Cardiac Syndrome X


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

  • 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. [3Low 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. [678]

Insulin resistance

Several studies support the presence of hyperinsulinemia in many patients with cardiac syndrome X. [91011Additionally, metformin has been shown to improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. [12]

Abnormal autonomic control

Abnormalities of the autonomic nervous system characterized by adrenergic hyperactivity and baroreceptor dysfunction have been demonstrated by several investigators. [13141516In patients with cardiac syndrome X, Camici et al showed improvement of coronary flow reserve by α-adrenergic blockade with doxazosin. [17]

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. [18]

Estrogen deficiency

Cardiac syndrome X frequently occurs in perimenopausal or postmenopausal women, supporting a pathogenic role for estrogen deficiency. [19In postmenopausal women with cardiac syndrome X, estrogen replacement therapy improves coronary endothelial function, decreases anginal frequency, and improves exercise-induced angina. [202122]


Approximately 20%-30% of patients undergoing coronary angiography for evaluation of anginalike chest pain may have nonobstructive coronary artery disease. [2324]

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. [2627282930However, 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. [31The 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.

Clinical Presentation


Individuals with cardiac syndrome X (CSX) are typically younger than those with angina due to obstructive coronary artery disease. [33]

Approximately half of patients with cardiac syndrome X have anginalike chest pain, while the remainder have atypical chest pain. The duration of anginal-type chest pain is often prolonged, [33and it often does not respond to sublingual nitroglycerin.

Rheumatologic disorders such as fibromyalgia and costochondritis and noncardiac causes of chest pain, such as esophageal dysfunction, have occasionally been reported in patients suspected to have cardiac syndrome X. [34Thus, a significant proportion of patients in whom cardiac syndrome X is diagnosed may have a noncardiac etiology for their chest discomfort.

Physical Examination

Abnormal physical findings that reflect ischemia, such as gallop sound and the murmur of mitral regurgitation, are uncommon in cardiac syndrome X.

Differential Diagnoses

  • Epicardial artery dysfunction (coronary artery spasm, coronary bridging)

  • Gastrointestinal disorders

  • Musculoskeletal disorders

  • Obstructive coronary artery disease

  • Psychological disorders

  • Pulmonary disorders

Imaging Studies

The resting electrocardiography (ECG) findings may be normal, but nonspecific ST-T–wave abnormalities are often observed, sometimes in association with the chest pain. Approximately 20% of patients with cardiac syndrome X (CSX) have positive results on exercise tests. However, many patients with this syndrome do not complete the exercise test because of fatigue or mild chest discomfort. Left ventricular function is usually normal at rest and during stress, unlike in obstructive coronary artery disease, in which function often becomes impaired during stress.

Other Tests

Multislice spiral computed tomography coronary angiography, positron emission tomography, and cardiovascular magnetic resonance imaging may become part of the diagnostic algorithm in future.

Along with routine laboratory studies, tests for cholesterol levels and inflammatory markers should be considered.


The criterion standard test to evaluate endothelial function is an invasive determination of coronary flow reserve via Doppler guidewire in the cardiac catheterization laboratory (ie, quantifying the coronary blood flow in response to nitroglycerine and acetylcholine infusion) (see image below).

Coronary blood flow in response to nitroglycerine (Coronary blood flow in response to nitroglycerine (NTG) and acetylcholine (ACH) infusion.

Although evidence of myocardial ischemia secondary to abnormal coronary reactivity testing can be detected noninvasively via single photon emission computed tomography, positron emission testing, and stress cardiac magnetic resonance imaging (see image below), the sensitivity and specificity of these measures remain incompletely characterized. [32]

Cardiac magnetic resonance imaging. Cardiac magnetic resonance imaging.

Treatment & Management

Updated: Dec 18, 2014 
  • Author: Subodh Raja Devabhaktuni, MD; Chief Editor: Richard A Lange, MD, MBA  more...

Medical Care

Cardiac syndrome X (CSX) is treated with lifestyle modification, [1including diet, exercise, smoking cessation, and weight reduction. A cardiac-prudent diet is advised.

Pharmacotherapy may involve the use of anti-anginal, anti-atherosclerotic, and anti-ischemic agents. [1]

Spinal cord stimulation: Spinal cord stimulation led to a significant reduction in chest pain and improved quality of life in about 50% of patients resistant to all other treatment. [35]

Psychological therapy: Cognitive behavioral therapy and group therapy have shown promising results in reducing episodes of chest discomfort over a period of 3-6 months. [3637They are more effective if started early.

Physical training: A physical training program may improve exercise capacity and reduce the frequency of chest pain episodes. [38]

Enhanced external counter pulsation (EECP): EECP may reduce symptoms through an improvement in endothelial function, promotion of collateralization, ventricular function enhancement, and peripheral effects resembling those seen with regular physical exercise. [39Bonetti et al reported successful treatment of CSX with severely symptomatic coronary endothelial dysfunction in the absence of obstructive coronary artery disease with standard 35-hour course of EECP therapy. [40]

Neurostimulation and stellate ganglionectomy may be alternative treatment options

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Beta-Blockers, Beta-1 Selective

Class Summary

Beta blockers seem to be most effective in reducing the frequency and severity of angina and in improving exercise tolerance. [414243]

Atenolol and metoprolol, in low doses, selectively block beta1 -adrenergic receptors in the heart and vascular smooth muscle. Pharmacodynamic consequences of beta1 -receptor blockade include decreases in (1) resting and exercise heart rate, (2) cardiac output, and (3) systolic and diastolic blood pressure. Like all selective adrenergic antagonists, they lose their selectivity for the beta1 receptor at higher doses and can competitively block beta2 -adrenergic receptors in the bronchial and vascular smooth muscles, potentially causing bronchospasm.

Actions that generally make beta blockers useful include a negative chronotropic effect that decreases the heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from the central nervous system (CNS), and suppression of renin release from the kidneys. Thus, beta blockers affect blood pressure via multiple mechanisms.

Metoprolol (Lopressor, Toprol-XL)

Metoprolol is a selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. During intravenous (IV) administration, carefully monitor blood pressure, heart rate, and the ECG. No dosage adjustment is required with renal failure.

Atenolol (Tenormin)

Atenolol selectively blocks beta1 receptors, with little or no effect on beta2 types.

Angiotensin-Converting Enzyme Inhibitors

Class Summary

The precise mechanism of action is not known. It is thought to be from increased bioavailability of nitric oxide [44and improvement in endothelial function. [45]

Angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and lower aldosterone secretion. They are effective and well-tolerated drugs with no adverse effects on plasma lipid levels or glucose tolerance.

Cough and angioedema are less common with newer members of this class than with captopril. Serum potassium and serum creatinine concentrations should be monitored for the development of hyperkalemia and azotemia.


Captopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. It is rapidly absorbed, but bioavailability is significantly reduced with food intake. Captopril achieves a peak concentration in 1 hour and has a short half-life. The drug is cleared by the kidney; impaired renal function requires reduction of the dosage. Captopril is absorbed well orally.

Give captopril at least 1 hour before meals. If it is added to water, use it within 15 minutes. The dose can be low initially, then titrated upward as needed and as tolerated by the patient.

Enalapril (Vasotec)

Enalapril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Lisinopril (Prinivil, Zestril)

Lisinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Benazepril (Lotensin)

Benazepril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.


Fosinopril is a competitive ACE inhibitor. It prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Quinapril (Accupril)

Quinapril is a competitive ACE inhibitor. It reduces angiotensin II levels, decreasing aldosterone secretion.

Ramipril (Altace)

Ramipril inhibits partially inhibits both tissue and circulating ACE activity, therefore reducing the formation of angiotensin II in the tissue and plasma.

Lipid-Lowering Agents, Statins

Class Summary

Statins improve the exercise tolerance in terms of duration, time to electrocardiographic changes on stress testing, and brachial artery flow–mediated dilation. [46The exact mechanism of benefit by statins is unclear, and several hypotheses have been proposed. Statins, especially atorvastatin and simvastatin, modulate lysyl oxidase transcriptional activity, counteracting the down-regulation of lysyl oxidase caused by tumor necrosis factor-alpha (TNF-alpha) in porcine, bovine, and human aortic endothelial cells. Statins can normalize vascular lysyl oxidase expression altered by atherogenic risk factors through a RhoA/Rho kinase-dependent mechanism. [47]

Simvastatin (Zocor)

Simvastatin competitively inhibits HMG-CoA reductase, which is responsible for the rate-limiting step in cholesterol synthesis. It may be administered 5-40 mg/day PO hs.

Pravastatin (Pravachol)

Pravastatin competitively inhibits HMG-CoA reductase, which is responsible for the rate-limiting step in cholesterol synthesis. It may be administered 10-20 mg PO hs; may increase to 40 mg hs.

Atorvastatin (Lipitor)

Atorvastatin competitively inhibits HMG-CoA reductase, which is responsible for the rate-limiting step in cholesterol synthesis. It may be administered 10 mg PO once daily; titrate to a maximum 80 mg/day, as necessary.

Rosuvastatin (Crestor)

Rosuvastatin competitively inhibits HMG-CoA reductase, which is responsible for the rate-limiting step in cholesterol synthesis. It may be administered 5 mg PO once daily; titrate up to 40 mg PO once daily.

Pitavastatin (Livalo)

Pitavastatin competitively inhibits HMG-CoA reductase, which is responsible for the rate-limiting step in cholesterol synthesis. It may be administered 2 mg PO once daily, not to exceed 4 mg/day.

Tricyclic Antidepressants

Class Summary

Agents in this class have demonstrated effectiveness in the treatment of psychosomatic and chronic pain.

Imipramine (Tofranil-Tofranil PM)

Imipramine improved the symptoms of patients with chest pain and normal coronary angiograms, possibly through a visceral analgesic effect. [48It may act by inhibiting reuptake of noradrenaline at synapses in central descending pain modulating pathways located in the brainstem and spinal cord.

Estrogen Derivatives

Class Summary

Hormone therapy may be beneficial in postmenopausal women. Hormone therapy significantly reduced the frequency of anginal episodes. [49Estrogen may act by improving endothelium-dependent coronary vasomotion. [50However, these benefits must be weighed against the overall effect of hormone therapy on cardiovascular outcomes. The Women's Health Initiative trial showed that estrogen-progestin replacement had no cardioprotective effect and may have produced harm, increasing the risk of coronary disease, stroke, venous thromboembolism, and breast cancer. [51]

Conjugated estrogens (Premarin)

Multiple aspects of menopause respond to estrogen replacement therapy, including vasomotor symptoms. Decisions for hormone replacement therapy should be made on an individual basis in consultation with a gynecologist. Dosing may need to be titrated individually, with each patient monitored for risks and adverse effects. Premarin is available in tablet form for oral administration in strengths of 0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg, and 2.5 mg


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