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Cardiology > Genetic determinants of CVD > Flashcards

Genetic determinants of CVD Flashcards

1
Q

Disorders affecting mainly the CV, disorders affecting many systems, including CV, common disorders

A
  1. familial cardiomyopathy, familial long QT, familial hypercholesterolemia
  2. lysosomal storage disorders (Fabry disease), marfan
  3. atherosclerosis, HTN
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2
Q

cardiomyopathy definition and causes

A
  • any disease of heart muscle

- many diff causes: ischemic, toxic (ethanol), infectious, idiopathic/primary

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3
Q

Most common cause of cardiomyopathy

A

-ischemic

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4
Q

3 basic types of primary cardiomyopathy pathophysiology

A
  • hypertrophic
  • dilated
  • restrictive: still walls
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5
Q

The end-stage of all types of cardiomyopathy is _________. Most forms are associated with ____, _____ or both.

A
  • dilated phenotype with CHF

- conduction defects, dysrhythmia, or both

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6
Q

Familial Hypertrophic cardiomyopathy

A
  • autosomal dominant, age-dependent, variable severity
  • base substitutions can tell us of prognosis/risk
  • abnormal hypertrophy, disarray of myofibrils, interstitial fibrosis
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7
Q

What is the most common cause of sudden death in young athletes?

A

-familal hypertrophic cardiomyopathy

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8
Q

About 1/3 of genes implicated in familial hypertrophic cardiomyopathy involve _______.

A
  • B-myosin heavy chain

- mutations at codon 403 have variable phenotypes, severity and prognosis

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9
Q

T/F: knowing the mutation in familial hypertrophic cardiomyopathy aids diagnosis

A

-true!!

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10
Q

6 syndromes that involve hypertrophic cardiomyopathy

A
  • noonan syndrome
  • friedreich ataxia
  • leigh syndrome (cytochrome oxidase deficiency)
  • LEOPARD syndrome
  • Costello syndrome
  • mito defects: seen in infancy/childhood
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11
Q

Compare # of genetic factors implicated in FHC and familial dilated cardiomyopathy

A

-MANY more in FDC and X-linked FDC

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12
Q

Arrhythmogenic Right Ventricular Dysplasia

A
  • multiple gene mutations, all involved with structure and function of desmesomes
  • Autosomal dominant; heart muscle is basically replaced with fat
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13
Q

Familial Dilated Cardiomyopathies generally involve mutated proteins involved in what?

A

-cytoskeletal mlcs that interact with ECM through integrins **and desmosomes*

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14
Q

Syndromic Restrictive Cardiomyopathies

A
  • Hemochromatosis: HFE
  • Amyloidoses
  • Fabry Disease -lysosomal storage dz
  • glycogen storage disorders
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15
Q

Syndromic Dilated Cardiomyopathies

A
  • neuromuscular : DMD, muscular dystrophies
  • mito disorders
  • carnitine deficiency etc
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16
Q

Pathogenetics definition

A

-study of how anomalies of the genome contribute to abnormal phenotypes

17
Q

Issues with pathogenetics

A
  • most mutations are missense and “private”; difficult to treat by gene therapy
  • 2 characteristics might be employed to manage: identify factors that reduce severity (variable expression) and those involved in late onset (time to dx and rx)
18
Q

In cardiac and skeletal muscle, as Ca2+ is released, force is generated. Mutant muscle is _______ to Ca2+ and consumes more ATP. 5 effects of this.

A
  • more sensitive to ca2+

- disarray, hypertrophy, abnormal gene expression, arrhythmia, myocyte stress and death –> fibrosis

19
Q

Potential therapies for hypertrophic CM

A
  • possibly design small mlc therapies for disruptions of huge structural mlcs
  • increase glycolysis to generate more ATP or calcium channel blockade
20
Q

Long QT syndrome defined by, predisposition to, and affects of

A
  • defined by primary defects in repolarization
  • predisposes to polymorphic ventricular tachycardia (torsade de pointes)
  • assoc with syncope, seizures, sudden death
21
Q

LQTS

A
  • most genetic forms are channelopathies
  • genetic heterogeneity: most autosomal dominant
  • variable expression: age, severity, electrophysiology, susceptibility to drugs
  • manifests in other systems: auditory
22
Q

Classification of LQTS

A
  1. Romano-Ward Syndrome: AD
  2. Jervell&Lange-Neilsen Syndrome: AR
  3. Brugada syndrome:AD; RBBB, ST elevation in V1-V3, sudden death
23
Q

LQTS prognosis/risk

A
  • risk of sudden death is <1%/year

- dysrhythmia in 25%

24
Q

Main protein in LQTS that cause several other disorders

A

-SCN5A: LQTS, dilated CM with conduction defects, Brugada syndrome

25
Q

T/F: LQTS can be drug induced

A

-true!

26
Q

Cardiovascular features of Marfan’s Syndrome

A
  • aortic root dilation
  • aortic dissection
  • aortic regurgitation due to stretching of sinuses of Valsalva
  • MV prolapse
27
Q

Pathology of Marfan’s in aorta

A

-medial degeneration

28
Q

Aortic Root dilatation: complications

A
  • Aortic regurg: CHF, sudden death

- Aortic dissection: suddent death, MI, organ ischemia (stroke), late rupture

29
Q

Marfan Syndrome CV surgical technique

A
  • Bentall Revolution: composite graft

- if done preventatively, can give long term life expectancy

30
Q

Causes of the dramatic increase in Marfan’s life expectancy in the mid-90s

A
  • increased awareness=earlier dx
  • regular follow-up
  • exercise modulation
  • B-blockers
  • prophylactic surgery
  • counseling about pregnancy
31
Q

Marfan’s Cause

A
  • fibrillin component of elastin: FBN1

- found in zonules, skin, aortic media, perichondrium

32
Q

Pathogenesis of Marfan

A

Pathogenesis: Long-standing perceptions are incorrect

  • The microfibril is not simply a reinforcing rod in the extracellular matrix
  • Microfibrils connect cell membranes to the matrix; defective microfibrils alters the phenotype of the smooth muscle cell
  • Microfibrils are mediators of signaling pathways, especially transforming growth factor ß1 (TGFß1)
33
Q

Mutations in FBN-1 lead to increased activity of _____ which can be crucial at early stages of development.

A
  • TFG-B1;

- normally, binding of large latent complex (LLC) to fibrillin keeps TGF-B inactive

34
Q

Issues of increases activity of TGF-B1

A
  1. spontaneous pneumothorax: too much TGFB leads to failure of terminal differentiation of alveoli (prevent this if you give TGFB antibodies)
  2. abnormal AV valve development: MV prolapse
35
Q

Losartan (Cozaar)

A
  • ARB that has antiTGFB effects
  • seen to prevent and correct aortic phenotype in mice: normal wall thickness and architecture
  • improves rate of aortic dilation in severely affected children with MFS

Cardiology (27 decks)

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