Flashcards in Lecture 41: Genetic Determinants of CV Disease Deck (23):
What are genetic disorders that primarily affect the CV system?
1. Familial cardiomyopathy
2. Familial long QT syndrome
3. Familial hypercholesterolemia
4. Lysosomal storage disorders such as Fabry disease
5. Marfan Syndrome
What are the etiologies of cardiomyopathy?
2. toxic (alcohol)
What are the 3 types of cardiomyopathy?
1. dilated (DCM)
2. hypertrophic (HCM)
3. restrictive (RCM)
What is the natural history of cardiomyopathy?
End-stage of all types is a dilated phenotype with congestive heart failure
Most forms associated with conduction defects or dysrhythmia
What are the genetic characteristics of hypertrophic cardiomyopathy?
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
What is the significance of the Noonan syndrome?
Can predispose one to hypertrophic cardiomyopathy
What is the significance of the three different codons on beta-myosin heavy chain in familial hypertrophic cardiomyopathy?
Same codon = different mortality rates
What are types of mutations that cause x-linked familial DILATED cardiomyopathy?
CMD3A defect in Tafazzin
XLCM defect in Dystorphin
Cytoskeletal genetic defects most common in DCM
What are the genetic factors of dilated cardiomyopathy?
Arrhythmogenic right ventricular dysplasia
Multiple gene mutations, all involved with structure and function of desmosomes
What are the characteristics of arrhythmogenic right ventricular dysplasia?
Mutatioins in desmosomes
A type of DCM
What are the genetic factors in syndromic restrictive cardiomyopathy?
Glycogen storage disease
Hemochromatosis (iron overload)
Most of these are metabolic disorders that accumulate in the heart
What is the hypothesis for the pathogenesis of primary cardiomyopathy?
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
What are the key characteristics of Long QT Syndrome?
Defined by primary defects in repolarization
Predisposes to polymorphic ventricular tachycardia (torsade de pointes, because of early after-depolarizations that can occur)
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
What are the genetic characteristics of LQTS?
Genetic forms are channelopathies
Most are autosomal dominant
Variable expression for age, severity and electrophysiology
What are the classification of LQTS?
1. Romano-Ward syndrome
2. Jervell and Lange-Nielsen Syndrome
3. Brugada Syndrome
What is the significance of SCN5A mutations in relation to Long QT?
Different mutations in SCN5A can lead to LQTS, DCM or Brugada syndrome
What are the CV features of Marfan syndrome?
1. aortic root dilatation (of sinus of Valsalva)
2. aortic dissection
3. aortic regurgitation
4. mitral valve prolapse
What are the complications of aortic root dilatation?
1. AR which leads to CHF and sudden death
2. Aortic dissection that can lead to death and MI
What is the treatment for Marfan Syndrome?
Bentall surgery for CV improvement
TGFBeta1 blockers, including angiotensin receptor blocker
What is the function of microfibril?
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
What is the significance of fibrillin?
Responsible for TBFbeta-1 sequestration
Loss of fibrillin activity = overexpression of TGFbeta = Marfan
This may be one cause of the symptoms of Marfan Syndrome
What is the pathogenesis of Marfan Syndrome?
1. Increased activity of TGFBeta 1 leads to failure of terminal differentiation of alveoli
2. Also causes abnormal AV valve development
-mitral valve prolapse
TGFbeta also secretes ECM