Lecture 10: Cardiomyopathies – Sarcomeric Disease Flashcards
What are cardiomyopathies?
Heterogenous group of dysfunctional conditions
What identifies a cardiomyopathy?
Anatomical conditions
What is cardiomyopathy caused by?
Disease, drugs, genetics, unknown
What is dilated cardiomyopathy and what is it caused by?
Chamber enlargement, caused by alcohol toxicity, virus or genetic metabolic abnormality
What is restrictive cardiomyopathy and what is it caused by?
Rigid ventricles, cannot fill or relax properly, caused by fibrosis and tumour
What is FHC?
Familial hypertrophic cardiomyopathy
What is characteristic of FHC and what is it caused by?
Disrupted myocyte geometry due to fibrosis
What is the risk of FHC?
1/500
What mode of inheritance does FHC follow?
Autosomal dominant
How many sarcomere mutations and how many myofilament genes in FHC?
> 450 mutations in 13 myofilament genes
How long is the cardiac sarcomere?
2um
What does titin do?
Springs thick filament to ends or sarcomere and moves it back and forwards to actin
What are the components of the thin filament?
Actin, troponin, tropomyosin
What are the components of myosin?
ELC - essential light chain
RLC - regulatory light chain
What happens when there is low calcium?
Actin myosin interaction blocked by TnT interaction
What happens when there is high calcium?
Calcium binds to TnC, pulls away TnI, allows tropomyosin to move away, actin and myosin cross bridge
What is the most commonly mutated sarcomeric protein and what are its features?
Beta myosin heavy chain
MYH7 gene
212 mutations
Affects 25-35% of people
What is a point missense mutation?
Different codon - change one aa in proton
What is a point nonsense mutation?
No aa coded (stop codon)- truncated protein
What is a frameshift mutation?
Insertion/deletion of a base - very different protein made
What is a poison peptide?
Affected allele makes defective protein - messes with normal allele protein
What is haploinsufficiency?
Normal allele doesn’t produce enough protein, imbalance in sarcomere components
What is a splice error?
Exons not assembled normally due to a mutation in the splice acceptor site
What happens when there is an MHC mutation?
Heart expresses beta and alpha forms, beta expressed in early development and failure and is more commonly mutated, if beta and alpha are mutated there is hyper contractility
What happens when troponin is mutated?
Increased calcium sensitivity
What happens when actin is mutated?
Reduced sliding velocity and myosin affinity
What happens when there is a structural mutation in the myofilaments?
Altered mechanical integrity, problems with energy production
What are the four regions of myosin mutation?
ATP binding site, actin binding pocket, hinge and lever, filament backbone
What happens in the FHC primary phenotype?
Increased calcium sensitivity, systolic function and ATP utilisation at low calcium levels.
Decreased diastolic function.
What happens in the FHC secondary phenotype?
Inefficient oxygen consumption, hypertrophy gene induction, reduced SR calcium loading, sarcomere trauma and necrosis
What gene in myosin leads to 70-80% function loss?
ArgGln
What gene in FHC is linked with increased LV hypertrophy?
ACE DD
Under what age is FHC the most common cause of death?
35
When does 70% of SCD in FHC occur?
During or immediately after exercise
What is SCD due to?
Ventricular triggered arrhythmia or conduction arrhythmia
What effect does exercise have on SCD?
Moderate exercise delays and strenuous exercise accelerates
What percentage of SCD does FHC account for?
33%
What is the male to female ratio of SCD?
M 9: F 1
What % of athletes have LV wall thickness as seen in FHC?
2%
What % of athletes have LV cavity size as seen in FHC?
15%
