Coronary microvascular dysfunction

Last revised by Joachim Feger on 12 May 2022

Coronary microvascular dysfunction (CMD) or coronary microvascular disease refers to a wide spectrum of clinical situations with an impairment of the coronary microcirculation and myocardial blood flow in subjects with respective risk factors. It can contribute to or induce myocardial ischemia

The terms ‘angina with normal coronary arteries’ and ‘cardiac syndrome X’ have been discouraged.

Coronary microvascular dysfunction is encountered in a high percentage of patients presenting with symptoms and signs of myocardial ischemia and affects patients with or without coronary artery disease 1. Women are more commonly affected in particular after menopause 1-3.

Risk factors for coronary microvascular dysfunction are not different from epicardial coronary artery disease and include the following conditions 1-3

Coronary microvascular dysfunction is regarded as a mechanism of myocardial ischemia and is associated with chronic and acute coronary syndromes. It can coexist and/or overlap with atherosclerotic or vasospastic epicardial coronary disease 1,2.

Beyond that coronary microvascular dysfunction is associated with multiple diseases including the following conditions 1-3.

Diagnostic criteria for coronary microvascular angina related to coronary microvascular dysfunction (according to COVADIS) 2,4:

  • symptoms indicating myocardial ischemia
  • absence of obstructive coronary artery disease
  • objective evidence of myocardial ischemia
  • impaired coronary microvascular function
    • reduced coronary flow reserve
    • increased coronary microvascular resistance
    • inducible microvascular spasms

The typical clinical presentation is chest pain (e.g. angina pectoris or atypical angina) or other symptoms such as dyspnea on exertion. Symptoms might be provoked by emotional stress or a variable threshold of physical activity or palpitations. Chest pain might persist for a longer time period after physical activity or in the post-exercise recovery period or at rest. Moreover, it might show a slow response or even worsen to sublingual short-acting nitrates 2-4

Stress or exercise electrocardiogram might reveal ST-segment depression and/or chest pain.

Complications of coronary microvascular dysfunction include the following conditions 1,2:

Coronary microvascular dysfunction is a multifactorial condition affecting the coronary microcirculation of diverse vascular compartments with a diameter of <500 µm leading to a diminished response of coronary flow to vasodilator stimuli, which can be characterized by a reduced coronary flow reserve (CFR <2.0 -2.5), an abnormally high index of coronary microvascular resistance (IMR >25), and/or an abnormal focal or diffuse vasoconstrictor response in the absence of significant epicardial coronary artery obstruction 1,2.

Different pathogenic mechanisms that can contribute to coronary microvascular dysfunction vary subject to the clinical setting and include the following 1-3:

  • endothelial dysfunction
  • microvascular remodeling
  • vasoconstriction
  • distal embolization
  • extramural compression
  • rarefactions of micro-vessels
  • autonomic dysfunction

There are different clinical classifications of coronary microvascular dysfunction 1-4

A classification presented by the ESC Working Group on Coronary Pathophysiology and Microcirculation is the following 1:

  • coronary microvascular dysfunction in chronic coronary syndrome
    • non-obstructive
    • obstructive coronary artery disease
  • coronary microvascular dysfunction in acute coronary syndrome
    • non-obstructive
    • obstructive coronary artery disease
    • coronary no-reflow phenomenon
  • coronary microvascular dysfunction after coronary revascularization

The small size of the anatomical and functional compartments of the coronary microcirculation makes direct imaging difficult. However, several imaging methods can aid in the evaluation of the response of myocardial blood flow to different stimuli e.g. vasodilator stress 1-6.

Moreover, imaging might be of help in indicating the diagnosis by showing myocardial ischemia in patients without obstructive epicardial coronary disease defined by a luminal reduction of >50% or preserved fractional flow reserve ≥0.8 or can visualize conditions that might be caused by microvascular diseases like myocardial infarction with non-obstructive coronary disease or the no reflow phenomenon in patients with myocardial infarction and microvascular obstruction 1,2.

Stress-related regional wall-motion abnormalities are usually absent. 

Reduction of coronary flow velocity ratio can be assessed in the left anterior descending artery after vasodilator stress if there is no significant epicardial coronary disease 1-3,5.

Coronary CTA can rule out significant coronary stenosis, which can aid in the diagnosis of patients with non-obstructive coronary disease.

Dynamic CT perfusion can be used to assess microvascular function after vasodilator stress 1-3.

Invasive coronary angiography (ICA) can rule out significant stenosis of the coronary epicardial arteries in patients with ischemia and non-obstructive coronary arteries (INOCA) 1

Combined invasive coronary motor testing with intracoronary acetylcholine for the assessment of the vasoconstrictor response as well as adenosine for assessment of the coronary flow reserve and microvascular resistance is used in the diagnosis of coronary microvascular dysfunction 1-3,5

Impaired coronary vasodilation (CFR <2.0-2.5) and increased microvascular resistance (IMR ≥25 units) indicate coronary microvascular dysfunction 1,2.

Cardiac MRI stress testing might show stress-induced perfusion defects and not show any associated regional wall-motion abnormalities after vasodilator stress 1,3.

Cardiac MRI can be used to assess coronary flow reserve 1-5.

PET-CT and PET-MR can quantify myocardial blood flow [mL/g/min] and demonstrate a reduction of myocardial flow reserve after intravenous injection of different flow tracers as 13N-ammonia, 82Rubidium or 15O-water 1-6.

The radiological report should include a description of the following features based on the AHA coronary artery segments or the cardiac segmentation model:

  • cardiac CT
    • documentation of presence or absence of obstructive coronary artery disease as per CAD-RADS
  • functional non-invasive testing
    • stress-induced perfusion defect 
    • stress induced-wall motion abnormalities 
    • coronary flow reserve if applicable

Coronary microvascular dysfunction is associated with a higher incidence of major adverse cardiovascular events and myocardial infarction in patients without and with evidence of obstructive coronary artery disease and is considered an independent prognostic predictor 1,2.

Similar to coronary artery disease the treatment concept of coronary microvascular dysfunction involves distinctive management steps also subject to the clinical setting 1-4:

  • lifestyle modification
    • smoking cessation
    • weight loss
    • exercise and physical training
  • pharmacological therapy
    • angiotensin-converting enzyme or angiotensin II receptor inhibitors
    • lipid-lowering agents 
    • anti-ischemic medications as beta-blockers or calcium channel blockers in variant angina for improvement of symptoms
    • antiplatelet therapy

The term microvascular angina has been first introduced by Cannon and Epstein in 1985 3,7

The main differential diagnosis of coronary microvascular dysfunction includes the following clinical conditions 1-3:

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