Association between long-term exposure to air pollution and risk of ischemia and non-obstructive coronary arteries: insights from the J-CMD study

Background Exposure to ambient particulate matter 2.5 (PM2.5) is associated with an increased risk of cardiovascular events and mortality. A previous single-center study suggested that high PM2.5 exposure in patients with ischemia and nonobstructive coronary arteries (INOCA) is associated with coronary vasomotor abnormalities. However, no large-population, multicenter study with interventional diagnostic procedures (IDP), including acetylcholine provocation test, index of microvascular resistance (IMR), and coronary flow reserve (CFR), has been conducted. The aim of this study was to investigate the association of long-term exposure to air pollution with INOCA using a nationwide registry in Japan. Methods This prospective, multicenter, nationwide registry enrolled 1410 patients who had typical or atypical angina-like chest pain and underwent IDP between August 2022 and December 2025. After excluding patients with obstructive coronary artery disease (n=324) and those with missing air pollution data (n=3), 1083 patients were finally analyzed. Air pollution exposure was estimated based on the municipality of the admitting hospital and the date of diagnosis, using data from local monitoring stations. Exposure concentrations were calculated as the 2-year averages with a 1-year lag preceding the diagnosis for PM2.5, photochemical oxidants (Ox), sulfur dioxide (SO2), nitrogen monoxide (NO), and nitrogen dioxide (NO2). Results Based on the results of IDP, 896 patients were identified as INOCA including 551 epicardial spasm, 200 microvascular spasm (MVS), 425 coronary microvascular dysfunction (CMD), and 197 combined type, and 187 patients as non-cardiac chest pain. Multivariable mixed-effects logistic regression models, adjusted for age, sex, smoking status, coronary risk factors, ambient temperature, and humidity, demonstrated that long-term exposure to SO2 was associated with an increased risk of epicardial spasm (OR: 2.47; 95% CI: 1.24 to 4.91, p=0.010), CMD (OR: 2.34; 95% CI: 1.21 to 4.51, p=0.011), and the combined type (OR: 2.75; 95% CI: 1.29 to 5.83, p=0.009). Furthermore, long-term exposure to PM2.5 was associated with an increased risk of the combined type (OR: 2.18; 95% CI: 1.11 to 4.32, p=0.025). Quantile-based g-computation analysis showed that the air pollutant mixture (consisting of PM2.5, SO2, and NO2) was associated with an increased risk of epicardial spasm (OR: 1.53; 95% CI: 1.18 to 1.98, p=0.002), CMD (OR: 1.39; 95% CI: 1.07 to 1.81, p=0.013), and combined type (OR: 1.72; 95% CI: 1.24 to 2.39, p=0.001). Conclusions This study demonstrated that long-term exposure to SO2 and PM2.5 is associated with INOCA endotypes. These findings suggest that air pollution is a modifiable risk factor for INOCA, even at levels below current environmental standards.