Metals Exposure and Cardiovascular Health: Characterizing Novel Risk Factors of Heart Failure

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

Urinary Metal Levels and Coronary Artery Calcification: Longitudinal Evidence in the Multi-Ethnic Study of Atherosclerosis (MESA)

Objective: Growing evidence indicates that exposure to metals are risk factors for cardiovascular disease (CVD). We hypothesized that higher urinary levels of metals with prior evidence of an association with CVD, including non-essential (cadmium , tungsten, and uranium) and essential (cobalt, copper, and zinc) metals are associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of atherosclerotic CVD. Methods: We analyzed data from 6,418 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with spot urinary metal levels at baseline (2000-2002) and 1-4 repeated measures of spatially weighted coronary calcium score (SWCS) over a ten-year period. SWCS is a unitless measure of CAC highly correlated to the Agatston score but with numerical values assigned to individuals with Agatston score=0. We used linear mixed effect models to assess the association of baseline urinary metal levels with baseline SWCS, annual change in SWCS, and SWCS over ten years of follow-up. Urinary metals (adjusted to μg/g creatinine) and SWCS were log transformed. Models were progressively adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors. Results: At baseline, the median and interquartile range (25th, 75th) of SWCS was 6.3 (0.7, 58.2). For urinary cadmium, the fully adjusted geometric mean ratio (GMR) (95%Cl) of SWCS comparing the highest to the lowest quartile was 1.51 (1.32, 1.74) at baseline and 1.75 (1.47, 2.07) at ten years of follow-up. For urinary tungsten, uranium, and cobalt the corresponding GMRs at ten years of follow-up were 1.45 (1.23, 1.71), 1.39 (1.17, 1.64), and 1.47 (1.25, 1.74), respectively. For copper and zinc, the association was attenuated with adjustment for clinical risk factors; GMRs at ten years of follow-up before and after adjustment for clinical risk factors were 1.55 (1.30, 1.84) and 1.33 (1.12, 1.58), respectively, for copper and 1.85 (1.56, 2.19) and 1.57 (1.33, 1.85) for zinc. Conclusion: Higher levels of cadmium, tungsten, uranium, cobalt, copper, and zinc, as measured in urine, were associated with subclinical CVD at baseline and at follow-up. These findings support the hypothesis that metals are pro-atherogenic factors.The Multi-Ethnic Study of Atherosclerosis (MESA) is supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). This publication was developed under the Science to Achieve Results (STAR) research assistance agreements, No. RD831697 (MESA Air) and RD-83830001 (MESA Air Next Stage), awarded by the U.S Environmental Protection Agency (EPA). It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. Dr. Maria Tellez-Plaza was supported by grants PI15/00071 and PI22/00029 from the Strategic Action for Health Research, Instituto de Salud Carlos III and the Spanish Ministry of Science and Innovation, and co-funded with European Funds for Regional Development (FEDER). The opinions and views expressed in this article are those of the authors and do not necessarily represent the official position of the Instituto de Salud Carlos III (Spain). Work in the authors? laboratories is also supported in part by NIH grants P42ES023716, P42ES010349, P42ES033719, P30ES009089, T32ES007322, R01ES029967, R01HL155576. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. This paper has been reviewed and approved by the MESA Publications and Presentations Committee.N

US drinking water quality: exposure risk profiles for seven legacy and emerging contaminants

Data de publicació electrònica: 22-09-2023Background: Advances in drinking water infrastructure and treatment throughout the 20th and early 21st century dramatically improved water reliability and quality in the United States (US) and other parts of the world. However, numerous chemical contaminants from a range of anthropogenic and natural sources continue to pose chronic health concerns, even in countries with established drinking water regulations, such as the US. Objective/methods: In this review, we summarize exposure risk profiles and health effects for seven legacy and emerging drinking water contaminants or contaminant groups: arsenic, disinfection by-products, fracking-related substances, lead, nitrate, per- and polyfluorinated alkyl substances (PFAS) and uranium. We begin with an overview of US public water systems, and US and global drinking water regulation. We end with a summary of cross-cutting challenges that burden US drinking water systems: aging and deteriorated water infrastructure, vulnerabilities for children in school and childcare facilities, climate change, disparities in access to safe and reliable drinking water, uneven enforcement of drinking water standards, inadequate health assessments, large numbers of chemicals within a class, a preponderance of small water systems, and issues facing US Indigenous communities. Results: Research and data on US drinking water contamination show that exposure profiles, health risks, and water quality reliability issues vary widely across populations, geographically and by contaminant. Factors include water source, local and regional features, aging water infrastructure, industrial or commercial activities, and social determinants. Understanding the risk profiles of different drinking water contaminants is necessary for anticipating local and general problems, ascertaining the state of drinking water resources, and developing mitigation strategies. Impact statement: Drinking water contamination is widespread, even in the US. Exposure risk profiles vary by contaminant. Understanding the risk profiles of different drinking water contaminants is necessary for anticipating local and general public health problems, ascertaining the state of drinking water resources, and developing mitigation strategies

Sustained Negative Mental Health Outcomes Among Healthcare Workers Over the First Year of the COVID-19 Pandemic: A Prospective Cohort Study.

Objective: To characterize the evolution of healthcare workers' mental health status over the 1-year period following the initial COVID-19 pandemic outbreak and to examine baseline characteristics associated with resolution or persistence of mental health problems over time. Methods: We conducted an 8-month follow-up cohort study. Eligible participants were healthcare workers working in Spain. Baseline data were collected during the initial pandemic outbreak. Survey-based self-reported measures included COVID-19-related exposures, sociodemographic characteristics, and three mental health outcomes (psychological distress, depression symptoms, and posttraumatic stress disorder symptoms). We examined three longitudinal trajectories in mental health outcomes between baseline and follow-up assessments (namely asymptomatic/stable, recovering, and persistently symptomatic/worsening). Results: We recruited 1,807 participants. Between baseline and follow-up assessments, the proportion of respondents screening positive for psychological distress and probable depression decreased, respectively, from 74% to 56% and from 28% to 21%. Two-thirds remained asymptomatic/stable in terms of depression symptoms and 56% remained symptomatic or worsened over time in terms of psychological distress. Conclusion: Poor mental health outcomes among healthcare workers persisted over time. Occupational programs and mental health strategies should be put in place

Influence of folic acid and vitamin B12 supplementation on arsenic methylation: A double-blinded, placebo-controlled trial in Bangladeshi children

Background: Inorganic arsenic is metabolized to monomethyl- (MMAs) and dimethyl- (DMAs) species via one-carbon metabolism (OCM); this facilitates urinary arsenic elimination. OCM is influenced by folate and vitamin B12 and previous randomized control trials (RCTs) showed that folic acid (FA) supplementation increases arsenic methylation in adults. This RCT investigated the effects of FA + B12 supplementation on arsenic methylation in children, a key developmental stage where OCM supports growth. Methods: A total of 240 participants (8–11 years, 53 % female) drinking from wells with arsenic concentrations > 50 μg/L, were encouraged to switch to low arsenic wells and were randomized to receive 400 μg FA + 5 μg B12 or placebo daily for 12-weeks. Urine and blood samples were collected at baseline, week 1 (only urine) and week 12. Generalized estimated equation (GEE) models were used to assess treatment effects on arsenic species in blood and urine. Results: At baseline, the mean ± SD total blood and urinary arsenic were 5.3 ± 2.9 μg/L and 91.2 ± 89.5 μg/L. Overall, total blood and urine arsenic decreased by 11.7% and 17.6%, respectively, at the end of follow up. Compared to placebo, the supplementation group experienced a significant increase in the concentration of blood DMAs 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) at 12 weeks. Similarly, there was a 1.62% (95% CI: 0.43, 20.83) significantly higher urinary %DMAs and −1.10% (95% CI: −1.73, −0.48) significantly lower urinary %MMAs in the supplementatio group compared to the placebo group after 1 week. The direction of the changes in the urinary %iAs, %MMAs, and %DMAs at week 12 were consistent with those at week 1, though estimates were not significant. Treatment effects were stronger among participants with higher baseline blood arsenic concentrations. Results were consistent across males and females, and participants with higher and lower folate and B12 status at baseline. Conclusion: This RCT confirms that FA + B12 supplementation increases arsenic methylation in children as reflected by decreased MMAs and increased DMAs in blood and urine. Nutritional interventions may improve arsenic methylation and elimination in children, potentially reducing arsenic toxicity while also improving nutritional status

Increasing of New CA-MRSA Infections Detected in people living with HIV Who Engage in Chemsex in Barcelona: An Ambispective Study

Abstract Introduction There are no data on community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections in the context of the chemsex phenomenon. This study aimed to characterize CA-MRSA-related infections in a cohort of people living with HIV (PLWH) who engage in chemsex. Methods At the Hospital Clinic of Barcelona, from February 2018 to January 2022, we analyzed CA-MRSA infections diagnosed in a cohort of PLWH who engage in chemsex. Epidemiological, behavioral and clinical variables were assessed. Mass spectrometry identification and antimicrobial susceptibility testing were performed on MRSA isolates. Pulse field electrophoresis was used to assess the clonality of the MRSA strains. The presence of Panton-Valentine leukocidin was also investigated. Results Among the cohort of 299 participants who engage in chemsex, 25 (8%) with CA-MRSA infections were identified, 9 at baseline and 16 with incident cases; the cumulative incidence was 5.5% (95% CI: 3.2%, 8.8%). The most common drugs were methamphetamine (96%) and GHB/GBL (92%). Poly-consumption and slamming were reported by 32% and 46%, respectively. CA-MRSA was isolated from the infection sites of 20 participants, and CA-MRSA colonization was confirmed in the remaining 5 persons. Seventy-one percent had used antibiotics in the previous year. All participants presented with skin and soft tissue infections, 28% required hospitalization, and 48% had recurrence. Of the 23 MRSA isolates further studied, 19 (82,6%) belonged to the same clone. Panton-Valentine leukocidin was detected in all isolates. Conclusion PLWH who engage in chemsex may present with CA-MRSA infections. Clinical suspicion and microbiological diagnosis are required to provide adequate therapy, and CA-MRSA prevention interventions should be designed

External validation of the INCREMENT-CPE mortality score in a carbapenem-resistant Klebsiella pneumoniae bacteraemia cohort: the prognostic significance of colistin resistance

External validation of the INCREMENT-CPE risk score (ICS) for 30-day all-cause mortality is needed. There is also scarce information about whether colistin resistance influences the prognosis of carbapenem-resistant Klebsiella pneumoniae (CRKp) bacteraemia. In this study, the ability of ICS to predict all-cause mortality in the KAPECOR cohort was calculated using the area under the receiver operating characteristic (AUROC) curve. The association of colistin resistance with mortality was studied. The ICS showed an AUROC curve of 0.77 (95% CI 0.68-0.86). A cut-off of 8 points showed 96.8% sensitivity and 50.7% specificity. Mortality of low-risk patients was not different in those treated with monotherapy versus combination therapy. However, mortality of high-risk patients treated with combination therapy (37.8%) was significantly lower than in those treated with monotherapy (68.4%) (P = 0.008). To study the prognostic significance of colistin resistance, 83 selected cases of bacteraemia due to colistin-susceptible CRKp were obtained from the INCREMENT cohort for comparison. Colistin resistance could not be shown to be associated with higher mortality in either the high-risk ICS group [adjusted odds ratio (aOR) = 1.56, 95% CI 0.69-3.33; P = 0.29] or in 37 ICS-matched pairs (aOR = 1.38, 95% CI 0.55-3.42; P = 0.49), or in a sensitivity analysis including only KPC isolates (aOR = 1.81, 95% CI 0.73-4.57; P = 0.20), but the precision of estimates was low. These results validate ICS for all-cause mortality and to optimise targeted therapy for CRKp bacteraemia. Colistin resistance was not clearly associated with increased mortality. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used