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Traces of non-essential and essential metals in urine were associated with increased risk of cardiovascular disease (CVD) and all-cause mortality, according to the largest epidemiological study on the topic to date.

Based on the Multi-Ethnic Study of Atherosclerosis (MESA), individual urinary metals were tied to incident events over more than 17 years when comparing the highest to lowest quartiles:

• Cadmium: HR 1.25 for CVD (95% CI 1.03-1.53) and HR 1.68 for death (95% CI 1.43-1.96)
• Tungsten: HR 1.20 for CVD (95% CI 1.01-1.42) and HR 1.16 for death (95% CI 1.01-1.33)
• Uranium: HR 1.32 for CVD (95% CI 1.08-1.62) and HR 1.32 for death (95% CI 1.12-1.56)
• Cobalt: HR 1.24 for CVD (95% CI 1.03-1.48) and HR 1.37 for death (95% CI 1.19-1.58)
• Copper: HR 1.42 for CVD (95% CI 1.18-1.70) and HR 1.50 for death (95% CI 1.29-1.74)
• Zinc: HR 1.21 for CVD (95% CI 1.01-1.45) and HR 1.38 for death (95% CI 1.20-1.59)

Increasing levels of the six metals, mixed, were associated with 29% more CVD and 66% more all-cause mortality after accounting for demographic, lifestyle, and clinical risk factors. Only cadmium and copper showed a positive linear dose-response relationship with both incident CVD and mortality, reported study authors led by Irene Martinez-Morata, MD, PhD, of Columbia University Mailman School of Public Health in New York City, in .

"Our findings support that urinary metal levels are a robust predictor of CVD risk and all-cause mortality," they said. "These associations with clinical events are consistent with our previous finding that these six metals were associated with higher levels of , supporting that atherosclerosis is a major underlying pathway explaining the association of metals with clinical events, and that those subclinical associations are clinically relevant."

"The magnitude of the associations for individual metals and the mixture was strongest for all-cause mortality even after accounting for cardiovascular risk factors in the models, supporting prior studies indicating that metals can impact human health beyond CVD endpoints," Martinez-Morata's group added.

Prior studies had established arsenic, cadmium, and lead as contaminant metals, exposure to them is now considered a CVD risk factor by the American Heart Association. In particular, cadmium is a known carcinogen with adverse effects on the kidneys, liver, and lungs. Smoking is a major source of cadmium.

Similar evidence of harm is scarce for the other non-essential toxic metals uranium and tungsten. Both are common exposures in the U.S. from drinking water, food, air pollution, and indoor dust. Martinez-Morata and colleagues singled out tungsten as not being regulated in public drinking water by the Environmental Protection Agency; its concentration estimates are therefore not available nationwide.

"For unregulated and less studied metals such as tungsten and cobalt, there is a critical need to understand the relative contributions of drinking water, food, and air to biomarkers reflecting internal dose. Understanding sources of excess exposure to essential metals, including the use of unregulated supplements, and the contamination of food is also needed," the investigators urged.

More research would be required before federal regulators take any action on these less studied metals, Martinez-Morata suggested in a press release.

Nevertheless, Cashell Jaquish, PhD, a genetic epidemiologist at the National Heart, Lung, and Blood Institute, still made a case for lowering environmental exposure to harmful metals.

"The findings underscore the importance of reducing environmental exposure to these metals, which have disproportionately affected minority and poorer communities," Jaquish said in the press release. "The results could lead to efforts to reduce metal exposure in our communities and thereby reduce health disparities in heart disease, the leading cause of death in this country."

As for cobalt, copper, and zinc, study authors explained that these essential metals are tightly regulated in the body, and elevated levels in the urine may represent early cardiometabolic dysregulation.

"While this is an ongoing field of study, high levels of essential metals in the urine can indicate an excess in exposure or loss of body reserves of these nutrients, which can occur when the metabolism is starting to malfunction, as it occurs in early stages of cardiovascular disease," said Martinez-Morata in a statement.

MESA has followed a racially diverse population since 2000, the present analysis relying on data collected up through 2019.

Included were 6,599 people who had urinary metals assessed at baseline (average 62.1 years old, 53% women). The median follow-up was 17.7 years.

Martinez-Morata's group measured 15 trace elements: cadmium, tungsten, uranium, cobalt, copper, zinc, arsenic, barium, cesium, lead, strontium, thallium, manganese, molybdenum, and selenium.

Incident CVD events were defined as myocardial infarction, resuscitated cardiac arrest, angina, stroke, atherosclerotic deaths, and other CVD deaths.

The observed associations between urinary metals and events persisted after adjustment for sociodemographic, behavioral, and clinical CVD risk factors, according to the investigators.

However, they acknowledged that they had relied on single spot measurements of urinary metals, which precluded them from analyzing changing or long-term exposure to these metals.

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