Lecture 41: Genetic Determinants of CV Disease

Question 1

What are genetic disorders that primarily affect the CV system?

Answer 1

1. Familial cardiomyopathy
2. Familial long QT syndrome
3. Familial hypercholesterolemia
4. Lysosomal storage disorders such as Fabry disease
5. Marfan Syndrome
6. Atherosclerosis
7. HTN

Question 2

What are the etiologies of cardiomyopathy?

Answer 2

1. ischemic
2. toxic (alcohol)
3. infectious
4. idiopathic

Question 3

What are the 3 types of cardiomyopathy?

Answer 3

1. dilated (DCM)
2. hypertrophic (HCM)
3. restrictive (RCM)

Question 4

What is the natural history of cardiomyopathy?

Answer 4

End-stage of all types is a dilated phenotype with congestive heart failure
Most forms associated with conduction defects or dysrhythmia

Question 5

What are the genetic characteristics of hypertrophic cardiomyopathy?

Answer 5

Autosomal dominant
Age-dependent
Variable severity
Most common cause of sudden death in young athletes
Certain mutations are more serious than others (so knowing the genetic defect can lead to prognosis)
Beta-myosin heavy chain, but everything else in muscle as well

Question 6

What is the significance of the Noonan syndrome?

Answer 6

Can predispose one to hypertrophic cardiomyopathy

Question 7

What is the significance of the three different codons on beta-myosin heavy chain in familial hypertrophic cardiomyopathy?

Answer 7

Same codon = different mortality rates

Question 8

What are types of mutations that cause x-linked familial DILATED cardiomyopathy?

Answer 8

CMD3A defect in Tafazzin
XLCM defect in Dystorphin
Cytoskeletal genetic defects most common in DCM

Question 9

What are the genetic factors of dilated cardiomyopathy?

Answer 9

Arrhythmogenic right ventricular dysplasia

Multiple gene mutations, all involved with structure and function of desmosomes

Question 10

What are the characteristics of arrhythmogenic right ventricular dysplasia?

Answer 10

Mutatioins in desmosomes

A type of DCM

Question 11

What are the genetic factors in syndromic restrictive cardiomyopathy?

Answer 11

Fabry disease
Glycogen storage disease
Hemochromatosis (iron overload)
Most of these are metabolic disorders that accumulate in the heart

Question 12

What is the hypothesis for the pathogenesis of primary cardiomyopathy?

Answer 12

Involvement of calcium and energy generation
Abnormal shifts in Ca between sarcomere and SR
Enhances contractility (enhanced in HOCM)
Enhances energy expenditure
Mutations will alter Ca cycling which deplete SR calcium sequestraton

Question 13

What are the key characteristics of Long QT Syndrome?

Answer 13

Defined by primary defects in repolarization
Predisposes to polymorphic ventricular tachycardia (torsade de pointes, because of early after-depolarizations that can occur)
Associated with
i. syncope
ii. seizures
iii. sudden death
Risk of sudden death <1%/year and dysrhythmia in 25%
Type I and Type III anti-arrhythmic drugs are contraindicated
Anything that prolongs QT will increase torsades de pointes

Question 14

What are the genetic characteristics of LQTS?

Answer 14

Genetic forms are channelopathies
Most are autosomal dominant
Variable expression for age, severity and electrophysiology

Question 15

What are the classification of LQTS?

Answer 15

1. Romano-Ward syndrome
2. Jervell and Lange-Nielsen Syndrome
3. Brugada Syndrome
   
   • RBBBB
   • ST elevation
   • sudden death

Question 16

What is the significance of SCN5A mutations in relation to Long QT?

Answer 16

Different mutations in SCN5A can lead to LQTS, DCM or Brugada syndrome

Question 17

What are the CV features of Marfan syndrome?

Answer 17

1. aortic root dilatation (of sinus of Valsalva)
2. aortic dissection
3. aortic regurgitation
4. mitral valve prolapse

Question 18

What are the complications of aortic root dilatation?

Answer 18

1. AR which leads to CHF and sudden death

2. Aortic dissection that can lead to death and MI

Question 19

What is the treatment for Marfan Syndrome?

Answer 19

Bentall surgery for CV improvement

TGFBeta1 blockers, including angiotensin receptor blocker

Question 20

What is the function of microfibril?

Answer 20

Mmicrobibril is not just something that reinforces ECM
Connects cell membranes to the matrix
Supports phenotype of smooth muscle cell
Mediators of signaling pathways, especially for TGFbeta 1

Question 21

What is the significance of fibrillin?

Answer 21

Responsible for TBFbeta-1 sequestration
Loss of fibrillin activity = overexpression of TGFbeta = Marfan
This may be one cause of the symptoms of Marfan Syndrome

Question 22

What is the pathogenesis of Marfan Syndrome?

Answer 22

1. Increased activity of TGFBeta 1 leads to failure of terminal differentiation of alveoli
   -Pneumothorax
2. Also causes abnormal AV valve development
   -mitral valve prolapse
   TGFbeta also secretes ECM

Question 23

How do you treat aortic diltation of children with Marfan Syndrome?

Answer 23

Losartan