Cardiovascular disease remains the leading causing of death worldwide. American Indians experience an elevated prevelance of cardiovascular disease (CVD) and chronic metal exposures. Determining the impact of metal exposures on CVD can inform prevention and exposure reduction strategies. This dissertation will advance environmental monitoring and biological monitoring of lead, uranium, and selenium exposures using both established biomarkers and novel epigenetic biomarkers to determine the associations of metals with CVD, leveraging the Strong Heart Study (SHS), a prospective cohort of CVD and its risk factors among American Indian adults from tribes and communities in Arizona, Oklahoma, North Dakota, and South Dakota. In Chapter 1, we discuss lead, uranium, and selenium, sources of exposure, and relevance to cardiovascular disease. This includes an overview of metal toxicokinetics and how we can assess these contaminants in both established biomarkers, including blood and urine, as well as in epigenetic biomarkers. In Chapter 2, we estimated urinary uranium concentrations from data on uranium in water among Strong Heart Family Study participants. These estimates were derived from relationships between urinary uranium and water uranium assessed in Strong Heart Family Study (SHFS) participants (n=1,356). Predictions were made using generalized linear models and included demographic and clinical participant characteristics in addition to other metal contaminants measured in water and urine. The root mean square error (RMSE) of the prediction model was 1.01, and predicted urine uranium levels were comparable (median: 0.04 μg/g creatinine, 25th-75th: 0.02-0.08 μg/g creatinine) to urine uranium measured in the SHFS (0.04 μg/g creatinine, 0.02-0.07 μg/g creatinine). These findings emphasize the contribution of uranium in water to urine uranium (reflecting internal dose), and demonstrate the relevance of estimating metal contaminants in urine for the SHS to inform relationships with health effects. In Chapter 3, we evaluated whether urinary uranium concentrations were associated with measures of cardiac geometry and functioning among 1,332 American Indian youth and young adults from the SHFS. Transthoracic echocardiography and blood pressure was assessed at baseline (2001-2003) and a follow-up visit (2006-2009). We estimated mean differences in measures of cardiac geometry and functioning at baseline and follow-up using linear mixed effect models with random intercept and slope over time. In fully adjusted models, a log-doubling of urinary uranium was positively associated with left ventricular (LV) mass index (mean difference: 0.49 g/m2, 95% CI: 0.07-0.92 g/m2), left atrial systolic diameter (0.02 cm, 0.01-0.03 cm), and stroke volume (0.66 mL, 0.25-1.08 mL) at baseline. At follow-up, uranium was associated with increases in left atrial diameter (0.02 cm, 0.01-0.03 cm), pulse pressure (0.28 mmHg, 0.05-0.52 mmHg), and incident LV hypertrophy (OR: 1.25, 95% CI: 1.06, 1.48). These findings support the need to determine the potential long-term clinical and subclinical cardiovascular effects of chronic uranium exposure in the general population, and the need for future strategies to reduce exposure. In Chapter 4, we evaluated if blood lead was associated with CVD incidence and mortality in 1,818 adult American Indian participants. This study estimated the risk of incident CVD and CVD deaths in models adjusted for demographic, lifestyle, and cardiovascular risk factors. Blood lead levels in American Indian adults were associated with increased risk of CVD and coronary heart disease (CHD) incidence and mortality. The hazard ratio (HR) (95% CI) of mortality per change across the 80th-20th quantiles in blood lead was 1.15 (1.02-1.30) for CVD overall and 1.22 (1.08-1.37) for CHD. The corresponding HR was 1.11 (1.01-1.22) for incident CVD and 1.12 (1.00-1.25) for incident CHD. These findings contribute to the evidence of lead as a CVD risk factor at low levels and highlight the importance of further reducing lead exposure in communities across the United States, including American Indian communities. In Chapter 5, we leveraged novel epigenetic biomarkers of lead exposure to investigate their association with cardiovascular disease (CVD) incidence and mortality among 2,231 participants of the Strong Heart Study. Blood DNA methylation was measured using the Illumina MethylationEPIC BeadChip at baseline (1989-1991) and epigenetic biomarkers of lead levels in blood, patella, and tibia were estimated using previously developed biomarkers of DNA methylation at specific CpG sites. In adjusted models, the hazard ratio (HR) (95% CI) of CVD mortality per doubling increase in lead epigenetic biomarkers were 1.42 (1.07-1.87) for tibia lead, 1.22 (0.93-1.60) for patella lead, and 1.57 (1.16-2.11) for blood lead. The corresponding HRs for incident CVD were 0.99 (0.83-1.19), 1.07 (0.89-1.29), and 1.06 (0.87-1.30). The association between the tibia lead epigenetic biomarker and CVD mortality was modified by sex (interaction p-value: 0.014), with men at increased risk (HR: 1.42, 95% CI:1.17-1.72) compared to women (HR: 1.04, 95% CI:0.89-1.22). These findings support that epigenetic biomarkers of lead exposure may capture some of the disease risk associated with lead exposure. In Chapter 6, we investigated the association between urinary selenium levels and DNA methylation (DNAm) among 1,357 participants free of CVD and diabetes in the SHS. Selenium concentrations were measured in urine (collected in 1989-1991) using inductively coupled plasma mass spectrometry. DNAm in whole blood was measured cross-sectionally using the Illumina Methylation EPIC BeadChip (850K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated CpG sites associated with urinary selenium levels. Across 788,368 CpG sites, five differentially methylated positions (DMP) (cg00163554, cg18212762, cg25194720, cg11270656, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top associated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Future analyses should explore these relationships prospectively and investigate the potential role of differentially methylated sites with disease endpoints. In Chapter 7, we evaluated if declines in blood lead were associated with changes in systolic and diastolic blood pressure in adult American Indian participants from the SHFS (n=285). Using generalized estimating equations, a significant non-linear association between declines in blood lead and declines in systolic blood pressure was detected, with significant linear associations where blood lead decline was 1 µg/L or higher. These findings suggest the need to further study the cardiovascular impacts of reducing lead exposures and the importance of lead exposure prevention. In conclusion, we find that established biomarkers of metal exposure reflecting internal dose such as blood and urine, as well as epigenetic biomarkers of metals exposures, were associated with subclinical CVD and CVD incidence and mortality. Findings concerning blood lead emphasize that low levels of lead remain relevant for CVD, and declines in blood lead even when small (1.0-10.0 µg/L), were associated with reductions in systolic blood pressure. Novelly, we present that urinary uranium levels were adversely associated with measures of cardiac geometry and left ventricular functioning among American Indian adults, and that future attention must be paid to investigating associations with subclinical disease. We also find utility in using epigenetic biomarkers to capture CVD risk, as tibia and blood epigenetic biomarkers of lead, were associated with increased risk of CVD mortality, and urinary selenium was associated with distinct changes in DNAm. Although further work must further validate these epigenetic biomarkers in different populations, future work must continue to investigate these epigenetic biomarkers given their potential to capture CVD risk.