Cardiac Syndrome X

Cardiac Syndrome X

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Cardiac syndrome X (CSX) is typical anginalike chest pain with evidence of myocardial ischemia in the absence of flow-limiting stenosis on coronary angiography. [1] Cannon et al termed this entity, characterized by a decrease in coronary flow reserve without epicardial artery stenosis, microvascular angina. [2] Cardiac syndrome X is a heterogeneous entity, both clinically and pathophysiologically, involving various pathogenic mechanisms.

Many mechanisms have been proposed to result in cardiac syndrome X, including the following:

Endothelial dysfunction (microvascular angina)

Myocardial ischemia

Insulin resistance

Abnormal autonomic control

Altered cardiac sensitivity

Estrogen deficiency

Endothelial dysfunction in cardiac syndrome X appears to be multifactorial and linked to risk factors such as smoking, obesity, hypercholesterolemia, and inflammation. [3] Low levels of high-density lipoprotein cholesterol (HDL-C) appears to be associated with systemic inflammation in cardiac syndrome X [4] ; elevated plasma C-reactive protein levels, a marker of inflammation, have been shown to correlate with disease activity and endothelial dysfunction. [5]

Endothelial dysfunction, with reduced bioavailability of endogenous nitric oxide and increased plasma levels of endothelin-1 (ET-1), may explain, at least in part, the abnormal coronary microvasculature in cardiac syndrome X. [6, 7, 8]

Several studies support the presence of hyperinsulinemia in many patients with cardiac syndrome X. [9, 10, 11] Additionally, metformin has been shown to improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. [12]

Abnormalities of the autonomic nervous system characterized by adrenergic hyperactivity and baroreceptor dysfunction have been demonstrated by several investigators. [13, 14, 15, 16] In patients with cardiac syndrome X, Camici et al showed improvement of coronary flow reserve by α-adrenergic blockade with doxazosin. [17]

Multiple studies have suggested that abnormalities in pain perception are the principal abnormality in patients with chest pain and normal findings on coronary angiography. Altered central neural handling of afferent signals may contribute to the abnormal pain perception in these patients. [18]

Cardiac syndrome X frequently occurs in perimenopausal or postmenopausal women, supporting a pathogenic role for estrogen deficiency. [19] In postmenopausal women with cardiac syndrome X, estrogen replacement therapy improves coronary endothelial function, decreases anginal frequency, and improves exercise-induced angina. [20, 21, 22]

Approximately 20%-30% of patients undergoing coronary angiography for evaluation of anginalike chest pain may have nonobstructive coronary artery disease. [23, 24]

Cardiac syndrome X is more common in women than in men. [25]

Cardiac syndrome X frequently occurs in perimenopausal and postmenopausal women.

Patients with angina and normal coronary arteries at angiography, fulfilling the diagnostic criteria of cardiac syndrome X, have an excellent prognosis. [26, 27, 28, 29, 30] However, an increased coronary atherosclerotic burden at 10-year follow-up was specifically observed in a group of women with cardiac syndrome X who also displayed coronary endothelial dysfunction. [31] The Women’s Ischemic Syndrome Evaluation study, the largest and most thoroughly investigated cohort of middle-aged women with cardiac syndrome X, showed that these patients often have atherosclerosis on intravascular coronary ultrasound and face a 2.5% annual rate adverse cardiac events. [32]

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Cannon RO, Epstein SE. «Microvascular angina» as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol. 1988. 62:1338–43.

Kaski JC. Cardiac syndrome X and microvascular angina. Kaski JC, ed. Chest Pain With Normal Coronary Angiograms: Pathogenesis, Diagnosis and Management. London, UK: Kluwer Academic Publishers; 1999. 1–12.

Tenekecioglu E, Yilmaz M, Demir S, et al. Lower hdl-cholesterol is associated with systemic inflammation in cardiac syndrome x. Minerva Med. 2014 Jul 16. [Medline].

Cosín-Sales J, Pizzi C, Brown S, Kaski JC. C-reactive protein, clinical presentation, and ischemic activity in patients with chest pain and normal coronary angiograms. J Am Coll Cardiol. 2003 May 7. 41(9):1468-74. [Medline].

Zeiher AM, Krause T, Schachinger V, Minners J, Moser E. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation. 1995 May 1. 91(9):2345-52. [Medline].

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 Jun 10. 328(23):1659-64. [Medline].

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Dean JD, Jones CJ, Hutchison SJ, Peters JR, Henderson AH. Hyperinsulinaemia and microvascular angina (“syndrome X”). Lancet. 1991 Feb 23. 337(8739):456-7. [Medline].

Botker HE, Moller N, Ovesen P, Mengel A, Schmitz O, Orskov H. Insulin resistance in microvascular angina (syndrome X). Lancet. 1993 Jul 17. 342(8864):136-40. [Medline].

Botker HE, Frobert O, Moller N, Christiansen E, Schmitz O, Bagger JP. Insulin resistance in cardiac syndrome X and variant angina: influence of physical capacity and circulating lipids. Am Heart J. 1997 Aug. 134(2 Pt 1):229-37. [Medline].

Jadhav S, Ferrell W, Greer IA, Petrie JR, Cobbe SM, Sattar N. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 2006 Sep 5. 48(5):956-63. [Medline].

Rosano GM, Ponikowski P, Adamopoulos S, Collins P, Poole-Wilson PA, Coats AJ. Abnormal autonomic control of the cardiovascular system in syndrome X. Am J Cardiol. 1994 Jun 15. 73(16):1174-9. [Medline].

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Montorsi P, Fabbiocchi F, Loaldi A, Annoni L, Polese A, De Cesare N. Coronary adrenergic hyperreactivity in patients with syndrome X and abnormal electrocardiogram at rest. Am J Cardiol. 1991 Dec 15. 68(17):1698-703. [Medline].

Adamopoulos S, Rosano GM, Ponikowski P, Cerquetani E, Piepoli M, Panagiota F. Impaired baroreflex sensitivity and sympathovagal balance in syndrome X. Am J Cardiol. 1998 Oct 1. 82(7):862-8. [Medline].

Camici PG, Marraccini P, Gistri R, Salvadori PA, Sorace O, L’Abbate A. Adrenergically mediated coronary vasoconstriction in patients with syndrome X. Cardiovasc Drugs Ther. 1994 Apr. 8(2):221-6. [Medline].

Rosen SD, Paulesu E, Wise RJ, Camici PG. Central neural contribution to the perception of chest pain in cardiac syndrome X. Heart. 2002 Jun. 87(6):513-9. [Medline].

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 May. 16(5):610-4. [Medline].

Roque M, Heras M, Roig E, Masotti M, Rigol M, Betriu A. Short-term effects of transdermal estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pectoris and normal results on coronary angiograms. J Am Coll Cardiol. 1998 Jan. 31(1):139-43. [Medline].

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 Apr 19. 54(1):13-20. [Medline].

Rosano GM, Peters NS, Lefroy D, Lindsay DC, Sarrel PM, Collins P. 17-beta-Estradiol therapy lessens angina in postmenopausal women with syndrome X. J Am Coll Cardiol. 1996 Nov 15. 28(6):1500-5. [Medline].

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 Apr. 25(5):1013-8. [Medline].

Kemp HG, Kronmal RA, Vlietstra RE, Frye RL. Seven year survival of patients with normal or near normal coronary arteriograms: a CASS registry study. J Am Coll Cardiol. 1986 Mar. 7(3):479-83. [Medline].

Kaski JC. Overview of gender aspects of cardiac syndrome X. Cardiovasc Res. 2002 Feb 15. 53(3):620-6. [Medline].

Chauhan A, Mullins PA, Thuraisingham SI, Petch MC, Schofield PM. Clinical presentation and functional prognosis in syndrome X. Br Heart J. 1993 Oct. 70(4):346-51. [Medline].

Romeo F, Rosano GM, Martuscelli E, Lombardo L, Valente A. Long-term follow-up of patients initially diagnosed with syndrome X. Am J Cardiol. 1993 Mar 15. 71(8):669-73. [Medline].

Radice M, Giudici V, Marinelli G. Long-term follow-up in patients with positive exercise test and angiographically normal coronary arteries (syndrome X). Am J Cardiol. 1995 Mar 15. 75(8):620-1. [Medline].

Kaski JC, Rosano GM, 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 Mar 15. 25(4):807-14. [Medline].

Lamendola P, Lanza GA, Spinelli A, Sgueglia GA, Di Monaco A, Barone L. Long-term prognosis of patients with cardiac syndrome X. Int J Cardiol. 2010 Apr 15. 140(2):197-9. [Medline].

Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation. 2004 Jun 1. 109(21):2518-23. [Medline].

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Kaski JC, Rosano GM, 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 Mar 15. 25(4):807-14. [Medline].

Mukerji B, Mukerji V, Alpert MA, Selukar R. The prevalence of rheumatologic disorders in patients with chest pain and angiographically normal coronary arteries. Angiology. 1995 May. 46(5):425-30. [Medline].

Jadhav S, Ferrell W, Greer IA, Petrie JR, Cobbe SM, Sattar N. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 2006 Sep 5. 48(5):956-63. [Medline].

Potts SG, Lewin R, Fox KA, Johnstone EC. Group psychological treatment for chest pain with normal coronary arteries. QJM. 1999 Feb. 92(2):81-6. [Medline].

Mayou RA, Bryant BM, Sanders D, Bass C, Klimes I, Forfar C. A controlled trial of cognitive behavioural therapy for non-cardiac chest pain. Psychol Med. 1997 Sep. 27(5):1021-31. [Medline].

Eriksson BE, Tyni-Lenne R, Svedenhag J, Hallin R, Jensen-Urstad K, Jensen-Urstad M. Physical training in Syndrome X: physical training counteracts deconditioning and pain in Syndrome X. J Am Coll Cardiol. 2000 Nov 1. 36(5):1619-25. [Medline].

Manchanda A, Soran O. Enhanced external counterpulsation and future directions: step beyond medical management for patients with angina and heart failure. J Am Coll Cardiol. 2007 Oct 16. 50(16):1523-31. [Medline].

Bonetti PO, Gadasalli SN, Lerman A, Barsness GW. Successful treatment of symptomatic coronary endothelial dysfunction with enhanced external counterpulsation. Mayo Clin Proc. 2004 May. 79(5):690-2. [Medline].

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 Oct 1. 84(7):854-6, A8. [Medline].

Bugiardini R, Borghi A, Biagetti L, Puddu P. Comparison of verapamil versus propranolol therapy in syndrome X. Am J Cardiol. 1989 Feb 1. 63(5):286-90. [Medline].

Fragasso G, Chierchia SL, Pizzetti G, Rossetti E, Carlino M, Gerosa S. Impaired left ventricular filling dynamics in patients with angina and angiographically normal coronary arteries: effect of beta adrenergic blockade. Heart. 1997 Jan. 77(1):32-9. [Medline].

Ozçelik F, Altun A, Ozbay G. Antianginal and anti-ischemic effects of nisoldipine and ramipril in patients with syndrome X. Clin Cardiol. 1999 May. 22(5):361-5. [Medline].

Morimoto S, Maki K, Aota Y, Sakuma T, Iwasaka T. Beneficial effects of combination therapy with angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor on vascular endothelial function. Hypertens Res. 2008 Aug. 31(8):1603-10. [Medline].

Kayikcio M, Payzih S, Yavuzgil O, Kultursay H, Can L, Soydan I. Benefits of statin treatment in cardiac syndrome X. Eur Heart J 2003;24:1999–2005. Coll Cardiol. 2007. 50:1523–31.

Rodriguez C, Alcudia JF, Martinez-Gonzalez J, Guadall A, Raposo B, Sanchez-Gomez S. Statins normalize vascular lysyl oxidase down-regulation induced by proatherogenic risk factors. Cardiovasc Res. 2009 Aug 1. 83(3):595-603. [Medline].

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Rosano GM, Peters NS, Lefroy D, Lindsay DC, Sarrel PM, Collins P. 17-beta-Estradiol therapy lessens angina in postmenopausal women with syndrome X. J Am Coll Cardiol. 1996 Nov 15. 28(6):1500-5. [Medline].

Roqué M, Heras M, Roig E, Masotti M, Rigol M, Betriu A. Short-term effects of transdermal estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pectoris and normal results on coronary angiograms. J Am Coll Cardiol. 1998 Jan. 31(1):139-43. [Medline].

Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17. 288(3):321-33. [Medline].

Subodh Raja Devabhaktuni, MD Resident Physician, Department of Internal Medicine, University of Nevada School of Medicine

Disclosure: Nothing to disclose.

Nirmal Sunkara, MD Chief Resident, Department of Internal Medicine, University of Nevada School of Medicine

Nirmal Sunkara, MD is a member of the following medical societies: American College of Physicians, American Medical Association

Disclosure: Nothing to disclose.

Kartika Shetty, MD, FACP Chief Hospitalist, Sound Physicians

Kartika Shetty, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, Association of Program Directors in Internal Medicine, Medical Council of India

Disclosure: Nothing to disclose.

Kasaiah Makam, MD Resident Physician, Department of Internal Medicine, University of Nevada School of Medicine

Kasaiah Makam, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Chowdhury H Ahsan, MD, PhD, MRCP, FSCAI Clinical Professor of Medicine, Director of Cardiac Catheterization and Intervention, Marlon Cardiac Catheterization Laboratory, Director of Cardiovascular Research, University Medical Center, University of Nevada School of Medicine

Chowdhury H Ahsan, MD, PhD, MRCP, FSCAI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, Society for Cardiovascular Angiography and Interventions, American Stroke Association

Disclosure: Received consulting fee from sanofi for consulting; Received honoraria from astra zeneca for speaking and teaching; Received honoraria from BI for speaking and teaching.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Richard A Lange, MD, MBA President, Texas Tech University Health Sciences Center, Dean, Paul L Foster School of Medicine

Richard A Lange, MD, MBA is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American Heart Association, Association of Subspecialty Professors

Disclosure: Nothing to disclose.

Cardiac Syndrome X

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