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The metals lead, cadmium mercury, arsenic, cobalt, and thallium have all been documented to cause disease and dysfunction of the heart and cardiovascular system.9,44
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Lead is a heavy metal and a chemical element that composes 0.002% of the Earth’s crust. It has a low melting point, is easily molded and shaped, and can be combined with other metals to form alloys. Because of these properties, lead has been used by humans for millennia and is used today in products as diverse as pipes, storage batteries, pigments, glazes, vinyl products, weights, shot and ammunition, cable covers, and radiation shielding. From the 1930s to the 1970s, lead was used extensively as a gasoline additive to improve engine performance.45 Lead is widespread in the modern environment. Global consumption of lead continues to increase, mainly because of rising demand for batteries.46
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Patients may be exposed to lead by either inhalation or ingestion. Inhalation is the most common route of adult exposure, and the most serious exposures occur among workers exposed occupationally.47 Workers at greatest risk include smelter and foundry workers, hazardous waste workers, construction workers exposed to lead-painted steel, shipyard workers, electrical workers, and home renovators sanding or removing old lead paint.47 For children, ingestion of lead paint chips or, more commonly, ingestion of the lead dust eroded from lead paint is the most common route of exposure.48 Persons of all ages may be exposed by ingestion of lead in drinking water.48 Ayurvedic and other nonprescription medications are further sources of exposure.49
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Lead is best known as a neurotoxin. At high levels, lead can cause acute encephalopathy with coma, convulsions, and death.48 At lower levels, it can cause injury to the central and peripheral nervous systems with loss of intelligence, shortening of attention span, disruption of behavior, and slowing of nerve conduction velocity. Children are especially vulnerable to these effects.50 There appears to be no threshold below which lead causes no injury to the human brain.50,51
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Cardiovascular toxicity, specifically increased incidence of hypertension and stroke, was reported more than a century ago among workers with poorly controlled, high-dose occupational exposures to lead.52 Recent large-scale epidemiologic studies have confirmed a relationship between lead and hypertension in the general US population even at very low blood lead levels.53,54,55 A recent systematic review found that the relationship between lead and hypertension is consistent across numerous high-quality studies and concluded that the association is causal.56 The hypertensive effects of lead have been confirmed experimentally.56
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Positive associations have also been identified between lead and coronary heart disease, stroke, alterations in cardiac rhythm, and peripheral arterial disease.57,58,59 The number of studies examining each of these outcomes is, however, relatively small, and the associations less well established than that between lead and hypertension.56 Associations between lead and cardiovascular effects have been observed at blood lead levels as low as 5 μg/dL.56
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Cadmium is a metallic element used in batteries, electronic equipment, metal coatings, and pigments.60 Virtually all high-dose exposure occurs in the workplace, and inhalation is the principal route of exposure.47 Workers at greatest risk of exposure include miners, smelter workers, electroplaters, battery manufacturers, and electronics workers. Nonoccupational exposure can occur through consumption of contaminated drinking water.60 Tobacco contains cadmium, and smokers consistently have higher body burdens of cadmium than nonsmokers. After it has been absorbed, cadmium is stored in the kidneys and liver and may remain in those organs for decades.61 Cadmium has been characterized as a human carcinogen by the International Agency for Research on Cancer.62 High-level exposure to cadmium is associated with impaired renal function and lung cancer.63,64,65
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A positive association between cadmium levels and increased blood pressure has been found in the general US population.66 Increased cadmium burden is associated with an elevated risk of coronary heart disease, stroke, and peripheral arterial disease.67 Cadmium exposure is associated with elevated circulating levels of inflammatory markers such as C-reactive protein and fibrinogen.68 Cadmium has been found to be an independent risk factor for atherosclerosis. Elevated cadmium levels are associated with increased carotid arterial intima-media thickness.69,70
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Mercury is a toxic metal that since antiquity has been used in pharmaceuticals and cosmetics and, more recently, in pesticides, dental fillings, and scientific and medical instruments.71 Two-thirds of all mercury in the environment is of anthropogenic origin. Combustion of coal in the generation of electricity (all coal contains some mercury) is the single major source of mercury emission to the environment.71 Waste incineration, including incineration of medical waste, is another important source. Artisanal gold mining, which uses mercury to remove gold from ore, is a major source of mercury exposure, especially in low-income and middle-income countries.72 Mercury exists in several distinct chemical forms with quite different toxicities. Metallic mercury and methylmercury are the two forms most highly toxic to the cardiovascular system.73
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Exposure to metallic mercury occurs most commonly in industry.47 Workers at highest risk of exposure today are artisanal gold miners, chloralkali workers, instrument makers, and workers in the electronics industry. In these workplaces, mercury vaporizes at ambient temperature, and inhalation is the principal route of occupational exposure. Ingestion exposure is not important because metallic mercury is poorly absorbed from the gut.
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Acute exposure to metallic mercury is associated with pneumonitis and, at very high levels, encephalopathy. Chronic exposure is linked to peripheral neuropathy with tremor, personality changes (erethism), and renal toxicity with proteinuria.47
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The cardiovascular effects of chronic occupational exposure to metallic mercury include dose-related increases in hypertension, increased carotid arterial intima-media thickness, coronary heart disease, MI, cerebrovascular accident, and cardiac death.9,74
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Methyl mercury is formed when airborne particles of metallic mercury emitted by industrial sources deposit in lakes, rivers, and oceans. The deposited mercury is transformed to methylmercury by marine microorganisms. Methylmercury is lipophilic and highly persistent in the environment. It bioaccumulates to reach particularly high levels in predatory fish at the top of the aquatic food chain such as bluefin tuna, shark, king mackerel, and swordfish. Consumption of contaminated fish is the major route of human exposure to methylmercury.74
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Methylmercury is a potent neurotoxin.73 The fetal brain is especially sensitive, and methylmercury crosses freely during pregnancy between the maternal and fetal circulations. Methylmercury has been associated with major outbreaks of developmental neurotoxicity, notably Minamata disease,75 as well as with widespread subclinical neurotoxicity.76
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Methylmercury is also a cardiovascular toxin. Methylmercury exposure is associated with disturbances in cardiac rhythm, specifically decreased heart rate variability,77 hypertension,78,79 increased carotid arterial intima-media thickness,80 accelerated progression of carotid atherosclerosis,81 increased risk of MI,80 and increased risk of coronary and cardiovascular death.80 Epidemiologic studies of populations exposed to methylmercury through consumption of fish and marine mammals have had to disentangle the adverse effects of methylmercury from the potentially beneficial effects of omega-3 fatty acids.81 Experimental studies corroborate the cardiovascular toxicity of methylmercury and suggest that methylmercury may contribute to progression of cardiovascular disease by causing oxidative stress,82 enhancing procoagulant activity of erythrocytes,83 or activating inflammatory mediators.84
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Arsenic is a toxic metalloid element that occurs naturally in the earth’s crust.85 Drinking water is the principal source of human exposure worldwide, and major problems of arsenic in drinking water are found in southeast Asia, Taiwan, Chile, Argentina, northern New England, and the American Southwest. High concentrations of arsenic are also released into the environment by polluting industries, and inhalation can be an important exposure route for people living near such industries as well as for workers exposed occupationally.85
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The International Agency for Research on Cancer classifies arsenic as a proven human carcinogen.86 Inorganic arsenic compounds have been shown in epidemiologic studies to cause cancer of the lung, urinary bladder, and skin. In addition, positive associations have been observed between inorganic arsenic compounds and cancer of the kidney, liver, and prostate.
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Arsenic exposure is strongly associated with increased risk of cardiovascular disease.1,87,88 Positive dose-response relationships have been documented between chronic arsenic exposure and carotid atherosclerosis,89 hypertension,90 and ischemic heart disease.91 Arsenic exposure has also been linked to increased risk of diabetes.91,92
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Chronic arsenic exposure is strongly associated with peripheral vascular disease. The severity appears related to cumulative dose and is greatest when exposure begins in utero or early childhood. The most severe cases can progress to endarteritis obliterans with frank gangrene of the extremities (black foot disease).93
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Experimental studies have found that arsenic appears to increase the production of reactive oxygen species and triggers inflammatory responses in endothelial cells. These changes appear to increase risk for atherosclerosis and cardiovascular disease.94
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Cobalt is a relatively rare element with properties similar to those of iron and nickel.47,95 It is an essential trace element necessary for the formation of vitamin B12.
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Excessive exposure to cobalt has been linked to cardiac disease. In 1966, a syndrome labeled “beer drinker’s cardiomyopathy” was recognized among heavy beer drinkers in Quebec City, Canada, and was characterized by pericardial effusion, elevated hemoglobin concentrations, and congestive heart failure. The appearance of the syndrome coincided temporally with addition of cobalt to beer.96 A similar cardiomyopathy has been reported in other groups chronically exposed to cobalt, among them beer-drinking populations and workers producing “hard metal,” an alloy that contains cobalt.47,97
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Experimental studies in a rat models suggest that cobalt may cause myocardial dysfunction and disease by suppressing respiratory chain enzymes in myocardial cells, thus leading to mitochondrial dysfunction.98
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Thallium is a highly toxic metallic element.99 It has been used as a rodenticide, although this use has not been permitted in the United States since 1972. It can be absorbed orally and transdermally. It has neither an odor nor a taste and has been used in poisonings and assassinations. Symptoms of acute intoxication include gastrointestinal symptoms, polyneuropathy, and dermatologic changes. Alopecia typically develops 3 to 4 weeks after exposure.100
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Cardiovascular manifestations of acute thallium poisoning are hypotension and bradycardia, apparently secondary to direct toxic effects of thallium on the sinus node and myocardium. Diagnosis is made by toxicologic screen. Because thallium exerts its toxicity by displacing potassium, treatment consists of potassium chloride and Prussian blue (potassium ferric hexacyanoferrate) plus supportive measures.100