Project Summary Cardiovascular diseases (CVD) are the primary cause of death and a major cause of years of life lost in the US and in the world. Cohort studies conducted in North America and Europe have provided crucial information in identifying exposure to ambient fine particulate matter (PM2.5) as a cause of increased CVD risks. They have also pointed out important directions for future research, including the differential toxicity of PM2.5 chemical constituents to CVD incidence, the shape of concentration-response (C-R) functions, impact of exposure time windows and indoor air pollution exposure. The objectives of our study are to assess the associations between long-term exposure to PM2.5 constituents and incident CVD, and investigate the impact of exposure time window and indoor air pollution on these associations. Approach. We will conduct a retrospective multi-cohort study in China using personal health records from five national cohorts with adjudicated CVD endpoints maintained by the Fuwai Hospital. To provide individual-level exposure trajectories for ~120,000 cohort participants during their follow-up period, we will develop an ensemble machine learning model using ground air quality measurements, satellite data, and air quality model simulations to generate 1 km resolution national PM2.5 mass and major constituent (sulfates, nitrates, elemental carbon, organic carbon, lead, and nickel) exposure estimates between 1998 and 2020 (Aim 1). Using cohort data from 2007 to 2020 for our main analyses, we will use Cox proportional hazard models to estimate the associations of long-term exposures to PM2.5 constituents and adverse cardiovascular outcomes including total CVD, acute myocardial infarction, and stroke (Aim 2). Variations of this model will be used to investigate the shape of the C-R functions (linear vs. non-linear) as well as the impact of exposure errors using exposure estimates between 1998 and 2020 (Aim 2a). We will also examine windows of susceptibility for CVD endpoints using both time-variant and time- invariant exposure metrics (Aim 2b). Finally, we will evaluate the confounding effect of indoor air pollution on the C-R functions using a sub-cohort with estimated personal PM2.5 exposure estimates based on Fuwai Hospital's ongoing Multi-Region Panel Study (Aim 2c). Expected Results. Given the tremendous variability in PM2.5 constituent concentrations in China over time and space, our findings will contribute new PM2.5 constituent-specific C-R functions in CVD burden calculation in both the US and the world. Our study will also expand our knowledge on important factors affecting these associations such as exposure window and indoor air pollution.

Narrative This study will assess the associations between long-term exposure to PM2.5 constituents and cardiovascular mortality and morbidity in a retrospective multi-cohort study. Usinig five national cohorts and multi-city indoor air pollution measurements in China, we will investigate the shape of the CVD concentration-response functions and the impacts of indoor air pollution and exposure windows. The findings of this study will provide additional scientific support for designing effective policy and public health actions to lower the CVD burden in both the US and China.