Cardiac Syndrome X

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



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

  • Insulin resistance

  • 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]



History and Physical Examination

Individuals with cardiac syndrome X (CSX) are typically younger than those with angina due to obstructive coronary artery disease.[38]

Approximately half of patients with cardiac syndrome X have recurrent angina-like chest pain epsidoes, whereas the remainder have atypical chest pain. The duration of anginal-type chest pain is often prolonged,[38]  and it often does not respond to sublingual nitroglycerin.

Some patients present with acute coronary syndrome (ACS). There is no significant blockage on coronary angiogram in around 15-20% of patients with non-ST-elevation myocardial infarction (MI).[39]  However, there are no data on presence of microvascular dysfunction in this patient population.

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.[40]  Thus, 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.

Exaggerated morning blood pressure surge may be an independent predictor for arterial stiffness (increased carotid-intima-media thickness) and diastolic dysfunction in patients with cardiac syndrome X.[41]  

Physical Examination

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



Diagnostic Considerations

Conditions to consider in the differential diagnosis of cardiac syndrome X (CSX) include the following:

  • Epicardial artery dysfunction: Coronary artery spasm, coronary bridging
  • Gastrointestinal disorders: Reflux disease, dysmotility, and hypersensitivity
  • Inflamatory disorders: Pericarditis, myocarditis
  • Musculoskeletal disorders: Costochondritis, radiculopathy
  • Obstructive coronary artery disease
  • Psychological disorders: Panic disorder, anxiety
  • Pulmonary disorders: Pulmonary embolism, pneumonia
  • Structural cardiac problems: Hypertrophy, valvular heart disease


Approach Considerations

Along with routine laboratory studies in patients with suspected cardiac syndrome X (CSX), tests for cholesterol levels and inflammatory markers should be considered.

Levels of vitamin D may be considered as clinically warranted. Vitamin D deficiency may be a risk factor, potentially related to increased inflammation leading to the development of endothelial dysfunction and microvascular angina. Levels of serum vitamin D in patients with cardiac syndrome X appear to be significantly lower than those who don't have this condition.[42]

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.

Heart rate variability appears to be associated with exercise capacity in patients with cardiac syndrome X, particularly in young individuals.[43]

Other imaging modalities

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


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).

Cardiac Syndrome X. Coronary blood flow in response Cardiac Syndrome X. 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.[37]

Cardiac Syndrome X. Cardiac magnetic resonance ima Cardiac Syndrome X. Cardiac magnetic resonance image.


Medical Care

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

Pharmacotherapy may involve the use of anti-anginal agents like beta blockers (first line of therapy), calcium channel blockers, and nitrates.[1] Cattaneo and colleagues recently reviewed evidence suggesting that the drug ranolazine is useful in the management of primary microvascular angina.[44]

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.[45]

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.[46, 47] They are more effective if started early. Tricyclic antidepressants and xanthine derivatives can be used in treating the hyperalgesia.

Physical training

A physical training program may improve exercise capacity and reduce the frequency of chest pain episodes.[48]  Adding a 4-week course of cardiac rehabilitation to usual care may increase the Duke Treadmill Score and exercise test duration as well as improve the resting oxygen pulse, peak oxygen, and first-minute recovery heart rate.[49]

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.[50] Bonetti 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.[51]


Neurostimulation and stellate ganglionectomy may be alternative treatment options.[1]



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.[52, 53, 54]

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[55] and improvement in endothelial function.[56]

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.[57] The 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.[58]

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.[48] It 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.[59] Estrogen may act by improving endothelium-dependent coronary vasomotion.[60] However, 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.[61]

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.