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 (O) on cardiovascular mortality are scarce and inconclusive. We aimed to investigate the association between cardiovascular mortality and a broad range of long-term O exposure levels.

Methods: This analysis included 3,206,871 participants aged 35-75 years enrolled in the ChinaHEART study. Participants were recruited from the 31 provinces of the Chinese mainland between January 2015 and December 2020. The five-year average O 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) years, 35,553 (1.1%) participants died from cardiovascular diseases (CVD). Following multivariable adjustment, nonlinear relationships were identified between O concentrations and CVD and ischemic heart disease (IHD) mortality, with inflection points at 85.44 and 88.15 μg/m, respectively. Above these points, a 10.0 μg/m increase in the O level was associated with a 13.9% (hazard ratio [HR]: 1.139, 95% confidence interval [CI]: 1.096-1.184) and 25.0% (HR: 1.250, 95% CI: 1.151-1.357) greater risk of CVD and IHD mortality, respectively. Conversely, O exposure exhibited a linear relationship with ischemic stroke mortality. Moreover, the metabolic factors explained more than half of the association between O exposure and CVD mortality.

Interpretation: Substantial influences of long-term O exposure on CVD mortality were identified, with notable mediation proportions attributed to metabolic factors. These findings could facilitate the air quality standard revisions and risk reduction strategy making in the future.

Funding: This study was supported by the CAMS Innovation Fund for Medical Science (2021-1-I2M-011), the CAMS Innovation Fund for Medical Science (CIFMS, 2022-I2M-C&T-A-010), the National High Level Hospital Clinical Research Funding (2022-GSP-GG-4), the Ministry of Finance of China and National Health Commission of China, the 111 Project from the Ministry of Education of China (B16005).