When testing Index of Microcirculatory Resistance (IMR), is hyperemia induced before or during the provocative test with Acetylcholine (ACh)?

Timing of Hyperemia in IMR Testing with Acetylcholine

Hyperemia is induced AFTER the acetylcholine (ACh) provocative test is completed, not before or during it. 1

Standardized Protocol Sequence

The 2024 ESC Guidelines provide a clear algorithmic approach for invasive coronary functional testing that separates ACh testing from hyperemic measurements:

Step 1: Acetylcholine Provocation Testing

• Perform ACh testing first with incremental doses (2 μg → 20 μg → 100 μg → 200 μg intracoronary over 60 seconds each) 1
• This assesses endothelium-dependent vasodilation at low doses (2-20 μg) and tests for vasospasm at high doses (100-200 μg) 1
• Stop ACh administration immediately if coronary vasospasm is induced at any dose 1
• Continuous Doppler flow monitoring, 12-lead ECG, and symptom monitoring occur throughout 1

Step 2: Reversal of Vasospasm

• Administer intracoronary nitroglycerine (200 μg) after completing ACh testing to reverse any vasospastic effects 1
• This also allows assessment of endothelium-independent epicardial coronary vasodilation 1

Step 3: Hyperemia Induction for IMR Measurement

• "At the end of the procedure, microcirculatory vasomotor response to i.v. administration of the endothelium-independent vasodilator adenosine is assessed and CFR, IMR, HMR, or MRR are measured" 1
• Adenosine (200 μg intracoronary or i.v. infusion) induces maximal hyperemia for measuring IMR and CFR 1
• IMR requires maximal hyperemia to be calculated accurately 2

Critical Rationale for This Sequence

The separation of ACh testing from hyperemic measurements is physiologically essential:

• ACh is an endothelium-dependent vasodilator that tests for vasospasm and endothelial dysfunction 1
• Adenosine is an endothelium-independent vasodilator that induces maximal hyperemia for structural microvascular assessment 1
• Performing ACh before adenosine allows differentiation between functional (vasospastic) and structural microvascular disease 1

Important Clinical Pitfall

Preceding ACh provocation can influence subsequent physiological measurements, particularly when the ACh test is positive 3:

• Resting mean transit time is significantly longer after positive ACh testing (1.22 ± 0.55 s) compared to negative ACh testing (0.74 ± 0.36 s, p < 0.001) 3
• However, IMR and CFR measurements remain valid despite this influence 3
• The standardized protocol accounts for this by administering nitroglycerine to reverse ACh effects before adenosine administration 1

Alternative Hyperemic Agent

If adenosine is contraindicated, papaverine can be used for hyperemia induction, though it carries risk of polymorphic ventricular tachycardia requiring precautionary measures 1