http://emedicine.medscape.

com/article/1967073-overview#showall

Author

Subodh Raja Devabhaktuni, MD Resident Physician, Department of Internal Medicine,

University of Nevada School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

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.

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.

Specialty Editor Board

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.

Chief Editor

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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Updated: Dec 18, 2014

Author: Subodh Raja Devabhaktuni, MD; Chief Editor: Richard A Lange, MD, MBA more...

Background
Cardiac syndrome X (CSX) is typical anginalike chest pain with evidence of myocardial
ischemia in the absence of ow-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.

Pathophysiology
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

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]

Insulin resistance

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]

Abnormal autonomic control

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 -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 deciency. [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]

Epidemiology
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.

Prognosis
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 Womens 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]

History
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, [33] and 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. [34] 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.

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-Twave
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.

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

Coronary blood ow in response to

nitroglycerine (NTG) and acetylcholine (ACH) infusion.

View Media Gallery

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.

View Media Gallery

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, anti-atherosclerotic, and anti-ischemic

agents. [1]

Spinal cord stimulation: Spinal cord stimulation led to a signicant 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. [36, 37]
They 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. [39]
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. [40]

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. [41, 42, 43]

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)

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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)

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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 [44] and 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
 View full drug information

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)

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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)

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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)

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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

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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)

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

aldosterone secretion.

Ramipril (Altace)
 View full drug information

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 owmediated dilation. [46] The exact mechanism
of benet 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)

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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)

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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)

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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)

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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)

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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)

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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. [49] Estrogen may act by improving
endothelium-dependent coronary vasomotion. [50] 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. [51]

Conjugated estrogens (Premarin)

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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.