Resting and stress coronary flow velocity for identification of different endotypes and risk classes in ANOCA patients beyond coronary flow velocity reserve

Abstract Background Coronary microvasculature disease (CMD) affects a subset of patients with angina with no obstructive coronary arteries (ANOCA) and is diagnosed with transthoracic echocardiography (TTE) through a reduction (≤2.0) of coronary flow velocity reserve (CFVR), measured as the stress/rest coronary flow velocity (CFV) ratio. Aim To assess the dominant (functional vs structural, high-rest vs low-stress CFV) mechanism of CMD and the corresponding long-term risk. Methods In a prospective multicenter study design, we enrolled 1,033 patients (age 63±11 years, 533 women, 230 diabetics, ejection fraction 59±5%) with ANOCA. Recruitment (years 2004-2022) involved 4 accredited laboratories, with inter-observer variability <10% for CFV. CFV was obtained with TTE by pulsed-wave Doppler in the mid-distal left anterior descending coronary artery at rest and after dipyridamole stress. All-cause death was the only end-point. A receiver operating characteristic analysis was used to obtain the best prognostic predictor, corresponding to >32 cm/s for resting and ≤53 cm/s for peak stress CFV. Results 289 patients (28%) showed a reduction in CFVR. Four groups were identified: normal rest and peak CFV (Group 1, n=465), abnormal rest and normal peak CFV (Group 2, n=350), normal rest and abnormal peak CFV (Group 3, n=210), abnormal rest and peak CFV (Group 4, n=8). During a mean follow-up of 4.8±4.1 years, 82 (8%) patients died. Eight-year mortality was 4% in Group 1, 11% in Group 2, 15% in Group 3, and 58% in Group 4 (p<0.0001). Yearly mortality was 2.3% in patients with isolated abnormal rest CFV as well as in those with isolated abnormal peak CFV (p=0.89) (Figure). Conclusion TTE allows phenotyping of the presence of CMD in the heterogeneous garden variety of ANOCA patients. High resting with reduced peak CFV is the less frequent, and by far more malignant, endotype.