Download Patho Ch12

Pathology Ch12 (part) pp531-500
The Heart
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Congenital Heart Disease
o Most CHD form during 3-8 week gestation
o Incidence up to 5%, 85% composed of the following:
 Most common are VSD (42%) > ASD (10%) > Pulmonary stenosis (8%) > Patent ductus arteriosus >
Tetralogy of Fallot > Coarcation of the aorta > AV septal defects > Aortic stenosis > Transposition of the
great arteries > Truncus arteriosus
 Surgical repair successful unless irreversible changes have occurred
o Cardiac Development
 Orchestrated by Wnt, SHH, VEGF, bone morphogenetic factor, TGFβ, FGF, Notch pathways
 Many inherited defects involve genes for transcription factors
 Mesoderm migrates to form first and second heart field @ day 15
 Both heart fields are multipotent, but express different transcription factors
 First field (Hand1) >> L ventricle
 Second field (Hand2 + FGF10) >> R ventricle, most of atria, outflow tracts
 Beating tube formed @ day 20
 Looping forms basic heart chambers @ day 28
 Neural crest cells migrate into outflow tract > separate outflow and form aortic arches
 Interstitial CT (future AV canal and outflow) enlarges to produce endocardial cushions
 Further separation of ventricles, atria, AV valves produce 4-chamber heart @ day 50
o Etiology and Pathogenesis
 Sporadic genetic abnormalities are major known cause of CHD
 Heterozygous nature of mutation indicates that 50% reduction in function is enough to alter phenotype
 Many transcription factors interact in large protein complexes > any one defect can give similar results
 Ex. GATA4, TBX4, or NKX2-5 > ASD/VSD
 Genes that encode for various pathway components
 Ex. NOTCH1 > bicuspid aortic valve; NOTCH2 > Tetralogy of Fallot
 Ex. Fibrillin (Marfan's) mutation > lower than normal TGFβ signaling > Marfan heart anomalies
 Chromosomal lesions
 Ex. deletion of 22q11.2 (TBX1 deletion) > DiGeorge syndrome (CATCH-22)
o Cardiac abnormality
o Abnormal facies
o Thymic aplasia
o Cleft palate
o Hypocalcemia
 Chromosomal aneuploidies
 Ex. Turner (45X), trisomies 13, 18, 21** (40% with DS have heart defects)
 Environmental factors alone or along with genetic factors
 Ex. Rubella infection, gestational diabetes, teratogen exposure, nutrition (folate)
o Clinical Features
 Left-to-Right Shunts
 Initially NOT associated with Cyanosis
 High pulmonary vascular resistance can reverse the shunt (R>L) and introduce poorly oxygenated
blood into systemic circulation [Eisenmenger syndrome]
 Atrial Septal Defect (ASD)
o Usually asymptomatic until adulthood
o Summary of developmental stages:
 Septum primum grows between R and L atria (opening "ostium primum")
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Ostium secundum develops before ostium primum is completely grown over
Septum secundum grows to the R of septum primum (opening "foramen ovale"
- continuous with ostium secundum, permit intrauterine shunting of blood)
 Septum secundum grows to form a flap of tissue over foramen ovale
 Flap of tissue permits shunting in fetal blood (higher R atrial pressure vs L)
 At birth, lungs expand > R atrial pressure drops > L atrial pressure closes flap
o Morphology (classified according to location)
 Secundum ASD (90%) > deficient septum secundum formation
 Primum anomalies (5%) > adjacent to AV valves
 Sinus venosus defects (5%) > near entrance of SVC
o Clinical Features
 ASDs result in L > R shunt
 Pulmonary blood flow up to 2-8x normal
 Murmur often present
 Generally well tolerated, and nonsymptomatic before age 30
 Irreversible pulmonary hypertension is unusual
 Mortality is low, and long-term survival is comparable to normal population
o Patent Foramen Ovale
 Closes permanently in 80% of people by age 2
 Can open in remaining 20% from sustained pulmonary hypertension
 Ventricular Septal Defect (VSD)
o Most common types of CHD
o Morphology (classified according to size and location)
 Membranous VSD (90%) > membranous septum, size of aortic valve orifice
 Infundibular VSD (10%) > below the pulmonary valve or in the muscular septum
o Clinical Features
 Most pediatric VSDs associated with other anomalies (ex. Tetralogy of Fallot)
 If diagnosed in adult, they're usually isolated anomalies
 Functional consequence depends on size of hole and R side malformation
 50% of small muscular VSDs close spontaneously
 Delayed treatment in hopes of spontaneous closure
 Large VSDs result in early R ventricular hypertrophy + pulmonary hypertension
 Lead to irreversible pulmonary vascular disease if not treated early
 Patent Ductus Arteriosus (PDA)
o Joins pulmonary artery and aorta, distal to origin of L subclavian artery
o Bypasses lungs during fetal life
o Constricts and closes 1-2 days after birth due to increased arterial oxygenation,
decreased pulmonary vascular resistance, and declining prostaglandin E
o Complete obliteration within first few months > ligamentum arteriosum
o Closure delayed in infants with hypoxemia
o Produce characteristic "machinery-like" murmur
o Should be closed as early as possible (easy surgery) unless required preserving for
infants with other cardiac malformations (via administering prostaglandin E)
Right-to-Left Shunts
 Produce hypoxemia and cyanosis
 Prolonged distal cyanosis can produce clubbing of finger tips "hypertrophic osteoarthropathy"
 Tetralogy of Fallot
o VSD, Pulmonary stenosis, Overriding aorta, R ventricular hypertrophy
o Morphology
 Heart enlarged and "boot-shaped" b/c of R ventricular hypertrophy
 Large VSD with aortic valve at superior border
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Clinical Features
 Clinical consequences depend on severity of pulmonary stenosis
 Severe stenosis > more hypoplastic (smaller/thin walled) pulmonary arteries +
larger overriding aorta
 Most infants are cyanotic at birth
 Obstruction becomes progressively worse with growth
 Surgery may be complicated
 Transposition of the Great Arteries
o Aorta arises from R ventricle, Pulmonary artery from L ventricle
o Atrial-Ventricular connections are normal (R to R, L to L)
o Results in separation of systemic and pulmonary circulations > incompatible with
postnatal life unless a shunt exists
o Without surgery most patients die within months
 Tricuspid Atresia
o Occlusion of the tricuspid valve orifice
o Mitral valve is larger than normal + R ventricular hypoplasia
o Requires extensive shunting to be compatible with life (ASD + VSD)
o Cyanosis present from birth and associated with high early mortality
Obstructive Lesions
 Coarcation of the Aorta
o Infantile form: proximal to a PDA
o Adult form: distal to arch vessels
o 50% of cases accompanied by biscupid aortic valve and other CHD
o Clinical Features
 Coarcation of aorta with PDA = cyanosis in lower half of body
 Req. surgical occlusion of PDA
 Coarcation of aorta w/o PDA = asymptomatic in childhood
 Collateral circulation = noticed by radiographic notching on ribs
 Hypertension in upper extremities
 Hypotension in lower extremities
 Pulmonary Stenosis and Atresia
o Obstruction at pulmonary valve > R ventricular hypertrophy
o Pulmonary trunk NOT dilated (may even be hypoplastic)
 Aortic Stenosis and Atresia
o Valvular, subvalvular, or supravalvular
 Valvular = cusps hypoplastic, dysplastic (thickened), or abnormal in number
o Obstruction of outflow tract > L ventricle hypoplasia (hypoplastic L heart syndrome)
 PDA has to be open to allow blood flow to aorta and coronary arteries
Ischemic Heart Disease (aka Coronary Artery Disease - CAD)
o Results from imbalance between myocardial supply (perfusion) and cardiac demand for O2 rich blood (ATP synth)
 Also limits availability of nutrients and removal of waste products
o 90% results from reduced blood flow due to obstructive atherosclerotic lesions in coronary vessels
 A lesion obstruction >75% of vessel defines significant CAD (symptomatic threshold)
 Usually slow progression of lesions until sudden onset of symptoms
 Slow progression allows collateral vessels to develop over time
 Common occlusions occur in the LAD, LCX, and RCA
o Can also be caused by coronary emboli, myocardial vessel inflammation, or vascular spasm
 Initiated by unpredictable and abrupt rupture/erosion/ulceration of atherosclerotic plaque
 Plaque changes precipitate formation of superimposed thrombus
 Thrombus partially or completely occludes the artery
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Epidemiology
 Leading cause of death in US
 Rate has fallen 50% since 60's due to prevention and diagnostic/therapeutic advances
 Effects of obesity boom to be determined
Consequence of Myocardial Ischemia
 Angina Pectoris
 Paroxysmal and recurrent attacks of substernal/precordial chest discomfort
 Caused by transient (15sec to 15min) myocardial ischemia that is insufficient to induce necrosis
 Interplay of decreased perfusion, increased demand, and coronary artery pathology
 Stable (aka Typical) Angina
o Imbalance in coronary perfusion relative to myocardial demand
o Produced by physical activity, excitement, or stress
o Deep, poorly localized pressure, squeezing, or burning sensation
o Usually relieved by rest (dec demand) or administering vasodilators (inc perfusion)
 Prinzmetal Variant Angina (uncommon)
o Caused by coronary artery spasm
o Angina attacks unrelated to physical activity, heart rate, or pressure
o Respond well to vasodilators
 Unstable (aka Crescendo) Angina
o Increasingly frequent, prolonged (>20min), or severe angina
o Frank pain, triggered by progressively lower levels of physical activity
o Usually caused by disruption of atherosclerotic plaque with superimposed partial
thrombosis and possibly embolization and/or vasospasm
o 1/2 of patients have evidence of myocardial necrosis.. acute MI may be imminent
 Myocardial Infarction
 Death of cardiac muscle due to prolonged severe ischemia
 Coronary Artery Occlusion (90% of cases)
o Atheromatous plaque undergoes acute change (intraplaque hemorrhage, erosion, etc.)
o Platelets adhere to subendothelial collagen and necrotic plaque content > microthrombi
o Vasospasm is stimulated from platelet granule release
o Tissue factor activate coagulation pathway > add bulk to thrombus
o Thrombus expands to completely occlude vessel in minutes
 Other possible triggers (10% of cases)
o Vasospasm w/ or w/o atherosclerosis (due to platelet aggregation or drug ingestion)
o Emboli from L atrium w/ atrium fibrillation or paradoxical emboli from R side of heart
o Ischemia without detectable/significant coronary atherosclerosis and thrombosis
 Disorders of small intramural coronary vessels
 Hematologic abnormalities (sickle cell)
 Amyloid deposition in vascular walls
 Lowered systemic blood pressure (shock)
 Inadequate myocardial protection during cardiac surgery
 Time of Onset of Key Events caused by Ischemia
o Cessation of aerobic metabolism within seconds > drop in ATP
o Myocardial contractility ceases <2 minutes of severe ischemia
o 50% normal ATP by 10 minutes, 10% normal ATP by 40 minutes
o Severe ischemia (<10% blood flow) lasting 20-40 minutes leads to necrosis (irreversible)
 Occurs first in subendocardium
o Damage to microvasculature after 1 hour
o Damage to 1/2 myocardium thickness within 2-3 hours
o Damage throughout myocardium within 6 hours
 Extent of Tissue Damage dictated by:
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o Location, severity, rate of development of coronary obstruction
o Size of vascular bed perfused by obstructed vessel
o Duration of occlusion
o Metabolic/oxygen needs of myocardium
o Extent of collateral blood vessels
o Presence, site, and severity of coronary arterial spasm
o Heart rate, cardiac rhythm, and blood oxygenation
Arteries and areas of Blood Supply
o Left Anterior Descending coronary artery (40-50%)
 Apex of heart, anterior wall of L ventricle, anterior 2/3 of ventricular septum
o Right coronary artery (right dominant circulation - 80% of people) (30-40%)
 R ventricular free wall, posterobasal wall of L ventricle, posterior 1/3 of
ventricular septum
o Left Circumflex coronary artery (assuming right dominant circulation) (15-20%)
 Lateral wall of L ventricle except at the apex
Patterns of Infarction
o Transmural Infarction
 Caused by occlusion of an epicardial vessel (w/o therapeutic intervention)
 Full thickness of ventricular wall
 Associated with chronic coronary atherosclerosis, acute plaque change, and
superimposed thrombosis
o Subendocardial (nontransmural) Infarction
 Subendocardial zone is least perfused > most vulnerable
 Typically involves inner 1/3 of ventricular wall
 Can be initial stages of transmural infarction or as a result from prolonged
severe hypotension (circumferential in the latter case)
o Multifocal Microinfarction
 When pathology involves only smaller intramural vessel
 May occur from microembolism, vasculitis, or vascular spasm
 Spasms exacerbated by catecholamines or certain drugs
 Vasospasm can lead to sudden cardiac death or ischemic dilated
cardiomyopathy (aka takotsubo cardiomypothy - broken heart syndrome)
Morphology
o Appearance of infarct depends on duration of survival following MI
o Highlight areas of necrosis by submerging tissue slices in triphenyltetrazolium chloride
 Brick-red on noninfarcted myocardium
 Infarct areas appear unstained and pale (no lactate dehydrogenase activity)
o 6-12 hours: wavy fibers at periphery of infarct
o 12-24 hours: reddish-blue discoloration (trapped blood)
o 1-3 days: nectoric muscle elicits acute inflammation
o 3-7 days: macrophages remove nectoric myocytes
o 10-14 days: rimmed by hyperemic zone of highly vascularized granulation tissue
o 2-8 weeks: fibrous scar
o Once completely healed age is impossible to determine (8 weeks looks like 10 years)
Infarct Modification by Reperfusion
o Restoration of blood flow in order to salvage cardiac muscle at risk > limit infarct size
o Prompt reperfusion is the preeminent objective for treatment of MI patients
o Accomplished by: thrombolysis, angioplasty, stent placement, CABG
o Salvages reversibly injured cells + alters morphology of necrotic cells (contraction bands)
o Can trigger lethal complications: arrhythmias, endothelial swelling (occlude capillaries)
o Biochemical abnormalities persist for days-weeks > "stunned" myocardiumm
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Clinical Features
o Clinical symptoms
 Prolonged (>30min) chest pain "crushing, stabbing, or squeezing"
 Rapid, weak pulse
 Profuse sweating (diaphoresis)
 Nausea or vomiting
 Dyspnea due to pulmonary congestion/edema
o Presence of myocardial proteins in plasma
 Cardiac-specific Troponins T and I (cTnT and CtnI)
 MB fraction of creating kinase (CK-MB)
 CKMB, cTnT, and CtnI elevates first 3-12 hours
 CKMB and cTnI peak at 24 hours
 CKMB returns to normal in 48-72 hours
 cTnI returns to normal in 5-10 days
 cTnT returns to normal in 5-14 days
o Characteristic electrocardiogram changes
 ST tombstones
 Consequences and Complications of Myocardial Infarction
o Poor prognosis with advanced age, female gender, diabetes mellitus, and previous MI
o Contractile dysfunction
o Arrythmias
 1/2 of deaths from acute MI occur within 1 hour due to fatal arrhythmia
o Myocardial rupture
 Usually when there is transmural necrosis in ventricle
 Rupture of ventricular free wall with hemopericardium and cardiac tamponade
 Rupture of ventricular septum > acute VSD > L to R shunting
 Papillary muscle rupture > severe mitral regurgitation
o Ventricular aneurysm
o Pericarditis
o Infarct expansion
o Mural thrombus
o Papillary muscle dysfunction
o Progressive late heart failure
Chronic Ischemic Heart Disease (aka Ischemic Cardiomyopathy)
 Progressive congestive heart failure due to accumulated ischemic myocardial damage
 Usually involves prior MI or coronary arterial interventions/surgery
 Usually appears after MI due to decompensation of hypertrophied noninfarcted myocardium
 Morphology: cardiomegaly, L ventricular hypertrophy/dilation, stenotic coronary atherosclerosis,
scars from old infarcts