Cardiac syndrome X
Synonyms and key words: Microvascular angina

# Overview
Cardiac syndrome X is angina associated with objective evidence of myocardial ischemia in the absence of epicardial  coronary artery disease.  Syndrome X has been hypothesized to be a disorder of the coronary microvasculature rather than the large caliber epicardial coronary arteries.

# Pathophysiology
- In a large percentage of patients, there is coronary microvascular dysfunction in which microvasculature cannot dilate to accommodate increased blood flow during exertion caused by an increased myocardial metabolic demand.
- There does not appear to be a systemic abnormality in vasomotor function as brachial artery reactivity is normal.
- The underlying pathophysiology is most likely heterogenous. Multiple pathophysiologic mechanisms have been proposed with variable data to support them such as: ischemia, adenosine, dysautonomia, female pattern, hypersensitivity, panic disorders, and viral infections.

### Ischemia is Present in Syndrome X
- Researchers debate whether ischemia is present in patients with syndrome X. There may be no wall motion abnormalities or coronary sinus lactate production during an episode of ischemic discomfort. This may be due to focal involvement of the myocardium.
- When coronary sinus samples of more sensitive markers of ischemia reperfusion/oxidative stress are analyzed such as lipid hydroperoxides (ROOHs) and conjugated dienes (CDs) before and after pacing, there is an increase in ROOH and CD levels (from 4.83 +/- 1.18 micromol/l at baseline to 7.88 +/- 1.12 micromol/l and from 0.038 +/- 0.002 to 0.051 +/- 0.003 arbitrary units, respectively, P < 0.01).
- In contrast,  ROOH and CD levels did not increase in control patients after pacing.

### Adenosine as a Cause of Chest Pain
- Both, endogenous and exogenous adenosine can cause chest discomfort through stimulation of sensory nerves in the heart.
- Huang et al have demonstrated that both A1- and A2-adenosine receptors are present on the cardiac sensory nerve endings of dorsal root ganglion neurons. These sensory neurons are active in the absence of ischemia but become further activated during myocardial ischemia.
- In one study in which adenosine was administered by infusion, 95% of patients with syndrome X experienced chest pain compared to only 40% of control patients (p<0.001).

### An Extension of Dysautonomias
Syndrome X has been associated with dysautonomias and with a greater frequency of autonomic symptoms such as:
- Tachycardia
- Dyspnea
- Dizziness
- Paresthesias
It has, therefore, been hypothesized that syndrome X may be an extension of abnormalities of the autonomic nervous system.

### Female Pattern of Atherosclerosis
- Although coronary arteriogram may appear normal, diffuse atherosclerosis may still be present. This is termed a female pattern of atherosclerotic disease.

### Enhanced Pain Sensitivity
- Patients with normal coronary arteries and myocardial ischemia have a lower pain threshold and a lower tolerance to pain induced by adenosine.

### Panic Disorder
- Approximately one third of patients with angina pectoris and normal coronary arteries are diagnosed with panic disorder.

### Viral Infection
- Viral infection of the coronary microvasculature may be related to the poor response to anti-ischemic drugs.
- Left ventricular endomyocardial biopsies were compared in patients with chronic stable angina versus patients with drug resistant syndrome X.  Interstitial and replacement fibrosis were present in all patients with syndrome X. Viral genomes were identified 69% of patients with CSX which included Epstein-Barr virus in four patients, adenovirus in three patients, human herpes virus (HHV) 6 in one patient, and Epstein-Barr adenovirus co-infection in one. Epstein-Barr and adenovirus were localised to both the cardiomyocytes as well as intramural vessels, while HHV-6 virus confined solely to the vessel wall.

# Epidemiology and Demographics
- Syndrome X occurs more often in women.
- 61.5% of women with syndrome X are postmenopausal at the time of onset.
- Some studies have found an increased risk of other vasospastic disorders in syndrome X patients, such as migraine and Raynaud's phenomenon.

# Natural History, Complications and Prognosis
- Syndrome X does not appear to be associated with an excess of major coronary events.
- In a longitudinal study of 99 patients with syndrome X followed for an average of 7 years (+/- 4 years deviation), left ventricular function was stable: fractional shortening at baseline was 35.4 +/- 4% vs. 35.6 +/- 3% at follow-up and congestive heart failure developed in only one patient. Symptomatic outcome varied across patients: where it did not change in about 65% of patients, improved in 10% of patients, and worsened in about a 25% of patients.
- The absence of significant coronary artery disease on coronary angiography is associated with a good prognosis. Among 3,136 patients with normal angiograms, the seven year survival rate was 96%.

# Risk Factors
- Female gender and left ventricular hypertrophy are associated with an excess risk of syndrome X.
- The onset in women often occurs after menopause.
- Syndrome X and its accompanying microvascular dysfunction are not associated with traditional cardiovascular risk factors.
- Syndrome X has been associated with elevations of inflammatory markers such as: C reactive protein and soluble CD40 ligand.

# Other Conditions to Distinguish Syndrome X From
- Syndrome X should be distinguished from prinzmetal's angina, a disorder which involves spasm of the main epicardial coronary arteries.
- Syndrome X involves dysfunction of the downstream microvasculature.
- Syndrome X must also be distinguished from esophageal spasm.

# Diagnosis

### Symptoms
- In one study, all 99 patients with syndrome X had exertional angina. 41 patients reported angina at rest.
- In patients with syndrome X, the anginal pain tends to last longer after cessation of exertion (> 10 minutes in 53% of patients) than is typical of patients with fixed obstructions of the epicardial arteries (pain generally lasts 2 to 5 minutes).
- Sublingual nitroglycerine is often not as effective in the patient with syndrome X as it is in the patient with obstructive epicardial disease, with only 42% of patients reporting relief.

### Ambulatory Holter Monitoring
- Approximately two thirds of patients (64/99 in one study) may experience ST segment depression on ambulatory Holter monitoring.

### Cardiac Magnetic Resonance Imaging (CMR)
- While there is no difference between control patients and patients with syndrome X in subepicardial perfusion, there is a greater relative magnitude of subendocardial hypoperfusion on CMR during adenosine infusion in patients with syndrome X.  As a result, the ratio of subendocardial to subepicardial myocardial-perfusion reserve index is significantly lower in patients with syndrome X.

### Diagnostic Studies and Criteria for Diagnosis
- Syndrome X is often a diagnosis of exclusion. The diagnostic criteria are as follows:
- There must be evidence of myocardial ischemia:  Diagnostic studies include an exercise ECG, stress scintigraphy, or stress echocardiography in conjunction with anginal chest discomfort.
- Angina: Angina pectoris must be present. The angina pectoris associated with syndrome X may last longer that the anginal discomfort associated with the fixed epicardial stenoses of atherosclerotic heart disease.
- Coronary angiogram: There is no narrowing of the epicardial arteries.  However, syndrome X may be associated with a reduction in coronary vasodilator reserve presumably due to abnormalities in the coronary microcirculation.  During stress, sampling of the coronary sinus may demonstrate the production of lactate by the myocardium.  Intracoronary acetylcholine can be administered to evaluate endothelium-dependent coronary flow reserve.

# Treatment
The mainstay of treatment in patients with syndrome X are calcium channel blockers, such as nifedipine and diltiazem.  Other therapies include:
- Nitrates: Sublingual nitroglycerine is often not as effective in the patient with syndrome X as it is in the patient with obstructive epicardial disease, with only 42% of patients reporting relief.
- Beta blockers
- Aminophylline: Evidence exists to suggest this therapy may be effective via inhibition of adenosine receptors.
- Estrogen: Evidence exists to suggest this therapy  may be effective in women.
- Ranolazine: In a recent randomized, controlled trial of ranolzazine in women with syndrome X, ranolazine was found to be superior to placebo with respect to physical functioning (p = 0.046), angina stability (p = 0.008), and quality of life (p = 0.021). With respect to objective quantitative measure, ranolazine administration tended to be associated with higher (improved) CMR mid-ventricular MPRI (2.4  vs. 2.1 , p = 0.074).  Women with a coronary flow reserve (CFR)  3.0 achieved significantly greater improvement in MPRI on ranolazine versus placebo ( in MPRI 0.48 vs. -0.82, p = 0.04).
- Estrogen replacement therapy: ERT or selective ERT may reduce the frequency of chest pain in post menopausal women with syndrome X.

# ESC Guidelines for Investigation in Patients with Syndrome X (DO NOT EDIT)

# ESC Guidelines for Pharmacological Therapy to Improve Symptoms in Patients with Syndrome X (DO NOT EDIT)