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November 30, 2021 Circulation. 2021;144:e368–e454. DOI: 10.1161/CIR.0000000000001029 e416 CLINICAL STATEMENTS AND GUIDELINES consistently identified as precursor for ACS.3-6 From the PROMISE trial, nonobstructive CAD was associated with a 3-fold increase in MACE risk over ∼2 years of follow-up.3 Additional analyses from the SCOT-HEART and PROMISE trials reveal that high-risk atherosclerotic plaque features are associated with an elevated MACE risk among patients with nonobstructive CAD.4,5 CCTA commonly identifies patients with nonobstructive CAD but can further define compositional alterations within the plaque (ie, noncalcified plaque) and positive remodeling.4,5,7,25,30 These plaque features have been associated with inducible ischemia, identified as precursors for ACS, and independently predict MACE.5,6,31 Recently, Williams et al reported that a low attenuation plaque burden was associated with a >6-fold increase in incident MI for patients with nonobstructive CAD.4 2. Controlled clinical trials reveal that FFR-CT improves diagnostic accuracy over and above obstructive CAD on CCTA when compared with invasive FFR.12,13 Multinational registries have examined the use of FFR-CT with regards to the use to drive clinical decision-making regarding the use of follow-up ICA and the safety of deferring coronary revascularization in patients with a negative FFR-CT.8-11 From the ADVANCE (Assessing Diagnostic Value of Noninvasive FFR-CT in Coronary Care) registry, FFR-CT changed treatment recommendations in two-thirds of patients, and there were no MACE at 90 days for patients with a negative FFR-CT.10 From the SYNTAX 3 trial,14 FFR-CT was performed in 223 patients. Treatment recommendations and selection of vessels for revascularization were guided by FFR-CT in ∼20% of patients. Stress Testing 3. Approximately 20% to 30% of patients with nonobstructive CAD will demonstrate ischemia.15-24 Patients who experience ischemia with nonobstructive CAD (INOCA – see Section 5.2.3) benefit from assessment of functional significance of an intermediate coronary stenosis as it provides insight into the patient’s presenting symptoms and can help guide clinical management. 5.2.3. Patients With Suspected Ischemia and No Obstructive CAD (INOCA) Recommendations for myocardial blood flow measurements using PET, echocardiography, and CMR are found in Section 5.2.2. Recommendations for Patients With INOCA Referenced studies that support the recommendations are summarized in Online Data Supplements 36 and 37. COR LOE Recommendations 2a B-NR 1. For patients with persistent stable chest pain and nonobstructive CAD and at least mild myocardial ischemia on imaging, it is reasonable to consider invasive coronary function testing to improve the diagnosis of coronary microvascular dysfunction and to enhance risk stratification.1-4 2a B-NR 2. For patients with persistent stable chest pain and nonobstructive CAD, stress PET MPI with MBFR is reasonable to diagnose microvascular dysfunction and enhance risk stratification.5-11 2a B-NR 3. For patients with persistent stable chest pain and nonobstructive CAD, stress CMR with the addition of MBFR measurement is reasonable to improve diagnosis of coronary myocardial dysfunction and for estimating risk of MACE.12-14 2b C-EO 4. For patients with persistent stable chest pain and nonobstructive CAD, stress echocardiography with the addition of coronary flow velocity reserve measurement may be reasonable to improve diagnosis of coronary myocardial dysfunction and for estimating risk of MACE. Synopsis Signs and symptoms of ischemia occur because of focal obstructive CAD, but INOCA is common and may result from alterations in flow within the microvasculature. Thus, many symptomatic patients without obstructive CAD on previous workup may be candidates for assessment of coronary microvascular dysfunction and other causes of INOCA.1 Patients at highest risk for coronary microvascular dysfunction include women, those with hypertension, diabetes, and other insulin-resistant states.15 There is substantive evidence that testing focusing on documentation of coronary or microvascular flow abnormalities can aid in the diagnosis of microvascular angina, and abundant evidence supports that the addition of flow alterations improves risk stratification. Invasive coronary reactivity testing allows for the assessment of vasospasm, in addition to nonendothelial–dependent and endothelium-dependent microvascular reactivity.2,4 From the National Institutes of Health-NHLBI-sponsored WISE (Women’s Ischemia Syndrome Evaluation), impaired coronary flow reserve (ie, <2.32) among women with no obstructive CAD was associated with an elevated hazard for major CAD events with lengthy follow-up of 10 years (P=0.03).2 Among women with no obstructive Downloaded from http://ahajournals.org by on October 7, 2026