Student Syllabus: Pathology of the Heart and Blood Vessels

Abbreviated Syllabus Download

PATHOLOGY OF THE HEART AND BLOOD VESSELS

Created by V’22 Cardio Group modified from Dr. Nicholas Robinson

Updated 3/27/20

Pathology of the Heart

Evaluation of the heart at necropsy

Position
- Abnormal position
  - Ectopia cordis – heart located outside of the chest
  - Pericardial diaphragmatic hernia
- Compression
  - Mediastinal mass
  - Pyothorax
Pericardium: Parietal layer, pericardial fluid, visceral layer
- - Abnormal pericardium
    - Red and thickened from edema and hyperemia
    - Chronicity (>48-72 hours) to injury – mesothelial cells proliferation → shaggy, roughened appearance
  - Pericardial effusion – excess pericardial fluid
    - Causes: tear of proximal great vessels, neoplasia, myocardial rupture, coagulopathies
    - Cardiac tamponade
    - Affects right ventricle the most during diastole
Abnormalities of the great vessels
Removal of the respiratory tract and heart en bloc
- Cardiac disease often affects the lungs and vice versa
- Trace pulmonary arteries
  - Look for evidence of thrombosis and/or endoarteritis
Evaluate cardiac chambers and valves by “following the flow”
Examine internal and external features/lesions
- Endothelium: lines chambers of the heart, normally thin and almost invisible
- Subendocardial tissue: composed of fibroblasts, nerves, collagen, veins, and conduction system
- Endocardial thickening
  - Result of fibrosis from a number of pathological conditions:
    - scarring from “jet lesions”
    - restrictive cardiomyopathy
    - fibroelastosis
  - Valvular structure
    - Dysplasia
      - AV valve most commonly affected
      - Focal or diffuse thickened with fibrosis and abnormal, fibrotic, and shortened chordae attachments
      - Some valve directly fused to the ventricular wall
    - Stenosis
      - Lesions affect the pulmonary valve more often, less in the aortic valve
      - Stenosis may be in the valve or supra/subvalvular
    - Rupture chordae → rapid valvular dysfunction and regurgitation
    - Myxomatous valvular degeneration (Endocardiosis)
      - The most common valvular lesion in dogs, often incidental finding in old dogs
      - Grossly: free edges of valves thickened by 1-2 mm, smooth, shiny opaque white nodules
      - Histologically: valve stroma is expanded by myxomatous materials
      - May see concurrent chordae thickening and rupture
      - in some small dogs → severe changes → marked deformation of the valves → valvular incompetency → secondary atrial enlargement and endocardial fibrosis
    - Valvular endocarditis (vegetation)
      - Fibrinous, yellow to tan to red irregular, roughened deposits on the valves
      - Usually bacterial in origin → large number of pathogens associated with this lesion
      - Histologically: vegetations are composed of fibrin, blood, inflammatory cells, and colonies of bacteria
      - Inflammation can spread down the chordae → rupture
      - Vegetations can break off → embolize into myocardium and lung
Heart is weighed after blood is removed and the great vessels trimmed off
- Cardiac diseases typically result in cardiomegaly rather than microcardia
- Normal heart weight in dogs: < 1% of body weight. Some dog breed (i.e. greyhound) have a higher normal heart:body weight ratio
- Obese animals → heart weight in the high normal heart to body weight ratio range should be viewed with suspicion for cardiomegaly
- Cats: absolute weight of the heart → useful indicator of disease
  - Cat hearts should weigh less than 18-20 grams.

Reaction of the heart to altered hemodynamics

Increased preload
- Increase blood volume → increased preload
- Acutely: stretching and dilation of the ventricle
  - Accommodate end diastolic volume
  - Increased pressure
- If preload persists → ventricle responds by laying sarcomeres in series
  - “eccentric hypertrophy”
  - Large volume chamber
- When limit is hit → congestive heart failure
  - Altered conduction
  - Perfusion to the area
  - Morphologic changes to valvular apposition
- Increased afterload
  - Increased resistance to the ejection of blood
  - More force needed to empty the ventricles → sarcomere laid in parallel
    - “concentric hypertrophy”
    - Thickened ventricular wall
  - Acquired disorder (e.g. hypertension)
    - Marked hypertrophy → Increased perfusion distance from capillaries to the cells (capillaries do not grow with the cells)
    - Hypoxia → abnormal conduction and dysrhythmias
  - Congenital cases (e.g. stenosis)
    - +/- Less severe hypertrophy
    - Cardiac hyperplasia with some matching capillary growth

Myocardial Pathology

Growth Disturbances
- Myocardial hypertrophy → increased muscle mass due to increase size of myocytes
  - Compensatory response to increased workload/stimulation (reversible if stimulation removed)
  - Primary Idiopathic Hypertrophic Cardiomyopathy → irreversible
  - 2 gross anatomic forms
    - Eccentric: enlarged ventricular chambers with thin-normal walls, result of increased blood volume load (e.g. valvular insufficiency or septal defect)
    - Concentric: small ventricular chambers with thick walls, result of increased pressure load (e.g. valvular stenosis, systemic hypertension, pulmonary disease)
  - 3 stages of hypertrophy
    - Initiation
    - Stable hyperfunction
    - Dysfunction
  - Right ventricular concentric hypertrophy
    - Dirofilariasis → pulmonary hypertension
    - Pulmonic stenosis in dogs
    - Pulmonary hypertension from hypoxia in high altitude (cattle)
    - Chronic alveolar emphysema (horses with heaves)
  - Left ventricular concentric hypertrophy
    - Subaortic stenosis
    - Hyperthyroidism
    - Systemic hypertension
  - Biventricular hypertrophy
    - Idiopathic Cardiomyopathy
    - Some congenital anomalies
    - End stages of heart disease due to other causes
Infiltration
- Fatty infiltration → adipocytes in myocardium → separate cardiomyocytes
  - Obese animals, not associated with dysfunction
  - Microscopic feature of arrhythmogenic right ventricular cardiomyopathy in certain dog breeds (e.g. Boxers)
Degeneration
- Fatty degeneration
  - Lipid droplets in the sarcoplasm
  - Light microscopy → clear vacuoles, special stains to confirm the lipid
  - Gross exam: heart may be pale pink to tan
  - Occurs with severe anemia, copper deficiency, other systemic disorders
- Hydropic degeneration
  - Vacuolated sarcoplasm, do not stain for lipid
  - Classically occurs with anthracyclines
- Lipofuscinosis
  - Accumulation of intralysosomal oxidized lipid residues
  - Light microscopy → yellow brown granules near the cardiomyocyte nuclei
  - Gross exam: heart may be brown or golden brown
  - Age-related change
  - Can occur in starvation or hereditary in Ayrshire cattle
- Myofibrillar degeneration
  - Disruption of sarcoplasm → loss of cross striations and pale pink cytoplasm
  - Classically seen with furazolidone toxicity in birds
  - Potassium deficiency in rats
  - Acute myocyte injury and many other toxicities
Necrosis & Mineralization
- Necrosis → result from many types of injury
  - Nutritional deficiency, toxin exposure, ischemia, metabolic disorder, physical injury, etc.
  - Examples: ionophore toxicity (equine), vitamin E-selenium imbalance (neonates/ juveniles), anthracycline toxicity (dogs), gossypol toxicosis (pigs)
- Necrotic myocardium
  - Gross exam: pale tan to white, sometimes gritty (rapid dystrophic mineralization)
  - Microscopic: Swollen hypereosinophilic fibers with shrunken nuclei and basophilic cytoplasmic granules
  - With chronicity, dead myofibrils are removed, myocytes may regenerate, and fibrosis can occur
- Mineralization → often occurs in conjunction with necrosis → calcium released from damaged sarcoplasmic reticulum
  - Prominent in hereditary calcinosis (mice), vitamin D toxicosis, spontaneous in aged rats and guinea pigs
- Mineralized myocardium
  - Gross exam: gritty, white
  - Microscopic exam: basophilic, angular
Cardiomyopathies
- Primary cardiomyopathies (Idiopathic) → underlying causes are largely unknown
  - Idiopathic Hypertrophic Cardiomyopathy (HCM)
    - Increased left ventricular +/- interventricular thickness (concentric hypertrophy), most common in cats
    - Gross: thick ventricle wall, small lumen. Weight > 20g
    - Microscopic: none to enlarged myocytes and fiber disarray
    - Pathophysiology: myocytes work harder and enlarge → hypertrophy reduces the compliance and diastolic function → impairs ventricular filling.
      - Obstruction of left ventricular outflow during systole can be seen → forces generated by the narrowed outflow tract by septal hypertrophy → anterior motion of mitral valve leaflet
      - Valvular displacement → mitral regurgitation → enlarge atria → blood stasis + inappropriate activation of endothelium → atrial thrombosis
    - Associated genetic defect → myosin binding protein C gene mutation
  - Idiopathic Dilated Cardiomyopathy (DCM)
    - Ventricular and atrial dilation with ventricular hypertrophy (eccentric). Dogs, cats, cattle, poultry. Hypertrophy may not be obvious
    - Subcategory: arrhythmogenic right ventricular cardiomyopathy
      - Associated with ventricular tachycardia, most prominently in Boxer dogs
      - Histopathology: right ventricle infiltrated by adipose and fibrous tissue
      - Gross: big, heavy, flabby heart
      - Microscopic: sometimes attenuated/wavy fibers
      - Pathophysiology: decreased contractility and declining stroke volume → compensatory Frank Starling and neurohormonal mechanisms → myocytes elongate
      - Long-term → compensatory mechanism not functional → myocyte degeneration → volume overload and failure
  - Restrictive Cardiomyopathy (RCM)
    - Primarily in cats, affecting left ventricle. Some evidence that RCM is preceded by endocarditis, but inciting cause is unknown
    - Gross: thickened white left ventricular endocardium
    - Microscopic: left ventricular endocardial and subendocardial fibrosis
    - Pathophysiology: endocardial/subendocardial fibrosis + infiltrates → impair diastolic filling (ventricle more rigid than normal)
- Secondary cardiomyopathies (known causes)
  - Heritable
    - DCM
      - Human: mutation in several contractile protein and ion channel genes
      - X-linked muscular dystrophy (Dogs), associated with subendocardial and interstitial fibrosis
    - HCM
      - Autosomal dominant in Maine Coon and American Shorthaired cats
      - Mutations in sarcomeric proteins → mutation in the myosin binding protein C has been identified in heritable HCM in cats
  - Nutritional
    - DCM: taurine deficiency
    - Myocardial necrosis (due to deficiency): selenium-vit E imbalance, potassium, copper, thiamine, magnesium
  - Toxic
    - Myocardial necrosis: cobalt, catecholamines, ionophores, vit D and calcinogenic plants, blister beetles, rapeseed oil, T-2 mycotoxin
  - Physical injury/Shock
    - Myocardial necrosis: CNS lesions and trauma, GDV, electrical defibrillation, hemorrhagic shock
    - Endocrine disorders → HCM: hyperthyroidism
  - Infections
  - Neoplastic
  - Systemic hypertension in cats → HCM: spontaneous hypertension, renal disease, hyperthyroidism, diabetes mellitus, primary aldosterism

Myocarditis → Inflammation of the myocardium, involve in a range of different inflammatory cells

Selected examples of etiologic agents

Autoimmune: poorly documented, a hypersensitivity reaction (eosinophilic myocarditis) in cattle to plant toxin is known
Parasitic:
- Sarcocytis spp Cysts: no immune reaction but may see eosinophils with degenerating cysts, multiple hosts
- Neospora caninum (dogs): myocarditis, myositis and encephalomyelitis
- Toxoplasma gondii (multiple hosts): myocarditis, systemic disease
- Larval tapeworms (multiple hosts): Taenia ovis, saginata, solium, and Echinococcus granulosum
- Trypanosom cruzi: Chagas disease, pyogranulomatous myocarditis
Bacterial and fungal
- Generally → suppurative to necrotizing lesions
- Any pyogenic bacterium, more common ones include: Actinobacillus equuli, Clostridium chauvoei, Aspergillus terreus, Histophilus somni, Streptococcus spp.
Viral
- Parvovirus and herpesvirus (puppies)
- Equine Herpesvirus – 1
- Foot and mouth disease → more necrotizing in young animals
- West Nile (raptors)
- Porcine circovirus/porcine parvovirus
- Encephalomyocarditis virus (swine, lab rodents)
Plant toxins: cardiac glycosides

Myocardial necrosis

Selected examples of etiologic agents

Vitamin E/Selenium responsive disease (pigs and ruminants)
- “mulberry heart” in pigs (2-4 months of age mainly)
- May see degeneration of arterioles in multiple organs
- “white muscle disease” in ruminants and horses → result of dystrophic mineralization of the myocardium
Ionophore and gossypol toxicosis
- Ionophore in ruminant feed → control coccidian parasites and promote growth
  - Mixing error → toxic doses added to feed
  - Horses are very sensitive → peracute myocardial necrosis
  - Gossypol → found in cottonseed meal, can be toxic in large quantities
Doxorubicin toxicosis
- Anthracycline chemotherapeutic agent
- In dogs, can cause myocardial acute necrosis and chronic degeneration/necrosis via peroxidative injury and blockage of DNA, RNA, and protein synthesis
Thromboembolic diseases
- - Systemic inflammation, coagulopathies, vasculitis can result in cardiac necrosis
  - Arteriosclerosis → rarely severe enough in animals to cause myocardial infarction

Myocardial neoplasia

Primary tumors of myocardial cells → very rare
Infiltrating tumors from other systems more commonly found
- Hemangiosarcoma in dogs
  - One of the most common tumors
  - Often found on the right auricular appendage
  - Histologically: tumor composed of bizarre spindle cells → irregular vasculature
- Peripheral nerve sheath tumors in cattle
  - Epicardial surface
  - Most considered incidental findings
  - Whirling spindle cells with supporting fibrous stroma
- Rhabdomyomas or muscular hamartomas
  - Rare
  - Most commonly found in pigs, have been reported in dogs, cattle, sheep
- B cell lymphoma
  - Bovine leukosis virus in cattle
  - Heart can be massively affected → little myocardium remaining with few or no clinical signs of heart failure
  - Usual site → right atrium
- Chemodectoma (aortic body tumors)
  - Heart base most often
  - May be an incidental finding

Pathology of Blood Vessels

Normal Vasculature Composition:

Arteries
- Intima: includes endothelial cells and the subintima
  - Normally impermeable to large molecules
  - Anti-inflammatory
  - Resists leukocyte adhesion and thrombosis, promotes vasodilation
- Media: composed of elastin fibers, smooth muscle, and extracellular matrix
  - Enables the contractile and elastic properties of the vessel
    - Aorta/pulmonary artery:allows for stretch during systole and recoil during diastole
    - Arterioles: more prominent muscle content allows for constriction/relaxation to regulate blood flow in response to circulating substances
  - Can also produce extracellular matrix and inflammatory mediators
- Adventitia: contains nerves, lymphatics, blood vessels
Veins are very similar to arteries EXCEPT:
- Thinner subendothelial layer and muscular media
- Typically lack intrinsic vasomotor activity → blood flow is dependent on external compression of the skeletal muscle and one-way valves

Vasculature Reactions

Intimal Thickening: non-contractile smooth muscle cells are recruited via endothelial signals into the intima, where they divide and produce ECM
- Usually a response to vessel injury or aging
- Even with normalization of the endothelial layer intimal thickening remains
Altered Thrombotic Surfaces:
- Physiologic: normal endothelial activation with maintenance of antithrombotic properties and appropriate smooth muscle tone
- Pathologic: endothelial dysfunction as a result of detrimental stimuli (e.g. viral/bacterial infections, hypertension) or excessive physiologic stimuli (persistent hypoxia/acidosis, cytokines)
  - Results in pro-thrombogenic surface and/or abnormal signaling to the underlying smooth muscle cells (altered vasoreactivity)
Altered vascular reactivity and medial proliferation: smooth muscle can dilate or constrict vessels in response to physiologic/pathologic stimuli

Arteriosclerosis: a common general reaction pattern to endothelial damage that results in a loss of elasticity and wall thickening
- Thickenings are grossly white and intimal surface may appear wrinkled
- Result of multiple causes (hypertension, calcification, plaques, etc) related to altered hemodynamics
  - Hypertension: causes increased extracellular matrix deposition in vessels due to protein leakage across damaged endothelia (“hyaline arteriosclerosis”)
  - Persistent Hypercalcemia/Inflammation/Aging: may cause arterial calcification (“medial sclerosis”)
Atherosclerosis: a type of arteriosclerosis that is uncommon in domestic animals (may occur in rabbits, chickens, parrots, non-human primates, and pigs)
- Regarded as a healing response to a chronic inflammatory condition that affects large elastic (aorta) and medium muscular (i.e. coronary, femoral) arteries
- Hallmark is yellow, irregular, and raised intimal “plaques” that protrude into the lumen and are often mineralized
  - Composed of foamy cells of likely smooth muscle origin, monocytes/macrophages, and accumulations of lipid
  - Plaques surfaces are highly thrombogenic and can cause ischemia
  - Pressure to the underlying media can weaken the vessel and cause pathologic dilation/rupture
- Pathogenesis:

Aneurysms: inherited/congenital or acquired focal abnormal dilation of the vessel wall
- Usually the result of vessel alternation in three ways:

1. 1. Congenital defects to connective tissue (e.g. Marfan syndrome)
  2. Increased collagen destruction/decreased collagen synthesis (e.g. protease activity in inflammatory conditions)
  3. Loss of smooth muscle and/or synthesis of non-elastic ECM (e.g. “cystic medial degeneration”)

- False aneurysm: a vessel bulge created by an extravasated focal hematoma forming in the wall between the tunica media and adventitia

Vascular Conditions in Veterinary Species

Vasculitis: inflammation within the blood vessel, causing vessel wall damage
- Hallmarks: perivascular/vascular fibrin deposition, endothelial and stromal cell necrosis, and/or collagen degeneration
  - NOTE: perivascular inflammatory cell presence is NOT sufficient to diagnose vasculitis!
- Can cause thrombosis and hemorrhage with downstream ischemia
- Some important causes of vasculitis include:
  - Viral Disease (ex. FIP, equine arteritis virus, African horse sickness, African swine fever, hog cholera/classical swine fever)
  - Autoimmune Disease (ex. polyarteritis nodosa, hypersensitivity vasculitides)
  - Bacterial/Rickettsial Agents (ex. Rocky Mountain fever, heartwater, hepatic abscesses in cattle)
  - Fungal Disease: (ex. mycotic ruminitis, guttural pouch mycosis)
  - Parasitic: (ex. Strongylus vulgaris, schistosomiasis, Dirofilaria immitis)
Arteriosclerosis:
- Systemic hypertension: can be a cause or effect of renal disease, or related to pheochromocytoma, diabetes mellitus, or hyperthyroidism (among others)
  - Self-perpetuating (increased pressures lead to medial hypertrophy/hyalinization → decreased perfusion → more hypertension)
  - Can also result in retinal degeneration, hemorrhage and detachment
- Pulmonary hypertension (PH): can be a cause or result of pulmonary arterial disease, or related to cardiac diseases (ex. left to right shunting) or medial proliferation secondary to arteritis
  - Hypoxia → pulmonary arterial constriction/hypertrophy → hypertension
  - Cattle and pigs can develop hypertensive heart failure at high altitudes
- Mineralization: dystrophic or metastatic types (ex. vitamin D toxicity, Johne’s disease in cattle, hypercalcemia)
- Uremia: endothelial damage causes fibrin leakage into the media and collagen degeneration within the wall
  - Calcification may also occur from hypercalcemia/hyperphosphatemia
Aneurysmal conditions: often secondary to inflammation or hemodynamic changes (ex. Marfan syndrome, Copper deficiency in swine)
Miscellaneous syndromes
- Cystic rete ovarii in cats, ovarian varicosities in horses, uterine artery rupture in horses: degenerative conditions of the reproductive vasculature that may result in infertility and/or hemoabdomen
- Aortic rupture in horses: uncommon but thought to be secondary to increased aortic pressure; hemorrhage can occur in the pericardium, myocardium or thoracic cavity
- Telangiectasia in the liver of cats/cattle: multifocal, small dilations of the hepatic sinusoids that present as blood filled plaques on the subcapsular surface
Neoplastic conditions
- Endothelial cell tumors
  - Hemangiomas/hamartomas: benign, proliferative conditions of endothelial cells often in the dermis/subcutis
    - Present as a red-pink nodule or plaque with or without ulceration (may look like granulation tissue in horses)
    - Complete excision is curative
  - Hemangiosarcoma: often very aggressive, malignant endothelial tumors
    - Cutaneous/peripheral soft tissue: less aggressive than visceral form
    - Visceral: commonly seen in right auricle, spleen, liver, kidney, and retroperitoneum with widespread metastasis to the lung, body cavities and brain
      - Clinical signs related to coagulation dysregulation from blood flowing/clotting in neoplastic vessels and/or hemoabdomen/hemothorax/hemopericardium
- Vascular wall tumors: benign/low-grade malignancies derived from smooth muscle of the wall (leiomyoangioma/angiosarcoma) or from supporting cells (hemangiopericytoma)
Malformation conditions of the vasculature
- AV fistulas: small abnormal connections between arteries and veins that bypass the capillary bed; can be the result of congenital factors, trauma or inflammation
- Portosystemic shunts: abnormal placement of a vessel connecting the portal and system circulation