Endotypes of angina with non-obstructive coronary arteries: a prospective multicentre study

Background and Aims Angina with non-obstructive coronary arteries (ANOCA) is a prevalent myocardial ischaemic syndrome, and women are disproportionately affected. Mechanisms of ischaemia are challenging to diagnose and treatment is empirical.Methods Consecutive patients with angina (or equivalent symptoms), no angiographically severe stenosis and fractional flow reserve > 0.80 undergoing coronary functional testing were prospectively enrolled in nine centres in Europe and North America. Haemodynamic endotypes were assessed measuring coronary flow reserve and resistance using an intracoronary pressure- and temperature-sensitive sensor and bolus thermodilution. Measurements were obtained during resting conditions and following adenosine and acetylcholine. Chest pain and electrocardiographic ischaemic changes were recorded. The participant characteristics of each haemodynamic endotype were investigated using regression analysis. A three-step Delphi consensus method was applied to identify endotype-specific therapies.Results Overall, 1001 participants (mean age 62 +/- 11years, 56% female) were enrolled and eight distinct endotypes were defined by adenosine testing (n = 3) and acetylcholine testing (n = 5), respectively: high resting coronary blood flow (n = 195, 19%); high resistance (n = 125, 13%); compensated high resistance (n = 112, 11%); epicardial coronary spasm (n = 162, 17%); microvascular spasm (n = 75, 8%); endothelial dysfunction (n = 96, 10%); ischaemia w/o haemodynamic changes (n = 68, 7%); and enhanced cardiac nociception (n = 79, 8%). More than one endotype occurred in 119 (12%) individuals and normal responses occurred in 234 (23%) individuals. Each endotype was associated with distinct clinical correlates. The Delphi consensus (100% 'agree' or 'strongly agree') identified endotype-specific medical therapy with a Likert scale score >= 6 for all endotypes.Conclusions In patients with suspected ANOCA, assessment of the symptomatic, electrocardiographic, and haemodynamic responses to adenosine and acetylcholine identifies distinct endotypes and enables mechanism-guided stratified medicine.