Angina with non-obstructive coronary artery disease (ANOCA) and coronary microvascular dysfunction (CMD) are two increasingly recognized conditions related with adverse prognosis and increased cardiovascular events [1]. Recently, the evaluation of coronary microcirculation in the setting of ANOCA was recommended in the 2024 European Society of Cardiology Guidelines for the Management of Chronic Coronary Syndromes, with a IB recommendation for invasively assessing coronary flow reserve (CFR) and/or index of microvascular resistance (IMR) [2]. Most frequently, the left anterior descending (LAD) artery is interrogated during these investigations. However, invasive CFR/IMR studies question the homogenous distribution of microcirculatory function and support multivessel evaluation of CMD [3]. Considering the inherent limitations of CFR and IMR, including suboptimal reproducibility, operator dependence, influence by epicardial disease and resting hemodynamics [4], novel indices such as microvascular resistance reserve (MRR) that overcome these pitfalls could be useful for more accurate CMD diagnosis, patient prognostication and investigation of any inhomogeneity of coronary microcirculation function [5,6].

In this context, Hoshino et al. [7] aimed to assess the homogeneity of MRR in coronary territories of ANOCA patients, with the use of non-invasive methods. The study included ANOCA symptomatic patients undergoing [15O]H2O positron emission tomography (PET) and three-vessel invasive assessment of fractional flow reserve (FFR). MRR was calculated by combining the invasive FFR with the non-invasive CFR, as derived by PET flow measurements, and was considered pathologic if found below or equal to 3.0. A total of 155 patients (50% male, mean age 59± 10 years) were included, with a total of 465 vessels (mean MRR: 3.92 ± 1.21) being analyzed. No significant differences in the MRR values were reported among the three coronary branches, with good correlation of MRR among the three coronary branches (r = 0.76 to 0.86) and small (2.4 to 7.5%) between-measurement mean differences. Regarding single-measurement reliability, the overall intra-class correlation coefficient for absolute agreement was 0.80 (95% CI: 0.74–0.85), while in 80% of patients, diagnostic concordance of CMD was present in all three vessels.

This study holds significant diagnostic implications for ANOCA patients. First, it showcases that microvascular function is homogenously distributed in all three coronary arteries, thus validating the current practice of single artery CMD investigation [2]. However, as some patients exhibited inter-territorial variability, identifying phenotypes needing multivessel investigation, such as those with borderline positive or negative values, is essential for establishing accurate and reproducible diagnostic protocols. Second, this study provides novel insights on the usefulness of non-invasive CMD assessment. Despite routine investigation of ANOCA patients with PET is unlikely in everyday practice, further development and validation of non-invasive CMD markers could allow to comprehensively evaluate both microcirculation and epicardial artery characteristics in a single examination, leading to improved detection of all contributors to myocardial ischemia and avoidance of unnecessary invasive procedures. Importantly, this fused assessment of epicardial and microvascular anatomy and physiology would allow better identification of pathophysiologic relations, including association of CMD with atherosclerotic lesion characteristics and high-risk plaques, therefore uncovering novel pathogenetic and treatment insights. These promising hypotheses require further research in the coming years, aiming to further enhance our diagnostic abilities and ultimately ANOCA patient management.