Genetic determinants of CVD Flashcards
Disorders affecting mainly the CV, disorders affecting many systems, including CV, common disorders
- familial cardiomyopathy, familial long QT, familial hypercholesterolemia
- lysosomal storage disorders (Fabry disease), marfan
- atherosclerosis, HTN
cardiomyopathy definition and causes
- any disease of heart muscle
- many diff causes: ischemic, toxic (ethanol), infectious, idiopathic/primary
Most common cause of cardiomyopathy
-ischemic
3 basic types of primary cardiomyopathy pathophysiology
- hypertrophic
- dilated
- restrictive: still walls
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
Familial Hypertrophic cardiomyopathy
- autosomal dominant, age-dependent, variable severity
- base substitutions can tell us of prognosis/risk
- abnormal hypertrophy, disarray of myofibrils, interstitial fibrosis
What is the most common cause of sudden death in young athletes?
-familal hypertrophic cardiomyopathy
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
T/F: knowing the mutation in familial hypertrophic cardiomyopathy aids diagnosis
-true!!
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
Compare # of genetic factors implicated in FHC and familial dilated cardiomyopathy
-MANY more in FDC and X-linked FDC
Arrhythmogenic Right Ventricular Dysplasia
- multiple gene mutations, all involved with structure and function of desmesomes
- Autosomal dominant; heart muscle is basically replaced with fat
Familial Dilated Cardiomyopathies generally involve mutated proteins involved in what?
-cytoskeletal mlcs that interact with ECM through integrins **and desmosomes*
Syndromic Restrictive Cardiomyopathies
- Hemochromatosis: HFE
- Amyloidoses
- Fabry Disease -lysosomal storage dz
- glycogen storage disorders
Syndromic Dilated Cardiomyopathies
- neuromuscular : DMD, muscular dystrophies
- mito disorders
- carnitine deficiency etc
Pathogenetics definition
-study of how anomalies of the genome contribute to abnormal phenotypes
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)
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
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
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
LQTS
- most genetic forms are channelopathies
- genetic heterogeneity: most autosomal dominant
- variable expression: age, severity, electrophysiology, susceptibility to drugs
- manifests in other systems: auditory
Classification of LQTS
- Romano-Ward Syndrome: AD
- Jervell&Lange-Neilsen Syndrome: AR
- Brugada syndrome:AD; RBBB, ST elevation in V1-V3, sudden death
LQTS prognosis/risk
- risk of sudden death is <1%/year
- dysrhythmia in 25%
Main protein in LQTS that cause several other disorders
-SCN5A: LQTS, dilated CM with conduction defects, Brugada syndrome
T/F: LQTS can be drug induced
-true!
Cardiovascular features of Marfan’s Syndrome
- aortic root dilation
- aortic dissection
- aortic regurgitation due to stretching of sinuses of Valsalva
- MV prolapse
Pathology of Marfan’s in aorta
-medial degeneration
Aortic Root dilatation: complications
- Aortic regurg: CHF, sudden death
- Aortic dissection: suddent death, MI, organ ischemia (stroke), late rupture
Marfan Syndrome CV surgical technique
- Bentall Revolution: composite graft
- if done preventatively, can give long term life expectancy
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
Marfan’s Cause
- fibrillin component of elastin: FBN1
- found in zonules, skin, aortic media, perichondrium
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)
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
Issues of increases activity of TGF-B1
- spontaneous pneumothorax: too much TGFB leads to failure of terminal differentiation of alveoli (prevent this if you give TGFB antibodies)
- abnormal AV valve development: MV prolapse
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
