Low-moderate urine arsenic and biomarkers of thrombosis and inflammation in the Strong Heart Study

Abstract

The underlying pathology of arsenic-related cardiovascular disease (CVD) is unknown. Few studies have evaluated pathways through thrombosis and inflammation for arsenic-related CVD, especially at low-moderate arsenic exposure levels (<100 μg/L in drinking water). We evaluated the association of chronic low-moderate arsenic exposure, measured as the sum of inorganic and methylated arsenic species in urine (ΣAs), with plasma biomarkers of thrombosis and inflammation in American Indian adults (45-74 years) in the Strong Heart Study. We evaluated the cross-sectional and longitudinal associations between baseline ΣAs with fibrinogen at three visits (baseline, 1989-91; Visit 2, 1993-95, Visit 3, 1998-99) using mixed models and the associations between baseline ΣAs and Visit 2 plasminogen activator inhibitor-1 (PAI-1) and high sensitivity C-reactive protein (hsCRP) using linear regression. Median (interquartile range) concentrations of baseline ΣAs and fibrinogen, and Visit 2 hsCRP and PAI-1 were 8.4 (5.1, 14.3) μg/g creatinine, 346 (304, 393) mg/dL, 44 (30, 67) mg/L, and 3.8 (2.0, 7.0) ng/mL, respectively. Comparing the difference between the 75th and the 25th percentile of ΣAs (14.3 vs. 5.1 μg/g creatinine), ΣAs was positively associated with baseline fibrinogen among those with diabetes (adjusted geometric mean ratio (GMR): 1.05, 95% CI: 1.02, 1.07) not associated among those without diabetes (GMR: 1.01, 95% CI: 0.99, 1.02) (p-interaction for diabetes = 0.014), inversely associated with PAI-1 (GMR: 0.94, 95% CI: 0.90, 0.99), and not associated with hsCRP (GMR: 1.00, 95% CI: 0.93, 1.08). We found no evidence for an association between baseline ΣAs and annual change in fibrinogen over follow-up (p-interaction = 0.28 and 0.12 for diabetes and non-diabetes, respectively). Low-moderate arsenic exposure was positively associated with baseline fibrinogen in participants with diabetes and unexpectedly inversely associated with PAI-1. Further research should evaluate the role of prothrombotic factors in arsenic-related cardiovascular disease.

Fig 1. Geometric mean ratios of fibrinogen, PAI-1, and CRP in relation to urine arsenic in the SHS main cohort by diabetes status.

Lines represent the geometric mean ratio (GMR) of baseline fibrinogen (left panel), PAI-1 at Visit 2 (center panel), or CRP at Visit 2 (right panel), by log-transformed urine arsenic concentrations (ΣAs, μg/g creatinine), with the 10th percentile (3.6 μg/g creatinine) as the reference. The GMR of baseline fibrinogen concentrations are from a linear mixed model and the GMR of Visit 2 PAI-1, and CRP concentrations are from a linear regression (see statistical methods for details). Arsenic was modeled using restricted quadratic splines of log-transformed urine arsenic (knots at the 10^th, 50^th, 90^th percentiles; 3.6, 8.4, and 22.4 μg/g creatinine, respectively). Models were fully-adjusted for all potential confounders in Model 2 (age, sex, education (no, some, or finished high school), smoking (never, former, current), alcohol drinking (never, former, current), BMI (kg/m²), LDL cholesterol (mg/dL), hypertension (yes/no), eGFR (mL/min/1.73 m²), and study center (AZ, OK, ND/SD).