Cardiac Syndrome X

Anginal syndrome with microvascular angina but normal coronary arteries.

The term cardiac syndrome X is most unsatisfactory as it implies uncertainty as to aetiology and perhaps an apocryphal status as a disease entity. It may also be confused with the similarly poorly named metabolic syndrome X.

Along with a better name, such as microvascular angina, firmer diagnostic criteria are desirable; first, to facilitate more meaningful research and. secondly, to permit evidence-based practice.¹ There is considerable evidence that what is labelled as cardiac syndrome X (CSX) is a very heterogenous group.² Suggested diagnostic criteria are:¹

• Typical stable angina exclusively or predominantly on exercise.
• Findings on investigation that are compatible with myocardial ischaemia or microvascular dysfunction:
  • This usually includes ST depression on exercise testing but other tests may also be required.
• Normal or near-normal coronary arteries on coronary angiography (<20% stenosis).
• No other specific disease such as variant angina, cardiomyopathy or valvular heart disease.

There is no evidence of coronary spasm. It is thought that the pathology lies in the microvasculature and this is not demonstrated on coronary angiography.³ There also appears to be endothelial dysfunction.⁴

Since the syndrome was first described in 1967, the incidence has been rising. This may represent a true rise in rate, a rise in the willingness of clinicians to make the diagnosis, or both. The literature comes from all over the world, suggesting that the disease has a universal distribution.

In contrast to coronary heart disease (CHD), it is rather more frequent in women than men and tends to affect patients around the age of 50.

Risk factors

Risk factors appear to have much in common with coronary artery disease (CAD):

• Hypercholesterolaemia
• Smoking
• Obesity
• Hypertension
• Insulin resistance or overt diabetes,¹ usually type 2
• Possibly low oestrogen levels, as it tends to occur around the menopause when oestrogen levels can be extremely low⁵
• Patients tend to be more unfit and out of condition than others of similar age and sex
• Low-grade chronic inflammation

Hypertension and diabetes used to be regarded as criteria that exclude permission to diagnose CSX, as they are known to be associated with endothelial dysfunction; however, as this would seem to be an underlying pathology, such a provision is illogical. Chronic inflammation is also associated with microvascular dysfunction in the absence of coronary atherosclerosis. The association between diabetes and CHD is very well known but what is less well appreciated is the similar association with rheumatoid arthritis.⁶

• Chest pain occurs on exertion but it may not be typical of CAD in its site and provoking factors.
• Symptoms are often severe and disabling.

As mentioned above, the history of angina should be typical and precipitated largely or wholly by exercise.

There are no characteristic clinical signs but the patient is more likely to be:

• Hypertensive
• Obese
• In poor physical condition

The whole spectrum of causes of chest pain must be considered; however, for special consideration are:

• Coronary heart disease
• Prinzmetal's angina
• Cardiomyopathy
• Chest pain with normal coronary arteries is not the same as cardiac syndrome X - the coronary microvasculature IS abnormal.

Investigations should be as for CHD:

• FBC in case of anaemia or polycythaemia.
• U&E, possibly before starting an ACE inhibitor.
• LFTs before starting a statin.
• Fasting lipids with a view to adjustment by diet or drugs.
• Fasting blood glucose, which may show impaired glucose tolerance or overt diabetes.
• Resting ECG as a baseline assessment.
• Exercise ECG, which may well show a positive result with ST depression on exercise.

A significant number of patients are too unfit to perform the Bruce protocol and so a thallium radionucleotide scan is required.

Coronary angiography shows normal arteries. In patients with positive exercise tests, coronary angiography shows obstruction in about 85% of men but only 70% of women.

Other tests that are employed will vary between departments. The term stress used here may mean exercise or a pharmacological stress. Techniques include:

• Reversible perfusion defect on stress myocardial scintillography
• Stress-induced reduction of blood flow on other tests including:
  • Cardiovascular magnetic resonance⁷
  • Positron emission tomography (PET)
  • Ultrasound
• Metabolic evidence of transient myocardial ischaemia, e.g:
  • PET
  • Magnetic resonance (MR) cardiography
  • Invasive procedures

Many of these are still largely research procedures.

The response to treatment is somewhat variable.¹

General measures

• Exercise regimes have a beneficial effect.^8,9
• Relaxation techniques including transcendental meditation reduce symptoms and improve exercise tolerance.¹⁰
• Weight loss reduces insulin resistance.
• Stop smoking if applicable.
• In patients refractory to other forms of treatment, transcutaneous electrical nerve stimulation (TENS) or spinal cord stimulation (SCS) may be of value.¹¹

Pharmacological

• Beta blockers are regarded as first-line.
• Where they are contra-indicated or a second-line drug is required, the non-dihydropyridine calcium channel blockers come next.
• Nitrates and nicorandil are also effective.
• ACE inhibitors improve exercise tolerance and possibly also reduce insulin resistance.¹² ACE inhibitors are beneficial for endothelial dysfunction, as demonstrated by their effect on microalbuminuria.
• Statins are used where cholesterol is elevated but they also stabilise the endothelial membrane.^5,13
• Aspirin may also be of value in reducing inflammation but the value of this is not well documented.¹⁴
• Oestrogen with methyl testosterone produced emotional benefit but no improvement in exercise parameters.¹⁵ HRT increases insulin resistance.¹⁶
• Imipramine may be beneficial in the management of pain.
• Even in women without diabetes, metformin may be beneficial but larger trials are required.¹⁷

Surgical

The pathology is in very small arteries that are too small for reconstruction.

• Statements about prognosis in this disease must be viewed with caution, as prognosis is dependent upon the criteria used for diagnosis.
• With the criteria used above, prognosis is remarkably good without the tendency to progress to myocardial infarction and death as in CHD, but there may be some groups with a higher inherent risk.¹⁸
• Patients suffering from angina-like chest pain, with normal coronary angiograms, have a good long-term prognosis which does not differ from the general population of the same age.
• Patients with positive stress tests will have less relief from their symptoms over many years than patients with negative stress tests.¹⁹
• The quality of life is not so encouraging as life expectancy. Symptoms will improve in about a third but in 10 to 20% they become worse. With such a low mortality but high morbidity, questions are invariably raised about the psychological component to this disease.
• There is some evidence to suggest an increased susceptibility to cardiac pain.¹

The aim of management is to improve the quality of life.

The BMA recommends that, for the purpose of the Qualities and Outcomes Framework, CSX should not be included in the CHD register.

Presumably, avoiding obesity and keeping physically active would protect against the condition.

1. Lanza GA; Cardiac syndrome X: a critical overview and future perspectives. Heart. 2007 Feb;93(2):159-66. Epub 2006 Jan 6. [abstract]
2. Kaski JC, Aldama G, Cosin-Sales J; Cardiac syndrome X. Diagnosis, pathogenesis and management. Am J Cardiovasc Drugs. 2004;4(3):179-94. [abstract]
3. Osamichi S, Kouji K, Yoshimaro I, et al; Myocardial glucose metabolism assessed by positron emission tomography and the histopathologic findings of microvessels in syndrome X. Circ J. 2004 Mar;68(3):220-6. [abstract]
4. Scudlova M, Skvarilova M, Bulava A; The importance of indicators of the initial phase of atherosclerosis in patients with microvascular angina. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2003 [abstract]
5. Kayikcioglu M, Payzin S, Yavuzgil O, et al; Benefits of statin treatment in cardiac syndrome-X1. Eur Heart J. 2003 Nov;24(22):1999-2005. [abstract]
6. Solomon DH, Goodson NJ, Katz JN, et al; Patterns of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis. 2006 Dec;65(12):1608-12. Epub 2006 Jun 22. [abstract]
7. Pennell DJ; Cardiovascular magnetic resonance: twenty-first century solutions in cardiology. Clin Med. 2003 May-Jun;3(3):273-8. [abstract]
8. Tyni-Lenne R, Stryjan S, Eriksson B, et al; Beneficial therapeutic effects of physical training and relaxation therapy in women with coronary syndrome X. Physiother Res Int. 2002;7(1):35-43. [abstract]
9. Eriksson BE, Tyni-Lenne R, Svedenhag J, et al; 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. [abstract]
10. Cunningham C, Brown S, Kaski JC; Effects of transcendental meditation on symptoms and electrocardiographic changes in patients with cardiac syndrome X. Am J Cardiol. 2000 Mar 1;85(5):653-5, A10. [abstract]
11. de Vries J, Dejongste MJ, Durenkamp A, et al; The sustained benefits of long-term neurostimulation in patients with refractory chest pain and normal coronary arteries. Eur J Pain. 2007 Apr;11(3):360-5. Epub 2006 Jun 9. [abstract]
12. 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 Nov 1;90(9):974-82. [abstract]
13. Fabian E, Varga A, Picano E, et al; Effect of simvastatin on endothelial function in cardiac syndrome X patients. Am J Cardiol. 2004 Sep 1;94(5):652-5. [abstract]
14. Li JJ, Li YS, Zhang Y, et al; Inflammation: a possible pathogenic link to cardiac syndrome X. Med Hypotheses. 2006;66(1):87-91. Epub 2005 Sep 21. [abstract]
15. 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 Jul-Aug;8(4):233-8. [abstract]
16. Assali AR, Jabara Z, Shafer Z, et al; Insulin resistance is increased by transdermal estrogen therapy in postmenopausal women with cardiac syndrome X. Cardiology. 2001;95(1):31-4. [abstract]
17. Jadhav S, Ferrell W, Greer IA, et al; 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. Epub 2006 Aug 17. [abstract]
18. Bugiardini R, Manfrini O, De Ferrari GM; Unanswered questions for management of acute coronary syndrome: risk stratification of patients with minimal disease or normal findings on coronary angiography. Arch Intern Med. 2006 Jul 10;166(13):1391-5. [abstract]
19. Scholz M, Wegener K, Unverdorben M, et al; Long-term outcome in patients with angina-like chest pain and normal coronary angiograms. Herz. 2003 Aug;28(5):413-20. [abstract]

• Cannon RO 3rd; Microvascular angina and the continuing dilemma of chest pain with normal coronary angiograms. J Am Coll Cardiol. 2009 Sep 1;54(10):877-85. [abstract]
• Seiden SW; Evaluating patients with persistent chest pain and no obstructive coronary artery disease. JAMA. 2009 Aug 12;302(6):622; author reply 623-4.