Heart Failure is a leading cause of death and disability worldwide. The identification of risk factors of heart failure in healthy individuals is key to improve disease prevention and reduce mortality. Metals exposures are recently established cardiovascular disease risk factors, but their association with heart failure remains understudied and prospective studies across diverse populations are needed. Metals are widespread in the environment, some of the sources of exposure include drinking water, air, and soil contamination. Some population groups, particularly American Indian, Hispanic/Latino, and Black communities in the United States are exposed to higher levels of environmental metals as a result of sociodemographic and structural factors including structural racism. These population groups suffer a higher burden of heart failure compared to White populations. Importantly, the burden of heart failure in American Indian communities in the United States, a population group with high rates of diabetes, hypertension, and other cardiovascular disease risk factors, is underreported, and key risk factors of heart failure in these population groups remain understudied. This dissertation characterized relevant risk factors of heart failure in American Indian participants from the Strong Heart Study. Towards the goal of identifying novel preventable cardiovascular disease risk factors, it comprehensively assessed the sources of exposure and biomarkers for multiple non-essential and essential metals with a focus on characterizing drivers of disparities in drinking water metal concentrations. Then, it evaluated the role of exposure to multiple metals (individually and as a mixture) on the risk of heart failure and overall cardiovascular disease and all-cause mortality, leveraging three geographically and racially and ethnically diverse population-based cohorts: the Multi-Ethnic Study of Atherosclerosis (MESA), the Strong Heart Study (SHS), and the Hortega cohort. Last, it identified and evaluated new opportunities for the mitigation of metal toxicity through nutritional interventions. Chapter 1 provides background information about heart failure epidemiology and pathophysiology, the role of environmental metals on cardiovascular disease, and introduces the dissertation framework necessary to contextualize the work included in this dissertation. Chapter 2 estimated the incidence of heart failure in the SHS, a large epidemiological cohort of American Indian adults from Arizona, Oklahoma, North Dakota, and South Dakota, followed from 1989-1991 through 2019. A parsimonious heart failure-risk prediction equation that accounts for relevant cardiovascular risk factors affecting American Indian communities was developed. The incidence rate of heart failure was 9.5 per 1,000 person-years, with higher rates across participants with diabetes, hypertension, and albuminuria. Significant predictors for heart failure risk at 5 and 10 years included age, smoking, albuminuria, and previous myocardial infarction. Diabetes diagnosis and higher levels of HbA1c were significant predictors of risk at 10 and 28 years. Models achieved a high discrimination performance (C-index (95%CI): 0.81 (0.76, 0.84) at 5 years, 0.78 (0.75, 0.81) at 10 years, and 0.77 (0.74, 0.78) up to 28 years), and some associations varied across HF subtypes. Chapter 3 developed a comprehensive overview of the main sources and routes of exposure, biotransformation, and biomarkers of exposure and internal dose for 12 metals/metalloids, including 8 non-essential elements (arsenic, barium, cadmium, lead, mercury, nickel, tin, uranium) and 4 essential elements (manganese, molybdenum, selenium, and zinc), providing a set of recommendations for the use and interpretation of metal biomarkers in epidemiological studies. Chapter 4 conducted the first nationwide geospatial analysis identifying racial/ethnic inequalities in arsenic and uranium concentrations in public drinking water across the conterminous United States using geospatial models. The association between county-level racial/ethnic composition and public water arsenic and uranium concentrations (2000-2011)was assessed. Higher proportions of Hispanic/Latino and American Indian/Alaskan Native residents were associated with 6% (95% CI: 4-8%), and 7% (3-11%) higher levels of arsenic, and 17% (13-22%), and 2% (-4-8%), higher levels of uranium, respectively, in public drinking water, after accounting for relevant social and geological indicators. Higher county-level proportions of non-Hispanic Black residents were associated with higher arsenic and uranium in the Southwest, where concentrations of these contaminants are high. These findings identified the key role of structural racism as driver of drinking water metal concentrations inequalities. Chapter 5 evaluated the prospective association between urinary metal levels, a established biomarker of internal dose, and incident heart failure across three geographically and ethnically/racially diverse cohorts: MESA and SHS in the United States, and the Hortega Study in Spain. These findings consistently identified significant associations across cohorts for cadmium (pooled hazard ratio: 1.15 (95% CI: 1.07, 1.24), tungsten (1.07 (1.02, 1.12)), copper (1.31 (1.18, 1.45)), molybdenum (1.13 (1.05, 1.22)), and zinc (1.22 (1.14, 1.32))). Higher levels of urinary metals analyzed as a mixture were significantly associated with increased incident heart failure risk in MESA and SHS, and non-significantly increased in the Hortega Study, which has a smaller number of events. Chapter 6 assessed the prospective association of urinary metals with incident cardiovascular disease and all-cause mortality in MESA, including a total of 6,599 participants at baseline (2000-2001), followed through 2019. Significant associations between higher levels of urinary cadmium, tungsten, uranium, cobalt, copper, and zinc, and higher risk of CVD and all-cause mortality were identified. A positive linear dose-response was identified for cadmium and copper with both endpoints. The adjusted HRs (95%CI) for an interquartile range (IQR) increase in the mixture of these six urinary metals and the correspondent 10-year survival probability difference (95% CI) were 1.29 (1.11, 1.56), and -1.1% (-2.0, -0.05) for incident CVD and 1.66 (1.47, 1.91), and -2.0% (-2.6, -1.5) for all-cause mortality. Chapter 7 investigated the effects of a nutritional intervention with folic acid (FA) and B12 supplementation on arsenic methylation in children exposed to high levels of drinking water arsenic in Bangladesh. The randomized controlled trial included a total of 240 children 8-11 years old. Compared to placebo, the supplementation group experienced a significant increase in the concentration of blood DMA, a non-toxic arsenic metabolite, by 14.0% (95%CI: 5.0, 25.0) and blood secondary methylation index (DMAs/MMAs) by 0.19 (95%CI: 0.09, 0.35). Similarly, there was a 1.62% (95%CI: 0.43, 2.83) significantly higher urinary %DMAs and -1.10% (CI: -1.73, -0.48) significantly lower urinary %MMAs compared to placebo group after 1 week. These results confirmed that FA+B12 supplementation increases arsenic methylation in children as reflected by decreased MMAs and increased DMAs in blood and urine. Altogether, the findings presented in this dissertation consistently identify the role of urinary metals as robust risk factors of heart failure, overall cardiovascular disease and all-cause mortality across diverse populations. With consistent findings across multiple assessments of the dose response relationship and mixture approaches. Additionally, this dissertation work contributes to address disparities in environmental exposures and heart failure burden, respectively, by characterizing the impact of structural racism drinking water metal exposures disparities and identifying relevant risk factors of heart failure in American Indian populations who are historically underrepresented in epidemiological cohorts. Last, this dissertation identifies the role of folic acid and B12 supplementation to reduce arsenic toxicity in children. These findings have direct clinical and policy implications, as they can inform the development of novel clinical guidelines to incorporate environmental factors in clinical risk prediction, and they can inform drinking water regulation and infrastructure efforts to support at risk communities and inform population-level nutritional recommendations and policies.

Sparse information is available concerning use of emergency departments (EDs) by the elderly in rural areas. We reviewed records of all patients seeking care at EDs of three rural hospitals during 7 days in October 1991. We found that elderly people did not use EDs in proportion to their numbers in the community (15.2% versus 19.3%). Compared with younger ED patients, more elderly patients required an ambulance (40.8% versus 10.7%), more needed hospitalization (38.4% versus 11.9%), and their ED stays were longer (140 minutes versus 89 minutes). Falls/injuries (18.7%) and cardiac illness (18.1%) were the most frequent reasons for ED visits by the elderly, and relatively few (2.8%) had confusion. More elderly patients arrived during daytime hours than during the night, and more on weekends than weekdays. Also, we found no difference between patients in the 65- to 74-year-old age group and those aged 75 years and older.