Basics
Description
- Stable angina with angiographically normal coronary arteries, (ie, Syndrome X), is a heterogeneous syndrome, characterized by:
- Both typical and atypical anginal chest pain with exertion
- ST-segment depression on exercise stress testing
- Angiographically normal coronaries
- Thought due to endothelial dysfunction of the coronary microvasculature with possible endocardial ischemia +/- abnormal pain perception with enhanced sensitivity to cardiac pain.
- Excludes patients with acute coronary syndromes or stress-induced cardiomyopathy
Epidemiology
- Females > Males
- Mean age at onset 49 yr
Incidence
- May occur in up to 20% of patients undergoing coronary angiography for chest pain.
- 40% of women and 10% of men referred for chest pain have normal coronary angiograms
Prevalence
Increasing in prevalence since described in 1973 �
Risk Factors
- Female sex
- Postmenopausal status
- HTN
- Hyperlipidemia
- DM
- Smoking
Pathophysiology
Coronary microvascular dysfunction leading to myocardial ischemia and angina and enhanced sensitivity to intracardiac pain �
Etiology
- Myocardial ischemia:
- Endothelial dysfunction: Imbalance in vasodilator and vasoconstrictor forces
- Abnormal autonomic control with increased sympathetic activation
- Occult coronary disease
- Estrogen deficiency in postmenopausal females
- Increased platelet aggregability
- Abnormal pain perception, also known as the "sensitive heart syndrome"�
Associated Conditions
30% of patients with Syndrome X have a treatable psychiatric disorder �
Diagnosis
History
Typical or atypical anginal chest pain; can occur with exercise or at rest and is prolonged, lasting several minutes �
Physical Exam
No specific physical exam findings �
Tests
Surgery
- Resting ECG: Transient ST segment depression with chest pain, rare ST-segment elevation
- Exercise ECG: Horizontal or downsloping ST-segment depression with exercise:
- Repeat exercise testing after nitrate administration may worsen in Syndrome X, in contrast to Prinzmetal angina and coronary atherosclerotic heart disease angina, which often improve with nitrates
- Myocardial perfusion imaging: Often abnormal stress perfusion with normal wall motion
- Cardiac magnetic resonance imaging (CMR): Lack of subendocardial hyperfusion during IV adenosine suggestive of ischemia in 20% of Syndrome X patients
- Coronary angiography: Completely normal coronary arteries:
- IV/intracoronary ergonovine or acetylcholine challenge to evaluate for epicardial coronary artery vasospasm
- Measurement of fractional flow reserve with a flow wire and intracoronary acetylcholine
- Intravascular US to assess for missed obstructive lesions
- Other testing (GI, musculoskeletal, psychiatric) as appropriate
Differential Diagnosis
- Coronary atherosclerotic heart disease
- Prinzmetal angina due to epicardial coronary artery vasospasm
- Mitral valve prolapse
- Noncardiac chest pain:
- GI: Esophageal dysmotility, GERD, GI masses
- Pulmonary: Bronchitis, pulmonary embolism
- Musculoskeletal: Costochondritis, muscular chest pain, fibromyalgia
Treatment
Medication
- Goal of pharmacologic therapy is to decrease symptoms and should be directed toward the likely mechanism (ie, ischemia vs. abnormal pain sensitivity)
- Hormone replacement therapy, although used in the past because of favorable effect on endothelial function, is not currently recommended due to increased cardiovascular, cancer, and venous thrombosis risks
First Line
- β-Blocking agents:
- May be most effective in patients with increased sympathetic activation
- Effective in reducing frequency and severity of angina and improving exercise tolerance
- Calcium channel blocking agents:
- Less effective in improving exercise tolerance, no effect on angina frequency
- ACE inhibitors + Statins:
- Favorable effects on endothelial function, vascular remodeling, and sympathetic activity with improved exercise duration and decreased angina frequency
- Nitrates and nicorandil:
- No large randomized studies in patients with angina and normal coronary arteries
- Effective in up to 40% of patients with Syndrome X
- Trimetazidine:
- Vasodilator, associated with improved time to ST-segment depression
Second Line
- Imipramine:
- A tricyclic antidepressant, 50 mg/d may decrease pain perception threshold by 50%, but up to 80% of patients have side effects
- Aminophylline:
- An adenosine receptor antagonist, may favorably affect exercise-induced angina and increase exercise tolerance
Additional Treatment
General Measures
- Reassurance of a benign prognosis
- Exercise training may decrease symptoms, increase exercise capacity, and improve endothelial function.
- Coronary risk factor reduction to improve endothelial function
- Medical therapy, psychiatric treatment, and physical training should be used together to reduce symptoms and improve quality of life.
Additional Therapies
- Transcutaneous electrical nerve stimulation (TENS):
- Stimulation of A-B fibers via the skin, indirectly delivering low-voltage electrical impulses to the spinal cord
- May reduce myocardial oxygen demand
- Spinal cord stimulation:
- Direct stimulation of the spinal cord via an electrode percutaneously placed into the epidural space
- May decrease angina and improve exercise tolerance and ECG findings
- Cognitive behavioral therapy
- AHA/ACC Guidelines for management:
- Class I: Medical therapy; cardiovascular risk factor reduction
- Class IIb: Intravascular US to evaluate for missed coronary stenosis; coronary angiography with provocative testing; Invasive physiological assessment (ie, FFR or CFR) 24-hr ambulatory ECG; hormone replacement therapy in postmenopausal women unless contraindicated; Imipramine, aminophylline, TENS unit, or spinal cord stimulation if failed above measures
- Class III: Medical therapy for patients with noncardiac chest pain
Ongoing Care
Prognosis
- Excellent prognosis, mortality similar to age- and sex-matched healthy controls in patients with no evidence of coronary atherosclerosis
- In patients with ejection fraction of ≥50%, 7-yr survival rate 96% with normal coronary angiogram
- Patients with abnormal nuclear myocardial resonance spectroscopy had similar rates of cardiovascular events as patients with known obstructive cardiovascular disease (43% vs. 48%).
Additional Reading
1Anderson �JL, Adams �CD, Antman �EM. ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction-Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50(7):652-726.2Cannon �RO. Microvascular angina and the continuing dilemma of chest pain with normal coronary angiograms. JACC. 2009;54(10);877-885. �[View Abstract]3Caudhary �I. Cardiac syndrome X: Angina pectoris with normal coronary arteries. Oct 16, 2008. UpToDate. http://uptodateonline.com/online/content/topic.do?topicKey=chd/225214Crea �F, Lanza �GA. Angina pectoris and normal coronary arteries: Cardiac syndrome X. Heart. 2004;90:457-463. �[View Abstract]5Kaski �JC, Aldama �G, Cosin-Sales �J. Cardiac syndrome X. Am J Cardiovasc Drugs. 2004;4:179-194. �[View Abstract]6Kemp �HG, Kronmal �RA, Vlietstra �RE. 7-year survival of patients with normal or near-normal coronary arteriograms: A CASS registry study. J Am Coll Cardiol. 1986;7:479-483. �[View Abstract]7Mirza �MA. Angina like pain and normal coronary arteries. Postgrad Med online. 2005;117:41-46. �[View Abstract]8Morrow �DA, Gersh �BJ, Braunwald �EJ. Chest pain with normal coronary arteriogram. In: Zipes �DP, Libby �P, Bonow �RO, Braunwald's Heart Disease, 7th ed. St. Louis: WB Saunders, 2005:1328-1329.9Panting �JR, Gatehouse �PD, Yang �GZ. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med. 2002;346:1948-1953. �[View Abstract]
Codes
ICD9
413.9 Other and unspecified angina pectoris �
SNOMED
233845001 cardiac syndrome X (finding) �
Clinical Pearls
- Syndrome X is angina without obstructive coronary disease. There is significant debate as to whether Syndrome X is due to microvascular disease.
- Management is difficult, and patients have widely different responses to therapies.
- Encouragement of risk factor modification and emphasis of the relatively low risk for future cardiac events is essential.
- Internet resources:
- NHLBI http://www.NHLBI.nih.gov
- AHA http://www.americanheart.org