JPC SYSTEMIC PATHOLOGY

CARDIOVASCULAR SYSTEM

February 2025

C-M05

 

Signalment (JPC #1948332): 13-year-old male Labrador retriever

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Heart: Diffusely, the lumina of large elastic and muscular coronary arteries are narrowed or occluded by thickened vessel walls. The internal elastic lamina is disrupted / discontinuous and the tunica intima and tunica media are markedly disorganized and expanded by multifocal to coalescing aggregates of lipid-laden macrophages with abundant foamy, microvacuolated cytoplasm (foam cells); numerous acicular cholesterol clefts (extracellular lipid); amphophilic granular cellular debris; rare, deeply basophilic fragmented material (mineral); hypertrophic smooth muscle cells with plump nuclei; and small amounts of plump fibroblasts with fibrous connective tissue. The tunica adventitia is expanded by fibrous connective tissue and low numbers of lymphocytes, plasma cells, and fewer macrophages that infiltrate into adjacent fibroadipose tissue.

 

MORPHOLOGIC DIAGNOSIS: Heart, epicardial arteries: Atherosclerosis, chronic, diffuse, severe, with intimal and medial foam cells, cholesterol clefts, mineralization, fibrosis, and smooth muscle hypertrophy, Labrador retriever, canine.

 

CONDITION: Atherosclerosis

 

GENERAL DISCUSSION:

• Arteriosclerosis refers to chronic arterial change characterized by hardening, loss of elasticity, and luminal narrowing; is the result of proliferative and degenerative (vs inflammatory) changes of tunica media and intima; common but of little clinical importance in domestic animals; classified into three groups:
• 1. Arteriolosclerosis affects small arteries and arterioles; subdivided into anatomic variants of hyaline and hyperplastic arteriolosclerosis
  • Common in animals with little clinical significance
  • Arteriosclerotic plaque result in slightly thickened and wrinkled tunica intima
• 2. Monckeberg medial sclerosis is characterized by calcified deposits in muscular arteries in older humans and may undergo osseous metaplasia; arterial medial calcification is frequent in animals; involves elastic and muscular arteries
  • Elastic arteries: Characterized by mineral deposits on elastic fibers of the tunica media
  • Muscular arteries: Mineral deposits form a complete ring of mineralization in the tunica media
  • Causes include ingestion of calcinogenic plants, vitamin D toxicosis and renal insufficiency; Johne’s disease in cattle (C-B03)
• 3. Atherosclerosis refers to arteriosclerosis with “degenerative fatty changes” composed of lipid, fibrous tissue, and calcium deposits in vessel walls; called “atheromas” or fibrofatty plaques; rare in domestic animals
  • Importance lies in animals as models for human disease
  • Affects the large elastic arteries (e.g. aorta, iliac) and medium-caliber muscular arteries (e.g., carotid, coronary, femoral)
  • Susceptible animals: Rabbits, chickens, pigs (most common domestic animal); common in humans
  • Less susceptible or in some cases resistant animals: Dogs, cats, cattle, goats, rats; infrequent in domestic animals
  • Dogs: 
    • Hypothyroid, diabetic, and dogs with breed-related hyperlipidemia (i.e. hyperlipidemia of miniature schnauzers) are predisposed 
    • Primary hyperlipidemia is an idiopathic, likely hereditary condition in miniature schnauzers
      • In dogs, deposition of lipids begins in the middle and outer layers of the media, especially of small muscular arteries, but may also be present in the intima
      • A recent study identified gonads of dogs as common locations for atherosclerosis, +/- amyloid deposits, associated with age and interstitial cell tumors (Ushio et al, Vet Pathol, 2021)
  • Complications of plaques: mineralization, ulceration, thrombi, intraplaque hemorrhage, aneurysmal dilation 

 

PATHOGENESIS:

• Not fully understood, but occurs when both endothelial damage and increased blood lipids are present; multiple events/theories unified into “response to injury hypothesis”:
• Chronic endothelial damage and dysfunction can be caused by hemodynamic disturbances (i.e. turbulence) and hypercholesterolemia (especially LDL & VLDL)
• Hyperlipidemia and endothelial injury > platelet adhesion and thrombosis > platelets release PDGF, EGF, TGFb> PDGF stimulates migration and proliferation of smooth muscle cells> at the same time there is monocyte migration into tunica intima and activation to macrophages (“foam cells”) > lipid accumulation > atherosclerosis
• There is accumulation of both intracellular and intercellular lipid within the forming plaque
• Hyperlipidemia leads to increased superoxide and oxygen free radicals
• Oxidation of lipids by free radicals produces oxidized low density lipoprotein (LDL), which is chemotactic for circulating macrophages
• Ingestion of LDL through scavenger receptor of macrophages produces “foam cells”
• Smooth muscle cells proliferate and migrate from the tunica media into the tunica intima (“myointimal cells”) in response to PDGF, FGF, TGFa and deposit extracellular matrix of collagen, elastin, and glycoproteins

 

TYPICAL CLINICAL FINDINGS:

• Clinical disease is infrequent in animals

 

TYPICAL GROSS FINDINGS:

·  Site predilections include lower abdominal aorta, coronary, popliteal, descending

   thoracic aorta, and internal carotid arteries

·  Arteries are thickened and less pliable

·  Variably-sized, yellow-brown plaques or nodules project into the lumen

·  Larger plaques may have a caseous core (athera means gruel)

·  Plaques are often located at arterial branch points (i.e. areas of hemodynamic     

   Turbulence

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Arteriosclerosis:

• Irregular internal elastic lamina, fragments, disruption
• Migration of smooth muscle cells from media to intima

Atherosclerosis:

·  Atheroma or sub-intimal fibrofatty plaque: Focal raised intimal plaque with lipid core covered by a fibrous cap

• Extracellular lipid characterized by the formation of cholesterol clefts
• Aggregates of lipid-laden macrophages (“foam cells”) and smooth muscle cells (intracellular lipid) fill the subintimal space and tunica media
• +/- cholesterol clefts, mineralization, ulceration, thrombosis, chondrocytes replacing smooth muscle cells, hemorrhage, and aneurysmal dilation

 

ADDITIONAL DIAGNOSTIC TESTS:

 

COMPARATIVE PATHOLOGY:

• Rabbits, chickens, pigs, and nonhuman primates are atherosensitive when given experimental high cholesterol diets
• Dogs, cats, cattle, and rats are atheroresistent on experimental high cholesterol diets
  • Recent report of spontaneous atherosclerosis in two cats of the Korat breed resulting in severe heart failure (Karkamo et al, J Comp Pathol, 2021)
  • Male dogs with obesity, hypothyroidism, hypercholesterolemia, hypertriglyceridemia and advanced age are at risk for atherosclerosis
  • Morphology of atherosclerosis in dogs is different than in humans; in dogs, lipid is present in the intima, but is primarily located in the media and adventitia of atherosclerotic arteries, however, in humans, lipid is present primarily in the intima
• Avian: Atherosclerosis can occur naturally in certain aged avian species
  • Most common vascular lesion in great vessels of aged Psittacines (Amazon parrots such as cockatiels, cockatoos, African grey parrots, blue-fronted Amazon parrot, and macaws) and increases with age (mostly 8 years older), inactivity (captivity), and high fat diet; sex predilection in females; typically found in ascending aorta, pectoral and carotid arteries, brachiocephalic trunks, and less commonly in the pulmonary arteries; grossly appear as variably thickened and yellow with yellow intimal plaques; many die due to severe narrowing of carotid arteries and resulting decreased blood supply to the brain 
    • Atherosclerosis has been observed in association with endogenous lipid pneumonia in a blue-fronted Amazon parrot (Grespan, Vet Pathol, 2023)
  • Marek’s disease is associated with atherosclerosis in chickens
  • Birds of prey: Common cause of death in aged captive raptors (black kites, falcon species, eagles, red tailed hawks, and owls); primarily affects large arteries (pulmonary artery, aorta, brachiocephalic trunk; suspected predisposition in Brahminy kites due to diagnosis in young birds; osseous metaplasia and deposition of collagen fibers possible in advanced lesions; in falcons and kites, dissecting aneurysms +/- rupture possible in advanced lesions
  • Emu: Sequela to prolonged feeding of rations high in cholesterol (eggs) and fat
  • Captive penguins: Variable rates of incidence, possibly due to age, species, diet, or climatic differences; Adélie and emperor penguins most commonly affected
  • Finches, hornbills, and rhamphastids: Common finding; affected sites include heart valves, great vessels, myocardial arteries, glomeruli, spleen, brain, and skin; develop signs of cardiopulmonary or CNS disease, or are often found dead
• Pigs: The only domestic species in which atherosclerosis develops commonly; Streptozotocin-induced diabetic, hypercholesterolemic pig model has been successfully used to induce coronary atherosclerosis and shares many features of the pathophysiology of hyperlipidemic vasculopathy in humans
  • Characterized by fatty streaks and atheromatous plaques in aorta, extramural coronary arteries, cerebral and iliac arteries
  • Pigs fed high saturated fat and cholesterol diet will develop advanced atherosclerotic lesions similar to ones seen in humans, but pigs fed normal diet are not likely to develop atherosclerosis  
• Rabbits: With endogenous hypercholesterolemia and atherosclerosis: Watanabe inheritable hyperlipidemic rabbits have LDL receptor defect; St. Thomas’s Hospital and Houston RT rabbit strains
  • Experimental intranasal or intravenous inoculation of laboratory rabbits with Chlamydophila pneumoniae has been shown to induce arterial thickening and acceleration of atherosclerosis in mildly hyperlipidemic rabbits
• Mice: APO-E deficient mice are prone to atherosclerosis
• NHPs: Well studied model of atherosclerosis with a complex pathogenesis; occasionally occurs in very old apes under poor husbandry conditions; more common in large elastic vessels such as iliac arteries, abdominal aorta, and aortic arch; +/- Monckeburg’s medial calcific arteriosclerosis (medial arteriosclerosis with mineralization)
• African elephants: Aorta, aortic branch arteries, and coronary arteries commonly affected; cause unknown with no correlation to serum lipid levels
• Cetaceans: Uncommon in captive and free ranging bottlenose dolphins

 

REFERENCES:

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3. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016:272; 314.
4. Gal A, Castillo-Alcala F. Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:681-682.
5. Grespan A, Fiedler RT, Guedini BT, et al. Endogenous lipid pneumonia associated with atherosclerosis in a blue-fronted Amazon parrot (Amazona aestiva). Vet Pathol. 2023:201:130-134.
6. Karkamo V, Airas N, Lindén J, et al. Severe spontaneous atherosclerosis in two Korat breed cats is comparable to human atherosclerosis. J Comp Pathol. 2021:188:52-61. 
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16. Ushio N, Chambers JK, Watanabe K, et al. Age-related arteriolar changes with lipid and amyloid deposits in the gonads of dogs. Vet Pathol. 2021:58(3):558-567. 
17. Wünschmann A, Armién AG, Höfle U, et al. Birds of Prey. In: Terio K, McAloose D, St. Leger J, eds, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:718.

 

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