Curr Treat Options Cardio Med (2015) 17:19 DOI 10.1007/s11936-015-0381-2
Heart Failure (W Tang, Section Editor)
Contribution of Environmental Toxins in the Pathogenesis of Idiopathic Cardiomyopathies Antonio L. Perez, MD, MBA W. H. Wilson Tang, MD* Address * Section of Advanced Heart Failure and Transplantation, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH 44195, USA Email: [email protected]
* Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Heart Failure Keywords Idiopathic cardiomyopathies I Pathogenesis I Environmental toxins I Myocardial toxicity
Opinion statement The pathogenesis of idiopathic cardiomyopathies is likely highly complex and remains elusive. Environmental toxins have been hypothesized to possibly cause a subset of cardiomyopathies. Epidemiological, preclinical, and small clinical studies have investigated the role of numerous elements and compounds in the pathogenesis of these myocardial disorders. In this review, we present the evidence implicating elements and environmental compounds in myocardial toxicity, including antimony, cobalt, mercury, aluminum, copper, and acrolein. We discuss their sources, toxic effects, and epidemiology, as well as identify groups at risk for toxic exposure. Through our discussion, we highlight areas where further investigation into the clinical effects of these possible toxins is warranted.
Introduction Idiopathic cardiomyopathies encompass a group of heterogeneous myocardial diseases that remain a diagnostic and therapeutic challenge in clinical practice. The pathogenesis of idiopathic cardiomyopathies is likely complex—arising from an interaction of variables such as host genetic susceptibility factors, post-translational alterations, microbial infections, and environmental contributors. Environmental toxins have long been
hypothesized to be possible causes for at least a subset of myocardial disorders, although identifying the causative agents has been challenging. Over the last six decades, numerous elements and compounds have been investigated for their possible roles in cardiomyopathy pathogenesis. Despite this longstanding clinical suspicion, now informed by numerous case series, animal studies, environmental surveys, and epidemiological
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research, few clinical studies have investigated the interactions of environmental toxins and cardiomyopathy. In one of these few clinical studies, Frustaci and colleagues identified a possible role for trace element toxicity—most notably for mercury and antimony—in the pathogenesis of human idiopathic dilated cardiomyopathy [1••]. This group analyzed the myocardial concentrations of 32 trace elements in biopsy samples from 13 subjects with idiopathic dilated cardiomyopathy and no known prior exposure to excessive amounts of trace elements. Control groups included patients with valvular or ischemia-mediated LV dysfunction, patients with valvular disease and normal LV function, as well as patients with normal cardiac function, a total of 39 patients. For each subject, biopsy samples were taken from the left ventricle as well as skeletal muscle using a metal-contamination-free technique; trace element concentrations were measured by neutron activation analysis. These elements included mercury, silver, arsenic, gold, barium, cobalt, iron, nickel, selenium, zinc, calcium, uranium, tin, and 19 others. Interestingly, mercury and antimony levels were increased on average over 10,000-fold in the 13 subjects with idiopathic dilated cardiomyopathy when compared to levels found in the controls. When compared to normal myocardial trace element levels identified by investigators through literature review, the mercury level range was 19×–1800× the
upper limit of normal (mean 370×) among the subjects. For antimony, this range was 57×–2800× the upper limit of normal (mean 550×). In addition, silver, arsenic, gold, chromium, lanthanum, and zinc levels in subjects were 10×–250× greater than corresponding levels in controls. Increased levels of these elements were not found in the subjects’ skeletal muscle biopsies, suggesting a myocardial-specific element accumulation. While this study is small and single-center, its findings do raise concern for an unidentified role for trace element toxicity in idiopathic dilated cardiomyopathy which merits further investigation. Despite this study’s possibly important implications, limited subsequent clinical research on trace element toxicity and cardiomyopathy has been pursued. With the etiologies of many cardiomyopathies still unidentified, this highlights the significant opportunities for both bench and clinical investigation in understanding toxin-mediated cardiomyopathies. In this review, we will discuss in detail the most prominently investigated environmental toxins—their sources, myocardial effects, hypothesized mechanisms of toxicity, and epidemiology—as well as present areas where further investigations are merited. Table 1 identifies specific populations who may be at risk for toxicity from the environmental exposures discussed herein.
Antimony Antimony (chemical symbol Sb) is a lustrous gray metalloid used today predominantly in flame retardants, in the form of halogenated antimony compounds, applied in children’s clothing, toys, fiberglass, aircrafts, and automobile seat covers. It is used in alloys with lead, such as lead-acid batteries to enhance charging capability, bullets, type metal, and solder. Antimony also serves as a fining agent to remove bubbles from TV screen glass. Medically, the antimony-based drugs meglumine antimoniate and sodium stibogluconate are used in therapy for leishmaniasis. Antimony is naturally present in the Earth’s crust and can be released into the environment by volcanic eruptions, sea spray, forest fires, and windblown dust [9]. The most recent US geological survey performed by the Agency for Toxic Substances and Disease Registry in 1992 concluded that the average antimony exposure in the general population from food, water, and air is low, with the majority of significant exposure being occupation-related or therapeutic [2]. Numerous preclinical studies have suggested that antimony exposure can result in myocardial injury. In vitro exposure of rat cardiomyocytes to potassium antimonyl tartrate has been shown to cause lethal oxidative stress and cell
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Table 1. Populations at risk for exposures to possible myocardial toxins At-risk populations Antimony [2]
Cobalt [3]
Mercury [4]
Aluminum [5]
Arsenic [6]
Copper [7]
Acrolein [8]
• Workers in coal-fire power plants, refuse incinerators, and smelting facilities • People who live near or work in waste sites that receive slag from smelters and fly ash from power plants or incinerators • Firefighters exposed to soot and ash • Workers in production and processing of antimony and antimony oxide • Workers in battery-forming areas of lead-storage battery plants • Workers in hard metal industries (e.g., tool production and grinding), coal mining, metal mining, smelting and refining, cobalt dye painters, and cobalt chemical production • People with cobalt-chromium joint implants • People who reside near industrial sites using cobalt or waste sites where cobalt is disposed • People in agricultural areas that use sewage sludge or cobalt-containing fertilizers • People who take cobalt-containing supplements or large amounts of vitamin B12 • Workers at nuclear and irradiation facilities or nuclear waste sites that handle cobalt isotopes • People residing near former mercury production or recycling facilities, mercury mines, chloralkali facilities, waste incinerators, or mercury waste sites • Recreational or subsistence fishers and hunters • Native American populations who consume large amounts of locally caught fish or marine mammals • People with mercury-containing dental amalgams • People who use mercury-containing consumer products, such as skin-lightening creams, make-up, soaps, and ethnic remedies • People living in buildings painted with mercury-containing latex paints • Workers in aluminum extraction, refining, casting, and welding • Workers in industries that use aluminum products, such as aircraft, automotive, and metal products • Workers in plumbing, heating, air conditioning, masonry, electrical work, and fabricated wire products • People living near industrial emission sources and waste sites • People with end-stage renal disease requiring hemodialysis • People consuming large amounts of antacids, buffered analgesics, or antidiarrheal medication • People consuming water from residential wells contaminated with aluminum • Workers in smelting facilities, coal-fired power plants, and incinerators • Workers in industries using or making pesticides that contain arsenic • People living in areas of volcanic activity • People living in areas with high natural or contaminant arsenic levels in water • Workers using arsenic-treated wood products • Workers in, or people who live near, copper smelters, ore-processing plants, steel plants, and refineries • People who live in areas with high copper water content • Workers involved in copper salt production used in agriculture and water treatment • People who have long-term frequent or prolonged contact with tobacco or marijuana smoke • People who live or work near dense traffic areas or locations with frequent smog • People who live or work near bodies of water being treated with acrolein to eliminate plants or aquatic animals • Patients receiving oxazaphosphorine drugs such as cyclophosphamide, of which acrolein is a metabolite
death mediated by elevation in intra-cellular calcium. Furthermore, studies have suggested that non-lethal doses of this antimony compound result in reduction in cardiomyocyte mobilization of calcium during excitation and contraction [10]. Cardiac death in animals associated with intra-vascular antimony infusion was demonstrated decades ago in dogs [11]. In guinea pigs,
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Curr Treat Options Cardio Med (2015) 17:19 antimony has been shown to increase QTc, induce ventricular arrhythmias, impair cardiomyocyte contraction, elongate whole-cell action potential, and reduce cardiomyocyte calcium current [12]. The clinical evidence of antimony-mediated cardiotoxicity has been mostly limited to patients with a history of receiving leishmaniasis therapy or specific occupational exposure. Significant incidence of cardiotoxicity subsequent to sodium stibogluconate therapy has been reported in patients with visceral leishmaniasis [13–15]. In one case series of 80 patients treated for leishmaniasis in India, 5 % died of ventricular arrhythmias, while EKG changes such as T-wave changes, prolonged QT, and ST segment changes were seen in 40 % of patients [14]. In another case series, six of eight patients exposed to the same batch of inappropriately diluted high-osmolarity sodium stibogluconate experienced congestive heart failure, while three died of cardiotoxicity [13]. While no study to date has clearly implicated antimony toxicity as the etiology of cardiomyopathy in patients who have no recognized prior significant exposure, Frustaci and colleagues did not find any prior history of toxic exposure in their subjects in whom they found an average of 10,000-fold antimony concentration on cardiac biopsies [1••]. These findings suggest that other unidentified sources of antimony cardiotoxicity may exist. Given the ubiquity of antimony in modern day consumer products, further investigation is warranted.
Cobalt Cobalt cardiotoxicity has been described most recently among patients who have undergone hip replacements and have experienced prosthesismediated intoxication [16, 17, 18•, 19]. Metallic degradation of joint arthroplasties can release alloys such as cobalt, chromium, titanium, and aluminum into the bloodstream. Case studies and series have reported episodes of acute cobalt intoxication in the weeks or months after a revision surgery in the setting of a joint prosthesis complication such as trauma or infection. Cobalt toxicity commonly causes neuropathy, profound hypothyroidism, dilated cardiomyopathy mostly through myofibrillar loss rather than fibrosis, pericardial effusion, cardiac arrhythmias, and acute liver injury [20]. In particular, some episodes of cobalt metallosis occur after fracture of the ceramic prosthetic joint head and subsequent revision with a metal-on-polyethylene joint pairing. Retained ceramic microparticles are believed to cause wear on the metal head, resulting in metallosis [21]. Case reports note that systolic function can improve after cobalt toxicity from an orthopedic prosthesis is identified and the source removed [17]. However, acute cobalt toxicity has been reported to cause fulminant heart failure, cardiac tamponade, and death [16]. Cobalt toxicity was first described in the 1960s, when cobalt used as part of a foaming agent applied to beer made in Quebec caused cardiomyopathy. Dozens of previously healthy men who frequently imbibed local beer developed what is now known to be classic signs and symptoms of cobalt toxicity, with 50 % dying as a result [22, 23]. In one study assessing the biochemical effects of cobalt exposure for
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24 weeks in rat myocardium, manganese superoxide dismutase and cellular respiratory cycle enzyme activity in affected cardiomyocytes were markedly reduced compared to the control, suggesting impaired antioxidant enzyme function and ATP production rate in the animals exposed to cobalt [24].
Mercury Environmental mercury is highly toxic and causes multi-system organ disease, including inhalational pneumonitis, central nervous system toxicity, seizures, acute tubular necrosis, immunologic glomerulonephritis, and nephrotic syndrome, with neurologic disease usually being most severe. Most known mercury contamination occurs in the setting of erosion, volcanic eruptions, metal smelting, and industrial production [25, 26]. Proposed mechanisms for mercury toxicity include glutathione depletion, production of reactive oxygen species, and interruption in selenium-dependent endogenous enzymatic reactions. Frustaci and colleagues showed significant elevation in mercury concentrations in myocardial biopsies—mean concentration 370× the upper limit of normal—from patients with idiopathic dilated cardiomyopathy in their cohort [1••]. Marine biologists have showed an association between increased mercury concentrations in the livers of pygmy sperm whales and cardiomyopathy [27]. Mercury also may contribute to myocarditis pathogenesis by enhancing viral infections [28]. Animal studies have suggested mercury-mediated enhancement of myocarditis in animals infected with Coxsackie B3, herpes simplex virus type 2, and encephalomyocarditis virus [29, 30, 31•, 32–35]. Mercury exposure in these animals resulted in enhanced viral replication by reducing host interferon and antibody and macrophage activity as well as inhibition of cytokine production. Mercury also binds selenium, thus decreasing the activity of seleniumdependent enzymes such as glutathione peroxidases and thioredoxin reductases and thereby possibly increasing oxidative injury in the setting of inflammatory processes such as viral infections [28]. Mercury has a very high binding affinity for selenium, which results in sequestration in lysosomes [36].
Other trace elements Frustaci and colleagues also suggest a role for silver, arsenic, gold, chromium, lanthanum, and zinc levels in idiopathic cardiomyopathies, given that their levels in cardiac biopsies from study subjects were 10×– 250× greater than corresponding levels in controls [1••]. To date, however, further work into the effects of these elements in myocardial disease is lacking. In another clinical study, serum copper levels in 54 patients with dilated cardiomyopathy were found to be statistically greater than those of controls [25], but there is a possibility that this can be due to underlying oxidative stress and endogenous copper handling rather than environmental exposure. Aluminum has been shown to accumulate in many organs, including the myocardium, in patients on chronic hemodialysis who take aluminum-containing drugs [37]. In
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Curr Treat Options Cardio Med (2015) 17:19 addition, arsenic was also found in excess concentrations in dilated hearts by Frustaci and colleagues, and has been associated with myocarditis in chronic toxicity [38]. These are only some of the known elemental toxins found in the failing hearts and do not even include any unknown or untested organic or inorganic toxins, or various genetic polymorphisms that render individuals more susceptible to such exposures.
Environmental aldehydes and air pollution The effects of ambient air poluation have been better quantified. Epidemiological studies have documented a strong association between cardiovascular disease risk and exposure to ambient pollution [30, 39•, 40]. These studies have suggested that particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5) contributes to cardiovascular mortality in tens of thousands of Americans annually, a significant portion of which may be mediated by environmental aldehydes [39•, 41]. Aldehydes are present in high concentrations in automobile exhaust, smog, and cigarette smoke; they are released into the atmosphere during combustion of organic material, such as coal, cotton, and wood. One such aldehyde, acrolein, is a ubiquitously found reactive compound, classified by the Environmental Protection Agency as a highpriority air and water toxin [42]. Acrolein and related aldehydes are present in food or cooking products, such as in coffee, cheese, donuts, and reheated cooking oils; cigarette smoke contains 50–70 ppm of acrolein, while acrolein concentrations of 0.04 to 2.2 ppm have been detected near oil refineries [43]. Indeed, acrolein from cigarette smoke is estimated to contribute to the vast majority of non-malignancy smokingrelated disease risk [44]. Endogenously, acrolein is a degradation product of polyamines and is a byproduct of myeloperoxidase activity from neutrophils [45]. Systemically, acrolein forms adducts with protein at sites of inflammation [46]. These acrolein-protein adducts have been found in atherosclerotic lesions [47]. The adducts can conjugate with low-density lipoprotein and induce macrophage foam cell formation [48]. Numerous animal studies have shown that aldehyde exposure can cause catastrophic organ toxicity, most notably in the heart and lungs [49, 50]. In one study, mice that were fed acrolein daily in doses comparable to daily human consumption in the USA for 48 days developed increased left ventricular dilatation, systolic dysfunction, and impaired relaxation when compared to controls [51]. Acrolein was found to result in both myocardial oxidative stress (with cardiomyocyte membrane-localized protein 4-hydroxy-trans-2-nonenal adducts) as well as nitrative stress, with increased protein-nitrotyrosine. Proteinacrolein complexes were also documented in animal plasma and myocardium, suggesting at least in part an infiltrative mechanism to acrolein-associated heart failure. Affected animals developed both cardiomyocyte hypertrophy and apoptosis, with documented upregulation in nuclear factor-kappa B, tumor necrosis factor-alpha, and interleukin-1 beta. In totem, this study suggested that long-term enteral exposure to acrolein in amounts comparable to current daily
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human consumption of unsaturated aldehydes may increase risk of dilated cardiomyopathy. Direct human data, however, are lacking. Epidemiological studies have also suggested that air pollution can exacerbate already existing coronary disease and heart failure, resulting in increased hospitalization and death. In one Lancet meta-analysis involving 35 international studies with a total of 4 million heart failure hospitalizations or deaths, these outcomes were positively associated with increasing concentrations of carbon monoxide, sulfur dioxide, nitrogen dioxide, and particulate air pollutants [52]. Pollutant concentration was measured within the 7 days prior to heart failure hospitalization or death. This study suggests that exposure to common air pollution is temporally associated heart failure morbidity and mortality. In an analysis from the Louisville Healthy Heart Study, acrolein exposure was found to be associated with increased risk of ischemic heart disease, as well as with markers of platelet activation and suppression of circulating angiogenic cells [53]. The level of the acrolein metabolite 3hydroxypropylmercapturic acid measured in urine was found to be higher in smokers than non-smokers. This urine metabolite was also found to be positively correlated with Framingham Risk Score, independent of smoking status.
Future directions and conclusion Research into the interactions between environmental toxins and idiopathic cardiomyopathy strongly suggests a role for numerous toxins in the pathogenesis of at least some patients with idiopathic myocardial disorders. There are numerous public health and clinical implications to identifying environmental toxins that may contribute to cardiomyopathies. Since exposure to these toxins can occur at work or be caused by industrial contamination of local environments, identifying particular toxins can allow for regulation of their handling and disposal as well as appropriate protection for workers and ecological monitoring. Extensive international regulation of mercury, for example, has eliminated its use in batteries and created cost-effective methods of safe disposal. Furthermore, cardiomyopathies caused by particular toxins likely display unique natural histories; identifying these toxins in individuals can allow cardiologists to tailor care by, for example, evaluating patients for advanced therapies earlier if medical therapies are known to be less effective. Multicenter studies examining the concentrations of trace elements and toxins in the myocardium from patients with idiopathic cardiomyopathy are glaringly lacking and required to validate findings from small studies completed to date. Lack of clinical research in this area is in part due to the relatively limited access to myocardial samples and the dearth of evidence that definitive diagnoses will lead to significant changes in medical therapies at present. While large levels of intoxication may result in the severe or catastrophic clinical presentations discussed here, it is possible that low levels of chronic toxin exposure also result in myocardial dysfunction. This degree of toxin exposure may
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lead to an indolent clinical course that currently characterizes the disease progression in many idiopathic cardiomyopathy patients, which can make identifying the toxin challenging. Undertaking clinical studies to understand the effects of environmental toxins on myocardial function remains an important imperative that should be part of our efforts to investigating the etiologies for cardiomyopathies that remain unknown.
Acknowledgments This work is supported in part by National Institutes of Health grant R01HL103931.
Compliance With Ethics Guidelines Conflict of Interest Dr. Antonio L. Perez declares no potential conflicts of interest. Dr. Wilson Tang is a section editor for Current Treatment Options in Cardiovascular Medicine. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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Heart Failure (W Tang, Section Editor)
Contribution of Environmental Toxins in the Pathogenesis of Idiopathic Cardiomyopathies Antonio L. Perez, MD, MBA W. H. Wilson Tang, MD* Address * Section of Advanced Heart Failure and Transplantation, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH 44195, USA Email: [email protected]
* Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Heart Failure Keywords Idiopathic cardiomyopathies I Pathogenesis I Environmental toxins I Myocardial toxicity
Opinion statement The pathogenesis of idiopathic cardiomyopathies is likely highly complex and remains elusive. Environmental toxins have been hypothesized to possibly cause a subset of cardiomyopathies. Epidemiological, preclinical, and small clinical studies have investigated the role of numerous elements and compounds in the pathogenesis of these myocardial disorders. In this review, we present the evidence implicating elements and environmental compounds in myocardial toxicity, including antimony, cobalt, mercury, aluminum, copper, and acrolein. We discuss their sources, toxic effects, and epidemiology, as well as identify groups at risk for toxic exposure. Through our discussion, we highlight areas where further investigation into the clinical effects of these possible toxins is warranted.
Introduction Idiopathic cardiomyopathies encompass a group of heterogeneous myocardial diseases that remain a diagnostic and therapeutic challenge in clinical practice. The pathogenesis of idiopathic cardiomyopathies is likely complex—arising from an interaction of variables such as host genetic susceptibility factors, post-translational alterations, microbial infections, and environmental contributors. Environmental toxins have long been
hypothesized to be possible causes for at least a subset of myocardial disorders, although identifying the causative agents has been challenging. Over the last six decades, numerous elements and compounds have been investigated for their possible roles in cardiomyopathy pathogenesis. Despite this longstanding clinical suspicion, now informed by numerous case series, animal studies, environmental surveys, and epidemiological
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research, few clinical studies have investigated the interactions of environmental toxins and cardiomyopathy. In one of these few clinical studies, Frustaci and colleagues identified a possible role for trace element toxicity—most notably for mercury and antimony—in the pathogenesis of human idiopathic dilated cardiomyopathy [1••]. This group analyzed the myocardial concentrations of 32 trace elements in biopsy samples from 13 subjects with idiopathic dilated cardiomyopathy and no known prior exposure to excessive amounts of trace elements. Control groups included patients with valvular or ischemia-mediated LV dysfunction, patients with valvular disease and normal LV function, as well as patients with normal cardiac function, a total of 39 patients. For each subject, biopsy samples were taken from the left ventricle as well as skeletal muscle using a metal-contamination-free technique; trace element concentrations were measured by neutron activation analysis. These elements included mercury, silver, arsenic, gold, barium, cobalt, iron, nickel, selenium, zinc, calcium, uranium, tin, and 19 others. Interestingly, mercury and antimony levels were increased on average over 10,000-fold in the 13 subjects with idiopathic dilated cardiomyopathy when compared to levels found in the controls. When compared to normal myocardial trace element levels identified by investigators through literature review, the mercury level range was 19×–1800× the
upper limit of normal (mean 370×) among the subjects. For antimony, this range was 57×–2800× the upper limit of normal (mean 550×). In addition, silver, arsenic, gold, chromium, lanthanum, and zinc levels in subjects were 10×–250× greater than corresponding levels in controls. Increased levels of these elements were not found in the subjects’ skeletal muscle biopsies, suggesting a myocardial-specific element accumulation. While this study is small and single-center, its findings do raise concern for an unidentified role for trace element toxicity in idiopathic dilated cardiomyopathy which merits further investigation. Despite this study’s possibly important implications, limited subsequent clinical research on trace element toxicity and cardiomyopathy has been pursued. With the etiologies of many cardiomyopathies still unidentified, this highlights the significant opportunities for both bench and clinical investigation in understanding toxin-mediated cardiomyopathies. In this review, we will discuss in detail the most prominently investigated environmental toxins—their sources, myocardial effects, hypothesized mechanisms of toxicity, and epidemiology—as well as present areas where further investigations are merited. Table 1 identifies specific populations who may be at risk for toxicity from the environmental exposures discussed herein.
Antimony Antimony (chemical symbol Sb) is a lustrous gray metalloid used today predominantly in flame retardants, in the form of halogenated antimony compounds, applied in children’s clothing, toys, fiberglass, aircrafts, and automobile seat covers. It is used in alloys with lead, such as lead-acid batteries to enhance charging capability, bullets, type metal, and solder. Antimony also serves as a fining agent to remove bubbles from TV screen glass. Medically, the antimony-based drugs meglumine antimoniate and sodium stibogluconate are used in therapy for leishmaniasis. Antimony is naturally present in the Earth’s crust and can be released into the environment by volcanic eruptions, sea spray, forest fires, and windblown dust [9]. The most recent US geological survey performed by the Agency for Toxic Substances and Disease Registry in 1992 concluded that the average antimony exposure in the general population from food, water, and air is low, with the majority of significant exposure being occupation-related or therapeutic [2]. Numerous preclinical studies have suggested that antimony exposure can result in myocardial injury. In vitro exposure of rat cardiomyocytes to potassium antimonyl tartrate has been shown to cause lethal oxidative stress and cell
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Table 1. Populations at risk for exposures to possible myocardial toxins At-risk populations Antimony [2]
Cobalt [3]
Mercury [4]
Aluminum [5]
Arsenic [6]
Copper [7]
Acrolein [8]
• Workers in coal-fire power plants, refuse incinerators, and smelting facilities • People who live near or work in waste sites that receive slag from smelters and fly ash from power plants or incinerators • Firefighters exposed to soot and ash • Workers in production and processing of antimony and antimony oxide • Workers in battery-forming areas of lead-storage battery plants • Workers in hard metal industries (e.g., tool production and grinding), coal mining, metal mining, smelting and refining, cobalt dye painters, and cobalt chemical production • People with cobalt-chromium joint implants • People who reside near industrial sites using cobalt or waste sites where cobalt is disposed • People in agricultural areas that use sewage sludge or cobalt-containing fertilizers • People who take cobalt-containing supplements or large amounts of vitamin B12 • Workers at nuclear and irradiation facilities or nuclear waste sites that handle cobalt isotopes • People residing near former mercury production or recycling facilities, mercury mines, chloralkali facilities, waste incinerators, or mercury waste sites • Recreational or subsistence fishers and hunters • Native American populations who consume large amounts of locally caught fish or marine mammals • People with mercury-containing dental amalgams • People who use mercury-containing consumer products, such as skin-lightening creams, make-up, soaps, and ethnic remedies • People living in buildings painted with mercury-containing latex paints • Workers in aluminum extraction, refining, casting, and welding • Workers in industries that use aluminum products, such as aircraft, automotive, and metal products • Workers in plumbing, heating, air conditioning, masonry, electrical work, and fabricated wire products • People living near industrial emission sources and waste sites • People with end-stage renal disease requiring hemodialysis • People consuming large amounts of antacids, buffered analgesics, or antidiarrheal medication • People consuming water from residential wells contaminated with aluminum • Workers in smelting facilities, coal-fired power plants, and incinerators • Workers in industries using or making pesticides that contain arsenic • People living in areas of volcanic activity • People living in areas with high natural or contaminant arsenic levels in water • Workers using arsenic-treated wood products • Workers in, or people who live near, copper smelters, ore-processing plants, steel plants, and refineries • People who live in areas with high copper water content • Workers involved in copper salt production used in agriculture and water treatment • People who have long-term frequent or prolonged contact with tobacco or marijuana smoke • People who live or work near dense traffic areas or locations with frequent smog • People who live or work near bodies of water being treated with acrolein to eliminate plants or aquatic animals • Patients receiving oxazaphosphorine drugs such as cyclophosphamide, of which acrolein is a metabolite
death mediated by elevation in intra-cellular calcium. Furthermore, studies have suggested that non-lethal doses of this antimony compound result in reduction in cardiomyocyte mobilization of calcium during excitation and contraction [10]. Cardiac death in animals associated with intra-vascular antimony infusion was demonstrated decades ago in dogs [11]. In guinea pigs,
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Curr Treat Options Cardio Med (2015) 17:19 antimony has been shown to increase QTc, induce ventricular arrhythmias, impair cardiomyocyte contraction, elongate whole-cell action potential, and reduce cardiomyocyte calcium current [12]. The clinical evidence of antimony-mediated cardiotoxicity has been mostly limited to patients with a history of receiving leishmaniasis therapy or specific occupational exposure. Significant incidence of cardiotoxicity subsequent to sodium stibogluconate therapy has been reported in patients with visceral leishmaniasis [13–15]. In one case series of 80 patients treated for leishmaniasis in India, 5 % died of ventricular arrhythmias, while EKG changes such as T-wave changes, prolonged QT, and ST segment changes were seen in 40 % of patients [14]. In another case series, six of eight patients exposed to the same batch of inappropriately diluted high-osmolarity sodium stibogluconate experienced congestive heart failure, while three died of cardiotoxicity [13]. While no study to date has clearly implicated antimony toxicity as the etiology of cardiomyopathy in patients who have no recognized prior significant exposure, Frustaci and colleagues did not find any prior history of toxic exposure in their subjects in whom they found an average of 10,000-fold antimony concentration on cardiac biopsies [1••]. These findings suggest that other unidentified sources of antimony cardiotoxicity may exist. Given the ubiquity of antimony in modern day consumer products, further investigation is warranted.
Cobalt Cobalt cardiotoxicity has been described most recently among patients who have undergone hip replacements and have experienced prosthesismediated intoxication [16, 17, 18•, 19]. Metallic degradation of joint arthroplasties can release alloys such as cobalt, chromium, titanium, and aluminum into the bloodstream. Case studies and series have reported episodes of acute cobalt intoxication in the weeks or months after a revision surgery in the setting of a joint prosthesis complication such as trauma or infection. Cobalt toxicity commonly causes neuropathy, profound hypothyroidism, dilated cardiomyopathy mostly through myofibrillar loss rather than fibrosis, pericardial effusion, cardiac arrhythmias, and acute liver injury [20]. In particular, some episodes of cobalt metallosis occur after fracture of the ceramic prosthetic joint head and subsequent revision with a metal-on-polyethylene joint pairing. Retained ceramic microparticles are believed to cause wear on the metal head, resulting in metallosis [21]. Case reports note that systolic function can improve after cobalt toxicity from an orthopedic prosthesis is identified and the source removed [17]. However, acute cobalt toxicity has been reported to cause fulminant heart failure, cardiac tamponade, and death [16]. Cobalt toxicity was first described in the 1960s, when cobalt used as part of a foaming agent applied to beer made in Quebec caused cardiomyopathy. Dozens of previously healthy men who frequently imbibed local beer developed what is now known to be classic signs and symptoms of cobalt toxicity, with 50 % dying as a result [22, 23]. In one study assessing the biochemical effects of cobalt exposure for
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24 weeks in rat myocardium, manganese superoxide dismutase and cellular respiratory cycle enzyme activity in affected cardiomyocytes were markedly reduced compared to the control, suggesting impaired antioxidant enzyme function and ATP production rate in the animals exposed to cobalt [24].
Mercury Environmental mercury is highly toxic and causes multi-system organ disease, including inhalational pneumonitis, central nervous system toxicity, seizures, acute tubular necrosis, immunologic glomerulonephritis, and nephrotic syndrome, with neurologic disease usually being most severe. Most known mercury contamination occurs in the setting of erosion, volcanic eruptions, metal smelting, and industrial production [25, 26]. Proposed mechanisms for mercury toxicity include glutathione depletion, production of reactive oxygen species, and interruption in selenium-dependent endogenous enzymatic reactions. Frustaci and colleagues showed significant elevation in mercury concentrations in myocardial biopsies—mean concentration 370× the upper limit of normal—from patients with idiopathic dilated cardiomyopathy in their cohort [1••]. Marine biologists have showed an association between increased mercury concentrations in the livers of pygmy sperm whales and cardiomyopathy [27]. Mercury also may contribute to myocarditis pathogenesis by enhancing viral infections [28]. Animal studies have suggested mercury-mediated enhancement of myocarditis in animals infected with Coxsackie B3, herpes simplex virus type 2, and encephalomyocarditis virus [29, 30, 31•, 32–35]. Mercury exposure in these animals resulted in enhanced viral replication by reducing host interferon and antibody and macrophage activity as well as inhibition of cytokine production. Mercury also binds selenium, thus decreasing the activity of seleniumdependent enzymes such as glutathione peroxidases and thioredoxin reductases and thereby possibly increasing oxidative injury in the setting of inflammatory processes such as viral infections [28]. Mercury has a very high binding affinity for selenium, which results in sequestration in lysosomes [36].
Other trace elements Frustaci and colleagues also suggest a role for silver, arsenic, gold, chromium, lanthanum, and zinc levels in idiopathic cardiomyopathies, given that their levels in cardiac biopsies from study subjects were 10×– 250× greater than corresponding levels in controls [1••]. To date, however, further work into the effects of these elements in myocardial disease is lacking. In another clinical study, serum copper levels in 54 patients with dilated cardiomyopathy were found to be statistically greater than those of controls [25], but there is a possibility that this can be due to underlying oxidative stress and endogenous copper handling rather than environmental exposure. Aluminum has been shown to accumulate in many organs, including the myocardium, in patients on chronic hemodialysis who take aluminum-containing drugs [37]. In
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Curr Treat Options Cardio Med (2015) 17:19 addition, arsenic was also found in excess concentrations in dilated hearts by Frustaci and colleagues, and has been associated with myocarditis in chronic toxicity [38]. These are only some of the known elemental toxins found in the failing hearts and do not even include any unknown or untested organic or inorganic toxins, or various genetic polymorphisms that render individuals more susceptible to such exposures.
Environmental aldehydes and air pollution The effects of ambient air poluation have been better quantified. Epidemiological studies have documented a strong association between cardiovascular disease risk and exposure to ambient pollution [30, 39•, 40]. These studies have suggested that particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5) contributes to cardiovascular mortality in tens of thousands of Americans annually, a significant portion of which may be mediated by environmental aldehydes [39•, 41]. Aldehydes are present in high concentrations in automobile exhaust, smog, and cigarette smoke; they are released into the atmosphere during combustion of organic material, such as coal, cotton, and wood. One such aldehyde, acrolein, is a ubiquitously found reactive compound, classified by the Environmental Protection Agency as a highpriority air and water toxin [42]. Acrolein and related aldehydes are present in food or cooking products, such as in coffee, cheese, donuts, and reheated cooking oils; cigarette smoke contains 50–70 ppm of acrolein, while acrolein concentrations of 0.04 to 2.2 ppm have been detected near oil refineries [43]. Indeed, acrolein from cigarette smoke is estimated to contribute to the vast majority of non-malignancy smokingrelated disease risk [44]. Endogenously, acrolein is a degradation product of polyamines and is a byproduct of myeloperoxidase activity from neutrophils [45]. Systemically, acrolein forms adducts with protein at sites of inflammation [46]. These acrolein-protein adducts have been found in atherosclerotic lesions [47]. The adducts can conjugate with low-density lipoprotein and induce macrophage foam cell formation [48]. Numerous animal studies have shown that aldehyde exposure can cause catastrophic organ toxicity, most notably in the heart and lungs [49, 50]. In one study, mice that were fed acrolein daily in doses comparable to daily human consumption in the USA for 48 days developed increased left ventricular dilatation, systolic dysfunction, and impaired relaxation when compared to controls [51]. Acrolein was found to result in both myocardial oxidative stress (with cardiomyocyte membrane-localized protein 4-hydroxy-trans-2-nonenal adducts) as well as nitrative stress, with increased protein-nitrotyrosine. Proteinacrolein complexes were also documented in animal plasma and myocardium, suggesting at least in part an infiltrative mechanism to acrolein-associated heart failure. Affected animals developed both cardiomyocyte hypertrophy and apoptosis, with documented upregulation in nuclear factor-kappa B, tumor necrosis factor-alpha, and interleukin-1 beta. In totem, this study suggested that long-term enteral exposure to acrolein in amounts comparable to current daily
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human consumption of unsaturated aldehydes may increase risk of dilated cardiomyopathy. Direct human data, however, are lacking. Epidemiological studies have also suggested that air pollution can exacerbate already existing coronary disease and heart failure, resulting in increased hospitalization and death. In one Lancet meta-analysis involving 35 international studies with a total of 4 million heart failure hospitalizations or deaths, these outcomes were positively associated with increasing concentrations of carbon monoxide, sulfur dioxide, nitrogen dioxide, and particulate air pollutants [52]. Pollutant concentration was measured within the 7 days prior to heart failure hospitalization or death. This study suggests that exposure to common air pollution is temporally associated heart failure morbidity and mortality. In an analysis from the Louisville Healthy Heart Study, acrolein exposure was found to be associated with increased risk of ischemic heart disease, as well as with markers of platelet activation and suppression of circulating angiogenic cells [53]. The level of the acrolein metabolite 3hydroxypropylmercapturic acid measured in urine was found to be higher in smokers than non-smokers. This urine metabolite was also found to be positively correlated with Framingham Risk Score, independent of smoking status.
Future directions and conclusion Research into the interactions between environmental toxins and idiopathic cardiomyopathy strongly suggests a role for numerous toxins in the pathogenesis of at least some patients with idiopathic myocardial disorders. There are numerous public health and clinical implications to identifying environmental toxins that may contribute to cardiomyopathies. Since exposure to these toxins can occur at work or be caused by industrial contamination of local environments, identifying particular toxins can allow for regulation of their handling and disposal as well as appropriate protection for workers and ecological monitoring. Extensive international regulation of mercury, for example, has eliminated its use in batteries and created cost-effective methods of safe disposal. Furthermore, cardiomyopathies caused by particular toxins likely display unique natural histories; identifying these toxins in individuals can allow cardiologists to tailor care by, for example, evaluating patients for advanced therapies earlier if medical therapies are known to be less effective. Multicenter studies examining the concentrations of trace elements and toxins in the myocardium from patients with idiopathic cardiomyopathy are glaringly lacking and required to validate findings from small studies completed to date. Lack of clinical research in this area is in part due to the relatively limited access to myocardial samples and the dearth of evidence that definitive diagnoses will lead to significant changes in medical therapies at present. While large levels of intoxication may result in the severe or catastrophic clinical presentations discussed here, it is possible that low levels of chronic toxin exposure also result in myocardial dysfunction. This degree of toxin exposure may
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lead to an indolent clinical course that currently characterizes the disease progression in many idiopathic cardiomyopathy patients, which can make identifying the toxin challenging. Undertaking clinical studies to understand the effects of environmental toxins on myocardial function remains an important imperative that should be part of our efforts to investigating the etiologies for cardiomyopathies that remain unknown.
Acknowledgments This work is supported in part by National Institutes of Health grant R01HL103931.
Compliance With Ethics Guidelines Conflict of Interest Dr. Antonio L. Perez declares no potential conflicts of interest. Dr. Wilson Tang is a section editor for Current Treatment Options in Cardiovascular Medicine. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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