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.

  • Review Article
  • Published:

Coronary microvascular dysfunction: sex-specific risk, diagnosis, and therapy

Nature Reviews Cardiology volume 12, pages 406–414 (2015)Cite this article

Subjects

Key Points

  • Coronary microvascular dysfunction (CMD) can present as chest pain with electrocardiographic changes and/or imaging abnormalities on stress testing, but no or nonobstructive coronary artery disease on angiography

  • CMD is an under-recognized and underdiagnosed condition that is associated with an increased incidence of adverse cardiac events

  • Risk factors for CMD seem to be similar to those for coronary artery disease, including hypertension, hyperlipidaemia, oestrogen deficiency in women, hyperglycaemia, chronic inflammation, and ageing; however, these factors do not fully account for the prevalence of CMD

  • CMD can be diagnosed using invasive angiography techniques, and novel noninvasive techniques (such as PET, transthoracic Doppler echocardiography, and cardiac MRI) are increasingly available

  • Supported by data from intermediate-outcome trials, treatment for CMD includes antiatherosclerotic and antianginal therapy, but trials to assess major adverse outcomes (such as death and myocardial infarction) are necessary

  • Most studies of CMD have focused on women; further evaluation is needed in men

Abstract

Cardiovascular disease is the leading cause of death worldwide. In the presence of signs and symptoms of myocardial ischaemia, women are more likely than men to have no obstructive coronary artery disease (CAD). Women have a greater burden of symptoms than men, and are often falsely reassured despite the presence of ischaemic heart disease because of a lack of obstructive CAD. Coronary microvascular dysfunction should be considered as an aetiology for ischaemic heart disease with signs and symptoms of myocardial ischaemia, but no obstructive CAD. Coronary microvascular dysfunction is defined as impaired coronary flow reserve owing to functional and/or structural abnormalities of the microcirculation, and is associated with an adverse cardiovascular prognosis. Therapeutic lifestyle changes as well as antiatherosclerotic and antianginal medications might be beneficial, but clinical outcome trials are needed to guide treatment. In this Review, we discuss the prevalence, presentation, diagnosis, and treatment of coronary microvascular dysfunction, with a particular emphasis on ischaemic heart disease in women.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Coronary reactivity testing.

Similar content being viewed by others

References

  1. Fihn, S. D. et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 130, 1749–1767 (2014).

    Article  PubMed  Google Scholar 

  2. Montalescot, G. 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. 34, 2949–3003 (2013).

    Article  PubMed  Google Scholar 

  3. Banks, K., Lo, M. & Khera, A. Angina in women without obstructive coronary artery disease. Curr. Cardiol. Rev. 6, 71–81 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sullivan, A. Chest pain in women: clinical, investigative & prognostic features. BMJ 308, 4 (1994).

    Article  Google Scholar 

  5. 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).

    Article  PubMed  Google Scholar 

  6. 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 (Suppl.), S21–S29 (2006).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Eastwood, J. A. et al. Anginal symptoms, coronary artery disease, and adverse outcomes in black and white women: the NHLBI-sponsored Women's Ischemia Syndrome Evaluation study. J. Womens Health 22 724–732 (2013).

    Article  Google Scholar 

  10. Johnson, B. D. 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. 27, 1408–1415 (2006).

    Article  PubMed  Google Scholar 

  11. Reis, S. E. et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am. Heart J. 141, 735–741 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Kothawade, K. & Bairey Merz, C. N. Microvascular coronary dysfunction in women: pathophysiology, diagnosis, and management. Curr. Probl. Cardiol. 36, 27 (2011).

    Article  Google Scholar 

  13. Sharaf, B. 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. 166, 134–141 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sedlak, T. L. et al. Sex differences in clinical outcomes in patients with stable angina and no obstructive coronary artery disease. Am. Heart J. 166, 38–44 (2013).

    Article  PubMed  Google Scholar 

  15. 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).

    Article  PubMed  Google Scholar 

  16. Maddox, T. M. et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA 312, 1754–1763 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Humphries, K. H., Pu, A., Gao, M., Carere, R. G. & Pilote, L. Angina with “normal” coronary arteries: sex differences in outcomes. Am. Heart J. 155, 375–381 (2008).

    Article  PubMed  Google Scholar 

  18. Jones, E., Eteiba, W. & Bairey Merz, N. Cardiac syndrome X and microvascular coronary dysfunction. Trends Cardiovasc. Med. 22, 161–168 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Murthy, V. L. et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 129, 2518–2527 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Arrebola-Moreno, A. L. et al. Coronary microvascular spasm triggers transient ischemic left ventricular diastolic abnormalities in patients with chest pain and angiographically normal coronary arteries. Atherosclerosis 236, 207–214 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Davis, K. B., Chaitman, B., Ryan, T., Bittner, V. & Kennedy, J. W. Comparison of 15-year survival for men and women after initial medical or surgical treatment for coronary artery disease: a CASS registry study. Coronary Artery Surgery Study. J. Am. Coll. Cardiol. 25, 1000–1009 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Shaw, L. J. 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 114, 894–904 (2006).

    Article  PubMed  Google Scholar 

  24. Shaw, L. J. et al. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology-National Cardiovascular Data Registry. Circulation 117, 1787–1801 (2008).

    Article  PubMed  Google Scholar 

  25. 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).

    Article  PubMed  Google Scholar 

  26. Pepine, C. J. et al. Some thoughts on the vasculopathy of women with ischemic heart disease. J. Am. Coll. Cardiol. 47 (Suppl.), S30–S35 (2006).

    Article  PubMed  Google Scholar 

  27. Erbel, R. et al. Value of intracoronary ultrasound and Doppler in the differentiation of angiographically normal coronary arteries: a prospective study in patients with angina pectoris. Eur. Heart J. 17, 880–889 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Mieres, J. H. et al. Signs and symptoms of suspected myocardial ischemia in women: results from the What is the Optimal Method for Ischemia Evaluation in WomeN? trial. J. Womens Health 20, 1261–1268 (2011).

    Article  Google Scholar 

  29. Safdar, B. et al. Gender-specific research for emergency diagnosis and management of ischemic heart disease: proceedings from the 2014 Academic Emergency Medicine Consensus Conference Cardiovascular Research Workgroup. Acad. Emerg. Med. 21, 1350–1360 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

  31. Herrmann, J., Kaski, J. C. & Lerman, A. Coronary microvascular dysfunction in the clinical setting: from mystery to reality. Eur. Heart J. 33, 2771–2783 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Eggers, K. M., Johnston, N., James, S., Lindahl, B. & Venge, P. Cardiac troponin I levels in patients with non-ST-elevation acute coronary syndrome-the importance of gender. Am. Heart J. 168, 317–324.e1 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Crea, F., Camici, P. G. & Bairey Merz, C. N. Coronary microvascular dysfunction: an update. Eur. Heart J. 1101–1111 (2013).

  34. Wessel, T. R. et al. Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE). Clin. Cardiol. 30, 69–74 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Suessenbacher, A. et al. Sex differences in independent factors associated with coronary artery disease. Wien. Klin. Wochenschr. 126, 718–726 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Huxley, R. R. & Woodward, M. Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies. Lancet 378, 1297–1305 (2011).

    Article  PubMed  Google Scholar 

  37. Almdal, T., Scharling, H., Jensen, J. S. & Vestergaard, H. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch. Intern. Med. 164, 1422–1426 (2004).

    Article  PubMed  Google Scholar 

  38. Moreau, P., d'Uscio, L. & Lüscher, T. F. Structure and reactivity of small arteries in aging. Cardiovasc. Res. 37, 247–253 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Michel, J. B. et al. Effect of chronic ANG 1-coverting enzyme inhibitors on aging processes. II. Large arteries. Am. J. Physiol. 267 (Pt 2), R124–R135 (1994).

    CAS  PubMed  Google Scholar 

  40. Rizzoni, D. et al. Relationships between coronary flow vasodilator capacity and small artery remodelling in hypertensive patients. J. Hypertens. 21, 625–631 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Mundhenke, M., Schwartzkopff, B. & Strauer, B. E. Structural analysis of arteriolar and myocardial remodelling in the subendocardial region of patients with hypertensive heart disease and hypertrophic cardiomyopathy. Virchows Arch. 431, 265–273 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Agabiti-Rosel, E. Structural and functional changes of the microcirculation in hypertension: influence of pharmacological therapy. Drugs 63, 19–29 (2003).

    Article  Google Scholar 

  43. Smith, S. M. et al. Cardiovascular and mortality risk of apparent resistant hypertension in women with suspected myocardial ischemia: a report from the NHLBI-sponsored WISE study. J. Am. Heart Assoc. 3, e000660 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Sucato, V. Evola, S., Novo, G. & Novo, S. Diagnosis of coronary microvascular dysfunction in diabetic patients with cardiac syndrome X: comparison by current methods [Italian]. Recenti Prog. Med. 104, 63–68 (2013).

    PubMed  Google Scholar 

  45. Girach, A. & Vignati, L. Diabetic microvascular complications—can the presence of one predict the development of another? J. Diabetes Complications 20, 228–237 (2006).

    Article  PubMed  Google Scholar 

  46. Di Carli, M. F., Janisse, J., Grunberger, G. & Ager, J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J. Am. Coll. Cardiol. 41, 2387–2393 (2003).

    Article  CAS  Google Scholar 

  47. Galderisi, M. et al. Coronary flow reserve in hypertensive patients with hypercholesterolemia and without coronary heart disease. Am. J. Hypertens. 20, 177–183 (2007).

    Article  PubMed  Google Scholar 

  48. Duvernoy, C. S. et al. Gender differences in myocardial blood flow dynamics: lipid profile and hemodynamic effects. J. Am. Coll. Cardiol. 33, 463–470 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Bonetti, P. O., Lerman, L. O. & Lerman, A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler. Thromb. Vasc. Biol. 23, 168–175 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Recio-Mayoral, A., Rimoldi, O. E., Camici, P. G. & Kaski, J. C. Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease. JACC Cardiovasc. Imaging 6, 660–667 (2013).

    Article  PubMed  Google Scholar 

  51. Lanza, G. A. et al. Assessment of systemic inflammation and infective pathogen burden in patients with cardiac syndrome X. Am. J. Cardiol. 94, 40–44 (2004).

    Article  PubMed  Google Scholar 

  52. Cosín-Sales, J., Pizzi, C., Brown, S. & Kaski, J. C. C-reactive protein, clinical presentation, and ischemic activity in patients with chest pain and normal coronary angiograms. J. Am. Coll. Cardiol. 41, 1468–1474 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Ishimori, M. et al. Myocardial ischemia in the absence of obstructive coronary artery disease in systemic lupus erythematosus. JACC Cardiovasc. Imaging 4, 27–33 (2011).

    Article  PubMed  Google Scholar 

  54. Caliskan, M. et al. Impaired coronary microvascular and left ventricular diastolic functions in patients with ankylosing spondylitis. Atherosclerosis 196, 306–312 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Reriani, M. et al. Microvascular endothelial dysfunction predicts the development of erectile dysfunction in men with coronary atherosclerosis without critical stenoses. Coron. Artery Dis. 25, 552–557 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Kaski, J. C. Cardiac syndrome X in women: the role of oestrogen deficiency. Heart 92 (Suppl. 3), iii5–iii9 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Rosano, G. M. et al. 17-beta-estradiol therapy lessens angina in postmenopausal women with syndrome X. J. Am. Coll. Cardiol. 28, 1500–1505 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Albertsson, P. A., Emanuelsson, H. & Milsom, I. Beneficial effect of treatment with transdermal estradiol-17-beta on exercise-induced angina and ST segment depression in syndrome X. Int. J. Cardiol. 54, 13–20 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Adamson, D. L., Webb, C. M. & Collins, P. Esterified estrogens combined with methyltestosterone improve emotional well-being in postmenopausal women with chest pain and normal coronary angiograms. Menopause 8, 233–238 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Mosca, L. et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation 123, 1243–1262 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Merz, C. N. et al. A randomized controlled trial of low-dose hormone therapy on myocardial ischemia in postmenopausal women with no obstructive coronary artery disease: results from the National Institutes of Health/National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE). Am. Heart J. 159, 987.e1–e7 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  63. Mehta, P. K. et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc. Imaging 4, 514–522 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Camici, P. G., d'Amati, G. & Rimoldi, O. Coronary microvascular dysfunction: mechanisms and functional assessment. Nat. Rev. Cardiol. 12, 48–62 (2015).

    Article  PubMed  Google Scholar 

  65. McArdle, B. et al. Cardiac PET: metabolic and functional imaging of the myocardium. Semin. Nucl. Med. 43, 434–448 (2013).

    Article  PubMed  Google Scholar 

  66. Gould, K. L. et al. Anatomic versus physiologic assessment of coronary artery disease: role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making. J. Am. Coll. Cardiol. 62, 1639–1653 (2013).

    Article  PubMed  Google Scholar 

  67. Valenta, I., Dilsizian, V., Quercioli, A., Ruddy, T. D. & Schindler, T. H. Quantitative PET/CT measures of myocardial flow reserve and atherosclerosis for cardiac risk assessment and predicting adverse patient outcomes. Curr. Cardiol. Rep. 15, 344 (2013).

    Article  PubMed  Google Scholar 

  68. Plank, F. et al. The diagnostic and prognostic value of coronary CT angiography in asymptomatic high-risk patients: a cohort study. Open Heart 1, e000096 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Hou, Z. H. et al. Prognostic value of coronary CT angiography and calcium score for major adverse cardiac events in outpatients. JACC Cardiovasc. Imaging 5, 990–999 (2012).

    Article  PubMed  Google Scholar 

  70. [No authors listed] Italian Society of Cardiovascular Echography (SIEC) Consensus Conference on the state of the art of contrast echocardiography. Ital. Heart J. 5, 309–334 (2004).

  71. Pathan, F. & Marwick, T. H. Myocardial perfusion imaging using contrast echocardiography. Prog. Cardiovasc. Dis. http://dx.doi.org/10.1016/j.pcad.2015.03.005.

  72. Bartel, T. et al. Noninvasive assessment of microvascular function in arterial hypertension by transthoracic Doppler harmonic echocardiography. J. Am. Coll. Cardiol. 39, 2012–2018 (2002).

    Article  PubMed  Google Scholar 

  73. Prescott, E. et al. Improving diagnosis and treatment of women with angina pectoris and microvascular disease: the iPOWER study design and rationale. Am. Heart J. 167, 452–458 (2014).

    Article  PubMed  Google Scholar 

  74. Caiati, C. et al. Validation of a new noninvasive method (contrast-enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with intracoronary Doppler flow wire. J. Am. Coll. Cardiol. 34, 1193–1200 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Meimoun, P. et al. Transthoracic coronary flow velocity reserve assessment: comparison between adenosine and dobutamine. J. Am. Soc. Echocardiogr. 19, 1220–1228 (2006).

    Article  PubMed  Google Scholar 

  76. Dimitrow, P. P. Transthoracic Doppler echocardiography—noninvasive diagnostic window for coronary flow reserve assessment. Cardiovasc. Ultrasound 1, 4 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Okayama, H. et al. Usefulness of an echo-contrast agent for assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery with transthoracic Doppler scan echocardiography. Am. Heart J. 143, 668–675 (2002).

    Article  PubMed  Google Scholar 

  78. Pizzuto, F. et al. Assessment of flow velocity reserve by transthoracic Doppler echocardiography and venous adenosine infusion before and after left anterior descending coronary artery stenting. J. Am. Coll. Cardiol. 38, 155–162 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Ueno, Y., Nakamura, Y., Takashima, H., Kinoshita, M. & Soma, A. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the right coronary artery by transthoracic Doppler echocardiography: comparison with intracoronary Doppler guidewire. J. Am. Soc. Echocardiogr. 15, 1074–1079 (2002).

    Article  PubMed  Google Scholar 

  80. 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).

    Article  PubMed  Google Scholar 

  81. Shufelt, C. L. et al. Cardiac magnetic resonance imaging myocardial perfusion reserve index assessment in women with microvascular coronary dysfunction and reference controls. Cardiovasc. Diagn. Ther. 3, 153–160 (2013).

    PubMed  PubMed Central  Google Scholar 

  82. Doyle, M. et al. Prognostic value of global MR myocardial perfusion imaging in women with suspected myocardial ischemia and no obstructive coronary disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. JACC Cardiovasc. Imaging 3, 1030–1036 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Freed, B. H. et al. Prognostic value of normal regadenoson stress perfusion cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 15, 108 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Dez Prez, R. D. et al. Cost-effectiveness of myocardial perfusion imaging: a summary of the currently available literature. J. Nucl. Cardiol. 12, 750–759 (2005).

    Article  Google Scholar 

  85. Mishra, J. P., Acio, E., Heo, J., Narula, J. & Iskandrian, A. E. Impact of stress single-photon emission computed tomography perfusion imaging on downstream resource utilization. Am. J. Cardiol. 83, 1401–1403 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. McCrohon, J. A. et al. Adjunctive role of cardiovascular magnetic resonance in the assessment of patients with inferior attenuation on myocardial perfusion SPECT. J. Cardiovasc. Magn. Reson. 7, 377–382 (2005).

    Article  PubMed  Google Scholar 

  87. Wei, J. et al. Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. JACC Cardiovasc. Interv. 5, 646–653 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Prasad, A. et al. Abnormal coronary microvascular endothelial function in humans with asymptomatic left ventricular dysfunction. Am. Heart J. 146, 549–554 (2003).

    Article  PubMed  Google Scholar 

  89. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Suwaidi, J. A. et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101, 948–954 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Kuruvilla, S. & Kramer, C. M. Coronary microvascular dysfunction in women: on overview of diagnostic strategies. Expert Rev. Cardiovasc. Ther. 11, 1515–1525 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gibson, C. M. et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 93, 879–888 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Manginas, A. et al. Estimation of coronary flow reserve using the Thrombolysis In Myocardial Infarction (TIMI) frame count method. Am. J. Cardiol. 83, 1562–1565 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Petersen, J. W. et al. TIMI frame count and adverse events in women with no obstructive coronary disease: a pilot study from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE). PLoS ONE 9, e96630 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Luo, C. et al. Thermodilution-derived coronary microvascular resistance and flow reserve in patients with cardiac syndrome X. Circ. Cardiovasc. Interv. 7, 43–48 (2014).

    Article  PubMed  Google Scholar 

  96. Fearon, W. F. et al. Comparison of coronary thermodilution and Doppler velocity for assessing coronary flow reserve. Circulation 108, 2198–2200 (2003).

    Article  PubMed  Google Scholar 

  97. 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).

    Article  PubMed  Google Scholar 

  98. Schlächinger, V., Britten, M. B., Zeiher, A. M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101, 1899–1906 (2000).

    Article  Google Scholar 

  99. Taqueti, V. R. et al. Interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease. Circulation 131, 528–535 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Taqueti, V. R. et al. Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization. Circulation 131, 19–27 (2015).

    Article  PubMed  Google Scholar 

  101. Demirkol, S. et al. Association between microvascular angina and erectile dysfunction. Int. J. Impot. Res. 26, 124–127 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Strain, W. D. et al. Attenuated systemic microvascular function in men with coronary artery disease is associated with angina but not explained by atherosclerosis. Microcirculation 20, 670–677 (2013).

    Article  PubMed  Google Scholar 

  103. Murthy, V. L. et al. Coronary vascular dysfunction and prognosis in patients with chronic kidney disease. JACC Cardiovasc. Imaging 5, 1025–1034 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Nakanishi, K. et al. Prognostic values of coronary flow reserve in long-term cardiovascular outcomes in patients with chronic kidney disease. Am. J. Cardiol. 112, 928–932 (2013).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  106. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Martino, S., Disch, D., Dowsett, S. A., Keech, C. A. & Mershon, J. L. Safety assessment of raloxifene over eight years in a clinical trial setting. Curr. Med. Res. Opin. 21, 1441–1452 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Barrett-Connor, E. et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N. Engl. J. Med. 355, 125–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Anand, S. S. et al. Risk factors for myocardial infarction in women and men: insights from the INTERHEART study. Eur. Heart J. 29, 932–940 (2008).

    Article  PubMed  Google Scholar 

  110. Stampfer, M. J., Hu, F. B., Manson, J. E., Rimm, E. B. & Willett, W. C. Primary prevention of coronary heart disease in women through diet and lifestyle. N. Engl. J. Med. 343, 16–22 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Samin, A., Nugent, L., Mehta, P. K., Shufelt, C. & Bairey Merz, C. N. Treatment of angina and coronary microvascular dysfunction. Curr. Treat. Options in Cardiovasc. Med. 12, 355–364 (2010).

    Article  Google Scholar 

  112. Stone, N. J. et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129 (Suppl. 2), S1–S45 (2014).

    Article  PubMed  Google Scholar 

  113. Reriani, M. K. et al. Effects of statins on coronary and peripheral endothelial function in humans: a systematic review and meta-analysis of randomized controlled trials. Eur. J. Cardiovasc. Prev. Rehabil. 18, 704–716 (2011).

    Article  PubMed  Google Scholar 

  114. Treasure, C. B. et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N. Engl. J. Med. 332, 481–487 (1995).

    Article  CAS  PubMed  Google Scholar 

  115. Ridker, P. M., MacFadyen, J., Libby, P. & Glynn, R. J. Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Am. J. Cardiol. 106, 204–209 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Shahin, Y., Khan, J. A., Samuel, N. & Chetter, I. Angiotensin converting enzyme inhibitors effect on endothelial dysfunction: a meta-analysis of randomised controlled trials. Atherosclerosis 216, 7–16 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bavry, A. A. et al. Aldosterone inhibition and coronary endothelial function in women without obstructive coronary artery disease: an ancillary study of the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE). Am. Heart J. 167, 826–832 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Garg, R. et al. Mineralocorticoid receptor blockade improves coronary microvascular function in individuals with type 2 diabetes. Diabetes 64, 236–242 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Fraker, T. D. Jr et al. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J. Am. Coll. Cardiol. 50, 2264–2274 (2007).

    Article  PubMed  Google Scholar 

  121. Heidenreich, P. A. et al. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA 281, 1927–1936 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  123. Lanza, G. A., Colonna, G., Pasceri, V. & Maseri, A. Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X. Am. J. Cardiol. 84, 854–856 (1999).

    Article  CAS  PubMed  Google Scholar 

  124. Kayaalti, F. et al. Effects of nebivolol therapy on endothelial functions in cardiac syndrome X. Heart Vessels 25, 92–96 (2010).

    Article  PubMed  Google Scholar 

  125. Togni, M. et al. Does the beta-blocker nebivolol increase coronary flow reserve? Cardiovasc. Drugs Ther. 21, 99–108 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Cannon, R. O. 3rd, Watson, R. M., Rosing, D. R. & Epstein, S. E. Efficacy of calcium channel blocker therapy for angina pectoris resulting from small-vessel coronary artery disease and abnormal vasodilator reserve. Am. J. Cardiol. 56, 242–246 (1985).

    Article  PubMed  Google Scholar 

  127. Thadani, U. Current medical management of chronic stable angina. J. Cardiovasc. Pharmacol. Ther. 9 (Suppl. 1), S11–S29 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. Opie, L. H. Calcium channel antagonists in the management of anginal syndromes: changing concepts in relation to the role of coronary vasospasm. Prog. Cardiovasc. Dis. 38, 291–314 (1996).

    Article  CAS  PubMed  Google Scholar 

  129. Timmis, A. D., Chaitman, B. R. & Crager, M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur. Heart J. 27, 42–48 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Chaitman, B. R. et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 291, 309–316 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Chaitman, B. R. et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J. Am. Coll. Cardiol. 43, 1375–1382 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Belardinelli, L., Shryock, J. C. & Fraser, H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart 92 (Suppl. 4), iv6–iv14 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  135. Johnson, B. D. et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary artery 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).

    Article  PubMed  Google Scholar 

  136. Pepine, C. J. Ischemic heart disease in women: facts and wishful thinking. J. Am. Coll. Cardiol. 43, 1727–1730 (2004).

    Article  PubMed  Google Scholar 

  137. Pepine, C. J. Ischemic heart disease in women. J. Am. Coll. Cardiol. 47 (Suppl.), S1–S3 (2006).

    Article  PubMed  Google Scholar 

  138. Wenger, N. K., Chaitman, B. & Vetrovec, G. W. Gender comparison of efficacy and safety of ranolazine for chronic angina pectoris in four randomized clinical trials. Am. J. Cardiol. 99, 11–18 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Skalidis, E. I., Hamilos, M. I., Chlouverakis, G., Zacharis, E. A. & Vardas, P. E. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease. Atherosclerosis 215, 160–165 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Villano, A. et al. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am. J. Cardiol. 112, 8–13 (2013).

    Article  CAS  PubMed  Google Scholar 

  141. Emdin, M, Picano, E., Lattanzi, F. & L'Abbate, A. Improved exercise capacity with acute aminophylline administration in patients with syndrome X. J. Am. Coll. Cardiol. 14, 1450–1453 (1989).

    Article  CAS  PubMed  Google Scholar 

  142. Chen, J. W., Hsu, N. W., Wu, T. C., Lin, S. J. & Chang, M. S. Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am. J. Cardiol. 90, 974–982 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Bøtker, H. E., Sonne, H. S., Schmitz, O. & Nielsen, T. T. Effects of doxazosin on exercise-induced angina pectoris, ST-segment depression, and insulin sensitivity in patients with syndrome X. Am. J. Cardiol. 82, 1352–1356 (1998).

    Article  PubMed  Google Scholar 

  144. Chen, J. W. et al. Effects of short-term treatment of nicorandil on exercise-induced myocardial ischemia and abnormal cardiac autonomic activity in microvascular angina. Am. J. Cardiol. 80, 32–38 (1997).

    Article  CAS  PubMed  Google Scholar 

  145. Vicari, R. M. et al. Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled, phase 2 trial. J. Am. Coll. Cardiol. 46, 1803–1811 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Denardo, S. J. et al. Effect of phosphodiesterase type 5 inhibition on microvascular coronary dysfunction in women: a Women's Ischemia Syndrome Evaluation (WISE) ancillary study. Clin. Cardiol. 34, 483–487 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Maddox, T. M. et al. Utilization of secondary prevention therapies in patients with nonobstructive coronary artery disease identified during cardiac catheterization: insights from the National Cardiovascular Data Registry Cath-PCI Registry. Circ. Cardiovasc. Qual. Outcomes 3, 632–641 (2010).

    Article  PubMed  Google Scholar 

  148. Kronhaus, K. D. & Lawson, W. E. Enhanced external counterpulsation is an effective treatment for syndrome X. Int. J. Cardiol. 135, 256–257 (2009).

    Article  PubMed  Google Scholar 

  149. Di Pede, F. et al. Immediate and long-term clinical outcome after spinal cord stimulation for refractory stable angina pectoris. Am. J. Cardiol. 91, 951–955 (2003).

    Article  PubMed  Google Scholar 

  150. van Peski-Oosterbaan, A. S. et al. Cognitive-behavioral therapy for noncardiac chest pain: a randomized trial. Am. J. Med. 106, 424–429 (1999).

    Article  CAS  PubMed  Google Scholar 

  151. Chauhan, A. et al. Effect of transcutaneous electrical nerve stimulation on coronary blood flow. Circulation 89, 694–702 (1994).

    Article  CAS  PubMed  Google Scholar 

  152. Lanza, G. A. et al. Effect of spinal cord stimulation on spontaneous and stress-induced angina and 'ischemic-like' ST-segment depression in patients with cardiac syndrome X. Eur. Heart J. 26, 983–989 (2005).

    Article  PubMed  Google Scholar 

  153. Anderson, J. L. et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 2002 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 116, 148–304 (2007).

    Google Scholar 

  154. Asbury, E. A., Kanji, N., Ernst, E, Barbir, M. & Collins, P. Autogenic training to manage symptomology in women with chest pain and normal coronary arteries. Menopause 16, 60–65 (2009).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors were supported by funding from the National Heart, Lung, and Blood Institute, numbers N01-HV-68161, N01-HV-68162, N01-HV-68163, and N01-HV-68164; grants K23HL105787, U0164829, U01 HL649141, U01 HL649241, T32HL69751, R01 HL090957, and 1R03AG032631 from the National Institute on Aging; GCRC grant MO1-RR00425 from the National Center for Research Resources; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, USA; The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA, USA; The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, USA; QMED, Inc., Laurence Harbor, NJ, USA; the Edythe L. Broad Women's Heart Research Fellowship; the Barbra Streisand Women's Cardiovascular Research and Education Program; and the Linda Joy Pollin Women's Heart Health Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Author information

Authors and Affiliations

  1. Barbra Streisand Women's Heart Center, Cedars–Sinai Heart Institute, Cedars–Sinai Medical Center, 127 South San Vicente Boulevard, A3600, Los Angeles, 90048, CA, USA

    Jenna Dean, Sherwin Dela Cruz, Puja K. Mehta & C. Noel Bairey Merz

Authors
  1. Jenna Dean
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sherwin Dela Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Puja K. Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Noel Bairey Merz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All the authors researched data for the article, discussed its content, wrote the manuscript, and reviewed/edited it before submission.

Corresponding author

Correspondence to C. Noel Bairey Merz.

Ethics declarations

Competing interests

P.K.M. has received research support from General Electric and Gilead, and has given lectures for the Medical Education Speakers Network (paid to Cedars-Sinai Medical Center). C.N.B.M. has given Continuing Medical Education lectures for Allegheny General Hospital, AHA, Bryn Mawr, Duke University, Emory University, Garden State, Gilead (Grant Review Committee), Japanese Circulation Society, Kaiser Permanente, Mayo Foundation, Preventive Cardiovascular Nurses Association, Practice Point Communications, University of California San Francisco, and Vox Media (paid to Cedars-Sinai Medical Center). C.N.B.M. has also received honoraria and consulting fees from NIH-SEP (Grant Review Study Section), Research Triangle Institute International, University of New Mexico, and Victor Chang Cardiac Research Institute; and has received research support from the Clinical Translational Science Institute, Flight Attendant Medical Research Institute, Gilead, and NIH. J.D. and S.D.C. declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dean, J., Cruz, S., Mehta, P. et al. Coronary microvascular dysfunction: sex-specific risk, diagnosis, and therapy. Nat Rev Cardiol 12, 406–414 (2015). https://doi.org/10.1038/nrcardio.2015.72

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2015.72

This article is cited by

Search

Advanced 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