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Flashcards in Genetic determinants of CVD Deck (35):
1

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

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

2

cardiomyopathy definition and causes

-any disease of heart muscle
-many diff causes: ischemic, toxic (ethanol), infectious, idiopathic/primary

3

Most common cause of cardiomyopathy

-ischemic

4

3 basic types of primary cardiomyopathy pathophysiology

-hypertrophic
-dilated
-restrictive: still walls

5

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

-dilated phenotype with CHF
-conduction defects, dysrhythmia, or both

6

Familial Hypertrophic cardiomyopathy

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

7

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

-familal hypertrophic cardiomyopathy

8

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

-B-myosin heavy chain
-mutations at codon 403 have variable phenotypes, severity and prognosis

9

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

-true!!

10

6 syndromes that involve hypertrophic cardiomyopathy

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

11

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

-MANY more in FDC and X-linked FDC

12

Arrhythmogenic Right Ventricular Dysplasia

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

13

Familial Dilated Cardiomyopathies generally involve mutated proteins involved in what?

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

14

Syndromic Restrictive Cardiomyopathies

-Hemochromatosis: HFE
-Amyloidoses
-Fabry Disease -lysosomal storage dz
-glycogen storage disorders

15

Syndromic Dilated Cardiomyopathies

-neuromuscular : DMD, muscular dystrophies
-mito disorders
-carnitine deficiency etc

16

Pathogenetics definition

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

17

Issues with pathogenetics

-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

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.

-more sensitive to ca2+
-disarray, hypertrophy, abnormal gene expression, arrhythmia, myocyte stress and death --> fibrosis

19

Potential therapies for hypertrophic CM

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

20

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

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

21

LQTS

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

22

Classification of LQTS

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

23

LQTS prognosis/risk

-risk of sudden death is <1%/year
-dysrhythmia in 25%

24

Main protein in LQTS that cause several other disorders

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

25

T/F: LQTS can be drug induced

-true!

26

Cardiovascular features of Marfan's Syndrome

-aortic root dilation
-aortic dissection
-aortic regurgitation due to stretching of sinuses of Valsalva
-MV prolapse

27

Pathology of Marfan's in aorta

-medial degeneration

28

Aortic Root dilatation: complications

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

29

Marfan Syndrome CV surgical technique

-Bentall Revolution: composite graft
-if done preventatively, can give long term life expectancy

30

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

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

31

Marfan's Cause

-fibrillin component of elastin: FBN1
-found in zonules, skin, aortic media, perichondrium

32

Pathogenesis of Marfan

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

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

-TFG-B1;
-normally, binding of large latent complex (LLC) to fibrillin keeps TGF-B inactive

34

Issues of increases activity of TGF-B1

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

Losartan (Cozaar)

-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