Metal Pollutants and Cardiovascular Disease: Mechanisms and Consequences of Exposure

Abstract

Introduction

There is epidemiological evidence that metal contaminants may play a role in the development of atherosclerosis and its complications. Moreover, a recent clinical trial of a metal chelator had a surprisingly positive result in reducing cardiovascular events in a secondary prevention population, strengthening the link between metal exposure and cardiovascular disease (CVD). This is, therefore, an opportune moment to review evidence that exposure to metal pollutants, such as arsenic, lead, cadmium, and mercury, are significant risk factors for CVD.

Methods

We reviewed the English-speaking medical literature to assess and present the epidemiological evidence that 4 metals having no role in the human body (xenobiotic), mercury, lead, cadmium, and arsenic, have epidemiologic and mechanistic links to atherosclerosis and CVD. Moreover, we briefly review how the results of the Trial to Assess Chelation Therapy strengthen the link between atherosclerosis and xenobiotic metal contamination in humans.

Conclusions

There is strong evidence that xenobiotic metal contamination is linked to atherosclerotic disease and is a modifiable risk factor.

1. Introduction

The result of a recent clinical trial of a metal chelator showing reduced cardiovascular events in a secondary prevention population highlights the potential connection between metal pollutants and cardiovascular disease (CVD). This is, therefore, an opportune moment to review the causal link between metal exposure and CVD. The most commonly used terms for metal pollutants, “heavy metals” or “toxic heavy metals”, refer to specific density, atomic weight, atomic number, or other chemical properties. We have chosen to use the term “xenobiotic”, to denote a foreign chemical substance found within an organism; – thus, xenobiotic metal.

2. Definitions

Xenobiotic metals have no biological role at any dose. These include lead, arsenic, mercury, cadmium, and many others. We will focus on these four toxic, xenobiotic, metals that are ranked among the top 10 on the current Agency for Toxic Substances and Disease Registry Priority List of Hazardous Substances¹. Arsenic, lead, and mercury are ranked as the top 3 hazardous substances.

3. Lead

Distribution

Lead is the most common toxic element. Volcanic activity and geochemical weathering are the greatest natural sources. Lead-based paints, gasoline additives, food-can soldering, battery making, and soldered joints of drinking water pipe systems represent anthropogenic sources of lead in the environment^2,3. Recommendations to limit lead paints since 1978 have led to substantial reductions in childhood lead toxicity⁴. Many children, however, continue to live in houses with either non-intact lead-based paint or high levels of lead in dust. Exposure to lead also occurs through airborne emissions and occupational exposures, water, foods, or occasionally through the use of alternative health-care products, such as herbal remedies⁵ (Table 1). Tetraethyl lead as a gasoline additive for land-based vehicles has now been largely banned worldwide. However it is still present in aviation fuel for piston engine aircraft. Particles of lead suspended in the atmosphere, along with fuel-based and other sources of lead^3,6, can represent a source of continued exposure.

Table 1.

Metal exposure, half-life, ingestion, excretion, ways to measure

Metal	Exposure	Half-life	Ingestion	Excretion	Measure
Lead	food, water, air, gasoline additives, food-can soldering, lead-based paints, ceramic glazes, drinking water pipe systems, folk remedies	In the blood 36 days In bones 20–30 years	Inhalation with 30–40% absorbed Ingestion with 5% absorbed in adults and up to 50% in children	Urine Sweat Hair Nails	Blood level X- ray fluorescence of bone Urine level
Cadmium	contaminated food (leafy vegetables, grains, organ meats, crustaceans), drinking water, inhalation of polluted air, occupational exposure in industries, tobacco smoke.	In liver 4–19 years In kidneys 6–38 years	Inhalation with 40–50% absorbed Ingestion with 3- 7% absorbed	No efficient excretory mechanism, small amounts excreted via urine	Blood level Urine level Biopsy of the liver, kidneys Hair
Mercury	contaminated fish, meat and organ tissue of marine mammals or feral wildlife, dental amalgams, skin- lightening creams, antiseptic facial products, mercury- containing laxatives or diuretics, teething powders, latex paint, thimerosal- containing vaccines	Elemental: In the blood 1–3 days In the whole body1- 3 weeks Inorganic: In the blood 1–3 weeks Organic: In the blood and the whole body 50 days	Elemental: Inhalation with 80% absorbed Ingestion with 0.01% absorbed Inorganic: Inhalation or inhalation with 10% absorbed Skin with 2–3% absorbed Organic: Inhalation or inhalation with 95–100% absorbed	Metabolized in the liver and excreted through the bile duct 10% excreted via urine	Blood level Urine level Toenail level
Arsenic	contaminated fish, tobacco smoke, arsenic treated wood, ingestion of high-arsenic drinking water	Inorganic: In the blood 4–6 hours Methylated: In the blood 20–30 hours	Inhalation with 40–60% absorbed Ingestion with 95% absorbed	Urine Nails Hair	Blood level Urine level Hair and nail levels

Absorption, body distribution and excretion

Approximately 30–40% of inhaled and 5–10% of ingested lead is absorbed into the bloodstream. GI absorption, however, can reach as high as 30–50% in children³ (Table 1). Once absorbed, 99% of lead binds to red blood cells and 1% remains in serum³. The half-life of lead in the bloodstream is relatively short (36 days); while in bones it is 20–30 years³. Absorbed lead is excreted from the body via urine, sweat, hair and nails^2,3.

Exposure evaluation

Blood lead assesses acute exposure to lead³. Blood lead levels, however, represent only recent short-term exposures, and account for about 1–5% of total body lead burden; the rest is stored in bone and other tissues³. Bone acts as an endogenous source of lead by continuous release of the metal to the plasma, long after exposure has ended, when the rate of bone turnover increases. Indeed, noninvasive X-ray fluorescence of bone is the most accurate technique to assess body lead burden^7,8. Urine lead may be used to assess lead exposure and for monitoring of therapy for lead toxicity.

Blood lead levels have exhibited a steady decline over the last decades, concurrent with the mandated discontinuation of leaded gasoline for ground vehicles. The mean blood lead level in the US population 30 years ago was 12.8 µg/dL, which decreased to 1.45 µg/dL more recently, with 99% of US adults having blood lead levels below 10 µg/dL⁹. Epidemiological data strongly suggest that there may be no safe threshold level for lead, however¹⁰.

Cardiovascular effects

Increased cardiovascular mortality has been attributed to both elevated blood and bone lead levels with stronger association shown for bone levels. ^11,12 (Figure 1a). Weisskopf et al. analyzed the association between tertiles of patella and tibia lead and mortality in 868 male participants of the Veterans’ Affairs Normative Aging Study¹³. After multivariable adjustments, when compared to the first tertile, participants in the third tertile were more likely to die from all causes (HR 2.52, 95% CI, 1.17–5.41, p=0.02), from cardiovascular causes (HR 5.63, 95% CI, 1.73–18.3, p=0.003), and nearly 10 times more likely to die from ischemic heart disease (HR 8.37, 95% CI, 1.29–54.4, p=0.01). In the second National Health and Nutrition Examination Survey (NHANES II) survey¹⁴, Lustberg et al reported that subjects with blood lead levels of 20–29 µg/dL had increased all-cause mortality (RR 1.46, 95% CI, 1.14–1.86) and circulatory mortality (RR 1.39, 95% CI, 1.01–1.91) compared with those having blood lead levels below10 µg/dL.

Figure 1.

a. Lead exposure: Odds Ratios for Mortality for Blood/Bone Lead

b. Cadmium Exposure: Odds Ratios for CVD or Mortality for Urine Cadmium

c. Mercury Exposure: Odds Ratios for CVD or Death

d. Arsenic Exposure: Odds Ratios for CVD and Death for Urine Arsenic

Menke et al. studied 13,946 adult participants of the NHANES III survey with blood lead levels <0.48 µmol/L (10 µg/dL) followed up for up to 12 years¹⁰. After multivariate adjustment, the risk of cardiovascular events was significantly greater in participants with the highest tertile of lead exposure (≥0.17 µmol/L or 3.62 µg/dL), compared with those in the lowest tertile (<0.09 µmol/L or 1.94 µg/dL). All-cause mortality was higher by 25% (HR 1.25, 95% CI, 1.04–1.51) in the third tertile vs. the first tertile, while cardiovascular mortality was higher (HR 1.55, 95% CI, 1.08–2.24), mortality from myocardial infarction was higher (HR 1.89, 95% CI, 1.04–3.43), and mortality from stroke was higher by more than 2-fold (HR 2.51, 95% CI, 1.20–5.26)¹⁰. The NHANES survey (1999–2000) showed that blood lead was associated with an increased prevalence of PAD, even at levels below current safety standards¹¹.

The association of lead exposure with hypertension is one of the best-established cardiovascular effects of this metal^15,16. Meta-analyses of 61 original studies, including approximately 60,000 participants¹⁷ showed that a doubling of blood lead was associated with an increase in SBP of 1.0–1.25 mmHg and DBP of 0.6 mmHg15. While modest in magnitude, these increases in SBP and DBP may have significant clinical relevance in large populations.

Lead exposure has also been linked to dyslipidemia and atherosclerosis^14,18,19. Experimental and human autopsy studies showed an association between lead exposure and aortic atherosclerotic plaque burden^14,19,20,21. There are some interesting findings that support the association of lead with atherosclerosis. For example, the cardioprotective antioxidant activity of HDL is partially mediated by paraoxonase activity, an enzyme that is closely bound to the HDL particle and involved in inhibition of LDL oxidation. Lead, as well as other metals, can inactivate paraoxonase and, therefore, promote LDL oxidation and atherosclerosis development^{22,23, 24}.

4. Cadmium

Distribution

Cadmium is considered one of the most toxic environmental substances due to its ubiquity, toxicity, and long half-life. Exposure to cadmium occurs through inhalation (particularly in active cigarette smokers), water consumption, industrial exposure, and contaminated food (Table 1). Tobacco plants are highly efficient in absorbing cadmium from soil, and accumulate it in the leaf²⁵. Therefore, any exposure to tobacco smoke leads to high exposure to cadmium²⁶, and smokers have cadmium levels that are at least twice as high as those of nonsmokers^25,27. High levels of cadmium can be found in vegetables, fruits, and grains, with the highest levels in greens and potatoes. Shellfish and organ meats contain elevated cadmium concentrations as well, and agricultural fertilizer has also been reported to contain cadmium^25,28,29.

Absorption, body distribution and excretion

Approximately 40–50% of inhaled and 3–7% of ingested cadmium is absorbed. Similar to lead, GI absorption of cadmium is greater in the young^25,30 (Table 1). Intestinal cadmium absorption occurs through a transporter shared with iron and when accompanied by iron deficiency, GI cadmium absorption may increase³¹. Once absorbed, cadmium is protein-bound via erythrocytes or albumin and undergoes hepatic conjugation to metallothionein, a cysteine-rich protein²⁵. This cadmium-metallothionein-cadmium complex then accumulates in the kidneys and may cause renal impairment²⁵. Cadmium is also stored in bones, pancreas, adrenals, testes, and placenta²⁵.

Cadmium has no efficient excretory mechanism

It is excreted in the urine, but it remains bound to metallothionein, which is almost completely reabsorbed in the renal tubules²⁵. Cadmium half-life in the liver is between 4 and 19 years, and in the kidneys is between 6 and 38 years^25,27.

Exposure evaluation

Cadmium levels can be measured in blood, urine, liver, kidney, hair and other tissues²⁵. Blood cadmium level is indicative of recent exposure²⁵. The geometric mean level in occupationally non-exposed adults in the United States is 0.315 µg/L. In heavy smokers this level may be as high as 1.58 µg/L (Table 1).

Urine cadmium reflects mainly total body burden, although urine levels change with recent exposure as well. In the U.S. general population, the geometric mean urinary cadmium level in adults is 0.232 µg/L (or 0.247 µg/g creatinine)³² (Table 1).

Cardiovascular effects

Cadmium is associated with cardiovascular and all-cause mortality (Figure 1b). Menke et al.²⁸ reported that every 2-fold increase in creatinine adjusted urinary cadmium levels in men is associated with an increase in risk of all-cause (HR 1.28, 95% CI, 1.15–1.23) and cardiovascular mortality (HR 1.21, 95% CI, 1.07–1.36). The risk of CAD-associated mortality was also increased (HR 1.36, 95% CI, 1.11–1.66). While these associations were not observed in women, other studies showed cardiovascular mortality to be associated with urinary cadmium levels in both genders^33,34. In a review published recently by Tellez-Plaza et al³⁵, based on 12 studies the pooled RRs for cardiovascular disease, CAD, stroke, and PAD were 1.36 (95% CI, 1.11–1.66), 1.30 (95% CI, 1.12–1.52), 1.18 (95% CI, 0.86–1.59), and 1.49 (95% CI, 1.15–1.92), respectively³⁵. The pooled RRs for CAD in men, women and never smokers were 1.29 (1.12, 1.48), 1.20 (0.92, 1.56) and 1.27 (0.97, 1.67), respectively³⁵. These are modest in magnitude, but quite consistent.

Cadmium has also been associated with PAD in both men and women^11,35,36,37. Blood and urine cadmium levels were 16% (95% CI, 4.7–28.7) and 36% (95% CI, 1–83) higher^11,37, respectively, in patients with PAD. After adjustment for age, sex, race, smoking status, and urinary creatinine, the odds ratio for PAD comparing the highest versus lowest quartile of urine cadmium distribution was 3.05 (95% CI, 0.97–9.58)³⁷.

The largest epidemiologic examination of the association between cadmium exposure and BP change was based on the 1999–2004 NHANES survey³⁸. Among 15,332 participants over 20 years of age, Tellez-Plaza et al. reported an association of blood, but not urine, cadmium levels with a modest elevation of blood pressure. The geometric mean of blood cadmium was 3.77 nmol/L (0.42 µg/L). Participants in the 90th percentile of blood cadmium distribution had 1.36 mmHg (95% CI, 0.24–3.24) higher SBP and 1.68 mmHg (95% CI, 0.57–2.78) higher DBP levels when compared to participants in the 10th percentile of blood cadmium distribution.

5. Mercury

Distribution

Mercury has been ranked as the third most toxic environmental hazard after arsenic and lead¹. Common sources of mercury exposure include proximity to mercury mining sites, recycling facilities, medical or municipal incinerators, coal-fired power plants, or mercury-containing latex paint³⁹. Dietary sources include fresh water fish or seafood⁴⁰ with high mercury content, high fructose corn syrup, rice, and other dietary products. Additionally, dental amalgam is a historic source of mercury exposure³⁸. There have also been reports of mercury contamination in beauty products, laxatives, and infant products^{39, 41}. Another potential source of mercury is thimerosal-containing vaccines (Table 1). Thimerosal, a controversial ethylmercury compound that has been used as a preservative in vaccines, has been completely removed from pediatric vaccines, and mostly removed from adult products.

Absorption, body distribution and excretion

Approximately 80% of inhaled and 0.01% of ingested elemental mercury is absorbed³⁸. For inorganic mercury, absorption of inhaled versus ingested mercury is equal (10%), while 2–3% of inorganic mercury is absorbed through the skin³⁸. Organic mercury (most commonly found in fish), if ingested or inhaled, is almost completely (95–100%) absorbed and is the most toxic form of mercury that is distributed to all organs and tissues including brain and placenta³⁸ (Table 1). Elimination of organic mercury from the body occurs through either demethylation to inorganic mercury or degradation to L-cystein complex in bile. About 10% of organic mercury is excreted through the urine. Selenium, vitamin C, and vitamin E can decrease toxic effects of mercury by multiple mechanisms^42,43,44.

Exposure evaluation

Blood, urine and toenail levels of mercury have been used to estimate mercury exposure³⁸ (Table 1). Blood mercury levels peak sharply during exposure and then decrease rapidly⁴⁵. The mean total mercury levels in whole blood and urine of the general population are approximately 1–8 µg/L and 4–5 µg/L, respectively⁴⁶. Mercury levels as high as 200 µg/L have been reported in individuals with high fish intake⁴⁶, which is striking in the context of United States’ occupational exposures being limited to less than 15 µg/L^38,47. Urine mercury may be used for assessment of inorganic mercury exposure, as organic mercury represents only a small fraction of urinary mercury. Urine mercury levels may vary greatly during the day and from day to day in the same individual, as well as show inter-individual variability, even in a setting of constant exposure³⁸. Current Occupational Safety and Health Administration (OSHA) recommendations require urinary mercury levels not to exceed 35 µg mercury per g of creatinine⁴⁷.

Cardiovascular effects

When evaluating the association of mercury levels and cardiovascular disease, it is important to note that this relationship may be confounded by fish consumption, which raises mercury levels, but lowers cardiovascular risk (Figure 1c).

In 1995, Salonen et al. reported an association between high levels of mercury exposure via freshwater fish consumption and risk of acute myocardial infarction (AMI), all-cause, and cardiovascular mortality⁴⁸. Men in the highest tertile of hair mercury content when compared to the lowest tertile had relative risk of fatal or non-fatal AMI of 1.69 (95% CI, 1.03–2.76, p=0.038), RR of cardiovascular disease of 2.9 (95% CI, 1.2–6.6, p=0.014) and relative risk of death from any cause of 2.3 (95% CI, 1.4–3.6, p<0.001). The relative risk of coronary death in this study was not associated with hair mercury content. In a case-control study, Guallar et al. showed an association between higher levels of toenail mercury and risk of non-fatal AMI⁴⁹. More recently, Mozaffarian et al. found no association between toenail mercury and CAD, stroke, or total cardiovascular disease in participants with either normal or low levels of selenium, which may protect against mercury toxicity⁴⁴.

Data regarding a relationship between mercury exposure and blood pressure changes are inconsistent^50,51,52,53. Studies of chronic occupational mercury exposure in miners revealed a 46% increase in incidence of hypertension when compared to age-matched controls⁵⁴. Correlations have been shown between hair or blood mercury and elevated BP^50,51.

6. Arsenic

Distribution

Arsenic is highly toxic to human health¹. Inorganic and most toxic forms of arsenic (arsenate and arsenite) are found in soils, crops and water, particularly in groundwater from deep wells, often used as drinking water. These compounds are also found in environmental tobacco smoke and arsenic-treated wood, used in the majority of outdoor wooden structures in the US⁵⁵. High levels of arsenic are present in agricultural fertilizer that is used for soil treatment; therefore, vegetables and fruits, if grown in this soil, contain high levels of arsenic⁵⁵ (Table 1). Arsenic has also been used as an additive to poultry feed to inhibit parasites. Arsenic is emitted by coal-burning power plants. As for organic forms of arsenic, large amounts of arsenobetaine or arsenocholine are found in contaminated fish; however, these forms are considered to be essentially nontoxic^55,56,57.

Absorption, body distribution and excretion

The primary routes of arsenic absorption are gastrointestinal and respiratory⁵⁵ (Table 1). Approximately 40–60% of inhaled and 95% of ingested arsenic is absorbed⁵⁵. Arsenic metabolism includes two main reactions: conversion of arsenate to arsenite by oxidation/reduction reactions forming glutathione-arsenic complexes, and methylation that occurs mainly in the liver producing water soluble monomethylarsinic acid and dimethylarsinic acid that are eliminated through the urine. Arsenic metabolism is an area of active investigation, as differences in methylation of arsenic have been associated with differences in health outcomes, including cardiovascular disease^55,58,59.

Exposure evaluation

Since arsenic is cleared from the blood within a few hours of exposure, measurement of blood arsenic can only be used to assess a very recent exposure⁵⁵ (Table 1). Typical values in non-exposed individuals should be less than 1 µg/L⁶⁰.

Urine is considered to be the most reliable body sample to detect arsenic exposure. The American Conference of Governmental Industrial Hygienists considers urine arsenic below 35 µg/L to be acceptable for non-toxic exposed individuals. Yet other reports⁶¹ suggest there may be no safe threshold of arsenic exposure. Arsenic can be detected in urine of people with no known exposure⁵⁵. This could be due to high consumption of certain seafood that contain non-toxic organic form of arsenic, arsenobetaine⁵⁵. Therefore, the measurement of speciated urinary arsenic, rather than total urinary arsenic, is preferred for assessments of cardiovascular toxicity. Finally, arsenic tends to accumulate in nails and hair, wherein acceptable levels of arsenic are less than 1 ppm⁶⁰.

Cardiovascular effects

There is only limited evidence on the relationship between arsenic and cardiovascular morbidity and mortality (Figure 1d). The only prospective cohort study, published recently by Moon et al, reported that long term exposure to low to moderate arsenic levels is associated with cardiovascular disease incidence and cardiovascular mortality⁶². Participants of this study had a median urinary arsenic level of 9.7 µg/g creatinine, with a range between 1 and 183.4 µg/g creatinine, and interquartile range (IQR) between 5.8 and 15.7 µg/g creatinine. The hazard ratios for cardiovascular disease mortality, CAD mortality, and stroke mortality per IQR were 1.65 (95% CI, 1.20–2.27; p<0.001 for trend), 1.71 (95% CI, 1.19–2.44; p<0.001 for trend), and 3.03 (95% CI, 1.08–8.50; p<0.001 for trend), respectively. The association of arsenic with CVD mortality was stronger in participants with diabetes. Evidence is also accumulating on the association between higher levels of arsenic exposure and CV morbidity and mortality in Bangladesh⁶³.

High levels of well-water arsenic exposure are recognized as being causative in the development of peripheral arterial disease^37,64,65, such as blackfoot disease. This is a severe form of PAD endemic to Taiwan characterized by thromboangiitis obliterans, severe arteriosclerosis and high levels of vessel wall arsenic^37,64,65. However, the generalizability of these findings is limited, due to the nature of the exposure (deep well water) and the extremely high estimated levels of arsenic exposure.

Finally, though the literature is limited, there is evidence to suggest that a positive relationship between arsenic exposure and hypertension⁶⁶.

7. Hypothetical mechanisms of metal toxicity

There are general mechanisms that apply to all toxic metals, and specific mechanisms that are idiosyncratic to the individual metal in question. These mechanisms center on oxidative stress. While the science underlying these mechanisms is accurately quoted, attribution of benefit to metal chelation because of these mechanisms has to be considered speculative. Moreover, the oxidative-stress = oxidative-damage hypothesis has been challenged as well.

Oxidative stress results from an imbalance between the production and detoxification of reactive oxygen species (ROS). The toxicity of ROS is based on their ability to oxidize intra- and extracellular structures such as proteins, lipids, and nucleic acids (Figure 2). Several enzyme systems are known to protect the body against ROS. These enzymes include superoxide dismutase, catalase, glutathione peroxidase, paraoxonase, thioredoxin, heme oxygenase, and others. Glutathione peroxidase is of particular interest.

Figure 2.

Toxicity of ROS (please see attached file)

Many metals have electron-sharing properties and, therefore, are capable of forming covalent bonds with sulfhydryl groups of proteins (e.g., glutathione, cystein, homocysteine, metallothionein, albumin). By binding to glutathione, these metals deplete its levels, and, therefore, increase the intracellular concentration of ROS. The consequences include promotion of lipid peroxidation, cell membrane damage, DNA damage, oxidation of aminoacids in proteins and, therefore, changes in their conformation and function, and inactivation of enzymes. According to current concepts of atherogenesis, oxidative modification of LDL, a free radical-driven lipid peroxidation process, is an early event in atherosclerosis development⁶⁸.

Many metals have been shown to increase lipid peroxidation^69,70. In addition, metal-related ROS-mediated changes include microtubule destruction, mitochondrial damage by disruption of the membrane potential, inhibition of ATP production, followed by dysfunction of ion transporters such as Ca-ATPase and Na-K-ATPase causing changes in calcium homeostasis⁷¹.

By binding to sulfhydryl groups of proteins not involved in the detoxification of ROS, metals may cause other biological impairments. Lead causes endothelial dysfunction by binding and inhibiting endothelial nitric oxide synthase (eNOS) and decreasing nitric oxide (NO) production^72,73. Mercury has also been reported to impair nitric oxide metabolism by binding to SH groups of NF-kB and changing its effects on gene expression, and, thus, resulting in decreased expression of inducible NOS (iNOS)⁷⁴. Cadmium has been shown to inhibit endothelial and calcium-calmodulin constitutive NOS as well⁷⁵. Arsenic exposure was linked to impairment of NO production and increased generation of ROS, perhaps by uncoupling of eNOS production⁷⁶.

There are additional, idiosyncratic mechanisms of toxicity. Thus, lead, competing with zinc, binds to sulfhydryl groups of delta-aminolevulinic acid dehydratase (ALAD, the enzyme involved in heme metabolism), preventing binding of ALAD to aminolevulinic acid (ALA)⁷⁷, generating ROS⁷⁸. Lead has also been shown to promote endothelial release of endothelin, to elevate serum levels of norepinephrine, angiotensin-converting enzyme (ACE) and thromboxane, and to decrease production of prostacyclin^79,80. All these changes may mediate vascular constriction. In addition, lead, being one of the calcium-like elements, competes with calcium for transport by channels and pumps in endoplasmic reticulum. Lead may also substitute for calcium in calcium-dependent processes, and can interact with calmodulin.

Arsenic inhibits pyruvate and alpha-ketoglutarate dehydrogenases, important enzymes of gluconeogenesis and glycolysis⁸¹. It can also replace phosphate in glycolysis, generating arseno-3-phosphoglycerate instead of 1,3-bisphosphoglycerate, which leads to uncoupling of oxidative phosphorylation⁸¹. Moreover, arsenic has been linked to increased intravascular inflammation by up-regulating interleukin 6, tumor necrosis factor alpha, and monocyte chemotactic protein, vascular cell adhesion molecule and intercellular adhesion molecule⁸². Furthermore, arsenic inhibits expression of peroxisome proliferator-activated receptor gamma causing hyperglycemia and dyslipidemia⁸³.

Macrophages and endothelial cells take up cadmium by endocytosis causing foam cell production followed by foam cell necrosis and endothelial cell disruption followed by endothelial cell necrosis. Once the endothelial layer is disrupted, cadmium reaches smooth muscle cells and accumulates there, activating smooth muscle cell proliferation and apoptosis. Cadmium may also substitute for iron and copper in proteins that contain these biologically necessary metals. As a result, iron and copper, after being released from its usual binding proteins, may produce ROS, as both elements can be more easily involved in reduction-oxidation reactions⁸⁴. Cadmium is also associated with perturbations in inflammation and coagulation, including elevated blood C-reactive protein and fibrinogen in a general US population, even after adjustment for other cardiovascular disease risk factors such as smoking^82,85,86. Moreover, cadmium exposure has been associated with elevations of mediators or markers of systemic inflammation, including IL-6, TNF-alpha, VCAM-1⁸⁷.

8. Oxidative stress, metals, and diabetes

Patients with diabetes are thought to be especially susceptible to oxidative stress. The formation of advanced glycation end-products, advanced lipoxygenation products, and protein oxidation products require non-enzymatically, metal catalyzed oxygen chemistry. These oxidized and crosslinked complexes are long-lived, and form the basis of diabetes complications, activating the receptor for advanced glycation end products⁸⁸ and multiple other downstream inflammatory cascades^89,90,91. And while the transition elements most closely associated with these reactions are iron and copper, xenobiotic transition elements, such as cadmium and others (cobalt and tungsten)⁹² might be also involved.

9. Potential Interventions

Chelation therapy with ethylenediamine tetraacetic acid (EDTA, edetate disodium) has been used to treat atherosclerotic disease since 1956⁹³, without a solid scientific base. In 2002, the Cochrane Collaborative⁹⁴ reported that there was insufficient evidence for or against chelation therapy to make a recommendation. Yet patients continued to seek, and practitioners to use, EDTA to prevent or treat atherosclerotic disease of the coronaries, carotids, and peripheral arteries. In 2002, the Trial to Assess Chelation Therapy (TACT), a 2 × 2 factorial trial testing EDTA infusions versus placebo and oral high-dose multivitamins and minerals versus oral placebo was designed⁹⁵ and funded. TACT enrolled 1708 patients⁹⁶ who had sustained a prior myocardial infarction, were at least 50 years old, and had a creatinine of 2.0 mg/dL or less. TACT administered 55,222 infusions of EDTA-based chelation or placebo. EDTA chelation significantly reduced a combined cardiovascular endpoint, with a 5-year number needed to treat of 18. In 633 patients who had diabetes⁹⁷, a diagnosis associated with a strong pro-oxidant state, the reduction in events was greater, with a 41% reduction in events and a number needed to treat of 6.5 patients over 5 years (unadjusted p=0.0002). Thus, although mechanisms were not elucidated nor care recommendations yet changed based on these extraordinary results, TACT provides a strong inferential basis for the conclusion that metal burden may be an under-recognized and modifiable risk factor for atherosclerotic disease.

10. Conclusions

Prudent public health measures should be taken to fully assess, then minimize, the public’s exposure to xenobiotic metals. In addition, given the present state of the science, it appears reasonable to consider the results of the recently published chelation trial (TACT) as biologically plausible and, in the selected patients, actionable.