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Microvascular Angina as a Cause of Ischemia: An Update

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Abstract

Since initial reports over four decades ago, the diagnosis and the management of “microvascular angina” continue to be a troublesome dilemma for physicians. Microvascular angina is suspected in those patients presenting with angina or angina-like chest pain whose coronary angiograms show no evidence of obstructive coronary artery disease. Many of these patients often complain of chest pain and disability for years, and the morbidity is considerable. Earlier reports have questioned the presence of ischemia in such patients. Recent investigations have sought to demonstrate an association of chest pain with the occurrence of adverse events including cardiac death and nonfatal myocardial infarction. The role of coronary microvascular function remains controversial with regards to pathophysiology, diagnosis and management.

Keywords

  • Women
  • Coronary vasospasm
  • Microvascular angina
  • Coronary microvascular dysfunction
  • Endothelial dysfunction
  • Coronary angiography
  • Non-obstructive coronary artery disease

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Abbreviations

ACC:

American College of Cardiology

ACE:

Angiotensin-converting enzyme

ACS:

Acute coronary syndromes

AHA:

American Heart Association

CAD:

Coronary artery disease

CASS:

Coronary Artery Surgery Study

CCB:

Calcium channel blockers

CCTA:

Coronary computed tomography angiography

CFR:

Coronary flow reserve

CMD:

Coronary microvascular dysfunction

CMRI:

Cardiac magnetic resonance imaging

CVD:

Coronary vascular dysfunction

ECG:

Electrocardiogram

EECP:

Enhanced external counterpulsation

EMMACE-2:

Evaluation of Methods and Management of Acute Coronary Events

ESC:

European Society of Cardiology

FFR:

Fractional flow reserve

GRACE:

Global Registry of Acute Coronary Events

HDL:

High-density lipoprotein

HOPE:

Heart Outcome Prevention Evaluation

IMR:

Index of microvascular resistance

IVUS:

Intravascular ultrasound

LDL:

Low-density lipoprotein

MVA:

Microvascular angina

PET:

Positron emission tomography

RCT:

Randomized clinical trials

SAQ:

Seattle Angina Questionnaire

SPECT:

single photon emission computed tomography

TIMI:

Thrombolysis in Myocardial Infarction

TTDE:

Transthoracic doppler echocardiography

VINTAGE-MI:

Vascular Interaction With Age in Myocardial Infarction

WISE:

Women’s Ischemia Syndrome Evaluation

References

  1. Sullivan AK, Holdright DR, Wright CA, et al. Chest pain in women: clinical, investigative, and prognostic features. BMJ. 1994;308:883–6.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

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

    PubMed  CrossRef  CAS  Google Scholar 

  3. 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.

    PubMed  CrossRef  Google Scholar 

  4. Sharaf BL, Pepine CJ, Kerensky RA, et al. Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation [WISE] Study Angiographic Core Laboratory). Am J Cardiol. 2001;87:937–41.

    PubMed  CrossRef  CAS  Google Scholar 

  5. Kemp HG, Kronmal RA, Vlietstra RE, Frye RL. Seven years survival of patients with normal or near normal coronary arteriograms: a CASS Registry study. J Am Coll Cardiol. 1986;7:479–83.

    PubMed  CrossRef  CAS  Google Scholar 

  6. Castelli WP. Epidemiology of coronary heart disease: the Framingham study. Am J Med. 1984;76:4–12.

    PubMed  CrossRef  CAS  Google Scholar 

  7. Weiner DA, Ryan TJ, McCabe CH, et al. Exercise stress testing: correlations among history of angina, ST-segment response and prevalence of coronary-artery disease in the Coronary Artery Surgery Study (CASS). N Engl J Med. 1979;301:230–5.

    PubMed  CrossRef  CAS  Google Scholar 

  8. Shaw LJ, Shaw RE, Bairey Merz CN, 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. 2008;117:1787–801.

    PubMed  CrossRef  Google Scholar 

  9. Jespersen L, Hvelulund A, Abildstrom 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.

    PubMed  CrossRef  Google Scholar 

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

    PubMed  CrossRef  Google Scholar 

  11. Hochman JS, McCabe CH, Stone PH, et al. Outcome and profile of women and men presenting with acute coronary syndromes: a report from TIMI IIIB. J Am Coll Cardiol. 1997;30:141–8.

    PubMed  CrossRef  CAS  Google Scholar 

  12. Hochman JS, Tamis JE, Thompson TD, et al. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. Global use of strategies to open occluded coronary arteries in acute coronary syndromes IIb investigators. N Engl J Med. 1999;341:226–32.

    PubMed  CrossRef  CAS  Google Scholar 

  13. Anand SS, Xie CC, Mehta S, et al. Differences in the management and prognosis of women and men who suffer from acute coronary syndromes. J Am Coll Cardiol. 2005;46:1845–51.

    PubMed  CrossRef  Google Scholar 

  14. De Ferrari GM, Fox KAA, White JA, et al. Outcomes among non-ST-segment elevation acute coronary syndromes patients with no angiographically obstructive coronary artery disease: observations from 37,101 patients. Eur Heart J Acute Cardiovasc Care. 2014;3:37–45.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  15. Bugiardini R, Yan AT, Yan RT, et al. Canadian Acute Coronary Syndrome Registry I and II Investigators. Factors influencing underutilization of evidence-based therapies in women. Eur Heart J. 2011;32:1337–44.

    PubMed  CrossRef  CAS  Google Scholar 

  16. Min JK, Dunning A, Lin FY, et al. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings. Results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol. 2011;58:849–60.

    PubMed  CrossRef  Google Scholar 

  17. Hoffman U, Ferencik M, Udelson JE, et al. Prognostic value of noninvasive cardiovascular testing in patients with stable chest pain: insight from the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain). Circulation. 2017;135:2320–32.

    CrossRef  Google Scholar 

  18. Shaw LJ, Bairey Merz CN, Pepine CJ, et al. Insight from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study. Part I: gender differences in traditional risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol. 2006;47:4s–20s.

    CrossRef  Google Scholar 

  19. Lloyd-Jones DM, Wilson PW, Larson MG, et al. Framingam risk score and prediction of lifetime risk for coronary artery heart disease. Am J Cardiol. 2004;94:20–4.

    PubMed  CrossRef  Google Scholar 

  20. Dorobantu M, Onciul S, Tautu OF, Cenko E. Hypertension and ischemic heart disease in women. Curr Pharm Des. 2016;22:3885–92.

    PubMed  CrossRef  CAS  Google Scholar 

  21. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J. 1986;111:383–890.

    PubMed  CrossRef  CAS  Google Scholar 

  22. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3:213–9.

    PubMed  CrossRef  CAS  Google Scholar 

  23. Kanaya AM, Grady D, Barret-Connor R. Explaining the sex differences in coronary heart disease mortality among patients with type 2 diabetes mellitus: a meta-analysis. Arch Intern Med. 2002;162:1737–45.

    PubMed  CrossRef  Google Scholar 

  24. Barrett-Connor EL, Cohn BA, Wingard DL, Edelstein SL. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo study. JAMA. 1991;265:627–31.

    PubMed  CrossRef  CAS  Google Scholar 

  25. Mygin ND, Michelsen MM, Pena A. Coronary microvascular function and cardiovascular risk factors in women with angina pectoris and no obstructive coronary artery disease: the iPOWER study. J Am Heart Assoc. 2016;5:e003064.

    CrossRef  Google Scholar 

  26. Badimon L, Bugiardini R, Cenko E, et al. Position paper of the European Society of Cardiology-working group of coronary pathophysiology and microcirculation: obesity and heart disease. Eur Heart J. 2017;38:1951–8.

    PubMed  CrossRef  Google Scholar 

  27. Ridker PM, Riafai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557–65.

    PubMed  CrossRef  CAS  Google Scholar 

  28. Ridker PM, Buring JE, Shih J, et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently women. Circulation. 1998;98:731–3.

    PubMed  CrossRef  CAS  Google Scholar 

  29. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  30. Cannon RO, Epstein SE. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol. 1988;61:1338–43.

    PubMed  CrossRef  Google Scholar 

  31. 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.

    PubMed  CrossRef  CAS  Google Scholar 

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

    PubMed  CrossRef  CAS  Google Scholar 

  33. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356:830–40.

    PubMed  CrossRef  CAS  Google Scholar 

  34. Lanza GA, Crea F. Primary coronary microvascular dysfunction. clinical presentation, pathophysiology, and management. Circulation. 2010;121:2317–25.

    PubMed  CrossRef  Google Scholar 

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

    PubMed  CrossRef  Google Scholar 

  36. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  37. 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.

    PubMed  CrossRef  Google Scholar 

  38. Bugiardini R, Badimon L, Collins P, et al. Angina, “normal” coronary angiography, and vascular dysfunction: risk assessment strategies. PLoS Med. 2007;4(2):e12.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  39. Pries AR, Habazettl H, Ambrosio G, et al. A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings. Cardiovasc Res. 2008;80:165–74.

    PubMed  CrossRef  CAS  Google Scholar 

  40. 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.

    PubMed  CrossRef  CAS  Google Scholar 

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

    PubMed  CrossRef  Google Scholar 

  42. Camici PG, Marraccini P, Lorenzoni R, et al. Coronary hemodynamics and myocardial metabolism in patients with syndrome X: response to pacing stress. J Am Coll Cardiol. 1991;17:1461–70.

    PubMed  CrossRef  CAS  Google Scholar 

  43. Cenko E, Bugiardini R. Vasotonic angina as a cause of myocardial ischemia in women. Cardiovasc Drugs Ther. 2015;29:339–45.

    PubMed  CrossRef  CAS  Google Scholar 

  44. Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA study (Abnormal Coronary Vascomotion) in patients with stable angina and unobstructed coronary arteries. J Am Coll Cardiol. 2012;59:655–62.

    PubMed  CrossRef  CAS  Google Scholar 

  45. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  46. Crake T, Canepa-Anson R, Shapiro L, Poole-Wilson PA. Continuous recording of coronary sinus oxygen saturation during atrial pacing in patients with coronary artery disease or with syndrome X. Br Heart J. 1988;59:31–8.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  47. Picano E, Lattanzi F, Masini M, Distante A, L’Abbate A. Usefulness of high dose dipyridamole-echocardiography test for diagnosis of syndrome X. Am J Cardiol. 1987;60:508–612.

    PubMed  CrossRef  CAS  Google Scholar 

  48. Panza JA, Laurienzo JM, Curiel RV. Investigation of the mechanism of chest pain in patients with angiographically normal coronary arteries using transesophageal dobutamine stress echocardiography. J Am Coll Cardiol. 1997;29:293–301.

    PubMed  CrossRef  CAS  Google Scholar 

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

    PubMed  CrossRef  Google Scholar 

  50. Britten MB, Zeiher AM, Schächinger V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron Artery Dis. 2004;15:259–64.

    PubMed  CrossRef  Google Scholar 

  51. 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.

    PubMed  CrossRef  Google Scholar 

  52. Pepine CJ, Anderson RD, Sharaf BL, 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. 2010;55:2825–32.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  53. Reis SE, Holubkov R, Conrad Smith AJ, 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. 2001;141:735–41.

    PubMed  CrossRef  CAS  Google Scholar 

  54. Hasdai D, Gibbons RJ, Holmes DR, et al. Coronary endothelial dysfunction is associated with myocardial perfusion defects. Circulation. 1997;96:3390–5.

    PubMed  CrossRef  CAS  Google Scholar 

  55. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med. 2002;346:1948–53.

    PubMed  CrossRef  Google Scholar 

  56. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  57. Cannon RO III, Dilsizian V, O’Gara PT, et al. Myocardial metabolic, hemodynamic, and electrocardiographic significance of reversible thallium-201 abnormalities in hypertrophic cardiomyopathy. Circulation. 1991;83:1660–7.

    PubMed  CrossRef  Google Scholar 

  58. Stolen KQ, Kemppainen J, Kalliokoski KK, et al. Myocardial perfusion reserve and peripheral endothelial function in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2004;93:64–8.

    PubMed  CrossRef  Google Scholar 

  59. Strauer BE, Brune I, Schenk H, Knoll D, Perings E. Lupus cardiomyopathy: cardiac mechanics, hemodynamics, and coronary blood flow in uncomplicated systemic lupus erythematosus. Am Heart J. 1976;92:715–22.

    PubMed  CrossRef  CAS  Google Scholar 

  60. Egashira K, Inou T, Hirooka Y, Yamada A, Urabe Y, Takeshita A. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med. 1993;328:1659–64.

    PubMed  CrossRef  CAS  Google Scholar 

  61. Drexler H, Zeiher AM, Wollschlager H, et al. Flow-dependent coronary artery dilatation in humans. Circulation. 1989;80:466–74.

    PubMed  CrossRef  CAS  Google Scholar 

  62. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  63. Zeiher AM, Krause T, Schachinger V, et al. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation. 1995;91:2345–52.

    PubMed  CrossRef  CAS  Google Scholar 

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

    PubMed  CrossRef  CAS  Google Scholar 

  65. 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.

    CrossRef  Google Scholar 

  66. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000;101:948–54.

    PubMed  CrossRef  CAS  Google Scholar 

  67. Schachinger V, Britten M, Zeiher A. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899–906.

    PubMed  CrossRef  CAS  Google Scholar 

  68. Neunteufl T, Heher S, Katzenschlager R, Wolfl G, Kostner K, Maurer G, Weidinger F. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol. 2000;86:207–10.

    PubMed  CrossRef  CAS  Google Scholar 

  69. 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.

    PubMed  CrossRef  Google Scholar 

  70. Choi BJ, Matsuo Y, Aoki T, et al. Coronary endothelial dysfunction is associated with inflammation and vasa vasorum proliferation in patients with early atherosclerosis. Arterioscler Thromb Vasc Biol. 2014;34:2473–7.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  71. Tuzcu EM, Kapadia SR, Tutar E, et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound. Circulation. 2001;103:2705–10.

    PubMed  CrossRef  CAS  Google Scholar 

  72. Jeremias A, Ge J, Erbel R. New insight into plaque healing after plaque rupture with subsequent thrombus formation detected by intravascular ultrasound. Heart. 1997;77:293.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  73. Ge J, Haude M, Görge G, Liu F, Erbel R. Silent healing of spontaneous plaque disruption demonstrated by intravascular ultrasound. Eur Heart J. 1995;16:1149–51.

    PubMed  CrossRef  CAS  Google Scholar 

  74. Skyschally A, Erbel R, Heusch G. Coronary microembolization. Circ J. 2003;67:279–86.

    PubMed  CrossRef  Google Scholar 

  75. Heusch G, Schulz R. Pathophysiology of coronary microembolisation. Heart. 2000;89:981–2.

    CrossRef  Google Scholar 

  76. Erbel R, Heusch G. Coronary microembolization. J Am Coll Cardiol. 2000;36:22–4.

    PubMed  CrossRef  CAS  Google Scholar 

  77. Cenko E, Ricci B, Kedev S, et al. The no-reflow phenomenon in the young and in the elderly. Int J Cardiol. 2016;222:1122–8.

    PubMed  CrossRef  Google Scholar 

  78. Hemingway H, Shipley M, Britton A, Page M, Macfarlane P, Marmot M. Prognosis of angina with and without a diagnosis: 11 year follow up in the Whitehall II prospective cohort study. BMJ. 2003;327:895.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  79. 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.

    PubMed  CrossRef  Google Scholar 

  80. Pepine CJ, Balaban RS, Bonow RO, et al. Women’s ischemic syndrome evaluation: current status and future research directions: report of the National Heart, Lung and Blood Institute workshop: October 2-4, 2002: section 1: diagnosis of stable ischemia and ischemic heart disease. Circulation. 2004;109:e44–6.

    PubMed  CrossRef  Google Scholar 

  81. 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.

    PubMed  CrossRef  Google Scholar 

  82. 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.

    PubMed  CrossRef  Google Scholar 

  83. Ruggeri A, Taruschio G, Loricchio ML, Samory G, Borghi A, Bugiardini R. The correlation between the clinical characteristics and psychological status in syndrome X patients. Cardiologia. 1996;41:551–7.

    PubMed  CAS  Google Scholar 

  84. Asbury EA, Collins P. Psychosocial factors associated with noncardiac chest pain and cardiac syndrome X. Herz. 2005;30:55–60.

    PubMed  CrossRef  Google Scholar 

  85. Asbury EA, Webb CM, Collins P. Group support to improve psychosocial well-being and primary-care demands among women with cardiac syndrome X. Climacteric. 2011;14:100–4.

    PubMed  CrossRef  CAS  Google Scholar 

  86. Asbury EA, Creed F, Collins P. Distinct psychosocial differences between women with coronary heart disease and cardiac syndrome X. Eur Heart J. 2004;25:1695–701.

    PubMed  CrossRef  Google Scholar 

  87. Bass C, Wade C, Hand D, Jackson G. Patients with angina with normal and near normal coronary arteries: clinical and psychosocial state 12 months after angiography. Br Med J (Clin Res Ed). 1983;287:1505–8.

    CrossRef  CAS  Google Scholar 

  88. Rutledge T, Reis SE, Olson M, et al. Depression is associated with cardiac symptoms, mortality risk, and hospitalization among women with suspected coronary disease: the NHLBI-sponsored WISE study. Psychosom Med. 2006;68:217–23.

    PubMed  CrossRef  Google Scholar 

  89. Hlatky MA, Pryor DB, Harrel FE Jr, Califf RM, Mark DB, Rosati RA. Factors affecting sensitivity and specificity of exercise electrocardiography. Multivariable analysis. Am J Med. 1984;77:64–71.

    PubMed  CrossRef  CAS  Google Scholar 

  90. Ashley EA, Myers J, Froelicher V. Exercise testing in clinical medicine. Lancet. 2000;356:1592–7.

    PubMed  CrossRef  CAS  Google Scholar 

  91. Coplan NL, Fuster V. Limitations of the exercise test as a screen for acute cardiac events in asymptomatic patients. Am Heart J. 1990;119:987–90.

    PubMed  CrossRef  CAS  Google Scholar 

  92. Bokhari S, Bergmann SR. The effect of estrogen compared to estrogen plus progesterone on the exercise electrocardiogram. J Am Coll Cardiol. 2002;40:1092–6.

    PubMed  CrossRef  CAS  Google Scholar 

  93. Palinkas A, Toth E, Amyot R, Rigo F, Venneri L, Picano E. The value of ECG and echocardiography during stress testing for identifying systemic endothelial dysfunction and epicardial artery stenosis. Eur Heart J. 2002;23:1587–95.

    PubMed  CrossRef  CAS  Google Scholar 

  94. Doyle M, Fuisz A, Kortright E, et al. The impact of myocardial flow reserve on the detection of coronary artery disease by perfusion imaging methods: an NHLBI WISE study. J Cardiovasc Magn Reson. 2003;5:475–85.

    PubMed  CrossRef  Google Scholar 

  95. Hachamovitch R, Berman DS, Kiat H, Cohen I, Friedman JD, Shaw LJ. Value of stress myocardial perfusion single photon emission computed tomography in patients with normal resting electrocardiograms: an evaluation of incremental prognostic value and cost-effectiveness. Circulation. 2002;105:823–9.

    PubMed  CrossRef  Google Scholar 

  96. Abdel Fattah A, Kamal AM, Pancholy S, et al. Prognostic implications of normal exercise tomographic thallium images in patients with angiographic evidence of significant coronary artery disease. Am J Cardiol. 1994;74:769–71.

    PubMed  CrossRef  CAS  Google Scholar 

  97. Wieneke H, Zander C, Eising EG, Haude M, Bockisch A, Erbel R. Non-invasive characterization of cardiac microvascular disease by nuclear medicine using single-photon emission tomography. Herz. 1999;24:515–21.

    PubMed  CrossRef  CAS  Google Scholar 

  98. Bamberg F, Sommer WH, Hoffmann V, et al. Meta-analysis and systematic review of the long-term predictive value of assessment of coronary atherosclerosis by contrast-enhanced coronary computed tomography angiography. J Am Coll Cardiol. 2011;57:2426–36.

    PubMed  CrossRef  Google Scholar 

  99. Hadamitzky M, Täubert S, Deseive S, Byrne RA, Martinoff S, Schömig A, Hausleiter J. Prognostic value of coronary computed tomography angiography during 5 years of follow-up in patients with suspected coronary artery disease. Eur Heart J. 2013;34:3277–85.

    PubMed  CrossRef  Google Scholar 

  100. Hou ZH, Lu B, Gao Y, et al. Prognostic value of coronary CT angiography and calcium score for major adverse cardiac events in outpatients. JACC Cardiovasc Imaging. 2012;5:990–9.

    PubMed  CrossRef  Google Scholar 

  101. Baldassarre LA, Raman SV, Min JK, et al.; American College of Cardiology’s Cardiovascular Disease in Women Committee. Noninvasive imaging to evaluate women with stable ischemic heart disease. JACC Cardiovasc Imaging. 2016;9:421–35.

    Google Scholar 

  102. Nakazato R, Arsanjani R, Achenbach S, et al. Age-related risk of major adverse cardiac event risk and coronary artery disease extent and severity by coronary CT angiography: results from 15 187 patients from the International Multisite CONFIRM study. Eur Heart J Cardiovasc Imaging. 2014;15:586–94.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  103. Pagidipati NJ, Hemal K, Coles A, et al. Sex differences in functional and CT angiography testing in patients with suspected coronary artery disease. J Am Coll Cardiol. 2016;67:2607–16.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  104. Hoffmann U, Ferencik M, Udelson JE, et al.; PROMISE Investigators. Prognostic value of noninvasive cardiovascular testing in patients with stable chest pain: insights from the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain). Circulation. 2017;135:2320–32.

    Google Scholar 

  105. Gulati M, RM C-DH, 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.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  106. Ahmadi N, Nabavi V, Hajsadeghi F, et al. Mortality incidence of patients with non-obstructive coronary artery disease diagnosed by computed tomography angiography. Am J Cardiol. 2011;107:10–6.

    PubMed  CrossRef  Google Scholar 

  107. Geltman EM, Henes CG, Senneff MJ, Sobel BE, Bergmann SR. Increased myocardial perfusion at rest and diminished perfusion reserve in patients with angina and angiographically normal coronary arteries. J Am Coll Cardiol. 1990;16:586–95.

    PubMed  CrossRef  CAS  Google Scholar 

  108. Saraste M, Koskenvuo J, Knuuti J, et al. Coronary flow reserve: measurement with transthoracic Doppler echocardiography is reproducible and comparable with positron emission tomography. Clin Physiol. 2001;21:114–22.

    PubMed  CrossRef  CAS  Google Scholar 

  109. Hozumi T, Yoshida K, Akasaka T, et al. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography: comparison with invasive technique. J Am Coll Cardiol. 1998;32:1251–9.

    PubMed  CrossRef  CAS  Google Scholar 

  110. Lethen H, Tries HP, Brechtken J, Kersting S, Lambertz H. Comparison of transthoracic Doppler echocardiography to intracoronary Doppler guidewire measurements for assessment of coronary flow reserve in the left anterior descending artery for detection of restenosis after coronary angioplasty. Am J Cardiol. 2003;91:412–7.

    PubMed  CrossRef  Google Scholar 

  111. Galiuto L, Sestito A, Barchetta S, et al. Noninvasive evaluation of flow reserve in the left anterior descending coronary artery in patients with cardiac syndrome X. Am J Cardiol. 2007;99:1378–83.

    PubMed  CrossRef  Google Scholar 

  112. Vogel R, Indermühle A, Reinhardt J, et al. The quantification of absolute myocardial perfusion in humans by contrast echocardiography: algorithm and validation. J Am Coll Cardiol. 2005;45:754–62.

    PubMed  CrossRef  Google Scholar 

  113. Bartel T, Yang Y, Muller S, et al. Noninvasive assessment of microvascular function in arterial hypertension by transthoracic Doppler harmonic echocardiography. J Am Coll Cardiol. 2002;39:2012–8.

    PubMed  CrossRef  Google Scholar 

  114. Poelaert JI, Schupfer G. Hemodynamic monitoring utilizing transesophageal echocardiography: the relationships among pressure, flow, and function. Chest. 2005;127:379–90.

    PubMed  CrossRef  Google Scholar 

  115. Sicari R, Nihoyannopoulos P, Evangelista A, et al.; European Association of Echocardiography. Stress echocardiography expert consensus statement: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J Echocardiogr. 2008;9:415–37.

    Google Scholar 

  116. Kuvin JT, Karas RH. Clinical utility of endothelial function testing: ready for prime time? Circulation. 2003;107:3243–7.

    PubMed  CrossRef  Google Scholar 

  117. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39:257–65.

    PubMed  CrossRef  Google Scholar 

  118. Deanfield J, Donald A, Ferri C, et al.; Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23:7–17.

    Google Scholar 

  119. Hayward CS, Kraidly M, Webb CM, Collins P. Assessment of endothelial function using peripheral waveform analysis. A clinical application. J Am Coll Cardiol. 2002;40:521–8.

    PubMed  CrossRef  CAS  Google Scholar 

  120. Wennberg DE, Kellett MA, Dickens JD, Malenka DJ, Keilson LM, Keller RB. The association between local diagnostic testing intensity and invasive cardiac procedures. JAMA. 1996;275:1161–4.

    PubMed  CrossRef  CAS  Google Scholar 

  121. Mathew J, Krishna A, Hallak AA, et al. Clinical and angiographic findings in black patients with suspected coronary artery disease. Int J Cardiol. 1997;62:251–7.

    PubMed  CrossRef  CAS  Google Scholar 

  122. Strauer BE. The significance of coronary reserve in clinical heart disease. J Am Coll Cardiol. 1990;15:775–83.

    PubMed  CrossRef  CAS  Google Scholar 

  123. Berry C, Corcoran D, Hennigan B, Watkins S, Layland J, Oldroyd KG. Fractional flow reserve-guided management in stable coronary disease and acute myocardial infarction: recent developments. Eur Heart J. 2015;36:3155–64.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  124. 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.

    PubMed  CrossRef  Google Scholar 

  125. Fearon WF, Balsam LB, Farouque HM, et al. Novel index for invasively assessing the coronary microcirculation. Circulation. 2003;107:3129–32.

    PubMed  CrossRef  Google Scholar 

  126. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371–5.

    PubMed  CrossRef  CAS  Google Scholar 

  127. Erbel R, Ge J, Görge G, et al. Intravascular ultrasound classification of atherosclerotic lesions according to American Heart Association recommendation. Coron Artery Dis. 1999;10:489–99.

    PubMed  CrossRef  CAS  Google Scholar 

  128. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–80.

    PubMed  CrossRef  CAS  Google Scholar 

  129. Erbel R, Ge J, Bockisch A, 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. 1996;17:880–9.

    PubMed  CrossRef  CAS  Google Scholar 

  130. 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.

    PubMed  CrossRef  Google Scholar 

  131. Papanicolaou MN, Califf RM, Hlatky MA, et al. Prognostic implications of angiographycally normal and insignificantly narrowed coronary arteries. Am J Cardiol. 1986;58:1181–7.

    PubMed  CrossRef  CAS  Google Scholar 

  132. Lichtlen PR, Bargheer K, Wenzlaff P. Long-term prognosis of patients with anginalike chest pain and normal coronary angiographic findings. J Am Coll Cardiol. 1995;25:1013–8.

    PubMed  CrossRef  CAS  Google Scholar 

  133. Pitts WR, Lange RA, Cigarroa JE, Hillis LD. Repeat coronary angiography in patients with chest pain and previously normal coronary angiogram. Am J Cardiol. 1997;80:1086–7.

    PubMed  CrossRef  CAS  Google Scholar 

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

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  135. 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.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  136. Murthy VL, Naya M, Foster CR, et al. Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. Circulation. 2012;126:1858–68.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  137. Taqueti VR, Hachamovitch R, Murthy VL, 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. 2015;131:19–27.

    PubMed  CrossRef  Google Scholar 

  138. Pries AR, Badimon L, Bugiardini R, et al. Coronary vascular regulation, remodelling, and collateralization: mechanisms and clinical implications on behalf of the working group on coronary pathophysiology and microcirculation. Eur Heart J. 2015;36:3134–46.

    PubMed  CrossRef  CAS  Google Scholar 

  139. Roe MT, Harrington RA, Prosper DM, et al. Clinical and therapeutic profile of patients presenting with acute coronary syndromes who do not have significant coronary artery disease. The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators. Circulation. 2000;102:1101–6.

    PubMed  CrossRef  CAS  Google Scholar 

  140. Cenko E, Bugiardini R. Barriers to risk stratification accuracy in ischemic heart disease in women: the role of non-obstructive coronary artery disease. Curr Pharm Des. 2016;22:3928–34.

    PubMed  CrossRef  CAS  Google Scholar 

  141. Fihn SD, Gardin JM, Abrams J, et al.; American College of Cardiology Foundation/American Heart Association Task Force. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126:e354–471.

    Google Scholar 

  142. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. J Am Coll Cardiol. 2011;57:1404–23.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  143. Van Horn L, Carson JA, Appel LJ, et al.; American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Stroke Council. Recommended Dietary Pattern to Achieve Adherence to the American Heart Association/American College of Cardiology (AHA/ACC) Guidelines: a scientific statement from the American Heart Association. Circulation. 2016;134:e505–29.

    Google Scholar 

  144. Hung C, Daub B, Black B, Welsh R, Quinney A, Haykowsky M. Exercise training improves overall physical fitness and quality of life in older women with coronary artery disease. Chest. 2004;126:1026–31.

    PubMed  CrossRef  Google Scholar 

  145. Eriksson BE, Tyni-Lennè R, Svedenhag J, et al. Physical training in Syndrome X: physical training counteracts deconditioning and pain in Syndrome X. J Am Coll Cardiol. 2000;36:1619–25.

    PubMed  CrossRef  CAS  Google Scholar 

  146. Tyni-Lenne R, Stryjan S, Eriksson B, Berglund M, Sylven C. Beneficial therapeutic effects of physical training and relaxation therapy in women with coronary syndrome X. Physiother Res Int. 2002;7:35–43.

    PubMed  CrossRef  Google Scholar 

  147. Asbury EA, Kanji N, Ernst E, Barbir M, Collins P. Autogenic training to manage symptomology in women with chest pain and normal coronary arteries. Menopause. 2009;16:60–5.

    PubMed  CrossRef  Google Scholar 

  148. Manfrini O, Pizzi C, Morgagni G, Fontana F, Bugiardini R. Effect of pravastatin on myocardial perfusion after percutaneous transluminal coronary angioplasty. Am J Cardiol. 2004;93:1391–3. A6

    PubMed  CrossRef  CAS  Google Scholar 

  149. Kayikcioglu M, Payzin S, Yavuzgil O, Kultursay H, Can LH, Soydan I. Benefits of statin treatment in cardiac syndrome-X1. Eur Heart J. 2003;24:1999–2005.

    PubMed  CrossRef  CAS  Google Scholar 

  150. Houghton JL, Pearson TA, Reed RG, et al. Cholesterol lowering with pravastatin improves resistance artery endothelial function: report of six subjects with normal coronary arteriograms. Chest. 2000;118:756–60.

    PubMed  CrossRef  CAS  Google Scholar 

  151. Caliskan M, Erdogan D, Gullu H, et al. Effects of atorvastatin on coronary flow reserve in patients with slow coronary flow. Clin Cardiol. 2007;30:475–9.

    PubMed  CrossRef  PubMed Central  Google Scholar 

  152. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G, Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–53.

    PubMed  CrossRef  CAS  Google Scholar 

  153. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74:1141–8.

    PubMed  CrossRef  CAS  Google Scholar 

  154. 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.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  155. Shahin Y, Khan JA, Samuel N, Chetter I. Angiotensin converting enzyme inhibitors effect on endothelial dysfunction: a meta-analysis of randomised controlled trials. Atherosclerosis. 2011;216:7–16.

    PubMed  CrossRef  CAS  Google Scholar 

  156. Manfrini O, Morrell C, Das R, et al. Evaluation of Methods and Management of Acute Coronary Events Study Group. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  157. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  158. Masumoto A, Mohri M, Takeshita A. Three-year follow-up of the Japanese patients with microvascular angina attributable to coronary microvascular spasm. Int J Cardiol. 2001;81:151–6.

    PubMed  CrossRef  CAS  Google Scholar 

  159. Adamson DL, Webb CM, Collins P. Esterified estrogens combined with methyltestosterone improve emotional well-being in postmenopausal women with chest pain and normal coronary angiograms. Menopause. 2001;8:233–8.

    PubMed  CrossRef  CAS  Google Scholar 

  160. 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.

    PubMed  CrossRef  CAS  Google Scholar 

  161. Sutsch G, Oechslin E, Mayer I, Hess OM. Effect of diltiazem on coronary flow reserve in patients with microvascular angina. Int J Cardiol. 1995;52:135–43.

    PubMed  CrossRef  CAS  Google Scholar 

  162. Russo G, Di Franco A, Lamendola P, et al. Lack of effect of nitrates on exercise stress test results in patients with microvascular angina. Cardiovasc Drugs Ther. 2013;27:229–34.

    PubMed  CrossRef  CAS  Google Scholar 

  163. Elkayam U, Kulick D, McIntosh N, Roth A, Hsueh W, Rahimtoola SH. Incidence of early tolerance to hemodynamic effects of continuous infusion of nitroglycerin in patients with coronary artery disease and heart failure. Circulation. 1987;76:577–784.

    PubMed  CrossRef  CAS  Google Scholar 

  164. Münzel T, Daiber A, Mülsch A. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005;97:618–28.

    PubMed  CrossRef  CAS  Google Scholar 

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

    PubMed  CrossRef  CAS  Google Scholar 

  166. Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006;295:58–64.

    PubMed  CrossRef  CAS  Google Scholar 

  167. Denardo SJ, Wen X, Handberg EM, 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. 2011;34:483–7.

    PubMed  PubMed Central  CrossRef  Google Scholar 

  168. Hasenfuss G, Maier LS. Mechanism of action of the new anti-ischemia drug ranolazine. Clin Res Cardiol. 2008;97:222–6.

    PubMed  CrossRef  CAS  Google Scholar 

  169. Salazar CA, Basilio Flores JE, Veramendi Espinoza LE, Mejia Dolores JW, Rey Rodriguez DE, Loza Munárriz C. Ranolazine for stable angina pectoris. Cochrane Database Syst Rev. 2017;2:CD011747.

    PubMed  Google Scholar 

  170. 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.

    PubMed  CrossRef  PubMed Central  Google Scholar 

  171. Bairey Merz CN, Handberg EM, Shufelt CL, et al. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Eur Heart J. 2016;37:1504–13.

    PubMed  CrossRef  CAS  Google Scholar 

  172. Tagliamonte E, Rigo F, Cirillo T, et al. Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease. Echocardiography. 2015;32:516–21.

    PubMed  CrossRef  Google Scholar 

  173. Sulfi S, Timmis AD. Ivabradine—the first selective sinus node I(f) channel inhibitor in the treatment of stable angina. Int J Clin Pract. 2006;60:222–8.

    PubMed  CrossRef  CAS  Google Scholar 

  174. Mengesha HG, Weldearegawi B, Petrucka P, Bekele T, Otieno MG, Hailu A. Effect of ivabradine on cardiovascular outcomes in patients with stable angina: meta-analysis of randomized clinical trials. BMC Cardiovasc Disord. 2017;17:105.

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  175. Villano A, Di Franco A, Nerla R, et al. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am J Cardiol. 2013;112:8–13.

    PubMed  CrossRef  CAS  Google Scholar 

  176. Cannon RO III, Quyyumi AA, Schenke WH, et al. Abnormal cardiac sensitivity in patients with chest pain and normal coronary arteries. J Am Coll Cardiol. 1990;16:1359–66.

    PubMed  CrossRef  Google Scholar 

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

    PubMed  CrossRef  Google Scholar 

  178. Sanderson JE, Woo KS, Chung HK, Chan WW, Tse LK, White HD. The effect of transcutaneous electrical nerve stimulation on coronary and systemic haemodynamics in syndrome X. Coron Artery Dis. 1996;7:547–52.

    PubMed  CrossRef  CAS  Google Scholar 

  179. Lanza GA, Sestito A, Sgueglia GA, et al. Effect of spinal cord stimulation on spontaneous and stress-induced angina and ‘ischemia-like’ ST-segment depression in patients with cardiac syndrome X. Eur Heart J. 2005;26:983–9.

    PubMed  CrossRef  Google Scholar 

  180. Sestito A, Lanza GA, Le Pera D, et al. Spinal cord stimulation normalizes abnormal cortical pain processing in patients with cardiac syndrome X. Pain. 2008;139:82–9.

    PubMed  CrossRef  Google Scholar 

  181. Jessurun GA, Hautvast RW, Tio RA, DeJongste MJ. Electrical neuromodulation improves myocardial perfusion and ameliorates refractory angina pectoris in patients with syndrome X: fad or future? Eur J Pain. 2003;7:507–12.

    PubMed  CrossRef  CAS  Google Scholar 

  182. de Vries J, Dejongste MJ, Durenkamp A, Zijlstra F, Staal MJ. The sustained benefits of long-term neurostimulation in patients with refractory chest pain and normal coronary arteries. Eur J Pain. 2007;11:360–5.

    PubMed  CrossRef  Google Scholar 

  183. Kitsou V, Xanthos T, Roberts R, Karlis GM, Padadimitriou L. Enhanced external counterpulsation: mechanisms of action and clinical applications. Acta Cardiol. 2010;65:239–47.

    PubMed  CrossRef  Google Scholar 

  184. Kronhaus KD, Lawson WE. Enhanced external counterpulsation is an effective treatment for Syndrome X. Int J Cardiol. 2009;135:256–7.

    PubMed  CrossRef  Google Scholar 

  185. Luo C, Liu D, Wu G, et al. Effect of enhanced external counterpulsation on coronary slow flow and its relation with endothelial function and inflammation: a mid-term follow-up study. Cardiology. 2012;122:260–8.

    PubMed  CrossRef  Google Scholar 

  186. Oliver MF. Risks of correcting the risks of coronary disease and stroke with drugs. N Engl J Med. 1982;306:297–29.

    PubMed  CrossRef  CAS  Google Scholar 

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Cenko, E., Amaduzzi, P.L., Bugiardini, R. (2018). Microvascular Angina as a Cause of Ischemia: An Update. In: Mehta, J., McSweeney, J. (eds) Gender Differences in the Pathogenesis and Management of Heart Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-71135-5_9

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