Ch. 16. 17. 19 Flashcards
Thoracic aortic aneurysm
widening/bulging of upper portion of the aorta at the descending thoracic aorta, ascending aorta or aortic arch
Aortic dissection
longitudinal tear between layers of the aorta = may worsen due to high pressure flow inside aorta
What is TAAD?
familial thoracic aortic aneurysm and dissection
In aortic dissection, where does the tear begin?
intima layer → media layer → blood fills tears = exacerbates divide → tear goes down the vessel (towards or away from the heart)
What is cystic medial necrosis?
media layer of aorta loses smooth muscle fibers and elasticity
What is the pathological basis for weakening of the aortic wall in familial TAAD?
cystic medial necrosis
What is an aortic aneurysm?
abnormal dilation of aorta at the level of ascending aorta or sinuses of Valsalva (descending aorta)
What are the 3 primary manifestations of TAAD
Dilation of aorta at level of ascending aorta or at level of sinuses of Valsalva (descending aorta) |
Dissection of the ascending aorta | both
How is diagnosis of TAAD confirmed?
measuring dimensions of the aorta at level of sinuses of Valsalva AND measuring ascending aorta via CT, MRI or transesophageal echocardiography
When diagnosing for TAAD, what are some differential diagnoses to consider?
Marfan’s syndrome | other connective tissue diseases
What is a proband?
individual on pedigree who’s disease forms the center of the investigation = person around whom a pedigree is drawn
Which screening technique is most preferred for TAAD and why?
CT = available, noninvasive and easily tolerated
How does CT give an accurate result for TAAD?
measures from center of intraluminal flow to each side of aortic wall = accurate true diameter
What are 2 things used to screen for TAAD?
CT | aortic dissection bundle questions
What symptom of TAAD must a clinician strongly consider using the Aortic Dissection Bundle Questions?
chest pain for any age
What is a Type A dissection of TAAD?
Progressive enlargement of ascending aorta → aortic dissection/rupture
What is a Type B dissection of TAAD?
enlargement at aortic arch or distal to the arch and propagate distally
What are 4 clinical features of aortic aneurysms?
anterior chest pain | posterior chest pain | both | referred pain to left/bilateral shoulder(s)
What are the 4 Ps regarding signs and symptoms of dissections?
pallor | paresthesias (pins and needles) | pulselessness | paralysis
What are the 2 loci associated with TAAD?
FAA1 and TAAD1
What are the 4 genes associated with TAAD?
TGFBR1, TGFBR2, MYH11, ACTA2
What inheritance pattern does TAAD have?
autosomal dominant
Which TAAD gene has full penetrance?
TAAD1
Which TAAD gene has decreased penetrance? Which gender is it most common under?
FAA1 = women
Which TAAD gene is associated with patent ductus arteriosus?
MYH11
What are 2 TAAD physical findings associated with mutations in the ACTA2 gene?
livedo reticularis | iris flocculi
What is livedo reticularis?
web-like purplish skin discoloration caused by constriction of deep dermal capillaries
What is iris flocculi?
ocular abnormality associated with ACTA2 mutation in TAAD
What syndrome is associated with TAAD gene mutation of TGFBR1 or TGFBR2?
Loeys-Dietz syndrome
What is variable expressivity with TAAD?
2 affected individuals in a family may have different onset = one has earlier onset and other has later onset
What are 2 syndromes associated with familial TAAD?
Marfan’s | Loeys-Dietz syndrome
Which 2 mutations account for the majority of mutations in TAAD?
TAAD1 and ACTA2
What defines hypercholesterolemia?
fasting total blood cholesterol level of >240mg/dL
What is TC and LDL-C in hypercholesterolemia?
TC = total serum cholesterol | LDL-C = low-density lipoprotein cholesterol
What is the inheritance pattern for hypercholesterolemia? Which is more common?
autosomal dominant (more common) | autosomal recessive
What is low-density lipoprotein?
responsible for transporting cholesterol to extrahepatic (outside of liver) tissues
What 3 tissues does hypercholesterolemia commonly affect?
skin, tendons, and arteries
What is the normal function of the LDL receptor?
sequester and eliminate LDL from blood = controlling TC levels
What does LDL do?
carries cholesterol in the blood –> LDL-C = LDL carrying a cholesterol molecule(s)
What is allelic variant in FH (familial hypercholesterolemia)?
more than 1,000 different defects on LDLR gene
What is atherosclerosis?
thickening of arterial walls due to lipid deposits = wall loses elasticity over time
What are the 2 less common forms of hypercholesterolemia?
high TC and high cholesterol
What are 2 effects of mutation of LDLR? (absent vs defective)
completely absent = more severe effects on phenotype | defect = still has LDL-C circulating but not as bad as latter
How do plaques in FH form?
injury to intima layer of vessel = oxidizes passing LDL-C = recruits monocytes at injury site –> monocytes phagocytize oxidized LDL-C –> foamy lipid-laden macrophages (foam cells) = plaques
What can cause injury to endothelium blood vessel walls?
infection, inflammation, smoking, and elevated LDL-C
What is angina?
inadequate O2 delivery to heart muscles = exertional chest pain, relieved at rest
How does atherosclerosis from FH cause angina and myocardia infarction?
70% plaque buildup in vessel = angina |
How does atherosclerosis from FH cause angina and myocardia infarction?
70% plaque buildup in vessel = angina | >70% plaque buildup in vessel = complete blockage = no O2 delivery to heart = MI
What are the 4 symptoms associated with FH?
atherosclerosis | xanthomas | xanthelasmata | arcus corneus
What is xanthomas?
abnormal growths in the tendons due to cholesterol deposit accumulation at tendons
What is TC and LDL-C in hypercholesterolemia?
TC = total serum cholesterol | LDL-C = low-density lipoprotein cholesterol
What is xanthelasmata?
cholesterol deposits under skin or eyelids = yellow discoloration
What is arcus corneus?
corneal disease due to cholesterol deposits at peripheral border of cornea
What are the 5 genes mutated involved in FH?
LDLR ; APOB ; LDLRAP1 ; PSCK9 : I gene
What effect does mutation in APOB have on FH?
familial defective apolipoprotein B-100 = LDL-C can’t bind LDL-C to surface receptors
What effect does mutation in LDLRAP1 have on FH?
receptors can’t transport sequestered LDL-C across membrane
Which FH gene mutation is autosomal recessive?
LDLRAP1
What kind of mutation does the PSCK9 mutated gene have in FH? What happens?
gain of function | PSCK9 breaks down LDL receptors at a HIGHER rate than normal
What kind of mutation does the mutated I gene have in FH? What happens?
loss of function | decreased activity of PCSK9 = decrease LDL receptor degradation = LDL-C can be uptaken into cell
What are the 4 screening methods for FH?
family history | pedigree | fasting lipid profile | cascade screening (family tracing)
What is the target goal for TC levels in FH?
100 mg/dL
What is Marfan’s Syndrome?
Connective tissue disorder that affects many organs such as eyes, aorta, skin. Characterized by long bones
What is the genetic cause of Marfan’s Syndrome?
de novo or inherited mutation in FBN1 gene on chromosome 15
What inheritance pattern does Marfan’s Syndrome follow?
autosomal dominant
What is the percent of Marfan Syndrome cases occurs due to de novo mutation?
25%
What is the typical body type of those with Marfan’s Syndrome?
tall thin stature with long thin arms and legs
What are 5 skeletal atypicalities of Marfan’s Syndrome?
arachnodactyly | dolichostenomelia | overcrowded teeth | scoliosis | chest deformities (pectus excavatum or pectus carinatum)
What is arachnodactyly?
long slender spiderlike fingers and toes comparison to soles and palms
What is dolichostenomelia?
arm span exceeding body height
What is pectus excavatum?
chest concaves in
What is pectus carinatum?
chest protrudes forward (ie: pigeon’s chest)
What are 2 ocular defects due to Marfan’s Syndrome?
myopia | ectopia lentis
What are 2 cardiac abnormalities due to Marfan’s Syndrome?
Valve defects (mitral and aortic = most common) | Valvular insufficiency
What are 4 symptoms of valvular insufficiency with Marfan’s Syndrome?
SOB | fatigue | palpitations | murmurs
What are 5 other associated findings with Marfan’s Syndrome?
spontaneous pneumothroax | hernias | bullae development in lungs | skin stretch marks | high risk pregnancies
What are the 2 things the clinical diagnosis of Marfan Syndrome is made based on?
family history and 4 physical examination findings
What 4 physical examination findings does the clinical diagnosis of Marfan’s Syndrome is made based on?
dura ectasia | ectopia lentis | aortic dilation/dissection at level of sinuses of Valsalva | 4 of 8 specified skeletal features
What is ectopia lentis?
displaced lens
What is dura ectasia?
stretching of dural sac in lumbosacral spine
What is the normal function of FBN1 gene?
normal protein fibrillin-1 which regulates growth/repair of tissues AND combines with other structural proteins to form microfibrils
What are microfibrils?
integral fibers that give strength and flexibility to all connective, load-bearing tissues
What is dominant negative mutation?
mutated allele disrupts the function of a normal allele in the same cell
How is a mutated FBN1 gene a dominant negative mutation?
mutated FBN1 gene inhibits production of normal fibrilin-1 protein = blocks formation of normal microfibrils —-> mutated protein in scaffold = loses integrity and strength of entire structure
What is the penetrance % of Marfan’s Syndrome?
100%
What is genetic heterogeneity?
different gene mutations lead to same/similar phenotype
How does Marfan’s Syndrome exhibit genetic heterogeneity and variable expressivity?
specific FBN1 mutations are scattered across gene –> combination of mutations will vary in expressivity
What is a genocopy?
similar phenotype expression but different genotypes (and different disease)
What are the 4 current surveillance recommendations for Marfan syndrome?
family and medical history | annual echocardiograms | molecular genetic testing | linkage analysis
What is Fredrickson classification in hyperlipidemia?
Method of determining the phenotype to select the appropriate pharmacotherapeutic agents.
What is the relationship between LDL-C and coronary artery disease?
reduction of one disease in adults is directly proportional to a reduction of the other disease.
ie: 5% reduction in LDL-C is equivalent to a 5% reduction in coronary events.
For TAAD associated with TGFBR2 mutations what congenital condition can be involved?
bicuspid aortic valve
What screening technique is used for any initial screening for TAAD?
CT
