Contaminant Metals as Cardiovascular Risk Factors: A Scientific Statement From the American Heart Association

Title Contaminant Metals as Cardiovascular Risk Factors: A Scientific Statement From the American Heart Association
Journal American Heart Association
Authors ite
Lamas, G. A., Bhatnagar, A., Jones, M. R., Mann, K. K., Nasir, K., Tellez-Plaza, M., Ujueta, F., Navas-Acien, A., & American Heart Association Council on Epidemiology and Prevention; Council on Cardiovascular and Stroke Nursing; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; and Council on the Kidney in Cardiovascular Diseas
Year Published 2023
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Abstract
Exposure to environmental pollutants is linked to increased risk of cardiovascular disease. Beyond the extensive evidence for particulate air pollution, accumulating evidence supports that exposure to nonessential metals such as lead, cadmium, and arsenic is a significant contributor to cardiovascular disease worldwide. Humans are exposed to metals through air, water, soil, and food and extensive industrial and public use. Contaminant metals interfere with critical intracellular reactions and functions leading to oxidative stress and chronic inflammation that result in endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function. Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis, and calcification as well as to increased risk of ischemic heart disease and stroke, left ventricular hypertrophy and heart failure, and peripheral artery disease. Epidemiological studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. Public health measures reducing metal exposure are associated with reductions in cardiovascular disease death. Populations of color and low socioeconomic means are more commonly exposed to metals and therefore at greater risk of metal‐induced cardiovascular disease. Together with strengthening public health measures to prevent metal exposures, development of more sensitive and selective measurement modalities, clinical monitoring of metal exposures, and the development of metal chelation therapies could further diminish the burden of cardiovascular disease attributable to metal exposure.

Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization

Title Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization
Journal Annals of Internal Medicine
Authors Wang, T. Y., Wahed, A. S., Morris, A., Kreuziger, L. B., Quigley, J. G., Lamas, G. A., Weissman, A. J., Lopez-Sendon, J., Knudson, M. M., Siegal, D. M., Kasthuri, R. S., Alexander, A. J., Wahid, L., Atassi, B., Miller, P. J., Lawson, J. W., Patel, B., Krishnan, J. A., Shapiro, N. L., Martin, D. E., … ACTIV-4C Study Group
Year Published 2023
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Environment and cardiovascular health: causes, consequences and opportunities in prevention and treatment

Title Environment and cardiovascular health: causes, consequences and opportunities in prevention and treatment
Journal Revista Española de Cardiología (English Edition)
Authors Arrarte, V., Báez-Ferrer, N., Benito, B., Campuzano Ruiz, R., Cecconi, A., Domínguez-Rodríguez, A., Rodríguez-Sinovas, A., Ujueta, F., Vozzi, C., Lamas, G. A., & Navas-Acién, A.
Year Published 2022
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Abstract
The environment is a strong determinant of cardiovascular health. Environmental cardiology studies the contribution of environmental exposures with the aim of minimizing the harmful influences of pollution and promoting cardiovascular health through specific preventive or therapeutic strategies. The present review focuses on particulate matter and metals, which are the pollutants with the strongest level of scientific evidence, and includes possible interventions. Legislation, mitigation and control of pollutants in air, water and food, as well as environmental policies for heart-healthy spaces, are key measures for cardiovascular health. Individual strategies include the chelation of divalent metals such as lead and cadmium, metals that can only be removed from the body via chelation. The TACT (Trial to Assess Chelation Therapy, NCT00044213) clinical trial demonstrated cardiovascular benefit in patients with a previous myocardial infarction, especially in those with diabetes. Currently, the TACT2 trial (NCT02733185) is replicating the TACT results in people with diabetes. Data from the United States and Argentina have also shown the potential usefulness of chelation in severe peripheral arterial disease. More research and action in environmental cardiology could substantially help to improve the prevention and treatment of cardiovascular disease.

The trial to assess chelation therapy 2 (TACT2): Rationale and design.

Title The trial to assess chelation therapy 2 (TACT2): Rationale and design
Journal American Heart
Authors Lamas, G. A., Anstrom, K. J., Navas-Acien, A., Boineau, R., Kim, H., Rosenberg, Y., Stylianou, M., Jones, T. L. Z., Joubert, B. R., Santella, R. M., Escolar, E., Aude, Y. W., Fonseca, V., Elliott, T., Lewis, E. F., Farkouh, M. E., Nathan, D. M., Mon, A. C., Gosnell, L., Newman, J. D., … TACT2 Investigators
Year Published 2022
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Abstract
The Trial to Assess Chelation Therapy 2 (TACT2) is an NIH-sponsored, randomized, 2×2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or Na2EDTA)-based chelation solution and twice daily oral, high-dose multivitamin and mineral supplements in patients with diabetes and a prior myocardial infarction (MI). TACT2 completed enrollment of 1000 subjects in December 2020, and infusions in December 2021. Subjects are being followed for 2.5 to 5 years. The primary endpoint is a composite of the time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial is designed to have >85% power to detect a 30% relative reduction in the primary endpoint for each active treatment versus placebo comparison. TACT2 also includes a Trace Metals and Biorepository Core Lab, which will test the novel hypothesis that the prognostic benefits of chelation, if present, are due to removal of lead and cadmium from patients. Most of the design features of TACT2 were chosen to replicate selected features of the first TACT trial, which demonstrated a statistically significant reduction in cardiovascular outcomes in the EDTA chelation arm compared with placebo among patients with a prior MI, with the largest effect in patients with diabetes. Results from TACT2, if concordant with TACT, will provide definitive evidence of the benefit of edetate disodium-based chelation on cardiovascular outcomes, as well as the possible clinical importance of longitudinal changes in toxic metal levels of participants.

Chelation Therapy in Patients With Cardiovascular Disease: A Systematic Review

Title Chelation Therapy in Patients With Cardiovascular Disease: A Systematic Review
Journal American Heart Association
Authors Ravalli, F., Vela Parada, X., Ujueta, F., Pinotti, R., Anstrom, K. J., Lamas, G. A., & Navas-Acien, A.
Year Published 2022
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Abstract
Background EDTA is an intravenous chelating agent with high affinity to divalent cations (lead, cadmium, and calcium) that may be beneficial in the treatment of cardiovascular disease (CVD). Although a large randomized clinical trial showed benefit, smaller studies were inconsistent. We conducted a systematic review of published studies to examine the effect of repeated EDTA on clinical outcomes in adults with CVD. Methods and Results We searched 3 databases (MEDLINE, Embase, and Cochrane) from database inception to October 2021 to identify all studies involving EDTA treatment in patients with CVD. Predetermined outcomes included mortality, disease severity, plasma biomarkers of disease chronicity, and quality of life. Twenty-four studies (4 randomized clinical trials, 15 prospective before/after studies, and 5 retrospective case series) assessed the use of repeated EDTA chelation treatment in patients with preexistent CVD. Of these, 17 studies (1 randomized clinical trial) found improvement in their respective outcomes following EDTA treatment. The largest improvements were observed in studies with high prevalence of participants with diabetes and/or severe occlusive arterial disease. A meta-analysis conducted with 4 studies reporting ankle-brachial index indicated an improvement of 0.08 (95% CI, 0.06-0.09) from baseline. Conclusions Overall, 17 studies suggested improved outcomes, 5 reported no statistically significant effect of treatment, and 2 reported no qualitative benefit. Repeated EDTA for CVD treatment may provide more benefit to patients with diabetes and severe peripheral arterial disease. Differences across infusion regimens, including dosage, solution components, and number of infusions, limit comparisons across studies. Additional research is necessary to confirm these findings and to evaluate the potential mediating role of metals. Registration URL: https://www.crd.york.ac.uk/; Unique identifier: CRD42020166505.

VVI pacing with normal QRS duration and ventricular function: MOST trial findings relevant to leadless pacemakers

Title VVI pacing with normal QRS duration and ventricular function: MOST trial findings relevant to leadless pacemakers
Journal Pacing and Clinical Electrophysiology
Authors Loring, Z., North, R., Hellkamp, A. S., Atwater, B. D., Frazier-Mills, C. G., Jackson, K. P., Pokorney, S. D., Lamas, G. A., & Piccini, J. P.
Year Published 2020
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Abstract
Leadless pacemakers (LPs) provide ventricular pacing without the risks associated with transvenous leads and device pockets. LPs are appealing for patients who need pacing, but do not need defibrillator or cardiac resynchronization therapy. Most implanted LPs provide right ventricular pacing without atrioventricular synchrony (VVIR mode). The Mode Selection Trial in Sinus Node Dysfunction (MOST) showed similar outcomes in patients randomized to dual-chamber (DDDR) versus ventricular pacing (VVIR). We compared outcomes by pacing mode in LP-eligible patients from MOST.

Possible differential benefits of edetate disodium in post-myocardial infarction patients with diabetes treated with different hypoglycemic strategies in the Trial to Assess Chelation Therapy (TACT)

Title Possible differential benefits of edetate disodium in post-myocardial infarction patients with diabetes treated with different hypoglycemic strategies in the Trial to Assess Chelation Therapy (TACT)
Journal Diabetes and its Complications
Authors Escolar, E., Ujueta, F., Kim, H., Mark, D. B., Boineau, R., Nahin, R. L., Goertz, C., Lee, K. L., Anstrom, K. J., & Lamas, G. A.
Year Published 2020
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Abstract
The NIH-funded Trial to Assess Chelation Therapy (TACT) randomized 1708 stable patients age ≥50 who were ≥6 months post myocardial infarction to 40 infusions of an edetate disodium-based regimen or placebo. In 633 patients with diabetes, edetate disodium significantly reduced the primary composite endpoint of mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.001). The principal secondary endpoint of a composite of cardiovascular death, myocardial infarction, or stroke was also reduced (HR 0.60, 95% CI 0.39-0.91, p = 0.017). It is unknown if the treatment effect differs by diabetes therapy.

Urinary Metal Levels after Repeated Edetate Disodium Infusions: Preliminary Findings

Title Urinary Metal Levels after Repeated Edetate Disodium Infusions: Preliminary Findings
Journal International Journal of Environmental Research and Public Health
Authors Alam, Z. H., Ujueta, F., Arenas, I. A., Nigra, A. E., Navas-Acien, A., & Lamas, G. A.
Year Published 2020
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Abstract
Environmentally acquired lead and cadmium are associated with increased cardiovascular disease risk. In the Trial to Assess Chelation Therapy, up to 40 infusions with edetate disodium over an approximately one-year period lowered the cardiovascular disease risk in patients with a prior myocardial infarction. We assessed whether a reduction in surrogate measures of total body lead and cadmium, post-edetate disodium urine lead and pre-edetate urine cadmium, could be detected after repeated edetate disodium-based infusions compared to the baseline. Fourteen patients with coronary artery disease received multiple open-label edetate disodium infusions. The urine metals pre- and post-edetate infusion, normalized for urine creatinine, were compared to urine levels pre and post final infusion by a paired t-test. Compared with the pre-edetate values, post-edetate urine lead and cadmium increased by 3581% and 802%, respectively, after the first infusion. Compared to baseline, post-edetate lead decreased by 36% (p = 0.0004). A reduction in post-edetate urine lead was observed in 84% of the patients after the final infusion. Pre-edetate lead decreased by 60% (p = 0.003). Pre-edetate lead excretion became undetectable in nearly 40% of patients. This study suggests that edetate disodium-based infusions may decrease the total body burden of lead. However, our data suggest no significant reduction in the body burden of cadmium

Differential Outcomes With Edetate Disodium-Based Treatment Among Stable Post Anterior vs. Non-Anterior Myocardial Infarction Patients

Title Differential Outcomes With Edetate Disodium-Based Treatment Among Stable Post Anterior vs. Non-Anterior Myocardial Infarction Patients
Journal Cardiovascular Revascularization Medicine
Authors Lewis, E. F., Ujueta, F., Lamas, G. A., Roberts, R. S., Mark, D. B., Nahin, R. L., Goertz, C., Stylianou, M., & Lee, K. L.
Year Published 2020
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Abstract
The Trial to Assess Chelation Therapy (TACT) found that chelation therapy significantly reduced clinical events in patients with a history of myocardial infarction (MI). The initial report of TACT included the observation of an interaction between edetate disodium infusions and MI location, as well as diabetes. Thus, we examined in greater detail the effect of edetate disodium chelation therapy as a function of MI location and diabetes.