Ambient Air Pollution and Subclinical Cardiovascular Disease Measured by Magnetic Resonance Imaging in the Canadian Alliance for Healthy Hearts and Minds Study

Background Long-term exposure to air pollution, even at levels below regulatory standards, has been associated with higher risk of cardiovascular-related mortality. Less is known about the association of air pollution and initial development of CVD in low-exposure settings in generally healthy human populations. Objective In the Canadian Alliance for Healthy Hearts and Minds Cohort Study (CAHHM), we aimed to investigate the association between low-level exposure to key air pollutants and subclinical carotid atherosclerosis in adults without known clinical CVD. To date, the association of ambient air pollution and atherosclerosis measured by magnetic resonance imaging (MRI) has not been studied. Methods We studied 6,645 Canadian adults recruited between 2014-2018 from the provinces of British Columbia, Alberta, Ontario, Quebec, and Nova Scotia, for whom average long-term exposures to nitrogen dioxide (NO2), ozone (O3), and fine particulate matter (PM2.5) were estimated for five years prior to the start of CAHHM recruitment, and who underwent MRI to assess carotid vessel wall volume (CWV). Linear mixed models were used to quantify associations between each air pollutant and CWV adjusting for individual-level and community-level risk factors for CVD. Secondary analyses included region-specific stratification and modeling the effect of one pollutant on CWV within low, medium, and high levels of a second pollutant to test for interactions. Results Higher PM2.5 was nominally associated with lower CWV (quintile 5: 893.3 mm3, quintile 1: 908.8 mm3; p-trend =0.05), but this was not robust in region-stratified analysis. Higher NO2 was associated with lower CWV (quintile 5: 889.5 mm3, quintile 1: 918.6 mm3; p-trend <.0001). Higher O3 was associated with higher CWV (quintile 5: 925.4 mm3, quintile 1: 899.7 mm3; p-trend =0.02). NO2 emerged as a consistent effect modifier of both PM2.5 and O3. Conclusion In a cohort of generally healthy adults living in Canada, a country with relatively low levels of air pollution, exposure to NO2 was negatively associated, and O3 was positively associated with CWV as a measure of subclinical atherosclerosis by MRI, while associations to PM2.5 were inconsistent. The reasons for these associations warrant further study. ### Competing Interest Statement Dr Anand reported receiving grants from Canadian Partnership Against Cancer, Heart and Stroke Foundation of Canada, and Canadian Institutes of Health Research, and a Canadian Institutes of Health Research Foundation grant during the conduct of the study and serving as the Tier 1 Canada Research Chair Ethnicity and Cardiovascular Disease and as the Michael G Degroote Heart and Stroke Foundation Chair in Population Helath Research, and receiving grants from Heart and Stroke Foundation of Canada and Canadian Institutes of Health Research, and receiving personal fees from Bayer outside the submitted work. Dr Friedrich reported receiving personal fees from Circle CVI Inc for serving as a board member and adviser and being a shareholder outside the submitted work. Dr de Souza has served as an external resource person to the World Health Organization's Nutrition Guidelines Advisory Group on trans fats, saturated fats, and polyunsaturated fats. The WHO paid for his travel and accommodation to attend meetings from 2012-2017 to present and discuss this work. He has presented updates of this work to the WHO in 2022. He has also done contract research for the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism, and Diabetes, Health Canada, and the World Health Organization for which he received remuneration. He has received speaker's fees from the University of Toronto, and McMaster Children's Hospital. He has held grants from the Canadian Institutes of Health Research, Canadian Foundation for Dietetic Research, Population Health Research Institute, and Hamilton Health Sciences Corporation as a principal investigator, and is a co-investigator on several funded team grants from the Canadian Institutes of Health Research. He has served as an independent director of the Helderleigh Foundation (Canada). He serves as a member of the Nutrition Science Advisory Committee to Health Canada (Government of Canada), and a co-opted member of the Scientific Advisory Committee on Nutrition (SACN) Subgroup on the Framework for the Evaluation of Evidence (Public Health England). All other authors declare no conflicts of interest. ### Funding Statement CAHHM was funded by the Canadian Partnership Against Cancer (CPAC), Heart and Stroke Foundation of Canada (HSF-Canada), and the Canadian Institutes of Health Research (CIHR). Financial contributions were also received from the Population Health Research Institute and CIHR Foundation Grant no. FDN-143255 to S.S.A.; FDN-143313 to J.V.T.; FDN 154317 to E.E.S and Project Grant no. P12-175346 to R.J.dS. In-kind contributions from A.R.M. and S.E.B. from Sunnybrook Hospital, Toronto for MRI reading costs, and Bayer AG for provision of IV contrast. The Canadian Partnership for Tomorrow's Health is funded by the Canadian Partnership Against Cancer and Health Canada, BC Cancer, Genome Quebec, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Dalhousie University, Ontario Institute for Cancer Research, Alberta Health, Alberta Cancer Foundation, and Alberta Health Services. The PURE Study was funded by multiple sources. The Montreal Heart Institute Biobank is funded by Mr André Desmarais and Mrs France Chrétien-Desmarais and the Montreal Heart Institute Foundation ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Hamilton Integrated Research Ethics Board gave ethical approval for this work (HiREB # 13-255). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors