E Characterising disease mechanisms in patients with angina and non-obstructive coronary arteries to stratify therapy

Angina with nonobstructive coronary arteries (ANOCA) is highly prevalent but there has been limited improvement in patient outcomes due to incomplete understanding of the underlying mechanisms. I sought to determine the relationship between invasive coronary physiological metrics in patients with undifferentiated ANOCA and their a) clinical phenotype and b) response to physiology-stratified therapy. Four parallel thematically linked clinical studies were performed in patients with ANOCA, classified according to endothelium-independent and -dependent vascular function. The first study was designed to reappraise the utility of exercise ECG treadmill tests (ETTs) in identifying an ischaemic substrate against the contemporary reference standard of comprehensive epicardial and microvascular physiology assessment. The second study was designed to assess the utility of coronary flow reserve (CFR), the most used measure to diagnose coronary microvascular disease (CMD) in the catheter laboratory, in predicting response to anti-ischaemic therapy in patients with ANOCA. The third study was designed to assess whether additional measurements made in the catheter laboratory, namely minimal microvascular resistance and acetylcholine flow reserve, provide incremental value in predicting therapeutic response compared to measuring CFR alone. The fourth study was designed to assess the utility of quantitative stress perfusion cardiac magnetic resonance imaging measures in predicting response to therapy in patients with ANOCA. One hundred and two patients were enrolled for study 1; 32 had ischaemia on ETT and 70 did not (groups were phenotypically similar). Ischaemia during ETT was 100% specific for CMD (defined as abnormal endothelium-independent or -dependent microvascular dysfunction). Acetylcholine flow reserve was the strongest predictor of inducible ischaemia. 87 patients underwent randomisation for study 2 and 3 (57 retrospectively classified as the impaired CFR (CMD) group and 30 as the normal CFR (reference) group; groups were phenotypically similar). Patients with an impaired CFR had a significantly greater increment in exercise time, in response to anti-ischaemic therapy, compared to those with a normal CFR. CFR was the strongest predictor of response on multivariate regression. Minimal microvascular resistance and acetylcholine flow reserve, in additional to CFR, provide incremental value in predicting response to anti-ischaemic therapy and should be considered for personalized therapy in patients with ANOCA. Ischaemic ECG changes on ETT are highly specific for CMD and can be used as a rule-in test in patients with ANOCA. Coronary flow reserve is the strongest independent predictor of response to anti-ischaemic therapy in patients with ANOCA, whilst minimal microvascular resistance and acetylcholine flow reserve may provide incremental value in personalizing therapy. Funding Medical Research Council Clinical Research Training Fellowship (MR/T029390/1).