PathExam2

Circadium rhythm – 24 hr rhythm. Cortisol exhibits diurnal variation
<24 hrs rhythm = Ultradian. >24 hr rhythm = Infradian
Analyte results vary according to time of last meal. Blood sugar. Triglycerides.
Drug metabolism

Reliability of testing method

recognized methodology against which new tests are compared

reproducibility of a result

frequency of patients with certain disease in the group tested

number of patients in whom disease develops in a 1 year period

Sensitivity = TP/(TP+FN) x 100%

Specificity = TN/(TN+FP) x 100%

ratio of true positive to all positive results
PPV = TP/(TP+FP) x 100%

ratio of true negatives to all negative results
NPV = TN/(TN+FN) x 100

renal disease, dehydration, shock, heart failure, etc.
Non renal? Catabolism or GI bleed.

late renal disease; poor renal perfusion, dehydration, etc. Insensitive but specific for renal impairment

prehapatic = hemolysis;
intrahepatic = hepatitis, cirrhosis
posthepatic = gallstone in bile duct

most common - liver, bone, placenta
others – intestine, some cancers

elevated non-specifically with variety of tissue damage. Isoenzymes can help narrow specific cause.
Small amount of tissue damage can cause large amount of plasma elevation.
High levels associated with breakdown of erythrocytes and platelets

AST = liver, cardiac, and skeletal muscle injury
ALT = liver disease.

CK-MB – very specific
AST and LD – nonspecific
myoglobin
Troponin I (and T) – high sensitivity and specificity for MI

AST
ALT (specific)
Alk Phos
Lactate Dehydrogenase
GGT (gamma glutamyl transferase)

Muscle – CK, AST, LD, Aldolase, myoglobin
Skeletal – Alk Phos

Decreased Prealbumin = impaired synthesis (malnutrition, malabsorption, hepatic dysfunction, chronic inflammation)
Decreased Albumin = increased loss (renal disease such as nephrotic syndrome, protein losing gastroenteropathy, ascites)

a-1-antitrypsin (A1AT). Decreased with emphysema and cirrhosis. Elevated during acute phase reactions to inhibit leukocyte elastase.

These are acute phase reactants and they elevate in response to acute inflammation.
•Alpha‐2‐macroglobulin: kinin inhibitor
•Haptoglobin‐carrier of free hemoglobin
•C‐reactive protein ‐ Sensitive indicator of tissue necrosis, acute infection and inflammation

“protein that reacts to C-substance of streptococci”
Coats bacteria; serves as opsinin
Acute phase reactant ‐fastest rising; doubles q 6 hours; reflects presence of bacterial infection; elevated in inflammatory response to autoimmunity, disease progression in RA
Can serve as predictive value for cardiovascular events such as MI and stroke

Causes are anything that can cause acute inflammation (infections, injury, ischemia, etc)
Reactants and reactions include Neutrophilia, Thrombocytosis (platelets increased), Fibrinogen increased, Alpha‐2‐macroglobulin increased, C‐reactive protein increased, Haptoglobin increased, Albumin decreased, Erythrocyte sedimentation rate increased

Erythryocyte Sedimentation Rate. Nonspecific indicator of inflammation. Increased ESR indicates increased globulins and fibrinogen and decreased albumin.

Albumin

Gamma globulins are produced by plasma cells.
Alpha and beta globulins are produced by liver.

B-cell immunodeficiencies

•Polyclonal gammopathy ‐ autoimmune disease; chronic infections
•Monoclonal ‐ plasma cell malignancy or premalignancy or lymphoma
•Oligoclonal ‐ small number of bands‐ CNS test (significance to be discussed later)
In other words, Polyclonal gammopathy = autoimmune disease while monoclonal gammopathy = cancer. Oligoclonal won’t be tested.

Exudates have high protein content (>3g/dL) and are usually purrulent. Caused by increased vascular permeability due to infections, repair (angiogenesis – new vessels are ‘leaky’), malignancy (increases angiogenesis)

Transudates have low protein content (<3g/dL) and are usually serrous. Caused by increased hydrostatic (such as heart failure), decreased oncotic pressure (such as in liver or kidney disease), lymphatic obstruction, primary salt retention.

Locations= lower legs, feet and extremities in general.

Causes= Impaired venous outflow, DVT or some other venous obstruction,

Generalized edema = heart failure.

Pathogenesis
• Right ventricular dysfunction increases venous hydrostatic press ‐ damming of blood
Clinical Correlate - RAP is high (>3mmHg). PAP is high (>9mmHG).

Pathogenesis
• Plasma volume expands; hydrostatic pressure increased
‐ Secondary to signals from poorly perfused kidneys
‐ mediated via renin‐angiotensin‐aldosterone axis
‐ minor contribution via ADH from post. pituitary
Clinical correlate - Ejection fraction is low (<55%).

Clinical features= Diffuse lung rales, scleral icterus, hepatomegaly, pitting edema and jugular distention. Pitting edema and jugular distension indicative of transudation due to high venous pressure.

Decreased osmotic pressure can be due to Increased protein loss such as Nephrotic syndrome (disease of renal glomeruli) or Protein losing enteropathy (GI loss). Can also be due to Decreased protein/albumin production due to severe liver disease (cirrhosis) or Malnutrition
Initial manifestation is often periorbital edema.

Lynphodema = Impaired lymphatic drainage leading to edema.
Causes = Primary cause is inherited or developmental defects in lymph vessels or nodes, e.g. Milroy’s disease. Secondary causes are acquired defects to lymph channels through trauma, radiation, metastatic cancer, extrinsic pressure on nodes (such as a tumor), or infections of the lymphatics.
Complications i= pain, peau d’orange, secondary infections, and lymphangiosarcoma (lymph vessel cancer).

Localized Edema aggravated by gravity. Lower extremities in ambulatory patients. Sacral edema in bed ridden patients.
Caused by impaired venous return.
Can occur w/o pathology (occupations that require long periods of standing; long car/plane rides; pregnancy).
Pathological causes would be right ventricular heart failure or DVT.

Causes = Left ventricular failure (most common), Renal failure, Adult respiratory distress syndrome, Pulmonary infections, Hypersensitivity rxns.

Morph = lungs 2‐3x increase in weight filled with frothy, blood tinged fluid. LM reveals hemosiderin‐laden macrophages in alveoli
(Prussian blue stain positive cytoplasm)

Clinical Features = Short of breath, Bilateral diffuce lung rales, Scleral icterus, Resting Tachypnea, Hepatomegaly, Bilateral pitting edema of the legs, Jugular distention

Associations= Hypertensive crisis (most important), encephalitis, trauma, hypernatremia.
Morph= Brain is swollen w/ flattened gyri and narrow sulci, papilledema present (important sign).

Serous effusion= Yellow colored fluid between serosa It's supposed to be there. If large amount, drain it and order cytology to check for cancer (per Finch lecture).
Serosanginous effusion= pink fluid (tinged with blood) due to Trauma, malignancy or pulmonary infarction
Chylous effusion= milky white fluid due to Traumatic disruption of thoracic duct or thoracic duct obstruction from a tumor
Bloody effusion= red fluid (more blood than serosanguinous), e.g. Hemothorax, hemoperitoneum, hemopericardium . All due to trauma or ruptured vasculature.

Hyperemia (erythema) = Active process; arteriole dilation causing a red color due to increased oxygenated blood.

Causes= exercise, inflammation - action of cytokines, TNF, others, act on endothelium to cause vasodilation

Congestion = Passive process. Impaired venous outflow from tissues /stasis causing a blue color (cyanosis) due to decreased oxygen. Commonly associated with edema.

Morph = Lungs - same as pulmonary edema; wet rubbery and brown with hemosiderin.
Liver - nutmeg liver
lower legs - edematous; brown induration
Spleen - enlarged and soft

Pathogenesis=Blood vessels dialate and circulation is impeded. Hypoxic injury leads to cell death leads to microscopic scarring. Capillary rupture produces focal hemorrhages, siderophores accumulate ( can see with prussian blue stain.)

Causes= Heart failure. Local venous obstruction.

Cause= Right sided Heart failure

Morph= Nutmeg liver w/ red brown depressed areas due to centrilobular hemorhagic necrosis.

Clinical Features= AST, ALT and LH are elevated. Persistant/ chronic congestion causes siderophores to accumulate and leads to fibrosis of the liver

Cause= Right sided heart failure, hepatic cirrhosis, portal vein occlusion
Morph= spleen is enlarged and soft.

Chronic venous insufficiency due to valve defects causes Brown coloration due to accumulation of hemosiderin‐laden macrophages in dermis
‐ Induration (in‐duro = to harden) due to fibrosis
Complication = stasis ulceration

Mass of blood confined within an organ, tissue or confined space.

bruise/ecchymosis: Blunt force injury damages small blood vessels w/o disruption of continuity of tissue

Large area greater than 1-2 cm of bruising. Changes over time as heme is converted to bilirubin and siderophages accumulate.
Red-Blue -> Blue-Green -> Gold-Brown

Punctate hemorrhages associted w/ thrombocytopenia, dysfunctional plattlets and suffocation

Confluent petechiae > 3mm, similar cause as petichiae but include vascular inflamation and trauma.

Bleeding into a joint

Laceration = Tear due to blunt force trauma, bridging strands are present
Incision = cut made by sharp cutting object, clean margins w/o bridging
Abrasion = Scrape in which superficial dermis is torn off by friction.

Epistaxis= Nosebleed
Hemoptysis= coughing up blood
Hematemesis=vommiting blood
Hematochezia= bright red blood in the stool
Melena=black digested blood in the stool
Hematuria=blood in the urine
Menorrhagia=excessive menstrual bleeding.

Initially you have vasoconstriction of muscular arteries, then platelets kick in.
1-Platlet adhesion to ECM via vonwillebrand factor and exposure to collagen.
2-Platelets become activated and undergo a shape change via actin / myosin in the platelets.
3-Granule release ( ADP and TXA2)
4-Recruitment of additional platelets
5-Platelet aggregation and formation of the primary hemostatic plug and phospholipid platform.

• Platelet adhesion to ECM, via vonWillebrand
factor and exposure to collagen
• Platelets activated with shape change ‐ actin‐myosin in platelets
• Granule release
• Recruitment of additional platelets
• Platelet aggregation and formation of primary
hemostatic plug ‐ phospholipid platform

Defects of adhesion
1-Von willibrand disease= deficiency in von willebrand factor
2-Bernard-Soulier syndrome= platelet dysfunction, GP1b defect

Defects of aggregation.
1-Glannsmann thrombasthenia= dysfunction of GP11b and GP111a

Signs and Symptoms of Primary hemostasis
• Superficial bleeds
• Epistaxis
• Bleeding gums
• Bleeding from gums
• Petechia
• Purpura
• Eccymosis
• Bleeding from GU

1-ADP receptor PY2 inhibitors - inhibits aggregation
2-GP11b and GP111a inhibitors - prevents fibrinogen bridge and thus aggregation
3-Aspirin / NSAIDS - Blocks cyclooxygenase action of arachidonic acid thus inhibition TXA2 production-> decreased aggregation
4-Prostacyling PGI2 - vasodilation and inhibition of plattlet aggregation
5-NO - vasodilation and inhibition of plattlet aggregation
6-Thromboxane - vasoconstriction and promotes plattlet aggregation

NOTE: Antiplatelet drugs effect function of platelets not their #’s

1-Thrombocytopenia= Decreased plattlet numbers, due to decreased production in bone marrow and increased peripheral destruction. See in autoimmunity (HIV)
2-Dysfunctional plattlets= Seen in Uremia (kidney failure) and the above drugs.

• Platelet adhesion to ECM, via vonWillebrand
factor and exposure to collagen
• Platelets activated with shape change ‐ actin‐myosin in platelets
• Granule release
• Recruitment of additional platelets
• Platelet aggregation and formation of primary
hemostatic plug ‐ phospholipid platform

Defects of adhesion
1-Von willibrand disease= deficiency in von willebrand factor
2-Bernard-Soulier syndrome= platelet dysfunction, GP1b defect

Defects of aggregation.
1-Glannsmann thrombasthenia= dysfunction of GP11b and GP111a

Signs and Symptoms of Primary hemostasis
• Superficial bleeds
• Epistaxis
• Bleeding gums
• Bleeding from gums
• Petechia
• Purpura
• Eccymosis
• Bleeding from GU

1-ADP receptor PY2 inhibitors - inhibits aggregation
2-GP11b and GP111a inhibitors - prevents fibrinogen bridge and thus aggregation
3-Aspirin / NSAIDS - Blocks cyclooxygenase action of arachidonic acid thus inhibition TXA2 production-> decreased aggregation
4-Prostacyling PGI2 - vasodilation and inhibition of plattlet aggregation
5-NO - vasodilation and inhibition of plattlet aggregation
6-Thromboxane - vasoconstriction and promotes plattlet aggregation

NOTE: Antiplatelet drugs effect function of platelets not their #’s

1-Thrombocytopenia= Decreased plattlet numbers, due to decreased production in bone marrow and increased peripheral destruction. See in autoimmunity (HIV)
2-Dysfunctional plattlets= Seen in Uremia (kidney failure) and the above drugs.

1-Thromboelastograph= used in some hospitals instead of bleeding time
2-Platelet function analyzer= Time to form a platelet plug, analogous to bleeding time
3-Bleeding time= poor reproducability but continues to be used
4-Platelet count= ref range is 150-350 x10^3 / mm^3
Platelet function/Bleeding time typically takes between 2-9 minutes. It is prolonged in Von willibrand disease, platelet dysfunction and reduced platelet number.

Aggregation mediators:
‐ ADP
‐ TxA2 (thromboxane)
‐ Thrombin
- Gp11b111a

• Tissue factor (TF) upregulated by vessel injury, activates VII to VIIa
• TF‐VIIa complex formed ‐activates IX -> IXa
• IXa binds to VIII = forms the tenase complex
• Factor X activated by either of two routes
1. IXa‐VIII (tenase complex)
2. TF‐VIIa
• Xa binds factor V (prothrombinase complex)
• Xa‐V activates prothrombin to thrombin
• Thrombin amplifies generation of more thrombin
• Tissue factor pathway inhibited

Prothombin Time (PT)
• Tissue factor, Ca++, phospholipid added to patient plasma to form clot
• Time to clot measured ~ 12‐14 seconds
• Prolonged in: ‐ extrinsic factor and common pathway factor deficiencies VII, X, V, II, I
• Used to monitor coumadin therapy ‐ INR: ratio of patient to control

Partial thromboplastin time , aPTT
• a (Activating factor), calcium, phospholipid added.
• Time to clot formation is measured: usually < 40 seconds
• Prolonged in ‐ deficiencies of XII, IX, XI, VIII, X, V, II, I
‐ circulating anticoagulants, eg. heparin or other inhibitors
• Monitors unfractionated heparin therapy

‐‐ Liver disease (severe) ‐ liver failure
‐‐ Vitamin K deficiency
‐‐ Anticoagulants drugs
‐‐ Disseminated intravascular coagulation due to consumption of procoagulants

--Factor VIII is x-linked. Screen=prolonged aPTT
--Factor IX is x-linked. Screen=prolonged aPTT.
--von Willebrand is autosomal dominant, and rarely recessive. Prolonged aPTT. Prolonged Bleeding Time.
--the remaining deficiencies are autosomal recessive

Dependant Factors: II, VII, IX, X

Causes: Malabsorption, Antibiotic Therapy, Dietary deficiency, Coumadin therapy, Neonates (sterile GI)

Labs: PT is prolonged early/first. PTT is only prolonged in severe deficiency

-physically inhibits platelet adhesion
-vasodilators also inhibit platelet aggregation (PGI2, NO, ADPase)
-anticoagulants (Antithrombin III, Protein C, Protein S)
-fibrinolytic – tPA (“clot buster”
- Heparin-like molecule is a cofactor for antithrombin
- Thrombomodulin binding: inhibits thrombin and activates protein C
- Tissue factor pathway inhibitor: complexes to and inactivates factor Xa and VIIa
- Thrombin binding to thrombomodulin

ATIII, Protein S, and Protein C
ATIII-heparin complex inhibits thrombin and other serine proteases IXa, Xa, Xia
Protein S and Protein C complex to inactivate Va, VIIIa
Clinical disease from deficiency is inherited thromophilia.

Actions = breakdown of fibrin to yield fibrin split products, FDPs, and d-dimer. Inhibits fibrin polymerization = limits coagulation
Labs = prolonged PT and d-dimers
Inhibitors = PAI (plasminogen activator inhibitor), alpha 2-plasmin inhibitor (neutralizes free plasmin)

Definition: pathologic process-formation of a clot within intact vascular system

Virchow’s Triad:
-endothelial injury - cigarette smoke, sepsis, malignancy
-stasis or turbulence of blood - atherosclerosis, aneurysms, A-fib, hyperviscosity, sickle cell
-blood hypercoagulability – primary or secondary thrombophilia

Factor V Leiden Mutation – 5-9% of Caucasians
Prothrombin 20210A mutation - 2% of population
Hyperhomocystenemia - 5-15% of Caucasians, E. Asians homozygous

Clinical features: Occurs in 5-9% of Caucasians. Up to 60% of patients with recurrent DVTs
Type of mutation: Single amino acid substitution (missence mutation)
Pathogenesis: factor Va that is resistant to digestion by activated protein C
Labs: activated protein C resistance, genetic testing for mutation

Single nucleotide change in untranslated region
Mutation results in increased levels of prothrombin
Increased prothrombin drives more fibrin = hypercoagulability
2% of population___3x increased risk of DVT

Mutation in MTHF-R enzyme (note: that abbr. looks a lot like the word I’m thinking while I type this and realize it’s only halfway through the objectives! MTHF-R!)
5-15% of Caucasians, E. Asians homozygous
Inhibits ATIII activity and thrombomodulin
Contributes to formation of atherosclerosis
Acquired form: B12 or folate deficient

High Risk Causes:
• Prolonged bed rest; immobilization (most important)
• Myocardial infarction; atrial fibrillation
• Tissue damage: surgery, esp orthopedic; fracture, burns, crush injury
• Cancer: procoagulant tumor products
• Prosthetic heart valves
• Disseminated intravascular coagulation
• Antiphospholipid antibody syndrome
• Age over 60; prior thrombosis at any time

Examples with less risk associated:
-hyperestrogenic states
-birth control pill use
-sickle cell anemia
-smoking
-obesity

Define: Heparin‐induced Thrombocytopenia
Pathogenesis: “think heparin allergy” Antibodies form to unfractionated heparin and cascade to create platelet rich thrombi
Clinical: thrombocytopenia due to platelet consumption (suspect when pt’s platelets drop by 50%). Rarely occurs with low molecular weight heparin and factor X inhibitor

Define: disorder of coagulation that causes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications. The syndrome occurs due to the autoimmune production of antibodies against phospholipid. May be primary: solitary autoimmune defect
May be secondary: to SLE (lupus)

Clinical Findings:
-repeated spontaneous abortions (antibody mediated inhibition of tPAno trophoblastic invasion of endometrium)
-cardiac valvular vegetations—Libman Sachs
-thrombocytopenia
-catastrophic antiphospholipid syndrome:
-widespread small vessel thrombi
-50% mortality

Yes. These questions are very repetitive and getting quite ridiculous.
Causes: Long periods of immobilization, primary thrombophilia, cancer, smoking, birth control, obesity, etc.
Consequences: emboli, infarct, etc.
Most common location: Deep veins of legs (90%).
Why: large vein, slower blood flow, prone to stasis and disruption

Cause: Atherosclerosis
Clinical: findings and consequences dependant on location.
Coronary artery thrombis = MI
Cerebral artery thrombis = CVA
Femoral artery thrombis = Gangrene of leg
Mural thrombis = with in chamber of heart (systemic emboli is most important source)

Embolus: detached solid, liquid, or gaseous mass that is carried by the blood to a site distant from its origin
Most common: thromboemolism (embolus of blood clot/thrombus)
Consequence: occlusion leading to infarct
Venous Emboli: peripheral veins to lungs (PE)
Arterial (systemic) emboli: heart, arteries to peripheral arteries (MI, stroke, gangrene, etc)

Most common source of PE (95%) is DVTs from the deep veins of the leg above the popliteal fossa
Other common source of PE is a R ventricular mural thrombus

Saddle Embolus: large embolus that occludes the bifurcation of the main pulmonary artery
Produces electrical mechanical dissociation (EKG activity with no pulse). Fatal.
*Know pic for test and don’t get tricked by a pick of a giant PE!

Massive simultaneous emboli: large embolus that occurs in bronchi and occludes 60% of pulmonary circulation. Causes obstructive shock. fatal

Smaller PEs: most are clinically silent because of their small size. Cause Pulmonary Infarct, Pulmonary hemorrhages and pulmonary HTN with cardiorespiratory compromise

Sources:
•Intracardiac mural thrombus (80% of time)—see Fig. 4.13
•Aortic Aneurysm (figure 4.13)—be able to ID on test!
•thrombi from ulcerated atherosclerosis
•valvular vegetation (endocarditis)
•paradoxical embolus

Emoblization Sites:
•lower extremities (75% of time)
•brain (most vulnerable)-occurs 10% of time
•intestines, kidneys, spleen
•retina (central artery of retina)

Disseminated Intravascular Coagulation is a thrombo-hemorrhagic disorder, a.k.a. consumptive coagulopathy. Systemic activation of coagulation pathways leads to thrombi throughout microcirculation. platelets and coagulation factors are consumed. Fibrinolysis is activated
- Can be acute, subacute, or chronic
- Can be a secondary complication of variety of diseases
Labs: Low platelets. Extremely prolonged PT.

Chronic DIC:
-presents typically as thromboembolism
- venous thrombi
- nonbacterial thrombotic endocarditis
Example is Trousseau Syndrome
-migratory thrombophlebitis in a patient with pancreatic cancer

-Occurs with trauma, usually fracture of long bones (marrow leaking = bad news bears)
-Fat/Bone marrow embolization is common in pts with severe injury
-fat embolism syndrome occurs in a minority of pts with embolis
- usually pt will have SOB followed by confusion, coma, 1-3 days after Fx; is fatal in 10% of pts.

Endogenous Air emboli are associated with:
Scuba/deep sea divers
Underwater caisson workers
Unpressurized aircraft in rapid ascent

Pathogenesis of decompression sickness:
-air at high pressure dissolves in blood and tissues (think Nitrogen and deep sea dive)
-rapid ascent -> depressurization ->nitrogen bubbles form in blood
-gas emboli form, occlude arteries ->ischemia
-caisson disease: ischemic infarcts of femoral heads, tibia, humeri

Clinical presentation:
-bends: pain in muscles, joints, arch back in pain
-chokes: respiratory distress
Tx in compression chamber

Clinical: SOB, shock, followed by sz, coma (due to massive cytokine release), DIC, fatal in 80% of cases
Morphology: fetal squames, hair, vernix fat, and meconium in pulmonary vessels
Mechanism: infusion of amniotic fluid into maternal circulation via tear in membranes and uterine wall

Dr. Devine. Are you kidding me with this lecture?????

Infarction: area of ischemic necrosis caused by occlusion of either the arterial supply or venous supply drainage of a tissue

See pictures of morphology in lecture

Morphology:
Wedge-shaped
Occluded vessel at apex
Fibrinous exudates on overlying serosa

Microscopic:
Initial hemorrhage
Coagulative necrosis
Hemosiderin-laden macrophages after 48 hours

Causes:
-venous occlusions: twisted ovaries, testes, etc.
-arterial occlusions in loose tissue (lungs)blood collects in infarcted area
-arterial occlusions in tissues with dual circulations: lungs, intestines
-occlusions in tissues previously congested
-occlusions where the blood flow is re-established

Arterial occlusions in solid organs: heart, spleen, kidney
Density of tissue limits seepage of blood from adjoining capillaries

Dietary excess: high cholesterol, high fat diets
Hypercholestermia/hyperlipidemia due to other disease
-metabolic syndrome due to obesity
-diabetes mellitus
-nephrotic syndrome
-hypothyroidism
-ETOH abuse
Familial hyperlidemias

LDL defects cause most cases of familial hypercholesterolemia
Problems can also be caused by defects in LPL, and apoproteins
LPL deficiency leads to High TG levels

Activation - Endothelial cells can respond to stimuli by adjusting usual (constitutive) functions and by expressing newly (inducible) acquired properties
Dysfunction – potentially reversible changes in functional state of endothelium in response to environmental stimuli

1. Migration of smooth muscle cells (SMC) from media to intima or SMC derived from circulating precursor cells
2. SMC proliferation (mitosis)
3. Elaboration of ECM by SMC

Cardiac Output and Total Peripheral Resistance

Essential HTN – primary HTN. Accounts for 90% - 95%
Secondary HTN – secondary to renal disease 5-10%
Benign HTN – Hypertension at modest level and fairly stable over years. 95% of cases
Malignant HTN - Systolic >200, diastolic > 120. Rapidly rising blood pressure, untreated leads to death within two years. May develop in previously normotensive person, often superimposed on pre‐existing benign condition

Genetic factors.
Environmental factors (smoking, diet, exercise, stress).
Vasoconstrictive influences
Reduced renal sodium excretion

1. Hyperplastic arteriolosclerosis: associated with malignant HTN
2. Hyaline arteriolosclerosis: associated with benign HTN and diabetes.

1. Atherosclerosis (dominant pattern) ‐ intimal fibrous plaques with lipid rich core
2. Monckeberg’s medial calcific sclerosis ‐ calcification of the media of muscular artery. Usually adult older than 50, no clinical significance
3. Arteriolosclerosis ‐ proliferation or hyaline thickening of walls of small arteries and arterioles

Lesion is an atheroma or fibrofatty plaque. Raised focal plaque within intima with a lipid core and covering fibrous cap

Constiutional risk factors for IHD (things you can’t change)
•Increasing age
•Male gender
•Family history – most significant independent risk factor
•Genetic abnormalities

Modifiable risk factors (things you can change)
•Hyperlipidemia – high cholesterol. Too much bad cholesterol
•HTN –
•Cigarette smoking
•Diabetes – uncontrolled DM increases risk
•Inflammation - CRP

Pathogenesis ‐ Response to injury hypothesis (Fig. 11‐9)
– Endothelial injury
– Accumulation of lipoproteins
– Monocyte adhesion to endothelium, migration into intima, transform into macrophages and foam cells
– Platelet adhesion
-Factor release from activated platelets, macrophages and vascular wall cells
–Smooth muscle cell proliferation and ECM production
–Lipid accumulation

• Endothelial injury
– Two most important causes are hemodynamic disturbances and hypercholesterolemia
• Hemodynamic disturbances
– Normal flow in vessels leads to induction of endothelial genes – products are protective
–Disturbed flow see plaque formation
• Lipids
– Dyslipoproteinemias – common examples
• Increased LDL cholesterol
• Decreased HDL cholesterol
• Increased levels of abnormal lipoprotein

Earliest lesion in atherosclerosis. Cause no disturbance in flow. Multiple yellow, flat spots, coalesce into elongated streaks. May appear as early as 1 yr. Always appear after 10 years. No clear cut relation to plaques.

1. Cells ‐ SMC’s, macrophages, T lymphocytes
2. ECM
3. Lipids ‐ intra and extracellular

– Calcification ‐ “pipe stem arteries”
– Rupture, ulceration or erosion of luminal surface with rupture may discharge debris into bloodstream (cholesterol emboli or atheroemboli)
– Superimposed thrombosis
– Hemorrhage
– Aneurysmal dilation
– Atheroembolism

Occurs in small vessels. Plaque gradually occludes vessel
lumen resulting in ischemic injury. Critical stenosis occurs when occlusion significantly limits flow and the demand exceeds supply. Typically occurs at 70% fixed occlusion. Patients develop angina

Acute coronary syndromes not necessarily due to severely stenotic significant lesion before acute change. Bad news for asymptomatic adults due to unpredictable risk of event. Three categories
– Rupture/fissuring- Exposes thrombogenic plaque
– Erosion/ulceration- Exposes thrombogenic subendothelial BM to blood
– Hemorrhage into the atheroma

superimposed thrombus on partially stenotic plaque can converts lesion to
total occlusion. Pieces can embolize. Potent activator of growth‐related signals in SMC’s

Atherosclerotic lesions cause disease by gradually narrowing of lumina with ischemia
of tissues. Acting as Site for thrombosis and embolization. Sudden occlusion of vessel by hemorrhage or superimposed thrombosis. Weakens vessel wall, leads to aneurysm or rupture.
1. Myocardial infarction (heart attack)
2. Cerebral infarction (stroke)
3. Aortic aneurysms
4. Peripheral vascular disease (gangrene of legs)

When an advanced vulnerable plaque shifts to one of the following:
- anuerysm and rupture
- occlusion and thrombus
- critical stenosis

Aneurysm: Localized abnormal dilation of vessel. Occurs most commonly in aorta or heart.
- A True aneurysm is bounded by complete (but attenuated) arterial wall components. Blood remains within confines of circulatory system. Examples: Atherosclerotic, syphilitic, left ventricle after MI and congenital.
- A False aneurysm, or pseudoaneurysm, occurs when extravascular hematoma that
communicates with intravascular space and causes a leak at anastomosis of vascular graft with artery.

Anything that weakens walls or CT surrounding them, such as:
Marfan syndrome - defective fibrillin
Loeys-Dietz Syndrom – mutant TGF-B receptors. Causes abnormal elastin, collegen I & III
Ehlers-Danlos Syndrome – defective collegen III synthesis
Vitamin C deficiency - Altered collegen cross-linking
Inflammation – disrupts balance between collagen degradation and synthesis (+MMP by macrophages)

Ischemia causes nonspecific degenerative changes. leads to scarring, inadequate ECM synthesis, increased amounts of amorphous ground substance

Atherosclerosis and HTN.
Mycotic aneurysms are due to vessel wall infection.

Where do aneurysms associated with atherosclerosis most commonly occur?
Abdominal aorta. (AAA)

Who is more likely to get a AAA (age, sex, lifestyle)? Men over age 50 who smoke

What is a major cause of AAA? Severe complicated atherosclerosis

Where are AAA’s usually located? Below renal arteries and before aorta bifurcation

Describe the gross appearance of a AAA? Big and gross

1.Rupture into peritoneal cavity, retroperitoneal tissue = potentially fatal hemorrhage
2.Impingement on adjacent structure
3.Occlusion of branch vessel = ischemia downstream
4.Embolism from atheroma or mural thrombus
5.Creation of abdominal mass – often palpably pulsating

> 6cm

As aneurysm encroaches on thoracic organs, can impinge on their function as well. Breathing. Swallowing. Coughing. Pain from bone erosion. Cardiac problems. Ruptures.
TAA’s are associate with syphilis.

Dissection of blood along the laminar planes of the aortic media, with formation of a blood filled channel within aortic wall. Often ruptures with massive hemorrhage. May or may not be associated with dilation

What two groups of patients do dissections occur in? Men 40-60 yrs. Marfan patients.

What is the major predisposing factor for dissections? HTN

What is the most frequent detectable microscopic lesion? Cystic medial degeneration

DB I – ascending and descending aorta
DB II – ascending only
DB III – descending only
I & II are considered Type A b/c they both involve ascending aorta. III is Type B

Sudden onset of excruciating pain, anterior chest, radiating to back, moving downward. Often confused with acute MI

Rupture of dissection into any of three major body cavities (pericardial, pleural or peritoneal)

1. What are the two most common mechanisms for vasculitis? Infectious pathogen and immune-mediated inflammation.

2. Why is it important to distinguish between the two? To determine best treatment.

3. What are the common clinical findings in vasculitis? Fever, myalgias, arthralgias, malaise. Tissue ischemia

1.Immune complex deposition
2.Antineutrophil cytoplasmic antibodies. Patients serum reacts with cytoplasmic antigens in neutrophils
3.Anti‐endothelial cell antibodies

Antineutrophil cytoplasmic antibodies.
1. Anti‐myeloperoxidase (MPO‐ANCA). Old p‐ANCA
2. Anti‐proteinase‐3 (PR3‐ANCA). Old c‐ANCA

Useful? ANCA titers closely associated with disease activity making them useful for diagnosis and following activity of disease

1. Giant cell (temporal) arteritis affects what size vessels? Large
2. What is the major morphologic finding? Granulomatous inflammation.
3. What age group is it seen in? Elderly
4. What are the symptoms? May have insidious presentation (fever, fatigue, weight loss) or sudden onset of headache, tenderness with swelling and redness, facial pain
5. How is a definitive diagnosis made? Isn’t. Answer is supposed to be biopsy, but notes say that Negative biopsy doesn’t rule out disease.
6. What disease is it commonly associated with? Polymyalgia rheumatica
7. What treatment is used? steroids

1. Takayasu arteritis affects what size vessel? Medium to Large
2. What is the other name ? Granulomatous vasculitis
3. What are the two main symptoms? Ocular disturbances and weak pulse
4. What are the major morphologic findings? Classically arotic arch, but can involve entire aorta, branches and pulmonary arteries. Irregular thickening of vessel wall with hyperplasia. Mononuclear inflammation, granulomatous
inflammation, then collagenous fibrosis
5. What age group? Younger than 50
6. What is the course of the disease? variable, rapid progression or quiescent stage after 1-2 yrs

1. PAN affects what size vessels? Small to medium arteries
2. PAN affects renal and visceral vessels, what does it spare? pulmonary
3. What are the morphologic features? Segmental transmural necrotizing inflammation.
Three stages:
• Acute ‐ fibrinoid necrosis, neutrophils, eosinophils, mononuclear cells
• Healing ‐ transmural scarring, continuing necrosis
• Healed ‐ fibrotic thickening
4.Do patients get glomerulonephritis? No
5.What age group? Young adults
6.Common manifestations? Fever of unknown origin, weight loss, hypertension, abdominal pain, melena, muscle aches and pains, peripheral neuritis. Renal artery often involved.
7.Natural course without treatment? With treatment? Fatal if untreated. 90% remission/cure with treatment
8.What is treatment? Corticosteroids and cyclophosphamide

1. What are the three features of Churg-Strauss syndrome? Granulomas, infiltration of vessels and perivascular tissue with eosinophils
2. What other vasculitis has the same characteristic lesion? PAN
3. What ANCA is it associated with? P-ANCA 50%

1. What is the other name for Kawasaki disease? Mucocutaneous lymph node syndrome
2. What arteries does it involve? Coronary arteries
3. What are the symptoms of mucocutaneous lymph node syndrome? Fever, conjunctival and oral erythema and erosion, edema of hands and feet, erythema of palms and soles and later desquamation. Cervical lymphadenopathy
4. Patients with MLNS develop what complications? cardiovascular sequelae (Aneurysm. MI. Heart Disease.)
5. What are the morphologic features? Transmural necrosis, inflammation like PAN but
not as severe necrosis

1. What size vessels are affected in microscopic polyangiitis? Small ones
2. How does it present? palpable purpura involving skin or involvement of mucous membranes, lungs, brain, heart, GI tract, kidneys and muscle. Involves hypersensitivity.
3. Major clinical features? hemoptysis, hematuria, proteinuria, arthralgias, bowel pain, muscle pain/weakness, hemorrhage
4. How is a definitive diagnosis made? Skin biopsy
5. What two features distinguish it from PAN? Size of vessels (small). Lesions all same age.
6.Morphologic features? Segmental fibrinoid necrosis or infiltration with neutrophils which fragment ‐ leukocytoclasia. Necrotizing glomerulonephritis and pulmonary capillaritis are common (unlike PAN)

1. What is the triad that characterizes Wegener Granulomatosis?
1. Acute necrotizing granulomas of upper and/or lower respiratory tracts
2. Necrotizing g or granulomatous vasculitis of small to medium size vessels mostly in lung and upper airway, can have other sites
3. Renal disease – focal necrotizing, often crescentic, glomerulonephritis
2. Major morphologic features of Wegener Granulomatosis?
• Inflammatory sinusitis due to mucosal granulomas
• Ulcerative lesions of nose, pharynx, or palate
–Necrotizing granulomas and necrotizing or granulomatous vasculitis
Renal lesions ‐ focal necrotizing or crescentic glomerulonephritis
3. What sex and age? 40 yr old men
4. Clinical features? Pneumonitis with bilateral nodular and cavitary infiltrates, chronic sinusitis, ulceration of nasopharynx, evidence of renal disease
5. Natural course of disease? Untreated – 80% die within one year
6. ANCA? C‐ANCA (PR3‐ANCA) in 95%

1. What is the other name for thromboangiitis obliterans? Buerger Disease
2. What group of people get it? Smokers under age 35
3. Morphologic features? Acute and chronic inflammation with luminal thrombosis. Microabscesses within thrombus, wall of granulomatous inflammation
4. What can be done to prevent further attacks? Stop smoking

1. What is Raynaud phenomenon? Exaggerated vasoconstriction of digital arteries and arterioles.
2. Clinical features? Paroxysmal pallor or cyanosis of digits of hands or feet. Involved digits show red, white, blue color changes, proximal to distal. Primary or secondary
3. Who gets primary? 3%-5% of young females
4. What precipitates attacks? Cold and emotion
5. Natural course of disease? benign
6. What is secondary Raynaud’s? Vascular insufficiency of extremities, secondary to arterial narrowing from various processes such as SLE, scleroderma, atherosclerosis and
Buerger disease

1. What are varicose veins? Abnormally dilated, tortuous veins due to increased intraluminal pressure and loss of vessel wall support
2. What veins are affected? Usually superficial leg veins
3. Predisposing factors? Obese or pregnant women. Occupations that require long hours on feet or long airplane or car travel. Family history could mean genetic vessel wall issues
4. Sequelae? Persistent extremity edema. Trophic skin changes - Stasis dermatitis, Ulcerations, Poorly healing wounds and infections may become chronic varicose ulcers. Vulnerable to injury. Embolism or other serious complications very RARE
5. Clinical symptoms? Venous stasis, Congestion, Edema, Pain, Thrombosis

1.What veins account for majority of cases of thrombophlebitis and phlebothrombosis? DVTs
2.Predisposing factors? Prolonged immobilization resulting in decreased blood flow through veins, most important. Congestive heart failure, neoplasia, pregnancy, obesity, Postoperative state, Systemic hypercoagulability
3.Local manifestations? Edema distal to occluded vein, Dusky cyanosis, Dilation of superficial veins, Heat, tenderness, redness, swelling, pain (Homan’s sign)
4.Serious complication? PE
5.What is migratory thrombophlebitis and other name? Trousseau sign. Thrombus disappears and appears at another site. Associated with paraneoplastic syndrome in cancer patients.

neoplasms that compress or invade superior vena cava. Lung cancer. Mediastinal lymphoma. Clinical complex of Dusky cyanosis, Marked dilation of veins of head, neck and arms

Neoplasms compress or invade inferior vena cave. Can migrate upwards. Liver and kidney cancers have propensity to grow into lumen of veins.
Clinical features are Marked leg edema, Distention of superficial veins of lower
Abdomen, Massive proteinuria (renal veins involved)

during ventricular contraction (systole)

1. –Frank‐Starling
2. –Myocardial hypertrophy with/without cardiac chamber dilation
3. –Activation of neurohumoral systems

1.What two features characterize CHF? Forward failure AND backward failure
2.What do the terms backward and forward failure refer to?
–Diminished cardiac output ‐ forward failure
–Damming back of blood ‐ backward failure
3.Does it represent a specific disease unto itself? No
4.What are the three most common underlying disease states for CHF?HTN, MI, DM

Concentric hypertrophy – pressure overload
Eccentric hypertrophy – volume overload

1.Increased heart weight
2.Progressive wall thinning
3.Chamber dilatation
4.Microscopic changes of hypertrophy

1. –Ischemic heart disease
2. –Hypertension
3. –Aortic and mitral valvular disease
4. –Nonischemic myocardial diseases

Atrial enlargement occurs, leads to atrial fibrillation
–May cause blood stasis with thrombus formation, especially in appendages
–Leads to increased risk for embolic stroke

Left atrial appendage (aka – left aurical)

– Perivascular and interstitial transudate
– Edematous widening of alveolar septa
– Accumulation of edema fluid in alveolar spaces

hemosiderin containing macrophages in alveoli

–Dyspnea ‐ breathlessness
–Orthopnea ‐ dyspnea on lying down relieved by sitting/standing
–Paroxysmal nocturnal dyspnea ‐ attacks of extreme dyspnea bordering on suffocation
–Cough

1. What is the most common cause of right heart failure? Left heart failure
2. Pure right-sided heart failure occurs with what? What is it called in this case? chronic severe pulmonary hypertension and is called cor pulmonale
3. What four changes occur in the liver?
1.“Nutmeg” liver ‐ chronic passive congestion, congested red centers of liver lobules surrounded by paler peripheral regions
2.Centrilobular necrosis
3.Central hemorrhagic necrosis ‐ severe, rapidly developing failure leads to rupture of sinusoids
4.Cardiac sclerosis ‐ long standing severe failure, central areas become fibrotic
4. What happens to the spleen? Congestive splenomegaly ‐ enlarged, firm spleen, may weigh 500 to 600 gm (150ml), fibrous thickening of sinusoidal walls
5. What is ascites? transudate in peritoneal cavity
6. What is anasarca?Massive generalized edema

1.Ischemic heart disease (80 to 90%)
2.Hypertensive heart disease and pulmonary hypertensive heart disease
3.Certain valvular disease
4.Congenital heart disease
5.Nonischemic (primary) myocardial disease

Artherosclerosis of coronary artery, a.k.a. CAD (coronary artery disease)

1.–Angina pectoris (three variants)
2.–Myocardial infarction
3.–Chronic ischemic heart disease
4.\–Sudden cardiac death

1.Changed lifestyles (decreased risk)
2.Diagnostic and therapeutic advances

1.
Disruption of previously, partially stenosing atherosclerotic plaque
2.
• Hemorrhage
• Rupture and fissuring
• Erosion/ulceration
3.
–Unstable angina,
–Acute MI
–Sudden cardiac death

Angina – chest pain from transient (<15 min.) ischemia. Does not cause cell death.
• Stable angina (typical)
Due to reduction of coronary perfusion to a critical level by chronic stenosing atherosclerosis. Relieved by rest and nitroglycerin
• Prinzmetal variant angina
–Pattern of episodic angina that occurs at rest
–Due to coronary artery spasm
–Elevation of ST segment on EKG
–Responds to nitroglycerin and calcium channel blockers
• Unstable (crescendo) angina
–Pain occurs with progressively increasing frequency, precipitated with less effort, often occurs at rest, of prolonged duration
–Induced by fissuring, ulceration or rupture of plaque with superimposed (partial) thrombus and possibly embolization
–Often prodromal of MI = preinfarction angina

MI - Heart Attack. Death of cardiac muscle resulting from ischemia
–Transmural (more common) necrosis involves full or nearly full thickness of ventricular wall in distribution of single coronary artery
–Subendocardial - necrosis limited to the inner 1/3 or at most 1/2 of the ventricular wall, extends laterally beyond perfusion area of single artery

women

90% follow Five proposed steps:
1. Sudden change in morphology of plaque (hemorrhage, fissuring/rupture, ulceration/erosion)
2. Platelet exposed to collagen and plaque, leads to platelet activation, aggregation with formation of platelet mass ‐ may give rise to emboli or occlusive thrombosis
3. Tissue thromboplastin released, activates extrinsic pathway of coagulation
4. Activated platelets release factors predisposing to coagulation and favoring vasospasm
5. Often, within minutes thrombus evolves to become completely occlusive

10% acute infarctions unrelated to atherosclerotic thrombosis
1. Vasospam +/‐ atherosclerosis may cause deficit
2. Emboli from left mural thrombosis, vegetative endocarditis, paradoxic emboli from right
3. Unexplained – no atherosclerosis or thrombosis

1. Location, severity and rate of development of coronary occlusion
2. Size of vascular bed perfused by vessel
3. Duration of occlusion
4. Metabolic/oxygen needs of at risk myocardium
5. Extent of collaterals
6. Presence site and severity of coronary arterial spasm
7. Alterations in blood pressure, heart rate and cardiac rhythm

• Gross features of MI
–After 2‐3 hours can highlight necrosis with histochemical method –triphenyltetrazolium (TTC)
–Colors noninfarct area red, infarct pale
• Morphologic sequence of events in MI
–Coagulation necrosis and inflammation (4-12 hrs)
–Formation of granulation tissue (7-10 days)
–Resorption of necrotic myocardium (3-7 days)
–Organization of granulation tissue to form scar (starts at 10-14 days. Scar complete at 2 months)

• Thrombolysis
–Dissolution of thrombus by streptokinase or tissue‐type plasminogen activator
–Doesn’t alter underlying plaque
• Balloon angioplasty (PTCA‐percutaneous transluminal coronary angioplasty)
–Eliminates thrombotic occlusion and some of obstruction due to underlying plaque
• Coronary arterial bypass graft (CABG)

–Reperfusion‐induced arrhythmias
–Myocardial hemorrhage with contraction bands
–Irreversible cell damage due to the reperfusion itself
–Microvascular injury
–Prolonged ischemic dysfunction “Stunned myocardium”

CK-MB and Cardiac Troponin (especially cTnI)
Both rise 2-4 hrs after MI and continue to increase until peak (18 hrs for CKMB. 24 hrs for Troponin). Troponin levels remain elevated for 4‐7 days, useful in making delayed diagnosis of MI as compared to CK‐MB which goes away after 48hrs

Diabetes, female, advanced age, previous MI

1. Cardiac arrhythmia's ‐ conduction disturbances or myocardial irritability
2. Contractile dysfunction
3. Cardiac rupture syndromes ‐ occur 3‐7 days post MI
4. Infarct extension ‐ new necrosis adjacent to old
5. Infarct expansion ‐ stretching, thinning dilatation of infarct region
6. Ventricular aneurysm ‐ late complication
7. Papillary muscle dysfunction
8. Mural thrombus
9. Progressive late heart failure
10. Right ventricular infarction
11. Pericarditis

Rupture of free ventricular wall 3-7 days post MI.

Acute mitral regurgitation

Infarct size, location and transmural extent

CIHD
Age group? elderly
Clinical history? Prior MI, CABG
Morphology? Heart is usually enlarged and heavy due to LV hypertrophy and dilation. Shows scars of previous infarcts and coronary vessel disease.

Unexpected death from cardiac causes. Symptomless or within 1 hr of symptoms

Lethal arrythmia

Diagnostic?
1. Left ventricular hypertrophy (concentric) in absence of other causative pathology
2. History or pathologic evidence of hypertension

What is the morphology?
– Left ventricular pressure overload leads to LV circumferential hypertrophy without dilation
– Symmetric wall thickening (may exceed 2 cm)
– Increased heart weight (may exceed 500 gm)
– Stiff heart, impairs diastolic filling
– Decompensation occurs with dilation, thinning of wall, enlarged heart

Clinical ?
– Compensated disease may be asymptomatic or
– Onset of atrial fibrillation (enlarged L atrium) and/or
– CHF with cardiac dilation

Cor pulmonale
What are the two types?
1. Acute ‐ RV dilation due to massive pulmonary embolism
2. Chronic ‐ RV hypertrophy and later dilation secondary to prolonged pressure overload from obstruction of pulmonary arteries or compression of septal capillaries

What are the four groups of disorders predisposing to cor pulmonale?
1. Diseases of Pulmonary Parenchyma
2. Diseases of Pulmonary Vessels
3. Disorders Affecting Chest Movement
4. Disorders Inducing Pulmonary Arterial Constriction

What is the gross morphology?
Right ventricular enlargement secondary to pulmonary hypertension caused by disorders that effect lungs or pulmonary vasculature

failure of valve to open completely

failure of valve to close completely

Intrinsic disease and Damage to supporting structures

Lesion - Cause
Mitral stenosis - rheumatic heart disease
Mitral insufficiency - myxomatous degeneration (mitral valve prolapse)
Aortic stenosis - calcification of aortic valves
Aortic insufficiency - dilation of ascending aorta, related to HTN and aging

1. Calcific aortic stenosis
2. Calcific stenosis of congenitally bicuspid aortic valve
3. Mitral annular calcification

1. What are the two types of calcific aortic stenosis?
i. Calcific stenosis of normal valve (age related)
ii. Calcific stenosis of congenitally bicuspid valve
2. Which is more common?Age related stenosis of normal valve
3. What does the term senile calcific aortic stenosis refer to? Age related stenosis. Wear and tear.
4. What is the hallmark lesion of calcific aortic stenosis? nodular masses of calcium within sinuses of Valsalva
5. What is the gross morphology?
Heaped up nodular masses of calcium within sinuses of Valsalva, primarily at base, no commissure fusion
6. What is the major difference between the calcification of a congenitally bicuspid valve and a normal aortic valve?Age of patient.

1. What is the anatomic change in the heart associated with mitral valve prolapse? Ballooning of mitral leaflets which are often thick and rubbery
Myxomatous degeneration ‐ attenuation of fibrosa layer of valve with deposition of mucoid material
2. Who is at increased risk of having MVP? Marfans, Ehlers‐Danlos
3. What are the serious complications?
• Infective endocarditis
• Mitral insufficiency
• Stroke of systemic infarct from thrombi that form on valve
• Arrhythmias, sudden death uncommon

Acute RF disease of childhood affects children 5‐15yrs old, 10 days to 6 weeks after throat infection. Cultures neg., antibodies to streptococcal enzymes present in serum (streptolysin O and DNAse B)
Most common Jones criteria in children are Carditis (50‐75%), migrating polyarthritis and fever. 1% die from fulminant RF. Disease can reactivated with each new infection.
Patient tend to have heart failure decades later, requiring surgical repair or
replacement of valves. Standard practice to give prophylactic antibiotics long‐term

Pancarditis = inflammation of the heart.
Myocardium (myocarditis) – inflammation of heart muscle.
Morphology shows Aschoff Bodies - Collagen surrounded by lymphocytes and plump macrophages
Pericardium ‐ fibrinous pericarditis
Endocardium (endocarditis) ‐ fibrinoid necrosis with small vegetations (verrucae)

Features of Chronic rheumatic heart disease
– Deforming fibrotic valve disease (mitral stenosis)
• Permanent dysfunction
• Severe, sometimes fatal, cardiac dysfunction decades later

Definition= Infection, invasion or coloniztion of the heart, such as the valves, mural endocardium, aorta, aneurysmal sac, cardiovascular prosthetis, by a microbe.
Types= Acute bacterial endocarditis and Subacute bacterial endocarditis

Acute bacterial Endocarditis
Rapid progession, over days and rapidly fatal, mortality of 30% or more despite therapy. Common cause Staph Aureus, common in IV drup users. Heart valve is normal prior to infection, new murmor forms due to vegetations. Early complications of bacteremia, embolization of vegetations and janeway lesions.
Subacute Bacterial endocarditis
Predisposing factors= Slow progression over weeks or months, slowly destructive and fatal, low mortality with therapy, common cause is Strep viridans (most common), Staph epi (infects artificial valves), strep bovis (not tested). Heart valve is abnormal prior to infection, any damage to the heart will increase risk of SBE. Murmors will be pre-existing. Complications are all emboli, plus ostlers nodes, glomerulornuphritis and clubing of the fingers.

1- Cerebral stroke and retinal emboli
2- Mycotic aneuysm
3-Valve complications/myocardial abcess
4-Spleneomegaly
5- Pneumonia/ infarction
6- Renal infarct/ abcess/ glomerulonephritis
7- Splinter hemorrhages/ janeway lesions
8- clubbing
9- Anemia of chronic dis. Osteomyletis
10- Hematuria

Morphology
Vegetations on heart valves, they become bulky and friable. Vegetations are located on the atrial side of AV valves and the ventricular surface of the semilunar valves. Valves invoved most commonly are the mitral and/or aortic. The tricuspid (seen in 50% of iv drug users) can be involved.
Cardia complications
1-Heart failure
2-Valvular disease= insuficiency/stenosis due to perforations and healing with fibrosis calcifications
3-Ring abcess= myocardium around valve is destroyed. Valve perforates and becomes insufficient.
4-Artificial valve dehiscence= not at high risk.
5-Suppurative pericarditis

Associations= debilitation, sepsis, cancer associated with Trousseau Syndrome, as well as hypercoagulable states.

Associations= Autoimmunity of SLE and antiphospholipid syndrome. Just know it is part of our differential.

Morphology= Cardiac lesions-> Fibrous intimal thickening of right ventricle, pulmonic/tricuspid valves.
Cause= Systemic serotonin, and other agents released by carcinoid tumors that are metastatic to the liver..
Other substances associated with similar morph= serotonergic drugs such as ergots, phen-phen.

Complications
1-Thromboembolic disease= occurs with mechanical valves, systemic emboli cause stroke, Gi infarction.
2-Infective Endocarditis= uncommon, but if occurs it is due to Staph Epi
3-Structural deteriorations= major bioprosthetic failure, valve can tear, calcifyor regurge.
4-Non-structural dysfunction= hemolytic anemia, inadequate healingparavalvular leak, or exuberant healing w/ fibrosis.

Bioprosthetic
No anticoagulants required
Will need to be replaced due to wear and tear.

Mechanical
Life long anticoagulants required
High rate of complications

Cardiomyopathy= Heart muscle disease resulting from a primary abnormality of the myocardium.
Dilated Cardiomyopathy
type of dysfunction= Systolic dysfunction
causes= Idiopathic, Previous myocarditis (viral chagas disease), Alcohol abuse or other toxicity, Peripartum cardiomyopathy, familial in 20-50%
morphology= Large globular-shaped, heavy heart (2-3x heavier). Mitral/tricuspid rugurgitation due to dilation. Mural thrombi are common.
Microscopically= myocyte hypertrophy and fibrosis.
clinical = Rapidly fatal heart failure. Short life span of roughly 2 years. Arrithmias are present.

Hypertrophic cardiomyopathy= know the classic bannana shaped ventricle
Type of dysfunction= Diastolic dysfunction
Cause= 100% genetic, mutation in autosomal dominant sarcomere protein.
Morph= Massive hypertrophy with out dilation, septum is enlarged bannana shaped left ventricle, myofibril disarray, myocite hypertrpphy and fibrosis
Clinical= Sudden unexplained sudden death in an athlete.

Restrictive Cardiomyopathy
Type of dysfunction= Diastolic dysfunction
Cause= Decreased compliance due to amyloidosis
Morph= Amyloidosis is an extracullar protein accumulation
Clinical= Seen in older individuals= senile cardiac amyloidosis, Arrythmisa occur if accumulation is in the copnduction pathway, heart failure. Transthyretin

Cause of Restrictive cardiomyopathy= Amyloidosis and radiation
Features are arrythmias and heart failure.

Inflamation of myocardium due to infection or autoimmunity (rheumatic fever)
Morph= If viral infection lots of lymphocytes. If hypersensitivity lots of eosinophils. If chaga lots of inclusions.

Cardiotoxic drugs not on test!!!.
Catecholamine / cocaine= contraction bands

Iron overload= Dilated heart with Prussian blue stain.
Hyperthyroidism= myocardial hypertrophy
Hypothyroidism= myxedema heart due to interstitial mucopolysacharide.

BNP= B natriuretic peptide is elevated
Creatinine and BUN are elevated due to poor renal perfusion
AST/ALT elevated due to liver congestion.

Clinical Features= Neck and shoulder pain they like to lean forward to relieve pain
Serous pericarditis= outcome= No adhesions, heals without sequelai. cause = virus.
Fibrinous pericarditis= outcome= adhesions or organization Cause= Acute MI, post Mi syndrome, rheumatic fever.. Clinically this causes a friction rub.
Purulent/supperative pericarditis= outcome= adhesion or organization which turns into mediastinal pericarditis or constrictive pericarditis. Cause= bacterial endocarditis or pneumonia. Clinically this cause friction rub.
Caseus pericarditis= outcome= is constrictive pericarditis. cause= tuberculosis. Clinically it cause friction rub.

Deletion is in the T-box transcription gene. TBX1 in deleted region is responsible for digeorge syndrome and velocardial syndrome.
Digeorge syndrome= Cleft palat, absent thymus or hypoplastic thymus, cardiac anomalies, and hypoplsia of the parathyroids/ hypoparathyroidism which leads to hypocalcemia.

Findings=
1-Cyanotic congenital heart disease
2-Inadequate oxygenation of blood cyanosis of skin and mucos membranes
3-Paradoxical emboli
4-Clubbing of fingers
5-Polycythemia= increased hct/RBC’s

Causes=
1-Tetralogy of Falot= most common
2- Transposition of the great arteris (TGA)
3- Total anomalous pulmonary venous conection (TAPVC)
4- Tricuspid atresia
5- Persistant truncus arteriosis
(All of them have a T in the name)

Findings=
1-Cyanosis initially abscent
2-Increased pulmonary blood flow
3-Pulmonary HTN
4-Eisenmengers Syndrome= late cyanotic congenital heart disease. L to R shunt becomes a R to L shunt due to pulmonary HTN.

Causes=
1-Ventricular septal defect= most common
2-Atrial septal defect
3-AV septal defect
4-Patent ductus arteriosus
(All of them have a D in the name)

Features / complications=
It is a L to R shunt, it may occur by itself or with other defect, it may be a asympomatic into adulthood, large defect present with neonatal CHF, pulmonic valve murmur and pulmonary HTN (uncommon)

Types=
Secundum type- Most common 90%
Primum type

Frequency= Foramen ovale fuses in 80%. The remaining 20% can re-open due to pulmonary HTN.
Significance= Can cause multiple or recurrent Pulmonary embolism

Frquency= 20-30% of congenital heart defects
Common location= Membranous septum
Outcomes= Large defect= CHF W/ murmur at birth, right ventricular hypertrophy and pulmonary HTN both occur early
Small defect= Loud murmur, complicated by a jet lesion and increased risk for infecrive endocarditis.

Features= L to R shunt that is ussually isolated. Presents with a machine like murmur. There is normal cardiac function at birth. Maintain patency for survival in some defect.
Maintenance of Patency= administer prostaglandin E.
To close W/O surgery= give ibuprofen or indomethicin.

Embriology= Failure of fusion of the endocardial cushions.
Common Association= 1/3 occur with down syndrome.

Components / Features=
1-Most common R to L shunt
2-VSD
3-Subpulmonary stenosis
4-Aorta overides the VSD= dextro position of aorta
5-Right ventricular hypertrophy
6-Forms a boot shaped heart
Morphological determinat=
Degree of subpulmonary stenosi determines the direction of shunting and the outcomes and severity of disease

The aortaa rises from the right ventricle and is anterior and to the right of the pulmonary artery. The pulmonary arises from the left ventricle

Persistant truncus Arteriosus= Single great artery overiding both ventricles. Failure of a true aorta and pulmonary artery to form.
Associated with VSD.
Tricuspid Atresia= complete occlusion of the tricuspid orifice. Associated with hypoplasia of the right ventricle

Coarctation of the aorta= It is an obstructive anaomaly due to narrowing or constriction of the aorta. In the adult form it is post ductal, meaning it is an infolding of the aorta opposite the ductus arteriosus.
Associations= Valve defects such as bicuspid aorta and berry aneurism.
Clinical Features=
1- upper body hypertension
2- Hypotension of the legs
-cold cyanotic legs, claudication, intermittant pain and limping brought on by walking.
3- Rib notching
4- murmur throughoutsy stole with a thrill.
5- cardio megally due to LV hypertrophy.

Hypoplastic left heart syndrom= Severe stenosis or atresia of the aortic valvewith underdeveloped left ventricle and aorta.

1- Thickened ascending aorta, the lumen becomes constricted leading to supravavular stenosis.
2- Multiple organ system disorder
3- Facial abnormalities= elfin flat nose.
4- Hypercalcemia ininfancy

1- Graft rejection
2- Complications of immunosuppression lymphoma, infection as in cytomegalovirus
3- Graft arteriopathy coronary artery stenosis occurs at accelerated pace