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. 2016 Dec 1;184(11):806-817.
doi: 10.1093/aje/kww002. Epub 2016 Nov 3.

Peripheral Arterial Disease and Its Association With Arsenic Exposure and Metabolism in the Strong Heart Study

Jonathan D Newman, Ana Navas-Acien, Chin-Chi Kuo, Eliseo Guallar, Barbara V Howard, Richard R Fabsitz, Richard B Devereux, Jason G Umans, Kevin A Francesconi, Walter Goessler, Lyle T Best, Maria Tellez-Plaza

Peripheral Arterial Disease and Its Association With Arsenic Exposure and Metabolism in the Strong Heart Study

Jonathan D Newman et al. Am J Epidemiol. .

Abstract

At high levels, inorganic arsenic exposure is linked to peripheral arterial disease (PAD) and cardiovascular disease. To our knowledge, no prior study has evaluated the association between low-to-moderate arsenic exposure and incident PAD by ankle brachial index (ABI). We evaluated this relationship in the Strong Heart Study, a large population-based cohort study of American Indian communities. A total of 2,977 and 2,966 PAD-free participants who were aged 45-74 years in 1989-1991 were reexamined in 1993-1995 and 1997-1999, respectively, for incident PAD defined as either ABI <0.9 or ABI >1.4. A total of 286 and 206 incident PAD cases were identified for ABI <0.9 and ABI >1.4, respectively. The sum of inorganic and methylated urinary arsenic species (∑As) at baseline was used as a biomarker of long-term exposure. Comparing the highest tertile of ∑As with the lowest, the adjusted hazard ratios were 0.57 (95% confidence interval (CI): 0.32, 1.01) for ABI <0.9 and 2.24 (95% CI: 1.01, 4.32) for ABI >1.4. Increased arsenic methylation (as percent dimethylarsinate) was associated with a 2-fold increased risk of ABI >1.4 (hazard ratio = 2.04, 95% CI: 1.02, 3.41). Long-term low-to-moderate ∑As and increased arsenic methylation were associated with ABI >1.4 but not with ABI <0.9. Further studies are needed to clarify whether diabetes and enhanced arsenic metabolism increase susceptibility to the vasculotoxic effects of arsenic exposure.

Keywords: arsenic; metabolism; peripheral vascular disease.

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Figures

Figure 1.
Figure 1.
Hazard ratios (HRs) for incident peripheral arterial disease (PAD) according to ankle brachial index (ABI) and urinary arsenic concentration (sum of inorganic arsenic levels) in the Strong Heart Study, 1989–1999. A) PAD defined as ABI <0.9; B) PAD defined as ABI >1.4. The curves represent adjusted HRs based on restricted quadratic splines with knots at the 10th, 50th, and 90th percentiles (4.06 μg/g, 9.84 μg/g, and 24.0 μg/g, respectively) of the distribution of the sum of urinary inorganic and methylated arsenic species (∑As). The reference value (HR = 1) was set at the 10th percentile of the ∑As distribution (4.06 µg/g). The models adjusted for sex, age, education, smoking, body mass index, low-density lipoprotein cholesterol, diabetes, hypertension, estimated glomerular filtration rate, and study center. The histograms (gray columns) represent the frequency distribution of urinary arsenic concentrations in the Strong Heart Study sample for 1989–1999. Dashed lines, 95% confidence intervals.
Figure 2.
Figure 2.
Hazard ratios (HRs) for incident peripheral arterial disease (PAD) according to ankle brachial index (ABI), by arsenic metabolite level, in the Strong Heart Study, 1989–1999. The curves represent adjusted HRs for incident PAD defined as ABI <0.9 (panels A and C) or ABI >1.4 (panels B and D) based on restricted quadratic splines with knots at the 10th, 50th, and 90th percentiles of the arsenic species distribution, corresponding to 8.1%, 13.8%, and 21.4%, respectively, for percent monomethylarsonous acid (MMA%) and 65.8%, 77.9%, and 86.6%, respectively, for percent dimethylarsinous acid (DMA%). The reference value (HR = 1) was set at the 10th percentile of the arsenic species distribution (8.1% for MMA% and 65.8% for DMA%). The models adjusted for sex, age, education, smoking, body mass index, low-density lipoprotein cholesterol, diabetes, hypertension, estimated glomerular filtration rate, study center, and the sum of inorganic arsenic species. The histograms (gray columns) represent the frequency distribution of urinary arsenic concentrations in the Strong Heart Study sample for 1989–1999. Dashed lines, 95% confidence intervals.
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