Association of long-term exposure to ozone with cardiovascular mortality and its metabolic mediators: evidence from a nationwide, population-based, prospective cohort study

Background Previous studies about chronic effects of ozone (O3) 3 ) on cardiovascular mortality are scarce and inconclusive. We aimed to investigate the association between cardiovascular mortality and a broad range of long-term O3 3 exposure levels. Methods This analysis included 3,206,871 participants aged 35-75 - 75 years enrolled in the ChinaHEART study. Participants were recruited from the 31 provinces of the Chinese mainland between January 2015 and December 2020. The fi ve-year average O3 3 concentrations before baseline visits were calculated to represent long-term exposure. Findings Over a median follow-up period of 4.7 (interquartile range: 3.7-6.2) - 6.2) years, 35,553 (1.1%) participants died from cardiovascular diseases (CVD). Following multivariable adjustment, nonlinear relationships were identified fi ed between O3 3 concentrations and CVD and ischemic heart disease (IHD) mortality, with inflection fl ection points at 85.44 and 88.15 mu g/m 3 , respectively. Above these points, a 10.0 mu g/m 3 increase in the O3 3 level was associated with a 13.9% (hazard ratio [HR]: 1.139, 95% confidence fi dence interval [CI]: 1.096-1.184) - 1.184) and 25.0% (HR: 1.250, 95% CI: 1.151-1.357) - 1.357) greater risk of CVD and IHD mortality, respectively. Conversely, O3 3 exposure exhibited a linear relationship with ischemic stroke mortality. Moreover, the metabolic factors explained more than half of the association between O3 3 exposure and CVD mortality. Interpretation Substantial influences fl uences of long-term O3 3 exposure on CVD mortality were identified, fi ed, with notable mediation proportions attributed to metabolic factors. These fi ndings could facilitate the air quality standard revisions and risk reduction strategy making in the future.