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Chemical-Induced Atrial Thrombosis in NTP Rodent Studies
1 Laboratory of Experimental Pathology Correspondence: Address correspondence to: Abraham Nyska, Laboratory of Experimental Pathology, NIEHS, Research Triangle Park, NC 27709, USA; e-mail:nyska{at}niehs.nih.gov
Cardiac thrombosis, one of the causes of sudden death throughout the world, plays a principal role in several cardiovascular diseases, such as myocardial infarction and stroke in humans. Data from studies of induction of chemical thrombosis in rodents help to identify substances in our environment that may contribute to cardiac thrombosis. Results for more than 500 chemicals tested in rodents in 2-year bioassays have been published as Technical Reports of the National Toxicology Program (NTP)  http://ntp-server.niehs.nih.gov/index . We evaluated atrial thrombosis induced by these chemical exposures and compared it to similarly induced lesions reported in the literature. Spontaneous rates of cardiac thrombosis were determined for control Fischer 344 rats and B6C3F1 mice: 0% in rats and mice in 90-day studies and, in 2-year studies, 0.7% in both genders of mice, 4% in male rats, and 1% in female rats. Incidences of atrial thrombosis were increased in high-dosed groups involving 13 compounds (incidence rate: 20–100%): 2-butoxyethanol, C.I. Direct Blue 15, bis(2-chloroethoxy)methane, diazoaminobenzene, diethanolamine, 3,3'-dimethoxybenzidine dihydrochloride, hexachloroethane, isobutene, methyleugenol, oxazepam, C.I. Pigment Red 23, C.I. Acid Red 114, and 4,4'-thiobis(6-t-butyl-m-cresol). The main localization of spontaneously occurring and chemically induced thromboses occurred in the left atrium. The literature survey suggested that chemical-induced atrial thrombosis might be closely related to myocardial injury, endothelial injury, circulatory stasis, hypercoagulability, and impaired atrial mechanical activity, such as atrial fibrillation, which could cause stasis of blood within the left atrial appendage, contributing to left atrial thrombosis. Supplementary data referenced in this paper are not printed in this issue of Toxicologic Pathology. They are available as downloadable files at http:taylorandfrancis.metapress.com/openurl.asp?genre=journal&issn=0192-6233. To access them, click on the issue link for 33(5), then select this article. A download option appears at the bottom of this abstract. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.
Key Words: Heart • left atrium • atrial thrombosis • F344 rats • B6C3F1 mice • chemical-induced • NTP studies Abbreviations: ATSDR, Agency for Toxic Substances and Disease Registry • 2-BE, 2-butoxyethanol • Blue 15, C.I. Direct Blue 15 • CEM, bis(2-chloroethoxy)methane • COX-2, cyclo-oxygenase-2 • DAB, diazoaminobenzene • DEL, diethanolamine • DMOB, 3,3'-dimethoxybenzidine dihydrochloride • F344, Fischer 344 • HCE, hexachloroethane • IBT, isobutene • ICAM-1, intercellular adhesion molecule-1 • MEG, methyleugenol • NO, nitric oxide • NOS, nitric oxide synthase • NTP, National Toxicology Program • OZP, oxazepam • Red 23, C.I. Pigment Red 23 • Red 114, C.I. Acid Red 114 • TBBC, 4,4'-thiobis(6-t-butyl-m-cresol) • tPA, tissue-type plasminogen activator • TTP, thrombotic thrombocytopenic purpura • VCAM-1, vascular cell adhesion molecule-1
Thrombosis constitutes a serious disorder that can prove fatal in humans with classical risk factors associated with myocardial infarction, one of the most important of which is change in the vascular wall (Lowe, 2004). Venous thrombosis becomes significant, for example, in aged women undergoing oral estrogen therapies; blood stasis and coagulability are involved in the induction of thrombosis (Rosendaal et al., 2002; Lowe, 2004). Mitral valve disease, atrial fibrillation, dilatation of the left atrium, bradycardia, a low cardiac output, and hypercoagulability generally summarize the causes of formation of left atrial thrombus in human cases; systemic diseases, such as malignant tumors, amyloidosis, and nephritic syndrome, have also contributed to development of intracardiac thrombus (Aoyagi et al., 2002). Atrial thrombosis sometimes occurs as a side effect after therapy involving central venous catheterization, heart valve replacement, or maintenance hemodialysis (Platt et al., 1980; Rotellar et al., 1996; Kingdon et al., 2001; Shapiro et al., 2002; Douketis, 2003; Nishimura et al., 2003). Recently, a cyclo-oxygenase-2(COX-2)-inhibitor, one of a category of nonsteroidal anti-inflammatory drugs, was withdrawn from the market because of a significant risk of cardiovascular thrombotic complications, such as development of cardiac thrombus and myocardial infarction (Konstam and Weir, 1999; Bing and Lomnicka, 2002; Schmidt et al., 2004). Inhibition of COX-2 may lead to increased prothrombotic activity by tipping the balance of prostacyclin/thromboxane in favor of thromboxane, a prethrombotic eicosaid (Mukherjee et al., 2001; Bing and Lomnicka, 2002). Thus, much attention has been focused upon cardiac thrombosis as one of several side effects induced by certain medical treatments in humans.
Of approximately 85,000 chemicals registered for use in the United States, with an additional 2,000 introduced annually, complete toxicological-screening data are obtainable for only 7%; for 40%, no data are available (Bennett and Davis, 2002). Although the NTP has compiled a large database of incidences of lesions seen in chemical-treated animals
The NTP has customarily used 2-year and short-term, preliminary rodent bioassays to assess the overall toxicity and carcinogenicity of the tested chemical and to identify potential human carcinogens. We searched all of the NTP data for more than 500 chemicals and identified 13 that appeared to induce atrial thrombosis. Table 1 lists aspects of the study design for each of these chemicals identified as possible inducers of atrial thrombosis, such as the animal species and the route, duration, and dose of the exposure. Using data from NTP rodent studies, we described the incidences of thrombosis in overall and early sacrificed animals exposed to these chemicals http://ntp-server.niehs.nih.gov/index, in addition to control animals. The standard bioassay included male and female B6C3F1 mice and F344 rats, although other strains were occasionally included, such as Swiss Webster mice that were used in the study of oxazepam. Rodents were typically exposed to a chemical at 6–8 weeks of age by a route of exposure chosen for its relevance to the known or suspected route(s) of human exposure. All procedures, care, and treatment of animals were in accordance with the principles of humane treatment outlined by the National Institutes of Health (Grossblatt, 1996).
Results from the testing of more than 500 chemicals in the NTP studies led to the identification of 8 compounds, some reported in the original investigations, that induced atrial thrombosis in rodent models: bis(2-chloroethoxy)methane, 2-butoxyethanol, C.I. Acid Red 114, C.I. Direct Blue 15, diazoaminobenzene, 3,3'-dimethoxybenzidine dihydrochloride, isobutene, and oxazepam. Moreover, our examination of the data revealed 5 additional chemicals that may also have induced this abnormality, although no description of the increased incidence of thrombosis was noted in the reports of the NTP studies: C.I. Pigment Red 23, diethanolamine, hexachloroethane, methyleugenol, and 4,4'-thiobis(6-t-butyl-m-cresol).
For pathological analysis, complete necropsies were performed on all animals using standardized methodology. At necropsy, all tissues, including masses and other macroscopic abnormalities, were removed and fixed in 10% neutral buffered formalin for microscopical evaluation. After fixation, the tissues were trimmed, dehydrated, cleared, and paraffin-embedded. Five-µm-thick sections were mounted onto glass slides, stained with hematoxylin and eosin (H&E), and examined microscopically. According to the "Guides for Toxicologic Pathology" (Ruben et al., 2000), we used the following criterion for the diagnosis of atrial thrombosis: the composition of fibrin, platelets, and mixed inflammatory cells in the atrial lumen. All data, including those from pathological examination, were obtained according to GLP standards, underwent extensive pathology peer review by an external expert panel advisory board, and are available online
The function of endothelium-derived nitric oxide synthase (eNOS) in early atrial thrombotic change was investigated. Paraffin-embedded heart sections from F344 rats, each of 10 controls and 10 or 13 animals exposed dermally to 600 mg/kg CEM for 2, 3, 5, and 16 days were analyzed immunohistochemically to determine the effects of treatment on the expression of eNOS To designate the grading of eNOS expression, the intensity of the immunopositivity and the relative area of the sections exhibiting staining in the endocardial cells in the left atrium were graded by 2 pathologists using a scale ranging from 0 (–) to 2 (++) as follows: (0) = no specific immunohistological reaction visible in endocardial cells, (1) = up to 50% of total area showing a weakly positive reaction, and (2) = up to 100% of total area showing a strongly positive reaction.
Historical control data from the NTP reports of cardiac thrombosis in both genders of B6C3F1 mice and F344 rats are shown in Table 2. In 90-day studies of rats and mice, no cardiac thrombosis occurred spontaneously. The rate of occurrence of cardiac thrombosis in 2-year mouse studies, however, was 20 of 2,798 males and 21 of 3,110 females (incidence rates: 0.71% and 0.68%, respectively). In the 2-year rat studies, the incidence rates were higher than those of mice: 4.11% in males (134/3,257) and 1.01% in females (44/4,352). In the 2-year studies, the incidence rates of dead or sacrificed moribund animals exhibiting thrombosis were 85% (17/20) for male mice, 81% (17/21) for female mice, 88% (118/134) for male rats, and 91% (40/44) for female rats. All of the cardiac thrombosis in these data was atrial, of which the main localization was left atrial. Although these historical control data include results from all kinds of dosing routes, such as feed, gavage, inhalation, dermal, drinking water, and vaginal application, some difference(s) might, nonetheless, exist among animals dosed by different routes (data not shown).
The spontaneous occurrence of atrial thrombosis, also called auricular thrombosis, has been reported in several animals: rats (MacKenzie and Alison, 1990; Lewis, 1992; Elwell and Mahler, 1999; Ruben et al., 2000; Elangbam et al., 2002), mice (Maita et al., 1988; Hagiwara et al., 1996; Elangbam et al., 2002), cotton rats (Sorden and Watts, 1996), hamsters (Liu and Tilley, 1980; Allen et al., 1985), monkeys (Wood et al., 1978; Kessler and London, 1982; Allen et al., 1985), dogs (Jubb and Kennedy, 1993; Ayers and Jones, 1978), and cats (Jubb and Kennedy, 1993; Ayers and Jones, 1978; Liu and Tilley, 1980). The highest incidence of spontaneous atrial thrombosis reported was 65% in retired breeding BALB/c female mice, probably related to abnormalities of blood coagulation (Hagiwara et al., 1996). Atrial thrombosis has been described in aged animals, including rats and mice, often associated with myocardial lesions, such as degeneration, focal inflammation, mineralization, amyloid deposition, or degenerative myxoid lesions in heart valves (Sorden and Watts, 1996; Ruben et al., 2000; Elangbam et al., 2002). Our historical control data of spontaneously occurring atrial thrombosis might be useful in the evaluation of possible chemical- and drug-related changes in the incidence of this condition, since, in F344 rats and B6C3F1 mice, few explicit reports exist (Ayers and Jones, 1978; Lewis, 1992). Our data reveal a lower incidence of spontaneous atrial thrombosis in F344 rats and B6C3F1 mice, compared to that in other murine strains. The relationship between the occurrence of atrial thrombosis and other cardiac lesions, especially spontaneous cardiomyopathy, is not clear, because animals with atrial thrombosis do not always exhibit a severe degree of cardiomyopathy, and animals with a severe degree of cardiomyopathy do not always develop atrial thrombosis (data not shown). Thus, our data indicate that spontaneous atrial thrombosis might not always be related to cardiomyopathy in F344 rats and B6C3F1 mice.
Genetic modifiers of the coagulation response have been examined as risk factors in cardiac thrombosis using several genetically modified mice: factor IX-overexpression mice with an abnormal blood-coagulation system (Ameri et al., 2003), tissue-type and/or urokinase plasminogen-activator knockout mice with disturbances in the fibrinolytic/coagulation cascade (Christie et al., 1999), and Atm/m mice showing a mutation in the antithrombin gene (Dewerchin et al., 2003). Additional reports have presented relationships between the occurrence of cardiac thrombosis and gene-modified murine strains, including ja/ja (jaundiced) mice with a deficiency in erythroid β-sectrin (Kaysser et al., 1997); β-tropomyosin-overexpression mice exhibiting abnormal cardiomyocytic contraction and relaxation, which culminates in altered blood flow and thrombus formation (Muthuchamy et al., 1998); tumor necrosis factor-
Table 1 presents the results of our examination of the data of these 13 compounds to determine the incidences and main localization of heart thrombosis. In the chemical-exposed animals exhibiting cardiac thrombosis, the incidence was 20–100% among the groups (Table 1). The incidence rate of dead or sacrificed-moribund animals exhibiting thrombosis was 78% (274/351 animals), similar to that of the spontaneous occurrence of thrombosis in control animals (Table 2). Thrombosis constitutes a serious disorder that can prove fatal in humans (Virmani et al., 2001; Lowe, 2004) and animals (Jubb and Kennedy, 1993). The data that we uncovered suggest that heart thrombosis could be the main cause of death and moribundity in rats and mice exposed to these chemicals. We formed 3 categories indicating possible relationships to other lesions: cardiac damage, hematological change, and the occurrence of multiple tumors.
Chronic heart failure in humans, known to confer upon patients a greater risk of thromboembolism, is likely related to numerous, diverse factors, such as vascular abnormalities, increased coagulability, impaired blood flow, and low cardiac output that promotes formation of fibrin-rich clots. In addition, defective endothelial function and significant levels of circulating aggregates of platelets have been demonstrated in heart-failure patients (De Lorenzo et al., 2003). Atrial thrombosis in humans can occur in association with cardiac dysfunction and abnormal blood flow (whirlpool) in the atrium (Suetsugu et al., 1988; Bilge et al., 1999; De Lorenzo et al., 2003). Autopsies and echocardiographic studies have indicated near-50% incidences of thromboembolic events in patients with acute and chronic heart failures (Asinger et al., 1981; De Lorenzo et al., 2003). We were able to identify 3 chemicals from the NTP database, which might induce atrial thrombosis secondary to myocardial injury. We made this identification based upon the progression and localization of this injury.
Bis(2-chloroethoxy)methane (CEM)
Diethanolamine (DEL) In the mouse 2-year dermal study (NTP, 1999), higher incidences of atrial thrombosis were noted in male and female mice treated with 160 mg/kg DEL (Table 1). The lesions were detected in 6 of 50 males and 4 of 50 females (incidence rates: 12% and 8%, respectively) without other heart lesions; however, atrial thrombosis was not attributed to chemical-induced toxicity in the original report. In the previous 13-week mouse studies, myocardial degeneration could be seen in high-dose groups (NTP, 1992c; Melnick et al., 1994). The possibility exists that DEL induced cardiac effects in the 2-year mouse study, although myocardial damage was not detected histopathologically. Atrial thrombosis may, therefore, have been induced by DEL via cardiac functional changes.
Oxazepam (OZP)
Other Chemicals That Induced Atrial Thrombosis Related to Myocardial Damage
In humans, chemically induced hemolysis is a well-known phenomenon occurring with some association with thrombosis. Antineoplastic drugs, such as deoxycoformycin, pentostatin, cisplatin, and mitomycin, have been associated in humans with thrombotic thrombocytopenic purpura (TTP) characterized by hemolysis and formation of microthrombi in many organs, including heart (Bonner and Erslev, 1994; Leach et al., 1999; Ezov et al., 2002; Dlott et al., 2004). The most tenable hypothesis holds that TPP results from the introduction into the circulation of one or more platelet-aggregating substances due to immune-mediated or drug-induced direct toxicity (Bonner and Erslev, 1994; Ezov et al., 2002; Dlott et al., 2004). The direct toxicity of mitomycin on endothelial function might play an important role in the pathogenesis of TTP (Dlott et al., 2004). In human myeloma patients, thalidomide induced atrial or deep-vein thrombosis, probably due to sinus rhythm in the heart (Urbauer et al., 2002; Jego et al., 2003). Retinoic acid induced intraventricular thrombosis in human leukemia patients (Barbui et al., 1998; Falanga et al., 2003). The mechanism has been in part mediated by an increased expression of adhesion molecules that facilitate adhesion of cells to vascular endothelium, thereby promoting localized coagulation (Torromeo et al., 2001). Several chemicals and drugs have induced methemoglobinemia, such as the antimalarials, chloroquine and primaquine; local anesthetics (lignocaine, benzocaine, and prilocaine); glyceryl trinitrate; sulphonamides; and phenacetin (Coleman and Coleman, 1996; Hall et al., 1986). The formation of methemoglobin induced by these chemicals, resulting in the production of blood clots, apparently occurs predictably within a thrombus (Moody, 2003). Drug-induced platelet antibodies have been demonstrated to downregulate or enhance platelet function (Kekomaki, 2003). Sulfonamides induced immune thrombocytopenia, decreased platelet production, or increased destruction of platelets (Van den Bemt et al., 2004). Heparin-induced thrombocytopenia complicated by thrombosis was associated with high levels of drug-dependent antibodies (Kekomaki, 2003). From the NTP database, we were able to select 5 chemicals that might induce atrial thrombosis secondary to or probably related to hematological changes, especially hemolytic anemia.
2-Butoxyethanol (2-BE) These histopathological changes in rats have provided models of sickle cell anemia in humans (Ghanayem et al., 2001; Ezov et al., 2002; Pathare et al., 2003). Metabolic activation of BE to form butoxyacetic acid (BAA) is a prerequisite for the development of hematotoxicity (Ghanayem et al., 1987, 2001; Ghanayem and Sullivan, 1993). Human erythrocytes exposed to BAA have manifested changes similar to those seen in rat erythrocytes, such as deformability, osmotic fragility, and changes in sodium content, though human erythrocytes appear to be relatively resistant to the hemolytic effects of BAA (Ghanayem, 1989; Ghanayem and Sullivan, 1993; Udden, 2002).
C.I. Pigment Red 23 (Red 23)
Diazoaminobenzene (DAB)
Methyleugenol (MEG)
4,4'-Thiobis(6-t-butyl-m-cresol) (TBBC)
In cancer of humans and animals, the development of thrombosis involves a complex interaction between the tumor cell, the patient, and the hemostatic system (Khato et al., 1977; Tanabe et al., 1999; Schafer et al., 2003). Hyperfibrinogenemia contributes to the hypercoagulable state due to a compensatory overproduction of clotting factors in cancer patients (Khato et al., 1977; Tanabe et al., 1999). Tumor-bearing mice given TNF exhibited intravascular clot formation with fibrin deposition in vivo. Activation of coagulation of the matrix from TNF-stimulated human endothelial cells was dependent on the presence of platelets, indicating their important role in propagating reactions leading to formation of fibrin in vitro (Tijburg et al., 1991; Jaimes et al., 2001). Neoplastic and/or endothelial cells in tumors, through expression of tissue factors or cytokines, such as TNF  , can activate coagulation (Ray, 2000; Philipp et al., 2003; Schafer et al., 2003). Some kinds of malignant tumors, such as lymphoma, stimulate megakaryocytopoiesis and platelet production during growth. The mechanisms may be related to the production by malignant tumors of an array of cytokines, such as IL-6, a potent stimulator of platelet production (Ray, 2000). In attempting to select chemicals from the NTP studies that might be inducers of atrial thrombosis and probably involved also in the occurrence of multiple tumors, we found and describe 3 of them next.
C.I. Acid Red 114 (Red 114)
C.I. Direct Blue 15 (Blue 15)
3,3'-Dimethoxybenzidine Dihydrochloride (DMOB)
Other Chemicals That Induced Atrial Thrombosis Related to Vascular Tumors
We could not speculate concerning the mechanism(s) of atrial thrombosis induced by 2 chemicals obtained from the NTP database and literature search, because no hematological changes or related lesions were induced.
Hexachloroethane (HCE)
Isobutene (IBT) Both of the aforementioned chemicals induced atrial thrombosis at increased incidences, compared to controls and NTP historical background data. Both HCE and IBT should be investigated further to distinguish between true and false positivity and clarify the mechanism(s) of the induction of atrial thrombosis.
Severe renal disease sometimes results in secondary myocardial fibrosis with the appearance of left atrial thrombosis in more advanced cases (Glaister, 1986; Citak et al., 2000). Researchers have speculated that lipoprotein in the human nephritic syndrome may promote thrombosis (Stenvinkel et al., 1993). Thromboembolism in patients with renal disease may be related to low levels of plasma antithrombin III and albumin and high levels of fibrinogen and cholesterol (Citak et al., 2000; Aoyagi et al., 2002). In our studies of 13 chemicals used to treat mice and rats, some compounds induced renal lesions in the same groups in which the increased incidences of atrial thrombosis occurred. The occurrence of atrial thrombosis, however, was not by itself related to chemical-induced renal lesions (data not shown). Spontaneous hippocampal neuronal necrosis that developed in aged male F344 rats used in NTP studies was reported to result from an impairment of cerebral perfusion, secondary to vascular obstruction caused by atrial thrombosis or the occurrence of leukemic cells and haemolytic anemia concomitant with mononuclear-cell leukemia, which commonly occurs in F344 rats (Barbolt and Everette, 1990). In our cases, no evidence could be discovered that atrial thrombosis was related to the occurrence of any neural lesions or leukemia induced by chemical exposure alone (data not shown).
Repeated inhalation of 3 ppm methyl isocyanate for 4 days induced left atrial thrombosis in F344 rats; dead animals exhibited severe lung toxicity (Mitsumori et al., 1987). Although this study was conducted by the NTP, we were unable to include this chemical in our investigation because of the inability to locate the study findings at the given web site Certain infectious pathogens have long been suspected of playing a role in the process leading to cardiac thromboembolic complications in humans and animals, such as acute myocarditis induced by encephalomyocarditis in mice (Tomioka et al., 1985), bacterial endocarditis or myocarditis in monkeys infected by Staphylococcus or other bacteria (Kessler and London, 1982; Wood et al., 1978), and chronic infection with Helicobactor pylori in mice resulting in increased platelet embolization after damage to mesenteric arterioles (Aguejouf et al., 2003). In our cases, no evidence was found that atrial thrombosis was related to the occurrence of systemic pathogenic infection (data not shown).
Our research suggests differing responses to chemical-induced atrial thrombosis of sex and strain of animals. The reason for the gender differences in 2-BE-induced toxicity may be different rates of production of sufficiently high levels of the hematotoxic metabolite, butoxyacetic acid (Koshkaryev et al., 2003). With respect to the strain difference of the occurrence of myocardial damage induced by CEM, the greater severity of CEM-induced heart toxicity in rats than mice may have been due to their higher rates of production of thiodiglycolic acid, a metabolite of CEM (Dunnick et al., 2004b). No data were available, however, from toxicokinetic studies of other chemicals, and differing sensitivities by sexes and strains were not described in these NTP studies. Future detailed investigations of the toxicokinetic characteristics of each chemical and its metabolite(s) are needed to clarify underlying reasons for gender and strain differences in chemically-induced atrial thrombosis.
Endothelial dysfunction is considered the major risk factor and a very early indicator of cardiovascular disease, including murine thrombosis (Carter and Gavin, 1989; Triggle et al., 2003). Impaired endothelium-dependent functions result primarily from decreased synthesis of endothelium-derived NO and/or an increase in the production of reactive oxygen species, such as superoxide (Triggle et al., 2003; Davis et al., 2004). Porcine atrial fibrillation causes a downregulation of the production of atrial eNOS and NO and a comparative increase in the expression of plasminogen activator inhibitor-1 in the left atrium during alterations comprising endocardial remodeling; these collective changes were considered one of the potential mechanisms for induction of left atrial thrombosis (Cai et al., 2002; Goette and Lendeckel, 2004). Nitric oxide also exerts powerful antithrombotic effects in atrial endothelium and causes inhibition of platelet activation (Goette and Lendeckel, 2004). We analyzed the expression of eNOS in the left atrial endocardial cells in rats exposed to 600 mg/kg CEM for 2, 3, 5, and 16 days (Figure 2a,b,c). In the endocardial cells of control rats, the mean scores were 1.7 to 2.2 (Figure 2a,b). In contrast, the scores of animals treated with CEM for 2 and 16 days decreased with statistical significance and were 1.4 and 0.7, respectively (Figure 2a,c). Histological evaluations indicating the significance of damage at these time points have been described (Dunnick et al., 2004a). In addition, atrial myocardial cells exhibited weak positivity for eNOS in some control animals (Figure 2b), similar to a localization reported previously (Balligand and Cannon, 1997). Treatment with CEM for 13 weeks induced left atrial thrombosis in rats (Table 1). Our data and review of the literature suggest that decreased expression of eNOS in atrial endocardial cells may be an important and critical factor involved in early changes leading to thrombus formation. Additional investigations are necessary to clarify the relationship(s) between eNOS expression and the induction of atrial thrombosis by the other chemicals that we have listed in this paper.
Data from the NTP rodent studies show that both spontaneously occurring and chemically inducible atrial thrombosis occurred mainly on the left side (Tables 1 and 2). Several researchers have addressed the reasons for such localization in humans and animals (Ayers and Jones, 1978; Lewis, 1992; Al-Saady et al., 1999; Bilge et al., 1999; Elwell and Mahler, 1999; Ruben et al., 2000; Cai et al., 2002). In humans, left atrial thrombosis has usually been considered the source of embolic events in acute infarction (Bilge et al., 1999), although it has been infrequently detected in the presence of sinus rhythm in the heart (Agmon et al., 2002). In canine cases, atrial thrombosis occurred as a terminal event in atrial fibrillation; the majority of cases may be attributable to eddying or stasis of blood in the atrium or its auricular appendage (Jubb and Kennedy, 1970). The incidence of thrombosis in atrial fibrillation implies a role for an atrial hemodynamic factor; atrial thrombosis has been associated with atrial fibrillation-induced structural changes in the atrium, such as decreased contraction and dilatation of the atrial appendage (Bankl et al., 1995; Al-Saady et al., 1999; Goette and Lendeckel, 2004). Approximately 90% of atrial thrombi in nonrheumatic atrial fibrillation were seen within the left atrial appendage in human patients (Al-Saady et al., 1999). Atrial fibrillation has been manifested in baseline electrocardiographs as cardiac rhythm showing irregular undulations of varying amplitude, contour, and spacing (Aronow, 2002). Also a common complication of cardiac operations leading to increased risk for thromboembolism, it is attributable to age-related structural changes in the human atrium, such as dilatation, muscular atrophy, decreased conduction throughout tissue, and fibrosis (Hogue and Hyder, 2000). The left atrial appendage, a long, tubular, hooked structure, is the remnant of the original embryonic left atrium; usually crenellated, with a narrow junction with the venous component of the atrium (Al-Saady et al., 1999); and closely related in its superior aspect to the pulmonary artery and inferomedially to the free wall of the left ventricle (Al-Saady et al., 1999; Nishimura et al., 2003). A possible reason for the onset of fibrillation may be stagnation of blood in the left atrial appendage (Suetsugu et al., 1988), which is a muscular chamber acting as a contractile pump with a characteristic pattern of contraction (Bilge et al., 1999). In rodents, this appendage appears to have a location similar to that in humans; cardiac hypertrophy occurs therein at an incidence of 77% in F344 rats aged 9 to 27 months (Boluyt et al., 1999). Local radiation administered to the rat heart induced fibrosis and thrombosis in the left atrium; considerable evidence has indicated that the left atrial appendage significantly contributes to left ventricular filling and plays a pivotal role in maintaining normal cardiac status, especially in states of cardiac disease (Kruse et al., 2001). The reason for the predilection for the appendage in atrial thrombosis may involve not only its distinctive anatomy, with the inner surface marked by muscular ridges, but also abnormalities in blood-flow patterns (Aronow, 1991; Bilge et al., 1999). Collectively, all of this information indicates that spontaneously occurring and chemical-induced murine atrial thromboses occur chiefly in the left side because of distinctive anatomical and hemodynamic characteristics of that region.
Mechanisms of putative pathogenesis of thrombosis have been indicated by several specific effects caused by thrombosis-producing compounds: endothelial damage (homocysteine, endotoxin, sodium acetriozate); alterations in pathophysiologic circulatory dynamics (ergotamine, pitressin, oral contraceptives, acetylcholine, autonomic blockers); changes in platelets (serotonin, progesterone, testosterone, somatotropic hormone, vincristine, congo red, ristocein, thrombin, epinephrine, adenosin diphosphate, Evans blue); and transformations in clotting factors (epinephrine, guanethidine, debrisoquin, thyramine, lactic acid, long-chain fatty acids, catecholamines, ACTH, thymoleptics, nictotine, oral contraceptives, mercuric chloride, corticosteroids, aminocaproic acid, aprotine) (Ramos et al., 2001). Our retrospective investigation and review of the literature suggest that endothelial injury, circulatory stasis, and/or hypercoagulability—even though indirect, or secondary, effects induced by chemicals—might predispose the individual to cardiac thrombi. The resulting impaired atrial mechanical activity, occurring as atrial fibrillation and congestive heart failure, might cause stasis of blood within the left atrium, contributing to left atrial thrombosis (Figure 3).
There are reports in the literature of human left atrial thrombosis following atrial fibrillation (Al-Saady et al., 1999; Goette and Lendeckel, 2004). No reports are available concerning the risk of heart thrombosis in humans exposed to any one of the 13 compounds that we have reported to be associated with atrial thrombosis in the NTP studies. Some COX-2-inhibitors, such as Vioxx, pose a significant risk of cardiovascular thrombotic complications (Konstam and Weir, 1999; Bing and Lomnicka, 2002; Schmidt et al., 2004). Preclinical studies of these compounds did not reveal any potential risk for development of cardiac thrombosis (U.S. FDA, 1999). Investigations are needed to elucidate the reasons for the present inability to detect potential risk of thrombotic development in laboratory animals exposed to COX-2 inhibitors. Potential factors may include suitability of the animal model, doses selected for the testing, and different mechanisms leading to development of thrombosis. Future detailed investigations of hematological and electrocardiological functions following exposure must be conducted to determine precisely which of these chemicals act as real inducers of cardiac toxicities. To concentrate on molecular functioning in such investigations could enhance understanding of the pathogenesis of chemical-induced atrial thrombosis, since the progression and risks to humans of this toxicity remain to be completely elucidated. Additional research must be completed to analyze the precise mechanism(s) of induction and provide understanding of potential extrapolations from rodents to humans of chemical-induced cardiovascular alterations.
We gratefully acknowledge Dr. Micheal P. Jokinen of Pathology Associates–A Charles River Company and Drs. June Dunnick and Robert R. Maronpot of the NIEHS for critical review of the manuscript. The authors declare that they have no competing financial interests.
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Toxicologic Pathology, Vol. 33, No. 5,
517-532 (2005)
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Abstract
Introduction
