What is functional microvascular dysfunction?

Functional Microvascular Dysfunction

Functional microvascular dysfunction is characterized by increased resting coronary blood flow linked to enhanced nitric oxide synthase activity, with preserved minimal microvascular resistance during hyperemia (IMR <25), distinguishing it from structural microvascular disease where endothelial dysfunction reduces flow augmentation during exercise. 1

Pathophysiological Distinction

Functional coronary microvascular dysfunction (CMD) represents a specific endotype within the broader spectrum of microvascular angina, defined by:

• Abnormally low resting microvascular resistance (4.2±1.0 mmHg/cm/s) compared to structural CMD (6.9±1.7 mmHg/cm/s) or controls (7.3±2.2 mmHg/cm/s), reflecting enhanced nitric oxide-mediated vasodilation at baseline 2
• Normal minimal microvascular resistance during hyperemia (IMR <25 or hyperemic MR <2.5 mmHg/cm/s), indicating preserved structural integrity of the coronary microcirculation 1, 2
• Impaired coronary flow reserve (CFR <2.5) despite normal hyperemic resistance, caused by the elevated baseline flow rather than fixed structural obstruction 1, 2

Hemodynamic Response to Stress

The functional endotype exhibits a maladaptive physiological response during exercise that differs fundamentally from structural CMD:

• Decreased coronary perfusion efficiency during exercise (from 61±12% at rest to 44±10% during exercise), reflecting impaired wave intensity and accelerating flow energy 2
• Lower systolic blood pressure response to exercise (161±27 mmHg) compared to structural CMD (188±25 mmHg), suggesting different systemic vascular regulation 2
• Inducible myocardial ischemia occurs in 82% of patients with functional CMD, with subendocardial:subepicardial perfusion ratio <1.0 during stress 2

Diagnostic Criteria

Functional CMD is diagnosed when all of the following are present:

• Symptoms of myocardial ischemia (effort or rest angina, exertional dyspnea) 1
• Absence of obstructive CAD (<50% diameter reduction or FFR >0.80) 1
• Impaired coronary flow reserve (CFR <2.5 by thermodilution or Doppler) 1
• Normal microvascular resistance indices (IMR <25, HMR <2.5 mmHg/cm/s) during hyperemia 1
• Negative acetylcholine provocation test at high doses (100-200 μg intracoronary), ruling out microvascular spasm 1

Clinical Significance

Functional CMD represents approximately 62% of all patients with impaired coronary flow reserve, making it the predominant endotype of microvascular angina 2. The enhanced nitric oxide synthase activity at rest paradoxically impairs the ability to further augment flow during stress, creating a demand-supply mismatch despite structurally intact microvessels 1.

Therapeutic Implications

The European Society of Cardiology recommends stratified medical therapy targeting the specific endotype:

• Beta-blockers (particularly nebivolol with nitric oxide-mediated vasodilation) improve CFR by 24-33% in functional CMD 3, 4
• ACE inhibitors enhance endothelium-dependent vasodilation and reduce left ventricular stiffness 3, 4
• Statins improve endothelial function through anti-inflammatory mechanisms beyond lipid-lowering 3, 4
• Target resting heart rate of 55-60 bpm to maximize diastolic perfusion time, compensating for the impaired perfusion efficiency during stress 4

Avoid beta-blockers if acetylcholine testing is positive, as functional CMD with vasospastic component requires calcium channel blockers instead 4.

Prognostic Considerations

Functional CMD carries significant prognostic implications despite preserved microvascular structure:

• Increased risk of major adverse cardiac events, myocardial infarction, heart failure with preserved ejection fraction, and death 3
• Impaired CFR <2.32 is associated with elevated hazard for major coronary events at 10-year follow-up 3
• Objective improvement in CFR to ≥2.5 should be targeted with repeat invasive coronary function testing at 3-6 months after medication optimization 4