment of hyperlipidemia in women. JAMA 291, 2243–2252 (2004).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Shekelle, P. G. et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J. Am. Coll. Cardiol. 41, 1529–1538 (2003).

    CAS  Article  Google Scholar 

  81. 81

    First International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-1. Lancet 2, 57–66 (1986).

  82. 82

    Institute of Medicine (eds Wizemann, T. & Pardue, M.) Exploring the Biological Contributions to Human Health: Does Sex Matter? (The National Academy Press, 2001).

  83. 83

    Aldea, G. S. et al. Effect of gender on postoperative outcomes and hospital stays after coronary artery bypass grafting. Ann. Thorac. Surg. 67, 1097–1103 (1999).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Stern, S. & Bayes de Luna, A. Coronary artery spasm: a 2009 update. Circulation 119, 2531–2534 (2009).

    PubMed  Article  Google Scholar 

  85. 85

    Selzer, A., Langston, M., Ruggeroli, C. & Cohn, K. Clinical syndrome of variant angina with normal coronary arteriogram. N. Engl. J. Med. 295, 1343–1347 (1976).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Seung-Woon, R. et al. The impact of gender difference on angiographic characteristics during intracoronary acetylcholine provocation test in Korean patients [abstract TCT-437]. J. Am. Coll. Cardiol. 60 (Suppl. B), B124 (2012).

    Google Scholar 

  87. 87

    Bory, M. et al. Coronary artery spasm in patients with normal or near normal coronary arteries. Long-term follow-up of 277 patients. Eur. Heart J. 17, 1015–1021 (1996).

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Pozzati, A., Pancaldi, L. G., Di Pasquale, G., Pinelli, G. & Bugiardini, R. Transient sympathovagal imbalance triggers “ischemic” sudden death in patients undergoing electrocardiographic Holter monitoring. J. Am. Coll. Cardiol. 27, 847–852 (1996).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Yoo, S. Y. & Kim, J. Y. Recent insights into the mechanisms of vasospastic angina. Korean Circ. J. 39, 505–511 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90

    Egashira, K. et al. Basal release of endothelium-derived nitric oxide at site of spasm in patients with variant angina. J. Am. Coll. Cardiol. 27, 1444–1449 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91

    Walling, A. et al. Long-term prognosis of patients with variant angina. Circulation 76, 990–997 (1987).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92

    Mishra, P. K. Variations in presentation and various options in management of variant angina. Eur. J. Cardiothorac. Surg. 29, 748–759 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  93. 93

    Waters, D. D. et al. Factors influencing the long-term prognosis of treated patients with variant angina. Circulation 68, 258–265 (1983).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 94

    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. 57, 147–152 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  95. 95

    Asbury, E. A., Creed, F. & Collins, P. Distinct psychosocial differences between women with coronary heart disease and cardiac syndrome X. Eur. Heart J. 25, 1695–1701 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  96. 96

    Camici, P. G. & Crea, F. Coronary microvascular dysfunction. N. Engl. J. Med. 356, 830–840 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97

    Khuddus, M. A. 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. 23, 511–519 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98

    Wenger, N. K. Women and coronary heart disease: a century after Herrick: understudied, underdiagnosed, and undertreated. Circulation 126, 604–611 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  99. 99

    Bairey Merz, C. N. et al. Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) study: part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J. Am. Coll. Cardiol. 47 (3 Suppl.), S21–S29 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  100. 100

    Jespersen, L. et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur. Heart J. 33, 734–744 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  101. 101

    Kaski, J. C. et al. Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. J. Am. Coll. Cardiol. 25, 807–814 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102

    Gulati, M. 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. 169, 843–850 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  103. 103

    Johnson, B. D. 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 109, 2993–2999 (2004).

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104

    Oerlemans, J. G., Lagro-Janssen, A. L. & Bakx, C. Angina pectoris and normal coronary arteries: prevalence and prognosis in men and women [Dutch]. Ned. Tijdschr. Geneeskd. 144, 522–527 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    von Mering, G. O. 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 109, 722–725 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  106. 106

    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 109, 2518–2523 (2004).

    Article  Google Scholar 

  107. 107

    Pepine, C. J. et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia: results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) Study. J. Am. Coll. Cardiol. 55, 2825–2832 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108

    Britten, M. B., Zeiher, A. M. & Schächinger, V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron. Artery Dis. 15, 259–264 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  109. 109

    Fragasso, G. et al. Coronary slow-flow causing transient myocardial hypoperfusion in patients with cardiac syndrome X: long-term clinical and functional prognosis. Int. J. Cardiol. 137, 137–144 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  110. 110

    Bugiardini, R., Borghi, A., Biagetti, L. & Puddu, P. Comparison of verapamil versus propranolol therapy in syndrome X. Am. J. Cardiol. 63, 286–290 (1989).

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Xhyheri, B. & Bugiardini, R. Diagnosis and treatment of heart disease: are women different from men? Prog. Cardiovasc. Dis. 53, 227–236 (2010).

    PubMed  Article  Google Scholar 

  112. 112

    Kaski, J. C., Rosano, G., Gavrielides, S. & Chen, L. Effects of angiotensin-converting enzyme inhibition on exercise-induced angina and ST segment depression in patients with microvascular angina. J. Am. Coll. Cardiol. 23, 652–657 (1994).

    CAS  PubMed  Article  Google Scholar 

  113. 113

    Nalbantgil, I. et al. Therapeutic benefits of cilazapril in patients with syndrome X. Cardiology 89, 130–133 (1998).

    CAS  PubMed  Article  Google Scholar 

  114. 114

    Pauly, D. F. 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. 162, 678–684 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115

    Akashi, Y. J., Nef, H. M., Mollmann, H. & Ueyama, T. Stress cardiomyopathy. Annu. Rev. Med. 61, 271–286 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116

    Yoshioka, T. et al. Clinical implications of midventricular obstruction and intravenous propranolol use in transient left ventricular apical ballooning (Tako-tsubo cardiomyopathy). Am. Heart J. 155, 526.e1–526.e7 (2008).

    Article  Google Scholar 

  117. 117

    Wittstein, I. S. et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N. Engl. J. Med. 352, 539–548 (2005).

    CAS  Article  Google Scholar 

  118. 118

    Bielecka-Dabrowa, A. et al. Takotsubo cardiomyopathy—the current state of knowledge. Int. J. Cardiol. 142, 120–125 (2010).

    PubMed  Article  Google Scholar 

  119. 119

    Akashi, Y. J., Goldstein, D. S., Barbaro, G. & Ueyama, T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation 118, 2754–2762 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  120. 120

    Edwards, F. H., Carey, J. S., Grover, F. L., Bero, J. W. & Hartz, R. S. Impact of gender on coronary bypass operative mortality. Ann. Thorac. Surg. 66, 125–131 (1998).

    CAS  PubMed  Article  Google Scholar 

  121. 121

    Weintraub, W. S., Wenger, N. K., Jones, E. L., Craver, J. M. & Guyton, R. A. Changing clinical characteristics of coronary surgery patients. Differences between men and women. Circulation 88, II79–II86 (1993).

    CAS  PubMed  Google Scholar 

  122. 122

    Woods, S. E., Noble, G., Smith, J. M. & Hasselfeld, K. The influence of gender in patients undergoing coronary artery bypass graft surgery: an eight-year prospective hospitalized cohort study. J. Am. Coll. Surg. 196, 428–434 (2003).

    PubMed  Article  Google Scholar 

  123. 123

    Vaccarino, V., Abramson, J. L., Veledar, E. & Weintraub, W. S. Sex differences in hospital mortality after coronary artery bypass surgery: evidence for a higher mortality in younger women. Circulation 105, 1176–1181 (2002).

    PubMed  Article  Google Scholar 

  124. 124

    Kelsey, S. F. et al. Results of percutaneous transluminal coronary angioplasty in women. 1985–1986 National Heart, Lung, and Blood Institute's Coronary Angioplasty Registry. Circulation 87, 720–727 (1993).

    CAS  PubMed  Article  Google Scholar 

  125. 125

    Holubkov, R. et al. Angina 1 year after percutaneous coronary intervention: a report from the NHLBI Dynamic Registry. Am. Heart J. 144, 826–833 (2002).

    PubMed  Article  Google Scholar 

  126. 126

    Jacobs, A. K. et al. Better outcome for women compared with men undergoing coronary revascularization: a report from the Bypass Angioplasty Revascularization Investigation (BARI). Circulation 98, 1279–1285 (1998).

    CAS  PubMed  Article  Google Scholar 

  127. 127

    Thompson, C. A. et al. Gender-based differences of percutaneous coronary intervention in the drug-eluting stent era. Catheter. Cardiovasc. Interv. 67, 25–31 (2006).

    PubMed  Article  Google Scholar 

  128. 128

    Abbott, J. D. et al. Gender-based outcomes in percutaneous coronary intervention with drug-eluting stents (from the National Heart, Lung, and Blood Institute Dynamic Registry). Am. J. Cardiol. 99, 626–631 (2007).

    CAS  PubMed  Article  Google Scholar 

  129. 129

    Argulian, E. et al. Gender differences in short-term cardiovascular outcomes after percutaneous coronary interventions. Am. J. Cardiol. 98, 48–53 (2006).

    PubMed  Article  Google Scholar 

  130. 130

    Yang, F., Minutello, R. M., Bhagan, S., Sharma, A. & Wong, S. C. The impact of gender on vessel size in patients with angiographically normal coronary arteries. J. Interv. Cardiol. 19, 340–344 (2006).

    PubMed  Article  Google Scholar 

  131. 131

    Mehilli, J. et al. Gender and restenosis after coronary artery stenting. Eur. Heart J. 24, 1523–1530 (2003).

    PubMed  Article  Google Scholar 

  132. 132

    Dickerson, J. A., Nagaraja, H. N. & Raman, S. V. Gender-related differences in coronary artery dimensions: a volumetric analysis. Clin. Cardiol. 33, E44–E49 (2010).

    PubMed  Article  Google Scholar 

  133. 133

    Vaccarino, V. et al. Sex differences in mortality after acute myocardial infarction: changes from 1994 to 2006. Arch. Intern. Med. 169, 1767–1774 (2009).

    PubMed  PubMed Central  Google Scholar 

  134. 134

    Vaccarino, V., Parsons, L., Every, N. R., Barron, H. V. & Krumholz, H. M. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N. Engl. J. Med. 341, 217–225 (1999).

    CAS  Article  Google Scholar 

  135. 135

    Andrikopoulos, G. K. et al. Younger age potentiates post myocardial infarction survival disadvantage of women. Int. J. Cardiol. 108, 320–325 (2006).

    PubMed  Article  Google Scholar 

  136. 136

    Koek, H. L. et al. Short- and long-term prognosis after acute myocardial infarction in men versus women. Am. J. Cardiol. 98, 993–999 (2006).

    PubMed  Article  Google Scholar 

  137. 137

    Radovanovic, D. et al. Gender differences in management and outcomes in patients with Acute Coronary Syndromes: results on 20,290 patients from the AMIS Plus Registry. Heart 93, 1369–1375 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  138. 138

    Vaccarino, V. et al. Sex differences in health status after coronary artery bypass surgery. Circulation 108, 2642–2647 (2003).

    PubMed  Article  Google Scholar 

  139. 139

    Vaccarino, V. et al. Gender differences in recovery after coronary artery bypass surgery. J. Am. Coll. Cardiol. 41, 307–314 (2003).

    PubMed  Article  Google Scholar 

  140. 140

    Abramson, J. L., Veledar, E., Weintraub, W. S. & Vaccarino, V. Association between gender and in-hospital mortality after percutaneous coronary intervention according to age. Am. J. Cardiol. 91, 968–971 (2003).

    PubMed  Article  Google Scholar 

  141. 141

    Rosengren, A. et al. Sex differences in survival after myocardial infarction in Sweden; data from the Swedish National Acute Myocardial Infarction Register. Eur. Heart J. 22, 314–322 (2001).

    CAS  PubMed  Article  Google Scholar 

  142. 142

    Russo, A. M. et al. Influence of gender on arrhythmia characteristics and outcome in the Multicentre UnSustained Tachycardia Trial. J. Cardiovasc. Electrophysiol. 15, 993–998 (2004).

    PubMed  Article  Google Scholar 

  143. 143

    Salomaa, V. et al. Decline in out-of-hospital coronary heart disease deaths has contributed the main part to the overall decline in coronary heart disease mortality rates among persons 35 to 64 years of age in Finland: the FINAMI study. Circulation 108, 691–696 (2003).

    CAS  PubMed  Article  Google Scholar 

  144. 144

    MacIntyre, K. et al. Gender and survival: a population-based study of 201,114 men and women following a first acute myocardial infarction. J. Am. Coll. Cardiol. 38, 729–735 (2001).

    CAS  PubMed  Article  Google Scholar 

  145. 145

    Centers for Disease Control and Prevention (CDC). State-specific mortality from sudden cardiac death—United States, 1999. MMWR Morb. Mortal. Wkly Rep. 51, 123–126 (2002).

  146. 146

    Njølstad, I., Arnesen, E. & Lund-Larsen, P. G. Smoking, serum lipids, blood pressure, and sex differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation 93, 450–456 (1996).

    PubMed  Article  Google Scholar 

  147. 147

    Kemp, H. G. Jr, Vokonas, P. S., Cohn, P. F. & Gorlin, R. The anginal syndrome associated with normal coronary arteriograms. Report of a six year experience. Am. J. Med. 54, 735–742 (1973).

    PubMed  Article  Google Scholar 

  148. 148

    Cannon, R. O. 3rd et al. Abnormal cardiac sensitivity in patients with chest pain and normal coronary arteries. J. Am. Coll. Cardiol. 16, 1359–1366 (1990).

    PubMed  Article  Google Scholar 

  149. 149

    Cannon R. O. 3rd & Epstein, S. E. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am. J. Cardiol. 61, 1338–1343 (1988).

    PubMed  Article  Google Scholar 

  150. 150

    Reis, S. E. et al. Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study. J. Am. Coll. Cardiol. 33, 1469–1475 (1999).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

The authors of this Review are members of the European Society of Cardiology Working Group on Coronary Pathophysiology and Microcirculation, and acknowledge the European Society of Cardiology for financial support. Dr Vaccarino is supported by the National Institutes of Health, grant K24HL077506.

Author information

Affiliations

Authors

Contributions

V. Vaccarino, R. Corti, O. Manfrini, E. Cenko, and R. Bugiardini researched data for the article. V. Vaccarino, L. Badimon, M. Dorobantu, O. Manfrini, A. Pries, E. Cenko, and R. Bugiardini contributed substantially to the discussion of content. The article was written by V. Vaccarino, R. Corti, and R. Bugiardini. V. Vaccarino, L. Badimon, R. Corti, C. de Wit, M. Dorobantu, O. Manfrini, A. Koller, E. Cenko, and R. Bugiardini reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Raffaele Bugiardini.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vaccarino, V., Badimon, L., Corti, R. et al. Presentation, management, and outcomes of ischaemic heart disease in women. Nat Rev Cardiol 10, 508–518 (2013). https://doi.org/10.1038/nrcardio.2013.93

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing