Heart and Toxins

By Dr. Meenakshisundaram Sundaram Ramachandran

The Heart and Toxins brings together global experts to provide the latest information and clinical trials that make the connection between genetic susceptibility, gene expression, and environmental factors in cardiovascular diseases. This unique reference, edited by renowned cardiologist Meenakshi Sundaram Ramachandran, solves the problem of managing multiple clinical cases of cardiovascular toxicity. It allows connections to be made between research, diagnosis, and treatment to avoid higher morbidity and mortality rates as a result of cardiovascular toxicity.

• Structured to bring together exploration into the epidemiology, molecular mechanism, pathogenesis, environmental factors and management in cardiovascular toxins
• Included various topics on cardiovascular toxins such as plant, chemical, animal, nanomaterial and marine biology induced cardiac damage – which are new ideas discussed in detail
• Comprehensive chapters on the cardiovascular toxicity from drugs, radiotherapy and radiological imaging
• Enables you to manage multiple clinical cases of cardiovascular toxicity
• Outlined conclusions at the end of each chapter providing “key learning points to help you organize the chapter’s details without losing insight

• Language: English
• Publisher: Academic Press
• Release date: Aug 12, 2014
• ISBN: 9780124165991

Book preview

Kingdom

Chapter 1

Epidemiology of Cardiovascular Toxins

Churchill Lukwiya Onen,    Centre for Chronic Diseases, Gaborone, Botswana

Complex interactions between humans and their diverse environments, compounded by diverse biological, social, and dietary factors, interplay to increase the risk of exposure to various cardiovascular toxins. The globalization of trade has diversified potential exposure to toxic agents and complicated the epidemiology of cardiovascular toxins. Tobacco is arguably the ultimate weapon of mass destruction, predicted to kill an estimated one billion people during this century, mostly in lower- and middle-income countries. An urgent call is being made for strict implementation of the WHO Framework Convention on Tobacco Control and its MPOWER strategy. Potential harmful effects of alcohol are concealed within the matrix of literature propagating cardiovascular benefits of moderate drinking. Perhaps health warnings similar to those on tobacco packages regarding the potential harmful cardiovascular effects of ethanol and various drugs are overdue. Unified global approaches to protect the environment will ensure reduced risk of air pollution and exposure to toxic heavy metals. Safety measures including better seafood processing will likely minimize the risk of exposure to marine toxins. The impact of many toxins could be greatly attenuated by the development and expanded use of evidence-based guidelines related to identification, characterization of their physicochemical and biological activities, and effective management of affected persons. Clear understanding of cardiovascular morbidity related to various toxins and their potential synergies must include the confounding roles of genetics, age, gender, and comorbidities. More prospective epidemiological studies to determine the strengths of association between toxins, cardiovascular morbidity, and mortality are needed to guide preventive efforts.

Keywords

epidemiology; cardiovascular; toxins; cardiotoxicity; morbidity; mortality

1.1 Introduction

Strictly speaking, the word toxins refers to poisonous substances produced during metabolism or growth of certain microorganisms, higher plants, or animals, whereas a poison is any substance that causes injury or illness or death of a living organism, as discussed here, to humans. Toxicity refers to the degree to which something is poisonous, and toxicology is the study of the adverse effects of chemicals on living organisms. Cardiovascular toxins¹,² have harmful effects on the circulatory system, resulting in symptoms and signs of injury, and may potentially cause death. A greater understanding of the distribution, determinants, secular trends, and deterrents of cardiovascular toxins may provide the solid epidemiological platform for developing, prioritizing, and evaluating public health programs against morbidity and mortality related to these toxins.

This chapter addresses the epidemiology of major categories of substances with clinically relevant cardiovascular toxic effects ranging from plant toxins, marine toxins, venomous reptiles, trichinellosis, arachnidism, scorpion venoms, air pollution, pesticides, fungicides, household materials, industrial toxins, tobacco use,³ alcohol, uremic toxins, nonsteroidal antiinflammatory drugs, chemotherapeutic agents and related substances, and finally heavy metals.

1.2 Plant Toxins

This section discusses two of the most important plant-derived cardiotoxins, namely the mineralocortioid effects of liquorice and cardiac glycosides. Widespread commercial and medicinal uses of plant sources of these compounds predispose to inadvertant or suicidal exposure.

1.2.1 Mineralocorticoid Effects of Liquorice

Liquorice comes from the root of Glycyrrhiza glabra, a legume related to beans and peas, that is native to the Mediterranean region, southern Europe, and central and southwest Asia. The plant is widely cultivated for commercial and traditional medicinal uses in many parts of the world. The extract of liquorice contains glycyrrhizic acid, a chemical that is 30 to 50 times sweeter than sugar. Traditional medicinal uses include treatment of chronic viral hepatitis in Japan, tuberculosis in China, and peptic ulcers and mouth ulcers in many other parts of the world. Liquorice is a common flavoring in commercial products such as candies, chocolates, tea, spices, tobacco, and liqueurs. In the Netherlands, Finland, and Scandinavian countries, liquorice mixed with ammonium chloride produces the salty taste of the popular salmiakki. Chinese cuisine commonly uses liquorice as a culinary spice to flavor broths and savory foods.

A linear dose–response relationship exists between amount of liquorice consumed and cardiovascular response, but doses as low as 50 grams consumed for two weeks can cause significant blood pressure elevation. Although any person might be at risk of liquorice mineralocorticoid effects, those who take it for medicinal uses—for example, as a laxative for chronic constipation, or as a habitual indulgence in glycyrrhizin-containing delicacies and flavorings—are at the greatest risk of adverse effects. Large doses of glycyrrhizic acid may lead to hypokalemia and elevated blood pressure due to its mineralocorticoid effects.⁴–⁶ Severe hypokalemia may result in cardiac arrhythmias, cardiac asystole, and risk of sudden death. It is generally recommended that no more than 100 grams of glycyrrhizic acid be consumed per day.

1.2.2 Cardiac Glycoside-Containing Plants

The diverse group of plants that contain cardiac glycosides include Digitalis purpurea, Digitalis lanata, Nerium oleander, Thevetia peruviana, and Strophanthus gratus. The seeds have the highest concentration of glycoside (4.8%), whereas the leaves, fruit, and milk from the plants contain approximately 0.07%, 0.045%, and 0.036% of glycoside, respectively. Ancient Egyptians and Romans long used cardiac glycoside-containing plants as emetics and for heart ailments. However, their toxicity was only recognized in 1785 after the seminal publication of William Withering.⁷ In other countries, oleander has been used as a medicinal plant for the treatment of leprosy, ringworm, malaria, and sexually transmitted diseases, and as abortifacients and appetizers. Toxicity may occur from consuming teas brewed from plant parts or after consuming leaves, flowers, blossoms, sap, berries, or seeds of plants containing cardiac glycosides; or from inappropriate therapeutic self-administration of plant extracts; or during suicide attempts. Toxic manifestations are identical to digoxin overdose and include nausea, vomiting, diarrhea, abnormal cardiac rhythms, sinus nodal dysfunctions, atrioventricular blocks, and premature ventricular contractions.

Ingestion of plants that contain cardiac glycosides is reportedly rare in the United States. Of the 1.33 million exposures to nonpharmaceutical substances reported to the American Association of Poison Control Centers in 2006, only 1405 (0.1%) were due to exposures to cardiac glycoside-containing plants.⁸ In Sri Lanka and India, increased suicidal or parasuicidal ingestion of yellow oleander (Thevetia peruviana) is associated with case fatality of 5 to 10% in untreated victims.⁹ Toxicity occurs with serum digoxin levels of >15 ng/ml. Detection of digoxin poisoning by plant-origin cardiac glycoside is difficult and complicated to interpret, and analyses may not detect all the plant forms of cardiac glycosides.¹⁰ Botanical identification of the suspected plant is helpful. Morbidity related to cardiac glycosides is made worse by advanced age, renal dysfunction, myocardial ischemia, hypothyroidism, hypoxia, and electrolyte imbalances, particularly hypokalemia, hyperkalemia, hypomagnesemia, and hypercalcemia. Plant-specific determinants of morbidity related to cardiac glycoside poisoning include plant species, part of plant ingested, specific type of glycoside contained, and concentration of glycoside in plant parts ingested, but mortality is rare.

Acute digoxin toxicity often occurs in younger patients and is associated with lower mortality risk. Elderly patients have higher mortality risk, particularly those with chronic digoxin toxicity and comorbidities such as cardiac and renal diseases. Prevention of further exposure to plant-origin cardiac glycoside includes removing the plant parts, particularly from patients with suicidal tendencies. Destruction of plant sources, deterrent measures to minimize human access to such plants, and public education regarding the dangers pertaining to injudicious use of cardiac glycoside-containing plants are appropriate public health strategies. Policies that counter potentially harmful botanical dietary supplementation are advocated.¹¹

1.3 Marine Toxins

Ciguatera poisoning is caused by eating fish that contain toxins produced by the dinoflagellate Gambierdiscus toxicus, a one-celled plant-like organism that grows on algae in tropical waters worldwide. These lipid-soluble toxins are transferred through the food chain as carnivorous fish consume contaminated herbivorous reef fish.¹² Toxin concentrations are highest in large, predatory fish such as barracuda, grouper, amberjack, snapper, triggerfish, and shark. Ciguatera is vastly underreported, but estimates of lifetime prevalence range from 7% in Puerto Rico to 70% in the Polynesian Islands. Most cases originate in the tropics and subtropics, between the latitudes 35° north and 35° south. However, many cases of ciguatera also occur in temperate regions because of increasing tourism and fish exportation. Ciguatera outbreaks have been reported in Puerto Rico, the Caribbean, Florida, California, and Guam.

More than 400 different fish species have been associated with ciguatera. Reef-dwelling tropical fish, such as barracuda, moray eel, amberjack, and certain types of grouper, mackerel, parrotfish, and red snapper, are the most common sources of ciguatera toxicity. Rare cases exist of ciguatera occurring after the ingestion of temperate-area fish, including farm-raised salmon. Disruption of the marine environment with resultant survival pressures increases the potential for ciguatoxic biotopes. Also, substantial increases in seafood consumption in recent years, together with globalization of the seafood trade, have increased potential exposure to these agents. In general, however, ciguatera from nontropical fish is extremely rare.

Despite similar acute and long-term symptoms of ciguatoxin poisoning, there are geographical variations in clinical symptomatology.¹³ Although gastrointestinal and neurological symptoms dominate clinical presentations, cardiovascular manifestations of ciguatoxin poisoning including bradycardia, heart block, and hypotension occasionally occur. The ciguatoxin case fatality rate is quite low (0.1%) with death usually due to cardiovascular collapse or respiratory failure. It is important to fish in safe harvest waters. Control measures include fish sample bioassay using cigua-check test kits.

Although ciguatera poisoning is a global phenomenon, most of it is confined to the warm waters and discrete regions of the Pacific Ocean, western Indian Ocean, and Caribbean Sea. Ciguatoxic fish rarely accumulate sufficient levels of ciguatoxin to be lethal at a single meal, probably because the fish itself succumbs to lethal effects of the toxin.¹⁴ Regional differences in clinical manifestations of ciguatera poisoning reflect differences in ciguatoxin levels in the herbivorous and carnivorous ciguateric fish species. Ciguateric fish from the Indian Ocean are more frequently contaminated by lethal levels of toxin.¹⁵ The extent of human exposure depends on dietary concentration of ciguatoxin and dietary intake rate of ciguatoxic fish. Within the fish, the level of toxin is directly related to the rate of toxin assimilation and inversely related to depuration rates. The biotransformation processes involving oxidation and spiroisomerization have not been easily quantifiable.

Preventive measures include safe storage of fish caught in warm waters, restricting the distribution of potentially ciguatoxic fish, and, at the individual level, restricting fish consumption to <250 g per meal. Other measures applicable to industry and government levels include introduction of fishing bans in high-risk waters and large-scale screening of fish captured in such waters.

A less common fish poisoning caused by scombroid toxicity usually begins within an hour of eating contaminated fish and is characterized by flushing, erythematous rash, palpitations, and tachycardia, resulting from excessive histamine release. Scombroid fish poisoning is a worldwide problem resulting from improper handling of fish, particularly mahi mahi, tuna, sardines, and mackerel; however, it may involve any fish containing high levels of free histidine, which is metabolized into histamine by contaminating bacteria. Control measures include appropriate preservation with proper chilling and temperature controls to limit histidine content to <50 particles per milliliter.

Jellyfish stings are also common in warm and cold coastal waters throughout the world. Most jellyfish envenomation in North America is mild, although some deaths from Portuguese man-of-war stings along the Atlantic coast of the United States have been reported. Irukandji syndrome, resulting from the sting by Carukia barnesi, causes a wide range of illness, including cardiac dysfunction and acute pulmonary edema.¹⁶,¹⁷ Most stings of another jellyfish, Chironex fleckeri, are not life threatening, but a smaller body mass exposed to numerous nematocysts determines morbidity and mortality. However, fatality due to stings from the major Australian box jellyfish Chironex fleckeri sometimes occurs because of rapid cardiorespiratory arrest, particularly in children.¹⁸ Chironex quadrigatus, a multitentacled box jellyfish, is responsible for fatalities in the Philippines and Japan. Most jellyfish stings occur during stinger season when the weather is fine, the waters are warm, and winds are still or mild. The majority of stings occur in shallow waters 1 to 2 m deep, often in the late afternoon or early evening.

The biological basis of the lethal activity of jellyfish venoms remains to be fully elucidated, with specific toxins yet to be characterized.¹⁹,²⁰ Given the harm caused by jellyfish to swimmers, preventive measures to protect swimmers should include warning signs on high-risk beaches during stinger season, protecting children from swimming in high-risk waters, and erecting offshore barriers at popular beaches to preserve coastal tourism. Skin scrapings and sticky tape samples from sting sites should be properly processed for nematocyst description and identification.

Other marine-based cardiotoxins include ostreolysins from edible oyster mushrooms (Pleurotus ostreatus), equinotoxins from sea anemone (Actinia equine), and conotoxins derived from marine snails (Conus geographus). These toxins cause perturbations of various ion channels; cardiac arrhythmias; and inotropic, chronotropic, and arterial blood pressure changes.²¹–²³ However, their epidemiological roles are poorly characterized.

1.4 Venomous Reptiles

Venomous reptiles are distributed in select habitats in temperate and tropical areas of the world and have adapted to terrestrial, arboreal, and aquatic environments. Venomous snakes are found in the families Columbridae, Elapidae, Hydrophiidae, and Viperidae and the subfamily Crotalinae. Sea snakes (Hydrophiidae) are a subfamily of elapid snakes that inhabit marine environments. Their common habitats include warm shallow waters, mangroves, muddy estuaries, and open oceans of western Australia and the Indian and western Pacific oceans. Their venoms are predominantly neurotoxic and myotoxic but may also cause cardiotoxicity. Persons at risk of sea snake bites include fishermen, divers, surfers, and swimmers. Most bites occur when sea snakes are disturbed, frightened, harassed, hooked, netted, or entangled. Beached sea snakes may be injured or exhausted but remain potentially venomous. The deadliest sea snakes, Enhydrina schistosa and Enhydrina zweifeli, are found in lagoons and estuaries of waters stretching from the Arabian Peninsula to Australia, respectively.

Five of the most poisonous land snakes, based on LD50 (i.e., a lethal dose of venom that kills 50% of laboratory animals), include the inland taipan (Oxyuranus microlepidotus), found only in Australia; the king cobra (Ophiophagus hannah), found in India and Southeast Asia; the boomslang (Dispholidus typus), a tree dweller found in the wooded grasslands of Sub-Saharan Africa (SSA); the black mamba (Dendroaspis polylepis), a large, aggressive, and territorial serpent found in most countries of SSA; and the bushmaster (Lachesis muta muta), the largest pit viper with nocturnal habits, that is found in remote, heavily forested tropical jungles of South and Central America. These deadly reptiles produce potent neurotoxic and hemotoxic venoms. Hemotoxic venoms affect the circulatory system by causing hemolysis and venous or arterial thrombosis. Cardiotoxicity is secondary to organ degeneration, generalized tissue damage, and hyperkalemia.

Very few countries possess reliable epidemiological reporting systems capable of providing precise data on snakebites. There is little experimental evidence to convincingly demonstrate that the total chemical or pharmacological effect of a whole venom is equal to the sum of the properties of the individual fractions or functions of the venom identified in toxicologic analyses. An extensive appraisal of the global situation by Chippaux²⁴ yielded regional profiles on incidence of snakebites, morbidity, and case fatality related to envenomation from various bites. The incidence, morbidity, case fatality, and mortality of snakebites depends on climatic conditions, the habitat of the reptile, interaction between humans and snakes, prevalent species of snakes in an area, type and degree of toxicity of the venom, level of care, and quality of reporting systems. In general, snakebite incidence is higher in warm regions where snakes are abundant and manual agricultural activities are prevalent. Also, rural areas characterized by high peasant farming activities and forests inhabited by hunter-gatherers or rubber tappers tend to have a higher incidence of snakebites.²⁵

Hazardous bites refer to snakebites that occur when humans encounter snakes in their natural habitats and are more common in middle- and low-income settings. Illegitimate bites are inflicted by a reptile in captivity or during snake handling and are on the increase in industrialized countries. In SSA, annual incidence of snakebites ranges from 12/100,000 of population in Senegal, 150/100,000 in Kenya, and 450/100,000 in Cameroon to 600/100,000 of population in Nigeria with a case fatality 5.9 to 12.3%. This wide range might reflect, at least in part, variations in estimation and reporting systems in different countries in SSA. The most common culprits include Causus maculatus (i.e., spotted night adder), Naja melanoleuca (i.e., black cobra), Dendroaspis spp. (i.e., green mamba), and Bitis gabonica (i.e., Gaboon viper).

Similarly wide variations in snakebite incidence have been reported in Asia. In Japan, for example, the incidence is 340/100,000 of population in the southern region compared to a national annual incidence of 1/100,000. Case fatality ranges from 0.7 to 1.0%. Trimeresurus spp. is the predominant culprit in Japan, China, and on the Korean peninsula; Russell’s viper accounts for 70% of bites in Myanmar; and in Sri Lanka, Calloselasma rhodostoma accounts for bite incidence, ranging from 6 to 18/100,000 of population. In Malaysia, Agkistrodon blomhoffii causes a 5% case fatality. In Oceania, Papua New Guinea, and the Pacific Islands, most snakebites are caused by Pseudonaja spp., Notechis spp., and Oxyuranus spp. Annual bite incidents range from 3 to 18/100,000 of population.

The highest mortality rates associated with snakebites occur in the tropical and subtropical regions of the world, especially in India and Oceania (Figure 1.1). Although an association of high annual snakebite mortality and poverty has been proposed,²⁶,²⁷ this view must be seen in the contextual framework of the warmer tropical and subtropical environments frequently inhabited by these reptiles, their complex interaction with human activities, health-seeking behavior of snakebite victims, and the quality of health care. In Nigeria, 80% of snakebites are first reported to traditional practitioners. In India, Malaysia, Papua New Guinea, and many of the Pacific Islands, for instance, annual snakebite death rate is 1000.9 to 10,000/100,000 of population despite gross disparities in their gross national incomes. Many African countries with some of the highest human development indices (>0.81) do not necessarily exhibit higher annual mortality rates than some south Asian countries. In high-risk settings, snakebite preventive measures should include provision of protective clothing, gloves, and gumboots for rural farmers; sufficient lighting; and clearing of dumps and bushes around homesteads and other places where humans dwell.

Figure 1.1 Global map of annual snakebite mortality. Source: Used with permission from Harrison et al., 2009.²⁶

Venomous lizards, belonging to the family Helodermatidae of the genus Heloderma, are found in the United States and Mexico.²⁸ Although the Gila monster (Heloderma suspectum) and the beaded lizard (Heloderma horridum) were believed to be the only two venomous lizards, as many as 100 species of lizards use venom; nine types of lizard toxins are shared with those of venomous snakes. Monitor lizards, found in Africa, Australia, and Asia, though venomous, often tend to avoid confrontation and therefore human bite incidents are rare. The Komodo dragon, found mainly on Komodo Island and smaller islands east of Java in Indonesia, has at least six venom glands on each side of its mandible and multiple ducts between its teeth. Its venom is believed to be similar to the toxin of the inland taipan. However, the effect of a Komodo dragon’s toxin is relatively mild in humans due to ineffective delivery methods during occasional human bites. Venoms of various species of monitor lizards found in arid, semiarid, and aquatic environments in the Old World cause hypotension and perturbations in blood clotting. Iguanians constitute nearly 1500 species of iguanas. They live in a wide range of habitats ranging from trees and water edges to arid areas in the Americas, Madagascar, Fiji, and Tonga. Some species of iguanas deliver small amounts of venom when they bite. Persons at risk include intruders into their habitats and pet owners or zoo workers.

Initial postinjection effects of Russell’s viper or cobra venom include rapid drop in mean arterial pressure, bradycardia, reduced cardiac output, and increased peripheral vascular resistance. The second phase of envenomation is characterized by a predominant role of vasodilators with increased return of blood to the left side of the heart, resulting in increased cardiac output, decreased peripheral vascular resistance, and return of mean arterial pressure to normal.

1.5 Trichinellosis

Helminthic infestation by Trichinella spiralis, a white intestinal nematode, is widely distributed, mainly in pork-rearing and game-eating regions of the world. Human trichinelosis has been documented in more than 55 countries of both the industrialized and nonindustrialized worlds, including North and South America, Europe, Africa, Asia, and the Pacific region.²⁹ The prevalence of human trichinellosis (also known as trichiniasis or trichinosis) is the highest in China, Thailand, Mexico, Argentina, Bolivia, the former Soviet Union, Romania, and other parts of central Europe. In 2004, Romania reported the highest incidence of trichinellosis in the world.³⁰ Seven Trichinella species are the ones most implicated in human disease: T. spiralis, which is found worldwide³¹; T. nativa, found in the arctic regions; T. nelsoni, found in SSA; T. brivoti found in Europe, western Asia, and western and southern Africa; T. murelli, found in the United States and Japan³²; T. papuae, found in Papua New Guinea and Thailand³³; and T. pseudospiralis, found in birds worldwide.³⁴

Reservoirs for Trichinella include pigs, dogs, cats, rats, horses, and other domestic animals. Adult worms develop rapidly within human intestinal epithelium following larval ingestion in infested pork. Mature female worms produce larvae, which penetrate lymphatics and venules and become widely distributed throughout the body. Larval encapsulation into muscles follows the inability of the parasite to complete its cycle in the human host. Cardiac complications tend to occur 3 to 6 weeks after infestation, and severe cases may lead to myocardial failure and occasionally death.

Those at high risk for trichinellosis include individuals in pig-farming communities and those who ingest game meat, wild pig, or boar; young men (<40 years); and tourists who may consume improperly cooked contaminated meat.³⁰,³⁵,³⁶

Cardiovascular complications represent the most important manifestation of moderate to severe trichinellosis.³⁷ Larvae do not encyst in cardiac muscle but elicit an intense eosinophilic inflammatory response and myocarditis, responsible for the cardiotoxicity of trichinellosis. Common electrocardiographic abnormalities include nonspecific ST-segment and T-wave changes, bundle branch block, and sinus tachycardia. Less frequent electrocardiogram (ECG) changes include sinus bradycardia, right bundle branch block, supraventricular tachycardia, premature ventricular contractions, and low QRS voltages.³⁸ Mortality in patients with serious trichinellosis is often as a result of heart failure and sometimes, severe arrhythmias.

Measures to mitigate or prevent trichinellosis include basic hygiene such as hand washing with soap by butchers; cleaning meat grinders thoroughly after each use; and avoiding undercooked pork, walrus, horse, bear, and other wild animal meat. Sufficient cooking of all parts of meat to 60 to 71°C or freezing to −15°C also reduces risk of infestation.

1.6 Arachnidism

Envenomations by arachnids cause significant medical illnesses worldwide. Important groups of spiders include the widow spiders (Latrodectus spp.), the recluse spiders (Loxosceles spp.), the Australian funnel web spider (Atrax and Hadronyche spp.), and the armed spider (Phoneutria spp.) from Brazil.³⁹ There are approximately 30 species of widow spiders in the world. Widow spiders and their webs are found outdoors in garages, trash piles, potted plants, trashcans, woodpiles, dry storage areas, outhouses, rustic recreational areas, and outdoor furniture. Widow spider bites occur when the spiders or their webs are disturbed by human activity such as picking up trash, potting plants, and moving wood piles; wearing garden shoes; and camping, hiking, or rock climbing.

Most bites in many parts of the world occur outdoors and in young men. In Europe and the Mediterranean regions, widow bites are occupational hazards of wheat farmers who might compress the spider against their bodies as they harvest the crop, and of other outdoor workers, including farm laborers and greenhouse keepers. Approximately 75% of widow bites are on the extremities. Steatoda spiders (false black widow spiders) are in the same family (Theridiidae) as the black widows and hence share a similar body form, which may cause confusion in identification. The false black widow is more likely to be found inside homes.

The effects of a spider bite depend on the venom’s toxicity; the amount injected, which depends on length of mouth parts (Chelicera); and the tissue-specific effects of the venom.⁴⁰ The majority of venomous spider bites are not associated with toxicity due to insufficient envenoming. Dangerous spiders deliver an adequate dose of potent venom in a single bite. Latrodectism and loxoscelism are the most important clinical syndromes resulting from spider bites. Latrodectism causes local, regional, or generalized pain associated with nonspecific symptoms and autonomic effects such as tachycardia and hypertension. Myocarditis is very rare but has been described.⁴¹ Bites by Phoneutria spp. spiders are common in Brazil, although only 0.5 to 1% result in severe envenomation, with most of these occurring in children. Cases of systemic envenomation in adults are very unusual. Life-threatening anaphylactic reactions with shock sometimes occur. Pulmonary edema from spider bites, with potential fatalities, is also rare but has been described.⁴²,⁴³

Anxiety reactions caused by the fear of widow spiders may confuse the clinical presentation of some patients. It must be remembered that only 1% of widow spider envenomation has life-threating effects. Expert identification of the biting spider is therefore essential, whenever possible. Prevention involves the use of protective clothing, including gloves, in spider-infested outdoor environments and keeping domestic settings clean. Care must be taken to inspect garden shoes and camping gear before wearing or using them.

1.7 Scorpion Envenomation

Scorpion envenomation is a common medical problem in many parts of the world, particularly in tropical and subtropical countries.⁴⁴ Although the most common toxic envenomation offenders arise from the Buthidae family of scorpions, cardiovascular effects of various scorpion venoms are remarkably similar. Cardiovascular effects of scorpion venoms have been reported from various parts of the world, including Brazil, Mexico, the southwestern United States, North Africa, southern parts of Africa, the Middle East, southern Spain, and India.

Effects of envenomation depend on the age of the scorpion, dose of venom delivered, and size of the victim. Reports of cardiovascular manifestations include hypertension (17.5–77%), pulmonary edema (7–32%), and myocardial damage. Hypertension is commonly observed in children and is severe in the majority of them. Electrocardiographic abnormalities include bradytachyarrhythmias, ST–T wave abnormalities (24–39%), QTc prolongation (53%), electrical alternans (13%), complete atrioventricular (AV) blockade (2.5%), shock-like syndrome (7–38%), and sudden cardiac death (7–11%).⁴⁵–⁴⁹ Other electrocardiographic abnormalities include atrial fibrillation, AV dissociation with accelerated junctional rhythm, premature atrial or ventricular contractions, ventricular tachycardia, or fibrillation. Conduction abnormalities such as left bundle branch block and first- and second-degree heart blocks are rare. Echocardiographic and radionuclide studies have shown depressed left ventricular (LV) function and mitral regurgitation after scorpion envenomation. Sudden severe blood pressure elevation may be accompanied by clinical manifestations of hypertensive encephalopathy.

Pathologically, macroscopic examination may reveal no gross cardiac abnormalities, but diffuse microscopic changes with marked mononuclear cellular infiltrates, focal necrosis, and subendocardial hemorrhages may be observed. Pathophysiological mechanisms of scorpion envenomation involve sudden massive release of vasopressor catecholamines,⁴⁶ resulting in myocardial inotropic effects, various arrhythmias, enhanced LV contractility, and systemic hypertension. The shock-like phenomenon results from the depressive cholinergic effect of the venom, catecholamine depletion, exaggerated beta-2 vasodilator effect of circulating catecholamines on the peripheral vascular bed, and hypovolemia due to excessive fluid loss.⁵⁰ Myocardial stunning may be an important predisposing factor to left ventricular failure. A scorpion sting is the most important arachnid envenomation causing adult morbidity and pediatric mortality.

At the population level, efforts must be made to educate everyone about conditions that foster envenomation such as poor hygiene or neglect of surroundings. Where possible, stones, garbage, and bushy fencing hedges and climbing plants should be removed from domestic areas. Good lighting and use of appropriate protective footwear are recommended. It is a good precaution to check, invert, and shake footwear vigorously before wearing them and to avoid sleeping on the ground at night during the summer in scorpion-prone areas. To decrease morbidity and attendant mortality related to envenomation, local populations can benefit from appropriate first aid measures and effective utilization of nearby health facilities. Care should be standardized at secondary and tertiary care facilities with ready availability of, or access to antivenom, whenever needed. Serious cases of envenomation require hospitalization and appropriate management.

1.8 Air Pollution

Air pollution is a complex heterogeneous mixture of gases, liquids, and particulate matter (PM). Primary air pollutants include sulfur dioxide, oxides of nitrogen, carbon monoxide, volatile organic compounds, and carbonaceous and noncarbonaceous particles. Secondary pollutants are formed by chemical reactions between primary air pollutants and atmospheric oxygen and water, the most familiar of which is ozone. The highest concentrations of classical indicators of air pollution (PM10, PM2.5, and sulfur dioxide) are found in Africa, Asia, and Latin America. Determinants of adverse effects of air pollution include fractional deposition of inhaled particles, degree of individual exposure, and variability in cumulative dose. Personal risk factors and deleterious effects of particulate air pollution include low socioeconomic status, a low level of education, extremes of age (the young and the elderly), undernutrition, obesity, diabetes mellitus, preexisting cardiovascular disease, and genetic susceptibility.⁵¹,⁵²

Several observational studies in the United States and Europe have demonstrated an association between fine particulate air pollution and increased risk for cardiovascular events in men and women.⁵³–⁵⁶ These risks are related to the composite effects resulting from both short- and long-term exposure to air pollution and to control measures that aim to reduce PM air pollution.⁵⁷–⁵⁹ The Women’s Health Initiative Observational Study⁵⁸ examined the database of more than 65,000 postmenopausal women without prior cardiovascular disease to evaluate the relationship between long-term exposure to air pollution and the risk of a cardiovascular event. Potential confounding factors, such as age, body mass index, and traditional cardiovascular risk factors, were corrected for. Each 10 µg/m³ increase in pollution was associated with increased risk of any cardiovascular event (hazard ratio 1.24) and death from cardiovascular disease (hazard ratio 1.76).

Jerret et al. analyzed data on 448,850 subjects from the second American Cancer Society Cancer Prevention Study, with 118,777 deaths during the 18-year follow up.⁶⁰ Multivariate analysis revealed that concentrations of fine PM that were ≤2.5 micron in aerodynamic diameter (PM2.5), but not ozone, were significantly associated with 1.2-fold increased relative risk of death from cardiovascular causes. However, Ruidavets et al. in the Toulouse MONICA project⁶¹ showed some marginal increase in risk of acute myocardial infarction (relative risk 1.05; P=0.009) related to 5 μg/m³ of ozone concentration. The relative risk was 1.14 in subjects aged 55 to 64 with no prior history of ischemic heart disease.

Short-term exposure to nitrous oxide and sulfur dioxide were not associated with significant risk of acute myocardial infarction. Pope⁶² reported a 1.3% increase in cardiovascular mortality for every 5 µg/m³ rise in PM2.5. A systematic review and meta-analysis done by Mustafic et al. revealed that, with the exception of ozone, all of the main air pollutants were significantly associated with increased risk of acute myocardial infarction.⁵⁴ The following are the relative risks associated with exposure: carbon monoxide, 1.048 (95% CI 1.026–1.070); nitrous dioxide, 1.011 (95% CI 1.006–1.016); sulfur dioxide, 1.010 (95% CI 1.003–1.017); PM10, 1.006 (95% CI 1.002–1.0009); and PM2.5, 1.025 (95% CI 1.015–1.036). Overall population-attributable risk varied from 0.6 to 4.5% depending on pollutants. All-cause mortality has also been shown to be higher among individuals with greater long-term exposure to PM2.5 in hospitalized survivors of acute coronary syndrome in England and Wales.⁶³

Peters et al. reported the link between increased PM with specific cardiac events including serious ventricular arrhythmias and myocardial infarction.⁶⁴,⁶⁵ Mechanistic considerations of the effects of fine air pollution have focused on autonomic nervous system alterations, myocardial ischemic responses, ion channel dysfunctions in myocardial cells, inflammatory responses resulting in endothelial dysfunction, release of various cytokines, nitric oxide, interleukins, thromboxane X2, endothelin-1, and eventual atherothrombosis. However, these pathogenic mechanisms are only beginning to be unraveled. Despite these intriguing associations between PM exposure and several parameters of cardiovascular dysfunction, evidence from published studies seems insufficient to conclusively determine their strength of association.⁶⁶

The complexity of conditions that predispose to increased risk of cardiovascular morbidity and mortality makes it difficult to place greater emphasis on the contribution of air pollution relative to other factors. Air pollution is presumably a relatively minor contributing factor embedded within a matrix of inborn factors (e.g., genetic, gender, age); traditional cardiovascular risk factors (e.g., hypertension, diabetes mellitus, obesity, dyslipidemia, psychosocial stress); other environmental factors (e.g., inadequate intake of fruits and vegetables, no or inadequate alcohol intake, tobacco use); and underlying cardiac disease (e.g., subclinical ischemic heart disease, cardiomyopathy, hypertensive heart disease).

Despite the complexity of determinants of susceptibility to air pollution, public information concerning the cardiovascular risk posed by air pollution should be communicated. Health measures to reduce the cardiovascular impact of air pollution should focus on entire communities and populations, particularly targeting the elderly, those with preexisting cardiovascular or respiratory diseases, the poorly educated, and those of low socioeconomic status. Policies that aim to promote cleaner air by reducing levels of pollution, adopting cleaner energy sources, improving air quality, and minimizing human exposure to air pollution must be advocated.⁵³

1.9 Pesticides

This section deals with cardiotoxicity resulting from the cholinergic effects of substances used industrially or for controlling pests in agricultural or domestic settings.

1.9.1 Organophosphate and Carbamate Poisoning

Although the use of organophosphates as insecticides has largely been replaced by availability of carbamates in the past two decades in developed countries, they are still widely available for industrial, agricultural, and household uses in developing countries because they are less expensive than the newer alternatives. An estimated three million people are exposed to organophosphates and carbamates annually, with some 300,000 fatalities.⁶⁷ Organophosphate insecticides include parathion, fenthion, malathion, diazinon, and dursban; methomyl and aldicard are the two commonly encountered carbamates. A number of countries have banned or restricted the use of organophosphorus-containing household roach and ant sprays.

Toxicity to organophosphates typically exhibits a triphasic response. First is the initial acute cholinergic crisis, followed by an intermediate syndrome, both of which are potentially fatal; and then the disabling nonlethal delayed polyneuropathy.⁶⁸ Organophosphates and carbamates are potent cholinesterase inhibitors, potentially resulting in cholinergic toxicity following excess exposure through skin, inhalation, or ingestion. The cholinergic phase is due to excessive accumulation of acetylcholine at muscarinic sites, resulting in sinus bradycardia among other muscarinic effects. The effects at nicotinic sites and the central nervous system have no cardiovascular components. The intermediate syndrome, which occurs 1 to 4 days after exposure to toxic levels of organophosphate, is predominantly neuromuscular with proximal muscle weakness, diaphragmatic paralysis, and cranial nerve palsies. Cardiac arrhythmias including heart block, QTc prolongation, and pleomorphic ventricular tachyarrhythmias resulting in torsades de pointes are uncommon but have been reported in some patients experiencing organophosphate poisoning.⁶⁹ At-risk groups include farm workers, peasant farmers, handlers, children, and those intending self-harm.⁷⁰

Fungicides are chemical substances that destroy or inhibit the growth of fungi. They have similar uses in agriculture, for lawns, and on golf courses as insecticides. It is important to strictly follow manufacturers’ instructions for use and to spray fungicides at specified times and intervals. Accidental contact of the chemical with any part of the body should be promptly washed, and eye splashes should be irrigated with clean water. Whenever possible, fungicides should be sprayed in calm weather conditions to avoid inhalation of aerosols and dust containing the chemicals.

Personal measures against organophosphate exposure involve maximum protective equipment including double layers of clothing and chemically resistant gloves, footwear, head gear, apron, and, where possible, effective masks. Backpack sprayers, working with hands, and knapsacks should be avoided when handling organophosphates and carbamates. The use of human flaggers should be avoided in agricultural fields. Also, the use of organophosphates when growing fruits and vegetables, such as apples, peaches, grapes, green beans, and peas, should be restricted. Such preventive measures are clearly impractical in low-resource settings.

1.10 Household Toxic Materials

Many household substances are potentially toxic. They can be grouped into organic solvents (e.g., antifreeze, windshield washer solution, artificial nail polish removers, petroleum, kerosene, lamp oil, paint thinner, furniture polish), disinfectants (e.g., drain cleaner, toilet bowl cleaners, mouthwashes), detergents (e.g., automatic dishwasher detergents, kitchen detergents), deodorants (e.g., perfumes, aftershave lotions), and designated poisons (e.g., antirodents, insecticides). Miscellaneous items include batteries, flaking paints, alcohol, and tobacco products. Some examples of common household materials with potential cardiotoxicity are discussed in this section.

Ethylene glycol (EG), a toxic, colorless, odorless, nonvolatile, and sweet-tasting industrial solvent, is the primary ingredient in antifreeze and hydraulic brake fluid. Its major metabolites are glycolic and oxalic acids, which cause metabolic acidosis and cardiovascular dysfunction. Determination of blood levels of ethylene glycol may not be immediately possible since it requires gas chromatography, and urine calcium oxalate crystals in suspected cases of EG poisoning may be nonspecific. Initial irritant effects of ingested ethylene glycol may cause nausea and vomiting, followed by neurological, cardiopulmonary, and renal toxicity. Cardiotoxicity, manifesting as dysrhythymias, hypotension, myocardial depression with or without heart failure, and sometimes focal myocardial hemorrhages, occurs as a result of metabolic acidosis and hypocalcaemia. Ingestion of 1 g of EG per kg of body weight is considered toxic. Children are often accidentally poisoned by ingestion of 10 to 30 mls because they are enticed by the sweet taste of EG. However, isolated or epidemic human poisoning may occur through suicide or through accidental or malicious adulteration of alcohol with EG. Certainly not all cases of EG poisoning are reported.

In 2002, there were 5816 human exposures to EG in the United States. In Australia, only 17 cases of EG poisoning were reported to the Victorian Poisons Information Centre in 2007 and 30 cases to The Children’s Hospital in New South Wales. Inhaled EG is unlikely to result in any significant toxicity. Contact contamination is easily treated by washing the affected area of the skin with mild soap and clean water or irrigating the conjunctiva with clean water. Contact lenses should be removed.

Although a number of U.S. states have advocated adding a bittering agent, such as denatonium benzoate, to minimize accidental and suicidal risks of antifreeze poisoning, studies have cast doubts on the impact that such measures would make.⁷¹,⁷² Difficulties in ascertaining initial diagnosis of EG poisoning result in life-threatening complications with high case fatality. The mortality rates related to EG poisoning range from 1 to 22%, depending on amount ingested, clinical index of suspicion, and level of care.⁷³ Presentation with severe metabolic acidosis is easily confused with lactic acidosis, diabetic ketoacidosis, methanol, and salicylic acid poisoning. State legislation also appears to have had little impact. The establishment of poison control centers and Toxic Exposure Surveillance Systems (TESS) as well as helplines and easy access to toxicologists like those in the United States may improve real-time toxicovigilance and reduce morbidity and case fatality related to common poisons.⁷⁴ Safe storage of potentially toxic household items should be regularly advocated.

Most disinfectants and antiseptics are locally irritating and potentially corrosive to skin, conjunctivae, and respiratory tract mucosae. External contamination by these chemicals is therefore unlikely to result in any systemic effect. Ingestion of phenolic and carbonic acid compounds accidentally or suicidally may cause cardiac dysrhythmias.⁷⁵ Aldehydes are volatile compounds with irritating effects to the eyes. Ingestion of formaldehyde or glutaraldehyde may result in circulatory collapse or death. Phenols and cresols, used as deodorants, have no reported cardiac toxicity.

1.11 Petrol, Paraffin, and lamp Oil

These products are highly inflammable organic hydrocarbons commonly used as fuel in combustion engines. Unleaded petrol contains benzene, trimethyl benzene, toluene, naphthalene, and methyl tert-butyl ether, which are potentially carcinogenic. Hydrocarbons generally exhibit low toxicity. Although sniffing petroleum products has reached epidemic proportions in low-income communities, especially among indigenous groups in Australia, New Zealand, some of the Pacific Islands, and Canada, there are few reported cases of cardiotoxicity.⁷⁶

1.12 Toxic Military and Industrial Chemicals

Chemicals used by the military include chlorine, ammonia, and hydrogen cyanide. Human exposure may occur during warfare or terrorist attacks; accidental explosions at munitions depots, chemical plants, and/or of transportation vehicles; or at wastewater plants. Industrial metal fumes containing barium have cardiotoxic effects.⁷⁷ Other industrial processes, such as metal hardening, arc-welding, ceramic glazing, or enameling, may give rise to barium-containing airborne particulate fumes and aerosols, which have a dose–effect toxic relationship. Other toxic heavy metals (e.g., lead, cadmium, mercury, and chromium) are dealt with in Section 1.19.

1.13 Tobacco and Cardiovascular Diseases

Cigarette smoking is the leading preventable cause of mortality, responsible for nearly six million deaths worldwide.⁷⁸ This toll is projected to rise to more than eight million deaths per year by 2030, with 80% of those deaths occurring in low- and middle-income countries where tobacco use is increasing. Indeed, the World Health Organization projects that tobacco will kill up to one billion people this century if the Framework Convention on Tobacco Control (i.e., WHO FCTC) is not implemented rapidly.⁷⁸ As shown in Figure 1.2, the highest smoking rates (>36.5%) are seen in most countries of northern Europe, Chile, Cuba, Greenland, and some of the Pacific Islands. Smoking rates of 28.6 to 36.5% are seen in the United States, Venezuela, Argentina, China, Australia, and New Zealand. Smoking rates are generally low in much of Sub-Saharan Africa except in Namibia, Zimbabwe, and the Republic of South Africa. However, since the introduction of the WHO FCTC: MPOWER strategy in 2008, more than a third of the global population (>2.3 billion people living in 92 countries) is now covered by at least one of the measures at the highest level of achievement. However, two-thirds of countries have not aired antitobacco campaigns to increase awareness on the dangers of tobacco use.

Figure 1.2 Global map showing the percentage of tobacco use among adults (age 15 and over), 2005. Source: From WHO, 2008.

Although nicotine is the most well-known, potently addictive, neuroteratogenic, and toxic cardiovascular substance in all forms of tobacco (smoked or smokeless), tobacco contains myriad other potentially toxic or carcinogenic agents, including heavy metals and metalloids, nitrosoamines, and gaseous complexes. Some of the toxic heavy metals found in tobacco such as lead, cadmium, and arsenic are discussed in Section 1.19.

Nicotine is the principal alkaloid in both commercial and homemade tobacco products, followed by nornicotine, anabasine, anatabine, and many other basic substances that contain a cyclic nitrogenous nucleus. Tobacco types, leaf position on the plant, agricultural practices, fertilizer treatment, degree of ripening, blending recipe, type and amount of additives (e.g., acetaldehyde, ammonia compounds), and product design are among some of the main factors that determine the levels of alkaloids in tobacco. The threshold dose of nicotine necessary to produce dependence has not been firmly established; neither have dose–response relationships between blood nicotine levels and cardiovascular risk. Smoking affects the physiologic, pathologic, hematologic, and metabolic factors leading to the initiation, progression, and sequelae of atherosclerosis. However, several epidemiological studies have yielded inconsistent cardiovascular effects of tobacco. Users of smokeless tobacco ingest levels of nicotine similar to those of smokers and this may be associated with increased risk of myocardial infarction and/or stroke, although the risk is less than from cigarette smoking.

The apparent paradoxic beneficial effects of smoking in patients receiving thrombolytic therapy for acute myocardial infarction in the GUSTO-I trial may be explained by the fact that smokers were significantly younger by a mean of 11 years and had less comorbidity or severe coronary artery disease than nonsmokers.⁷⁹ In the INTERHEART study, a case-control examination of acute myocardial infarction involving more than 27,000 participants from 52 countries, current smoking was associated with a 3-fold greater risk of nonfatal acute myocardial infarction compared with never smoking and the risk increased by 5.6% for every additional cigarette smoked.⁸⁰ The risk of acute myocardial infarction associated with chewed tobacco and smoking beedies were similar to the risk associated with current smoking, while secondhand smoking showed a dose-related risk ranging from 1.24-fold in those least exposed to 1.62-fold in most-exposed individuals.⁸⁰

Some of the epidemiological studies failed to demonstrate any significantly greater all-cause and disease-specific mortality in users of smokeless tobacco compared with mortality in nonsmokers.⁸¹ However, a 2006 WHO report concluded that all tobacco products were harmful and addictive and that all cause disease and death. Properly implemented, the WHO FCTC and MPOWER strategies are key to the global control of the use of tobacco.⁷⁸ In reiterating some of WHO’s major messages, education, communication, and training must target the most vulnerable populations in middle- and low-income countries especially children, adolescents, and women; universal implementation of health warnings on all tobacco products should include various languages and graphic images, to cover minorities, the illiterate, and those with sensory disabilities. Cessation of tobacco use should be encouraged and bans on tobacco advertising, promotion, and sponsorships should be enforced across the board.

1.14 Cardiovascular Toxicity of Alcohol

Alcoholic beverages are widely consumed worldwide. Consumption of alcohol in moderation has been inversely related to coronary heart disease and possibly all-cause mortality. However, no standardized amounts of ethanol have been established in the commonly stated 1 to 2 drinks per day for women and 2 to 4 drinks per day for men due to differences in beverage brands. A meta-analysis of 34 prospective studies showed a J-shaped relationship between alcohol and total mortality.⁸² The maximum protection from 4 g per day of alcohol for women was 18% while 6 g per day gave men a maximum protection of 17%. Higher consumption was associated with increased mortality.

Excessive intake of alcohol, particularly binge drinking or drinking to become intoxicated, has numerous potential harmful effects. Alcohol consumption rates tend to rise during festivities, ceremonies, parties, and holidays with parallel trends in tobacco smoking. The highest levels of ethanol consumption occur in countries within the WHO European Region, the Americas, the Western Pacific, and southern Africa. Countries in North Africa and much of the WHO African, Eastern Mediterranean, and Southeast Asia regions have low alcohol consumption (Figure 1.3). Consumption of homemade or illegally produced alcohol or industrial alcohol (methanol) may be associated with a greater risk of harm because of potentially dangerous impurities and contaminants.

Figure 1.3 Global map showing the total adult (age 15 years and over) per capita consumption of pure alcohol (in liters), 2005. Source: From WHO, 2010.

Although there are regional differences, globally the most frequently used alcoholic beverages are spirits (45.7%), beers (36.3%), wine (8.6%), and other brews (10.5%). Drinking among young people (13–15 years old) is increasing at alarming rates in most countries. In children, alcohol intake occurs through accidental ingestion and occasionally as a result of child abuse. More than 60 major types of diseases and injuries are causally linked to harmful use of alcohol, resulting in approximately 2.5 million deaths annually (4% of global all-cause mortality). Individuals with a history of hemorrhagic stroke, liver disease, pancreatic disease, alcoholism, gastritis, Barrett’s esophagitis, or cancer are at increased risk of the harmful effects of alcohol.

The association between chronic alcohol consumption and alcoholic heart disease in human beings is well recognized. There is a U- or J-shaped relationship between alcohol consumption and survival from cardiac disease. Chronic alcohol consumption is the leading cause of secondary cardiomyopathy, a heart muscle disease associated with long-term alcohol consumption. In the United States, long-term heavy consumption of any type of alcoholic beverage is the leading cause of a nonischemic dilated cardiomyopathy in men and women of all races.

The fact that only a minority of persons with chronic alcoholism have this condition suggests the possibility of genetic vulnerability. Polymorphism of the angiotensin converting enzyme (ACE) gene has been implicated in cardiac dysfunction associated with vulnerability to alcoholic cardiomyopathy.⁸³ This complication tends to occur in those who have been drinking more than 80 to 90 g of ethanol per day for 5 to 15 years. Despite lower mean lifetime ethanol dose, women appear to be at greater risk of alcoholic cardiomyopathy. This sex differential of risk is partially explained by excessive accumulation of ethanol metabolites in women due to lower gastric metabolism and enhanced hepatic metabolism; both mechanisms contribute to higher acetaldehyde concentration in the blood of women who drink.⁸⁴

Consumption of alcohol is also associated with increased risk of atrial fibrillation (AF) or flutter in men.⁸⁵ In the Danish Diet, Cancer, and Health Study of nearly 48,000 middle-aged participants (mean age 56), daily alcohol consumption by men was twice that of women. The greater sensitivity of women to the effects of ethanol may therefore not entirely explain the 1.5-fold increased risk of AF or flutter in men; the disparity in daily alcohol consumption needs to be taken into account. The Framingham Heart study⁸⁶ showed significantly increased risk of AF among subjects consuming >36 g per day (>3 drinks/day). The Copenhagen City Heart study of 16,415 women and men also showed no significant association of moderate alcohol consumption and risk of AF. But men who drank 35 g of alcohol or more per week had nearly 1.5-fold increased risk of AF; few women consumed this amount of alcohol.⁸⁷

Furthermore, persons who consume various alcoholic beverages excessively and for a long time also exhibit significantly higher risk of prolonged QTc interval and higher QTc dispersion and other arrhythmias than control groups. Atrial fibrillation occurs in up to 60% of binge drinkers with or without underlying alcoholic cardiomyopathy. There is a positive correlation between alcoholic cardiomyopathy and cirrhosis. Beriberi heart disease, due to nutritional deficiency of thiamine, must be differentiated from alcoholic heart muscle disease. Beriberi heart disease is rapidly reversible after thiamine therapy, manifests predominantly as high-output right heart failure, and exhibits normal myocardial histology.

As with tobacco, control of the harmful effects of alcohol requires determined and concerted efforts of individuals and communities galvanized by institutional, organizational, national, and international policies. Bills, acts, and legislation against drunk driving and the sale of alcohol to minors, and banning of alcohol advertising and marketing all require appropriate power of enforcement with commensurate penalties to reduce alcohol-related harm. High levels of morbidity, mortality, violence, crime, and road traffic accidents, in addition to the negative social impact of alcohol, including family disruption, alcoholism, and a spiral of poverty, are persuasive reasons for public campaigns against excessive drinking.

1.15 Cardiovascular Effects of Caffeine

Other than water, coffee is arguably the most consumed beverage worldwide. Exposure to caffeine is generally lifelong in most consumers. Despite the widespread belief in the link between coffee consumption and cardiac arrhythmias, there is little conclusive evidence of detrimental cardiovascular effects of coffee, and divergent notions persist regarding its potential harmful versus beneficial effects. An extensive literature search over a decade in the early 1990s by Myers⁸⁸ concluded that moderate ingestion of coffee did not increase the frequency or severity of cardiac arrhythmias in normal persons, patients with ischemic heart disease, or those with preexisting serious ventricular ectopy. The Danish Diet, Cancer, and Health Study of nearly 48,000 participants also showed no link between caffeine consumption and the risk of atrial fibrillation or flutter.⁸⁹

Using the lowest quintile of caffeine consumption as the reference, the adjusted hazard ratios for the second, third, fourth, and fifth quintiles (plus 95% confidence interval, CI) were 1.12 (0.87–1.44), 0.85 (0.65–1.12), 0.92 (0.71–1.20), and 0.91 (0.70–1.19), respectively. More recent systematic review and meta-analysis of observational studies also showed no association between caffeine consumption and the risk of atrial fibrillation.⁹⁰ In fact, low-dose caffeine might have protective cardiovascular effects. In nonhabitual coffee drinkers, there might be acute blood pressure elevation but this phenomenon is not observed in habitual coffee drinkers.⁹¹

There has been no conclusive data on the association of caffeine and cause-specific mortality. The Health Professionals follow-up study and the Nurses’ Health Study, involving 41,736 men followed up for 18 years and 86,214 women followed up for 24 years respectively, showed no association between regular coffee consumption and all-cause mortality in either men or women.⁹² A much larger prospective study by Freedman et al.⁹³ of more than 400,000 men and women during more than 5 million person-years showed an inverse association between coffee consumption and total and cause-specific mortality. A recent study of a multiethnic urban population in northern Manhattan found a strong inverse association between coffee and vascular-related mortality among Hispanics only.⁹⁴

More recent data from the Aerobics Center Longitudinal Study in South Carolina adds a new twist to the association between coffee consumption and all-cause and cardiovascular mortality.⁹⁵ This study enrolled 43,727 participants aged 20 to 87 and followed up for a mean of 17 years (nearly 700,000 person-years). Data were obtained through in-person interviews. During the study period, there were 2512 deaths, one-third of which were due to cardiovascular causes. Multivariate analyses adjusted the data for age, baseline examination, body mass index, hypertension, diabetes mellitus, lipid profiles, use of decaffeinated beverages (coffee, tea), tobacco use, and physical inactivity. Men who drank >28 cups of coffee per week (>4 cups/day) had higher all-cause mortality (hazard ratio (HR)=1.21, 95% CI 1.0–1.40). In younger age groups (<55 years), excessive intake of coffee (>28 cups/week) was positively associated with higher all-cause and cardiovascular disease mortality in both men and women (HR=1.56, 95% CI 1.30–1.87 in men; HR=2.13, 95% CI 1.20–3.59 in women).

Like alcohol, determining the dose of coffee is fraught with lack of standardization of the cup of coffee, strength, type, method of preparation, and caffeine content. Also, different species and preparations of coffee may have varying chemical compositions. However, this recent observation, plus several case reports suggesting a possible association between intake of unusually large amounts of caffeine and cardiac arrhythmias, makes it prudent to advise susceptible patients to avoid ingesting very large quantities of caffeine, particularly those patients with underlying cardiac disease.

1.16 Cardiovascular Effects of Antiretroviral Drugs

The interaction between the human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), antiretroviral drugs (ARVs), and cardiovascular disease (CVD) is complex and incompletely understood. Highly active antiretroviral therapy (HAART) is associated with clustering of cardiovascular risk factors resulting from class- and nonclass-specific metabolic effects of ARVs on lipids, glucose, insulin sensitivity, and anthropometric body changes characteristic of lipodystrophy. A paradoxical overall effect on CVD may be observed in untreated or early HIV infection. However, it becomes difficult to disentangle the effects of HIV itself, antiretroviral therapy, and the impact of improved longevity in those on HAART.

Of the drugs considered, only indinavir, ritonavir-boosted lopinavir, didanosine, and abacavir are associated with a significantly increased risk of myocardial infarction.⁹⁶ In a recent systematic review, Bavinger et al.⁹⁷ found increased relative risk (RR) of myocardial infarction associated with recent exposure (within the last 6 months) to abacavir (RR=1.92; 95% CI 1.51–2.42) and protease inhibitors (RR=2.13; 95% CI 1.06–4.28). The risk increased with each additional year of exposure to indinavir (RR=1.11; 95% CI 1.05–1.17) and lopinavir (RR=1.22; 95% CI 1.01–1.47). In general, evidence of an association between the use of antiretrovival therapy and cardiovascular disease from most observational studies is mixed. However, it provides sufficient stimulus for further investigation of the relationship.

1.17 Uremic Toxins

Chronic kidney disease (CKD) is a worldwide public health problem with increasing incidence and prevalence, poor outcomes, and high cost for care. Atherosclerotic vascular disease risk in end-stage renal disease (ESRD) is 5 to 30 times that in the general population. Many cardiovascular risk factors are more prevalent in ESRD than in the general population, which may explain some but probably not all, of the increased atherosclerotic vascular disease risks in patients with CKD.⁹⁸ Also, lower estimated glomerular filtration rate (eGFR) and higher albuminuria are risk factors for all-cause and cardiovascular mortality in high-risk populations, independent of each other and of cardiovascular risk factors.⁹⁹ The National Institute of Diabetes’ HEMO Study identified ischemic heart disease as a major cause of cardiac hospitalizations and cardiac deaths.¹⁰⁰ In the United States, white individuals who are on dialysis experience much higher overall and cardiovascular mortality rates than black individuals despite a more favorable risk-factor profile, implying an important racial difference.¹⁰¹

The European Uremic Toxin Work Group (EUTox) produced guidelines related to identification, characterization, and biological activities of uremic toxins.¹⁰² There are three groups of uremic toxins, divided according to their physicochemical characteristics: small water-soluble compounds (<500 Da), of which urea is a prototype; small protein-bound solutes such as phenols; and middle molecules (>500 Da) such as β-2 microglobulin. Cyanate spontaneously transformed from urea increases as renal function decreases. The potential toxin and active form of cyanate (i.e., isocyanic acid). carbamoylated amino acids, proteins, and other molecules may change their structure, charge, and function. These products of carbamoylation can modify the molecular activity of enzymes, cofactors, hormones, low-density lipoproteins, antibodies, receptors, and transport proteins.¹⁰³

Asymmetric dimethylarginine (ADMA), which is significantly increased in ESRD, is the most specific endogenous compound with inhibitory effects on nitric oxide (NO) synthesis.¹⁰⁴ ADMA causes cerebral vasoconstriction and inhibition of acetylcholine-induced vasorelaxation, and has been implicated in the development of hypertension, adverse cardiovascular events, and mortality.¹⁰⁵–¹⁰⁷ Symmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor ADMA. However, SMDA does not directly inhibit NOS but is a competitor of arginine transport and is eliminated through renal excretion.¹⁰⁸ SDMA is also involved in the inflammatory process of CKD, activating NF-κB and resulting in enhanced expression of IL-6 and TNF-α.¹⁰⁹ Hyperphosphatemia promotes the development and progression of secondary hyperparathyroidism and predisposes to metastatic calcification when the product of serum calcium and phosphorus (Ca×PO4) is elevated. Both of these conditions may contribute to the substantial morbidity and mortality seen in patients with