What are the recommended tests for diagnosing microvascular dysfunction in a patient?

Diagnostic Testing for Microvascular Dysfunction

Non-Invasive Testing (First-Line Approach)

For patients with suspected microvascular dysfunction presenting with angina and non-obstructive coronary arteries, non-invasive testing should begin with quantitative assessment of coronary flow reserve (CFR) using PET, cardiac MRI perfusion imaging, or transthoracic Doppler echocardiography of the left anterior descending artery. 1

Recommended Non-Invasive Modalities

• PET imaging is the preferred non-invasive reference standard for measuring myocardial blood flow reserve (MBFR), with a threshold of <2.5 indicating microvascular dysfunction 1
• Stress CMR perfusion imaging is recommended in patients with moderate to high pre-test likelihood (15%-85%) of obstructive CAD to diagnose and quantify myocardial ischemia and estimate risk of major adverse cardiovascular events 1
• Transthoracic Doppler echocardiography of the LAD artery provides CFR measurement and has prognostic value, though it measures flow velocities rather than absolute myocardial blood flow 1
• Myocardial contrast echocardiography (MCE) can assess capillary blood flow through destruction-reperfusion imaging, with reduced MBF reserve depicting microcirculatory abnormalities in the absence of obstructive CAD 1

Critical Prerequisite

• Coronary CTA or invasive coronary angiography must first exclude obstructive epicardial coronary artery disease before attributing symptoms to microvascular dysfunction 1

Invasive Testing (Gold Standard for Definitive Diagnosis)

Guidewire-based invasive coronary functional testing should be considered (Class IIa recommendation) in patients with persistent symptoms but angiographically normal coronary arteries or moderate stenoses with preserved FFR/iFR. 1

Comprehensive Invasive Protocol

The standardized invasive assessment combines three components performed in a single catheterization procedure: 1

1. Basic Coronary Hemodynamic Assessment

• Coronary flow reserve (CFR) measured by thermodilution or Doppler flow velocity, with CFR <2.0-2.5 indicating microvascular dysfunction 1
• Index of microvascular resistance (IMR) measured by combining intracoronary pressure with thermodilution data, with IMR ≥25 units indicating structural microvascular dysfunction 1
• Hyperemic microvascular resistance (HMR) measured by Doppler flow velocity, with values >2.5 mmHg/cm/s considered abnormal 1
• Continuous thermodilution shows significantly less variability than bolus thermodilution on repeated measurements 1

2. Endothelial Function Testing

Intracoronary acetylcholine (Ach) provocation testing is the preferred method for assessing endothelium-dependent vasodilation and diagnosing vasospastic angina. 1

• Ach is administered as graded infusion or bolus, starting at low doses to assess microvascular endothelial dysfunction, then higher doses to provoke epicardial or microvascular vasospasm 1
• The left anterior descending artery is the preferred target vessel due to its myocardial mass and coronary dominance 1
• Ergonovine is an alternative provocative agent with similar safety profile when administered via selective intracoronary infusion 1
• Hyperventilation and cold pressor tests have low sensitivity and are not recommended 1

Critical Safety Considerations

• Selective intracoronary infusion (not intravenous) is essential for safety 1
• Triggered spasm is readily controlled with intracoronary nitrates 1
• Prophylactic ventricular pacing or selective LAD infusion prevents significant bradycardia when testing vessels supplying the AV node 1

Diagnostic Thresholds and Interpretation

Abnormal Values Indicating Microvascular Dysfunction

• CFR <2.0-2.5 (varies by measurement technique: thermodilution CFR <2.5, Doppler CFR <2.5) 1
• IMR ≥25 units indicates structural microvascular disease 1
• HMR >2.5 mmHg/cm/s by Doppler assessment 1
• PET MBFR <2.32 associated with elevated hazard for major coronary events at 10-year follow-up 2

Distinguishing Microvascular Angina from Vasospastic Angina

This distinction is critically important because beta-blockers are first-line therapy for microvascular angina but absolutely contraindicated in vasospastic angina. 3, 2

• Microvascular angina: Abnormal CFR <2.0 or IMR ≥25 with negative acetylcholine provocation test 1, 3
• Vasospastic angina: ECG changes and angina in response to acetylcholine with epicardial vasoconstriction >90% diameter reduction 1
• Mixed pattern: Both conditions can coexist, associated with worse prognosis 1

Clinical Algorithm for Test Selection

Step 1: Rule Out Obstructive CAD

• Perform coronary CTA or invasive coronary angiography to exclude epicardial stenoses 1

Step 2: Non-Invasive Functional Assessment

• If high-quality PET available: Measure MBFR as reference standard 1
• If CMR expertise available: Stress perfusion CMR for combined ischemia detection and CFR assessment 1
• If limited resources: Transthoracic Doppler echocardiography of LAD for CFR 1

Step 3: Consider Invasive Testing If:

• Symptoms persist despite initial management 1
• Non-invasive tests are equivocal or technically limited 1
• Tailored therapy based on specific endotype is desired (improves angina severity by 11.7 units on Seattle Angina Questionnaire) 2

Important Caveats and Pitfalls

Methodological Differences Between Techniques

• PET measures absolute myocardial blood flow while transthoracic Doppler measures flow velocities, leading to systematic differences (median MBFR 2.68 vs CFVR 2.31) with modest correlation (r=0.36) 4
• There is only modest correlation between MBF reserve values measured by different techniques and modalities 1
• Despite methodological differences, all techniques have prognostic value when abnormal 1, 5

Technical Limitations

• Transthoracic Doppler: 5% of patients have insufficient image quality 6
• Non-invasive methods provide limited assessment of endothelial function, which requires selective acetylcholine infusion 1
• Only hybrid techniques (CCTA with perfusion, PET-CT) offer combined epicardial and microvascular assessment in a single test 1

Clinical Context Matters

• Secondary microvascular dysfunction must be excluded: LV hypertrophy (hypertrophic cardiomyopathy, aortic stenosis, hypertensive heart disease), inflammation (myocarditis, vasculitis) 1
• Microvascular dysfunction is more common in women than men, with overall prevalence of 41% in selected patients without obstructive CAD 1
• The presence of microvascular dysfunction confers worse prognosis than originally recognized, with increased morbidity, mortality, and impaired quality of life 1

Specialist Referral Recommendation

Referral to a specialist with expertise in coronary microvascular disease and invasive coronary function testing is recommended because specialist-guided testing changes management in approximately 20% of patients and enables stratified medical therapy that significantly improves angina severity and quality of life. 2