Cardiac Syndrome X

Updated: Dec 24, 2020
  • Author: Subodh R Devabhaktuni, MD; Chief Editor: Richard A Lange, MD, MBA  more...
  • Print


Cardiac syndrome X (CSX) is broadly defined as typical angina-like chest pain with evidence of myocardial ischemia in the absence of flow-limiting stenosis on coronary angiography. [1] [ref60} Cannon et al termed this entity, characterized by a decrease in coronary flow reserve without epicardial artery stenosis, microvascular angina (MVA). [2]

Cardiac syndrome X has been largely replaced by MVA, and it is diagnosed when the pathogenesis is unkown (ie, without epicardial artery stenosis  or abnormal flow reserve). Cardiac syndrome X is a heterogeneous entity, both clinically and pathophysiologically, involving various pathogenic mechanisms. This condition is also known as angina with normal coronary arteries. [3]

Kanar and Sunbul have proposed the following definition of cardiac syndrome X [4] :

  • Typical stable angina, exclusively or predominantly induced by effort
  • Findings on workup compatible with myocardial ischemia/coronary microvascular dysfunction
  • Angiography findings of normal or near normal coronary arteries
  • No other specific cardiac disease is present (eg, variant angina, cardiomyopathy, valvular disease)




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

  • Endothelial dysfunction (MVA) - This is the prevailing theory at present

  • Myocardial ischemia

  • Abnormal autonomic control

  • Altered cardiac sensitivity

  • Estrogen deficiency

Endothelial dysfunction

Endothelial dysfunction in cardiac syndrome X appears to be multifactorial and linked to risk factors such as smoking, obesity, hypercholesterolemia, and inflammation. [5] Low levels of high-density lipoprotein cholesterol (HDL-C) appears to be associated with systemic inflammation in cardiac syndrome X [6] ; elevated plasma C-reactive protein levels, a marker of inflammation, have been shown to correlate with disease activity and endothelial dysfunction. [7]

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. [8, 9, 10]

Insulin resistance

Several studies support the presence of hyperinsulinemia in many patients with cardiac syndrome X. [11, 12, 13] Additionally, metformin has been shown to improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. [14]

Abnormal autonomic control

Abnormalities of the autonomic nervous system characterized by adrenergic hyperactivity and baroreceptor dysfunction have been demonstrated by several investigators. [15, 16, 17, 18] In patients with cardiac syndrome X, Camici et al showed improvement of coronary flow reserve by α-adrenergic blockade with doxazosin. [19]

Altered cardiac sensitivity

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. [20]

Estrogen deficiency

Cardiac syndrome X frequently occurs in perimenopausal or postmenopausal women, supporting a pathogenic role for estrogen deficiency. [21] In postmenopausal women with cardiac syndrome X, estrogen replacement therapy improves coronary endothelial function, decreases anginal frequency, and improves exercise-induced angina. [22, 23, 24]



Approximately 20%-30% of patients undergoing coronary angiography for evaluation of angina-like chest pain may have nonobstructive coronary artery disease. [25, 26]

Cardiac syndrome X (CSX) is more common in women than in men. [27, 28, 29]

Cardiac syndrome X frequently occurs in perimenopausal and postmenopausal women. [30]



Patients with angina and normal coronary arteries at angiography, fulfilling the diagnostic criteria of cardiac syndrome X (CSX), have an excellent prognosis based on the past evidence. [31, 32, 33, 34, 35] However, more recent studies showed 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. [29, 36]

The Women’s Ischemic Syndrome Evaluation study (WISE study), the largest and most thoroughly investigated cohort of middle-aged women with cardiac syndrome X, showed that 5-year annualized event rates for cardiovascular events were 16.0% in women with nonobstructive coronary artery disease (CAD) (stenosis in any coronary artery of 1%-49%) and 7.9% in women with normal coronary arteries (stenosis of 0% in all coronary arteries). [37]