Environmental Arsenic Exposure and Risk of Cardiovascular Disease
Background: Environmental exposure to inorganic arsenic (iAs), one of the most abundant elements in the earth’s crust, is widely recognised as a major global health risk – millions of people are estimated to be chronically exposed to arsenic worldwide. Yet, compared to arsenic-related cancer and skin lesions, research on arsenic-related cardiometabolic disease, particularly at lower exposure levels, has been limited. This PhD thesis aims to investigate the epidemiological relationship between chronic environmental arsenic exposure and several sub-types of cardiometabolic disease, with a primary focus on cardiovascular disease (CVD), specifically myocardial infarction (MI), as well as diabetes mellitus (DM) and hypertension. Data sources: Firstly, to explore the relationship between toenail arsenic (including arsenic metabolites and metabolism markers) with MI, the Bangladesh Risk of Acute Vascular Events (BRAVE) study, a case-control study of 1,532 MI cases and 1,334 controls, was used. Secondly, to explore the dose-response relationship between arsenic and several CVD endpoints, a systematic review and two-stage dose-response meta-analyses were performed on 35 studies. Thirdly, to assess the association of environmental arsenic exposure with two major CVD risk factors, diabetes mellitus and hypertension, a systematic review and two-stage dose-response meta-analyses were performed on 71 studies. Lastly, to explore whether genetic variation may be at least partially responsible for inter-individual variation in arsenic-related cardiometabolic disease susceptibility, a narrative systematic review on 14 unique candidate gene-environment (cGxE) studies reporting on 650 single nucleotide polymorphisms (SNPs) in 145 genes was used. Main results: In BRAVE, MI was positively associated with higher toenail monomethylated arsenic (MMA) in μg/g, higher MMA% and a higher primary methylation index (PMI) in both categorical and continuous logistic regression models, and negatively associated with higher iAs% and a higher secondary methylation index (SMI). No statistically significant associations were found for total arsenic (tAs), iAs and dimethyalated arsenic (DMA) in μg/g, nor for DMA%. Dose-response meta-analyses found consistent positive associations between water arsenic concentrations and coronary heart disease (CHD) [fatal, non-fatal, overall], non-fatal stroke, CVD (fatal, non-fatal, overall), hypertension, DM type 2, and gestational diabetes mellitus (GDM). Analyses on low water arsenic concentrations showed positive associations below 10 μg/l for several of the cardiometabolic outcomes studied. From the total of 35 studies on CVD endpoints, and 71 studies on hypertension or DM, only 4 (low quality) studies reported statistically significant negative associations. In the narrative systematic review, 29 SNPs in 21 genes as well as 3 haplotypes (involved in e.g. arsenic metabolism, DNA damage repair, endothelial function, inflammation) were indicative of SNP-arsenic interactions associated with cardiometabolic outcomes. Conclusion: This PhD thesis presents further supports evidence that people exposed to chronic environmental arsenic pollution may be at greater risk for cardiovascular disease, hypertension, diabetes mellitus type 2 and gestational diabetes. Evidence is most conclusive at moderate and high levels of arsenic exposure (i.e., water arsenic > 100 μg/l). However, results at lower arsenic levels suggest that a potential downward revision of the World Health Organization (WHO) guidelines (10 μg/l) may be beneficial for health protection. Whilst studies on individual arsenic species and arsenic metabolism markers are less consistent, results in this thesis suggest a potential role for arsenic metabolism in the development of CVD – potentially particularly at lower arsenic levels. Various SNPs and genes have been suggested to be involved in the susceptibility to cardiometabolic disease, however, these results should be approached with appropriate caution due to the lack of reproducible findings, and the cGxE nature of the included studies. Overall, further long-term prospective studies of individual person data that assess arsenic through different media and include speciation analyses, combined with experimental, mechanistic and genetic studies, are needed to improve understanding of the observed relationship between arsenic and cardiometabolic disease, and the ways in which arsenic may disrupt cell physiology and promote pathophysiology.
Arsenic, Cardiovascular disease, Environmental pollution, Myocardial infarction, Toxic metals
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