Microvascular Angina Cardiac Syndrome X

Synonyms: microvascular angina

Microvascular Angina (previously known as Cardiac syndrome X (CSX)) is characterised by angina-like chest discomfort, ST-segment depression during exercise, and normal coronary arteries at angiography. CSX is much more common in women than in men. CSX is not necessarily benign and is linked to adverse cardiovascular outcomes and a poor quality of life.^{[1, 2, 3]}

There is no standard agreed definition for CSX.^[4]There are numerous causes for chest pain in patients with CSX that range from non-cardiac to coronary microvascular dysfunction (CMD).^[5]However, the term CSX is often used synonymously with CMD.

Myocardial ischaemia may result from different types of functional disease involving the coronary arteries (eg, coronary artery vasospasm), the coronary microcirculation or both. An accurate assessment of these components after exclusion of organic coronary artery disease (CAD) is very important because a correct diagnosis has relevant prognostic and therapeutic implications.^[2]

There is a separate Coronary Artery Vasospasm article. The remainder of this article is mainly focused on CMD. The cause of microvascular angina seems very likely to be organic and functional abnormalities of the small arteries of the heart.^[6]

Diabetes mellitus, coronary artery spasm, left ventricular hypertrophy and cardiomyopathy preclude the diagnosis of CMD.^[7]

Epidemiology^[8]

A review found that, among patients suspected of having myocardial ischaemia, 41% of women, as compared to only 8% of men, showed insignificant CAD on coronary angiography.

The prevalence of microvascular angina is estimated to be up to 30% of stable angina patients with non-obstructive coronary arteries. 19% of women presenting with acute coronary syndrome, 30% of women presenting with unstable angina, 9.1% of women with non-ST-elevation myocardial infarction and 10% of women with ST-elevation myocardial infarction were determined to have normal or non-obstructive coronary arteries using coronary angiography. Overall, 10-25% of women with acute coronary syndrome have a 'normal' coronary angiography. 

Nearly 50% of people with CAD have CMD.^[9]

Risk factors

These are in common with CAD and include:^[10]

• Postmenopausal women.
• Hypercholesterolaemia.
• Smoking.
• Obesity.
• Hypertension.
• Insulin resistance or overt diabetes mellitus.
• Low-grade chronic inflammation.

Presentation

Presents with persistent chest pain, evidence of angina, and ischaemic-type ST-segment depression and/or non-invasive perfusion or wall motion abnormality during stress testing.^[11]See also the separate Stable Angina article.

Symptoms

• Chest pain occurs on exertion but it may not be typical of CAD in its site and provoking factors.
• Symptoms are often severe and disabling.

Signs

There are no characteristic clinical signs but examination may reveal underlying cardiovascular risk factors - eg, hypertension and obesity.

Differential diagnosis^[12]

The whole spectrum of causes of chest pain must be considered. See the separate Chest Pain and Cardiac-type Chest Pain Presenting in Primary Care articles. However, possible differential diagnoses for special consideration are:

• CAD.
• Coronary artery vasospasm.
• Cardiomyopathy.

Investigations

Investigations should be as for CHD:

• FBC (to exclude anaemia or polycythaemia).
• U&E (if starting an angiotensin-converting enzyme (ACE) inhibitor).
• LFTs (before starting a statin).
• Fasting lipids (with a view to adjustment by diet or drugs).
• Fasting blood glucose (may show impaired glucose tolerance or overt diabetes).

Non-cardiac aetiologies of chest pain, including musculoskeletal, psychiatric, gastrointestinal and pulmonary disorders, must be excluded. Those with angina-like chest pain and even some with atypical features, including more frequent or persistent pain and inconsistent response to sublingual nitrates, should undergo stress testing.

The gold standard for diagnosis of CMD is invasive coronary reactivity testing on coronary angiography.^{[13, 7]}

Intracoronary acetylcholine has been used for the assessment of coronary vasomotor function.^[10]Its administration causes vasodilation under normal conditions but, in the absence of a functional endothelium, it leads to vasoconstriction by the unopposed stimulation of muscarinic receptors on vascular smooth muscle cells. Bradykinin and substance P are alternative agents.^[14]

Non-invasive methods, such as positron emission tomography (PET), Doppler echocardiography and gadolinium perfusion cardiac MRI are increasingly being used to evaluate for the presence of CMD.^[15]

Management

Treatment of CSX includes lifestyle modification and anti-anginal, anti-atherosclerotic and anti-ischaemic medications. Non-pharmacological options include cognitive behavioral therapy, enhanced external counterpulsation, neurostimulation and stellate ganglionectomy.^[1]

Effective treatment of microvascular angina requires aggressive risk factor modification (exercise is one of the most effective treatment modalities). Several other treatment strategies have been shown to relieve anginal symptoms as well as improve vascular function, including beta-blockers, ACE inhibitors, ranolazine, L-arginine and statins. Oestrogen replacement therapy may also have a role for affected women. Nitrates may be effective for symptom relief.^[16]

Other treatments include relaxation techniques, hypnotherapy and cognitive behavioural therapy.

General measures

• Exercise regimes have a beneficial effect.^[17]
• Weight loss reduces insulin resistance.
• Stop smoking if applicable.

Pharmacological^{[5, 17]}

Studies have shown variable results with regard to specific pharmacological treatments for CMD. Treatment options include: 

• Beta-blockers, which work by lowering adrenergic tone and reducing myocardial oxygen demand, as well as enhancing endothelium-dependent vasodilation.
• Calcium-channel blockers, which have been shown to decrease microvascular tone and relieve spasm and are therefore beneficial for patients with CMD.
• Sublingual nitrates, which may benefit symptomatic episodes; however, long-acting nitrates have proven disappointing.
• Xanthine derivatives such as aminophylline, which have been shown to improve the time to exercise-induced angina, time to ST depression, and the magnitude of ST depression in patients with CSX. They could be used where chronic airways disease and CSX co-exist.
• ACE inhibitors, which are beneficial for endothelial dysfunction, as demonstrated by their effect on microalbuminuria. However, there is a lack of consistent well-constructed evidence to support their use.
• Statins, which are used where cholesterol is elevated but also stabilise the endothelial membrane.^[3]
• Imipramine, which may be beneficial in pain modulation.^[18]
• Even in women without diabetes, metformin may improve vascular function and decrease myocardial ischaemia. Larger trials are required.

Other treatments^[5]

Spinal cord stimulaters and enhanced external counterpulsation (EECP) have been studied in patients with chest pain without obstructive CAD. Spinal stimulation is believed to modulate pain-related nerve signals and increase myocardial blood flow though effects on sympathetic tone. EECP increases diastolic blood flow to the heart.

Prognosis^[8]

Symptoms may improve but CMD is not benign and is associated with an annual 2.5% cardiac event rate.^[13]

Patients with microvascular angina have a 1.5-fold increase in mortality compared with those without any evidence of myocardial ischaemia. In addition, more than 40% of patients are re-admitted to the hospital for chest pain and 30% undergo repeat coronary angiography. They also have a worse quality of life when compared to healthy counterparts.

Therefore, many patients with chest pain, without significant obstruction on coronary angiography, are often inappropriately reassured and remain untreated. 

Prevention

Presumably, avoiding obesity and keeping physically active would protect against CHD and CMD.