Is functional coronary microvascular dysfunction in a patient with a history of coronary microvascular dysfunction, currently on nebivolol (beta blocker) and amlodipine (calcium channel blocker), of a spastic or structural nature?

Coronary Microvascular Dysfunction: Distinguishing Spastic from Structural Mechanisms

Coronary microvascular dysfunction can be either functional (spastic) or structural in nature, and both mechanisms frequently coexist in the same patient—the key distinction lies in measuring index of microvascular resistance (IMR) during hyperemia, where functional CMD shows normal IMR (<25) with elevated resting flow, while structural CMD demonstrates elevated IMR (≥25) with impaired endothelial function. 1, 2

Pathophysiological Distinction

The 2024 ESC Guidelines explicitly state that microvascular angina results from both structural and functional changes that may co-exist and contribute to MVA. 1 This is not an either-or diagnosis—most patients have elements of both mechanisms.

Functional (Spastic) CMD Characteristics:

• Elevated resting coronary blood flow linked to enhanced nitric oxide synthase activity 2, 3
• Normal minimal microvascular resistance during hyperemia (IMR <25 units, HMR <2.5 mmHg/cm/s) 2, 3
• Abnormal vasoconstriction of coronary arterioles causing dynamic arteriolar obstruction 1
• Represents approximately 62% of all patients with impaired coronary flow reserve 2
• Characterized by inability to further augment flow during stress despite already elevated baseline flow 3

Structural CMD Characteristics:

• Reduced resting flow with impaired capacity for flow augmentation during exercise 3
• Elevated minimal microvascular resistance (IMR ≥25 units) during hyperemia 2, 4
• Endothelial dysfunction that reduces flow augmentation during exercise 2, 3
• Associated with cardiovascular risk factors: smoking, age, diabetes, hypertension, dyslipidemia 1
• Linked to inflammatory conditions (SLE, rheumatoid arthritis) 1

Diagnostic Algorithm

The 2024 ESC Guidelines emphasize that invasive coronary function testing is essential to determine the final endotype so that appropriate treatment can be initiated. 1

Required Diagnostic Criteria:

1. Symptoms of myocardial ischemia (effort or rest angina, exertional dyspnea) 2
2. Absence of obstructive CAD (<50% diameter reduction or FFR >0.80) 2
3. Impaired coronary flow reserve (CFR <2.5 by thermodilution or Doppler) 1, 2

Distinguishing the Endotypes:

• Measure IMR during hyperemia: IMR <25 = functional CMD; IMR ≥25 = structural CMD 2, 4
• Acetylcholine provocation testing at high doses (100-200 μg intracoronary): negative test rules out microvascular spasm in functional CMD 2
• Assess resting coronary blood flow: elevated in functional CMD (24.6 cm/s) vs. normal in structural CMD (16.6 cm/s) 3

Common Pitfall:

The 2019 ESC Guidelines warn that development of angina in response to acetylcholine without angiographically evident epicardial spasm, with or without ST-segment changes, suggests microvascular spasm and should be treated accordingly. 1 This is critical because your patient is already on nebivolol (beta-blocker), which is absolutely contraindicated in vasospastic angina as it can precipitate coronary spasm. 4, 5

Clinical Implications for Your Patient

Given that your patient is currently on nebivolol (beta-blocker) and amlodipine (calcium channel blocker), this suggests their clinician suspects either:

1. Structural CMD (appropriate for beta-blocker therapy) 4, 5
2. Functional CMD without vasospastic component (appropriate for beta-blocker therapy) 5

However, if there is any vasospastic component (either epicardial or microvascular), beta-blockers are absolutely contraindicated because they leave α-mediated vasoconstriction unopposed. 4, 5

Critical Next Step:

Acetylcholine provocation testing must be performed to rule out vasospastic angina before continuing beta-blocker therapy. 5 The 2024 ESC Guidelines recommend this testing in all patients with ANOCA to determine the final endotype. 1

Prognostic Considerations

Both functional and structural CMD carry similar adverse prognosis, with no significant difference in major adverse cardiac events (MACE) or target vessel failure (TVF) at 5-year follow-up between the two endotypes (p=0.88 for MACE, p=0.55 for TVF). 6

The key prognostic marker is impaired CFR itself, which is unequivocally associated with increased MACE and TVF rates over 5 years, regardless of whether microvascular resistance is elevated or normal. 6 Specifically, CFR <2.32 is associated with elevated hazard for major coronary events at 10-year follow-up. 2

Treatment Strategy Based on Endotype

If Structural CMD (IMR ≥25):

• Uptitrate beta-blocker (nebivolol or carvedilol) to target resting heart rate 55-60 bpm 4, 5
• Optimize ACE inhibitor therapy to improve endothelium-dependent vasodilation 4
• Continue aggressive statin therapy for anti-inflammatory effects on endothelial function 4
• Target CFR improvement to ≥2.5 and IMR reduction to <25 with repeat invasive testing at 3-6 months 4

If Functional CMD (IMR <25):

• Beta-blockers improve CFR by 24-33% through heart rate reduction and increased diastolic perfusion time 2, 5
• ACE inhibitors enhance endothelium-dependent vasodilation 2
• Statins improve endothelial function through anti-inflammatory mechanisms 2

If Vasospastic Component Present:

• Immediately discontinue beta-blocker 4, 5
• Calcium channel blockers become first-line therapy (your patient is already on amlodipine) 1
• Consider adding ranolazine or nicorandil for refractory symptoms 5

The 2024 ESC Guidelines emphasize that 80% of ANOCA patients show endothelial dysfunction, 60% have MVA/VSA, and both mechanisms frequently coexist, making comprehensive invasive testing essential rather than assuming one mechanism over another. 1