What are the 6 steps in the natural history of atherosclerosis?

During which stages is growth mainly due to lipid accumulation, smooth muscle and collagen increased, and thrombus formation?

What is the age of earliest onset for each type?

Stages 1-4=due mainly to lipid accumulation

Stage 5=Smooth muscle and collagen increase

Stage 6= thrombus or hematoma

First decade is 1-2

3rd decade is 3-4

forth decade on is 5-6

When staining for fibrous tissue, what stain should be used?

What color does fibrous tissue show with this stain?

Trichrome stain

Blue

Small: 

-Atheromas occlude lumens and cause ischemia

-Plaques can break off and cause thrombi

Large:

-Friable atheromas can shed emboli

What makes a plaque vulnerable?

What drug class can help prevent thrombus formation?

Contains large areas of foam cells, extracellular lipid, thin fibrous caps, few muscle cells, or have clusters of inflammatory cells

Balance of the synthetic and degradative activity of collage is the major determinant of the cap's stability

Statins

1. Onset of ATP depletion-within seconds.

2. Loss of contractility (2 minutes)

3. ATP reduced to 50% (10 min.)

4.ATP reduced to 10% (40 min.)

5. Irriversible injury (20-40mins)

6. Microvascular injury (1 hour)

0-1/2 hr: No gross or microscopic changes (reversible injury)

30 min-4 hr: Micro - can see waviness of fibers at border 

4-12 hr: Gross-dark mottling; Micro: early coagulation necrosis with nuclear pyknosis, cytoplasmic hypereosinophilia; early neutrophilic infiltrate

1-3 days: Gross: mottling with yellow-tan center; Micro: coagulation necrosis and interstitial neutrophilic infiltrate

3-7 days: Gross: central yellow, hyperemic margin; Micro: disintegration of dead myofibers with their phagocytosis by macrophages

7-10 days: Gross: yellow-tan and soft with depressed red-tan margins; Micro: early granulation tissue at margins

10-14 days: Gross: red-gray depressed borders; Micro: well-established granulation tissue

2-8 weeks: Gross: scar; Micro: collagen deposition with decreased cellularity

>2 months: Gross: complete scar; Micro: collagenous scar

According to Polson and Gee regarding hemoglobin color changes:

red dark / red black< 24 h

greenish tingearound day 7

yellowaround day 14

resolutionup to 30 days

Atherosclerotic plaque thrombosis

Coronary artery occlusion

Lack of oxygen to cardiac muscle

Myocardial infarction

What factors influence cardiac output?

What factors influence peripheral resistance?

How is BP generated?

Cardiac Output:

Blood volume (sodium, mineralocorticoids, atriopeptin)

Heart rate

contractility

Periph resistance:

Constrictors (angiotensin II, Catecholamines, thromboxane, leukotrienes, endothelin)

Dilators (Prostaglandins, Kinins, NO)

Local factors (Autoregulation via pH or hypoxia)

Neural factors (alpha or beta receptor activity)

BP is a combonation of CO and PR.

What are the 3 types of cardiomyopathy?

Which is most common?

Dilated CM (congestive) Most common

Hypertrophic CM

Restrictive CM

Idiopathic

Viral myocarditis – i.e. Coxsackie B virus 

Alcohol (ethanol) toxicity

Pregnancy (Peripartum CM)

Genetic – 20-30% of DCM’s are familial

Drug toxicity – (i.e. Adriamycin)

Sarcoidosis

50% of cases are familial – AD with variable expression

Genetic defects arise from mutations in any one of four genes that encode proteins for cardiac sarcomeres

Beta-myosin heavy chain (35%)

Troponin T (15%)

Myosin-binding protein C (15%)

Alpha-tropomyosin (<5%)

What are the clinical findings of hypertrophic cardiomyopathy?

What is the treatment?

A common cause of sudden death in young athletes

Impaired diastolic filling of massively hypertrophied LV

May see LV outflow tract obstruction 

Exertional dyspnea due to decreased cardiac output and increased pulmonary venous pressure

Harsh systolic ejection murmur

Angina with focal ischemia

Atrial fibrillation with mural thrombi

Bacterial endocarditis of the Mitral Valve

Treatment: Excision of part of IVS; ventricular relaxation

What are the causes of restrictive cardiomyopathy?

What is the morphology of this disease?

idiopathic, radiation fibrosis, amyloidosis, hemochromatosis, sarcoidosis, metastases, products of inborn errors of metabolism

Ventricles are of normal size

Ventricular cavities are not dilated

Dilatation of the atria commonly seen

Histo: patchy or diffuse interstitial fibrosis of varying severity +/- material infiltrating the myocardium (i.e. amyloid)

Mitral Stenosis

Post-inflammatory scarring (RHD)

Mitral Regurgitation

Leaflet/Commissure

Tensor apparatus

Annulus

Mitral Stenosis – Rheumatic Heart Disease

Mitral Insufficiency – MVP (myxomatous degeneration)

Aortic Stenosis – Calcification

Aortic Insufficiency – Dilatation of ascending aorta (due to HTN, aging)

Migratory polyarthritis of large joints

Carditis

Subcutaneous nodules

Erythema marginatum

Sydenham chorea

Deforming fibrotic valvular disease (MS)

Aschoff bodies – seen in acute RF

Fibrinous (“bread-and-butter”) pericarditis

Valves: left-sided valves show fibrinoid necrosis of cusps with small verrucous vegetations along lines of closure

Pathogenesis

Antibodies directed against M proteins of group A strep cross-react with tissue glycoproteins in the heart and joints

Clinical Features

Acute rheumatic fever typically appears in children 5-15 years old

Antibodies to streptolysin O and DNAase B

Carditis and arthritis

What are the major infective agents that cause infective valvular heart disease in:

A patient with a native abnormal valve

IVDA (right sided valves)

Prosthetic valves

What can be seen morphologically?

Native abnormal valve: strep viridans

IVDA (right-sided valves): staph aureus

Prosthetic valves: staph epidermidis 

Bulky, friable lesions

The most consistent clinical sign is fever

Murmurs can be appreciated, especially with left-sided lesions

Other clinical findings include subungal (splinter) hemorrhages, petechiae, and Roth spots

Mitral valve most often affected (non-IVDA)

Aortic valve involvement associated with sudden death

What are two non-infective sources of endocarditis?

What can be seen and what are the volunerable populations to these diseases?

Nonbacterial Thrombotic Endocarditis

Deposition of small non-destructive masses of fibrin and platelets on leaflets

Seen in the debilitated, especially cancer pts

Associated with hypercoagulable states (i.e. mucin-secreting pancreatic adenocarcinoma)

Libman-Sacks Endocarditis

SLE pts with mitral and tricuspid vegetations leading to regurgitation

Small, sterile vegetations on the undersurfaces of AV valves

Involves the right side of the heart in pts. with carcinoid syndrome

Flushing, cramps, n/v, diarrhea

Fibrous intimal plaque-like thickening on the endocardium and valve leaflets

Composed of smooth muscle and collagen in an acid mucopolysaccharide matrix 

Carcinoid tumors release bioactive substances (i.e. serotonin, kallilkrein, bradykinnin, histamine, prostaglandins)

Correlation of urinary excretion of 5-hydroxyindoleacetic acid (serotonin metabolite) with the severity of right-sided cardiac lesions

What is the rate of complications in individuals with replacement heart valves?

What are the 4 most common complications?

Thromboembolism – prophylatic anticoagulation

Infective Endocarditis – staph skin contaminants

Structural deterioration – porcine valves

Hemolysis – high blood shear

Filariasis:

Parasitic infection

Causes fibrosis of lymphatics and nodes within inguinal region

Resulting edema of lower limbs and external genetalia

Describe when hyperemia can be seen?

What is the purpose of this?

an active response that can normally be seen in working skeletal muscle.  Commonly associated with inflammation and the vasodilation of "blushing".

Allows for more flow of immune cells to a problem area, and slows down flow to keep them there.

Central veins and sinusoids distended with blood

May see central hepatocellular degeneration

Periportal hepatocytes better oxygenated

"Nutmeg liver"

Centrally red-brown and slightly depressed

Hepatocellular loss

Surrounded by uncongested, tan liver

Engorgement of the sinusoids with blood

Name 2 organs that are very hard to infarct?

Why is this?

Lung and liver

Dual blood supply

What can be seen morphologically with chronic passive congestion of the liver?

What about clinically?

What is the pathology?

Centrilobular necrosis

Hepatocyte drop-out

Hemorrhage and hemosiderin-laden macrophages

Cirrhosis

Can see hepatomegally as a result of a slow onset of heart failure causing slow, passive liver congestion.  

Chronic ischemia causes death of hepatocytes and replacement by fibrous material.

Acute:

Tissue engorged, hemorrhagic and wet appearing grossly

Dependent septal engorgement. May hear crackles on PFT, but gross changes are probably elusive

Chronic:

Septa become thickened and fibrotic

Alveolar spaces contain numerous hemosiderin laden macrophages

What role does intact endothelium have in preventing thromboembolism?

What properties does it possess?

intact endothelial cells serve primarily to inhibit platelet adherence and blood clotting

Endothelium has antiplatelet, anticoagulant and fibrinolytic properties.

Antithrombins

Proteins C & S

What area of the body is most at risk for hemodynamic stasis?

What is the highest risk in this area?

How can this be prevented?

Lower extremities (MC is spider veins)

Need to worry about DVT from the deep veins of the leg.

Walking/moving legs (as on a long airplane flight)

Which of the 3 dominant causes of thrombosis is MOST potent?

Where is this most important in terms of incidence?

Endothelial injury

Can cause thrombosis by itself

Most important in regions of high flow such as heart and arterial vessels rate

Thrombus formation in cardiac chambers such as post MI

Ulcerated plaques in arteries

vasculitis

Endothelial injury

Alterations in normal blood flow (causes endothelial injury/dysfunction)

Hypercoaguability

Prevent dilution of activated clotting factors

Retard inflow of clotting factor inhibitors

Promote endothelial cell activation

Arterial thrombi:

Atherosclerosis- major factor in arterial thrombi

Cardiac mural thrombi due to MI and cardiac dyskinesia or rheumatic heart disease causing atrial thrombi due to mitral valve stenosis

Embolization to spleen, brain, kidneys

Morphology

Grow retrograde to site of attachment and show lines of Zahn- alternating platelet and fibrin

Venous thrombi:

Most in superficial or deep veins of legs

Superficial-saphenous veins,varicosities

Deep- larger veins at or above knee( popliteal, femoral,iliac), more likely to embolize, asymptomatic in > 50% (wow!! Does that scare you!!!)

Morphology

Venous – sites of stasis

extend in direction of blood flow(toward heart)

 red(stasis) thrombi

Stasis(ie cardiac failure, enforced inactivity, post surgery or trauma)

Hypercoagulable states

Amniotic fluid infusion

Late pregnancy/postpartum

Tumor associated procoagulant release(Trousseau syndrome)

What is the etiology and pathology of disseminated intravascular coagulation?

What is this usually associated with?

Dysfunctional coagulation system resulting in widespread development of fibrin thrombi throughout vasculature

Generally microscopic 

Associated with fibrinolytic system in overdrive

So have clots and bleeding, massively decreased platelets,decreased thrombin.etc

Propagation-enlarge

Embolization- dislodge and travel to other sites

Dissolution- dissolve due to fibrinolysis

Organization and recanalization-inflammation and fibrosis with eventual development of new vascular channels in the clot

What is the most serious predisposing factor for a pulmonary embolism?

What is the most common area of origin?

Stasis

Deep veins of the leg.

What is the pathology of a systemic embolism?

What are the most common origins of this type of embolism?

Thrombi traveling through the arterial circulation

MC from intracardiac mural thrombi

MC from LV wall infracts

A patient who recently had a large supply box fall on his right arm presents with tachypnea,dyspnea and tachycardia, neurologic symptoms and thrombocytopenia. Symptoms began 1-3 days post injury.

This is most likely:

Red (hemorrhagic)

Venous occlusions (torsions)

Loose tissues like lungs

Tissues with dual circulations

Previously congested tissues

When blood flow is re-established to a site from previous

White(anemic)

Arterial occlusions in solid organs

Cardiogenic

hypovolemic

Septic

Waterhouse-Friderichsen syndrome

Overwhelming menigococcalsepticemia

Bilateral 

Massive hemorrhgic necrosis of entire gland

Acute adrenal insufficiency

In a lung expriencing shock, what can be seen morphologically?

What changes are mediated by neutrophils in this condition?

Hyaline membranes

Type II pneumocyte proliferation

Fibrosis and organization of exudate

Intersitial edema

Necrosis of endothelial cells

Microthrombi

Necrosis of alveolar epithelium

Fever of unknown origin

Unexplained multisystemic disease

Peripheral neuropathy

Arthritis without known cause

Unexplained myositis

Unexplained GN

Rash

Unexplained ischemia

Immune complex deposition

Antineutrophil cytoplasmic antibodies (ANCAs)

Anti- endothelial cell ABs

Immune mediated!

What is the most common target of c-ANCA?

What about p-ANCA?

The most common target for c-ANCA is PR-3

The most common target for p-ANCA is myeloperoxidse (MPO)

What is the most common type of vasculitis in the elderly?

What is the etiology?

What part of the body is mainly affected?

What is the epidemiology and clinical presentation?

How is this treated?

Giant cell (temporal) arteritis

Acute and chronic inflammation

 often with granulomatous inflammation

 of small to large arteries

Principally arteries in the head are

 affected esp. temporal, vertebral, 

 opthalmic arteries and the aorta 

The pathogenesis is unknown (?immunologic

 reaction against an arterial wall component)

assoc. with HLA-DR4

Patients are usually in the 5th decade of life

with constitutional symptoms; facial pain

or headache along he course of the 

temporal artery—maybe painful to 

palpate

Treatment is with anti-inflammatory

 agents

What disorder is considered "young age temporal arteritis" due to its similarity to temporal arteritis?

Where does this disorder usually act on?

What can be seen clinically?

Takayasu Arteritis (think asian patients mostly)

Classically involves the aortic arch

and its branches

Clinically, due to narrowing of 

great vessels patients exhibit

ocular disturbances, weakening

pulses of the upper extremities, coldness

or numbness of fingers, retinal hemorrhage

blindness, HTN…more distal aortic 

involvement may lead to claudication of legs  

What size arteries are affected by polyarteritis nodosa (PAN)?

What is the epidemiology and clinical presentation of this disorder?

What percent of patients have Hep. B antigen in their serum who have PAN?

What test can be used to rule IN a vasulitis as opposed to other diseases?

PAN is a systemic, segmental vasculitis of medium or small sized arteries (not arterioles, capillaries or venules).

Patients are generally young adults

and vascular involvement is widely

scattered (as are symptoms)

which include fever of unknown origin, 

weight loss, HTN, abdominal pain, 

melena, neuritis, muscular aches,etc

30%

CRP

What characteristics in a patient are very indictive of a patient with PAN?

How can this be treated?

What is an "allergic variant of PAN" that can be seen in children and adults?

Think YOUNG and Male

Think systemic (usually not lung though)

Think small and medium size arteries

Because of above the systems VARY depending on the system involved

Do your ANCA studies looking for anti MPO

Bx. An affected artery

Treat with steroids because people can die from this disease (you may have assumed this already I hope)

Churg-Strauss syndrome

What is the triad seen in Wegener's granulomatosis?

How can this be treated?

1)Acute necrotizing granulomas of the 

upper respiratory tract, lower respiratory

tract (or both),

2) necrotizing or granulomatous

vasculitis affecting small to medium sized

vessels (capillaries, venules, arterioles, arteries)

3) renal disease (focal necrotizing glomerulitis)

immunosuppression

In Thromboangiitis Obliterans (Buerger Disease), what is a characteristic population that has this disorder?

What symptoms can be seen?

Smokers

Pain (claudication)

Thrombophlebitis

Ulceration and gangrene

Raynaud phenomena

    - Rupture (risk increases as size increases over 4cm in diameter)

    - Obstruction (thrombus)

    - Impingement on an adjacent structure (ureter, erosion of vertebra)

    - Embolization of thrombus

 1. men in the 4th-6th decade of life with antecedent hypertension

      2.  younger patients with a systemic or localized connective tissue abnormality (ex. Marfan syndrome)

- Barbiturates

Theophylline

- Cocaine

- Doxorubicin (anticancer drug)

A 31 year old male patient presents with sudden onset of heart failure and no history of atherosclerosis. You hear a regurg. murmur on ascultation. What should you SUSPECT?

What is the most common cause, and how can this be treated?

Myocarditis

Coxsackie virus (need supportive treatment)

What is the most common kind of endocarditis?

How can you make a diagnosis for valvular complications?

What are common complications?

Subacute

Transesophageal echo

Valve insufficiency, arrhytmias, thrombi (mural in origin)

What statistical term describes the likelihood of a + test in a patient who has a disease of interest?

What about the chance of a - test?

Sensitivity

Specificity