JPC SYSTEMIC PATHOLOGY
Signalment (JPC #1948332): 13-year-old male Labrador retriever
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, mineral, hypertrophic smooth muscle cells and small amounts of fibrous connective tissue (the latter two within the tunica media) . 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, coronary arteries: Atherosclerosis, diffuse, severe, with intimal and medial foam cells, cholesterol clefts, mineralization and smooth muscle hypertrophy, Labrador retriever, canine.
- Arteriosclerosis refers to chronic arterial change characterized by hardening, loss of elasticity and luminal narrowing; results from proliferative and degenerative (vs inflammatory) changes of tunica media and intima are classified into three groups:
- Arteriolosclerosis affects small arteries and arterioles with the anatomic variants of hyaline and hyperplastic arteriolosclerosis
- Common in animals with little clinical significance
- Arteriosclerotic plaque result in slightly thickened and wrinkled tunica intima
- 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
- Atherosclerosis refers to arteriosclerosis with “degenerative fatty changes” composed of lipid, fibrous tissue and calcium deposits in vessel walls; called “atheromas” or fibrofatty plaques
- Importance lies in animals as models for human disease
- Affects elastic arteries (e.g. aorta, carotid, iliac) and large and medium-sized muscular arteries
- Susceptible animals: rabbits, chickens, pigs
- Less susceptible or in some cases resistant animals: dogs, cats, cattle, goats, rats
- Hypothyroid or diabetic dogs predisposed; infrequent in domestic animals (most common in pig), but common in humans
- 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
- Complications of plaques: mineralization, ulceration, thrombi, intraplaque hemorrhage, aneurysmal dilation
- 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 (ie 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:
- Irregular internal elastic lamina, fragments, disruption
- Migration of smooth muscle cells from media to intima
- 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, hemorrhage and aneurysmal dilation
ADDITIONAL DIAGNOSTIC TESTS:
- Sudan IV stain can be used to visualize lipid deposits grossly
- Horse, ruminants, carnivores: usually manifest uncomplicated version with absence of focal degeneration in the sclerotic plaques an no lipid deposition
- Pigs: 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 saturation fat diet and cholesterol will develop advanced atherosclerotic lesions similar to ones seen in human but pigs fed normal diet are not likely to develop atherosclerosis
- Atherosclerosis can occur naturally in certain aged avian species
- High prevalence of athlerosclerosis in Quaker parrots, with male being slightly more susceptible
- Commonly occurs in great vessels in aged Psittacines (cockatiels, Amazon parrots, African grey parrots, macaws) and increases with age, inactivity (captivity) and high fat diet; sex predilection in females
- Male dogs with obesity, hypothyroidism, hypercholesterolemia, hypertriglyceridemia and advanced age are at risk for atherosclerosis
- The domestic cat fed a high fat diet will 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
- Rabbits: 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
- APO-E deficient mice are prone to atherosclerosis
- NHPs: Cardiovascular disease mortality increases in aging apes; idiopathic myocardial fibrosis and cardiomyopathy predominate, with arteriosclerosis of intramural coronary arteries; similar lesions are uncommonly noted in wild apes; vascular changes in the heart and kidneys and aortic dissections in gorillas and bonobos suggest that hypertension may be involved in the pathogenesis; chronic kidney disease is common in some aging apes and is linked with cardiovascular disease in orangutans
- 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
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