JPC SYSTEMIC PATHOLOGY

CARDIOVASCULAR SYSTEM

April 2022

C-M07

 

Signalment (JPC #2307591):  13-year-old female owl monkey (Aotus sp.)

 

HISTORY:   This monkey was found moribund at the bottom of the cage.  

 

HISTOPATHOLOGIC DESCRIPTION:  

Slide A: Heart, left ventricle:  Multifocally affecting 40% of the myocardium, predominately affecting the papillary muscles and inner aspect of the myocardium, there is moderate to marked loss of cardiomyocytes with replacement by hypertrophied fibroblasts and fibrous connective tissue (fibrosis).  Remaining myocytes are variably sized and exhibit the following changes: increased diameter (hypertrophy); shrunken, individualized, and surrounded by fibrous connective tissue (atrophy); contain pale granular or vacuolated sarcoplasm (degeneration); or are shrunken with hypereosinophilic sarcoplasm, loss of cross striations, and pyknotic nuclei (necrosis).  The endocardium is similarly expanded by fibrosis.  Multifocally within the epicardium, the subepicardial connective tissue, and myocardium are low numbers of lymphocytes, plasma cells, macrophages, and rare neutrophils, ectatic lymphatics (edema), and scattered small foci of hemorrhage.  Many myocytes contain variable amounts of golden-brown perinuclear pigment (lipofuscin).  

 

Slide B: Lung:  Multifocally, 80% of alveoli are variably filled with mildly increased numbers of macrophages with foamy cytoplasm or intra-cytoplasmic hemosiderin pigment (“heart failure cells”) and few extravasated erythrocytes.   Multifocally alveolar septa are thickened up to 50um by congestion, macrophages, eosinophilic finely beaded material (fibrin), and edema.    

 

Lymph node, site not specified:  Diffusely, subcapsular and medullary sinuses contain many erythrocytes (draining hemorrhage) and increased numbers of macrophages that exhibit erythrophagocytosis and hemosiderosis.

 

Trachea:  No significant lesions. 

 

Slide C: Liver: Affecting 70% of the liver parenchyma, there is diffuse, marked, centrilobular to midzonal necrosis and hemorrhage with variable retention of architecture. Hepatocytes within affected areas are lost and replaced by, or are individualized and widely separated by hemorrhage and fibrin with minimal necrotic debris. There is marked dilation of sinusoids with congestion.  Remaining hepatocytes contain few to many variably sized, clear, discrete, cytoplasmic vacuoles (lipid-type vacuolar change/degeneration) and/or fine, brown, cytoplasmic (lipofuscin, hemosiderin, or copper).  There are bile plugs within canaculi (cholestasis). Kupffer cells within sinusoids contain brown, granular, intracytoplasmic pigment (hemosiderin). Multifocally portal areas contain ectatic lymphatics filled with eosinophilic, proteinaceous material (edema).

 

MORPHOLOGIC DIAGNOSIS: 

1. Heart, left ventricle:  Myocardial loss and atrophy, multifocal to coalescing, marked, with fibrosis, owl monkey (Aotus sp.), non-human primate.
2. Lung:   Alveolar histiocytosis, diffuse, moderate, with hemosiderosis, congestion, and edema.
3. Lymph node, site not specified:  Draining hemorrhage, diffuse, moderate, chronic-active.
4. Liver:   Necrosis, centrilobular to midzonal, diffuse, severe, with hemorrhage, hemosiderosis, congestion, edema, and lipid-type vacuolar degeneration (chronic passive congestion).

 

CONDITION:  Aotus cardiomyopathy 

 

GENERAL DISCUSSION: 

• Cardiomyopathy is a very common cause of morbidity and mortality in Aotus monkeys (i.e. owl monkeys in the genus Aotus)
• Up to 40% of deaths have evidence of cardiovascular disease (ventricular dilation or left ventricular hypertrophy)
• Concurrent renal disease is often present and is also a common cause of morbidity and mortality in this species
• The association of heart disease and renal disease is suggestive of cardiorenal syndrome which has been described in older humans; in this condition the initial cardiac dysfunction leads to progressive kidney dysfunction; likewise, the continuing kidney dysfunction contributes to further decline of the heart 

 

PATHOGENESIS:

• Unknown
• Suspected mechanisms include captivity-induced hypertension, renal-induced hypertension, and heredity  

 

TYPICAL CLINICAL FINDINGS:

• Clinical signs vary; often asymptomatic prior to death
• Ascites, dyspnea, mouth breathing, reduced exercise tolerance, subcutaneous edema, and hepatomegaly
• Some monkeys exhibit paralysis (partial or complete) from secondary thromboembolic disease

 

TYPICAL GROSS FINDINGS: 

• Mild to severe hypertrophy of the left ventricular free wall and interventricular septum; pale streaks in the myocardium
• Occasionally dilative cardiomyopathy and pericardial effusion
• Pulmonary congestion and edema
• Chronic passive congestion of the liver, centrilobular necrosis (nutmeg liver)
• Subcutaneous edema (especially the eyelids, muzzle, and bottle jaw); ascites, hydrothorax
• If concurrent renal disease is present, the renal surface is pitted and rough with small white foci present on the capsular and cut surface

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Heart:

• Vary from focal areas of necrosis to diffuse interstitial fibrosis depending on the stage of disease
• Myofiber atrophy and loss; remaining myofibers disorganized with loss of linear organization

• Lung: alveolar histiocytosis with erythrophagocytosis and hemosiderosis ("heart failure cells"), edema, foamy macrophages, and congestion
• Liver: congestion, centrilobular to midzonal necrosis, and vacuolar degeneration of hepatocytes
• Kidney: glomerular hypercellularity, dilated renal tubules, diffuse interstitial fibrosis, and a variable mononuclear cell infiltrate

 

ULTRASTRUCTURE 

• Early:   Enlarged cardiomyocytes with increased myofilaments, mitochondria, and sarcoplasmic reticulum volume
• End-stage (terminal):  Degenerative cardiomyocytes appear dark with thick filaments, clumped and streaming Z band material, and proliferation and dilation of sarcoplasmic reticulum

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Echocardiography, radiographs, and electrocardiography
• Left ventricular diameter and ejection fraction are the best measurements for diagnosis
• Although cardiac troponins are useful markers of cardiac damage in many species,  they may not be reliable indicators of myocardial disease in the owl monkey 
• Serum concentrations of CK, AST, and LDH in owl monkeys with proteinuria are good screening tests for the presence of subclinical cardiac disease

 

DIFFERENTIAL DIAGNOSIS:

• Cardiac lesions resulting from infectious etiologies may have a similar gross appearance
• Trypanosoma cruzi (C-P06): "Chagas disease"; myocardiofibrosis or necrosis; cardiac and skeletal muscle pseudocysts with amastigotes; mononuclear myocarditis; parallel, rod-like kinetoplast 

 

COMPARATIVE PATHOLOGY:

Cardiomyopathy in other species:

• Cats:

• Hypertrophic cardiomyopathy (diastolic disorder; most common) (C-M10):

• Inherited form - autosomal dominant in Maine Coon and Ragdoll cats; mutation in myosin binding protein C3 (MyBPC3)
• This is not to be confused with the concentric cardiac hypertrophy which occurs secondary to hyperthyroidism in cats
• Microscopically, there is myofiber disarray and interstitial fibrosis

• Restrictive cardiomyopathy:

• Results in impaired filling of ventricles during diastole
• AKA “left ventricular endocardial fibrosis” – endocarditis may initiate the lesion
• Microscopically, there is thickening of the endocardium and mural thrombi

• Dilated cardiomyopathy: secondary to taurine deficiency
• Arrythmogenic right ventricular cardiomyopathy (ARVC)-like syndrome: right ventricular inflammation, necrosis, atrophy, fibrosis and replacement with adipose tissue
• Excessive moderator bands (AKA false tendons):

• Probably a congenital defect
• Results in left sided heart failure because the bands connect the papillary muscle to the interventricular septum
• Microscopically, the moderator bands are composed of Purkinje cells, mature collagen, and an endothelial lining

• Dogs:

• Dilated cardiomyopathy: 

• Giant and large breed dogs affected (St. Bernard, Irish Wolfhound, Estrela Mountain dogs, Great Dane); African wild dogs
• Suspect it has a genetic basis, but there have been no cytoskeletal genes identified as the cause
• Other possible causes: carnitine deficiency; taurine deficiency; hypothyroidism 
• Results in congestive heart failure
• 2 microscopic forms:

• Fatty infiltration-degenerative type
• Attenuated wavy fiber type

• ARVC in dogs is a variant of DCM:

• Boxer dogs (may be due to deletion in the striatin gene)
• Right ventricular myocyte loss and replacement with fibroadipose tissue

• Hypertrophic cardiomyopathy: less common than DCM in dogs
• Canine X-linked muscular dystrophy:

• Golden retrievers are model of human disease
• Develop Duchenne cardiomyopathy
• Causes cardiac insufficiency from extensive subepicardial fibrosis

• Woolly monkeys:   Spontaneous hypertension (U-M01) reported as a cause of dilated cardiomyopathy
• Gelada baboons and other primates: Vitamin E deficiency reported to cause cardiomyopathy
• Apes:  

• Cardiovascular disease is a very common factor in deaths of zoo and laboratory apes; reported in deaths of 45% of bonobos, 41% of gorillas, 38% of zoo chimpanzees, >50% of colony chimpanzees, and 20% of orangutans
• Dissecting myocardiofibrosis (also known as fibrosing cardiomyopathy, idiopathic myocardial fibrosis, interstitial myocardiofibrosis) is most common form of cardiovascular disease, followed by aortic dissection, atherosclerosis, and valvular disease
• Myocardiofibrosis may be secondary to arteriosclerosis and left ventricular hypertrophy in apes
• Associated with sudden and anesthetic death and cardiac arrhythmias
• Increased cardiac fibrosis has been found to correspond to increased glomerulosclerosis and tubulointerstitial fibrosis in aged chimpanzees 
• Recent retrospective study (Strong et al., Vet Pathol. 2020) identified myocardial fibrosis in 31/33 zoo-housed chimpanzees vs. 0/25 sanctuary-housed chimpanzees; possible association with low vitamin D due to lack of UV exposure

• Rhesus macaques: Arteriosclerosis is a common background finding; increases with age; strong association between arteriosclerosis and hypertension and diabetes; degenerative and fibrosing cardiomyopathy also increases with age recent study of rhesus macaques showed high risk (46%) of sudden death associated with idiopathic concentric hypertrophy of the left ventricle
• Other NHPs:   Cardiomyopathy also reported in squirrel monkeys, common marmosets, and cynomologous macaques
• African grey parrots: Cardiomyopathy of undetermined origin reported 
• Red pandas:  Myocardial fibrosis and hypertrophic cardiomyopathy common in aged captive animals
• Sea otters:  Myocarditis and dilated cardiomyopathy associated with domoic acid exposure; 3^rd most common primary cause of death in southern sea otters
• California sea lions:  Domoic acid is associated with cardiomyocyte degeneration and necrosis leading to secondary cardiomyopathy
• Ferrets:  Both dilated and restrictive cardiomyopathy reported in animals >6 months old; dilated form is more common
• Hedgehogs:  High incidence of cardiomyopathy (up to 38% mortality); males > females
• Rodents:  Cardiomyopathy common in aged mice, rats, hamsters; increased severity with age; males > females; associated with spontaneous atrial thrombosis and coagulopathy in Syrian hamsters; reported in woodchucks
• Cetacea:  Cardiomyopathy described in pygmy and dwarf sperm whales; males >females 

 

REFERENCES:

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4. Chilton J, Wilcox A, Lammey M, Meyer D. Characterization of a cardiorenal-like syndrome in aged chimpanzees (Pan troglodytes). Vet Pathol. 2016;53(2):417-424.

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