CHAPTER 110: ENVIRONMENT AND HEART DISEASE

People in today’s ever more densely populated, tightly interconnected, highly urbanized and warming world are surrounded by a complex array of environmental threats to health that include air pollution, water pollution, toxic chemicals, changing dietary patterns, emerging infectious diseases, the urban built environment, noise, and global climate change. Numerous etiologic associations have been established between environmental exposures and disease, including cardiovascular disease.¹

Pollution is the single most important environmental cause of disease and death.^2,3 The World Health Organization estimates that household air pollution causes 4.3 million deaths annually in persons of all ages^4,5; many of these deaths are due to heart disease and stroke.⁶ Ambient air pollution causes 3.7 million deaths,⁷ and many are due to heart disease and stroke. Polluted drinking water, poor sanitation, and inadequate hygiene cause 842,000 deaths.⁸ Polluted dust and soil at active and abandoned mines, smelters, industrial facilities, and hazardous waste sites kill tens of thousands more.⁹

Toxic chemicals in the environment are significant causes of disease, specifically cardiovascular disease.² Substances known to be cardiotoxic and reviewed in this chapter include air pollution^2,3; metals,⁹ including lead, mercury, arsenic, cobalt, and thallium; halogenated hydrocarbons, including chlorinated, brominated, and fluorinated compounds; organophosphate insecticides; nitrates; and carbon disulfide. Diseases of the heart and cardiovascular system that are linked to toxic chemical exposures in the environment include arrhythmias, hypertension, peripheral vascular injury, cardiomyopathy, acute myocardial infarction (MI), stroke, and sudden death. Toxic chemicals that disrupt endocrine signaling can increase risk for cardiovascular disease by causing elevated lipid levels and increasing risk for obesity, the metabolic syndrome, and diabetes.^10,11

Likelihood is high that, beyond the known cardiotoxic chemicals, there are other chemicals in the modern environment whose toxicity to the heart and cardiovascular system has not yet been recognized.¹² These undiscovered cardiotoxins will be found hidden in plain sight among the more than 80,000 new synthetic chemicals that have been invented in the past half century, that are used widely today in myriad consumer products and that, because of failure of stewardship by the chemical industry and by governments, have never been tested for safety or toxicity.¹² People are widely exposed to these materials, and annual national surveys conducted by the Centers for Disease Control and Prevention find measurable levels of more than 100 untested synthetic chemicals in the bodies of virtually all Americans.¹³

Two additional environmental exposures that increase risk of cardiovascular disease are noise and global climate change. These are discussed in this chapter.

Given the widespread exposure of the American population to multiple environmental chemicals of unexamined toxicity, every physician is advised to obtain a brief history of occupational and environmental exposure from every new patient and to ask more detailed follow-up questions or seek consultation with a specialist in occupational and environmental medicine if the initial screen raises suspicion of toxic exposure. Straightforward screening algorithms have been developed in occupational and environmental medicine.¹⁴ The most intense exposures typically occur in occupational settings, and most discoveries of new associations between toxic chemicals and disease have been made by physicians examining working populations.

Cardiovascular and other diseases caused by harmful exposures in the environment can be prevented. Alert physicians who have recognized “sentinel events”—previously undiscovered linkages between disease in their patients and toxic hazards in the environment—have time and again played critically important roles in disease prevention.¹⁵ Examples include Irving Selikoff’s recognition of the associations between asbestos, lung cancer, and malignant mesothelioma, a discovery that led to bans on most uses of asbestos¹⁶; Herbert Needleman’s discovery of widespread, low-level lead toxicity in American children, which led to the removal of lead from paint and gasoline¹⁷; and discovery by the investigators in the Framingham Heart Study of the major environmental risk factors for cardiovascular disease, discoveries that have contributed to a greater than 50% reduction over the past five decades in mortality from cardiovascular disease in the United States and in countries around the world.¹⁸ Alert physicians who discover previously unrecognized associations between environmental hazards and cardiovascular disease have the opportunity to make similarly important contributions to the prevention of disease.

Air pollution is a complex mix of gases—ozone, oxides of nitrogen, and carbon monoxide—and particulate matter.^2,3 A rapidly expanding body of research, especially large epidemiologic studies that combine state-of-the-art assessments of pollution exposure and chemistry with sophisticated markers of cardiovascular disease have substantially advanced knowledge of the effects of air pollution on health and disease.^19,20,21 These studies consistently find that airborne particulate matter, especially fine particles with mean diameter of less than 2.5 μm, is closely linked to diseases of the heart and cardiovascular system.^22,23,24 Especially informative have been epidemiologic studies that combine state-of-the-art measures of air pollution with sophisticated assessments of the pathophysiologic changes that are recognized precursors of cardiovascular disease, such as elevations in blood pressure, alterations in cardiac rhythm, the development and progression of atherosclerosis, and the development of insulin resistance.^1,25,26

Particulate Air Pollution

Particulate air pollution is a complex mix of airborne particles that vary in size and chemical composition depending on their origin. Many contain toxic metals and other potentially harmful materials, and their toxicity is magnified by their high surface-to-volume ratio, which increases their biological reactivity.^2,3

Combustion of fossil fuels is the most important source of atmospheric particulates in the modern urban environment. Emissions from both stationary sources—factories and coal-fired power plants—as well as from mobile sources—cars, trucks, and buses—contribute to overall exposure, and the mix of stationary and mobile sources varies from city to city.^2,3,5 By contrast, in much of the developing world, the major source of airborne particulates is household air pollution created by the burning of biomass—wood and dried cow dung—in poorly ventilated cook stoves.^4,19,20

Particle size is a major determinant of the health impacts of airborne particulates. Larger particles with mass median airborne diameters of 10 μm and above (PM10) are usually filtered out of inhaled air in the upper airways and do not penetrate deeply into the lungs, except when concentrations are so high that the normal physiologic defenses are overwhelmed, as happened in New York City after the attacks on the World Trade Center²⁷ and as occurs in highly polluted indoor environments in the developing world.²⁰ By contrast, fine particles (< 2.5 μm in diameter) are capable of penetrating deep into the tracheobronchial tree. Ultrafine particles (< 0.1 μm) may actually translocate from inhaled air across the alveolar membranes to enter the systemic circulation. Most current US air regulations focus on fine particles.²⁸

The association between particulate air pollution and cardiovascular health has been studied extensively, and knowledge in this field has grown rapidly in the past decade. Particulate pollution is associated with hypertension,²⁶ increased serum lipid levels, and accelerated progression of atherosclerosis.^29,30,31 Clinically, elevated levels of airborne particulate are associated with increased numbers of emergency department visits and increased hospital admissions for acute MI.^32,33,34,35 Particulate air pollution is associated also with increased incidence of cardiac arrhythmias,^35,36 increased cardiovascular disease mortality,^22,23 and increased incidence of stroke.²⁴ In a recent national US study, it was estimated that each 10-μg/m³ decrease in concentration of fine particulate matter is associated with an increased life expectancy of 0.61 years.³⁷

The mechanisms through which airborne particulates increase the risk of cardiovascular morbidity and mortality are the subject of active investigation. Toxicologic studies suggest that exposures to fine particles induce atherosclerosis and accelerate development of atherosclerotic plaques by increasing oxidative stress, insulin resistance, endothelial dysfunction, and propensity to coagulation.^38,39,40 Forastiere and Agabiti³⁸ have developed a schematic to explain this sequence (Fig. 110–1).

Carbon Monoxide

Carbon monoxide (CO) is a colorless, odorless, highly toxic gas produced by the incomplete combustion of hydrocarbons. Automotive exhaust is the major environmental source in modern cities. Other sources include improperly adjusted gas heaters, old appliances, wall ovens, stoves, tobacco smoking, and charcoal grilles. CO exerts its toxicity by binding strongly to hemoglobin to block transport of oxygen to tissues. The heart and brain are especially vulnerable. At high doses, CO is acutely toxic, and inhalation exposure can be rapidly fatal.

Initial recognition of the relationship between chronic CO exposure and heart disease came from studies of cigarette smokers who had stopped smoking. Although the incidence of nonmalignant lung disease and lung cancer took years to return to baseline following cessation of smoking, the incidence of acute cardiac events decreased sharply within 24 hours of smoking cessation, a time course consistent with acute reduction in exposure to CO.⁴¹ The relationship between CO exposure and heart disease is further substantiated by studies showing that daily variation in ambient CO levels is associated with concomitant variation in hospital admissions for ischemic heart disease and heart failure.^42,43

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

Lead

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

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

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

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

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

Cadmium

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

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

Mercury

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

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.

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

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

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

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

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

Arsenic

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

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.

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

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

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

Cobalt

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.

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

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

Thallium

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

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

The halogenated hydrocarbons are a large and diverse family of synthetic chemicals that have as their common feature a chemical bond between a carbon atom and one or more halogen atoms (chlorine, bromine, or fluorine). The carbon-halogen bond is extremely strong. Consequently, many halogenated hydrocarbons are extremely persistent in the human body and in the environment.

Halogenated hydrocarbons have been used in a wide range of products from electrical insulation (polychlorinated biphenyls [PCBs]) to flame retardants (polybrominated diphenyl ethers [PBDEs]) and water repellents (perfluorinated compounds). Some, such as dioxins and furans, are produced as inadvertent by-products in chemical manufacture or released to the environment through combustion of materials containing chlorine. Because of their lipophilic nature, halogenated hydrocarbons readily cross the placenta and blood-brain barrier. They concentrate and may persist for years in adipose tissues. Depending on their chemical composition and structure, halogenated hydrocarbons have multiple and varied toxicities, among them neurotoxicity, carcinogenicity, and ability to disrupt endocrine function. A number of halogenated hydrocarbons are toxic to the heart and cardiovascular system.

Manufacture and use of many of the older, chlorine-based halogenated hydrocarbons has declined sharply in countries around the world in recent years under the terms of the Stockholm Convention, a global treaty designed to protect human health and the environment against these persistent pollutants by restricting and ultimately eliminating their production, use, trade, release, and storage.¹⁰¹ By contrast, manufacture and use of the brominated hydrocarbons and of many of the fluorocarbons is strong and increasing.

Halogenated Alkanes

Some volatile halogenated alkanes (eg, halothane, methoxyflurane, enflurane) were used many years ago as anesthetics. These compounds are cardiotoxic and depress heart rate, conduction, and contractility. They can also provoke arrhythmias.¹⁰² Experimental evidence suggests that these compounds exert their toxicity by interacting with cardiac potassium channels as well as with calcium and sodium channels.¹⁰³ This toxicity appears to be potentiated by catecholamines. These compounds have, for the most part, been replaced by less toxic anesthetic agents.

Halogenated Solvents

High-level, brief exposures to halogenated solvents (eg, trichloroethylene 1,1,1-trichloroethane) have been recognized for many decades to be associated with central nervous system intoxication and acute death, caused apparently by sudden cardiac arrhythmias.⁴⁷ High-dose exposures to these compounds may occur in occupational settings and also among persons who “sniff” solvents as a means of intoxication. The suspected mechanism of toxicity, as in the case of halogenated anesthetics, appears to involve disruption of potassium, calcium, and sodium channels.¹⁰³

Methylene Chloride

The halogenated solvent dichloromethane (methylene chloride) is uniquely toxic to the heart and cardiovascular system because its metabolism produces significant amounts of CO.¹⁰⁴ Epidemiologic studies of chemical workers occupationally exposed to dichloromethane have observed excess mortality from heart disease.^105,106,107

Dioxins

Dioxins are a family of chlorinated hydrocarbon compounds with a common cyclic chemical structure.¹⁰⁸ Dioxins are highly persistent in humans and the environment. They are lipophilic and bioaccumulative. Exposures to dioxin, and specifically to the highly toxic dioxin congener 2,3,7,8-tetracloro-p-dibenzodioxin (TCDD), have occurred among workers in the chemical industry, particularly workers producing herbicides,¹⁰⁹ and in military personnel in the Vietnam War who applied dioxin-contaminated herbicide (Agent Orange). In the general population, exposure results most commonly from consumption of foods, especially meats, in which TCDD has accumulated. TCDD exposure has also occurred in community populations exposed to TCDD from industrial releases.¹¹⁰

TCDD has been linked to elevations in population prevalence of cardiovascular risk factors, specifically increased rates of insulin resistance and type 2 diabetes in studies of American and Korean Vietnam War veterans exposed militarily to TCDD-contaminated herbicide,^111,112 in persons in the general US population examined through the National Health and Nutrition Examination Survey (NHANES) study,¹¹³ and in the general population of Japan.¹¹⁴ TCDD was associated with increased mortality from diabetes among community residents in Seveso, Italy, exposed after an industrial explosion.¹¹⁵ TCDD and other persistent organic pollutants are associated with hypertension in the general population¹¹⁶ and with increased risk of obesity and the metabolic syndrome.¹¹⁷

A systematic review of 12 epidemiologic studies (10 of them in occupationally exposed populations) found a consistently positive, dose-related, statistically significant association between high-level TCDD exposure and mortality from ischemic heart disease as well as a more modest association with mortality from all forms of cardiovascular disease.¹¹⁸

Toxicologic studies of TCDD corroborate these epidemiologic findings. Chronic exposure of rats to TCDD produced a dose-related increased incidence of degenerative cardiovascular lesions, including cardiomyopathy and degenerative arteritis.¹¹⁹ Mice exposed subchronically to TCDD had increased blood pressure, elevated triglycerides, elevated low-density lipoprotein, elevated total cholesterol, increased cardiac weight, and increased risk of cardiovascular disease.¹²⁰ They also showed elevated levels of markers of oxidative stress. Atherogenic apolipoprotein E (apoE) –/– mice exposed subchronically to TCDD developed earlier and more severe atherogenic plaques.¹²¹ Mixtures of TCDD and other halogenated pollutants have been shown to induce insulin resistance and to downregulate two insulin-induced genes centrally involved in lipid homeostasis.¹²² TCDD and structurally similar PCBs appear to exert their cardiovascular toxicity through a variety of pathophysiologic mechanisms, including oxidative stress, inflammation, and direct cardiotoxicity, possibly mediated through disruption of mitochondrial function.¹²³

Polychlorinated Biphenyls

PCBs, another family of chlorinated hydrocarbons, were previously used in a wide variety of industrial applications, most notably as insulating liquids in electrical generators and capacitors.¹²⁴ Because of their environmental persistence and toxicity, manufacture and use of PCBs was banned in the United States in 1977, but PCBs released to the environment many decades ago are still abundant in the environment, especially in riverine and marine sediments. PCBs bioaccumulate in the aquatic food chain and reach the highest levels in predatory marine species such as bluefin tuna, shark, king mackerel, and swordfish. Consumption of contaminated fish is the major current route of exposure.

The most highly cardiotoxic PCBs are congeners that most closely resemble TCDD, (eg, PCB-126). Dioxin-like PCBs have been linked to cardiovascular risk factors, specifically to components of the metabolic syndrome, high blood pressure, elevated triglycerides, and glucose intolerance^{116,125,126,127} and to increased risk for obesity and diabetes.^117,128

Epidemiologic studies of industrial workers exposed occupationally to PCBs find excess mortality from cardiovascular disease that increases with the duration of employment.¹²⁹ Studies of Native American populations heavily exposed to PCBs through a traditional diet high in fish find associations of serum PCB levels with elevated serum lipids and cardiovascular disease risk.¹³⁰

Toxicologic data on PCBs are consistent with these epidemiologic findings. Chronic exposure of rats to PCB-126 produced a dose-related increased incidence of degenerative cardiovascular lesions, including cardiomyopathy and degenerative arteritis.¹³¹ PCB-126 also increased heart weight, serum cholesterol, and blood pressure.¹³¹

Polybrominated Diphenyl Ethers

PBDEs are a class of bromine-based synthetics used as flame retardants in polymers and textiles.¹³² They are incorporated into numerous consumer products, including computers, television sets, mobile phones, electronics and electrical items, polyurethane foam mattresses, carpets, upholstered furniture, and draperies. PBDEs typically constitute between 5% and 30% of these products’ net weight. Their use has increased substantially in the past decade, and PBDEs have become major environmental pollutants. PBDEs are lipophilic, accumulate in adipose tissue, and are biologically persistent.

PBDEs are not firmly bound to the materials into which they are incorporated and consequently are released from consumer products to contaminate the home environment. Exposures to PBDEs in house dust are estimated to account for more than 80% of current US intake.¹³³ In the developing world, PBDE exposure is linked to contact with electronic waste (e-waste).¹³⁴

Human body burdens of PBDEs have increased markedly in recent years. Reflecting differences in regulatory strategy between the United States and the European Union, PBDE levels in US residents are 10 to 20 times higher than in Europeans. PBDE levels in US residents are doubling every 4 to 6 years.¹³⁵ PBDEs are endocrine disruptors, and they disrupt thyroid function.¹²⁸ They are developmental neurotoxicants.¹³⁶

PBDE levels are significantly associated with the metabolic syndrome and diabetes at levels of exposure currently seen in the general US population.¹³⁷ A recent report suggests an association between PBDE exposure and children’s cardiovascular responses to stress.¹³⁸ No data are currently available on possible associations between PBDEs and other risk factors for cardiovascular disease.

Perfluorinated Compounds

Perfluoroalkyl acids (PFAAs)—perfluorooctanyl sulfonate (PFOS), perfluorooctanoic acid (PFOA), and their congeners—have been used extensively in the production of fluoropolymers. Members of this class of synthetic chemicals have powerful surfactant and water-repelling properties and have been used in textiles, carpets, upholstery, food packaging, lubricants, electronics, and frying pans.¹³⁹

PFAAs have become widely distributed in the global environment, and like many other halogenated hydrocarbons, they are environmentally persistent. Measurable levels of PFOS and PFOA are found in the serum of a high proportion of US residents through national biomonitoring surveys conducted by the Centers for Disease Control and Prevention.¹³ Environmental concentrations have begun to decline since 2000 when 3M, the major manufacturer, instituted a phase-out in production of materials containing PFOS.¹⁴⁰

Acute, high-level exposures to perfluorinated solvents have been associated with cardiac arrhythmias in laboratory technicians using these compounds to prepare frozen sections for microscopic examination.¹⁴¹ Cardiac arrhythmias have also been documented in refrigeration technicians chronically exposed to fluorocarbon compounds.¹⁴²

Data on possible chronic cardiovascular toxicity of PFAAs are limited and inconsistent. A cross-sectional study undertaken in Denmark found that increased levels of perfluorinated compounds in overweight 8- to 10-year-old children were associated with higher insulin and triglyceride concentrations.¹⁴³ A cohort mortality study of US workers occupationally exposed to PFAAs found borderline significant increases in mortality from diabetes and cerebrovascular disease (standardized mortality ratio, 1.8).¹⁴⁴ However, by contrast, a prospective, population-based cohort mortality study in rural Sweden found no statistically significant associations between levels of seven of the eight perfluoroalkyl substances at baseline and subsequent risk for developing coronary heart disease.¹⁴⁵

The organophosphates are a large family of synthetic compounds designed to induce acute neurotoxicity through inhibition of the enzyme acetylcholinesterase. The first organophosphates were produced in the 1930s for use in chemical warfare. Now classified as weapons of mass destruction, production of these highly toxic organophosphate “nerve gases” is strictly limited by international treaty. Nonetheless, in recent years, they have been used in warfare (in Kurdistan) and in terrorist attacks (in Tokyo). The possibility of future use is, unfortunately, real.

Less acutely, toxic organophosphates are widely used today as insecticides in agriculture as well as in the home environment. Acetylcholinesterase inhibition is the mechanism of their insecticidal action. Populations at greatest risk of exposure include farm workers, pesticide applicators, farm workers’ children inadvertently exposed to pesticides carried home on workers’ clothing, and persons living near farms who may be exposed to airborne “drift.”¹⁴⁶ Exposure of the general population occurs through consumption of pesticide-treated fruits and vegetables and also results from pesticide application in houses and apartments.¹⁴⁷ Children are particularly at risk of exposure because of their diets and oral-exploratory behavior coupled with their unique biological vulnerability.^148,149 Prenatal exposures are especially dangerous and can result in persistent neurodevelopmental impairment with loss of cognition (lowered IQ) and altered behavior.

Acute organophosphate poisoning can result from ingestion, inhalation, or dermal or ocular absorption.⁴⁷ Signs and symptoms of acute organophosphate poisoning include miosis (pathognomonic but not always present), excessive salivation, vomiting, diarrhea, muscle fasciculation, respiratory depression, bronchospasm, and acute pulmonary edema. Deaths are most commonly caused by respiratory failure. Management consists of supportive care, oxygen, and atropine in escalating doses. In the case of occupational exposure, it is important to decontaminate the skin because of risk of transdermal absorption.

Key cardiac manifestations of acute organophosphate poisoning are bradycardia, ST-segment elevation, and atrioventricular conduction disturbances. Sinus tachycardia is seen in some cases.¹⁵⁰ Longer lasting cardiac changes include QT prolongation and polymorphic tachycardia (torsade de pointes). Complex ventricular arrhythmias are a frequently overlooked and potentially lethal aspect of acute organophosphate poisoning that can cause sudden cardiac death. Cardiac monitoring of acutely intoxicated patients for relatively long periods of time and early aggressive treatment of arrhythmias are critically important to patient survival.¹⁵⁰

The cardiovascular consequences of chronic exposure to organophosphates are largely unexplored. In rodents chronically exposed to organophosphates at dose levels that produced no overt toxicity, cardiac enlargement was observed and was attributed to hypertrophy of cardiac myocytes.¹⁵¹

The most important decision to be made in the immediate aftermath of a suspected chemical weapons attack is whether the causal agent is an organophosphate. This decision is crucial because of all the currently known chemical weapons, only organophosphate intoxication has a readily available, rapidly acting, specific antidote—atropine.¹⁵² On-scene medical triage and treatment are additional key components of management that are proven to save many lives in response to terrorist events. Decontamination of the skin of patients and provision of personal protective equipment for healthcare workers are essential.¹⁵³

The clinical manifestations of poisoning by the organophosphate “nerve gases” are similar to those of acute organophosphate insecticide poisoning, but with more rapid onset and greater severity. Cardiac manifestations include premature ventricular contractions, QT prolongation, and rarely cardiomyopathy.^150,154

Occupational exposures to nitroglycerin and other aliphatic nitrates are strongly linked to excess risks of acute angina, MI, and cardiovascular death.⁴⁷ These associations have been studied especially closely among workers in the explosives industry, where the risk of death from cardiac disease among workers exposed to nitroglycerin and trinitrotoluene was elevated two- to three-fold after 20 years of employment. Exposures to these compounds may also occur among workers in the pharmaceutical manufacturing industry.¹⁵⁵

Carbon disulfide (CS₂) is an industrial solvent, a colorless, highly volatile liquid used in the manufacture of rayon, cellophane, carbon tetrachloride, dyes, and rubber.¹⁵⁶ CS₂ has been used in the production of rocket fuels and in grain fumigation. Exposure occurs primarily in occupational settings, and inhalation is the typical route of exposure.⁴⁷

Long-term occupational exposure to CS₂ is associated with an increased risk of cardiovascular disease.^157,158 CS₂ increases oxidative stress,¹⁵⁹ interferes with lipid metabolism,¹⁶⁰ increases risk of hypertension,¹⁶¹ and causes functional changes in vessel walls, indicative of atherosclerosis.^162,163 The atherogenic effects of CS₂ have been replicated in an experimental study.¹⁶⁴

A growing body of evidence indicates that chronic exposure to noise, especially in modern urban environments, can adversely affect health and increase risk for ischemic heart disease. A recent meta-analysis of 10 studies examining the cardiovascular effects of road and aircraft noise exposure conducted since the mid-1990s found that relative risk for ischemic heart disease increased by 6% with each 10-dB increase in average noise exposure. The exposure-response relationship was linear and appeared to begin at an average noise level of 50 dB.¹⁶⁵ Concomitant exposure to air pollution does not appear to account for the association between noise exposure and heart disease.¹⁶⁶

Noise appears to exert its adverse effects on the cardiovascular system primarily by increasing risk for hypertension, which in turn increases risk for MI and stroke. Chronic night time noise appears to be especially hazardous and is associated with disruptions of sleep and increases in stress hormone levels and oxidative stress, which in turn may result in endothelial dysfunction and arterial hypertension.¹⁶⁷ Epidemiologic findings on the association between noise and cardiovascular disease are corroborated by experimental studies.¹⁶⁸

The principal driver of global climate change is a steady increase in atmospheric levels of carbon dioxide, methane, and other so-called “greenhouse gases” that trap heat above the surface of the earth. Expert scientific reviews have determined that increasing combustion of fossil fuels is the major underlying cause of the increase in greenhouse gases.¹⁶⁹

Global climate change has multiple consequences relevant to human health. These include including increasing global surface temperatures; changing patterns of precipitation; increased frequency, intensity, duration, and spatial extent of extreme weather events; and rising sea levels with coastal flooding.^169,170

The health effects of climate change include disease or injury directly associated with extreme weather and climate events, such as dehydration from extreme heat exposure and drowning secondary to flooding following heavy precipitation. Additionally, there are indirect effects such as injuries, illnesses, and deaths resulting from changes to ecosystems and diminished air quality.^171,172

The cardiovascular consequences of global climate change will largely be the result of increased surface temperatures. It is projected that by 2050, major US cities such as New York and Chicago may experience as many as three times their current average number of days hotter than 32°C (90°F). High temperatures are strongly associated with elevated levels of air pollution.¹⁷¹ The combination of extreme heat and increased levels of air pollution will lead to increased incidence and mortality from heart disease and stroke.^22,23,24,25 The posttraumatic stress disorder and depression, which are associated with climate-related natural disasters such as extreme storms, coastal flooding, and forced migration, will further exacerbate the impacts of heat and pollution and may be expected to further increase risk of cardiovascular disease, especially in highly vulnerable populations.¹⁷²

We would like to thank Dr Michele A. La Merrill, who contributed to the previous version of this chapter in the 13th edition.