American Journal of Cardiovascular Drugs

, Volume 14, Issue 1, pp 31–40 | Cite as

Management of Microvascular Angina Pectoris

  • Gaetano A. Lanza
  • Rossella Parrinello
  • Stefano Figliozzi
Therapy in Practice

Abstract

Microvascular angina (MVA) is defined as angina pectoris caused by abnormalities of small coronary arteries. In its most typical presentation, MVA is characterized by angina attacks mainly caused by effort, evidence of myocardial ischemia on non-invasive stress tests, but normal coronary arteries at angiography. Patients with stable MVA have excellent long-term prognoses, but often present with persistent and/or worsening of angina symptoms. Treatment of MVA is initially based on standard anti-ischemic drugs (beta-blockers, calcium antagonists, and nitrates), but control of symptoms is often insufficient. In these cases, several additional drugs, with different potential anti-ischemic effects, have been proposed, including ranolazine, ivabradine, angiotensin-converting enzyme (ACE) inhibitors, xanthine derivatives, nicorandil, statins, alpha-blockers and, in perimenopausal women, estrogens. In patients with ‘refractory MVA’, some further alternative therapies (e.g., spinal cord stimulation, pain-inhibiting substances such as imipramine, rehabilitation programs) have shown favorable results.

References

  1. 1.
    Lanza GA, Crea F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation. 2010;121:2317–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356:830–40.PubMedCrossRefGoogle Scholar
  3. 3.
    Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med. 2010;363:498.Google Scholar
  4. 4.
    Di Franco A, Milo M, Laurito M, Nerla R, Lanza GA. Comparisons of clinical and angina characteristics between patients with cardiac syndrome X and patients with coronary artery disease. It J Practice Cardiol. 2012;1:15––21. (http://www.ancecardio.it).Google Scholar
  5. 5.
    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.PubMedCrossRefGoogle Scholar
  6. 6.
    Picano E, Lattanzi F, Masini M, Distante A, L’Abbate A. Usefulness of a high-dose dipyridamole-echocardiography test for diagnosis of syndrome X. Am J Cardiol. 1987;60:508–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coll Cardiol. 1991;17:499–506.PubMedCrossRefGoogle Scholar
  8. 8.
    Lanza GA, Camici PG, Galiuto L, et al. Methods to investigate coronary microvascular function in clinical practice. J Cardiovasc Med (Hagerstown). 2013;14:1–18.CrossRefGoogle Scholar
  9. 9.
    Taylor AJ, Cerqueira M, Hodgson JM, et al. ACCF/SCCT/ACR/AHA/ ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography. J Cardiovasc Comput Tomogr. 2010;4:407.e1–33.Google Scholar
  10. 10.
    Opherk D, Zebe H, Weihe E, et al. Reduced coronary dilatory capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms. Circulation. 1981;63:817–25.PubMedCrossRefGoogle Scholar
  11. 11.
    Chauhan A, Mullins PA, Taylor G, Petch MC, Schofield PM. Both endothelium-dependent and endothelium-independent function is impaired in patients with angina pectoris and normal coronary angiograms. Eur Heart J. 1997;18:60–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Sestito A, Lanza GA, Di Monaco A, et al. Relation between cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X. J Cardiovasc Med (Hagerstown). 2011;12:322–7.CrossRefGoogle Scholar
  13. 13.
    Egashira K, Inou T, Hirooka Y, Yamada A, Urabe Y, Takeshita A. Evidence of impaired endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary angiograms. N Engl J Med. 1993;328:1659–64.PubMedCrossRefGoogle Scholar
  14. 14.
    Motz W, Vogt M, Rabenau O, Scheler S, Lückhoff A, Strauer BE. Evidence of endothelial dysfunction in coronary resistance vessels in patients with angina pectoris and normal coronary angiograms. Am J Cardiol. 1991;68:996–1003.PubMedCrossRefGoogle Scholar
  15. 15.
    Chauhan A, Mullins PA, Taylor G, Petch MC, Schofield PM. Effect of hyperventilation and mental stress on coronary blood flow in syndrome X. Br Heart J. 1993;69:516–24.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Ong P, Athanasiadis A, Mahrholdt H, Borgulya G, Sechtem U, Kaski JC. Increased coronary vasoconstrictor response to acetylcholine in women with chest pain and normal coronary arteriograms (cardiac syndrome X). Clin Res Cardiol Clin Res Cardiol. 2012;101:673–81.CrossRefGoogle Scholar
  17. 17.
    Lanza GA, Lüscher TF, Pasceri V, et al. Effects of atrial pacing on arterial and coronary sinus endothelin-1 levels in syndrome X. Source Am J Cardiol. 1999;84:1187–91.CrossRefGoogle Scholar
  18. 18.
    Lanza GA, Giordano A, Pristipino C, et al. Abnormal cardiac adrenergic nerve function in patients with syndrome X detected by [123I]metaiodobenzylguanidine myocardial scintigraphy. Circulation. 1997;96:821–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Dean JD, Jones CJ, Hutchison SJ, Peters JR, Henderson AH. Hyperinsulinaemia and microvascular angina (“syndrome X”). Lancet. 1991;337:456–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Lanza GA, Sestito A, Cammarota G, et al. Assessment of systemic inflammation and infective pathogen burden in patients with cardiac syndrome X. Am J Cardiol. 2004;94:40–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Rosano GM, Collins P, Kaski JC, Lindsay DC, Sarrel PM, Poole-Wilson PA. Syndrome X in women is associated with oestrogen deficiency. Eur Heart J. 1995;16:610–4.PubMedGoogle Scholar
  22. 22.
    Cannon RO 3rd, 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.PubMedCrossRefGoogle Scholar
  23. 23.
    Pasceri V, Lanza GA, Buffon A, Montenero AS, Crea F, Maseri A. Role of abnormal pain sensitivity and behavioral factors in determining chest pain in syndrome X. J Am Coll Cardiol. 1998;31:62–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Kaski JC, Rosano GMC, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventricular function: long-term follow-up study. J Am Coll Cardiol. 1995;25:807–14.PubMedCrossRefGoogle Scholar
  25. 25.
    Lamendola P, Lanza GA, Spinelli A, et al. Long-term prognosis of patients with cardiac syndrome X. Int J Cardiol. 2010;15(140):197–9.CrossRefGoogle Scholar
  26. 26.
    Al 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.Google Scholar
  27. 27.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Fragasso G, Chierchia SL, Pizzetti G, et al. Impaired left ventricular filling dynamics in patients with angina and angiographically normal coronary arteries: effect of beta adrenergic blockade. Heart. 1997;77:32–9.PubMedGoogle Scholar
  29. 29.
    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.PubMedCrossRefGoogle Scholar
  30. 30.
    Leonardo F, Fragasso G, Rossetti E, et al. Comparison of trimetazidine with atenolol in patients with syndrome X: effects on diastolic function and exercise tolerance. Cardiologia. 1999;44:1065–9.PubMedGoogle Scholar
  31. 31.
    Romeo F, Gaspardone A, Ciavolella M, Gioffrè P, Reale A. Verapamil versus acebutolol for syndrome X. Am J Cardiol. 1988;62:312–3.PubMedCrossRefGoogle Scholar
  32. 32.
    Ferrini D, Bugiardini R, Galvani M, et al. Opposing effects of propranolol and diltiazem on the angina threshold during an exercise test in patients with syndrome X. G Italian Cardiol. 1986;16:224–31.Google Scholar
  33. 33.
    Lindqvist M, Kahan T, Melcher A, Ekholm M, Hjemdahl P. Long-term calcium antagonist treatment of human hypertension with mibefradil or amlodipine increases sympathetic nerve activity. J Hypertens. 2007;25:169–75.PubMedCrossRefGoogle Scholar
  34. 34.
    Cannon RO, Watson RM, Rosing DR, Epstein SE. Efficacy of calcium channel blocker therapy for angina pectoris resulting from small-vessel coronary artery disease and abnormal vasodilator reserve. Am J Cardiol. 1985;56:242–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Ozçelik F, Altun A, Ozbay G. Antianginal and anti-ischemic effects of nisoldipine and ramipril in patients with syndrome X. Clin Cardiol. 1999;22:361–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Li L, Gu Y, Liu T, et al. A randomized, single-center double-blinded trial on the effects of diltiazem sustained-release capsules in patients with coronary slow flow phenomenon at 6-month follow-up. PLoS One. 2012;7:e38851.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Montorsi P, Cozzi S, Loaldi A, et al. Acute coronary vasomotor effects of nifedipine and therapeutic correlates in syndrome X. Am J Cardiol. 1990;66:302–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Bugiardini R, Borghi A, Biagetti L, Puddu P. Comparison of verapamil versus propranolol therapy in syndrome X. Am J Cardiol. 1989;63:286–90.PubMedCrossRefGoogle Scholar
  39. 39.
    Sütsch 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.PubMedCrossRefGoogle Scholar
  40. 40.
    Harrison DG, Bates JN. The nitrovasodilators: new ideas about old drugs. Circulation. 1993;87:1461–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Lamendola P, Nerla R, Pitocco D, et al. Effect of ranolazine on arterial endothelial function in patients with type 2 diabetes mellitus. Atherosclerosis. 2013;226:157–60.PubMedCrossRefGoogle Scholar
  42. 42.
    Keating GM. Ranolazine: a review of its use in chronic stable angina pectoris. Drugs. 2008;68:2483–503.PubMedCrossRefGoogle Scholar
  43. 43.
    Villano A, Di Franco A, Nerla R, et al. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am J Cardiol. 2013;1(112):8–13.CrossRefGoogle Scholar
  44. 44.
    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.PubMedCrossRefGoogle Scholar
  45. 45.
    Borer JS, Fox K, Jaillon P, Lerebours G, for the Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina. A randomized, double blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817–23.Google Scholar
  46. 46.
    Minamino T, Kitakaze M, Morioka T, et al. Bidirectional effects of aminophylline on myocardial ischemia. Circulation. 1995;92:1254–60.PubMedCrossRefGoogle Scholar
  47. 47.
    Crea F, Pupita G, Galassi AR, et al. Role of adenosine in pathogenesis of anginal pain. Circulation. 1990;81:164–72.PubMedCrossRefGoogle Scholar
  48. 48.
    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. 1989;14:1450–3.PubMedCrossRefGoogle Scholar
  49. 49.
    Lanza GA, Gaspardone A, Pasceri V, et al. Effects of bamiphylline on exercise testing in patients with syndrome X. G Italian Cardiol. 1997;27:50–4.Google Scholar
  50. 50.
    Radice M, Giudici V, Pusineri E, et al. Different effects of acute administration of aminophylline and nitroglycerin on exercise capacity in patients with syndrome X. Am J Cardiol. 1996;78:88–90.PubMedCrossRefGoogle Scholar
  51. 51.
    Yoshio H, Shimizu M, Kita Y, et al. Effects of short-term aminophylline administration on cardiac functional reserve in patients with syndrome X. J Am Coll Cardiol. 1995;25:147–51.CrossRefGoogle Scholar
  52. 52.
    Elliott PM, Krzyzowska-Dickinson K, Calvino R, Hann C, Kaski JC. Effect of oral aminophylline in patients with angina and normal coronary arteriograms (syndrome X). Heart. 1997;77:523–6.PubMedGoogle Scholar
  53. 53.
    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.PubMedCrossRefGoogle Scholar
  54. 54.
    Pauly DF, Johnson BD, Anderson RD. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Kaski JC, Rosano G, Gavrielides S, Chen L. Effects of angiotensin-converting enzyme inhibition on exercise-induced angina and ST segment depression in patients with microvascular angina. J Am Coll Cardiol. 1994;23:652–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Nalbantgil I, Onder R, Altintig A, et al. Therapeutic benefits of cilazapril in patients with syndrome X. Cardiology. 1998;89:130–3.PubMedCrossRefGoogle Scholar
  57. 57.
    Chen JW, Hsu NW, Wu TC, et al. 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. 2002;90:974–82.PubMedCrossRefGoogle Scholar
  58. 58.
    Camici P, Marracini P, Gistri R, et al. Adrenergically mediated coronary vasoconstriction in patients with syndrome X. Cardiovasc Drugs Ther. 1994;8:221–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Rosen SD, Lorenzoni R, Kaski JC, Foale RA, Camici PG. Effect of alpha1-adrenoceptor blockade on coronary vasodilator reserve in cardiac syndrome X. J Cardiovasc Pharmacol. 1999;34:554–60.PubMedCrossRefGoogle Scholar
  60. 60.
    Galassi AR, Kaski JC, Pupita G, Vejar M, Crea F, Maseri A. Lack of evidence for alpha-adrenergic receptor-mediated mechanisms in the genesis of ischemia in syndrome X. Am J Cardiol. 1989;64:264–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Chen JW, Lee WL, Hsu NW, 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. 1997;80:32–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Yamabe H, Namura H, Yano T, et al. Effect of nicorandil on abnormal coronary flow reserve assessed by exercise 201Tl scintigraphy in patients with angina pectoris and nearly normal coronary arteriograms. Cardiovasc Drugs Ther. 1995;9:755–61.PubMedCrossRefGoogle Scholar
  63. 63.
    Nalbantgil S, Altinti A, Yilmaz H, Nalbantgil II, Önder R. The effect of trimetazidine in the treatment of microvascular angina. Int J Angiol. 1999;8:40–3.PubMedCrossRefGoogle Scholar
  64. 64.
    Fábián E, Varga A, Picano E, Vajo Z, Rónaszéki A, Csanády M. Effect of simvastatin on endothelial function in cardiac syndrome X patients. Am J Cardiol. 2004;94:652–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Kayikcioglu M, Payzin S, Yavuzgil O, Kultursay H, Can LH, Soydan I. Benefits of statin treatment in cardiac syndrome-X. Eur Heart J. 2003;24:1999–2005.PubMedCrossRefGoogle Scholar
  66. 66.
    Collins P. Role of endothelial dysfunction and oestrogens in syndrome X. Coron Artery Dis. 1992;3:593–8.CrossRefGoogle Scholar
  67. 67.
    Rosano GMC, Peters NS, Lefroy D, et al. Symptomatic response to 17b-estradiol in women with syndrome X. J Am Coll Cardiol. 1996;28:1500–5.PubMedCrossRefGoogle Scholar
  68. 68.
    Albertsson PA, 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. 1996;54:13–20.PubMedCrossRefGoogle Scholar
  69. 69.
    Jhund PS, Dawson N, Davie AP, et al. Attenuation of endothelin-1 induced vasoconstriction by 17beta estradiol is not sustained during long-term therapy in postmenopausal women with coronary heart disease. J Am Coll Cardiol. 2001;37:1367–73.PubMedCrossRefGoogle Scholar
  70. 70.
    Anderson GL, Limacher M, Assaf AR, et al. Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701–12.PubMedCrossRefGoogle Scholar
  71. 71.
    Cannon RO 3rd, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med. 1994;330:1411–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Cox ID, Hann CM, Kaski JC. Low dose imipramine improves chest pain but not quality of life in patients with angina and normal coronary angiograms. Eur Heart J. 1998;19:250–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Norrsell H, Eliasson T, Mannheimer C, et al. Effects of pacing-induced myocardial stress and spinal cord stimulation on whole body and cardiac norepinephrine spillover. Eur Heart J. 1997;18:1890–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Eliasson T, Albertsson P, Hårdhammar P, Emanuelsson H, Augustinsson LE, Mannheimer C. Spinal cord stimulation in angina pectoris with normal coronary arteriograms. Coron Artery Dis. 1993;4:819–27.PubMedCrossRefGoogle Scholar
  75. 75.
    Lanza GA, Sestito A, Sandric S, et al. Spinal cord stimulation in patients with refractory anginal pain and normal coronary arteries. Italian Heart J. 2001;2:25–30.Google Scholar
  76. 76.
    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.PubMedCrossRefGoogle Scholar
  77. 77.
    Sgueglia GA, Sestito A, Spinelli A, et al. Long-term follow-up of patients with cardiac syndrome X treated by spinal cord stimulation. Heart. 2007;93:591–7.PubMedCrossRefGoogle Scholar
  78. 78.
    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.PubMedCrossRefGoogle Scholar
  79. 79.
    Kronhaus KD, Lawson WE. Enhanced external counterpulsation is an effective treatment for Syndrome X. Int J Cardiol. 2009;135:256–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Lanza GA. Alternative treatments for angina. Heart. 2007;93:544–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Asbury EA, Slattery C, Grant A, Evans L, Barbir M, Collins P. Cardiac rehabilitation for the treatment of women with chest pain and normal coronary arteries. Menopause. 2008;15:454–60.PubMedCrossRefGoogle Scholar
  82. 82.
    Bass C, Wade C. Chest pain with normal coronary arteries: a comparative study of psychiatric and social morbidity. Psychol Med. 1984;14:51–61.PubMedCrossRefGoogle Scholar
  83. 83.
    Potts SG, Lewin R, Fox KAA, Johnstone EC, Cay EL. Group psychological treatment for chest pain with normal coronary arteries: a controlled trial. QJM. 1999;92:81–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Gaetano A. Lanza
    • 1
  • Rossella Parrinello
    • 1
  • Stefano Figliozzi
    • 1
  1. 1.Department of Cardiovascular Sciences Istituto di CardiologiaUniversità Cattolica del Sacro CuoreRomeItaly

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