** Cardiovascular System **

Elastic Arteries : aorta (common carotid, subclavian, common iliac)

- elastic vers in tunica media (40-70layers)
- concentric layers ( like shingles ), have fenestrations (permit di usion) , vascular smooth muscle btw elastic bers
- >> Marfan’s syndrome
- Expansion ( systole ), Elastic Recoiling (intra vascular pressure)
- [Link] : endothelial cells, subendothelial ct, IEL not conspicuous
- [Link] : 40-70 layers , Smooth muscle cells, type 3 collagen
- [Link] : dense irregular ct, prevents excessive expansion
Muscular Arteries : medium sized (brachial, radial, femoral, tibial)
- distributing arteries > most abundant in body > more smooth muscle
- lose elastic bers > form EEL
- [Link] : distinct IEL
- [Link] : 8-40 layers , Smooth muscle cells, few elastic bers, distinct EEL
- [Link] : dense ct, collagen & elastic bers (vasa vasorum & nerves)
Small Artery :
- [Link] : endothelial cells, subendothelial ct, IEL
- [Link] : 3-8 layers , Smooth muscle cells
- [Link] : ct - type 1 collagen, ill-de ned
Arteriole : smallest arteries < 0.1mm in diameter
- high resistance : major determinant of blood pressure
- [Link] : endothelial cells
- [Link] : 1-2 layers , Smooth muscle cells
- [Link] : ill-de ned, merge with surrounding ct
Precapillary sphincter : regulate blood ow to capillary bed
1. food intake > increase ow to GI tract , decrease ow to other areas
2. exercise > increase blood ow to skeletal muscle

Capillaries : luminal diameter 7-9 microns

- single layer of endothelial cells + basal lamina
- permits exchange
- encircled by pericytes (rouget cells)
1. continuous / somatic capillary
- continuous basal lamina, uninterrupted endothelium, tight junction
- complete control over di usion, endocytosis, exocytosis
- vessels form carriers (brain, thymus, lung, testis)
- in CT, Muscle, Nerve, Exocrine glands, cerebral cortex
2. fenestrated / visceral capillary
- continuous basal lamina, uninterrupted endothelium, tight junction
- fenestrated (80-100mm) - numerous pinocytotic vesicles
- thin, non membranous diaphragm across fenestrations (not in glomerular capillaries of kidney)
- in Peptide-secreting endocrine, ciliary processes (eye), choroid plexus (ventricles), kidney-glomeruli, lamina propria
3. discontinuous / sinusoidal
- discontinuous basal lamina, absence of tight junction, large fenestrations, separated by wide irregular gaps
- fenestration : large & variable , allow macro molecules passage
- in liver, spleen, bone marrow
Post capillary venule
- endothelial lining, basal lamina & pericytes > vasoactive agents (histamine)
- high endothelial venules - in lymphatic system >> in ammation > leukocyte exudation
- cuboidal, ovioid nuclei (= high endothelial vessels) >> homing e ect > recruit lymphocytes
- >> Loosest Zonula Occludens >> immune cells entry
Muscular Venules
- distal to post capillary venules,
- [Link] : endothelial cells
- [Link] : 1-2 layers , Smooth muscle cells
- [Link] : thin (but thickest among 3 layers) , no pericytes
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 1. Medium (muscular) Vein
- [Link] : endothelial cells, thin sub-endothelial CT , form valves ( bro elastic CT support)
- [Link] : circular Smooth muscle cells
- [Link] : thicker than [Link]
2. Large (muscular) vein
- [Link] : endothelial cells, sub-endothelial CT
- [Link] : thin, circular , Smooth muscle cells, collagen, bers, broblasts
- [Link] : thickest layer, longitudinal smooth muscle bundles, collagen, elastic bers, broblasts
Lymphtic system
- return excess tissue uid to circulation
- blind-ended lymphatic capillaries > circulation (unidirectional valves)
- sluggish (aided by adjacent skeletal muscles) > have valves
- tube of endothelium, no continuous basal lamina, high permeability
- lack tight junction (protein & large molecules return to vascular compartment)
- NOT present in Nervous tissue, Bone marrow, Cartilage
- >> impaired >> edema
Hypertension - cause damage to smaller blood vessels > scarring, hardening, narrowing of bv > less elastic
- major determinant : Arterioles
1. symmetrical hypertrophy (Muscular Media M)
2. extensive reduplication IEL
3. brotic thickening of intima
>> reduce lumen diameter >> atherosclerosis
- atheroma / ber fatty plaques >> weakening of [Link]
- hardening of arteries >> arteriosclerosis (old age)
LDL (triglycerides & lipids) - insoluble in water > excessive LDL > endothelial cell produce free radicals > oxidize LDL
>> initiate monocyte migration into [Link] > become macrophage > SMC migrate from [Link] to [Link] (subendo.)
>> SMC & macrophage engulf oxidized LDL >> form foam cells
SMC proliferate & secrete collagen and ECM >> form Thick fatty streak
SMA > cytokines >> convert fatty streak to brofatty plaques >> luminal obstruction & aneurysm (weakened wall)

Aortic Dissection > a ect thoracic Aorta ( hypertension & CT disorder - Marfan) > medial Hematoma ([Link])
>> burst through [Link] >> fatal consequences

Varicose vein - increased intraluminal pressure & loss of support > reverse blood ow (damages valve)
- ex) leg, anorectal (hemorrhoids), spermatic cord (varicocele), esophageal varices

Lymphedema : trauma, post-surgical, post radiation, in ammation, parasitic obstruction (metastasis)

- ex) penoscrotal lymphedema, larial (parasitic bug bite), leg & arms
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** Mediastinum **
- Thoracic compartment btw 2 pleural sacs
- thoracic organs except lung, highly mobile
-
- Plane of Ludwig (transthoracic plane)
- anterior boundary - Manubriosternal Joint (angle of Louis) , 2nd costal cartilage
- posterior boundary - T4/5 intervertebral disc
- Superior Vena Cava enters pericardium, arch of aorta, Trachea bifurcation, pulmonary trunk bifurcation

- superior mediastinum :
- superior- 1st rib, T1, jugular notch
- inferior - transthoracic plane
- posterior - T1-4 vertebrae
- anterior - manubrium
- esophagus, thoracic duct, trachea, aortic arch, L&R brachiocephalic vein, sVC, pulmonary artery,
- Nerve (vagus, phrenic, recurrent laryngeal)

Thymus :
- anterior part of superior mediastinum, posterior to manubrium
- involutes after puberty (replaced by fat)
- Artery : internal thoracic & anterior intercostal
- Venous : brachiocephalic, internal thoracic, inferior thyroid vein
- lymphatic : parasternal, brachiocephalic, tracheobronchial lymph
Trachea :
- continuation of larynx (C6)
- anterior to esophagus, terminates at transthoracic plane > bifurcate > L&R main bronchi
- aortic arch & azygos vein cross over
Aortic Arch & branches (3 branches)
- brachiocephalic trunk (R subclavian, R common carotid)
- left common carotid
- left subclavian
Brachiocephalic Vein
- union of subclavian + internal jugular vein
- posterior to sternoclavicular joints
Subclavian Artery (3 parts)
- 1st part : vertebral A, internal thoracic A, thyrocervical trunk
- 2nd part : costocervical trunk
- 3rd part : dorsal scapular (arise from 1st or 2nd part of subclavian artery)
- >> axillary artery (lateral border of rib 1)
Nerves of Mediastinum
- vagus nerve : travel along common carotid A. >> esophageal plexus >> anterior vagal trunk (L) & Poster (R)
- parasympathetic & visceral a erent to thoracic viscera
- recurrent laryngeal nerve : from vagus > arch of aorta (L) & Rt subclavian (R)
- Phrenic N : enter superior mediastinum (btw subclavian artery & brachiocephalic vein) > pericardium > diaphragm
- sensory & motor innervation > diaphragm
Thoracic Outlet Syndrome
- extra rib (C7 & Rib 1), muscular abnormalities , trauma, tumor
- >> compression of axillary inlet : subclavian artery/vein : thrombosis / embolization
- >> nerve (C8 -T1) : sensory de cit, muscle wasting
- >> neurological pain, paresthesia, paresis/paralysis
- >> vascular pallor, pulselessness, poikilothermia (cold), edema (venous compression)

Interior Mediastinum : (Anterior, Middle, Posterior)

- superior : transthoracic palne
- inferior : diaphragm
- anterior : body of sternum
- posterior : T5-T12
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Anterior mediastinum : anterior - sternum, posterior - pericardium
- thymus, lymph nodes, connective tissue
Middle mediastinum : brous layer & parietal layer of serous pericardium on all sides
- heart (ascending aorta, intrapericardial SVC, pulmonary trunk) , main bronchi
Posterior mediastinum : anterior - pericardium, posterior - vertebrae T5-T12
- sympathetic chain, esophagus, esophageal plexus, azygos venous system, descending thoracic aorta, thoracic duct
Sympathetic chain & splanchnic nerves
- Greater (T5-9) : joins celiac ganglion
- Lesser (T10-11) : joins portico-renal ganglion
- Least (T12) : joins renal plexus
Esophagus : pharynx from C6 > superior thoracic aperture > diaphragm T10 > stomach (cardiac sphincter)
- esophageal constriction : pharynx (C6), arch of aorta cross over, Left bronchus (T4/5), Esophageal hiatus (T10)
- Thoracic : thoracic aorta & bronchial arteries, esophageal plexus, sympathetic trunks,
- azygos, hemiazygos vein, thoracic duct, posterior mediastinal nodes
- Abdominal : left gastric artery, left inferior phrenic artery, vagal trunks, greater splanchnic nerves
- left gastric vein, left gastric nodes
Azygos system
- drain back, thoracoabdominal wall, mediastinal viscera
- azygos & hemiazygos accessory >> ascending lumbar & subcostal vein
- left inferior hemiazygos veins & upper left (T5-8) accessory hemiazygos >> cross over >> azygos
- azygos (right side of body, posterior mediastinum) > inferior & thoracic vertebrae > arch T4 > SVC
Desceding Thoracic Aorta
- branches : posterior intercostal arteries , 1 / 2 bronchial arteries , pericardial & mediastinal branches, esophageal,
- superior phrenic, subcostal artery
- trajectory : aortic arch (T4-5) > left side of esophagus > down > aortic hiatus (T12) > abdominal aorta
Diaphragm : separate thorax & abdomen
- three opening : T8 IVC, T10 esophagus (left) , T12 Aorta (midline)
- central tendon , costal part of diaphragm (muscle) , Cura- dorsal mesentery of esophagus, phrenic nerve
Thoracic duct : largest & most prominent lymphatic vessel in body
- start: cisterna chyli > aortic hiatus (diaphragm) > azygos(R) & aorta(L), esophagus (A), Vertebral (P) > Cross T5 (L)
- >> enter root of neck >> drain to left subclavian & left internal jugular veins
- carry lymph from entire body ( except right head, right neck, right upper limb, right thorax )
- abdomen, pelvis, perineum, lower limb, posterior diaphragmatic & posterior mediastinal nodes,
- descending trunk (6-7) intercostal spaces both side, lymphatic trunks from upper left 5-6 intercostal spaces
- left jugular trunk : left head, left neck, left subclavian trunk, left upper limb
-
injuries : a ect lung, great vessel, esophagus, spine, lymph nodes, penetrating trauma (surgery)
- catheterization (internal jugular vein), surgery (esophagostomy)
symptoms: chylothorax, chylomediastinum, chylopericardium (Chyle = uid mixture of lipid, protein, lymphocytes)
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 ** Anatomy of Heart **
- in middle mediastinum
- surrounded by pericardium - 3 layers
-
- outer brous layer : S- great vessel adventitia, I- pericardiophrenic ligament
- A- sternopericardial ligament, P- bronchopericardial membrane
- inner serous layer : parietal & visceral
- pericardial cavity : lled with small amount of serous uid
- Aterial supply : pericardiophrenic (Internal thoracic), musculophrenic (internal thoracic), inferior phrenic,
thoracic aorta, coronary (visceral serous)
- venous drainage : azygous, internal thoracic, superior phrenic, cardiac (visceral serous)
- nerve innervation : phrenic nerve - somatic pain ( brous only), vagus - parasympathetic,
- sympathetic chain, cardiac plexus (visceral a erent)
- transverse sinus : A- aorta & pulmonary trunk, P- sup. vena cava, S- Rt pulmonary artery, I- Atria
- oblique sinus ( cul-de-sac formed ) : A- Lt atrium, P- esophagus & descending aorta
Pericardial e usion
- uid accumulation in pericardial cavity - beyond 30-50ml
- may be slow or rapid
- many possible causes : systemic in ammation (CT dx), Metastasis, hypothyroidism, renal dx, infection
- symptoms : dyspnea, reduced exercise tolerance, eventually progress to impaired cardiac fx, tamponade
Cardiac Tamponade
- uid, pus, gas, blood, tissue accumulation >> impaired Cardiac Output
- pulses paradoxus : exaggerated fall of systolic bp (10mmHg) - inspiration
- Beck’s Triad
- 1) ^ outside pressure >> V End-diastolic ventricular lling >> V SV >> V systolic bp
- 2) ^ outside pressure >> V end-systolic atrial lling >> ^ pressure in atria >> ^ pressure in jugular vein
- 3) ^ uid >> V cardiac heart sound
- treatment : pericardiocentesis
- paratyphoid approach : tip of diploid / btw diploid & Lt costal margin, angled toward Lt shoulder
- apical approach : Lt 5th & 6th intercostal space

Rt Atrium : blood from SVC & IVC, crest terminalis separate atrium & pectinate muscle, internal septum - fossa ovalis
Rt Ventricle : Thinner wall, larger cavity, moderator band connect ant. papillary muscle & septum, purkinje ber (RBB)
Lt Ventricle : Thicker wall, smaller cavity, 2 papillary muscle, aortic outlet is smooth

Atriocentricular valve : attached to brous skeleton, each cusp connect 2 papillary muscle, close when lled with blood
Semilunar valve :
- Aortic : Right, Left, Posterior // 2 coronary cusps // aortic sinuses ll after ventricular contraction close valves
- Pulmonary : right, left, anterior
Valve auscultation
Aortic : Rt sternal border 2nd intercostal
Pulmonary : Lt costal border 2nd intercostal
Tricuspid : Lt sternal border 5th intercostal
Mitral : Lt midclavicular 5th intercostal

SA node (pacemaker) : SVC & Rt atrium

AV node : Atrioventricular septum (coronary sinus)
AV bundle : membranous part of interventricular septum
Lt & Rt Bundle Branch : muscular part of inter ventricular septum & walls around apex
Purkinje bers : ventricular walls & papillary muscles

Visceral E erent :
preganglionic syspathetic (T1-4) > postganglionic sympathetic cervical & upper thoracic chain ganglia (Splanchinic)
+ preganglionic parasympathetic (Vagus)

>> Cardiac Plexus >> super cial part around great vessels ( ligaments arteriosum ) >>> HR, Contraction, CO
>> Deep part, posterior to left atrium ( anterior to tracheal bifurcation)
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 Visceral A erent :
Detect BP change & Body chemistry (aortic body & sinus) > > Cardiac brach to vagus > brain
+ Detect/indirect damage - visceral pain > Cardiac Plexus > splanchnic > spinal cord > referred pain
+ brain (T1-4)
Heart blood supply
1. Lt coronary : ant. 2/3 of interventricular septum, Lt ventricle, Lt atrium, AV bundle & branches, circum ex
small cardiac vein, right marginal vein, middle cardiac vein
2. Rt coronary : pot. 1/3 of interventricular septum, Rt ventricle, Rt atrium, pos Lt vent & atrium, SA node, AV node
right marginal, great cardiac vein

Chest Pain
1. myocardial infarction : severe chest heaviness or pressure > 20min, sweating, clenched st, nausea
2. pleural pain : acute sharp pain, breathing coughing, pneumonia, pulmonary embolism, viral respiratory infection
3. intercostal pain : sharp pain, thorax unilaterally worsen (chest wall movement), breathing
4. pericardial pain : continuous central chest pain , pericarditis, radiate both shoulders, alleviated by sitting forward

Splitting patterns of the second heart sound.

HEART Origen and location Normal/abnormal Normal splitting Inspiration produce a drop in intrathoracic pressure ,
PHYSIOLOGIC increasing venous return, increasing right ventricular filling,
SOUNDS increasing right ventricular stroke volume, which produces a
delayed closure of the pulmonic valve.
S1 Mitral and tricuspid valve closure Normally present
Loudest at mitral valve region Wide splitting Conditions that delay RV emptying:
• Pulmonic stenosis
S2 Aortic and pulmonary valve closure Normally present • Right bundle branch block
Loudest at left upper external border
Fixed splitting Conditions:
S3 In early diastole during rapid It is not normally present, however, if • Atrial septal defect: left-to-right shunt increases right
ventricular filling phase it is found in children, young adults and atrium and right ventricle volumes, increasing flow
through pulmonic valve which produce a great delay in
pregnant women it can be a normal the pulmonic valve.
Abnormal in adults:
• Dilated ventricles (more common) Paradoxical Normal order of valve closure of is reversed (P2 occurs
• Increased filling pressure: mitral splitting before delayed A2). During inspiration P2 closes later and
regurgitation, heart failure. moves closer to A2, paradoxically eliminating the split
usually heard in expiration.
S4 During late diastole (“atrial kick”) Abnormal regardless of patient age Conditions:
Best heard at apex with patient in left • High atrial pressure • Aortic stenosis
• Left bundle branch block
lateral decubitus position • Ventricular hypertrophy
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• Stiff left ventricular wall

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SYSTOLIC MURMURS

HEART MURMURS Description Causes

Aortic stenosis Crescendo-decrescendo systolic Age-related calcification
ejection murmur
Mitral regurgitation Holosystolic, high-pitched Ischemic heart disease
Delayed Right Ventricular emptying: “blowing murmur” (post-MI)
Loudest in the apex and radiates Rheumatic fever
• Pulmonic stenosis
toward the axilla
• Right bundle branch block
Mitral valve prolapse Late systolic crescendo murmur Myxomatous degeneration:
MOST FREQUENT with midsystolic click (MC) due to • Marfan syndrome
VALVULAR LESION • Ehlers-Danlos
sudden tension of the chordae
Left-to-right shunt: syndrome
tendineae. Rheumatic fever
• Atrial septal defect Best heard over the apex
Loudest just before S2
Tricuspid Holosystolic, high-pitched Right ventricle dilation
regurgitation “blowing murmur” Rheumatic fever
Delay aortic valve closure:
Loudest at the tricuspid area
• Aortic stenosis
Ventricular septal Holosystolic, harsh-sounding
• Left bundle branch block defect murmur loudest at tricuspid area

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DIASTOLIC MURMURS Bedside maneuvers

Bedside maneuver Cardiovascular effect Murmur/sound changes

HEART MURMURS Description Causes
Inspiration Increases VR to the RA Increase the intensity of right heart
Aortic regurgitation High pitched “blowing” early diastolic Aortic root dilation
Bicuspid aortic valve sounds
decrescendo murmur.
Long diastolic murmur. Endocarditis Hand grip Increase in afterload Increase intensity of:
Rheumatic fever
Head bobbing (in severe cases) • Mitral regurgitation
Mitral stenosis Delayed rumbling mid-to-late Sequela of Rheumatic Fever • Aortic regurgitation
diastolic murmur that follows a • Ventricular septal defect
Decrease intensity of:
• Aortic stenosis
Valsalva (phase II) Decrease preload Decrease intensity of most murmurs
Increase intensity of hypertrophic
CONTINUOUS MURMURS Standing up
cardiomyopathy murmur

HEART MURMURS Description Causes Rapid squatting Increases VR, preload, Increase intensity of:
Congenital rubella
and afterload • Mitral regurgitation
Patent ductus Continuous machine-like murmur.
Prematurity • Aortic regurgitation
arteriosus Best heard at left infraclavicular area.
Loudest at S2
• Ventricular septal defect

VR: venous return; RA: right atrium;

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** Aortic Arch **

Pharyngeal arches
- component of pharyngeal apparatus >> later form face & neck
- begin to develop in 4th week : neural crest cell > migrate > form arches
- craniocaudal sequence : 6 pairs of arches
Arch artery - Aortic Arches
- from aortic sac (most distal part of truncus arteriosus - tubular heart)
- supply pharyngeal arch
- enter/connect to paired dorsal aorta (also receive blood from umbilical & vitelline arteries)
- appear in cranial to caudal direction
- Each arch has its own nerve, cartilage, artery
Circulation
Sinus venosus > primordial atrium > primordial ventricle (SA valves & AV canal) > bulbus cordis & truncus arteriosus >
>> aortic sac > pharyngeal arch arteries > dorsal aorta for embryo > umbilical vesicle > placenta

Aortic Arch
- day 27: 1st arch disappear > form maxillary artery
- later : 2nd arch disappear > form hyoid & stapedial arteries
- 3rd arch > common carotid artery + rst part of internal carotid
- 4th arch > (L) arch of aorta + ® proximal part of subclavian artery
- 5th arch > regress / never form
- 6th arch > pulmonary arch ( (R) right pulmonary artery , (L) left pulmonary artery + ductus arteriosus )
- Dorsal Aorta > (R) disappear btw 7th intersegmental artery & left dorsal aorta , (L) descending aorta
** Recurrent Laryngeal Nerve
- (R) 6th distal pharyngeal arch disappear > hook around 4th arch - subclavian artery)
- (L) 6th distal pharyngeal arch persist > ductus arteriosus > ligamentum arteriosum
Anomalous Right Subclavian Artery
- right 4th aortic arch obliterate + persistent distal right dorsal aorta
- >> anomalous artery cross midline >> compress esophagus
Double Aortic Arch
- Normal : Proximal Arch : Left 4th aortic arch & aortic sac // Distal Arch : Left dorsal Aorta
- Pathogenesis : right dorsal aorta btw 7th intersegmental artery & left dorsal aorta persists
- vascular ring > surround trachea & esophagus > compress > problem breathing & swallowing
Right Aortic Arch
- Normal : Proximal Arch : Left 4th aortic arch & aortic sac // Distal Arch : Left dorsal Aorta
- Pathogenesis : entire right dorsal aorta persist, left distal dorsal aorta involution
- Without retroesophageal > ligamentum arteriosum pass right pulmonary artery to right aorta arch
- with retroesophageal > ligamentum arteriosum form ring > compress trachea & esophagus
** Circulation **

Cardiovascular changes during Pregnancy

1. ^ CO
2. V Systemic vascular resistance
3. ^ Blood volume & RBC mass
4. V Blood Pressure
>> ensure adequate uteroplacental circulation ( fetal growth & development )

Maternal : labor & delivery

Co ^ by 70%
- ^ SV & HR
- HR due to pain & anxiety
- ^ venous return >> ^ preload >> ^ SV
Postpartum ( after delivery )
- temporary ^ Venous Return >> ^ SV & CO
- after 24 hr delivery >>> MBP & SV normal
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Fetal Circulation : 4 shunts
1. umbilical / placenta
2. ductus venosus
3. foramen ovale (FO)
4. ductus arteriosus (DA)

Fetal cardiovascular response to acute hypoxia

Neonatal Hypoxia
- pulmonary vascular resistance & pressure remains high , ductus arteriosus remain patent (open)
- >> right to left shunt
- >> early gestation : tachycardia, no increase peripheral vascular resistance
- >> late gestation : acute hypoxia, CV response, perfusion & cardiac output
Acute Hypoxia : vasoconstriction, hypertension, bradycardia (fetal late heart rate deceleration)
- decrease blood oxygen level
- chemoreceptor re ex : constriction of bv in nonvital peripheral areas (kidney, GI, Lower extremities)
- more blood ow to vital organs (adrenal glands, heart, brain)
Birth - Fetal to Neonate Changes
1. Clamping umbilical cord >> ^ Left ventricle pressure >> Closure of foramen ovale
2. Entry of Air to lungs >> V pulmonary vascular resistance >> Rt ventricle perfuse lung
3. ^ oxygen concentration >> closure of ductus arteriosus >> systemic & pulmonary circulation, vasoconstrict in body

Summary: Cardiovascular changes fetus vs neonate.

[Link]. CV-DLA.3 and 4
Fetus Neonate
Pressure Pulmonary circulation Pressure reversal!!
high pressure. 1. Systemic resistance inc. Inc O2 tension results in
Right (RA, RV ) > Left vasoconstriction. No low resistance placenta.
2. Dec pulmonary resistance. Pulmonary vessels
vasodilate. Inc blood flow to LA.
3. Reduced blood flow to RA- occlusion umbilical vein.
Left (LA, LV) pressures > Right
Placental Yes Removed. Vasoconstriction of placental vessels at
circ birth. Red blood flow RA.
Lungs Little blood flow 10%, 100% cardiac output (CO), low resistance. Increased
high resistance venous return to LA, increased pressures
Ductus Open Closes due to pressure difference, inc O2 tensions,
art. dec prostaglandins. Muscular wall vasocontricts
Foramen Open Closes. Pressure reversal causes flap over foramen
ovale ovale to close
Ductus Open Closes 2-3 months. remnant
venosus
Ventricle RV thicker LV thicker

Ductus Arteriosus : closure

Fetal vs Neonate
- active agent : PGE(prostaglandin) regulates ductus arteriosus (DA) muscle sphincter
- fetus : high levels of PGE > relax smooth muscle ductus arteriosus ( PGE due to hypoxia )
- Neonate : ^ PO2 >> V PGE >> ductus arteriosus muscular wall constrict
- premature / abnormal mature infant : DA fails to constrict >> Patent Ductus Arteriosus (PDA)
PDA
- persistent shunt (descending aorta & left pulmonary artery)
- blood ow from aorta >> pulmonary artery (pressure gradient)
- pulmonary circulation & LA & LV volume overloaded >> LV dilation & left sided heart failure
- Features of PDA : murmur heard during systole & diastole > continuous murmur
- treatment : surgical closure
Symptoms : 2-3 days after birth
- continuous blood ow into pulmonary circulation > continuous murmur
- left > right blood shunting >> pulmonary edema, hemorrage, bronchopulmonary dysplasia
Foramen Ovale
- normal : pressure reversal causes ap over foramen ovale to close
- premature infant : left > right shunting
- Patent Foramen Ovale : failure to close
>> could have Cryptogenic Stroke > absence of identi ed cardioembolic or large vessel source
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Persistent Pulmonary Hypertension
- pulmonary vascular resistance remains abnormally high after birth
- right > left shunting of blood through fetal circulatory pathways
- hypoxemia develop > X respond to respiratory support
>> cyanosis, tachypnea, respiratory distress
>> loud S2, harsh systolic murmur (secondary to tricuspid regurgitation)
>> systemic hypotension > shock, poor cardiac function, perfusion

** Development of Heart & Pericardium **

Heart (develop from cariogenic mesoderm)

- 3rd week : 2 angioblastic cords (endothelial strands) > form 2 heart tubes > tubular heart (single tube)
- epicardium : from mesothelial cells of sinus venosus
- myocardium : from myoblast ( rst heart eld)
- endocardium : from primitive heart tube
Formation of Transverse Pericardial Sinus
- formed by degeneration of central part of dorsal mesocardium
- space behind aorta & pulmonary trunk
subdivision of Tubular Heart
- truncus arteriosus, bulbus cordis, primitive ventricle, primitive atrium, sinus venosus
- cephalic arterial end : continuous with aortic sac
- caudal venous end : open into sinus venosus , from placenta & embryo & yolk sac
sinus venosus : receive from ( vitelline + common cardinal + umbilical ) veins

Day 23-28 : Cardiac looping

- bulbus cordis & ventricle grow faster
- undergo dextral loop > dorm U shape bulboventricular loop > apex to the left
- primitive atrium & sinus venosus move dorsal to TA & BC & ventricle
Dextocardia & Situs Invertus
- Dextocardia : L-loop > apex to right
- Situs Invertus : abdominal organs also found reversed
Primitive Atrium : Left & Right Auricle (rough internal surface, trabeculated appearance)
Sinus Venosus : Left horn (mostly obliterates) > coronary sinus & oblique vein of left atrium
Right horn >> Sinus Venarum > smooth walled part of right atrium

Primitive Ventricle : trabeculated part of right & left ventricle

Bulbus Cordis : form out ow tracts of right & left ventricles
right > conus arteriosus (infundibulum)
left > aortic vestibule

Truncus Arteriosus : Left > ascending aorta, Right > pulmonary trunk

end of 4th week : partitioning of atrioventricular canal

- AV endocardial cushions develop (from cardiac jelly & neural crest cell) > form dorsal & ventral wall
- endocardial cushion grow > fuse > divide canal into right & left AV canal > form AV valve
end of 4th week : Atrial partitioning
- septum primum grows from roof of atrium > endocardial cushions > closes foramen primum > foramen secundum
- foramen primum space btw septum primum & endocardial cushions
- opening btw free edges of septum secundum & septum primum >> foramen ovale
- FO is open when Right atrial pressure is greater than Left
Atrial Septal defect - ostium secundum defect
- patent foramen ovale defect
- disrupted or absent septa
- intracardiac shunting of blood (L > R)
- most common but least severe, Female to Male ratio 2:1
- defect of both septa primum & secundum > excess resorption of primum > X close foramen
> abnormal resorption of primum > extra fenestration
> defective secundum > large FO
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Atrial Septal Defects - Endocardial cushion defect + foramen primum defect
- less common ASD
- primum not fused with endocardial cushion
- cleft in anterior cusp of mitral valve > AV valve defect
- intracardiac shunting of blood (L > R)
Atrial Septal Defects - Sinus Venosus Defect
- in sinus venarum - opening of SVC
- incomplete resorption of right horn (sinus venosus) into right atrium
- abnormal development of septum secundum
- intracardiac shunting of blood (L > R)
Atrial Septal Defects - Common Atrium
- prevalent in patients w/ ostium primum, ostium secundum, sinus venosus defect
- complete absence of interatrial septum
Partitioning of Common Ventricle
- Myocytes from primitive ventricle > muscular interventricular IV septum - develops rst > IV foramen
- Bulbar ridges & muscular IV septum fuse with endocardial cushion > form membranous IV septum > closure IV F.
Partitioning of Bulbus Cordis & Truncus Arteriosus (aorticopulmonary septum ) 5th week
- bulbar ridges form within bulbar cordis
- truncal ridges develop within truncus arteriosus >> 180 degree spiral
- ridges grow >> fuse > form aorticopulmonary septum >> divide into pulmonary trunk & ascending aorta
Ventricular Septal Defect (VSD)
- more common in males , 25% of congenital heart defect , intracardiac shunting of blood (L > R)
1. Muscular : no muscular septum > common ventricle , simultaneously (swiss cheese VSD) or isolation
2. Membranous : most common type, no membranous septum, incomplete closure of IV foramen

Development of Heart Valves - endocardial cushion

1. semilunar valve (aorta & pulmonary) : 3 swelling of subendocardial cushion > thin walled cusps
2. atrioventricular valve (mitral & tricuspid) : localized proliferation of endocardial cushion tissue (AV canal)

Neural Crest Cells > endocardial cushion, bulbar ridges, truncal ridges, spiral septum,
membranous inter ventricular septum, semilunar valve, atrioventricular valve, pharyngeal arch

Vitelline Vein : umbilical vesicle > oxygen depleted blood > heart
- right : hepatic portal system & terminal IVC
- left : regress
Umbilical Vein : Placenta > oxygenated blood > Embryo
- Right umbilical & cranial left umbilical : degenerate
- Caudal left umbilical : umbilical vein > IVC (ductus venous) > heart (bypass capillary network of liver)
Common Cardinal Vein : body > deoxygenated blood > heart
- major venous drainage system
- anterior : cranial
- posterior : caudal
- common : together
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** clinical embryology of Heart **

Fetal Circulation
1. umbilical vein from placenta
2. ductus venosus bypass liver sinusoid
3. foramen ovale bypass lung
4. ductus arteriosus

Neonatal Circulation
1. foramen ovale closes > fossa ovalis & limbus of fossa ovalis
2. ductus arteriosus closes > Ligamentum arteriosum
3. ductus venosus > Ligamentum venosum
4. contraction & brosis of umbilical vein > ligamentum teres hepatis

Ectopia Cordis
- heart in abnormal location
- thoracic ectopia cordis : heart exposed on thoracic wall
- faulty development of sternum & pericardium
- widely separated halves of sternum, open pericardial sac
- abdominal ectopia cordis : heart protrudes through diaphragm into abdomen
>> death , infection, cardiac failure, hypoxemia

Congenital Heart Defects (CHD) - 80% unknown

- infections > rubella > in early pregnancy > Patent Ductus Arteriosus
- chromosomal abnormalities > Turner Syndrome (Coarctatio of Aorta)
> Down syndrome (endocardial cushion defect > ASD/VSD/PDA)
- variable deletion of Chromosome 22 > DiGeorge / conotruncal anomaly face syndrome / CATCH-22 syndrome
- environmental factors (maternal alcohol abuse, maternal diabetes interfere)
- well tolerated in fetal life >> more apparent once maternal circulation lost
- symptoms: murmurs, dyspnea, recurrent pulmonary infection, cardiac failure, pulmonary hypertension, endocarditis
- >> abnormal cardiac shunt >> (Right to left // Left to right)
Down syndrome - trisomy 21
- Atrioventricular septal defect (AVSD - most frequent)
- primum type ASD & membranous type VSD
- isolated ASD or VSD
- tetralogy of fallot (VSD, pulmonary stenosis, right ventricle hypertrophy, misplaced aorta)
- PDA
Right to Left shunt
- deoxygenated systemic venous blood bypass lung >> cyanosis & blue babies
- cyanosis : bluish discoloration of skin & mucous membranes (deoxyhemoglobin concentration > deoxygenation)
- central : lips, core, tongue
- peripheral : extremities or ngers
- treatment : surgical treatment of Ductus Arteriosus (PDA)
- disease : truncus arteriosus, transposition of great vessels, tricuspid atresia, anomalous pulmonary venous return
Tetralogy of Fallot
1. VSD (membranous) - failed fusion of ridges
2. pulmonary stenosis - anterior superior displacement of bulbar (infundibular) septum
3. right ventricle hypertrophy - increased workload resulting from pulmonary stenosis
4. overriding aorta - rides over inter ventricular septum
>> TET SPELL > cyanosis occurs with vigorous crying, feeding or agitation
>> Right to Left shunt
>> common CDH in DiGeorge , Down, fetal alcohol syndrome

Right to Left shunt - Persistent Truncus Arteriosus

- neural crest cell migration failure >> X aorticopulmonary septum
- VSD always present >> truncus arteriosus straddles VSD
- >> Mild Cyanosis
- >> Microdeletion Chromosome 22 / DiGeorge syndrome
Right to Left shunt - Transposition of Great Vessel
- faulty neural crest cell migration > X spiral twisting > switching of Aorta & pulmonary trunk >> severe cyanosis
- lethal unless ASD, VSD, PDA
- cause : maternal diabetes
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Right to Left shunt - Total Anomalous Pulmonary Venous Return
- Abnormal drainage of pulmonary vein > systemic venous circulation >> sever cyanosis
- lethal unless ASD, VSD, PDA
- common sites: SVC, brachiocephalic vein, coronary sinus, IVC, portal vein / hepatic vein
Left to Right Shunt - CHD
- back leak of blood from systemic to pulmonary
- pulmonary ow larger than systemic ow
- VSD, ASD, PDA, AVSD
- acyanotic
- excess volume through right heart & pulmonary circuit >> pulmonary hypertension > right ventricular hypertrophy
Ductus Arteriosus
- essential shunt of intrauterine life
- functional closure within rst few days of birth
- anatomical closure by 12th week
- >> IF NOT CLOSE >> L-R shunt
Left to Right Shunt - PDA
- frequent in female
- maternal rubella infection in early pregnancy
- down syndrome
- failure of contraction of ductus arteriosus muscular wall : premature infants, hypoxia, low birth weight, high altitude
- medication : prostaglandin > allow patency while awaiting surgery (when Right to Left shunt)
- diagnosis : echocardiography / color ow doppler technique
- treatment : anti-prostaglandin, NSAID - indomethacin , surgery
Eisenmenger’s syndrome - reversal of shunt
- Large VSD, PDA, AVSD >> quick pulmonary hypertension >> reverse blood ow >> late cyanosis
- thickens pulmonary artery walls
- 1-2 years for VSD, PDA, AVSD
- few decades for ASD
Coarctation of Aorta
- congenital narrowing of aorta (arch of aorta)
- male to female ration 2:1
- 20% in Turner syndrome
- abnormal involution small distal segment of left dorsal aorta
- muscle tissue of ductus arteriosus incorporate into wall of Aorta >> constrict and DA closes at birth
- 1. directly opposite to DA
- 2. Preductal : before birth, blood ows through ductus to descending aorta > lower body
- 3. Postductal : develop collateral circulation during fetal life > assist passage of blood to lower body
Collateral Pathway
- subclavian artery > internal thoracic > anterior intercostal artery > posterior intercostal > descending aorta
- increased size of internal thoracic & posterior intercostal arteries
- inferior rib notching (3rd -8th) >> increased sized & pressure of intercostal collaterals
>> headache, fatigue, underdeveloped lower extremities (cyanotic), Cardiomegaly
>> pulse and blood pressure disparity btw upper & lower limbs
treatment : prostaglandin to keep DA open >> surgical intervention
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** BLOOD **
Blood - specialized CT
- cell: erythrocytes, leucocytes, thrombocytes
- Ground Substance : plasma (protein rich)
- 7-8% body weight
- deliver nutrients & oxygen to body tissue
- transport waste and carbon-dioxide away
- transport hormone , humoral agents, immune system cells
- maintain homeostasis > bu er , thermoregulation , coagulation
- embryonic : umbilical vesicle (yolk sac)
- fetal : liver & bone marrow
- adult : bone marrow
55% plasma / 45% Cells (99& RBC, 1% WBC & platelets)
hematocrit : volume of packed erythrocytes
serum : plasma without clotting factor

Plasma - pH control & osmolarity for metabolism

- 91-92% water
- 7-8% protein : albumin, globulins, brinogen
- 1-2% other : electrolytes, non-protein nitrogen, nutrients, blood gas, regulatory hormones enzymes
- easily travel through blood vessel wall
- assist forming interstitial uid >> CT most similar to plasma
Plasma Protein - made in LIVER
Albumin : (most abundant)
- concentration gradient btw blood extracellular tissue uid - colloid osmotic pressure
- if leaks out > swollen ankle
- carrier protein for hormones, metabolites, drugs
Globulins :
- immunoglobulins - antibodies
- non immune globulins - help maintain osmotic pressure + carrier protein for hemoglobin
Fibrinogen : (largest protein)
- converted to brin (when needed)
Cells - RBC & WBC
Erythrocytes (RBC)
- no nucleus or organelle
- 7-8um, life span 120days
- biconcave disk , max surface area for gas exchange, exible shape for narrow passage, membrane protein (shape)
- contain hemoglobin >> red color >> 1/3 of cell weight (eosin stained)
hemoglobin : 4 polypeptide chains (a, b, d, r) > iron-containing heme group
- HbA (a2b2) - 96% >> HbA1c binds irreversibly to glucose
- HbA2 (a2d2) - 1.5-3%
- HbF (a2r2) - 1% >> abundant in fetus, binds O2 strongly, high in sickle cell & thalassemia

cytoskeleton : band 4.1 protein complex, band 4.2 ankyrin, band 3 bind hemoglobin, glycophorin C attach to
membrane, glycosylated protein antigen A,B,O

Leukocytes (WBC)
- granulocytes (both azurophilic + speci c scecondary granules) : neutrophils, eosinophils, basophils
- agranulocytes (only azurophilic) : lymphocytes (t & b cells, natural killer cell) , monocytes
- thrombocytes : (platelets) - special cell fragments
- have nucleus & few organelles >> protective function, great motility, move from blood to other tissue
- have azurophilic granules (primary) - large lysosomes > destroy foreign body
Neutrophils - 60~70% of circulating leukocytes , life span 2-5days, nucleus 2-4 lobes, band cell, could have barr body
- speci c : enzymes, compliment activators, antimicrobial peptides
- azurophilic : myeloperoxidase, acid hydrolases, defensin, cathelicidin
- tertiary : phosphatase, metalloproteinase
>> rst to react to tissue damage >> active phagocytes for bacteria
- lysozyme destroy bacteria > defensin break bacterial cell wall > strong oxidant destroy bacteria
Eosinophil - 2~4%, nucleus bilobed, large uniform sized granules, stain eosinophilic (orange red)
- 4 protein : major basic protein (MBP) - crystalloid, ECP - cationic protein , EPO - peroxidase , EDN - neurotoxin
- enzymes : histaminase, sulfatase, collagenase, cathepsin
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 - leave capillaries >> enter tissue uid
- MBP, ECP, EPO >> cytotoxic e ect > protozoans & helminthic parasite
- EDN >> nervous system dysfunction
- histaminase > neutralize histamine, arylsulphatase neutralize leukotrienes (basophils & mast cell)
- antibody-antigen (immune) complex internalized by eosinophils

Basophils - 1%, nucleus irregular s-shaped bilobed

- cytoplasm - large variable sized, stain blue / purple > basic dyes - obscure nucleus
- speci c granules contain - heparin (sulphate)- anticoagulant, histamine (vasoactive vasodilator) & leukotrienes
(constrict smooth muscle in pulmonary airway) , IL-4 & IL-13 (promote synthesis IgE antibodies)
- heighten in ammatory response >> hypersensitivity reaction (allergic)
Lymphocytes - 20~25%, small medium & large sized lymphocytes, dark oval round nucleus
- cytoplasm thin, pale blue rim around nucleus - contain azurophilic granules, ribosomes
- both in blood & lymph
- immunocompetent cell : recognize & respond to antigen
- T cell (di erentiate in thymus) : cell mediated immunity, long life span, attack virus fungi cancer cell & bacteria
- B cell (from bone marrow) : production of antibodies, destroy bacteria & toxin, produce antibodies, variable life span
- Natural Killer cell (NK) : attack microbes, tumor cells, destroy foreign invaders directly
Monocyte - 3~8%, nucleus indented (kidney shape), cytoplasm foamy blue gray - contain azurophilic granules
- Largest WBC - remain in blood only 3 days > migrate to tissue
- become macrophage : histiocyte (CT), alveolar dust cell (lung), Kup er cell (liver)
- take longer to get to infection // but arrive in large number
- enter in ammation site > macrophage > antigen-presenting cell >> cluster >> giant cell (at chronic infection site)
Thrombocyte (platelets) - 250,000 ~ 400,000 platelets / uL
- 5~9 day lifespan, formed in bone marrow from megakaryocytes, fragments form platelet, removed in spleen / liver
- alpha contain : clotting factor + platelet derived growth factor
- >> vascular endothelial proliferate, smooth muscle & broblast repair damage vessels
- Dense contain : ADP, ATP, Ca++, Serotonin, brin-stabilizing factor, thromboxane A2 producing enzyme
- platelet pull on brin thread > clot retraction > release factor XIII > stabilize brin > repair blood vessel
WBC count
neutrophils 60~70% : ^ acute bacterial infection
lymphocytes 20~25% : ^ chronić infection / cancer
monocyte 3~8% : ^ fungal / viral infection
eosinophil 2~4% : ^ parasitic infection
basophil 1% : ^ allergic reaction

sampling technique
venipuncture : take from vein > hypodermic needle & syringe
- median cubital vein > vein less pressure , closer to surface
nger or heel prick : common for diabetics to monitor blood sugar, used for infants

anemia - lack of su cient healthy RBC > fatigue, weakness, pale skin, short breath, dizziness, cold hand & feet
- female once a month // chronic due to underlying condition
Polycythemia - higher number of RBC > dizziness, headache, excess sweat, itchy, blurred vision, reddish, bleeding
- primary ( polycythemia vera, blood cancer ) // secondary ( altitude or dx caused reduced oxygen lv )

Poikilocytosis - poikilocytes in blood >> RBC distorted shape >> more than 10% of total cell
- membrane abnormality // traumatic condition >> Teardrop cell (dacrocytes) , Fragmented cell (schistocytes)
Anisocytosis - RBC unequal sizes - detected in peripheral smears
- can signify conditions >> anemia & thalassemia
Hereditary Spherocytosis - decfective gene : spectrum, ankyrin, band 3 & 4 protein
- essential protein for normal biconcave shape or erythrocyte >> spherical shape

Thalassemia - hereditary hypo chromic anemia (decreased a or b chains)

- b thalassemia : decreased or absent b chains > excess a chains > X form tetramers
- bind to RBC membrane >> produce membrane damage + form toxic aggregates
Sickle cell anemia - genetic defect in hemoglobin (Hb-S) - hydrophilic glutamic acid > hydrophobic valine (in 6 b chain)
- reduced oxygen level >> sickle HbS
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** Chylomicrons, VLDL, LDL metabolism **
lipids - hydrophobic >> tranported by albumin (free fatty acids) & Lipoprotein (nonpolar TAG & cholesterol ester)

Lipoprotein - spherical, outer shell - phospholipid monolayer (apo-lipo-protein & free cholesterol) > inside hydrophobic
- separated by ultra-centrifugation (size & density) // protein electrophoresis (charge by apoproteins)
- UC: chylomicron (on top), VLDL (very low density), IDL (intermediate), LDL (low), HDL (high density)
- (largest, most TAG) - (TAG rich) - (cholesterol rich) -(smallest, apo-protein rich)

Chylomicron (intestinal mucosal cell) > Microsomal TAG transfer protein (MTP) assemble apo B-48 & lipid >> release
>> lymph (contain dietary lipids & lipid soluble vitamins) > Blood > Nascent CM + HDL (CII + E) > (lipase cleave TAG)
> remnant taken up by liver (need Apo E receptor)

Apo B-48 (synthesized through post transcriptional editing of mRNA)

- Apo B gene >> in liver : Apo B-100 // in intestine : Apo B-48
- cytidine deaminase > form stop codon UAA > translate 48% of mRNA Apo B gene
Lipoprotein Lipase (LPL) - in capillaries of heart, muscle, adipose tissue >> cleave TAG > release FA
- need Apo C-II (from HDL > CM & VLDL)
- Largest amount found in Heart >> well oxygenated heart >> use FA for energy metabolism
- In Fat Tissue >> insulin dependent >> to store TAG in fat cells
VLDL (released from liver) > Apo B-100 > Blood (contain TAG & cholesteryl ester) + Apo CII + E
> lipase cleave TAG form FA > for Heart metabolism / fat cell storage / LDL distribute cholesteryl ester (plasma memb)
>> remnant IDL >> Taken up by live (Apo E) // provide TAG for Hepatic Lipase >> form LDL (Apo B100) >> transport
>> cholesteryl ester >> form plasma membrane (peripheral cell) // liver up take (need Apo B100)
// LDL oxidized >> oxLDL >> enter macrophage (SR-A receptor) >> foam cell > proin ammatory mediator
** High LDL & oxLDL >> Increase risk for Atherosclerosis (fatty streak >> brofatty atheroma)

HDL lled with cholesteryl ester (blood) > give apo CII & apo E > Chylo & VLDL
- reverse cholesterol transport to liver ( need Apo A )

VLDL >> Lipoprotein Lipase (heart, muscle, fat) >> IDL (blood) >> Hepatic Lipase (liver) >> LDL (blood)

Liver uptake
LDL receptor + Apo B100 >> LDL endocytosis >> clathrin coat >> free cholesterol, FA, AA
IDL & CM >> uptake by Apo E >> recycled
>> high cytosolic Free cholesterol >> Activate ACAT (Acyl CoA cholesterol Acyl Transferase) >> Cholesteryl Ester
>> inhibit gene expression (HMG CoA reductase & LDL receptor)

Apo B-48 de ciency : low CM level

Apo B-100 de ciency : low VLDL IDL LDL > Abetalipoproteinemia (MTP de ciency), hypobetalipoproteinemia (x Apo B)
Apo E de ciency : high CM IDL remnant > Hyperlipoproteinemia Type III (dysbetalipoproteinemia)
Apo C-II de ciency : high CM VLDL > Hypertriacylglycerolemia, Hyperlipoproteinemia Type I, IV, V

** HDL & Lipoprotein Disorder **

HDL - circulating Reservoir - give Apo C / E to CM & VLDL
- prevent fatty streak formation > reverse cholesterol transport

Cholesterol ABC transporter + ABCA1 -cholesterol transporter (Macrophage) >> release Free Cholesterol

nascent HDL (disc shape) >> from liver / intestine (contain PC & apolipoprotien) >> release to blood
>> give CM & VLDL >> Apo C-II / Apo E
>> HDL use Apo A-1 to activate LCAT >> ll with CE >> globular shape

Lecithin-Cholesterol-Acyl-Transferase (LCAT - from liver) release to blood >> + Free Cholestrol

>> binds to HDL (Apo A-1 activates LCAT)
>> use FA from Phosphatidylcholine (PC) of HDL (memb) >> form Cholesteryl Ester in blood >> move inside of HDL
>> HDL bind to SR-B1 (liver) >> CE ow into liver
** SR-B1 also found in steroid hormone synthesizing tissue >> release Free Cholesterol (to blood)

CE from HDL > Cholesteryl Ester Transfer Protein (CETP) > give VLDL CE >> LDL >> Liver ( also possible )
(form hydrophobic channel) > give HDL TAG (exchange)
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** Hypolipidemia & Hyperlipidemia **

Hypolipidemia
1. Hypoalphlipoproteinemia : low HDL ( hereditary: Tangier dx - ABCA1 cholesterol Transporter )
( Acquired: hypertriacylglycerolemia , obesity, smoking, de cient LCAT / Apo A1 )

Tangier Dx : extremely low HDL > orange colored Tonsils (all children)
- peripheral neuropathy & premature MI (30%)
- macrophages lled with cholesterol > enlarged liver & spleen > corneal opacities
- genetic defect of ABCA1 >> less Free Cholesterol >> Low HDL >> More Foam Cells
2. Abetalipoproteinemia & Hypobetalipoproteinemia : low VLDL, LDL, CM
(MTP de ciency , Apo B de ciency )
>> reduce CM & VLDL release >> Low blood TAG (below 19mg/dL) and Cholesterol level (below 50mg/dL)
>> failure to thrive, fat malabsorption, severe neonatal steatorrhea, TAG accumulation in liver & intestine
>> retinitis pigmentosa, progressive blindness, peripheral neuropathy (Vit A/E), acanthocytosis (RBC with spicules)

Hyperlipidemia

high Cholesterol = above 200mg/dL

normal LDL (100-130 mg/dL), HDL (50/70 mg/dL), VLDL (20-30 mg/dL)
Normal fasting TAG = 100-150 mg/dL (mostly found in VLDL, CM - not during fasting)
abnormal increase in CM / VLDL >> high TAG in blood

abnormal lipoprotein pattern = dyslipidemia

High LDL > 160 mg/dL
High TAG > 200 mg/dL
Low HDL < 40 mg/dL

- primary : genetic disorder

- defective clearance / overproduction of TAG & LDL
- excessive clearance / underproduction of HDL
- secondary : smoking, sedentary life, unhealthy diet, diabetes, obesity, metabolic syndrome , alcohol, chronic kidney
- hyperthyroidism, cholestatic liver dx, HIV, speci c drug treatment
- Friedewald Equation :
- LDL = total C - [HDL + TAG/5]
1. Hypertriacylglycerolemia (high Cholesterol) : Hyperlipidemia Type I (CM) , IV (VLDL) , V (both)

Type I - familial hyperchylomicronemia (rare)

- high serum TAG ( >750 mg/dL) >> normally CM absent during fasting
- vial lipemia plasma - milky turbid blood >> creamy layer on top after 4 hours
-
- lipoprotein lipase de ciency , Apo C-II de ciency , Apo A-IV de ciency
- lipemia retinalis (creamy white vessel) , hepatosplenomegaly, recurrent epigastric pain > Pancreatitis (TAG >1000mg)
- xanthomas - eruptive > Trunk, buttock, extremities
Type IV - familial Hyperprebetalipoproteinemia (common)
- high VLDL (also named prebetalipoprotein) , normal LDL, low HDL
- TAG 200-500mg/dL , lipemic turbid plasma
- LPL de ciency , VLDL overproduction, low HDL
- high TAG >> increase risk of Pancreatitis & CVD
Type V - familial mixed hypertriacylglycerolemia
- high CM, high VLDL
- lipemic plasma - turbid high VLDL bottom + creamy layer on top high CM
2. Hypercholesterolemia (high TAG) : Hyperlipidemia Type IIa (LDL), IIb (LDL & VLDL), III (IDL, CM, VLDL)

Type IIa - familial hypercholesterolemia (common) - risk of CVD & MI

- treatment : diet, weight loss, exercise, statins, bile acid biding drug, brates
- heterozygous FH : adult onset (cholesterol 250-500mg/dL)
- homozygous FH : rare, childhood MI and death
- defective LDL-receptor (AD) // diminished clearance of LDL (Apo B100)
- tendon xanthomas , xanthelasma (eyelids)
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Type IIb - familial combined Hyperlipidemia (common)
- high LDL, VLDL, lipemic turbid serum
- risk of CVD & MI
- combined with smoking diabetes, obesity, metabolic syndrome, unhealthy lifestyle
- heterozygous : puberty onset (cholesterol 250-500mg/dL, TAG 250-750mg/dL, xanthomas are rare)
- complex dx : overproduction of Apo B 100 & VLDL, Defective clearance of LDL
Type III - dysbetalipoproteinemia (rare)
- high chylomicron remnants & IDL, abnormal b-VLDL
- total cholesterol 250-500 mg/dL & TAG 250-500 mg/dL (b-VLDL)
- adult onset + accelerated atherosclerosis
- Apo E de ciency ( lack Apo E3, homozygous for Apo E2)
- palmar xanthomas, tubereruptive xanthomas (elbos & knee)

Hyperlipidemia
- use lipoprotein electrophoresis to recognize abnormal lipoprotein separation
Treatment : increase LDL-receptor >> uptake more LDL into liver, reduce blood cholesterol
a. stimulate LDL-r synthesis >> low hepatic free cholesterol
- statin drug >> competitively inhibit HMG CoA reductase >> inhibit cholesterol synthesis
b. increase LDL-r recycling & decrease degradation
- PCSK9-inhibitor drug (when statin X work)
- protein convertase subtilisin / kexin type 9 ( serine protease ) >> prevent LDL-r recycling >> degrade LDL-r
- PCSK9 synthesized in liver > released to blood > bind LDL-r > prevent endosome formation > lysosome degrade
- PCSK9-inhibitor = human monoclonal antibody (injected every two weeks or monthly)

LDL- B
- is smaller than LDL- A
- penetrates endothelium easily
- oxidized to ox-LDL >> small, easily trapped and oxidized >> form foam cells
- form from >> saturated FA, Trans-FA, cleavage of TAG in LDL-A ( hepatic lipase )
Lipoprotein (a) = Lp(a)
- similar to LDL
- but has Apo(a) linked to Apo B-100 (disul de bond)
- structural analog to plasminogen >> compete for binding to brin >>> reduce removal of blood clots
- trigger MI or stroke

Drugs for treating Hypercholesterolemia

1. plant sterols & stanols - reduce cholesterol uptake
2. ezetimibe - inhibit speci c intestinal cholesterol transporter
3. bile acid binding drug (cholestyramine) - reduce bile acid reuptake >> increase hepatic LDL-r synthesis
4. partial ileal bypass surgery - reduce bile acid reuptake >> increase hepatic bile acid synthesis > ^ LDL-r synthesis
5. inhibit hepatic cholesterol synthesis (statin) - inhibit HMG-CoA reductase > inhibit cholesterol synthesis
6. PCSK9-inhibitor - increase recycling of LDL-r >> reduce LDL-r degradation
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** Nutritional Aspect of CVD 1 **

Individual Risk factors

- genetic : predisposition, family history
- age : men >= 45 yo, women >= 55
Modi able risk factors
- diet : high trans fat, saturated fats, salt and re ned sugar, Trans Fat, hydrogenated oils
- smoking : cigarettes, cigars, pipe
- physical inactivity : sedentary life-style >> need to include exercise & healthy weight
- excessive alcohol intake : reduce alcohol intake
Clinical conditions risk factors
- dyslipidemia : high LDL, high VLDL, low HDL
- hypertension : BP > 130/90 mmHg
- obesity : BMI >= 30
- diabetes : blood glucose >= 126mg/dL
- metabolic syndrome : all of the above (abnormal cholesterol, obese, insulin resistance, high BP)
Dietary fatty acids have metabolic effects related to CHD

• Figure 27.15 Ferrier p. 364

[Link].0236

Cardioprotective dietary FA
1. Monounsaturated : Oleic acid (18:1)
2. Polyunsaturated : w-6 (linoleic acid 18, arachidonic acid 20)
3. Polyunsaturated : w-3 (a-linolenic acid 18, eicosapentaenoic acid EPA 20, Docosahexaenoic acid DHA 22)

Dyslipidemia - correlated to BMI

- overweight and obesity >> risk factors >> Increase TAG & cholesterol
Diagnosis of Central Obesity
- waist circumference of more than 40 inches (men) // 35 inches (women)
- waist to hip ratio men >1 // women > o.8
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- apple shape >> high visceral fat - more weight able waist >> Increase VLDL >> dyslipidemia
- Pear shape >> more weight below waist
Obesity & Mortality
- increased risk of mortality with increased aging.
- strongest relationship in individuals less than 55 yo
- after 74 >> not observed anymore
- 1. hypertension
- 2. dyslipidemia
- 3. type 2 diabetes
- 4. CVD
- 5. many other chronic conditions
>> Health Bene t after weight loss >> decrease ( BP, TAG, Blood Glucose level ), increase HDL
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 ** Nutritional Aspect of CVD 2 **

Dietary Recommendations
1. Reduce salt intake
- salt >> increase BP, CHD & stroke risk
- use spices instead fo NaCl
2. Reduce re ned Sugar
- high glcemic index >> raise blood glucose lv >> elevate Insulin
- insulin stimulates FA synthesis & VLDL release
3. Dietary bers
- bers absorb 10-15 times its own weight in water
- soluble ber : increase satiety, delay gastric emptying, fermented by intestinal bacteria,
- reduce bile acid reabsorption, lower LDL blood level
- insoluble ber : add to bulk of stool, help food pass quickly, stool softener
4. Moderate Alcohol consumption - protect CHD
- reduce LDL blood level
- Red wine > contain resveratrol > reduce Foam Cell , protect against oxLDL
- beer > Vit B rich > protect against homocysteine
Homocysteine & Vascular DX
1. high homocysteine blood level >> risk for CVD
2. homocystinuria - hereditary dx > develop premature vascular dx > thrombosis
3. Vit B de ciency > high homocysteine > reduced by supplementation with folates, B6, B12

Micronutrients protect against CHD

1. Trace Minerals - protect against ROS damage
2. Vit C & E - work together in water & lipid phase
3. Radical Scavengers in vegetables, fruit, spices >> phytochemical, polyphenol, avonoid, isoprenoid, carotenoid

DASH diet - Dietary Approaches to Stop Hypertension

1. low Na, reduced intake of processed food
2. cooked with no added table salt
3. low saturated fats & no trans fat
4. rich K, Ca, Mg, Fiber & Protein
e ect >> reduce BP, LDL, Weight

>> increase fruit, vegetable, nuts, sh

>> no trans fat, less palmitate, increase olive oil, increase w-3, moderate cholesterol, reduce red meat
>> reduce table sugar, choose low GI Carbohydrates

Bene t of Mediterranean diet

- Mediterranea vs Western
- has more MUFA & less saturated FA >> high oleate / palmitate ration
- low in read meat >> overall reduced CHD risk
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 ** Primary & Secondary Hemostasis **

Hemostasis
1. vascular spasm / vasoconstriction
- trauma to vessel wall > smooth muscle contraction
- local myogenic spams
- endothelin & serotonin released
- nervous re exes
** but only transient, NOT long term cessation

2. platelet plug formation / primary hemostasis

- form plugs > less blood loss
- small cuts : sealed by platelet plugs
- LAB TEST : bleeding time & platelet aggregation test
- stages : Platelet Adhesion > Activation > Recruitment & Aggregation
- (normally negative on both platelet & endothelial cell will prevent adhesion)
- Gp-la & Gp-lb + bind to subendothelial collagen & vWf
-
- initial platelet adhesion > platelet activation (shape change) > degranulation + thromboxane A2
- degranulation >> ADP activation & binds to neighboring platelet > increase intracellular Ca, decrease cAMP
- >> increase thromboxane A2
Ca activate Phospholipase A2 Thromboxane synthase
Membrane Phospholipid > Arachidonic Acid > Prostaglandin G2 > Prostaglandin H2 > TXA2 enhance vasoconstriction
Cyclo-oxygenase(COX)

von Willebrand factor

1. platelet Gp-la binds collagen > pseudopods develop > promote platelet-platelet interaction
2. Von Willebrand factor binds to Gp-lb > change platelet membrane
3. Expose GPIIb/IIIa > bind to brinogen (main determinant of Platelet Aggregation)

** Gplb defect - Bernard - Soulier syndrome

** GpIIb/IIIa defect - Glanzmann Thrombasthenia

vWF - bridge btw GP-Ib & collagen bers > facilitate adhesion & aggregation
- vWF with Factor VIII >> prevent degradation (secondary hemostasis)
- ** vWF de ciency >> defect in platelet plug formation & coagulation
3. blood coagulation / secondary hemostasis
- conversion of blood > solid gal state
- soluble brinogen > insoluble brin (require thrombin) > stablize platelet plug
- synthesized by liver
- brin aggregate & link > by hydrogen bond (non covalent) > form brin polymer (soft clot)
- FXIII > thrombin > FXIIIa (highly speci c transglutaminase)
- brin polymer (soft clot) > (covalent cross-linking) > Stable Polymer (hard clot)
Thrombin formation
- transform proenzyme > active form (irreversible proteolytic activation) >> Enzyme Ampli cation
Thrombin - FIIa
- activate FXII, FXI, FVIII, FVII, FV, FI( brinogen > brin), FXIII (activate stable thrombus)
- activate platelet & anticoagulant system
APTT Key Facts of clotting cascade
Factor I – Fibrinogen
Factor II- Prothrombin • Conversion of fibrinogen to fibrin (4c) and stabilization of fibrin
PT-Prothrombin time/ INR Factor III-Tissue factor (6c) requires thrombin (IIa)
Factor IV- Calcium
Factor
Factor
V
VII
• Thrombin formation requires factor Xa (Xa,Va,Ca2+, platelet
1i Factor VIII phospholipids-Prothrombinase complex - 2c)
Factor IX
1e Factor
Factor
X
XI
• Xa generated by
2i
Factor XII – Extrinsic pathway (1e-3e) – through VII and III (activated on injury)
5i Factor XIII
2e
LEGEND:
– Intrinsic pathway (1i-5i) – through XII, XI, IX and VIII
3i 3e Green – Common pathway factors

4i 1c
Blue – Extrinsic pathway factors
Black – Intrinsic pathway factors
• Laboratory tests for the coagulation cascade:
2c
– Prothrombin time (INR): Extrinsic pathway
3c
– Activated Partial Thromboplastin time (aPTT): Intrinsic pathway
Clotting factor song:
[Link] 35
34 [Link]. 0250
4c 5c 6c [Link]. 0250

4. clot stabilization and resorption

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** Eicosanoids **
20-c (Eicosa) Fatty Acid
- lipid derived mediator
- have local e ect - autocoids
- synthesized in small amount & short half-life
- attach to G-protein coupled receptors > intracellular change in cAMP // intracellular Ca level (Gs, Gi, Gq)
Membrane Phospholipid > Phospholipase A2 > Arachidonic Acid (20c fatty acid) > Cyclooxygenase / Lipoxygenase
w-6 (prostanoids) / (leukotrienes)
Prostanoids
- formed from COX
- depends on tissue, stimulus, substrate lipid (arachidonic acid)
-
- PGE2 - activated macrophage > mediate in ammatory response > vasodilation, pain, fever, protect gastric mucosa
- PGF2a - uterine tissue > facilitate contraction > induce labor, vascular smooth muscle contraction
- PGI2 - endothelium > inhibit platelet aggregation, vasodilation
- TXA2 - activated platelet > facilitate platelet aggregation, vasoconstriction

Cyclooxygenase Pathway
- forms prostanoids >> ( PGG2 >> PGH2 ) - unstable >> ( PGE2, PGF2, PGI2, TXA2)
- COX-1 > constitutive enzyme
- COX-2 > inducible enzyme (in ammation)
Precursor of Eicosanoids
- arachidonic acid (20C FA - 4 double bond - w-6 FA)
- from linoleic acid
- most common precursor of series 2 prostanoids
- PGI2, TXA2
- Eicosapentaenoic acid (20C FA - 5 double bond - w-3 FA)
- a-linolenic acid
- precursor of series 3 prostanoids
- PGI3, TXA3
** TXA3 less potent than TXA2 >> more w-3 >> more TXA3 >> decrease risk of Platelet Aggregation

Inhibitors of Eicosanoids
- cortisol : inhibit Phopholipase A2, inhibit arachidonic acid release, inhibit COX2, anti-in ammatory
- aspirin & NSAID : inhibit COX1 & COX2
- selective COX2 inhibitor : Celecoxib, Diclofenac
Aspirin (low dose - 81mg) Summary:
- irreversible inhibitor of COX
- inhibit platelet COX > less TXA2 synthesis (no nucleus)
- endothelium can make new enzyme >> PGI2 synthesis not a ected
- ( PGI2 >> TXA2 ) - inhibit platelet aggregation (anti-thrombogenic agent)
Lipoxygenase Pathway

Leukotrienes
- cysteine leukotrienes (LTC4, LTD4, LTE4) >> ^ vascular permeability
- released by mast cell
- mediate allergic & anaphylactic response
- bronchoconstriction (asthma) & airway obstruction
- components of SRS-A (slow reacting substance of anaphylaxis)
Inhibitors of Eicosanoid synthesis
- cortisol : inhibit Phospholipase A2, decease arachidonic acid, inhibit prostanoid & leukotrienes synthesis
- anti-in ammatory & anti-allergic agent
- lipoxygenase inhibitor reduce Leukotrienes formation >> anti-allergic agent (management of asthma)
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** Hematopoiesis **
- the process of producing Formed Elements of blood
- >> erythrocytes, leukocytes, platelets.
Totipotent - ability to develop >> all tissue
- embryonic : endoderm, mesoderm, ectoderm
- extra-embryonic : placental, amnion, chorion
- pluripotent : ability to develop into all cells >> 210 di erentiated adult cell types
- pluripotent stem cell (PPSC) : capable of all blood cell & self renewal
- Hematopoietic Stem Cells (HSC) : give rise to multiple colonies of progenitor stem cells
- Progenitor cell : common myeloid progenitor + common lymphoid progenitor >> Colony Forming Unit
- CMP > granulocytes, erythrocytes, monocytes, megakaryocytes (GEMM)
- CLP > T cells, B cells, NK cells
- precursor cells : morphologically distinct, no self renewal
- multipotent : develop into small number of di erent cell types
- unipotent : develop into a single cell type
Yolk-Sac phase : 3-8 weeks, First trimester
Hepatic phase : major blood forming organ Liver & Spleen > Second Trimester
Bone marrow Phase : begins during 2nd trimester, involves other lymphatic tissues

Stem cell niche - ( endosteal niche - spongy / cancellous bone ) - spatial structure for HSC to maintain & self-renewal
- storage of quiescent stem cell
- self renewal
- inhibition of di erentiation
- HSC in contact with osteoblast lining endosteum, osteoblast regulate HSC
HSC - in cavity of long & axial bones > surrounded by stroma
Stroma : give rise to Firbroblasts, Adipocytes, Endothelial cells, Osteoblasts

Vascular Niche - where endothelial cells, broblast, adipocytes are found

- balance HSC quiescence, self-renewing activity, production of early progenitors
- site of proliferation, di erentiation, maturation of multipoint progenitors
- secretion of growth factors by stroll cells
Bone marrow structure
- structure : reticular bers, veins, arteries, sinusoids, islands of cells
- red marrow : active hematopoiesis
- yellow marrow : fat, capillaries, reticular cells, inactive hematopoiesis
Hematopoietic Growth Factors - regulate proliferation & maturation
- progenitor cells have receptors > for speci c cytokines & growth factors (glycoproteins)
- Erythropoietin (EPO) : produced by kidneys, increase erythrocyte precursors
- Thrombopoietin (TPO) : hormone from liver, stimulates thrombocyte formation
- Cytokines : local hormones of bone marrow, stimulate other marrow cells proliferation
- colony-stimulating factor (CSF) & interleukin stimulate leukocyte production
- ** IF NO Growth Factors >>> hematopoietic cells will die

Myelopoiesis
- Erythropoiesis - form erythrocytes - occur is adult red bone marrow
- main stimulus : hypoxia
- produced by kidney
- proerythroblast : no hemoglobin, large nucleus, basophilic cytoplasm (14-19um)
- basophilic erythroblast : some hemoglobin, condensing nucleus (12-17um)
- polychromatophilic erythroblast : muddy cytoplasm (12-15um)
- orthochromatophilic (late) erythroblast : increased hemoglobin (8-12um)
- reticulocyte : no nucleus, some ribosomes (blue with cresol blue stain) (7-8um)
- erythrocyte : only hemoglobin, no ribosomes (7.8um)
- granulocytopoiesis - form granulocytes
- controlled by cytokines ( take about 11days )
- myeloblast : no granules, cytoplasmic blebs (12-14um)
- promyelocyte : large nucleus, azurophilic granules (16-24um)
- myelocyte : condensed rounded nucleus, speci c granules (10-12um)
- metamyelocyte : kidney-shaped nucleus, speci c granules
- band (stab) : C-shaped nucleus, speci c granules
- mature form : neutrophil, eosinophil, basophil
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- monocytopoiesis - form monocytes
- monoblast : large, undi erentiated cells
- promonocyte : kidney-shaped nucleus , azurophilic
- monocyte : sky blue cytoplasm, kidney-shaped nucleus
- enter circulation, proceed to tissue spaces, di erentiate into macrophages
- thrombopoiesis - form thrombocytes
- controlled by thrombopoietin
- megakaryoblast : endomitosis, polyploid (25-40um)
- megakaryocyte : large multi-lobed nucleus (40-100um)
- platelets formed from fragments of megakaryocyte cytoplasm (1000s per cell)
- platelet demarcation channels
Lymphopoiesis - form lymphocytes
- B = bursa equivalent, T = thymus
- lymphoblast : large, undi erentiated cells
- prolymphocytes : medium-sized cell, condensing chromatin, no cell surface antigens
- some migrate from bone marrow to thymus, divide, di erentiate to T-cells
- others remain in bone marrow, di erentiate to B-cells, migrate to lymph tissues
Adult Stem Cell Plasticity
- ability of stem cells to form specialized cell types of other tissues >> for cell-based therapies
- Hematopoietic stem cell > neurons & glial cells, Skeletal muscle cells, cardiac muscle cells, liver cells
- Bone marrow stroll cells > Cardiac muscle cell, Skeletal muscle cells
- Neural stem cells > blood cells, Skeletal muscle cells

Myelopoiesis
• Erythropoiesis
– Formation of erythrocytes
• Granulocytopoiesis
– Formation of granulocytes
• Monocytopoiesis
– Formation of monocytes
• Thrombopoiesis
– Formation of
thrombocytes
( platelets)

Lymphopoiesis
– Formation
of lymphocytes

16
[Link].0211
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** Fibrinolysis & Disorder of Hemostasis **

Clotting Cascase
- conversion of brinogen to brin (4c) > stabilization of brin (6c)
- all require Thrombin (FIIa)
- Thrombin Formation require Factor Xa (Xa, Va, Ca+, platelet phospholipids = prothrombinase complex -2c)
-
- Platelet activation > expose phospholipid on surface > facilitate secondary hemostasis (coagulation cascade)
- >> provide binding sites for clotting factors > ensure clotting occur (platelet plug)
-
- VIIIa, PL, Ca, IXa >> activate FX

Vit K & r-Carboxylation

- Vit K dependent factors : Prothrmobin (FII), VII, IX, X, protein C & S
- FII, VII, IX, X + Polypeptide >> r-glutamyl carboxylase + Vit K >> Mature FII, FVII, FIX, FX + Carboxyglutamate (Gla)
- ** Warfarin inhibits VKOR (vitamin K epoxide reductase) - inhibit regenerating active Vit K
- r-carboxylation >> allow Ca+ binding - has 2 adjacent negatively charged carboxylate groups
- clotting factor - Ca complex > bindis phospholipid on platelet membranes
>> Vit K de ciency : prolonged Prothrombin time (INR)
>> Factor VII (extrinsic pathway) - very sensitive to Vit K

Calcium Ion (factor IV)

- Ca is required in ALL STEPS of Vit K dependent clotting factors : (FII), VII, IX, X
- Calcium Chelators (EDTA / oxalate) >> added to blood in vitro >> prevent clotting & remain uid state
- supernatant - Plasma (has coagulation factors)
- serum - supernatant after clotting (no coagulation factors)
4. Fibrinolysis - dissolution of brin clot (Tertiary Hemostasis)
- D-dimer level > elevated in deep vein thrombosis
- Highly elevated D-dimer level >> pulmonary embolism

Vessel Injury
4. Fibrinolysis - Dissolution of the fibrin clot
Collagen
exposure
(Tertiary hemostasis)
Platelet adhesion Tissue factor
Inactive Plasminogen incorporated
in the clot
Platelet activation
Endothelin, Serotonin
Platelet phospholipid
+ 1. Tissue Plasminogen Activator
2. Streptokinase/ Urokinase
Vasoconstriction Thromboxane A2, ADP

Blood coagulation
Platelet aggregation
Cascade -
Antiplasmin Active Plasmin (proteolytic)
Reduced Blood flow Thrombin
Platelet plug
Fibrin degradation
Fibrin Products (FDP)
Fibrin
Plasmin
degradation Secondary
hemostatic plug 16
Fibrin D-dimers 14
[Link]. 0258
products (FDP) [Link]. 0245

Anti-coagulant Factors
- endothelial PGI2 (prostacyclin) & NO > Prevent platelet aggregation (thromboxane antagonist)
- antithrombin-III > inactivate thrombin & FXa > prevent clotting
- Heparin (glycosaminoglycan) activate anti-thrombin-III
- protein C & S (Vit K dependent)
- thrombomodulin + thrombin >> activate protein C > binds to protein S > inactivate FVa & FVIIIa
Pharmacology
- aspirin : inhibit TXA2 formation - irreversible inhibitor of COX > decrease TXA2:PGI2 ratio
- heparin : activate antithrombin III & inactivate thrombin
- warfarin (oral anticoagulant) : blocks Vit K epoxide reductase (VKOR) in liver
- inhibit mature Vit K dependent clotting factors
- Streptokinase / Urokinase : thrombolytic agent - plasminogen activator >> convert plasminogen to plasmin
- tissue Plasminogen activator : dissolve a thrombus
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Hemostasis defect & disorder
- increased bleeding, bleeding following surgery, epistaxis (nose bleed), hematoma
Clotting pathway Disorder :
- Hemophilia A & B - inherited coagulation disorder - intrinsic coagulation pathway defect
- x-linked recessive , increased APTT
- FVIII low in Hemophilia A // Factor IX low in hemophilia B
- easy bruising, massive hemorrhage, hemarthrosis - hemorrhage in joints
- Vit K de ciency
Platelet Plug formation defect :
- Von Willebrand dx - most common
- instability of FVIII >> increased APTT , increased bleeding time, ristocetin assay abnormal, low vWF level
- increased mucosal bleeding, early bruising, epistaxis, prolonged bleeding after tooth extraction
- treatment : inject vWF
- platelet defect (Thrombocytopenia, Benard-soulier syndrome, Glanzmann thrombasthenia)
- increased bleeding time, platelet aggregation test abnormal , low platelet count (thrombocytopenia)
- normal platelet count > ow cytometry : Benard (GpIb) & Glanzmann (GpIIb/IIIa)

Mediators of Acute Inflammation

Cell-derived Mediators Principal Sources Actions
Histamine Mast cells (also basophils & platelets) Vasodilation, increased vascular permeability, endothelial activation

Serotonin Platelets Vasodilation, increased vascular permeability

Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever

Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion &
activation

Nitric oxide Endothelium, macrophages Vascular smooth muscle relaxation & vasodilation, killing of microbes

Cytokines (TNF, IL-1) Macrophages, endothelial cells, mast Local endothelial activation & expression of adhesion molecules, fever,
cells pain
Chemokines Leukocytes, activated macrophages Chemotaxis, leukocyte activation

Plasma Protein-derived Mediators Principal Sources Actions

Complement products (C5a, C3a) Plasma (produced in liver) Leukocyte chemotaxis & activation, vasodilation (mast cell stimulation)
Kinins (bradykinin) Plasma (produced in liver) Increased vascular permeability, smooth muscle contraction, vasodilation,
pain

Role of Mediators in Acute Inflammation [Link].0426

14

Role Mediators

Vasodilation Prostaglandins, nitric oxide, histamine

Increased vascular permeability Histamine, serotonin, bradykinin, leukotrienes

Chemotaxis, leukocyte Cytokines (TNF, IL-1), chemokines, C3a, C5a, leukotrienes, bacterial products &
recruitment & activation peptides
Fever Cytokines (IL-1, TNF), prostaglandins

Pain Prostaglandins, bradykinin

Tissue damage Leukocyte lysosomal enzymes, reactive oxygen species, nitric oxide

15
[Link].0426
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 ** In ammation **

Protective response to cell & tissue injury

- function : remove initial cause of injury (microbe, toxin), remove necrotic cells & tissues
- components : vascular & leukocyte reaction > activated in response to in ammatory stimulus
1. acute (-itis)
- rapid onset - typically within minutes
- short duration - hours or a few days
- characteristic : 5 cardinal signs, neutrophil migration
- redness (rubor) - hyperemia
- swelling (tumor) - uid exudation & hyperemia
- heat (color) - hyperemia
- pain (dolor) - release of bradykinin & PGE2
- loss of function (functio laesa) - combined e ects, mainly swelling and pain
- components
- 1. vascular dilation : relaxation of vascular smooth muscle > blood engorgement > hyperemia
- 2. endothelial activation : plasma protein leakage > edema, produce vasodilator, express adhesion molecule
- plasma protein : coagulation cascade ( brinogen, prothrombin, FVIII, vWF)
- acute phase reactants (C-reactive protein)
- complement protein (C3a,C5a)
- circulating immunoglobulins (antibodies) >> opsonization
- 3. neutrophil activation & migration : increased adhesion molecule, motility, capacity for bacterial killing
neutrophil migration (Acute In ammatory Exudate)
- neutrophil express cell-cell recognition
- neutrophil slowed down by selecting receptors on endothelial cells
- neutrophils begin to roll on surface
- integrin - ICAM-1 interactions provide rm adhesion to endothelium
- neutrophil extends pseudopod btw endothelial cells
- neutrophil exits circulation & enter connective tissue > migration by chemoattractant molecule > to perivascular CT
- neutrophil attracted to tissue damage site by Complement Component C5a & LTB4 (Chemotaxis) - form brin
Morphological Acute In ammation
1. suppurative / purulent > pus-containing exudative in ammation
- abscess > rich in neutrophils > bacterial infection >> pyogenic bacteria
- pyogenic bacterias : Staphylococci, Streptococci ([Link]) & [Link]
- Ex) lobar pneumonia (consolidated alveoli) , bronchopneumonia, acute appendicitis
2. brinous in ammation
- exudate in brinous in ammation >> high plasma protein content
- brinogen > converted to brin >> form mat , causing adhesion btw adjacent surfaces
- associated with serous membrane-lined cavities (pleural, pericardial, peritoneal)
3. serous in ammation
- accumulation of uid, low plasma protein & cell content (transudate)
- skin in response to burn, serous membrane-lined cavities
- pleural e usions > classi ed as transudative vs exudative
- transudate ( speci c gravity < 1.02, protein content < 25g/L )
- Exudate ( speci c gravity > 1.02, protein content > 25g/L )
factors that determine outcome
- severity of tissue damage, capacity of stem cell to replace specialized cell (regeneration), damage causing agent

Outcomes of Acute In ammation

1. Resolution - complete restitution of normal tissue architecture & function
- neutrophil & necrosis tissue removed > via lymphatic drainage
- ex) sun burn, pneumonia - alveolar cells regrowth
2. Healing by brosis (scar formation) - lack ability to regenerate specialized cells
- necrotic debris & acute in ammatory exudate removed by macrophages
- defect lled by ingrowth of granulation tissue (organization) >> brous (collagenous) scar
3. Abscess formation - localized pus > extensive tissue damage > pyogenic bacteria
- acute : expansion limited by organization & repair
- chronic : abscess encapsulated by granulation & brous tissue
- increased risk of chronic in ammation >> organization overwhelmed, expansion of abscess
4. Progression to chronic in ammation
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 2. Chronic
- may follow acute in ammation if stimulus persist - ongoing tissue damage
- insidious, low-grade response without acute reaction
- long duration (weeks~months)
- characteristic : macrophages, lymphocytes, proliferation of blood vessels, brosis, tissue destruction
in ltrate of Chronic In ammation
- plasma cells : purplish cytoplasm, eccentric ‘clock face’ nuclei - di erentiated B lymphocytes > produce antibodies
- lymphocytes : dark round nuclei, thin rim cytoplasm, include both helper & cytotoxic T cell & B cell
- macrophages : oval kidney shaped nuclei, phagocytic & antigen-presenting
- eosinophil : bilobed nuclei - release granule contents, include MBP, e ective in killing parasites
- broblast : secrete extracellular matrix including collagen, disappear when injurious stimulus removed
a. non-speci c
- following acute in ammation > no adequate neutralization of noxious stimulus
b. speci c
- immunological agent : virus - infected cells, fungi, protozoa, hypersensitivity reaction, autoimmune condition
- low toxicity organisms : Treponema sp. (syphilis & yaws)
- infective organisms > grow within cells (viruses, mycobacteria sp.)
- hypersensitivity reaction (extrinsic allergic alveolitis)
- autoimmune condition (systemic lupus erythematosus - SLE)
- infections by fungi, protozoa, parasites
- nonimmunological : foreign body reaction, inert noxious materials
- suture material
- wood/vegetable matter
- metal or glass splinters
- inorganic materials > silica & beryllium
- foreign materials may excite a chronic in ammatory response (with/without discrete granuloma formation)
- Types
- 1. non-granulomatous
- 2. granulomatous
- presence of granulomas
- presence of epithelioid macrophages & multinucleate giant cells > 20 nucei
- distinct pattern of chronic in ammation
- attempt to contain persistent agent that is di cult to eradicate
2 types of giant cells
a. foreign body giant cells (non-immunological agents)
- nuclei centrally grouped
b. langhan’s giant cells (immunological agents)
- nuclei arranged in horse shoe - at periphery
- ex) tuberculosis, sarcoidosis, leprosy
- tuberculosis granuloma : caused by mycobacterium tuberculosis
- morphology : caseating granuloma, central necrosis, epithelioid macrophages
langhan’s giant cells, lymphocytes

Chronic Inflammation Summary

32
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**
Superoxide formation
by the ETC and cytochromes is normal Enzymatic superoxide scavenging
Superoxide is an anion radical
Superoxide dismutase (SOD)
Superoxide is formed from The electron transport chain is in the inner mitochondrial membrane. uses two superoxides as substrates
molecular oxygen after uptake of one electron The electrons are meant to react with oxygen only at the last step of the
ETC to form water. At the level of Coenzyme Q, one electron can escape, and forms
bind to molecular oxygen and form superoxide. hydrogen peroxide and oxygen as products.
Cytochromes P450 are a group of enzymes that use molecular oxygen
O2 + e- leads to O2.- and form a hydroxyl group. In this complex process radicals are generated O2.- + O2.-
(superoxide anion radical) and superoxide is formed.
2 H+
[Link].0271

H2O2 + O2
[Link].0271 [Link].2

Hydrogen peroxide is used or scavenged by catalase Hydrogen peroxide and also organic peroxides are
Hydrogen peroxide
scavenged by glutathione peroxidase
can lead to hydroxyl radicals
Catalase is found mainly in peroxisomes and uses Glutathione peroxidase needs selenium as cofactor
hydrogen peroxide for detoxification of toxins. and uses 2 molecules of reduced glutathione (GSH). H2O2 can diffuse through membranes.
GSH is g-glutamyl-cysteinyl-glycine
It can nonenzymatically react with superoxide or ferrous iron
When the peroxisomal hydrogen peroxide level gets too high,
then catalase degrades hydrogen peroxide using which leads to formation of hydroxyl radicals.
two hydrogen peroxides as substrates at the same time. H2O2 plus 2 GSH 2 H2O plus GSSG
Hydroxyl radicals are formed in the :
H2O2 + H2O2
ROOH plus 2 GSH ROH plus GSSG 1. Haber-Weiss reaction
2. Fenton reaction
2 H2O + O2
[Link].0272 [Link].0272 [Link].0

Hydroxyl radical OH. Hydroxyl radical OH.

is formed from hydrogen peroxide is the most detrimental ROS. Compartmentation of free radical defenses
SOD in cytosol needs copper and zinc,
in mitochondria needs manganese
Free radical-mediated
Hydroxyl radical is also formed from watercellular injury
during ionizing radiation. in extracellular space needs copper
HYDROGEN PEROXIDE and superoxide: (Haber-Weiss reaction) Radiation: damage to the skin, mutations, cancer and death.
H2O2 + O2.- + H+

OH. + H2O + O2

HYDROGEN PEROXIDE and ferrous iron: (Fenton reaction)

H2O2 + Fe 2+ MBMB p.442 [Link].0273

Mitochondrial DNA is more susceptible to ROS damage than nuclear

OH. + OH- + Fe 3+ [Link].0273
DNA as it does not have histones and it is close to the ETC (CoQ)
and superoxide formation.
[Link].0274 [Link].

Radical scavengers Deficiency of superoxide dismutase (SOD) leads to

1. Enzymes: Amyotrophic Lateral Sclerosis (ALS)
Superoxide dismutases, catalase and glutathione peroxidase. ALS is a deadly degenerate disease of upper and lower motor
Cofactors needed are copper, zinc, manganese, iron and selenium. neurons that control voluntary muscle movement.
ALS is also known as Lou Gehrig’s
The neurons eventually die and lead to the lack of neuron transmission
2. Endogenous natural scavengers: disease. He was a famous baseball player
to the muscle cells.
Uric acid, bilirubin, glutathione and other
who became ill and passed away.
Symptoms:
90% of the time the cause is idiopathic. In Difficulty breathing, vocal cord dysfunction.
3. Dietary radical scavengers the remaining 10% the cause is due to a Head drop due to weakness of the neck muscles.
Vitamins C and E, carotenoids, flavonoids, phytochemicals,
hereditary defect of the gene for Muscle weakness, twitching, atrophy, dysphagia, hyper-reflexia.
superoxide dismutase.
polyphenols, isoprenoids, PUFA and many more. Onset mostly after 40-50 years of age.
[Link].0276 [Link].0276
[Link].0275

Chronic granulomatous disease Myeloperoxidase (MPO) Oxygen-dependent system

(CGD) deficiency Molecular oxygen + Molecular oxygen +
NADPH NADPH + Arginine

NADPH oxidase Deficiency Myeloperoxidase deficiency NADPH oxidase Inducible NO synthase

(respiratory burst test negative) (respiratory burst test positive)
Superoxide Superoxide Superoxide Nitric oxide

Non-enzymatic
Lack of hypochlorous acid (HOCL) in Superoxide dismutase Superoxide dismutase
Lack of superoxide formation
in phagocytes leads to less phagolysosomes leads to less destruction
of fungi. Hydrogen peroxide Hydrogen peroxide Peroxynitrite
ROS, RNOS, and HOCL.
Normal destruction of bacteria.
plus chloride ions ferrous iron or superoxide
Severe recurrent infections: Recurrent fungal infections Non-enzymatic
- fungal with candida albicans. Myeloperoxidase
- bacterial
Hypochlorous acid Hydroxyl radical
pneumonia
[Link].0278 [Link].0277
** Pentose Phosphate Pathway / RBC / WBC **

Pentose Phosphate Pathway = Hexose monophosphate = 6-phosphogluconate pathway

- occur in cytosol
- not producing energy
-
- active in liver, lactating mammary gland, adipose tissue (NADPH for FA biosynthesis)
- active in Adrenal Cortex, testes, ovaries (NADPH for synthesis of steroid hormones)
- active in Erythrocytes (NADPH for reduction of glutathione)
- active in WBC & macrophages (NADPH for phagocytosis)
-
- Oxidative Phase (irreversible) - enzyme : dehydrogenase (G6PD)
- provide 2NADPH & 2H+ >> for reductive biosynthetic reactions
- provide ribulose 5-phosphate = pentose (PRPP) >> for purine & pyrimidine nucleotide biosynthesis >> nucleic acid
-
- Non-oxidative phase (reversible) - enzyme : transketolase (+ thiamine pyrophosphate TPP) & transaldolase
- in cells that do not require Pentose Phosphate
- convert excess ribulose 5-phosphate >> glycolytic intermediates >> recycle carbon atoms

NADPH
- used for reductive biosynthetic reaction in FA synthesis & synthesis of steroid hormones
- in RBC : detoxi cation fo hydrogen peroxide (H2O2) & ROS
- Oxidant drugs (sulfa drug / primaquine) or infection or Fava Bean >> increase ROS production
- >> in RBC >> detoxi ed by glutathione peroxidase + reduced GSH + selenium enzyme
- >> oxidized GS-SG >> glutathione reductase + NADPH >> reduce GSH
- ** defective PPP >> H2O2 accumulation >> RBC damage >> Hemolysis
- in cytochrome P450 system (drug metabolizing enzymes)
- phagocytosis in WBC (form reactive oxygen species)
- neutrophil & macrophages > increase Oxygen consumption > increase ROS generation > Respiratory Burst
- NADPH oxidase >> superoxide free radical >> H2O2 >> hydroxyl radicals >> HOCL >> kill bacteria/infection
- synthesis of Nitric Oxide (NO)
G6PD de ciency
- x-linked recessive >> hemolysis
- allelic heterogeneity (G6PD-A : young RBC have su cient amount of enzyme) (G6PD-m : no su cient)
-
- reduced activity of G6PD >> impair NADPH formation >> reduced glutathione pool
- >> mature RBC >> unable to synthesize new enzymes ( NO nuclear, NO organelles )
- >> impaired RBC detoxi cation & H2O2 accumulation >> Damage of FA >> RBC lysis (hemolysis)
- denaturation of proteins due to GSH depletion >> formation of Heinz Bodies (denatured insoluble proteins)
-
- Precipitating Factors : Oxidants, Antibiotic (sulfa drugs), antimalarials (primaquine), antipyretic (aspirin), fava bean
RBCs: Detoxification of H2O2
Overview of non-oxidative phase of PPP
Non-oxidative phase: Interconversion of pentoses (Reactive oxygen species)
3 molecules of Ribulose 5-P
Interconversion of pentoses
Glucose 6-P Glucose 6-P Glucose 6-P Drugs/ Infection/
Ribose 5-P Xylulose 5-P Xylulose 5-P Fava beans
1
Ribulose 5-P Ribulose 5-P Ribulose 5-P
4
Reactive oxygen species 2 GSH NADP+
Epimerase (reduced)
Isomerase H2O2 Glutathione
5 2 molecules of Fructose 6-P Glyceraldehyde 3-P
2 3
Glutathione reductase
Ribose 5-P Xylulose 5-P Xylulose 5-P Pentose
Glycolytic intermediates 14 peroxidase
[Link]. 0266
GS-SG NADPH+H+ phosphate
13 2H2O (oxidized)
[Link]. 0266
pathway
Xylulose 5-P Ribose 5-P 26
[Link]. 0268 [Link]. 0268

6 Transketolase TPP Non-oxidative phase Inherited disorders characterized by defective phagocytosis

Glyceraldehyde 3-P
• NADPH oxidase deficiency: Chronic granulomatous disease
Sedoheptulose 7-P
Transketolase and thiamine (TPP) (CGD): Severe persistent bacterial and fungal infections
7 Transaldolase
• Neutrophils show lack of increased oxygen consumption on
Erythrose 4-P
• Transketolase uses TPP (thiamine pyrophosphate) as phagocytosis (defective respiratory burst/ negative respiratory burst
Fructose 6-P
Xylulose 5-P coenzyme test)
8 Transketolase • Transketolase activity in RBCs used an index of • Myeloperoxidase deficiency: Increased risk of fungal infections
TPP nutritional thiamine (vitamin B1) status • Normal respiratory burst (Positive respiratory burst) but decreased
Fructose 6-P
Glyceraldehyde 3-P • Laboratory test to identify nutritional thiamine HOCl formation
deficiency
15
[Link]. 0266 • G6PD deficiency usually does NOT affect WBCs

• Patients with beriberi (thiamine deficiency) have low • DLA: Reactive oxygen species
erythrocyte transketolase activity • Differentiate other immunodeficiency disorders: ADA and Di George syndrome
25
[Link]. 0279
17
[Link]. 0266
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** G6PD de ciency **

G6PD
- rate limiting step of Pentose Phosphate Pathway
- producte NADPH & Ribose
- NADPH >> essential to maintain reduced GSH pool >> protect RBC from oxidative damage
- X-linked recessive // Males are hemizygous for X chromosome >> more male have G6PD de ciency
- RBC >> shorter half life , less tolerant to exogenous oxidative agents
- Drugs make G6PD worse : sulfonamides, antimalarial drugs - primaquine, fava bean >> hemolytic anemia
- Advantage : selective advantage >> protection against malarial parasite
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