Practical Cardiovascular Medicine. Elias B. Hanna

response to acetylcholine and ischemic defects on nuclear testing,¹²⁸ and another found an increased prevalence of abnormal stress testing (77%) in patients with abnormal vasomotion.¹³⁰ Yet, stress imaging with echo or SPECT is not very sensitive; stress imaging with PET or MRI is preferred to detect abnormal vasodilatory reserve. Unlike nuclear SPECT imaging, nuclear PET can quantify the absolute myocardial flow, both at rest and after stress and their ratio (<2-2.5 is abnormal).

      Microvascular dysfunction is mostly prevalent in women, while epicardial vasospasm is nearly as prevalent in men as in women.^120,121 In ACOVA and in 2 other large studies, ~20% of men with chest pain and unobstructed coronary arteries had microvascular dysfunction, and ~20% had macrovascular spasm; ~70% of women had abnormal vasomotor response (microvascular dysfunction ~40%; macrovascular spasm ~30%).^6,120,121 The prevalence of microvascular dysfunction actually increases with age (mean age 58-64).

      In macrovascular spasm, pain is predominantly a resting pain, while in microvascular dysfunction, pain is predominantly exertional or mixed resting/exertional (70%). ^120-122

      β-blockers, CCBs, nitrates, ranolazine, statins, and ACE-Is have been used for this syndrome with a variable success rate. Unlike in macrovascular spasm, β-blockers are recommended and were first-line treatment in CorMicA trial; ¹²² they are efficacious via a reduction of exertional myocardial O2 demands, as in obstructive CAD, not via a direct microvascular effect. Nitrates are not microvascular dilators but lessen ischemia through preload reduction. Ranolazine appears to be particularly effective in reducing angina and improving myocardial flow, via improving diastolic relaxation.¹³¹ In one study of microvascular dysfunction, L-arginine, a precursor of NO available as an over-the-counter supplement, significantly improved myocardial flow.¹³²

Appendix 4. Women with chest pain and normal coronary arteries

      Women with typical angina frequently (~50%) do not have any significant CAD. In the WISE study, ~60% of women with chest pain undergoing coronary angiography (median age, 58) did not have any significant CAD, despite an abnormal stress test in the majority of them;¹³³ ~50% of women with chest pain and no obstructive CAD had microvascular dysfunction (as assessed by coronary flow reserve). ¹³⁴ Other studies showed a 70% combined prevalence of vasomotor abnormalities in women with possible or typical angina and no CAD.^6,120–122 As such, 50% of women without CAD continue to have chest pain for over a year, with a significant risk of MI (5.5%), HF (7.5%), stroke, and combined cardiovascular events (20%) at 6-year follow-up, higher than patients without persistent chest pain, albeit far lower than patients with CAD.^133-135 Microvascular dysfunction may be present without any stress test abnormality.¹³⁴ Perfusion stress PET or MRI is preferred.

      The high rate of events on follow-up may be directly related to the following:

       Ischemic events/MI triggered by coronary vasospasm.

       Endothelial dysfunction and abnormal response to acetylcholine predicts the future development of obstructive CAD,¹³⁵ and a 14% risk of cardiac events, including progressive CAD, at 3 years.¹³⁶

       Since patients with spasm and endothelial dysfunction have underlying atherosclerosis, erosion of non-obstructive plaque is another potential mechanism of MI. A dysfunctional endothelium may contribute to plaque destabilization and erosion because of its reduced antioxidative potential.

      The chicken or the egg dilemma: Diastolic dysfunction with elevated LVEDP may be the cause but also the consequence of microvascular dysfunction, especially in patients without significant LV concentric remodeling. This partly explains HF events in these patients.¹³⁷

      In sum, abnormalities of coronary flow may be due to obstructive CAD, coronary epicardial spasm, or microvascular spasm/ dysfunction. While obstructive CAD is associated with the highest risk of events, abnormal vasomotion is associated with an intermediate risk of events, including MI, arrhythmias, and progressive CAD, higher than in patients with no CAD and normal vasomotion.

Appendix 5. Diagnostic strategy for ischemia with non-obstructed coronary arteries (INOCA)

      In patients undergoing coronary angiography for typical angina who are found to have unobstructed coronary arteries, the following invasive strategy may be performed to diagnose “coronary vasomotion disorders:”

       Intracoronary acetylcholine assessment for macrovascular spasm and macrovascular endothelial dysfunction. Normally, when the endothelium is normal, acetylcholine vasodilates the coronary arteries at the macro- and microvascular levels. Macrovascular spasm is defined as >75-90% epicardial narrowing. Macrovascular endothelial dysfunction is defined as a paradoxical, mild diffuse narrowing of the epicardial coronary arteries >20% with acetylcholine (not as severe as vasospasm).

       Intracoronary acetylcholine assessment of the microcirculation if no macrovascular spasm occurs, via ST-segment response (Ong et al studies and CorMicA) or via coronary blood flow measurement.6,120–122 In microvascular endothelial dysfunction, coronary blood flow declines with acetylcholine, or remains unchanged (<50% increase).

        Intravenous adenosine assessment of the microcirculation via coronary flow reserve OR index of microvascular resistance*Coronary blood flow may be calculated using a Doppler wire (flow=velocity x vessel area), but also a more widely available FFR pressure wire that has a temperature sensor. The wire is advanced midway in the coronary artery. Depending on the transit time of a 3-ml saline injection through the coronary guiding catheter, the thermodilution sensor estimates coronary flow at rest and during IV adenosine-induced hyperemia (flow=1/transit time)*Coronary flow reserve (CFR) is the ratio of flow or velocity with adenosine vs rest. CFR < 2.3 (2-2.5) is abnormal.*Index of microvascular resistance is calculated with the FFR wire at hyperemia (=distal coronary pressure/flow). An index ≥25 is indicative of microvascular dysfunction.

      Acetylcholine causes vasodilatation if the endothelium is intact and able to generate NO, whereas adenosine vasodilates by directly acting on smooth muscle cells; thus, acetylcholine tests “NO- or endothelium-dependent” vascular function, whereas adenosine tests “endothelium-independent” function. Acetylcholine is administered in slow, incremental intracoronary boluses, over 3 min for each, and adenosine is administered as IV infusion.

      Albeit safe, the acetylcholine testing is skipped at some institutions. By adopting this protocol in patients with angina and unobstructed coronary arteries, macrovascular endothelial dysfunction is found in ~40%, microvascular dysfunction in 30-50%, and epicardial vasospasm in 20-30% of patients.^{120–122,130,138,139} Overall, abnormal vasomotion is found in ~70% of patients. Preferably, microvascular dysfunction is assessed in each coronary artery, as microvascular dysfunction is frequently a localized process and patients most commonly have microvascular dysfunction in one vessel (nearly equal distribution among LAD and RCA, less likely in LCx).¹³⁸ For safety, most studies have only assessed one vessel, the LAD ^122,130,139

      Also, consider performing FFR if diffuse luminal irregularities are present (the mild diffuse epicardial disease may be significant in ~5% of the cases). If bridging is present, consider calculating diastolic FFR using dobutamine.

      CorMicA trial showed that anti-anginal therapy tailored to the results of the above functional testing significantly improves angina severity and quality of life, compared to presumptive therapy.¹²² As such, patients with microvascular angina received: (1 ^st line) ß-blocker; ( 2 ^nd line) CCB; (3 ^rd line) ranolazine. Patients with epicardial vasospasm received CCB +/-nitrates.

       Non-invasive strategy- Microvascular dysfunction may also be diagnosed non-invasively, after a negative coronary angiogram, via adenosine stress PET or adenosine MRI perfusion