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Exposure to certain toxic metals, even at low levels, can promote atherosclerosis progression in the carotid, femoral, and coronary arteries, suggests new research that implicates arsenic, atomoxetine alcohol interaction cadmium, and titanium, in particular, as potential culprits.

The analysis of 1873 adults, nearly all men, in the longitudinal Aragon Workers Health Study was based on data obtained at their annual health exams as workers at an auto assembly factory in Spain.

Participants, ranging in age from 40 to 55 years, were measured for exposure to nine toxic metals, the remaining six being uranium, barium, chromium, antimony, tungsten, and vanadium.

The study, published December 9 in Arteriosclerosis, Thrombosis and Vascular Biology, showed arsenic and cadmium most closely linked to increased plaque levels in the carotid arteries, whereas cadmium and titanium were risk factors for femoral artery disease.

Arsenic and cadmium can be found in tobacco, food, and water, while titanium is primarily derived from dental and orthopedic implants, pacemaker encasings, cosmetic products, and some food, the report states.

Whereas previous studies have looked at the impact of such toxic metals in the carotids, the current research focused on whether they have a role in the progression of subclinical carotid, femoral, or coronary artery atherosclerosis, it notes.

By looking at multiple vascular territories, the researchers felt they could “accomplish an earlier and better risk assessment of environmental-related cardiovascular disease,” said senior author Maria Tellez-Plaza, MD, PhD, from the National Center for Epidemiology and the Instituto de Salud Carlos III in Madrid.

“The scientific evidence supporting that arsenic and cadmium have adverse clinical cardiovascular effects is strong and was, thus, not surprising,” said Tellez-Plaza. But the reported association of these metals with subclinical atherosclerosis across several different vascular beds, she added, was in fact novel.

“The results for the femoral territory were specially exciting; in addition, we have newly identified titanium exposure as a potentially relevant atherosclerosis factor.”

Aruni Bhatnagar, PhD, not associated with the study, said he was also surprised to learn of the connection between titanium and atherosclerosis. “Titanium was the interesting factor that hasn’t been [measured] before,” he said.

“The real importance of this work is that they were able to measure all these metals and then find out which were more likely to be associated,” observed Bhatnagar, an expert in environmental cardiology at the University of Louisville, Kentucky.

The study’s participants underwent a medical examination for body mass index, blood pressure, blood glucose levels, and cholesterol and triglyceride levels, and underwent carotid and femoral ultrasounds and coronary calcium scans. Urine samples were collected to assess metal exposure from air, water, and food.

Annual occupational health visits, conducted from 2011 to 2014, were used to record socioeconomic and health information, including education level, smoking status, and medication use.

The research showed older adults had higher levels of most of the metals measured, whereas those who had smoked at any time showed higher levels of arsenic, cadmium, chromium, and titanium than nonsmokers. The few women in the study had higher metal levels in urine tests than men.

The adjusted odds ratio (OR) for association with subclinical atherosclerosis in at least one of the vascular territories, 80th vs the 20th percentiles for metal prevalence, were:

  • 1.25 (95% CI, 1.03 – 1.51) for arsenic  

  • 1.67 (95% CI, 1.22 – 2.29) for cadmium

  • 1.26 (95% CI, 1.04 – 1.52) for titanium

The corresponding OR in the carotids for arsenic was 1.24 (95% CI, 1.05 – 1.47) and for cadmium was 1.38 (95% CI, 1.05 – 1.81); the OR for cadmium in the femoral arteries was 1.72 (95% CI, 1.30 – 2.28).

Cadmium also showed a positive association with degree of coronary artery calcification as a continuous variable, the report notes.

Titanium was associated with the presence of femoral artery plaques with an OR of 1.25 (95% CI, 1.05 – 1.48), and of significant coronary artery calcification with an OR of 1.16 (95% CI, 1.00 – 1.34) territories.

Bhatnagar said the next step would be to do similar testing in a more general population to get more clarity on the source of exposure. “Before we all get really concerned, we do need to make sure this is not some sort of industrial exposure, given that these were [mostly male] auto workers,” he said.

Tellez-Plaza agrees that more research is needed, especially in women, although there is no reason to believe the potential atherogenic effects of metals would be any different. “Additional prospective studies to evaluate the atherosclerosis change over time associated to metals are needed,” she added.

Once the association between these toxic metals and atherosclerosis is confirmed in a more general population, Bhatnagar observed, more attention needs to be paid to environmental pollutants that could be contributing to heart disease risk.

“The whole idea that, just like cancer, exposure to adverse environments and environmental conditions can cause heart disease is something we need to look at,” he said.

In a previous report, for example, Tellez-Plaza and colleagues observed that about one-third of the 43% drop in cardiovascular mortality in the United States during a recent period covering several decades could be attributed to a decline in environmental lead and cadmium.

The authors note that current environmental, occupational, and food-safety standards for cadmium, arsenic, and other metals might be insufficient to protect people from metal-related health risks.

“Intensified metal exposure prevention thus gives a great opportunity for cardiovascular disease prevention,” she said. She encourages physicians to monitor patient’s metal concentrations with blood and urine tests to possibly carry out more intensified cardiovascular health monitoring.

“Overall, physicians are at a privileged place to inform and empower cardiovascular disease patients so that they can entertain actions to take care of their environmental health by themselves,” she said.

Tellez-Plaza said the findings could also have clinical implications in supporting the use of chelation therapy as an effective secondary cardiovascular prevention intervention. “Now we are starting to see clinical trials on chelation therapy, which removes metals from the body through urinary excretion, that reported substantial beneficial effects compared to placebo among patients with a previous myocardial infarction.” 

The trial was supported by the Strategic Action for Research in Health Sciences and CIBERCV. Tellez-Plaza was supported by the Third AstraZeneca Award for Spanish Young Researchers; disclosures for the other authors are in the report.

Arterioscler Thromb Vasc Biol. Published online December 9, 2021. Abstract

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