COMPLETE LECTURE: Cardiovascular Physiology & Pathology (Pages 300-307)

PAGE 300 - AUTOREGULATION

What is Autoregulation?

LUNGS

• Hypoxia = low oxygen level.
• In most organs, when there is low oxygen, blood vessels DILATE (vasodilation) to bring more blood and therefore more oxygen to that tissue.
• But in the lungs, when a region is poorly ventilated (not getting good air), the tiny blood vessels supplying that region CONSTRICT - they clamp down.
• Why? Because if a part of the lung is not getting air (for example due to a mucus plug), there is no point sending blood there - that blood will come back deoxygenated anyway. So the lung redirects blood away from poorly ventilated areas to well-ventilated areas. This is called Hypoxic Pulmonary Vasoconstriction (HPV).
• This is unique ONLY to the pulmonary vasculature. The right side note says: "only well-ventilated areas are perfused; in other organs, hypoxia causes vasodilation."

HEART

• The heart autoregulates by releasing local chemical messengers (metabolites).
• NO = Nitric Oxide - a powerful vasodilator. Endothelial cells lining coronary vessels release NO when they sense increased metabolic demand.
• CO₂ = Carbon dioxide - when the heart is working hard, it produces CO₂ as a byproduct. High CO₂ causes vasodilation to increase blood supply.
• ↓O₂ = Low oxygen - unlike the lungs, low O₂ in heart/coronary vessels causes vasodilation (opposite to lungs!).
• Net result: when the heart works harder, these metabolites accumulate and dilate coronary vessels, bringing more blood and oxygen to the hardworking myocardium.

BRAIN

• The brain is exquisitely sensitive to CO₂ levels.
• When brain activity increases, CO₂ production increases, which lowers pH (makes it more acidic).
• Both high CO₂ and low pH cause cerebral vasodilation - bringing more blood to active brain areas.
• This is why hyperventilation (which blows off CO₂) causes cerebral vasoconstriction and can cause dizziness or fainting - you've lowered CO₂, removed the vasodilatory stimulus.
• Note: the brain does NOT rely on oxygen sensing for autoregulation as much as CO₂/pH.

KIDNEYS

1. Myogenic mechanism: The afferent arteriole (the vessel leading INTO the glomerulus/filter unit of the kidney) can sense stretch. When BP rises, the vessel wall is stretched. The smooth muscle in the wall responds by contracting (constricting) to resist the increased flow. Think of it as a blood vessel that fights back when you push more blood through it. This prevents the delicate glomerular capillaries from being damaged by high pressure.
2. Tubuloglomerular feedback (TGF): There are special cells called the macula densa at the end of the loop of Henle. They sense how much salt (specifically Cl⁻) is in the tubular fluid passing by. If filtration rate is too high, more salt reaches the macula densa. It signals the afferent arteriole to constrict, reducing filtration. It's a feedback loop between the tubule and the glomerulus.

SKELETAL MUSCLE

• C = CO₂
• H = H⁺ (hydrogen ions / acidity)
• A = Adenosine (released when ATP breaks down during exercise)
• L = Lactate (product of anaerobic metabolism in hard-working muscles)
• K = K⁺ (potassium ions leak out of repeatedly firing muscle cells)

SKIN

• The skin's main purpose from a vascular standpoint is thermoregulation.
• In cold environments: sympathetic nervous system releases norepinephrine → α1 receptors on skin vessels → vasoconstriction → less heat lost through skin. This is why you look pale and feel cold.
• In hot environments: sympathetic tone is withdrawn → vasodilation → skin flushes red and gets warm → heat dissipates.
• Skin doesn't primarily use local metabolites like other organs; it listens to the sympathetic nervous system.

PAGE 301 - CAPILLARY FLUID EXCHANGE (STARLING FORCES)

The Four Starling Forces

• Hydrostatic pressure = the physical pressure of blood being pumped through the vessel.
• Think of it like water pressure in a hose. High pressure inside the capillary pushes fluid through tiny pores in the capillary wall, OUT into the surrounding tissue (interstitium).
• This force FAVORS FILTRATION (fluid leaving the capillary).

• The tissue surrounding the capillary also has some pressure.
• Normally this is very low (even slightly negative), which actually sucks fluid out of the capillary and INTO the tissue.
• But when it rises (as in edema), it pushes fluid back in.

• Oncotic pressure (also called colloid osmotic pressure) is the osmotic pull created by PROTEINS dissolved in plasma - mainly albumin.
• Proteins are large molecules that cannot cross capillary walls easily. Because they are stuck inside the capillary, they create an osmotic gradient that PULLS water toward them (into the capillary).
• This force OPPOSES filtration - it tries to keep fluid inside the vessel.
• Think of albumin as a sponge inside the vessel saying "come back, water!"

• The tissue outside also contains some proteins (though much less than plasma).
• These interstitial proteins create their own osmotic pull, drawing fluid OUT of the capillary.
• Normally this force is small because there are few proteins in the interstitium.

The Starling Equation

• Jv = net fluid movement. If positive → net filtration (fluid goes out). If negative → net reabsorption (fluid comes back in).
• Kf = filtration coefficient = how permeable (leaky) the capillary wall is to fluid. A higher Kf means even small pressure differences cause large fluid shifts.
• Pc - Pi = the NET hydrostatic pressure gradient pushing fluid out.
• πc - πi = the NET oncotic pressure gradient pulling fluid in.
• σ (sigma) = reflection coefficient = how impermeable the capillary is to PROTEIN. If σ = 1, proteins can't cross at all (perfect reflection). If σ = 0, proteins cross freely and there's no osmotic effect.

EDEMA - "excess fluid outflow into interstitium"

• In heart failure (HF), the heart can't pump properly. Blood backs up in the venous system, raising venous (and therefore capillary) pressure. Higher Pc = more fluid pushed out = edema.
• In right heart failure: edema in the legs (peripheral edema).
• In left heart failure: edema in the lungs (pulmonary edema).

• Toxins, bacteria, and burns damage capillary walls, making them leakier.
• Even normal pressures now cause more fluid to leak out.
• This is the basis of septic edema and burn edema.

• Normally the lymphatic system drains protein that leaks into the interstitium.
• If lymphatics are blocked (by cancer, parasites like filariasis, or surgical removal), proteins accumulate in the tissue.
• These proteins raise πi, pulling more fluid out of capillaries.
• This is called lymphedema - it is a "pitting" edema initially but becomes non-pitting (brawny) over time as fibrosis develops.

• Nephrotic syndrome: kidneys are leaking albumin into the urine (massive proteinuria).
• Liver failure: the liver makes albumin; if the liver fails, albumin production drops.
• Protein malnutrition (Kwashiorkor): not enough dietary protein to maintain albumin levels.
• All of these reduce albumin/plasma protein → reduce the oncotic pull keeping fluid inside vessels → fluid leaks out → edema. The classic example is the swollen belly of a malnourished child.

PAGE 302 - CONGENITAL HEART DISEASES (RIGHT-TO-LEFT SHUNTS / "THE 5 T'S")

Overview: Right-to-Left vs Left-to-Right Shunts

• Left-to-right shunts: Blood flows from the left (oxygenated) side to the right (deoxygenated) side. The extra blood volume floods the pulmonary circulation. These cause "late" cyanosis (initially no cyanosis, cyanosis develops only if Eisenmenger develops).
• Right-to-left shunts: Deoxygenated blood bypasses the lungs and enters systemic circulation. These cause "early" cyanosis = "blue babies." They need urgent treatment at birth.

The 5 T's (Right-to-Left Shunts)

1. Truncus arteriosus (1 vessel)
2. Transposition (2 switched vessels)
3. Tricuspid atresia (3 = Tri)
4. Tetralogy of Fallot (4 = Tetra)
5. TAPVR (5 letters in the name = Total Anomalous Pulmonary Venous Return)

"Early cyanosis - 'blue babies.' Often diagnosed prenatally or become evident immediately after birth. Usually require urgent surgical treatment and/or maintenance of a PDA via prostaglandin therapy."

• Cyanosis = bluish discoloration of skin/lips from deoxygenated hemoglobin in circulation.
• In right-to-left shunts, deoxygenated blood bypasses the lungs and mixes directly into systemic circulation. This is called a shunt - a pathway that bypasses normal circulation.
• PDA = Patent Ductus Arteriosus - a fetal blood vessel connecting the aorta and pulmonary artery that normally closes after birth. In some heart defects, keeping this open allows mixing of oxygenated and deoxygenated blood, maintaining some oxygen delivery to the body.
• Prostaglandin E1 (PGE1) is used to KEEP the ductus arteriosus open (patent) when it is needed to maintain cardiac output or oxygenation until surgery.

Persistent Truncus Arteriosus

• Normally, during fetal development, a single great vessel (the truncus arteriosus) is divided by a spiral septum into two vessels: the aorta and the pulmonary artery.
• If this septum fails to form, you are left with ONE big vessel coming out of the heart instead of two. This single vessel receives blood from BOTH ventricles.
• VSD = Ventricular Septal Defect - a hole in the wall between the left and right ventricles. This almost always accompanies truncus arteriosus because the same developmental process forms both the aorticopulmonary septum and part of the ventricular septum.
• Blood from both sides of the heart mixes in this single vessel. The result is cyanosis.

D-Transposition of the Great Arteries (D-TGA)

• Normally: LV → Aorta (body), RV → Pulmonary artery (lungs).
• In D-TGA: the great vessels are SWITCHED. RV → Aorta (body), LV → Pulmonary artery (lungs).
• This creates TWO PARALLEL CIRCUITS instead of one series circuit:
  • Body → RV → Aorta → Body (deoxygenated blood going round and round)
  • Lungs → LV → Pulmonary artery → Lungs (oxygenated blood going round and round)
• The two circuits don't communicate → baby is severely cyanotic from birth.
• To survive, there MUST be a communication (shunt) somewhere - VSD, PDA, or patent foramen ovale - to allow SOME mixing of oxygenated blood into the systemic circuit.

• Normally the septum spirals as it forms, which is what causes the aorta and PA to wrap around each other in the normal configuration.
• In D-TGA, the septum doesn't spiral - the vessels are parallel (side by side), creating a narrow cardiac silhouette on chest X-ray that looks like an egg balanced on a string.
• The "string" is the narrow superior mediastinum (the vessels are parallel, not crossing).

Tricuspid Atresia

• Tricuspid valve connects right atrium to right ventricle.
• Atresia = complete absence/closure.
• If there's no tricuspid valve, blood cannot flow from right atrium to right ventricle → right ventricle is tiny (hypoplastic) from lack of use.
• For survival: need an ASD (hole between atria) so blood from the right atrium can cross to the left side, PLUS a VSD or PDA to get SOME blood to the lungs.

• RA enlarges because blood is backing up (tall P-waves on ECG = enlarged atria).
• LV enlarges because it is doing all the work (left axis deviation on ECG).

Tetralogy of Fallot (TOF) - Most Important!

• Infundibular septum = the part of the septum separating the outflow tracts of the two ventricles.
• Displacement of this septum causes all 4 components of TOF.

• Stenosis = narrowing.
• The displaced septum narrows the outflow tract leading to the pulmonary artery.
• This creates obstruction to blood leaving the RV toward the lungs.
• This is the most important component because its severity determines how cyanotic the patient is.

• The RV has to pump against the obstruction (pulmonary stenosis), so it hypertrophies (thickens its walls) - like a weight-lifter's arm.
• On chest X-ray, the enlarged RV tips the cardiac apex upward, giving the heart a boot shape ("coeur en sabot").

• The aorta sits directly over the VSD hole, so it receives blood from BOTH ventricles.
• This means deoxygenated blood from the RV goes directly into the aorta and out to the body = cyanosis.

• The hole in the ventricular septum that allows RV blood to mix with LV blood and enter the overriding aorta.

• Tet spells = episodes of sudden severe cyanosis in infants with TOF.
• Triggered by anything that increases oxygen demand (crying, feeding, exercise) or decreases systemic vascular resistance.
• During a spell, the right-to-left shunt suddenly increases → more deoxygenated blood into systemic circulation → baby turns very blue, may become unconscious.

• SVR = Systemic Vascular Resistance.
• Children with TOF instinctively squat after exertion. Why? Squatting compresses the femoral arteries and increases SVR. Higher SVR on the left side means the pressure gradient across the VSD decreases (less "push" from right to left), so less deoxygenated blood enters systemic circulation. Cyanosis improves.
• This is a classic clinical finding and a classic exam question.

• 22q11 deletion syndromes include DiGeorge syndrome and velocardiofacial syndrome. They are associated with cardiac outflow tract defects including TOF, truncus arteriosus, and others.

Total Anomalous Pulmonary Venous Return (TAPVR)

• Normally, oxygenated blood from the lungs drains via pulmonary VEINS into the LEFT atrium.
• In TAPVR, pulmonary veins drain into the RIGHT side instead (into the SVC, inferior vena cava, coronary sinus, etc.).
• All pulmonary venous return goes to the right heart → oxygenated and deoxygenated blood mix in the right atrium.
• For any oxygenated blood to reach the systemic circulation, an ASD must be present (allowing mixed blood to cross to the left side).
• CO = Cardiac Output.

Ebstein Anomaly

• The tricuspid valve leaflets are displaced downward into the right ventricle. This means a portion of the RV above the displaced valve behaves functionally like an atrium ("atrialization of the ventricle").
• This makes the effective RV very small, and the tricuspid valve doesn't close properly → tricuspid regurgitation (blood leaks backward from RV to RA).
• Accessory conduction pathways (like those causing Wolff-Parkinson-White syndrome) are associated.
• Right-sided HF: because the RV is functionally small and the tricuspid is leaky.
• Lithium taken during pregnancy (especially first trimester) is the classic teratogen linked to Ebstein anomaly.

PAGE 303 - LEFT-TO-RIGHT SHUNTS (Continued)

Introduction to Left-to-Right Shunts

• In left-to-right shunts, oxygenated blood crosses from the left to the right side. The systemic circulation still gets oxygenated blood, so patients are NOT cyanotic initially.
• However, the right side and pulmonary circulation are getting flooded with extra blood → over time this damages pulmonary vessels → Eisenmenger syndrome (late cyanosis develops when the shunt reverses direction).
• VSD is the most common congenital heart disease overall.

• Right-to-left shunts: early cyanosis.
• Left-to-right shunts: "later" cyanosis.
• O₂ saturation ↑ in RV and pulmonary artery (because oxygenated blood from LV is crossing over into the right side - this is how you diagnose left-to-right shunts on cardiac catheterization, you see a "step-up" in O₂ saturation).

Ventricular Septal Defect (VSD)

• VSD = hole in the wall between left and right ventricles.
• Small VSDs often close on their own (the child literally grows out of it).
• Large VSDs force large amounts of blood from LV (high pressure) to RV (low pressure) every heartbeat. The pulmonary vessels must handle this extra blood.
• Over years, the pulmonary arteries remodel (Eisenmenger) and eventually pulmonary pressure may exceed systemic → shunt reverses → right-to-left shunt → cyanosis.
• LV overload: the LV has to pump extra blood every beat (all the blood that leaked to the right PLUS the normal systemic output) → LV enlarges → heart failure.

Atrial Septal Defect (ASD)

• ASD = hole in the wall between left and right atria.
• On auscultation: the extra blood crossing from left to right increases RV volume → RV takes longer to empty → pulmonic valve closes late → wide split S2. This splitting doesn't change with breathing (fixed), unlike the normal respiratory variation in S2 splitting.

• Ostium secundum ASD: the most common type, occurs in the middle of the interatrial septum (at the foramen ovale). Usually isolated.
• Ostium primum ASD: occurs lower, near the AV valves. Often associated with Down syndrome and other cardiac defects (part of AV canal/endocardial cushion defects).

• Foramen ovale is a normal fetal opening in the interatrial septum that should close after birth (as left atrial pressure rises and the two flaps of tissue are pushed together and fuse).
• A Patent Foramen Ovale (PFO) is when this flaplike opening fails to fuse but can still open under certain conditions (like Valsalva or coughing when right pressure temporarily exceeds left).
• An ASD is a TRUE defect in the septal tissue (tissue is missing, not just unfused flaps).

• This "step-up" in O₂ saturation at the level of the right atrium (on catheterization) confirms ASD. Oxygenated blood from the LA is crossing into the RA.

• Paradoxical embolism: a blood clot forms in a leg vein → travels to the right heart → but instead of going to the lungs (where it would cause pulmonary embolism), it crosses through the ASD to the LEFT side → enters systemic circulation → can cause stroke!
• This can happen even in PFO patients during Valsalva or weight lifting when right atrial pressure momentarily exceeds left.

Patent Ductus Arteriosus (PDA)

• Ductus arteriosus = fetal blood vessel connecting the pulmonary artery to the aorta (just distal to the left subclavian artery).
• In fetal life: lungs are not working, so blood in the pulmonary artery is diverted through the ductus AWAY from the lungs and into the aorta (right to left). This is NORMAL in utero.
• After birth: lungs expand, pulmonary vascular resistance drops dramatically, oxygen rises → the ductus arteriosus normally closes within hours to days (mediated by the rise in oxygen and the drop in prostaglandins).
• If it stays open (patent): now that pulmonary resistance is low, blood flows from the HIGH PRESSURE aorta to the LOW PRESSURE pulmonary artery (left to right) → lungs are flooded with extra blood.
• RVH and LVH: right side is handling extra pulmonary blood; left side handles extra returned blood from lungs.

• Because blood flows through the PDA throughout the ENTIRE cardiac cycle (both systole and diastole), you hear a continuous murmur that sounds like a machine running - it doesn't stop between heartbeats.

• PGE = prostaglandin E. This is what keeps the ductus open during fetal life (produced by the placenta and the ductus wall). Low oxygen also helps keep it open.
• After birth, oxygen rises and prostaglandins fall → ductus constricts and closes.
• Clinically: If you need to CLOSE a PDA, use indomethacin or ibuprofen (NSAIDs block prostaglandin synthesis). If you need to KEEP a PDA open (in certain congenital heart defects like D-TGA), give prostaglandin E1 (alprostadil).

• As PDA leads to Eisenmenger, the shunt reverses (becomes right to left).
• Deoxygenated blood from the pulmonary artery enters the aorta DISTAL to the left subclavian artery.
• Result: upper body (head, arms) gets oxygenated blood from the normal aortic arch → no cyanosis.
• Lower body gets the deoxygenated blood → cyanosis of the lower extremities.
• This is called differential cyanosis - upper body pink, lower body blue. Pathognomonic (characteristic) of PDA with Eisenmenger.

Eisenmenger Syndrome

• This is the final common pathway of untreated large left-to-right shunts.
• The pulmonary vasculature is flooded with excess blood for years → the vessels respond by thickening their walls (smooth muscle hypertrophy, intimal proliferation) → pulmonary vascular resistance progressively rises → pulmonary arterial hypertension develops.
• Now the RV has to pump against very high resistance → RVH (right ventricle hypertrophies).
• Eventually RV pressure exceeds LV pressure → the shunt REVERSES (now flows right to left) → deoxygenated blood enters systemic circulation → CYANOSIS.
• Clubbing = enlargement of fingertips due to chronic hypoxia (the exact mechanism involves megakaryocytes and platelet-derived growth factors reaching the peripheral circulation).
• Polycythemia = the body makes more red blood cells to compensate for chronic hypoxia (erythropoietin production is stimulated by hypoxia).
• Once Eisenmenger syndrome develops, the defect CANNOT be surgically corrected (you cannot now close the hole because the RV needs the right-to-left shunt as a "pop-off valve" - close it and the patient dies from acute RV failure). Lung or heart-lung transplant is the only cure.

PAGE 304 - COARCTATION OF AORTA, HYPERTENSION

Coarctation of the Aorta

• Coarctation = narrowing/constriction.
• The aorta (main blood vessel leaving the heart) is abnormally narrowed.
• The classic location is just at the level of the ductus arteriosus (juxtaductal) - this is the most common type.
• Bicuspid aortic valve: normally the aortic valve has 3 leaflets; bicuspid = only 2. This is one of the most common congenital heart defects (1-2% of population) and frequently co-occurs with coarctation.
• Turner syndrome (45,X): girls with only one X chromosome. Classic features include short stature, webbed neck, primary amenorrhea, and coarctation of the aorta.

• Above the coarctation (upper body): high blood pressure because blood is being pushed against the obstruction. The upper extremity BP is high.
• Below the coarctation (lower body): reduced blood flow → cool, pale extremities, weak/absent femoral pulses.
• Brachiofemoral delay: when you feel the radial pulse (arm) and the femoral pulse (groin) simultaneously, the femoral pulse arrives later - because blood has to pass through the narrowed aorta. Normal people have simultaneous pulses.
• Claudication = cramping pain in leg muscles due to inadequate blood supply, especially during walking/exercise.

• The body is clever - it develops collateral pathways (alternative routes) to get blood past the obstruction.
• Intercostal arteries (which run along the underside of each rib) enlarge massively to carry blood around the narrowing.
• These enlarged, pulsating arteries erode the undersurface of the ribs → on chest X-ray you see notches in the inferior borders of ribs 3-9.
• Rib-notching is a classic radiological sign of coarctation.

• Berry aneurysms at the circle of Willis (brain arteries): the hypertension in the upper body also puts stress on cerebral arterial walls → aneurysms form that can rupture → subarachnoid hemorrhage.
• Infective endocarditis: turbulent flow at the coarctation site and through an abnormal bicuspid valve predisposes to infection.

Persistent Pulmonary Hypertension of the Newborn

• In the fetus, pulmonary vascular resistance is HIGH (lungs don't need to work in utero).
• At birth, as the newborn takes its first breaths, lungs expand, oxygen levels rise, and PVR should DROP dramatically - allowing blood to flow through the lungs and become oxygenated.
• If PVR doesn't drop (persistence), the baby effectively continues to have "fetal circulation" - right-to-left shunting through the PDA and foramen ovale.
• Blood bypasses the lungs → systemic hypoxemia.

• Meconium aspiration: meconium (fetal stool) in amniotic fluid can be inhaled at birth → airway obstruction and chemical pneumonitis → hypoxia → pulmonary vasoconstriction (remember, lungs vasoconstrict in response to hypoxia!) → elevated PVR.
• Neonatal pneumonia creates the same hypoxic environment.

• Pre-ductal = blood sampled from the arm (before the ductus arteriosus junction with the aorta).
• Post-ductal = blood sampled from the leg (after the ductus junction).
• If deoxygenated blood is entering the aorta via a patent ductus → lower leg O₂ saturation.
• This is the same differential cyanosis concept as in PDA.

Congenital Cardiac Defect Associations

Hypertension

• This is the current definition (ACC/AHA 2017 guidelines).
• "Persistent" means it must be documented on multiple occasions, not just one elevated reading.

• All modifiable except age, family history, and race.
• Black patients have both higher incidence and more severe hypertension, partly due to higher salt sensitivity and possibly genetic factors.

• Primary (essential) hypertension = no identifiable cause. It's multifactorial (genes + lifestyle + diet + aging).
• Mechanistically, it results from either too much cardiac output (CO) or too much peripheral vascular resistance (TPR). Usually both are involved.
• Remember: BP = CO × TPR. Any increase in either raises BP.

• Secondary hypertension (10%) has an identifiable cause:
  • Renal parenchymal disease (most common secondary cause)
  • Renovascular disease including fibromuscular dysplasia (characteristic "string of beads" appearance on angiography of the renal artery - seen in young women) and atherosclerotic renal artery stenosis (older men)
  • Primary hyperaldosteronism (Conn syndrome) - excess aldosterone → Na retention → ↑ BP
  • Obstructive sleep apnea - repeated hypoxia → sympathetic activation → sustained hypertension

• Hypertensive urgency: BP ≥ 180/120 mmHg WITHOUT end-organ damage. Treat carefully over hours.
• Hypertensive emergency: BP ≥ 180/120 mmHg WITH acute end-organ damage including:
  • Encephalopathy (brain swelling - headache, confusion)
  • Stroke
  • Retinal hemorrhages and exudates, papilledema (damage to blood vessels in the eye)
  • MI (myocardial infarction - heart attack)
  • HF (heart failure)
  • Aortic dissection
  • Acute kidney injury
  • Microangiopathic hemolytic anemia (RBCs shear against damaged small vessels)
  • Eclampsia (hypertension in pregnancy with seizures)
  • Arterioles show fibrinoid necrosis (vessel walls develop protein deposits and die)

• Concentric LVH = the LV wall thickens (hypertrophies) in response to chronically pumping against high resistance. The chamber size stays the same but walls get thick (concentric). Mediated by angiotensin II and endothelin.
• CKD (hypertensive nephropathy) = chronic kidney disease from long-standing hypertension damaging renal vessels.

PAGE 305 - HYPERLIPIDEMIA SIGNS & ATHEROSCLEROSIS

Hyperlipidemia Signs

• Histiocytes = macrophages in tissue. When they engulf excess lipid, they become "foam cells" and appear as yellow deposits under the skin.
• Xanthelasma = flat yellow patches on the eyelids. Common in people with high LDL cholesterol (and also in some people with normal lipids).
• These are cosmetically bothersome but clinically important as signs of underlying lipid disorder.

• Familial hypercholesterolemia (FH): autosomal dominant disorder caused by mutations in the LDL receptor gene. LDL cannot be cleared from blood → extremely high LDL (often >300-400 mg/dL in heterozygotes, >800 mg/dL in homozygotes).
• Hard, firm nodules form in tendons due to cholesterol deposits.
• Achilles tendon thickening is nearly pathognomonic (diagnostic) of FH.

• Corneal arcus = white/gray ring at the periphery of the cornea.
• In people >60, it is common and normal (arcus senilis).
• In people <45, it suggests familial hypercholesterolemia or other significant lipid disorder.

Atherosclerosis

• Arteriosclerosis = general term for hardening/stiffening of arteries (loss of elasticity).
• Atherosclerosis = specifically the buildup of lipid-rich plaques (atheromas) within the tunica intima (the innermost layer of the artery).
• Affects large and medium arteries; does NOT affect capillaries or veins (with rare exceptions).

• This is the order of most commonly affected vessels.
• Abdominal aorta is the most commonly affected → aneurysm.
• Coronary arteries → angina, MI.
• Popliteal artery → peripheral artery disease.
• Carotid artery → stroke.
• Circle of Willis → intracerebral disease.

• Modifiable: hypertension, tobacco smoking, dyslipidemia (↑ LDL, ↓ HDL), diabetes.
• Non-modifiable: age, male sex, postmenopausal status, family history.

• Atherosclerosis is often silent until a vessel is significantly narrowed (>70% typically before symptoms).
• Angina = chest pain from coronary artery narrowing (heart muscle doesn't get enough blood during exertion).
• Claudication = leg pain from peripheral artery narrowing.

1. Endothelial cell dysfunction: damaged endothelium (from hypertension, smoking, high glucose, high LDL) loses its protective properties. Normally endothelium resists monocyte adhesion - damaged endothelium expresses adhesion molecules.
2. Macrophage and LDL accumulation: monocytes from the blood adhere to the damaged endothelium and migrate into the intima, where they differentiate into macrophages. LDL (especially oxidized LDL) also enters the intima.
3. Foam cell formation: macrophages ingest the oxidized LDL → become engorged with lipid droplets → become "foam cells" (look foamy under microscope).
4. Fatty streaks: accumulation of foam cells in the intima forms flat yellow streaks visible with the naked eye. These are the earliest visible lesion. They can be found even in children and teenagers.
5. Smooth muscle cell migration (involves PDGF and FGF): PDGF (Platelet-Derived Growth Factor) and FGF (Fibroblast Growth Factor) released by macrophages and platelets stimulate smooth muscle cells from the media to migrate into the intima and proliferate.
6. Proliferation and extracellular matrix deposition: smooth muscle cells in the intima produce collagen, elastin, and other matrix proteins → forms a fibrous cap over the lipid core.
7. Fibrous plaque: the mature stable plaque with a fibrous cap overlying a lipid core + necrotic debris + foam cells + inflammatory cells.
8. Complex atheromas: calcification occurs (calcium deposits in the plaque - detectable by CT coronary calcium score). Plaques can ulcerate, rupture, thrombose.
9. Calcification: calcium content correlates with risk of complications. Heavily calcified plaques are stable but indicate significant disease burden.

PAGE 306 - CHOLESTEROL EMBOLI, ARTERIOLOSCLEROSIS, AORTIC ANEURYSM

Cholesterol Emboli Syndrome

• When large atherosclerotic plaques rupture (spontaneously or during invasive procedures), showers of cholesterol crystals are released into the bloodstream.
• These tiny crystals lodge in small arteries throughout the body.
• Livedo reticularis = mottled, lace-like purple skin discoloration from small vessel obstruction.
• Digital ischemia ("blue toe syndrome") = toes turn blue/purple despite palpable pulses.
• Gut ischemia: if mesenteric vessels are affected.
• Acute renal failure: if renal arteries are affected.
• The fact that larger pulses remain palpable distinguishes this from a large embolic event.
• Often follows invasive vascular procedures (angiography, angioplasty) which can dislodge plaques.

Arteriolosclerosis

• Under the microscope: homogeneous pink (hyaline) material deposited in the arteriolar wall.
• Hyaline = glass-like appearance under H&E stain.
• Plasma proteins (especially albumin) leak into the wall due to increased pressure (hypertension) or glycation damage (diabetes).
• The wall thickens → lumen narrows → ischemia of downstream tissue (especially in kidneys → hypertensive nephrosclerosis).

• Under the microscope: concentric layers of smooth muscle cells - looks like the layers of an onion.
• Occurs in MALIGNANT hypertension (rapidly escalating, very severe hypertension).
• Smooth muscle cells proliferate in response to extreme pressure.
• This pattern is pathognomonic of malignant hypertension.

Aortic Aneurysm

• Aneurysm = localized abnormal dilation of a blood vessel ≥50% of normal diameter.
• The aorta is the most commonly affected artery.
• Pain = danger sign (the aorta is normally painless - when it hurts, something bad is happening).

Thoracic Aortic Aneurysm

• Cystic medial degeneration: the media (middle layer) of the aortic wall breaks down - smooth muscle cells degenerate and are replaced by cystic mucoid material. This weakens the wall.
• Marfan syndrome: FBN1 mutation → defective fibrillin → connective tissue weakness in the aortic media → cystic medial degeneration → aneurysm and/or dissection.
• Vasa vasorum = "vessels of the vessels" - tiny arteries that supply the outer walls of large vessels like the aorta. In tertiary syphilis, Treponema pallidum causes obliterative endarteritis (inflammation and occlusion) of the vasa vasorum → the aortic wall is starved of nutrition → weakens → aneurysm.
• Syphilitic aneurysms classically affect the ascending aorta and aortic arch.
• Aortic root dilation (the very beginning of the aorta) can stretch the aortic valve ring → aortic regurgitation (valve can't close properly, blood leaks backward).

Abdominal Aortic Aneurysm (AAA)

• The aortic wall is destroyed by inflammatory cells (neutrophils, macrophages) and matrix metalloproteinases (enzymes that break down collagen and elastin).
• All 3 layers of the vessel wall (intima, media, adventitia) are involved - true "transmural" process.

• Smoking is the #1 modifiable risk factor. It causes oxidative stress and inflammation in the aortic wall.
• Screening: US abdomen recommended for males 65-75 who ever smoked.

• The classic teaching: AAA rupture = the "triad":
  1. Pulsatile abdominal mass (you can feel it pulsating)
  2. Sudden severe abdominal or back pain (blood tracking into retroperitoneum)
  3. Hypotension (shock from massive internal bleeding)
• This is a surgical emergency with high mortality.

• The infrarenal aorta (below the renal artery origins) has fewer vasa vasorum (the tiny nutrient vessels for the aortic wall) compared to the thoracic aorta → wall gets less nutrition → more vulnerable to degeneration → aneurysm occurs here most commonly.

PAGE 307 - TRAUMATIC AORTIC RUPTURE, AORTIC DISSECTION, SUBCLAVIAN STEAL SYNDROME

Traumatic Aortic Rupture

• MVA = Motor Vehicle Accident.
• In rapid deceleration, the heart and arch of the aorta (mobile structures) continue moving forward while the descending aorta (tethered at the ligamentum arteriosum) remains fixed.
• This creates a shearing force exactly at the junction = the aortic isthmus (just distal to where the left subclavian artery branches off).
• Widened mediastinum on chest X-ray = blood leaking into the mediastinum from the torn aorta → classic sign; any trauma patient with this finding needs urgent CT aortogram.

Aortic Dissection

• Normal aorta: 3 layers (intima = inner, media = middle, adventitia = outer).
• In dissection: blood tears through the intima and enters the media, creating a FALSE CHANNEL (false lumen) that runs longitudinally along the aorta.
• The real channel is the "true lumen"; the space created by dissecting blood is the "false lumen."

• Hypertension creates pulsatile mechanical stress on the aortic wall with every heartbeat. Over time, this can create an intimal tear.
• Marfan syndrome weakens the media (cystic medial degeneration) → easier to dissect.

• Tearing/ripping chest pain radiating to the back is the classic description. Unlike MI (which is more pressure/squeezing), dissection pain is maximally severe from onset and feels like something tearing.
• Unequal BP in arms: if the dissection flap occludes the origin of the left subclavian artery, the left arm BP will be lower than the right.

• As blood fills the false lumen in the mediastinum, the shadow of the mediastinum on CXR widens.

• The dissecting flap can occlude any artery branching off the aorta (coronary arteries → MI; carotid arteries → stroke; renal arteries → kidney failure; spinal arteries → paraplegia; mesenteric arteries → bowel ischemia).

• Stanford Type A (proximal): involves the ASCENDING aorta ± arch ± descending.
  • Treatment: EMERGENCY SURGERY. If left untreated, risk of rupture into pericardium (cardiac tamponade) or aortic regurgitation is very high.
• Stanford Type B (distal): involves ONLY the descending aorta, BELOW the left subclavian artery.
  • Treatment: β-blockers first (to reduce heart rate and force, reducing pulsatile stress on the aorta), then vasodilators if needed to lower BP further.
  • No surgery unless complications develop (ischemia, expansion).

• Type I: ascending + descending (= Stanford A with extension)
• Type II: ascending only (= Stanford A)
• Type III: descending only (= Stanford B)

Subclavian Steal Syndrome

• The vertebral artery normally flows from the subclavian artery → upward into the brain.
• If the subclavian artery is BLOCKED (stenosis) proximal to the vertebral artery origin, blood cannot flow forward past the blockage.
• The arm is now receiving blood via a REVERSED vertebral artery: blood flows DOWN the vertebral artery from the brain into the subclavian artery → "steals" blood from the brain.
• When you exercise the arm, the arm's demand increases → more blood is stolen from the vertebral artery → reduced posterior brain (brainstem/cerebellum) blood flow → symptoms.

• Paresthesia = pins and needles / numbness.
• Vertebrobasilar insufficiency = symptoms from the brainstem and cerebellum not getting enough blood: dizziness, vertigo, drop attacks, visual disturbances.
• The clinical clue: systolic BP difference >15 mmHg between the two arms (the affected arm has lower BP because the subclavian is blocked).

• Takayasu arteritis = large vessel vasculitis (inflammation of aorta and major branches) that predominantly affects young Asian women. It can cause subclavian stenosis.
• Heart surgery (specifically CABG using the internal mammary artery) can occasionally result in a steal phenomenon.

SUMMARY TABLE for Quick Review