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Original Research |

Association Between Exposure to Low to Moderate Arsenic Levels and Incident Cardiovascular Disease: A Prospective Cohort Study ONLINE FIRST

Katherine A. Moon, MPH; Eliseo Guallar, MD, DrPH; Jason G. Umans, MD, PhD; Richard B. Devereux, MD; Lyle G. Best, MD; Kevin A. Francesconi, PhD; Walter Goessler, PhD; Jonathan Pollak, MPP; Ellen K. Silbergeld, PhD; Barbara V. Howard, PhD; and Ana Navas-Acien, MD, PhD
[+] Article and Author Information

This article was published at www.annals.org on 24 September 2013.


From Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Medical Institutions, Baltimore, Maryland; National Center for Cardiovascular Research, Madrid, Spain; MedStar Health Research Institute, Hyattsville, Maryland; Georgetown University and Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC; New York Presbyterian Hospital/Weill Medical College of Cornell Medical Center, New York, New York; Missouri Breaks Industries Research, Timber Lake, South Dakota; and Karl-Franzens University, Graz, Austria.

Editor's Note: This online-first version will be replaced with a final version when it is included in the issue. The final version may differ in small ways.

Note: Ms. Moon and Dr. Navas-Acien had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Grant Support: By the National Heart, Lung, and Blood Institute (HL090863; 5T32HL007024; and Strong Heart Study grants HL41642, HL41652, HL41654, and HL65521) and the National Institute of Environmental Health Sciences (P30ES03819 and R01ES021367).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1159.

Reproducible Research Statement:Study protocol: The original study proposal funded by the National Institutes of Health and the manuscript proposal approved by the Strong Heart Study Publications and Presentations Committee are available from Dr. Navas-Acien (e-mail, anavas@jhsph.edu). Statistical code: Available from Dr. Navas-Acien (e-mail, anavas@jhsph.edu). Data set: As with other National Heart, Lung, and Blood Institute cohorts, the Strong Heart Study data are not publicly available. Outside investigators may apply to use the data generated according to the established protocols for Strong Heart Study Resource and Data Sharing, including community approval, through formal application (http://strongheart.ouhsc.edu/datarequest.html).

Requests for Single Reprints: Ana Navas-Acien, MD, PhD, Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 North Wolfe Street, Room W7513D, Baltimore, MD 21205; e-mail, anavas@jhsph.edu.

Current Author Addresses: Ms. Moon: Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 North Wolfe Street, Room W7604, Baltimore, MD 21205.

Dr. Guallar: Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, 2024 East Monument Street, Room 2-639, Baltimore, MD 21205.

Drs. Umans and Howard: MedStar Health Research Institute, 6525 Belcrest Road, Suite 700, Hyattsville, MD 20782.

Dr. Devereux: Weill Medical College of Cornell Medical Center, 520 East 70th Street, Room K-4, New York, NY 10021.

Dr. Best: 1935 188th Avenue NW, Watford City, ND 58854.

Drs. Francesconi and Goessler: Institute for Chemistry - Analytical Chemistry, Karl Franzens University, Stremayrgasse 16/3. Stock, 8010 Graz, Austria.

Mr. Pollak: Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 North Wolfe Street, Room W7508A, Baltimore, MD 21205.

Dr. Silbergeld: Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 North Wolfe Street, Room E6644, Baltimore, MD 21205.

Dr. Ana Navas-Acien: Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 North Wolfe Street, Room W7513D, Baltimore, MD 21205.

Author Contributions: Conception and design: E. Guallar, J. Pollak, B.V. Howard, A. Navas-Acien.

Analysis and interpretation of the data: K.A. Moon, E. Guallar, K.A. Francesconi, W. Goessler, J. Pollak, E.K. Silbergeld, B.V. Howard, A. Navas-Acien.

Drafting of the article: K.A. Moon, L.G. Best, A. Navas-Acien.

Critical revision of the article for important intellectual content: K.A. Moon, E. Guallar, J. Pollak, E.K. Silbergeld, B.V. Howard, A. Navas-Acien.

Final approval of the article: E. Guallar, L.G. Best, W. Goessler, J. Pollak, E.K. Silbergeld, B.V. Howard, A. Navas-Acien.

Provision of study materials or patients: L.G. Best.

Statistical expertise: E. Guallar, J. Pollak, A. Navas-Acien.

Obtaining of funding: E. Guallar, L.G. Best, B.V. Howard, A. Navas-Acien.

Administrative, technical, or logistic support: L.G. Best, W. Goessler, A. Navas-Acien.

Collection and assembly of data: L.G. Best, W. Goessler, J. Pollak, B.V. Howard, A. Navas-Acien.


Ann Intern Med. Published online 24 September 2013 doi:10.7326/0003-4819-159-10-201311190-00719
Text Size: A A A

Background: Long-term exposure to high levels of arsenic is associated with increased risk for cardiovascular disease, whereas risk from long-term exposure to low to moderate arsenic levels (<100 µg/L in drinking water) is unclear.

Objective: To evaluate the association between long-term exposure to low to moderate arsenic levels and incident cardiovascular disease.

Design: Prospective cohort study.

Setting: The Strong Heart Study baseline visit between 1989 and 1991, with follow-up through 2008.

Patients: 3575 American Indian men and women aged 45 to 74 years living in Arizona, Oklahoma, and North and South Dakota.

Measurements: The sum of inorganic and methylated arsenic species in urine at baseline was used as a biomarker of long-term arsenic exposure. Outcomes were incident fatal and nonfatal cardiovascular disease.

Results: A total of 1184 participants developed fatal and nonfatal cardiovascular disease. When the highest- and lowest-quartile arsenic concentrations (>15.7 vs. <5.8 µg/g creatinine) were compared, the hazard ratios for cardiovascular disease, coronary heart disease, and stroke mortality after adjustment for sociodemographic factors, smoking, body mass index, and lipid levels were 1.65 (95% CI, 1.20 to 2.27; P for trend < 0.001), 1.71 (CI, 1.19 to 2.44; P for trend < 0.001), and 3.03 (CI, 1.08 to 8.50; P for trend = 0.061), respectively. The corresponding hazard ratios for incident cardiovascular disease, coronary heart disease, and stroke were 1.32 (CI, 1.09 to 1.59; P for trend = 0.002), 1.30 (CI, 1.04 to 1.62; P for trend = 0.006), and 1.47 (CI, 0.97 to 2.21; P for trend = 0.032), respectively. These associations varied by study region and were attenuated after further adjustment for diabetes, hypertension, and kidney disease measures.

Limitations: Direct measurement of individual arsenic levels in drinking water was unavailable.

Conclusion: Long-term exposure to low to moderate arsenic levels was associated with cardiovascular disease incidence and mortality.

Primary Funding Source: National Heart, Lung, and Blood Institute and National Institute of Environmental Health Sciences.

Figures

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Appendix Figure 1.

Strong Heart Study clinic visits, follow-up, and data used in the present study.

* Urinary arsenic concentrations were only available for 380 participants.

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Figure 1.

Hazard ratios for cardiovascular disease and coronary heart disease incidence and mortality, by urinary arsenic concentration (n= 3575).

Solid lines represent adjusted hazard ratios based on restricted quadratic splines for the log-transformed sum of inorganic and methylated arsenic species, with knots at the 10th, 50th, and 90th percentiles (3.8, 9.7, and 24.0 µg/g creatinine, respectively). The dotted lines represent upper and lower 95% CIs. The reference was set at the 10th percentile of the arsenic distribution (3.8 µg/g creatinine). Adjustment factors were the same as those for model 2 in Tables 1 and 2. The bars represent a histogram of urinary arsenic distribution among participants (the extreme tails of the histogram were truncated because only 1 participant had a urinary arsenic level <1.6 µg/g creatinine and 31 had a level >54.6 µg/g creatinine).

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Appendix Figure 2.

Hazard ratios for stroke incidence, by urinary arsenic concentration (n= 3575).

The solid line represents the adjusted hazard ratio based on restricted quadratic splines for the log-transformed sum of inorganic and methylated arsenic species, with knots at the 10th, 50th, and 90th percentiles (3.8, 9.7, and 24.0 µg/g creatinine, respectively). The dotted lines represent upper and lower 95% CIs. The reference was set at the 10th percentile of the arsenic distribution (3.8 µg/g creatinine). Adjustment factors were the same as those for model 2 in Tables 1 and 2. The bars represent a histogram of urinary arsenic distribution among participants (the extreme tails of the histogram were truncated because only 1 participant had a urinary arsenic level <1.6 µg/g creatinine and 31 had urinary arsenic levels >54.6 µg/g creatinine).

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Appendix Figure 3.

Hazard ratios and 95% CIs for cardiovascular disease and coronary heart disease mortality when an interquartile range of urinary arsenic concentrations is compared, by participant characteristics at baseline (n= 3575).

Hazard ratios for cardiovascular disease and coronary heart disease mortality were stratified by each subgroup of interest, and associated P values for interaction were obtained from stratified Cox proportional hazards models with log-transformed arsenic (sum of inorganic and methylated arsenic species) as a continuous variable, adjusted for the same covariates as those in model 2 in 1 and 2. The interquartile range of urinary arsenic concentrations was 5.8 to 15.7 µg/g creatinine. For cardiovascular disease and coronary heart disease mortality hazard ratios by methylation indices (below and above the median proportions of inorganic arsenic, MMA, and DMA), the data set was restricted to participants with detectable inorganic arsenic, MMA, and DMA concentrations (n = 3381). For this subset, the corresponding urinary arsenic interquartile range was 6.1 to 16.2 µg/g creatinine. DMA = dimethylarsinate; HR = hazard ratio; MMA = monomethylarsonate.

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Appendix Figure 4.

Hazard ratios and 95% CIs for cardiovascular disease incidence when an interquartile range of urinary arsenic concentrations is compared, by participant characteristics at baseline (n= 3575).

Hazard ratios for cardiovascular disease incidence (fatal and nonfatal events) were stratified by each subgroup of interest, and associated P values for interaction were obtained from stratified Cox proportional hazards models with log-transformed arsenic (sum of inorganic and methylated arsenic species) as a continuous variable, adjusted for the same covariates as those in model 2 in the main analysis. The interquartile range of urinary arsenic concentrations was 5.8 to 15.7 µg/g creatinine. For cardiovascular disease incidence hazard ratios by methylation indices (below and above median proportions of inorganic arsenic, MMA, and DMA), the data set was restricted to participants with detectable inorganic arsenic, MMA, and DMA concentrations (n = 3381). For this subset, the corresponding urinary arsenic interquartile range was 6.1 to 16.2 µg/g creatinine. DMA = dimethylarsinate; HR = hazard ratio; MMA = monomethylarsonate.

Grahic Jump Location
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Appendix Figure 5.

Hazard ratios and 95% CIs for coronary heart disease incidence when an interquartile range of urinary arsenic concentrations is compared, by participant characteristics at baseline (n= 3575).

Hazard ratios for coronary heart disease incidence (fatal and nonfatal events) were stratified by each subgroup of interest, and associated P values for interaction were obtained from stratified Cox proportional hazards models with log-transformed arsenic (sum of inorganic and methylated arsenic species) as a continuous variable, adjusted for the same covariates as those in model 2 in the main analysis. The interquartile range of urinary arsenic concentrations was 5.8 to 15.7 µg/g creatinine. For coronary heart disease hazard ratios by methylation indices (below and above median proportions of inorganic arsenic, MMA, and DMA), the data set was restricted to participants with detectable inorganic arsenic, MMA, and DMA concentrations (n = 3381). For this subset, the corresponding urinary arsenic interquartile range was 6.1 to 16.2 µg/g creatinine. DMA = dimethylarsinate; HR = hazard ratio; MMA = monomethylarsonate.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 6.

Hazard ratios and 95% CIs for stroke incidence when an interquartile range of urine arsenic concentrations is compared, by participant characteristics at baseline (n= 3575).

Hazard ratios for stroke incidence (fatal and nonfatal events) were stratified by each subgroup of interest, and associated P values for interaction were obtained from stratified Cox proportional hazards models with log-transformed arsenic (sum of inorganic and methylated arsenic species) as a continuous variable, adjusted for the same covariates as those in model 2 in the main analysis. The interquartile range of urine arsenic concentrations was 5.8 to 15.7 µg/g creatinine. For stroke incidence hazard ratios by methylation indices (below and above median proportions of inorganic arsenic, MMA, and DMA), the data set was restricted to participants with detectable inorganic arsenic, MMA, and DMA concentrations (n = 3381). For this subset, the corresponding urine arsenic interquartile range was 6.1 to 16.2 µg/g creatinine. DMA = dimethylarsinate; HR = hazard ratio; MMA = monomethylarsonate.

Grahic Jump Location
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Figure 2.

Hazard ratios for cardiovascular disease incidence and mortality, stratified by study region.

The lines represent adjusted hazard ratios based on restricted quadratic splines for the log-transformed sum of inorganic and methylated arsenic species, with knots at the 10th, 50th, and 90th percentiles (3.8, 9.7, and 24.0 µg/g creatinine, respectively). The solid lines indicate participants from Arizona, the dotted lines indicate those from the Dakotas, and the dashed lines indicate those from Oklahoma. The reference was set at the 10th percentile of the arsenic distribution (3.8 µg/g creatinine). Adjustment factors were the same as those for model 2 in Tables 1 and 2. The bars represent a histogram of urinary arsenic distribution among participants (the extreme tails of the histogram were truncated because only 1 participant had a urinary arsenic level <1.6 µg/g creatinine and 31 had urinary arsenic levels >54.6 µg/g creatinine).

Grahic Jump Location
Grahic Jump Location
Figure 3.

Hazard ratios for cardiovascular disease incidence and mortality, stratified by diabetes status.

The lines represent adjusted hazard ratios based on restricted quadratic splines for the log-transformed sum of inorganic and methylated arsenic species, with knots at the 10th, 50th, and 90th percentiles (3.8, 9.7, and 24.0 µg/g creatinine, respectively). The solid lines indicate participants with diabetes at baseline, and the dotted lines indicate those without diabetes at baseline. The reference was set at the 10th percentile of the arsenic distribution (3.8 µg/g creatinine). Adjustment factors were the same as those for model 2 in Tables 1 and 2. The bars represent a histogram of urinary arsenic distribution among participants (the extreme tails of the histogram were truncated because only 1 participant had a urinary arsenic level <1.6 µg/g creatinine and 31 had urinary arsenic levels >54.6 µg/g creatinine).

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