JPC SYSTEMIC PATHOLOGY

CARDIOVASCULAR SYSTEM

APRIL 2022

C-M04

 

Signalment (JPC #1176745):  Age and gender unspecified Sprague-Dawley rat

 

HISTORY:  Incidental finding

 

HISTOPATHOLOGIC DESCRIPTION:  Mesentery, arteries:  Diffusely, mesenteric arteries are tortuous and thickened up to 3mm diameter with variably narrowed lumina due to markedly thickened walls. The tunica media and tunica adventitia are diffusely markedly expanded by reactive fibroblasts, collagen, numerous small caliber blood vessels, and clear space (edema), and these two layers often blend together with discontinuous external elastic laminae. The internal elastic lamina is discontinuous and the tunica intima is markedly expanded by thick bands of deeply eosinophilic, hyalinized fibrin admixed with cellular and karyorrhectic debris (fibrinoid necrosis). The arterial walls are transmurally infiltrated by numerous viable and degenerate neutrophils, fewer macrophages, lymphocytes, plasma cells, rare multinucleate giant cells, eosinophils, and necrotic debris (necrotizing vasculitis).   Arterial lumina are lined by hypertrophied, reactive endothelium and are rarely occluded by organizing fibrin thrombi.  Inflammatory cells and fibroblasts extend into the perivascular connective tissue which contains many small caliber blood vessels and edema.  

 

Mesentery:  Multifocally, there is moderate atrophy of mesenteric fat with increased numbers of spindle to stellate cells (fibroblasts), edema, and numerous small caliber blood vessels (granulation tissue).

 

Small intestine:  Essentially normal.

 

MORPHOLOGIC DIAGNOSIS:  Arteries, mesenteric:  Arteritis, proliferative, fibrinoid and necrotizing, chronic-active, diffuse, severe, Sprague-Dawley rat, rodent.

 

CONDITION:  Polyarteritis nodosa 

 

SYNONYMS:  Panarteritis; periarteritis nodosa; systemic necrotizing vasculitis

 

GENERAL DISCUSSION:

• “Polyarteritis nodosa” applies to a mixed group of arteritides which occur sporadically in all species of domestic animals, based upon classic polyarteritis nodosa in humans, in which small and medium-sized arteries undergo severe necrotizing inflammation, often in a sharply segmental (nodose) pattern, and with a predilection for branching points; arterioles, capillaries, and venules not involved
• Chronic progressive degenerative disease that most often occurs in aging rats, with higher incidence in males
• In rats, occurs most often in the muscular medium-sized arteries of the mesentery, pancreas, kidney, pancreaticoduodenal artery, and testis, but also seen in other visceral locations, including hepatic (Carlson, Toxicol Pathol. 2020), coronary, uterine, cerebral, and adrenal arteries; spares the pulmonary circulation, large arteries, and glomeruli
• Most often in Sprague-Dawley and spontaneously hypertensive (SHR) strains, and rats in late-stage chronic nephropathy

 

PATHOGENESIS:

• Unknown
• Thought to be an immunologically mediated disease (type III hypersensitivity)
  • Antigen:antibody complexes form in bloodstream (Ag > Ab) with immune complex deposition in arterial walls
  • Inflammation and/or activation of complement 
• Recruitment of WBCs results in tissue damage due to release of lysosomal enzymes and generation of toxic free radicals
• Fibrinoid necrosis and arteritis

                                                                 

TYPICAL CLINICAL FINDINGS: 

 

TYPICAL GROSS FINDINGS:

• Thick, tortuous, gray to red, hard, segmentally affected, medium-sized muscular arteries
• Spares pulmonary arteries, large arteries, and glomeruli
• Focal hemorrhage
• May have aneurysmal dilatations

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Fibrinoid necrosis with neutrophilic and mononuclear infiltration of the intima and media
• With chronicity, transmural fibrosis and inflammation
• Mural thrombosis is common; chronic lesions may exhibit recanalization
• Narrowing or occlusion of the vascular lumen may occur
• All stages of arterial lesions can be seen simultaneously within an individual, and potentially within the same vessel

 

DIFFERENTIAL DIAGNOSIS:

• Drug-induced vascular lesions can mimic the spontaneous disease
• Numerous etiologic entities can cause arteritis in domestic animals (vasculitis):
  • Bacteria:   Salmonella, Erysipelothrix, beta-hemolytic Streptococcus, Rickettsia rickettsii
  • Viruses:   Equine viral arteritis (arterivirus, Arteriviridae), equine herpesvirus-1 (brain), bovine viral diarrhea and border disease (pestivirus, Flaviviridae), classical swine fever (pestivirus, Flaviviridae), African swine fever (Asfarviridae), malignant catarrhal fever (alcelaphine herpesvirus-1 or ovine herpesvirus-2; Gammaherpesviridae)
  • Fungi:  Aspergillus, Zygomycetes
  • Metazoan parasites:  Strongylus vulgaris (C-P02), Dirofilaria immitis (C-P03), Schistosoma spp. (D-P20), Elaeophora schneideri, Onchocerca armillatus, Angiostrongylus spp.

 

COMPARATIVE PATHOLOGY:

• Humans:   Classic polyarteritis nodosa affects young adults, often targeting renal and visceral vessels, but sparing the pulmonary circulation; 30% of cases are associated with hepatitis B antigen 
• Dogs:  Idiopathic necrotizing polyarteritis (idiopathic canine polyarteritis,  juvenile polyarteritis syndrome, “beagle pain syndrome”):  
  • Clinical signs:   Recurrent fever, hyperesthesia, severe pain on manipulation of the neck, cervical rigidity, hunched body posture, and anorexia; some affected dogs asymptomatic
  • Small to medium sized muscular coronary arteries of heart, cranial mediastinum,  cervical spinal meninges, epididymis, thymus
  • Intimal and medial fibrosis, rupture of elastic laminae, perivasculitis, thrombi, aneurysms; splenic, renal and hepatic amyloidosis
  • Usually acute, but can be chronic (affecting all layers of vascular tunic)
• Cats:   Report in a young cat (Salvadori, J Comp Pathol. 2019); lesions consistent with polyarteritis nodosa, affecting small, medium, and large vessels of heart, kidneys, small and large intestine, mesentery, liver, and thyroid, with multifocal, meningeal vasculitis associated with focal infarction of the frontal lobe and necrotizing polyneuropathy; central and peripheral nervous system lesions are new finding in cats
• Mice:   Polyarteritis is common in mice that are prone to autoimmune disease, including MRL and NZB mice; may affect vessels of tongue, head, pancreas, urinary bladder, heart, kidneys, mesentery, uterus, testes, gastrointestinal tract; may result in vestibular syndrome when vessels of the head are affected
• Sheep:  
  • Similar presentation as in other species; however, lesions similar to polyarteritis nodosa, or idiopathic systemic necrotizing vasculitis, are reported in sheep clinically susceptible to ovine herpesvirus-2 (OvHV-2; malignant catarrhal fever) (Pesavento, Vet Pathol. 2019)
  • Lambs:   Recent report (Wessels, J Vet Diagn Invest. 2017) of systemic necrotizing polyarteritis in three unrelated lambs; lesions involved small intestine, abomasum, mesentery, kidney, heart with concurrent lymphocytic enteritis 
• Göttingen minipigs:  Occasionally observed background change in preclinical toxicology studies; most commonly reported in cardiac and extracardiac vessels, vagina, oviduct, rectum, epididymis, spinal cord, pancreas, urinary bladder, kidneys and stomach (Dincer, Toxicol Pathol. 2018)

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed., Ames, IA: John Wiley & Sons Inc; 2016:99,156.
2. Carlson T, Yee L. Spontaneous necrotizing hepatic arteriopathy in male Sprague-Dawley rats. Toxicol Pathol. 2020;48(7):905-908.
3. Dincer Z, Piccicuto V, Walker UJ, et al. Spontaneous and drug-induced arteritis/polyarteritis in the Göttingen minipig-review. Toxicol Pathol. 2018;46(2):121-130.
4. Gal A, Castillo-Alcala F. Cardiovascular system and lymphatic vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:697.
5. Mitchell RN, Halushka MK. Blood vessels. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier Saunders Co; 2021:513.
6. Pesavento PA, Dange RB, Ferreras MC, et al. Systemic necrotizing vasculitis in sheep is associated with ovine herpesvirus 2. Vet Pathol. 2019;56(1):87-92.
7. Robinson WF, Robinson NA. Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:70-71.
8. Salvadori C, Vezzosi T, Marchetti V, et al. Polyarteritis nodosa in a cat with involvement of the central and peripheral nervous systems. J Comp Pathol. 2019;167:6-11.
9. Wessels M, Strugnell B, Woodger N, et al. Systemic necrotizing polyarteritis in three weaned lambs from one flock. J Vet Diagn Invest. 2017;29(5):733-737. 

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