What is cardiac syndrome X?

What is Cardiac Syndrome X?

Cardiac syndrome X is a clinical entity defined by the triad of typical exercise-induced angina, objective evidence of myocardial ischemia (ST-segment depression on exercise testing or positive stress imaging), and normal or non-obstructed coronary arteries on angiography. 1

Key Diagnostic Criteria

The classical definition requires all three components 1:

• Typical exercise-induced angina (with or without additional resting angina and dyspnea)
• Positive exercise stress ECG or other stress imaging modality showing objective ischemia
• Normal coronary arteries on angiography (no obstructive coronary artery disease)

Clinical Presentation

Cardiac syndrome X is more common in women than men, particularly postmenopausal women. 1 The chest pain presentation varies considerably:

• Most commonly occurs with activity, simulating stable angina pectoris 1
• Can present with chest pain at rest that may be prolonged and unresponsive to nitroglycerin 1
• Chest pain occurs frequently, typically several times per week with a stable pattern 1
• May accelerate in frequency or intensity, mimicking unstable angina 1

Important Distinctions

This entity must be differentiated from:

• Metabolic syndrome X (insulin resistance, hyperinsulinemia, dyslipidemia, hypertension, abdominal obesity) 1
• Noncardiac chest pain (esophageal dysmotility, fibromyalgia, costochondritis) 1
• Vasospastic angina (must rule out coronary spasm by absence of ST-segment elevation during pain or by provocative testing) 1

Pathophysiology

The underlying mechanisms are multifactorial and not completely understood, but the most frequently proposed causes include 1:

• Impaired endothelium-dependent arterial vasodilation with decreased nitric oxide production
• Impaired microvascular dilation (non-endothelium-dependent)
• Increased sensitivity to sympathetic stimulation
• Coronary vasoconstriction in response to exercise
• Increased plasma endothelin levels correlating with impaired coronary microvascular dilation 1
• Abnormal pain perception and increased responsiveness to pain 1

In a subset of patients, microvascular dysfunction can be demonstrated, and this entity is commonly referred to as "microvascular angina." 1

Prognosis

The prognosis regarding mortality was traditionally considered favorable, but more recent evidence suggests a more nuanced picture 1:

• Older studies (CASS registry) reported 96% 7-year survival rate in patients with anginal chest pain and normal coronary arteriograms 1
• More recent data from WISE indicate the prognosis is not entirely benign with respect to cardiac death and nonfatal MI, particularly in patients with documented ischemia on testing 1
• Morbidity is high with continuing episodes of chest pain, hospital readmissions, and impaired quality of life 1
• Emerging evidence suggests that impaired endothelial dysfunction may identify a subgroup at risk for future development of atherosclerotic coronary disease 1
• Prognosis is related to the extent of angiographic disease across the range of 20% stenosis to obstructive lesions 1

Diagnostic Confirmation

The diagnosis is suggested by the clinical triad and can be confirmed through 1:

• Provocative coronary angiographic testing with acetylcholine for coronary endothelium-dependent function
• Adenosine testing for non-endothelium-dependent microvascular function
• Myocardial perfusion scanning may show abnormalities due to patchy abnormal microvascular response to exercise 1
• Magnetic resonance imaging may suggest myocardial ischemia 1

Management Approach

Medical therapy with nitrates, beta blockers, and calcium channel blockers (alone or in combination) is recommended (Class I recommendation, Level of Evidence B). 1

Additional considerations for refractory cases include 1:

• Imipramine or aminophylline may be considered for continued pain despite Class I measures (Class IIb, Level of Evidence C)
• Transcutaneous electrical nerve stimulation or spinal cord stimulation for continued pain (Class IIb, Level of Evidence B)
• Intracoronary ultrasound may be considered to assess atherosclerosis extent and rule out missed obstructive lesions (Class IIb, Level of Evidence B)
• Invasive physiological assessment (coronary flow reserve measurement) may be considered if angiography does not reveal a cause (Class IIb, Level of Evidence C)

Critical Pitfall

Do not prescribe nitrates, beta blockers, and calcium channel blockers for patients with noncardiac chest pain (Class III recommendation, Level of Evidence C). 1 This underscores the importance of confirming objective evidence of ischemia before diagnosing cardiac syndrome X and initiating antianginal therapy.