SM02 Mini1 Flashcards

(52 cards)

1
Q

what are the subtypes of cardiomyopathy?

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

cause of hypertrophic cardiomyopathy

A

dz of sarcomere

thickening of cardiomyocyte due to hypersensitivity to ATP or Ca2+

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3
Q

presentation of hypertrophic cardiomyopathy

A

increased ventricular wall thickness

cardiac hypertrophy in absence of increased external load

preserved systolic function

impaired diastolic function

septum predominant site of involvement

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4
Q

most frequent genetic mutations in familial hypertrophic cardiomyopathy?

A
  • 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%
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5
Q

presentation of dilated cardiomyopathy (DCM)

A

left ventricular chamber enlargement & systolic dysfunction

normal or modest increase in ventricular wall thickness

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6
Q

genetics of dilated cardiomyopathy

A

**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

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7
Q

cause of glycogen cardiomyopathy

A

defects in genes of metabolism associated w/lysosome

cellular glycogen deposition observed

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8
Q

presentation of glycogen cardiomyopathy

A

hypotonia (decreased muscle tone)

electrophysiological dysfunction (caused by myocyte & myofiber disarray)

myocyte hypertrophy

cardiac fibrosis

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9
Q

mutations associated with glycogen cardiomyopathy

A
  • 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
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10
Q

presentation of restrictive cardiomyopathy (RCM)

A

normal or decreased volume of BOTH ventricles

bi-atrial enlargement

impaired ventricular filling w/restrictive physiology

normal wall thickness

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11
Q

genetic cause of restrictive cardiomyopathy

A

mutation of cardiac troponin I

familial & unrelated mutation

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12
Q

dz process of arrhythmogenic right ventricular cardiomyopathy

A

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

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13
Q

cause of arrhythmogenic right ventricular cardiomyopathy

A

dz of desmosome

5 different desmosomal component mutations

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14
Q

channelopathy

A

abnormality in ion channel function

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15
Q

cardiac channelopathies

A

mutations of specific ion channel proteins

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16
Q

What are the major cardiac channelopathies?

A
  • long QT syndromes
  • short QT syndrome
  • Brugada syndrome
  • conduction dz
  • sinus node dysfunction
  • catecholaminergic polymorphic ventricular tachycardia (CPVT)
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17
Q

what channel(s) are most important for repolarization?

A

K+ channels

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18
Q

what channel(s) are most important for depolarization?

A

Ca2+ & Na+ channels

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19
Q

clinical presentation of Long QT syndromes

A

frequently in childhood

syncopal episodes

potentially lethal torsades de pointes tachyarrhythmias

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20
Q

genetics of Long QT syndromes

A

autosomal recessive form associated w/deafness

8 gene mutations encoding ion channel subunites associated w/syndrome

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21
Q

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

A

loss of function

net reduction in outward repolarizing K+ current

prolongs action potential repolarization time

long QT

22
Q

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

A

gain of function

increased inward Na+ current during action potential plateau

shifting balance to prolonged repolarization (longer to travel)

23
Q

physiological cause of Short QT syndrome

A

repolarization is hastened by enhanced outward current during repolarization

K+ leaving cell faster than normal

24
Q

clinical presentation of Short QT syndrome

A

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
* **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
52