SM02 Mini1

Question 1

what are the subtypes of cardiomyopathy?

Answer 1

1. hypertrophic
2. dilated
3. glycogen
4. restrictive
5. arrhythmogenic right ventricular

Question 2

cause of hypertrophic cardiomyopathy

Answer 2

dz of sarcomere

thickening of cardiomyocyte due to hypersensitivity to ATP or Ca²⁺

Question 3

presentation of hypertrophic cardiomyopathy

Answer 3

increased ventricular wall thickness

cardiac hypertrophy in absence of increased external load

preserved systolic function

impaired diastolic function

septum predominant site of involvement

Question 4

most frequent genetic mutations in familial hypertrophic cardiomyopathy?

Answer 4

• beta-myosin heavy chain
  
  • part of myosin motor unit
  • frequency= 35-50%
• cardiac troponin T
  
  • anchors troponins to tropomyosin
  • frequency= 15-20%
• cardiac myosin-binding protein C
  
  • anchors myosin to titin
  • frequency= 15-20%

Question 5

presentation of dilated cardiomyopathy (DCM)

Answer 5

left ventricular chamber enlargement & systolic dysfunction

normal or modest increase in ventricular wall thickness

Question 6

genetics of dilated cardiomyopathy

Answer 6

**affected proteins function to transmit force generated during contraction**

dz of cardiac cytoskeleton

cause sarconere to contract w/less force

35% of cases are familial

autosomal dominant is most common

can also be autosomal recessive, X-linked, matrilinear

linked to 25 different chromosomal loci & genes

Question 7

cause of glycogen cardiomyopathy

Answer 7

defects in genes of metabolism associated w/lysosome

cellular glycogen deposition observed

Question 8

presentation of glycogen cardiomyopathy

Answer 8

hypotonia (decreased muscle tone)

electrophysiological dysfunction (caused by myocyte & myofiber disarray)

myocyte hypertrophy

cardiac fibrosis

Question 9

mutations associated with glycogen cardiomyopathy

Answer 9

• 1,4-glucosidase→ Pompe dz
  
  • lysosomal acid
  • recessively inherited
• lysosome-associated membrane protein→ Danon dz
  
  • X-linked
  • enzyme deficiency
• galactosidase A→ Fabry dz
  
  • X-linked
  • lysosomal hydrolase deficiency

Question 10

presentation of restrictive cardiomyopathy (RCM)

Answer 10

normal or decreased volume of BOTH ventricles

bi-atrial enlargement

impaired ventricular filling w/restrictive physiology

normal wall thickness

Question 11

genetic cause of restrictive cardiomyopathy

Answer 11

mutation of cardiac troponin I

familial & unrelated mutation

Question 12

dz process of arrhythmogenic right ventricular cardiomyopathy

Answer 12

progressive loss of myocytes

replaced by fatty or fibrofatty tissue

progresses from epicardium to endocardium

mostly in right ventricle, but can be seen in left ventricle

Question 13

cause of arrhythmogenic right ventricular cardiomyopathy

Answer 13

dz of desmosome

5 different desmosomal component mutations

Question 14

channelopathy

Answer 14

abnormality in ion channel function

Question 15

cardiac channelopathies

Answer 15

mutations of specific ion channel proteins

Question 16

What are the major cardiac channelopathies?

Answer 16

• long QT syndromes
• short QT syndrome
• Brugada syndrome
• conduction dz
• sinus node dysfunction
• catecholaminergic polymorphic ventricular tachycardia (CPVT)

Question 17

what channel(s) are most important for repolarization?

Answer 17

K⁺ channels

Question 18

what channel(s) are most important for depolarization?

Answer 18

Ca²⁺ & Na⁺ channels

Question 19

clinical presentation of Long QT syndromes

Answer 19

frequently in childhood

syncopal episodes

potentially lethal torsades de pointes tachyarrhythmias

Question 20

genetics of Long QT syndromes

Answer 20

autosomal recessive form associated w/deafness

8 gene mutations encoding ion channel subunites associated w/syndrome

Question 21

what effects are seen when K⁺ channel subunits are mutated?

Answer 21

loss of function

net reduction in outward repolarizing K⁺ current

prolongs action potential repolarization time

long QT

Question 22

what effect are seen when Na⁺ pore channel protein is mutated?

Answer 22

gain of function

increased inward Na⁺ current during action potential plateau

shifting balance to prolonged repolarization (longer to travel)

Question 23

physiological cause of Short QT syndrome

Answer 23

repolarization is hastened by enhanced outward current during repolarization

K⁺ leaving cell faster than normal

Question 24

clinical presentation of Short QT syndrome

Answer 24

very rare (30-40 recorded patients)

high rate of sudden death

exceptionally short QT interval= 300ms

Question 25

genetic cause of Short QT syndrome

Answer 25

gain of function mutation 3 different gene mutations identified

Question 26

clinical presentation of Brugada syndrome

Answer 26

ST segment elevation in right precordial (chest) leads risk of sudden cardiac death endemic in East & Southeast Asia

Question 27

physiological cause of Brugada syndrome

Answer 27

Na⁺ comes in too slowly Na⁺ channel does not allow cardiomyocytes to depolarize quickly enough repolarization starts before depolarization is complete opposite effects as Long QT syndrome

Question 28

genetics of Brugada syndrome

Answer 28

autosomal dominant mutation of pore formings cardiac Na⁺ channel or its auxillary subunit

Question 29

what other disorder can result from cardiac pore forming Na⁺ channel protein mutations?

Answer 29

cardiac conduction dz

Question 30

what causes sick sinus syndrome?

Answer 30

recessive form of loss of function mutation of SCN5A (cardiac pore-forming Na⁺ channel protein)

Question 31

what does a mutation of the funny channel cause?

Answer 31

autosomal dominant sinus node dysfucntion

Question 32

physiological cause of catecholaminergic polymorphic ventricular tachycardia?

Answer 32

too much Ca²⁺ leaking into cell or from sarcoplasmic reticulum causes prolonged sarcomere contraction causes ventricular tachycardia

Question 33

what protein mutations cause CPVT?

Answer 33

ryanodine receptor channel (RYR2) or calsequestrin (CASQ2)

Question 34

where is the majority of cholesterol synthesized in the body?

Answer 34

liver & intestines

Question 35

what is the building block for cholesterol synthesis?

Answer 35

acetyl CoA

Question 36

how is mevalonate made from acetyl CoA?

Answer 36

acetyl CoA (2C) x2→ acetoacetyl CoA (4C) acetoacetyl CoA + acetyl CoA via **HMG-CoA synthase**→ HMG-CoA (beta-hydroxy-beta-methyl-glutaryl CoA) (6C) HMG-CoA + 2NADPH + 2H⁺ via **HMG-CoA reductase**→ mevalonate (6C) + CoA-SH

Question 37

what is the rate limiting step of cholesterol synthesis?

Answer 37

HMG-CoA reductase creation of mevalonate

Question 38

how are 2 activate isoprenes made from mevalonate?

Answer 38

transfer of 3 ATP actiavtes C5 & -OH of C3 PO₄^2- leaves C3 & CO₂ of C1 leaves→ creates double bond between C1 (was C2) & C2 (was C3)→ isoprene (5C) isoprene isomers readily change back & forth

Question 39

explain condensation of isoprenes to squalene

Answer 39

opposite isomers of isoprenes attach head to tail (5C +5C) 10C + isoprene (5C)→ 15C x2→ squalene (30C)

Question 40

what methods are used to regulate HMG-CoA reductase?

Answer 40

* transcriptional control * proteolytic degradation * covalent modification

Question 41

how is HMG-CoA reductase transcriptionally controlled?

Answer 41

cholesterol binds SCAP to SREBP in ER membrane when cholesterol levels in cell drop→ cholesterol dettaches from SCAP→ SCAP/SREBP move to Golgi membrane→ S1P & S2P cleave SREBP→ DNA binding domain of SREBP is release, translocates to nucleus, & induces HMG-CoA transcription HMG-CoA is only transcribed when cholesterol levels are low

Question 42

how is MHG-CoA reductase marked for proteolytic degradation?

Answer 42

when sterol levels are high HMG-CoA is ubiquitinylated & extracted from ER membrane→ degraded by proteosome known as ERAD (ER associated degradation)

Question 43

how is HMG-CoA reductase covalently modified?

Answer 43

short-term regulatory mechanism AMP-activacted kinase phosphorylates HMG-CoA→ inactive form high levels of glucagon, sterols, and glucocorticoids & low levels of ATP→ activate AMP-activated kinase insulin, thyroid hormone, & high levels of ATP activate a phosphatase that dephosphorylates HMG-CoA to active form

Question 44

what is cholesterol used for in the body?

Answer 44

* membranes * cholesterol ester: storage form in cytosolic droplets * synthesized by ACAT * biliary cholesterol * bile acid formation: rate-limited by CYP7A1 * steroid hormones

Question 45

how are foam cells formed?

Answer 45

when macrophages take up excess LDL start of atherosclerosis

Question 46

how many C atoms are in a molecule of cholesterol?

Answer 46

27

Question 47

what activates ACAT?

Answer 47

high intracellular levels of cholesterol

Question 48

how do the statins work to reduce cholesterol synthesis?

Answer 48

competitive inhibition of HMG-CoA reductase

Question 49

Mevalonic aciduria

Answer 49

* cause: deficiency of mevalonate kinase * **only** pre-squalene disorder * symptoms: recurrent fevers beginning in infancy→ w/hepatosplenomegaly, lymphadenopathy, abd pain, diarrhea, arthralgia, & rashes

Question 50

Smith-Lemli-Opitz syndrome

Answer 50

* most common post-squalene disorder * cause: autosomal recessive deficiency of 7-dehydrocholesterol reductase (7DHCR) * major malformation syndrome (syndactylyl of toes 2/3)

Question 51

CHILD syndrome

Answer 51

* **c**ongenital **h**emidysplasia w/**i**chthyosiform erythroderma and **l**imb **d**efects * cause: X-linked dominant (more females) * **lack 3-beta-hydroxy sterol dehydrogenase** * symptoms: unilateral ichthyosiform skin lesions @ birth w/sharp demarcation at midline, face is usually spared