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Flashcards in SM02 Mini1 Deck (52):
1

what are the subtypes of cardiomyopathy?

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

2

 cause of hypertrophic cardiomyopathy

dz of sarcomere

thickening of cardiomyocyte due to hypersensitivity to ATP or Ca2+

3

presentation of hypertrophic cardiomyopathy

increased ventricular wall thickness

cardiac hypertrophy in absence of increased external load

preserved systolic function

impaired diastolic function

septum predominant site of involvement

4

most frequent genetic mutations in familial hypertrophic cardiomyopathy?

  • 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%

5

presentation of dilated cardiomyopathy (DCM)

left ventricular chamber enlargement & systolic dysfunction

normal or modest increase in ventricular wall thickness

6

genetics of dilated cardiomyopathy

**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

 

7

cause of glycogen cardiomyopathy

defects in genes of metabolism associated w/lysosome

cellular glycogen deposition observed

8

presentation of glycogen cardiomyopathy

hypotonia (decreased muscle tone)

electrophysiological dysfunction (caused by myocyte & myofiber disarray)

myocyte hypertrophy

cardiac fibrosis

9

mutations associated with glycogen cardiomyopathy

  • 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

10

presentation of restrictive cardiomyopathy (RCM)

normal or decreased volume of BOTH ventricles

bi-atrial enlargement

impaired ventricular filling w/restrictive physiology

normal wall thickness

11

genetic cause of restrictive cardiomyopathy

mutation of cardiac troponin I

familial & unrelated mutation

12

 dz process of arrhythmogenic right ventricular cardiomyopathy

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

13

cause of arrhythmogenic right ventricular cardiomyopathy

dz of desmosome

5 different desmosomal component mutations

14

channelopathy

abnormality in ion channel function

15

cardiac channelopathies 

mutations of specific ion channel proteins

16

What are the major cardiac channelopathies?

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

17

what channel(s) are most important for repolarization?

K+ channels

18

what channel(s) are most important for depolarization?

Ca2+ & Na+ channels

19

clinical presentation of Long QT syndromes

frequently in childhood

syncopal episodes

potentially lethal torsades de pointes tachyarrhythmias

20

genetics of Long QT syndromes

autosomal recessive form associated w/deafness

8 gene mutations encoding ion channel subunites associated w/syndrome

21

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

loss of function

net reduction in outward repolarizing K+ current

prolongs action potential repolarization time

long QT

22

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

gain of function

increased inward Na+ current during action potential plateau

shifting balance to prolonged repolarization (longer to travel)

23

physiological cause of Short QT syndrome

repolarization is hastened by enhanced outward current during repolarization

K+ leaving cell faster than normal

24

clinical presentation of Short QT syndrome

very rare (30-40 recorded patients)

high rate of sudden death

exceptionally short QT interval= 300ms

25

genetic cause of Short QT syndrome

gain of function mutation

3 different gene mutations identified

26

clinical presentation of Brugada syndrome

ST segment elevation in right precordial (chest) leads

risk of sudden cardiac death

endemic in East & Southeast Asia

27

physiological cause of Brugada syndrome

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

28

genetics of Brugada syndrome

autosomal dominant

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

29

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

cardiac conduction dz

30

what causes sick sinus syndrome?

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

31

what does a mutation of the funny channel cause?

autosomal dominant sinus node dysfucntion

32

physiological cause of catecholaminergic polymorphic ventricular tachycardia?

too much Ca2+ leaking into cell or from sarcoplasmic reticulum

causes prolonged sarcomere contraction

causes ventricular tachycardia

33

what protein mutations cause CPVT?

ryanodine receptor channel (RYR2)

or 

calsequestrin (CASQ2)

34

where is the majority of cholesterol synthesized in the body?

liver & intestines

35

what is the building block for cholesterol synthesis?

acetyl CoA

36

how is mevalonate made from acetyl CoA?

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

37

what is the rate limiting step of cholesterol synthesis?

HMG-CoA reductase

creation of mevalonate

38

how are 2 activate isoprenes made from mevalonate?

transfer of 3 ATP actiavtes C5 & -OH of C3

PO42- leaves C3 & CO2 of C1 leaves→ creates double bond between C1 (was C2) & C2 (was C3)→ isoprene (5C)

isoprene isomers readily change back & forth

39

explain condensation of isoprenes to squalene

opposite isomers of isoprenes attach head to tail      (5C +5C)

10C + isoprene (5C)→ 15C x2→ squalene (30C)

40

what methods are used to regulate HMG-CoA reductase?

  • transcriptional control
  • proteolytic degradation
  • covalent modification

41

how is HMG-CoA reductase transcriptionally controlled?

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

42

how is MHG-CoA reductase marked for proteolytic degradation?

when sterol levels are high

HMG-CoA is ubiquitinylated & extracted from ER membrane→ degraded by proteosome

known as ERAD (ER associated degradation)

43

how is HMG-CoA reductase covalently modified?

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

44

what is cholesterol used for in the body?

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

45

how are foam cells formed?

when macrophages take up excess LDL

start of atherosclerosis

46

how many C atoms are in a molecule of cholesterol?

27

47

what activates ACAT?

high intracellular levels of cholesterol

48

how do the statins work to reduce cholesterol synthesis?

competitive inhibition of HMG-CoA reductase

49

Mevalonic aciduria

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

50

Smith-Lemli-Opitz syndrome

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

51

CHILD syndrome

  • congenital hemidysplasia w/ichthyosiform erythroderma and limb defects
  • 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

52