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

<div><p>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 75^th and the 25^th 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.</p></div

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

<p>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).</p

Selected characteristics of Strong Heart Study main cohort participants at baseline (Visit 1) by quartiles of baseline urine arsenic (ΣAs, μg/g creatinine).

<p>Selected characteristics of Strong Heart Study main cohort participants at baseline (Visit 1) by quartiles of baseline urine arsenic (ΣAs, μg/g creatinine).</p

Concentrations of plasma fibrinogen, PAI-1, and CRP at Visit 2 by participant characteristics and diabetes status at baseline in Strong Heart Study main cohort participants.

<p>Concentrations of plasma fibrinogen, PAI-1, and CRP at Visit 2 by participant characteristics and diabetes status at baseline in Strong Heart Study main cohort participants.</p

Geometric mean ratios (95% confidence interval) of baseline fibrinogen, Visit 2 PAI-1, and Visit 2 CRP by baseline urine arsenic concentrations by diabetes status in the Strong Heart Study main cohort.

<p>Geometric mean ratios (95% confidence interval) of baseline fibrinogen, Visit 2 PAI-1, and Visit 2 CRP by baseline urine arsenic concentrations by diabetes status in the Strong Heart Study main cohort.</p

Metabolites associated with body mass index in American Indians.

<p>Metabolites associated with body mass index in American Indians.</p

The number of SNPs in each TMCC prevalence range with a statistically significant different PAF than HapMap CEU or CHD MAFs.

<p>The number of SNPs in each TMCC prevalence range with a statistically significant different PAF than HapMap CEU or CHD MAFs.</p

The proportion of PAFs in ranges for TMCC and HapMap populations.

<p>The proportion of PAFs in ranges for TMCC and HapMap populations.</p

Separation of individuals with normal body weight versus those with abdominal obesity by a multi-metabolites score comprising of all metabolites significantly associated with waist circumference using sparse partial least-squares discriminant analysis.

<p>Separation of individuals with normal body weight versus those with abdominal obesity by a multi-metabolites score comprising of all metabolites significantly associated with waist circumference using sparse partial least-squares discriminant analysis.</p

Clinical characteristics of the study participants according to obesity (N = 431).

<p>Clinical characteristics of the study participants according to obesity (N = 431).</p