SM02 Mini1 Flashcards Preview

Question 1

1

what are the subtypes of cardiomyopathy?

Answer

hypertrophic
dilated
glycogen
restrictive
arrhythmogenic right ventricular

Question 2

2

cause of hypertrophic cardiomyopathy

Answer

dz of sarcomere

thickening of cardiomyocyte due to hypersensitivity to ATP or Ca²⁺

Question 3

3

presentation of hypertrophic cardiomyopathy

Answer

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

4

most frequent genetic mutations in familial hypertrophic cardiomyopathy?

Answer

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

5

presentation of dilated cardiomyopathy (DCM)

Answer

left ventricular chamber enlargement & systolic dysfunction

normal or modest increase in ventricular wall thickness

Question 6

6

genetics of dilated cardiomyopathy

Answer

**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

7

cause of glycogen cardiomyopathy

Answer

defects in genes of metabolism associated w/lysosome

cellular glycogen deposition observed

Question 8

8

presentation of glycogen cardiomyopathy

Answer

hypotonia (decreased muscle tone)

electrophysiological dysfunction (caused by myocyte & myofiber disarray)

myocyte hypertrophy

cardiac fibrosis

Question 9

9

mutations associated with glycogen cardiomyopathy

Answer

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

10

presentation of restrictive cardiomyopathy (RCM)

Answer

normal or decreased volume of BOTH ventricles

bi-atrial enlargement

impaired ventricular filling w/restrictive physiology

normal wall thickness

Question 11

11

genetic cause of restrictive cardiomyopathy

Answer

mutation of cardiac troponin I

familial & unrelated mutation

Question 12

12

dz process of arrhythmogenic right ventricular cardiomyopathy

Answer

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

13

cause of arrhythmogenic right ventricular cardiomyopathy

Answer

dz of desmosome

5 different desmosomal component mutations

Question 14

14

channelopathy

Answer

abnormality in ion channel function

Question 15

15

cardiac channelopathies

Answer

mutations of specific ion channel proteins

Question 16

16

What are the major cardiac channelopathies?

Answer

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

Question 17

17

what channel(s) are most important for repolarization?

Answer

K⁺ channels

Question 18

18

what channel(s) are most important for depolarization?

Answer

Ca²⁺ & Na⁺ channels

Question 19

19

clinical presentation of Long QT syndromes

Answer

frequently in childhood

syncopal episodes

potentially lethal torsades de pointes tachyarrhythmias

Question 20

20

genetics of Long QT syndromes

Answer

autosomal recessive form associated w/deafness

8 gene mutations encoding ion channel subunites associated w/syndrome

Question 21

21

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

Answer

loss of function

net reduction in outward repolarizing K⁺ current

prolongs action potential repolarization time

long QT

Question 22

22

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

Answer

gain of function

increased inward Na⁺ current during action potential plateau

shifting balance to prolonged repolarization (longer to travel)

Question 23

23

physiological cause of Short QT syndrome

Answer

repolarization is hastened by enhanced outward current during repolarization

K⁺ leaving cell faster than normal

Question 24

24

clinical presentation of Short QT syndrome

Answer

very rare (30-40 recorded patients)

high rate of sudden death

exceptionally short QT interval= 300ms

Question 25

25

genetic cause of Short QT syndrome

Answer

gain of function mutation

3 different gene mutations identified

Question 26

26

clinical presentation of Brugada syndrome

Answer

ST segment elevation in right precordial (chest) leads

risk of sudden cardiac death

endemic in East & Southeast Asia

Question 27

27

physiological cause of Brugada syndrome

Answer

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

28

genetics of Brugada syndrome

Answer

autosomal dominant

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

Question 29

29

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

Answer

cardiac conduction dz

Question 30

30

what causes sick sinus syndrome?

Answer

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

Question 31

31

what does a mutation of the funny channel cause?

Answer

autosomal dominant sinus node dysfucntion

Question 32

32

physiological cause of catecholaminergic polymorphic ventricular tachycardia?

Answer

too much Ca²⁺ leaking into cell or from sarcoplasmic reticulum

causes prolonged sarcomere contraction

causes ventricular tachycardia

Question 33

33

what protein mutations cause CPVT?

Answer

ryanodine receptor channel (RYR2)

or

calsequestrin (CASQ2)

Question 34

34

where is the majority of cholesterol synthesized in the body?

Answer

liver & intestines

Question 35

35

what is the building block for cholesterol synthesis?

Answer

acetyl CoA

Question 36

36

how is mevalonate made from acetyl CoA?

Answer

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

37

what is the rate limiting step of cholesterol synthesis?

Answer

HMG-CoA reductase

creation of mevalonate

Question 38

38

how are 2 activate isoprenes made from mevalonate?

Answer

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

39

explain condensation of isoprenes to squalene

Answer

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

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

Question 40

40

what methods are used to regulate HMG-CoA reductase?

Answer

transcriptional control
proteolytic degradation
covalent modification

Question 41

41

how is HMG-CoA reductase transcriptionally controlled?

Answer

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

42

how is MHG-CoA reductase marked for proteolytic degradation?

Answer

when sterol levels are high

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

known as ERAD (ER associated degradation)

Question 43

43

how is HMG-CoA reductase covalently modified?

Answer

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

44

what is cholesterol used for in the body?

Answer

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

Question 45

45

how are foam cells formed?

Answer

when macrophages take up excess LDL

start of atherosclerosis

Question 46

46

how many C atoms are in a molecule of cholesterol?

27

Answer

high intracellular levels of cholesterol

Answer

competitive inhibition of HMG-CoA reductase

Answer

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

Answer

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

Answer

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

Question 47

47

what activates ACAT?

Question 48

48

how do the statins work to reduce cholesterol synthesis?

Question 49

49

Mevalonic aciduria

Question 50

50

Smith-Lemli-Opitz syndrome

Question 51

51

CHILD syndrome

Question 52

52

Who Is It For?

SM02 Mini1 Flashcards Preview

Biochem > SM02 Mini1 > Flashcards

what are the subtypes of cardiomyopathy?

hypertrophic dilated glycogen restrictive arrhythmogenic right ventricular

cause of hypertrophic cardiomyopathy

dz of sarcomere thickening of cardiomyocyte due to hypersensitivity to ATP or Ca2+

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

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%

presentation of dilated cardiomyopathy (DCM)

left ventricular chamber enlargement & systolic dysfunction normal or modest increase in ventricular wall thickness

genetics of dilated cardiomyopathy

cause of glycogen cardiomyopathy

defects in genes of metabolism associated w/lysosome cellular glycogen deposition observed

presentation of glycogen cardiomyopathy

hypotonia (decreased muscle tone) electrophysiological dysfunction (caused by myocyte & myofiber disarray) myocyte hypertrophy cardiac fibrosis

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

presentation of restrictive cardiomyopathy (RCM)

normal or decreased volume of BOTH ventricles bi-atrial enlargement impaired ventricular filling w/restrictive physiology normal wall thickness

genetic cause of restrictive cardiomyopathy

mutation of cardiac troponin I familial & unrelated mutation

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

cause of arrhythmogenic right ventricular cardiomyopathy

dz of desmosome 5 different desmosomal component mutations

channelopathy

abnormality in ion channel function

cardiac channelopathies

mutations of specific ion channel proteins

What are the major cardiac channelopathies?

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

what channel(s) are most important for repolarization?

K+ channels

what channel(s) are most important for depolarization?

Ca2+ & Na+ channels

clinical presentation of Long QT syndromes

frequently in childhood syncopal episodes potentially lethal torsades de pointes tachyarrhythmias

genetics of Long QT syndromes

autosomal recessive form associated w/deafness 8 gene mutations encoding ion channel subunites associated w/syndrome

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

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)

physiological cause of Short QT syndrome

repolarization is hastened by enhanced outward current during repolarization K+ leaving cell faster than normal

clinical presentation of Short QT syndrome

very rare (30-40 recorded patients) high rate of sudden death exceptionally short QT interval= 300ms

genetic cause of Short QT syndrome

gain of function mutation 3 different gene mutations identified

clinical presentation of Brugada syndrome

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

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

genetics of Brugada syndrome

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

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

cardiac conduction dz

what causes sick sinus syndrome?

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

what does a mutation of the funny channel cause?

autosomal dominant sinus node dysfucntion

physiological cause of catecholaminergic polymorphic ventricular tachycardia?

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

what protein mutations cause CPVT?

ryanodine receptor channel (RYR2) or calsequestrin (CASQ2)

where is the majority of cholesterol synthesized in the body?

liver & intestines

what is the building block for cholesterol synthesis?

acetyl CoA

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

what is the rate limiting step of cholesterol synthesis?

HMG-CoA reductase creation of mevalonate

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

explain condensation of isoprenes to squalene

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

hypertrophic

dilated

glycogen

restrictive

arrhythmogenic right ventricular

dz of sarcomere

thickening of cardiomyocyte due to hypersensitivity to ATP or Ca²⁺

increased ventricular wall thickness

cardiac hypertrophy in absence of increased external load

preserved systolic function

impaired diastolic function

septum predominant site of involvement

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%

left ventricular chamber enlargement & systolic dysfunction

normal or modest increase in ventricular wall thickness

defects in genes of metabolism associated w/lysosome

cellular glycogen deposition observed

hypotonia (decreased muscle tone)

electrophysiological dysfunction (caused by myocyte & myofiber disarray)

myocyte hypertrophy

cardiac fibrosis

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

normal or decreased volume of BOTH ventricles

bi-atrial enlargement

impaired ventricular filling w/restrictive physiology

normal wall thickness

mutation of cardiac troponin I

familial & unrelated mutation

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

dz of desmosome

5 different desmosomal component mutations

long QT syndromes

short QT syndrome

Brugada syndrome

conduction dz

sinus node dysfunction

catecholaminergic polymorphic ventricular tachycardia (CPVT)

K⁺ channels

Ca²⁺ & Na⁺ channels

frequently in childhood

syncopal episodes

potentially lethal torsades de pointes tachyarrhythmias

autosomal recessive form associated w/deafness

8 gene mutations encoding ion channel subunites associated w/syndrome

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

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)

repolarization is hastened by enhanced outward current during repolarization

K⁺ leaving cell faster than normal

very rare (30-40 recorded patients)

high rate of sudden death

exceptionally short QT interval= 300ms

gain of function mutation

3 different gene mutations identified

ST segment elevation in right precordial (chest) leads

risk of sudden cardiac death

endemic in East & Southeast Asia

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

autosomal dominant

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

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

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

too much Ca²⁺ leaking into cell or from sarcoplasmic reticulum

causes prolonged sarcomere contraction

causes ventricular tachycardia

ryanodine receptor channel (RYR2)

or

calsequestrin (CASQ2)

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

HMG-CoA reductase

creation of mevalonate

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

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

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

transcriptional control

proteolytic degradation

covalent modification

when sterol levels are high

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

known as ERAD (ER associated degradation)

membranes

cholesterol ester: storage form in cytosolic droplets

synthesized by ACAT

biliary cholesterol

bile acid formation: rate-limited by CYP7A1

steroid hormones

when macrophages take up excess LDL

start of atherosclerosis

cause: deficiency of mevalonate kinase

only pre-squalene disorder

symptoms: recurrent fevers beginning in infancy→ w/hepatosplenomegaly, lymphadenopathy, abd pain, diarrhea, arthralgia, & rashes

most common post-squalene disorder

cause: autosomal recessive deficiency of 7-dehydrocholesterol reductase (7DHCR)

major malformation syndrome (syndactylyl of toes 2/3)

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