Urinary Arsenic and Cadmium Associations with Findings from Cranial MRI in American Indians: Data from the Strong Heart Study
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ABSTRACT: Background:
Arsenic and cadmium are known cardiovascular toxicants that pose disproportionate risk to rural communities where environmental exposures are high. American Indians have high vascular risk, which may be attributable in part to these exposures. Objective:
We examined urine metal concentrations in association with magnetic resonance imaging findings of vascular brain injury or cerebral atrophy in adult American Indians. Methods:
We measured arsenic and cadmium in American Indian participants from the Strong Heart Study (1989–1991) and evaluated these associations with later (2010–2013) measures of infarct, hemorrhage, white matter hyperintensity (WMH) grade, brain and hippocampal volume, and sulcal and ventricle atrophy using nested multivariate regression analyses. Results:
Among participants with available data ( Discussion:
This population-based cohort of American Indian elders had measured values of urine arsenic and cadmium several times higher than previous population- and clinic-based studies in the United States and Mexico, and comparable values with European industrial workers. Our findings of associations for arsenic and cadmium exposures with vascular brain injury are consistent with established literature. Environmental toxicant accumulation is modifiable; public health policy may benefit from focusing on reductions in environmental metals. https://doi.org/10.1289/EHP6930
SUBMITTER: Suchy-Dicey A
PROVIDER: S-EPMC7745762 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:The Cerebrovascular Disease and its Consequences in American Indians study conducted cranial MRI examination of surviving participants of the Strong Heart Study, a longitudinal cohort of elderly American Indians. METHODS:Of the 1,033 recruited participants, some were unable to complete the MRI (n = 22), some scans were unusable due to participant motion or technical errors (n = 13), and one community withdrew consent after data collection (n = 209), leaving 789 interpretable MRI scan images. Six image sequences were obtained in contiguous slices on 1.5T scanners. Neuroradiologists graded white matter hyperintensities (WMH), sulci, and ventricles on a 0- to 9-point scale, and recorded the presence of infarcts and hemorrhages. Intracranial, brain, hippocampal, and WMH volumes were estimated by automated image processing. RESULTS:The median scores for graded measures were 2 (WMH) and 3 (sulci, ventricles). About one-third of participants had lacunar (20%) or other infarcts (13%); few had hemorrhages (5.7%). Findings of cortical atrophy were also prevalent. Statistical analyses indicated significant associations between older age and findings of vascular injury and atrophy; male gender was associated with findings of cortical atrophy. CONCLUSIONS:Vascular brain injury is the likely explanation in this elderly American Indian population for brain infarcts, hemorrhages, WMH grade, and WMH volume. Although vascular brain injury may play a role in other findings, independent degenerative other disease processes may underlie abnormal sulcal widening, ventricular enlargement, hippocampal volume, and total brain volume. Further examination of risk factors and outcomes with these findings may expand the understanding of neurological conditions in this understudied population.
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Project description:Cadmium (Cd) is an environmental pollutant that has been associated with cardiovascular disease in populations, but the relationship of Cd with hypertension has been inconsistent. We studied the association between urinary Cd concentrations, a measure of total body burden, and blood pressure in American Indians, a US population with above national average Cd burden. Urinary Cd was measured using inductively coupled plasma mass spectrometry, and adjusted for urinary creatinine concentration. Among 3714 middle-aged American Indian participants of the Strong Heart Study (mean age 56 years, 41% male, 67% ever-smokers, 23% taking antihypertensive medications), urinary Cd ranged from 0.01 to 78.48 μg g-1 creatinine (geometric mean=0.94 μg g-1) and it was correlated with smoking pack-year among ever-smokers (r2=0.16, P<0.0001). Participants who were smokers were on average light-smokers (mean 10.8 pack-years), and urinary Cd was similarly elevated in light- and never-smokers (geometric means of 0.88 μg g-1 creatinine for both categories). Log-transformed urinary Cd was significantly associated with higher systolic blood pressure in models adjusted for age, sex, geographic area, body mass index, smoking (ever vs never, and cumulative pack-years) and kidney function (mean blood pressure difference by lnCd concentration (β)=1.64, P=0.002). These associations were present among light- and never-smokers (β=2.03, P=0.002, n=2627), although not significant among never-smokers (β=1.22, P=0.18, n=1260). Cd was also associated with diastolic blood pressure among light- and never-smokers (β=0.94, P=0.004). These findings suggest that there is a relationship between Cd body burden and increased blood pressure in American Indians, a population with increased cardiovascular disease risk.
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Project description:Telomere length, a marker of biological aging, has been associated with cardiovascular disease (CVD). Increased arterial stiffness, an indicator of arterial aging, predicts adverse CVD outcomes. However, the relationship between telomere length and arterial stiffness is less well studied. Here we examined the cross-sectional association between leukocyte telomere length (LTL) and arterial stiffness in 2,165 American Indians in the Strong Heart Family Study (SHFS). LTL was measured by qPCR. Arterial stiffness was assessed by stiffness index β. The association between LTL and arterial stiffness was assessed by generalized estimating equation model, adjusting for sociodemographics (age, sex, education level), study site, metabolic factors (fasting glucose, lipids, systolic blood pressure, and kidney function), lifestyle (BMI, smoking, drinking, and physical activity), and prevalent CVD. Results showed that longer LTL was significantly associated with a decreased arterial stiffness (β=-0.070, P=0.007). This association did not attenuate after further adjustment for hsCRP (β=-0.071, P=0.005) or excluding participants with overt CVD (β=-0.068, P=0.012), diabetes (β=-0.070, P=0.005), or chronic kidney disease (β=-0.090, P=0.001). In summary, shorter LTL was significantly associated with an increased arterial stiffness, independent of known risk factors. This finding may shed light on the potential role of biological aging in arterial aging in American Indians.
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Project description:OBJECTIVES:Deficient plasminogen activator inhibitor-1 (PAI-1) prevented hypertension in mice. Plasma PAI-1 was associated with hypertension in cross-sectional analyses, but the prospective association of PAI-1 with incident hypertension in large epidemiological studies is scarce. METHODS:Leveraging two longitudinal cohorts of American Indians in the Strong Heart Study (SHS, N?=?1019) and the Strong Heart Family Study (SHFS, N?=?1502), we examined the prospective association of plasma PAI-1 with incident hypertension by multivariate logistic regression, adjusting for age, sex, study site, smoking, drinking, dietary sodium, obesity, lipids, fasting glucose, kidney function, inflammation, and follow-up years. Family relatedness in the SHFS was accounted for using the GLIMMIX procedure. Plasma PAI-1 level at baseline was measured by immunoassay. All participants were free of hypertension, cardiovascular diseases, and chronic kidney disease at baseline. RESULTS:A total of 305 and 258 participants, respectively, from the SHS (57?±?7 years) and the SHFS (33?±?13 years) developed incident hypertension during follow-up. In the SHS, higher level of log-transformed PAI-1 was associated with 1.35-fold increased risk of hypertension [odds ratio (OR) (95% confidence interval): 1.35 (1.06-1.72)]. Analysis using categorical PAI-1 (in tertiles) showed that participants in the highest tertile (?58?ng/ml) had 63% increased risk for hypertension [OR?=?1.63 (1.12-2.37)] compared with those in the lowest tertile (<33?ng/ml). This association was confirmed in the SHFS with similar effect sizes [OR?=?1.41 (1.11-1.81) for log-transformed PAI-1; OR?=?1.64 (1.08-2.50) for categorical PAI-1: ?58 vs. <33?ng/ml]. CONCLUSION:A higher level of plasma PAI-1 is significantly associated with hypertension in American Indians, independent of established risk factors. The potential causality warrants further investigation.
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Project description:Dyslipidemia is an independent and modifiable risk factor for aging and age-related disorders. Routine lipid panel cannot capture all individual lipid species in blood (i.e., blood lipidome). To date, a comprehensive assessment of the blood lipidome associated with mortality is lacking in large-scale community-dwelling individuals, especially in a longitudinal setting. Using liquid chromatograph-mass spectrometry, we repeatedly measured individual lipid species in 3,821 plasma samples collected at two visits (~ 5.5 years apart) from 1,930 unique American Indians in the Strong Heart Family Study. We first identified baseline lipids associated with risks for all-cause mortality and CVD mortality (mean follow-up period: 17.8 years) in American Indians, followed by replication of top hits in European Caucasians in the Malmö Diet and Cancer-Cardiovascular Cohort (n = 3,943, mean follow-up period: 23.7 years). The model adjusted age, sex, BMI, smoking, hypertension, diabetes, and LDL-c at baseline. We then examined the associations between changes in lipid species and risk of mortality. Multiple testing was controlled by false discovery rate (FDR). We found that baseline levels and longitudinal changes of multiple lipid species, e.g., cholesterol esters, glycerophospholipids, sphingomyelins, and triacylglycerols, were significantly associated with risks of all-cause or CVD mortality. Many lipids identified in American Indians could be replicated in European Caucasians. Network analysis identified differential lipid networks associated with risk of mortality. Our findings provide novel insight into the role of dyslipidemia in disease mortality and offer potential biomarkers for early prediction and risk reduction in American Indians and other ethnic groups.
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Project description:The Cerebrovascular Disease and its Consequences in American Indians (CDCAI) Study recruited surviving members of a 20-year, longitudinal, population-based cohort of American Indians focused on cardiovascular disease, its risk factors, and its consequences. The goal of the CDCAI Study is to characterize the burden, risk factors, and manifestations of vascular brain injury identified on cranial MRI. The CDCAI Study investigators enrolled 1,033 participants aged 60 and older from 11 American Indian communities and tribes in the Northern Plains, Southern Plains, and Southwestern United States. In addition to cranial MRI performed according to standardized protocols, participants underwent extensive medical interview, clinical examination, neurocognitive testing, physical function evaluation, electrocardiogram, and provided blood and urine specimens. Participants also self-administered questionnaires covering demographics, quality of life, and medical history. This report describes the design, implementation, and some of the unique challenges of this study and data collection.
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Project description:Essentials Plasminogen activator inhibitor-1 (PAI-1) advanced cellular senescence in experiment studies. No population study exists on the association between PAI-1 and biological aging in American Indians. We found cross-sectional and longitudinal associations between higher PAI-1 and shorter telomere length. Our findings suggest a pathway linking PAI-1 with biological aging beyond metabolic factors.SummaryBackground Plasminogen activator inhibitor-1 (PAI-1) promotes cellular aging both in vitro and in vivo. Telomere length is a marker of biological aging. Objectives To examine the cross-sectional and longitudinal associations between plasma PAI-1 and leukocyte telomere length in a large-scale epidemiological study of American Indians. Methods We measured leukocyte telomere length (LTL) and plasma PAI-1 in 2560 American Indians who were free of overt cardiovascular disease (CVD) and participated in the Strong Heart Family Study (SHFS) clinical examination in 2001-2003. LTL and PAI-1 were repeatedly measured in 475 participants who attended SHFS clinical visits in both 2001-2003 and 1998-1999. A generalized estimating equation model was used to examine the cross-sectional and longitudinal associations between PAI-1 and LTL, adjusting for known risk factors. Results A higher level of plasma PAI-1 was negatively associated with shorter age-adjusted LTL (β = -0.023; 95% CI, -0.034 to -0.013). This association was attenuated (β = -0.015; 95% CI, -0.029 to -0.002) after adjustments for demographics, study site, lifestyle (smoking, drinking and physical activity) and metabolic factors (obesity, blood pressure, fasting glucose, insulin, lipids and kidney function). Further adjustment for hsCRP did not change this association (β = -0.015; 95% CI, -0.029 to -0.001). Longitudinal analysis revealed that change in plasma PAI-1 was also inversely associated with change in LTL after adjusting for demographics, follow-up years, lifestyle factors, changes in metabolic factors, baseline levels of PAI-1 and LTL (β = -0.0005; 95% CI, -0.0009 to -0.0001). Conclusions A higher level of plasma PAI-1 was associated with shorter LTL in American Indians. This finding may suggest a potential role of PAI-1 in biological aging among American Indians.
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Project description:Background: Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations.Methods: The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses.Results: CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10-20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10-7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10-4.Conclusion: In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation.
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