Skip to main content


We’d like to understand how you use our websites in order to improve them. Register your interest.

Spontaneously occurring cardiovascular lesions in commonly used laboratory animals


The search for new chemical entities which are clinically effective and do not adversely affect the cardiovascular system is an ongoing objective. In vivo studies designed to detect potential drug-induced cardiovascular toxicity typically utilize both rodent and non-rodent species. An important component of such studies includes the microscopic evaluation of tissues for histopathologic changes. A factor which could potentially complicate this type of evaluation relates to the potential for laboratory animals to develop natural or spontaneous pathological cardiovascular lesions. Some types of these naturally occurring alterations are similar to those induced by chemical compounds and thus could confound accurate interpretation. Accurate morphologic analysis becomes contingent upon the ability to distinguish spontaneous cardiovascular changes from actual drug-induced lesions. A summary of some of the more frequently reported spontaneous cardiovascular alterations in commonly-used laboratory animals is presented below. Special emphasis is given to the spectrum of spontaneous background myocardial pathology that might be encountered during preclinical studies conducted to identify potential cardiotoxic actions of anticancer agents.


The initial search for new, effective, and safe therapeutic agents involves the evaluation of drug activity in various animal models. Preclinical studies, as part of this process, have played an important role in identifying and elaborating the characteristics of drug-induced toxicity. These studies, undertaken in multiple species, include a portion that is designed to detect an agent’s potential for exerting adverse cardiovascular toxicity. Cardiotoxicity has been identified as a major adverse dose-limiting side effect associated with a number of chemotherapeutic agents. The first reports indicating that cardiotoxicity could pose a serious clinical problem to patients undergoing chemotherapy were reported with the anthracycline antineoplastic agents daunorubicin [1] and doxorubicin [2]. Initially, anthracyclines were responsible for the majority of chemotherapy-induced cardiotoxic reports. However, over the years additional research has led to an increase in the number and types of antineoplastic agents available for use (monoclonal antibodies, immune checkpoint inhibitors, protein kinase inhibitors). Correspondingly, many of these agents have been associated with chemotherapy-related adverse cardiovascular effects [3,4,5,6]. A variety of chemotherapeutic compounds have also been found to induce cardiac alterations in preclinical studies (Table 1).

Table 1 Cardiotoxic Effects of Selected Chemotherapeutic Agents in Animals

Even though the animals usually selected to be used in preclinical studies are young and healthy, there are reports that indicate some of these normal nontreated animals are prone to develop abnormal cardiovascular alterations. Such spontaneously occurring pathological lesions may confound cardiovascular safety assessments [29, 30]. In such cases, accurate pathologic analysis becomes contingent on the ability to distinguish spontaneous cardiovascular changes from actual drug-induced lesions. Some lesions might mimic those induced by chemical compounds and thus might compromise the interpretation of cardiotoxicity studies, particularly if the lesions are similar to those induced by test agents. An example of a possible spontaneous lesion complication is rodent progressive cardiomyopathy, which occurs spontaneously in young and old animals and that may be exacerbated by drug treatment or even mimic drug-induced injury [31, 32].

Here we present an overview of some cardiovascular lesions that spontaneously occur in the species most commonly utilized in animal research and toxicity testing. Special emphasis has been given to the spectrum of spontaneous background myocardial pathology that might be encountered during preclinical studies initiated to identify potential cardiotoxic actions of anticancer agents.


Rodent progressive cardiomyopathy

Evidence of spontaneous cardiomyopathy has been reported in at least two common strains of mice (BALBc/Cr and B6C3f1) [32,33,34,35,36]. Early morphologic changes consisted of myocyte degeneration and necrosis without concomitant inflammatory infiltrates and fibrosis. In some instances, the only discernible alteration was a few small, irregular foci of fibrosis [32,33,34,35], most often in the wall of the left ventricle and interventricular septum. The lesions were generally not severe but could have become so with age.

Myocardial mineralization

Myocardial mineralization has been reported in various inbred mouse strains (DBA/2, C, C3H, BALB/c, A, CBA, and CHI) [37]. Mineralization was detectable as early as 1 month after birth. The primary location varied by strain: the epicardium in BALB/c, the myocardium in C3H and C3Hf, and the epicardium and myocardium of the right ventricle in DBA/2 [37]. These mineralization’s have been called several names, with dystrophic cardiac calcinosis or mineralization being the most common. The frequency and severity of mineralization in these animals can be influenced by age, sex, diet, and number of pregnancies [37,38,39,40]. The cause has been ascribed to focal myocyte necrosis [37], spontaneous myocarditis [41], and innate immunologic activity [39]. Macroscopically, some instances of epicardial and myocardial mineralization appear as multiple small, white-to-yellow specks [37]. Microscopically, areas of mineralization can contain prominent eosinophilic infiltrates [41]. Calcified lesions in BALB/cByJ mouse hearts also included immune cells, collagen fibers, and degenerating myocytes [39]. Myocardial mineralization can possibly occur as a result of alterations in other organs such as the kidney [30].

Atrial thrombosis

Atrial thrombosis occasionally occurs spontaneously in certain strains of mice (BALB/c, TS, RF, C, DBA) [37, 42]. The atria appear grossly swollen, firm, and mottled. A gray-to-tan thrombus in these atria can vary from recently formed layers of thrombin to older, organized thrombi with fibrous connective tissue [37]. Some thrombi may extend into the orifice of the mitral valve. Thrombi appear to develop more often in the left atria but can occur in both atria [37]. In mice, atrial thrombi can be influenced by heredity, sex, age, diet, and number of pregnancies [37]. Atrial thrombosis has also been observed in mice treated with the antineoplastic agent, doxorubicin [13, 43].

Vascular injury

Spontaneous systemic vascular injury (synonyms for vascular injury include vasculitis, arteritis, polyarteritis, periarteritis, and necrotizing arteritis) occurs in both inbred and outbred strains of mice. Vascular injury is a conspicuous morphologic finding in most murine models susceptible to autoimmune disorders (MRL/lpr, NZB, NZB/W, BXSB, and SNF1) [44]. In MRL/lpr mice, inflammatory vascular lesions spontaneously develop in lymphoid and other tissues [44]. These lesions are located mainly in small and medium-sized muscular arteries and are described as a necrotizing arteritis or necrotizing polyarteritis with a component of fibrinoid necrosis [45]. Initially, neutrophilic granulocytes accumulate near necrotic vessel walls. Subsequently, histocytes, lymphocytes, and fibroblasts appear in the medial and adventitial portions of the affected vessels. The lesions can be present in many tissues but are most consistently found in the kidney and urinary bladder. The necrotizing vasculitis in MRL mice is morphologically similar to the polyarteritis nodosa in humans with systemic lupus erythematosus [45].

Spontaneous vascular injury has been observed in 10 to 55% of BALBc mice [46], where it is mainly confined to the base of the aorta. The prevalence can be affected by diet, sex, and age [30]. The incidence of arterial lesions (necrotizing polyarteritis) was associated with elevated blood pressure in eight inbred strains and one random-bred group of mice [47].


Rodent progressive cardiomyopathy

Rats are susceptible to several naturally occurring myocardial degenerative alterations (myocyte degeneration or necrosis, inflammation, and fibrosis) that meet the definition of cardiomyopathy. These spontaneous alterations occur at varying degrees of incidence and severity in common strains of rats [31, 32, 35, 48, 49].

Spontaneous progressive cardiomyopathy was first thought to appear in rats that were at least one year of age [50]. However, spontaneous myocardial lesions have been detected in animals as young as 3 months old [48, 51]. These lesions tend to be more prevalent in hypertensive rats, in which they become more severe with age, and the incidence is higher in males than females [32, 51]. Morphologic changes typically follow a pattern that begins with focal to multifocal myocyte degeneration and necrosis, varying degrees of inflammation and interstitial cell infiltration, and ultimately, fibrosis. Inflammatory lesions are more common in younger rats, whereas fibrotic lesions are more common in older ones [32, 35, 48]. The most common sites of these spontaneous myocardial alterations reported by Chanut, et al. were the left ventricle, right ventricle and septum [48] and the papillary muscles, the subendocardial areas of the left ventricle, and the septum [32, 35, 51].

Left ventricular hypertrophy

Left ventricular wall thickness and left ventricular chamber size can vary between strains. For example, wall thickness was increased, and chamber size decreased in hearts from Sprague-Dawley compared to hearts from Lewis rats [49]. These differences appear related to myocyte dimensions as myocyte cell size in hearts from Sprague-Dawley rats are larger than those in Lewis rats [49]. Left ventricular hypertrophy was detected in 38% of the 104 Sprague-Dawley rats and 13% of the 64 Lewis rats studied. Spontaneous left ventricular hypertrophy occurred in animals that were less than 3 months old.

Endomyocardial fibrosis

Rats appear to be susceptible to a proliferative form of left ventricular subendocardial fibrosis [52]. Macroscopically, the affected subendocardial surface appears white and thickened. Microscopically, the lesion consists of a proliferation of fibroblast-like cells that are often confined to, or that are more severe in, the left ventricle [37, 52]. The incidence of endomyocardial lesions is 1 to 7% in several strains of rats and is higher in older animals [37].

Myocardial mineralization

Mineral deposition has been reported to occur in association with aging in many strains of mice and rats, most frequently following injury to the myocardium [30]. Myocardial mineralization has been observed to commence by 6 months of age in Fisher rats [53]. Myocardial mineralization can occur simultaneously with progressive cardiomyopathy or as a result of advanced renal disease [30]. The initiating factor might involve a systemic calcium-phosphorus imbalance [30].

Necrotizing Vasculitis

Spontaneous vascular alterations with varying incidence and anatomic distribution have been described in certain strains of rats, including spontaneous hypertensive rats [54]. This vascular lesion is more prevalent in males and appears as a degenerative necrotizing arteritis and polyarteritis nodosa that affects the small and medium-sized arteries in a variety of tissues, especially the mesentery, testes, and pancreas [30]. The pathogenesis of the necrotizing vasculitis has not been defined but might be initiated by immune complex deposition [54]. Characteristics include focal fibrinoid necrosis associated with inflammation, endothelial proliferation, and disruption or duplication of the elastic lamina [30]. The incidence of these vascular alterations can be influenced by diet, sex, age, and arterial pressure [30].


Chronic Valvular disease

Chronic valvular heart disease, also referred to as endocardiosis or myxomatous valve degeneration, is a common myocardial lesion in dogs [55, 56]. The atrioventricular valves, especially the mitral valve fibrosa, are most often affected [55,56,57,58,59]. Male and smaller breeds of dogs are more susceptible [57]. The cellular constituents and intracellular matrix of the valvular apparatus (valve leaflets and chordate tendineae) are altered. Initially, fibroelastic proliferation causes mild nodular thickening of the leaflets [58]. The severity of nodular thickening, which can occur in both the mitral and aortic valves, increases with age and is thought to be caused by the normal hemodynamic action of the heart. In most instances, these alterations are not clinically important [58]. A more ominous change is mucoid degeneration of the valvular leaflets. Water and stainable mucopolysaccharides accumulating on leaflet cells is an early indication of this lesion [56]. Over time, degenerative changes can result in ballooning of the cusp, mitral incompetence, and clinically important congestive heart failure [58]. The incidence of this disease is thought to increase with age. However, early valvular changes have been observed in 1-year-old dogs and in both young and adult beagle dogs [56, 60]. The causes and pathogenesis of spontaneous chronic valvular lesions in dogs is not fully understood.

Dilated cardiomyopathy

Spontaneous dilated (congestive) cardiomyopathy has been observed in dogs [61], more commonly in large-breed, middle-aged, male dogs [37]. The primary characteristics are ventricular dilatation and systolic pump failure [37]. The most common functional abnormalities are a rapid and irregular heart rate and congestive heart failure [61, 62]. Clinical signs include ascites, weight loss, weakness, and cough [62]. Macroscopically, the four chambers of the heart are dilated and enlarged. The ventricular walls are thin and contain small atrophic papillary muscles [62]. Microscopically, scattered foci of necrosis (especially near the left ventricular papillary muscles) and fibrosis can be observed [62]. In many cases, the factors provoking dilated cardiomyopathy are not obvious.

Cardiac hypertrophy

Cardiac hypertrophy occurs occasionally in various breeds of dogs and may be present without clinical signs [37]. This condition occurs most commonly in male dogs [36]. Necropsy findings in 10 dogs with naturally occurring cardiac disease closely resembled hypertrophic cardiomyopathy in humans [63]. Microscopic findings included ventricular hypertrophy, decreased left ventricular cavity size, and left atrial dilatation [63,64,65]. Symmetric septal hypertrophy was a common finding [64, 65].

Myocardial inflammation and necrosis

Spontaneously occurring necrotic lesions have been observed in the myocardia of beagle dogs. In 50 dogs ranging from less than 1 year to more than 5 years old, foci of degenerate or necrotic myocytes were found in 9 [66]. In 160 healthy control beagle dogs 9 to 20 months old, small areas of myocardial inflammation were found in 5% of males and in 2% of females [67]. Other alterations, which were not severe, included myxomatous (cartilaginous) changes in the cardiac skeleton (at the base of the heart) and variable degrees of Purkinje fiber vacuolation. Spontaneous myocardial lesions in control animals were not confined to any specific region of the heart [30, 67, 68].

Spontaneous vascular lesions

Background vascular lesions have been noted in healthy, non-treated beagle dogs [30]. The main morphological categories of spontaneous arterial lesions are degenerative, proliferative, or inflammatory [69]. In many instances, the frequency and severity of degenerative and proliferative arterial lesions increase with age or with diseases, such as those caused by infectious agents [69, 70]. However, acute and chronic systemic polyarteritis can occur spontaneously with no apparent cause. This type of vascular lesion has also been called idiopathic arteritis, polyarteritis, periarteritis, panarteritis, systemic vasculitis, perivascular vasculitis, necrotizing vasculitis, beagle pain syndrome, and idiopathic febrile necrotizing arteritis [70].

Beagle pain polyarteritis syndrome affects the small-to-medium muscular arteries in several organs, including the heart [70]. The most commonly affected cardiovascular site is the right coronary artery [70, 71]. Acute vascular changes range from histiocytic-lymphocytic periarterial infiltration to transmural neutrophilic inflammation with fibrinoid necrosis [71]. Subacute and chronic lesions show intimal hyperplasia with varying levels of ruptured internal elastic laminae and perivascular inflammatory cell infiltration [71]. Necrotic or inflammatory foci have also been noted in small, stenotic, intramyocardial arteries, as well as at sites where vessel blockage restricted blood flow into large branches of the coronary arteries [55].

The incidence of spontaneous arteritis in beagle dogs ranges from 3% to more than 30% [72, 73]. In another study, healthy control dogs had a very low incidence (1/103 and 1/98 in male and female dogs, respectively) of coronary artery alterations [67]. The incidence of arteritis appears to be slightly higher in males [73, 74].

Miniature pigs


The incidence of spontaneous hypertrophic cardiomyopathy is 5 to 23% in several breeds of pigs [75]. The condition in pigs is in many ways morphologically and biochemically similar to that in humans [76]. These similarities include increased heart weight, thickening of the left and right ventricular free walls and septum (increased collagen matrix), disorientation of myocytes, myocardial fibrosis, and abnormalities in intramural coronary arteries [75, 77].

Congestive cardiomyopathy has also been observed in pigs [78]. Affected animals had concomitant conditions, such as aortic stenosis, pericarditis, and endocarditis, which may have contributed to a congestive cardiomyopathy-like syndrome. A similar type of spontaneous cardiomyopathy has not been detected in Göttingen miniature pigs [79].

Myocardial lesions

Spontaneous cardiac lesions in Göttingen mini pigs are rare. A comprehensive cardiac evaluation of 835 untreated control Göttingen mini pigs found one animal, or at most only a few, with myocarditis, inflammatory necrosis, pericarditis, epicardial or subepicardial edema, focal fibrosis, hemorrhage, arteritis or periarteritis, focal mineralization, or focal mononuclear cell infiltration [79].

Vascular lesions

Older pigs are prone to atherosclerosis (mainly in the elastic arteries and medium-to-large muscular arteries, such as the coronary arteries) [37]. Several inflammatory diseases affecting pigs are associated with an arteritis or vasculitis syndrome. This syndrome begins as acute necrosis of the tunica media (in the arteries and small arterioles) and progresses to thrombosis and infarcts in a variety of organs [80]. Background vascular alterations in healthy Göttingen mini pigs are generally focal and mild [79, 81]. Spontaneous arteritis in the small-to-medium arterioles and arteries has been detected in Göttingen mini pigs with idiopathic thrombocytopenia [80]. In some instances, these lesions had progressed to necrosis of the tunica media, thrombosis, and concentric laminar thickening of vascular walls that caused myocardial infarction [80].


Myocardial alterations

Spontaneous myocardial alterations have been observed in the hearts from untreated control monkeys (cynomolgus, marmoset, and rhesus) [67, 82, 83]. The two most commonly reported myocardial alterations are focal inflammatory cell infiltrate (minimal to mild) and focal myocarditis (minimal to moderate). The inflammatory infiltrate consists of single or multiple aggregates of mononuclear cells (mainly lymphocytes) scattered throughout the myocardium (mainly the interstitium, perivascular spaces, or subepicardial or epicardial fat tissue) and that appeared to be unrelated to any specific myocyte injury [67, 82, 83]. Focal myocarditis, a second, less-common lesion, was characterized by mild-to-moderate aggregates of mixed inflammatory cells (granulocytes, macrophages, and lymphocytes). Focal myocarditis occurred at sites of myocyte injury (necrosis, karyomegaly, fibrin deposition). Both the inflammatory cell infiltration and the focal myocarditis were primarily in the subendocardial and subepicardial areas of the heart, including the base of the dorsal papillary muscle [82, 83].

Anisokaryosis and karyomegaly of cardiac myocyte nuclei have been found primarily in the left ventricle and intraventricular septum. Most of these nuclear changes were not prominent [67, 84].

Spontaneously occurring myocardial cell necrosis has been detected in experimental (20%) and breeding primates (30%) (Macaca nemestrina and Macaca fascicularis) [85]. Morphologic changes included multifocal areas of myocardial necrosis with concurrent lymphocytic infiltration. Both acute and chronic necrotic lesions were present, implying that the pathogenic process was either continuous or involved multiple components. This type of lesion might be induced by the stress-associated release of catecholamines that can occur with routine handling of the monkeys during experimental procedures [86]. The histologic characteristics of the lesion were similar to the necrotic alterations reported in monkeys after catecholamine administration [87].

The impact of the geographic source of cynomolgus macaque on differences in spontaneous cardiac pathology and response to xenobiotics revealed a novel spectrum of cardiac findings in Mauritian-source animals that had not been observed in Indonesian-source cynomolgus macaques [88]. When compared to predominantly Indonesian macaques, a higher incidence of myocardial degeneration was observed with additional novel findings including macroscopic and microscopic subendocardial hemorrhage with hemosiderin, myocardial fibrosis, and arterial medial degeneration/hemorrhage. Other findings including inflammatory cell infiltrates, anisokaryosis, and squamous plaques were observed with a comparable incidence as reported in Indonesian macaques [67]. Myocardial degeneration, subendocardial hemorrhage, and myocardial fibrosis can mimic test-article-related cardiac toxicity; therefore, a thorough understanding of the incidence and severity of spontaneously occurring cardiac lesions is necessary to prevent misidentifying test-article-related cardiac findings in different genetic sources of cynomolgus macaques in nonclinical safety testing.

Alterations such as myocardial mineralization, endocarditis, pericarditis, myocardial fibrosis, extramedullary hematopoiesis, squamous plaques, squamous epithelial plaques, and ectopic thyroid tissue have a low incidence in monkeys [67, 82, 83]. Spontaneous myocardial lesions have also been reported in baboon and chimpanzee hearts [89, 90].

Vascular lesions

Spontaneous vascular lesions have been reported in healthy monkeys. The accumulation of mucopolysaccharides (without lipid accumulation) in the intima of the aorta or coronary arteries (cynomolgus, marmoset, and rhesus) was a common incidental finding in untreated control cynomolgus monkeys [82]. The incidence of coronary arteritis was reported to be minimal in cynomolgus monkeys (0.5%) [82, 91].


Differentiating drug-induced structural changes in cardiovascular tissues from naturally occurring cardiovascular lesions in laboratory animals is essential in preclinical safety testing of new drugs. We hope this review will raise awareness of spontaneously occurring cardiovascular lesions observed in commonly used laboratory animals and aid pathologists and toxicologists in their safety assessments during drug development.


  1. 1.

    Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA. Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia. Cancer. 1967;20(3):333–53.

  2. 2.

    Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973;32(2):302–14.

  3. 3.

    Babiker HM, McBride A, Newton M, Boehmer LM, Drucker AG, Gowan M, et al. Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system. Crit Rev Oncol Hematol. 2018;126:186–200.

  4. 4.

    Han X, Zhou Y, Liu W. Precision cardio-oncology: understanding the cardiotoxicity of cancer therapy. NPJ Precis Oncol. 2017;1(1):31.

  5. 5.

    Lee CS. Mechanisms of Cardiotoxicity and the Development of Heart Failure. Crit Care Nurs Clin North Am. 2015;27(4):469–81.

  6. 6.

    Stellitano A, Fedele R, Barilla S, Iaria A, Rao CM, Martino M. Chemotherapy and Cardiotoxicity in Hematologic Malignancies. Curr Cancer Drug Targets. 2017;17(4):311–24.

  7. 7.

    Fedele C, Riccio G, Coppola C, Barbieri A, Monti MG, Arra C, et al. Comparison of preclinical cardiotoxic effects of different ErbB2 inhibitors. Breast Cancer Res Treat. 2012;133(2):511–21.

  8. 8.

    Wolf A, Couttet P, Dong M, Grenet O, Heron M, Junker U, et al. Preclinical evaluation of potential nilotinib cardiotoxicity. Leuk Res. 2011;35(5):631–7.

  9. 9.

    Herman EH, Knapton A, Rosen E, Thompson K, Rosenzweig B, Estis J, et al. A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat. Toxicol Pathol. 2011;39(7):1091–106.

  10. 10.

    Cooper S, Sandhu H, Hussain A, Mee C, Maddock H. Ageing alters the severity of Sunitinib-induced cardiotoxicity: Investigating the mitogen activated kinase kinase 7 pathway association. Toxicology. 2019;411:49–59.

  11. 11.

    Lim AY, Segarra I, Chakravarthi S, Akram S, Judson JP. Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice. BMC Pharmacol. 2010;10:14.

  12. 12.

    Ozkan G, Ulusoy S, Alkanat M, Orem A, Akcan B, Ersoz S, et al. Antiapoptotic and antioxidant effects of GSPE in preventing cyclosporine A-induced cardiotoxicity. Ren Fail. 2012;34(4):460–6.

  13. 13.

    Fujihira S, Yamamoto T, Matsumoto M, Yoshizawa K, Oishi Y, Fujii T, et al. The high incidence of atrial thrombosis in mice given doxorubicin. Toxicol Pathol. 1993;21(4):362–8.

  14. 14.

    Agen C, Bernardini N, Danesi R, Della Torre P, Costa M, Del Tacca M. Reducing doxorubicin cardiotoxicity in the rat using deferred treatment with ADR-529. Cancer Chemother Pharmacol. 1992;30(2):95–9.

  15. 15.

    Herman EH, Ferrans VJ. Preclinical animal models of cardiac protection from anthracycline-induced cardiotoxicity. Semin Oncol. 1998;25(4 Suppl 10):15–21.

  16. 16.

    O'Connell JL, Romano MM, Campos Pulici EC, Carvalho EE, de Souza FR, Tanaka DM, et al. Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes. Exp Toxicol Pathol. 2017;69(4):213–9.

  17. 17.

    Duran JM, Makarewich CA, Trappanese D, Gross P, Husain S, Dunn J, et al. Sorafenib cardiotoxicity increases mortality after myocardial infarction. Circ Res. 2014;114(11):1700–12.

  18. 18.

    Zhang P, Yi LH, Meng GY, Zhang HY, Sun HH, Cui LQ. Apelin-13 attenuates cisplatin-induced cardiotoxicity through inhibition of ROS-mediated DNA damage and regulation of MAPKs and AKT pathways. Free Radic Res. 2017;51(5):449–59.

  19. 19.

    Bahadýr A, Ceyhan A, Öz Gergin Ö, Yalçýn B, Ülger M, Özyazgan TM, et al. Protective effects of curcumin and beta-carotene on cisplatin-induced cardiotoxicity: An experimental rat model. Anatol J Cardiol. 2018;19(3):213–21.

  20. 20.

    Lian Y, Gao L, Guo P, Zhao Y, Lin T. Grape Seed Proanthocyanidins Extract Prevents Cisplatin-induced Cardiotoxicity in Rats. Food Science and Technology Research. 2016;22(3):403–8.

  21. 21.

    El-Agamy DS, Elkablawy MA, Abo-Haded HM. Modulation of cyclophosphamide-induced cardiotoxicity by methyl palmitate. Cancer Chemother Pharmacol. 2017;79(2):399–409.

  22. 22.

    Kumar S, Gupta RK, Bhake AS, Samal N. Cardiotoxic effects of high doses of cyclophosphamide in albino rats. Arch Int Pharmacodyn Ther. 1992;319:58–65.

  23. 23.

    O'Connell TX, Berenbaum MC. Cardiac and pulmonary effects of high doses of cyclophosphamide and isophosphamide. Cancer Res. 1974;34(7):1586–91.

  24. 24.

    Kumar S, Gupta RK, Samal N. 5-fluorouracil induced cardiotoxicity in albino rats. Mater Med Pol. 1995;27(2):63–6.

  25. 25.

    Tsibiribi P, Bui-Xuan C, Bui-Xuan B, Lombard-Bohas C, Duperret S, Belkhiria M, et al. Cardiac lesions induced by 5-fluorouracil in the rabbit. Hum Exp Toxicol. 2006;25(6):305–9.

  26. 26.

    Keirstead ND, Bertinetti-Lapatki C, Knapp D, Albassam M, Hughes V, Hong F, et al. Temporal Patterns of Novel Circulating Biomarkers in IL-2-mediated Vascular Injury in the Rat. Toxicol Pathol. 2015;43(7):984–94.

  27. 27.

    Tochinai R, Ando M, Suzuki T, Suzuki K, Nagata Y, Hata C, et al. Histopathological studies of microtubule disassembling agent-induced myocardial lesions in rats. Exp Toxicol Pathol. 2013;65(6):737–43.

  28. 28.

    Al-Harbi NO. Carfilzomib-induced cardiotoxicity mitigated by dexrazoxane through inhibition of hypertrophic gene expression and oxidative stress in rats. Toxicol Mech Methods. 2016;26(3):189–95.

  29. 29.

    Berridge BR, Van Vleet JF, Herman E. Chapter 46 - Cardiac, Vascular, and Skeletal Muscle Systems A2 - Haschek, Wanda M. In: Rousseaux CG, Wallig MA, editors. Haschek and Rousseaux's Handbook of Toxicologic Pathology. 3rd ed. Boston: Academic Press; 2013. p. 1567–665.

  30. 30.

    Greaves P. Chapter 7 - Cardiovascular System. In: Greaves P, editor. Histopathology of Preclinical Toxicity Studies (Fourth Edition). Boston: Academic Press; 2012. p. 263–324.

  31. 31.

    Hailey JR, Maleeff BE, Thomas HC, Pearse G, Klapwijk JC, Cristofori PG, et al. A Diagnostic Approach for Rodent Progressive Cardiomyopathy and Like Lesions in Toxicology Studies up to 28 Days in the Sprague Dawley Rat (Part 1 of 2). Toxicol Pathol. 2017;0192623317743938.

  32. 32.

    Jokinen M, Lieuallen W, Johnson C, Dunnick J, Nyska A. Characterization of spontaneous and chemically induced cardiac lesions in rodent model systems: the national toxicology program experience. Cardiovasc Toxicol. 2005;5(2):227–44.

  33. 33.

    Bellini O, Casazza AM, DiMarco A. Histological and histochemical studies of myocardial lesions in BALBc/Cr mice. Lab Anim Sci. 1976;26:329–33.

  34. 34.

    Elwell MR, Mahler JF. Heart, blood vessels and lymphatics. In: Maronpot R, Boorman G, Gaul B, editors. Pathology of the Mouse Reference and Atlas. Vienna, IL: Cache River Press; 1999.

  35. 35.

    Jokinen MP, Lieuallen WG, Boyle MC, Johnson CL, Malarkey DE, Nyska A. Morphologic Aspects of Rodent Cardiotoxicity in a Retrospective Evaluation of National Toxicology Program Studies. Toxicol Pathol. 2011;39(5):850–60.

  36. 36.

    Ruben Z, Arceo RJ, Bishop SP, Elwell MR, Kerns WD, Mesfin GM, et al. Non-proliferative Lesions of the Heart and Vasculature in Rats. Guides for Toxicologic Pathology. Washington, DC: STP/ARP/AFIP; 2000. (photomicrographs)

  37. 37.

    Van Vleet JF, Ferrans VJ. Myocardial diseases of animals. Am J Pathol. 1986;124(1):98–178 (photomicrographs).

  38. 38.

    Eaton GJ, Custer RP, Johnson FN, Stabenow KT. Dystrophic cardiac calcinosis in mice: genetic, hormonal, and dietary influences. Am J Pathol. 1978;90(1):173–86 (photomicrographs).

  39. 39.

    Glass AM, Coombs W, Taffet SM. Spontaneous cardiac calcinosis in BALB/cByJ mice. Comp Med. 2013;63(1):29–37 (photomicrographs).

  40. 40.

    Maeda N, Doi K, Mitsuoka T. Development of heart and aortic lesions in DBA/2NCrj mice. Lab Anim. 1986;20(1):5–8 (photomicrographs).

  41. 41.

    Hirasawa M, Kitaura Y, Deguchi H, Ukimura A, Kawamura K. Spontaneous myocarditis in DBA/2 mice. Light microscopic study with transmission and X-ray analytical electron microscopic studies. Virchows Arch. 1998;432(5):461–8 (photomicrographs).

  42. 42.

    Fry RJ, Hamilton KH, Lisco H. Thrombi in the Left Atrium of the Heart in Mice. Arch Pathol. 1965;80:308–13 (photomicrographs).

  43. 43.

    Solcia E, Ballerini L, Bellini O, Magrini U, Bertazzoli C, Tosana G, et al. Cardiomyopathy of doxorubicin in experimental animals, Factors affecting the severity, distribution and evolution of myocardial lesions. Tumori. 1981;67(5):461–72 (photomicrographs).

  44. 44.

    Luzina IG, Handwerger BS. Lessons from animal models of vasculitis. Curr Rheumatol Rep. 2000;2(5):369–75 (photomicrographs).

  45. 45.

    Hewicker M, Trautwein G. Sequential study of vasculitis in MRL mice. Lab Anim. 1987;21(4):335–41 (photomicrographs).

  46. 46.

    Ramot Y, Manno RA, Okazaki Y, Krakovsky M, Lamensdorf I, Meiron M, et al. Spontaneous aortitis in the Balb/c mouse. Toxicol Pathol. 2009;37(5):667–71 (photomicrographs).

  47. 47.

    Mullink JWMA, Haneveld GT. Polyarteritis in mice due to spontaneous hypertension. J Comp Pathol. 1979;89(1):99–106 (photomicrographs).

  48. 48.

    Chanut F, Kimbrough C, Hailey R, Berridge B, Hughes-Earle A, Davies R, et al. Spontaneous Cardiomyopathy in Young Sprague-Dawley Rats: Evaluation of Biological and Environmental Variability. Toxicol Pathol. 2013;41(8):1126–36 (photomicrographs).

  49. 49.

    McAdams RM, McPherson RJ, Dabestani NM, Gleason CA, Juul SE. Left Ventricular Hypertrophy is Prevalent in Sprague–Dawley Rats. Comp Med. 2010;60(5):357–63 (photomicrographs).

  50. 50.

    Anver MR, Cohen BJ, Lattuada CP, Foster SJ. Age-associated lesions in barrier-reared male Sprague-Dawley rats: a comparison between Hap: (SD) and Crl:COBS [R]CD[R](SD) stocks. Exp Aging Res. 1982;8(1 Pt 1):3–24.

  51. 51.

    Ruben Z, Miller JE, Rohrbacher E, Walsh GM. A potential model for a human disease: spontaneous cardiomyopathy-congestive heart failure in SHR/N-cp rats. Hum Pathol. 1984;15(10):902–3.

  52. 52.

    Boorman GA, Zurcher C, Hollander CF, Feron VJ. Naturally occurring endocardial disease in the rat. Arch Pathol. 1973;96(1):39–45 (photomicrographs).

  53. 53.

    Mackenzie WF, Alison RH. Heart. In: Boorman GA, Eustis SL, Elwell MR, Mongtgomery Jr CA, editors. Pathology of the Fischer Rat. San Diego, CA: Academic Press; 1990. p. 469–71. (photomicrographs).

  54. 54.

    Bishop SP. Animal models of vasculitis. Toxicol Pathol. 1989;17(1 Pt 2):109–17. (photomicrographs).

  55. 55.

    Luginbuhl H, Detweiler DK. Cardiovascular lesions in dogs. Ann N Y Acad Sci. 1965;127(1):517–40.

  56. 56.

    Wagner BM. Myocardial disease in man and dog, some properties. Ann N Y Acad Sci. 1968;147(8):354–62 (photomicrographs).

  57. 57.

    Atkins C, Bonagura J, Ettinger S, Fox P, Gordon S, Haggstrom J, et al. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med. 2009;23(6):1142–50.

  58. 58.

    Pomerance A, Whitney JC. Heart valve changes common to man and dog: a comparative study. Cardiovasc Res. 1970;4(1):61–6 photomicrographs.

  59. 59.

    Zook BC. Some spontaneous cardiovascular lesions in dogs and cats. Adv Cardiol. 1974;13:148–68.

  60. 60.

    Zaldivar R. Incidence of spontaneous diseases in a Beagle colony. J Am Vet Med Assoc. 1967;151(9):1186–9.

  61. 61.

    Freeman LM, Rush JE. Nutrition and cardiomyopathy: lessons from spontaneous animal models. Curr Heart Fail Rep. 2007;4(2):84–90.

  62. 62.

    Sandusky GE Jr, Capen CC, Kerr KM. Histological and ultrastructural evaluation of cardiac lesions in idiopathic cardiomyopathy in dogs. Canadian journal of comparative medicine Revue canadienne de medecine comparee. 1984;48(1):81–6. (photomicrographs).

  63. 63.

    Liu SK, Maron BJ, Tilley LP. Canine hypertrophic cardiomyopathy. J Am Vet Med Assoc. 1979;174(7):708–13 (photomicrographs).

  64. 64.

    Liu SK, Maron BJ, Tilley LP. Hypertrophic cardiomyopathy in the dog. Am J Pathol. 1979;94(3):497–508 (photomicrographs).

  65. 65.

    Liu SK, Tilley LP. Animal models of primary myocardial diseases. Yale J Biol Med. 1980;53(3):191–211 (photomicrographs).

  66. 66.

    Oghiso Y, Fukuda S, Iida H. Histopathological studies on distribution of spontaneous lesions and age changes in the beagle. Nihon juigaku zasshi The Japanese journal of veterinary science. 1982;44(6):941–50. (photomicrographs).

  67. 67.

    Keenan CM, Vidal JD. Standard morphologic evaluation of the heart in the laboratory dog and monkey. Toxicol Pathol. 2006;34(1):67–74 (photomicrographs).

  68. 68.

    Hottendorf GH, Hirth RS. Lesions of spontaneous subclinical disease in Beagle dogs. Vet Pathol. 1974;11(3):240–58.

  69. 69.

    Kelly DF. Classification of naturally occurring arterial disease in the dog. Toxicol Pathol. 1989;17(1 Pt 2):77–93.

  70. 70.

    Clemo FA, Evering WE, Snyder PW, Albassam MA. Differentiating spontaneous from drug-induced vascular injury in the dog. Toxicol Pathol. 2003;31(Suppl):25–31.

  71. 71.

    Snyder PW, Kazacos EA, Scott-Moncrieff JC, HogenEsch H, Carlton WW, Glickman LT, et al. Pathologic features of naturally occurring juvenile polyarteritis in beagle dogs. Vet Pathol. 1995;32(4):337–45 (photomicrographs).

  72. 72.

    Hartman HA. Spontaneous extramural coronary arteritis in dogs. Toxicol Pathol. 1989;17(1 Pt 2):138–44. (photomicrographs).

  73. 73.

    Son WC. Idiopathic canine polyarteritis in control beagle dogs from toxicity studies. J Vet Sci. 2004;5(2):147–50 (photomicrographs).

  74. 74.

    Spencer A, Greaves P. Periarteritis in a beagle colony. J Comp Pathol. 1987;97(2):121–8 (photomicrographs).

  75. 75.

    S-k L, Chiu YT, Shyu JJ, Factor SM, Chu R, Lin JH, et al. Hypertrophic cardiomyopathy in pigs: quantitative pathologic features in 55 cases. Cardiovasc Pathol. 1994;3(4):261–8 (photomicrographs).

  76. 76.

    Lin JH, Huang SY, Lee WC, Liu SK, Chu RM. Echocardiographic features of pigs with spontaneous hypertrophic cardiomyopathy. Comp Med. 2002;52(3):238–42 (photomicrographs).

  77. 77.

    Chiu YT, Liu SK, Liu M, Chen SP, Lin YH, Mao SJ, et al. Characterization and quantitation of extracellular collagen matrix in myocardium of pigs with spontaneously occurring hypertrophic cardiomyopathy. Cardiovasc Pathol. 1999;8(3):169–75 (photomicrographs).

  78. 78.

    Hsu FS. Du S-J. Cardiac diseases in swine. In: Roberts HR, Dodds WJ, editors. Pig Model for Biomedical Research. Taiwan, Republic of China: Pig Research Institute; 1982. p. 134–43.

  79. 79.

    Jeppesen G, Skydsgaard M. Spontaneous Background Pathology in Göttingen Minipigs. Toxicol Pathol. 2014:1–10 (photomicrographs).

  80. 80.

    Maratea KA, Snyder PW, Stevenson GW. Vascular lesions in nine Gottingen minipigs with thrombocytopenic purpura syndrome. Vet Pathol. 2006;43(4):447–54 (photomicrographs).

  81. 81.

    Svendsen O. The minipig in toxicology. Exp Toxicol Pathol. 2006;57(5-6):335–9.

  82. 82.

    Chamanza R, Marxfeld HA, Blanco AI, Naylor SW, Bradley AE. Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. Toxicol Pathol. 2010;38(4):642–57 photomicrographs.

  83. 83.

    Chamanza R, Parry NM, Rogerson P, Nicol JR, Bradley AE. Spontaneous lesions of the cardiovascular system in purpose-bred laboratory nonhuman primates. Toxicol Pathol. 2006;34(4):357–63 (photomicrographs).

  84. 84.

    Lowenstine LJ. A primer of primate pathology: lesions and nonlesions. Toxicol Pathol. 2003;31(Suppl):92–102.

  85. 85.

    Cowan MJ, Giddens WE Jr, Reichenbach DD. Selective myocardial cell necrosis in nonhuman primates. Arch Pathol Lab Med. 1983;107(1):34–9.

  86. 86.

    Zabka TS, Irwin M, Albassam MA. Spontaneous cardiomyopathy in cynomolgus monkeys (Macaca fascicularis). Toxicol Pathol. 2009;37(6):814–8 (photomicrographs).

  87. 87.

    Khullar M, Datta BN, Wahi PL, Chakravarti RN. Catecholamine-induced experimental cardiomyopathy--a histopathological, histochemical and ultrastructural study. Indian Heart J. 1989;41(5):307–13.

  88. 88.

    Vidal JD, Drobatz LS, Holliday DF, Geiger LE, Thomas HC. Spontaneous findings in the heart of Mauritian-origin cynomolgus macaques (Macaca fascicularis). Toxicol Pathol. 2010;38(2):297–302 (photomicrographs).

  89. 89.

    Seiler BM, Dick EJ Jr, Guardado-Mendoza R, VandeBerg JL, Williams JT, Mubiru JN, et al. Spontaneous heart disease in the adult chimpanzee (Pan troglodytes). J Med Primatol. 2009;38(1):51–8 (photomicrographs).

  90. 90.

    Weber HW, Van Der Walt JJ, Greeff MJ. Spontaneous cardiomyopathies in Chacma baboons. Recent Adv Stud Cardiac Struct Metab. 1973;2:361–75.

  91. 91.

    Ito T, Chatani F, Sasaki S, Ando T, Miyajima H. Spontaneous lesions in cynomolgus monkeys used in toxicity studies. Jikken dobutsu Experimental animals. 1992;41(4):455–69 (photomicrographs).

Download references


The authors wish to thank Drs. Brian Berridge and Steven Lipshultz for valuable input and critical review of the manuscript.

Availability of data and material

Data sharing not applicable to this article as no data sets were generated or analyzed during the current study.


The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute.

Author information




EH and SE contributed equally in writing the manuscript. Both authors read and approved the final manuscript. Both authors read and approved the final manuscript.

Corresponding author

Correspondence to Sandy Eldridge.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Herman, E., Eldridge, S. Spontaneously occurring cardiovascular lesions in commonly used laboratory animals. Cardio-Oncology 5, 6 (2019).

Download citation


  • Antineoplastic cardiotoxicity
  • Pathology
  • Rat
  • Mouse
  • Dog
  • Monkey
  • Pig