Lecture 10: Cardiomyopathies – Sarcomeric Disease

Question 1

What are cardiomyopathies?

Answer 1

Heterogenous group of dysfunctional conditions

Question 2

What identifies a cardiomyopathy?

Answer 2

Anatomical conditions

Question 3

What is cardiomyopathy caused by?

Answer 3

Disease, drugs, genetics, unknown

Question 4

What is dilated cardiomyopathy and what is it caused by?

Answer 4

Chamber enlargement, caused by alcohol toxicity, virus or genetic metabolic abnormality

Question 5

What is restrictive cardiomyopathy and what is it caused by?

Answer 5

Rigid ventricles, cannot fill or relax properly, caused by fibrosis and tumour

Question 6

What is FHC?

Answer 6

Familial hypertrophic cardiomyopathy

Question 7

What is characteristic of FHC and what is it caused by?

Answer 7

Disrupted myocyte geometry due to fibrosis

Question 8

What is the risk of FHC?

Answer 8

1/500

Question 9

What mode of inheritance does FHC follow?

Answer 9

Autosomal dominant

Question 10

How many sarcomere mutations and how many myofilament genes in FHC?

Answer 10

> 450 mutations in 13 myofilament genes

Question 11

How long is the cardiac sarcomere?

Answer 11

2um

Question 12

What does titin do?

Answer 12

Springs thick filament to ends or sarcomere and moves it back and forwards to actin

Question 13

What are the components of the thin filament?

Answer 13

Actin, troponin, tropomyosin

Question 14

What are the components of myosin?

Answer 14

ELC - essential light chain

RLC - regulatory light chain

Question 15

What happens when there is low calcium?

Answer 15

Actin myosin interaction blocked by TnT interaction

Question 16

What happens when there is high calcium?

Answer 16

Calcium binds to TnC, pulls away TnI, allows tropomyosin to move away, actin and myosin cross bridge

Question 17

What is the most commonly mutated sarcomeric protein and what are its features?

Answer 17

Beta myosin heavy chain
MYH7 gene
212 mutations
Affects 25-35% of people

Question 18

What is a point missense mutation?

Answer 18

Different codon - change one aa in proton

Question 19

What is a point nonsense mutation?

Answer 19

No aa coded (stop codon)- truncated protein

Question 20

What is a frameshift mutation?

Answer 20

Insertion/deletion of a base - very different protein made

Question 21

What is a poison peptide?

Answer 21

Affected allele makes defective protein - messes with normal allele protein

Question 22

What is haploinsufficiency?

Answer 22

Normal allele doesn’t produce enough protein, imbalance in sarcomere components

Question 23

What is a splice error?

Answer 23

Exons not assembled normally due to a mutation in the splice acceptor site

Question 24

What happens when there is an MHC mutation?

Answer 24

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

Question 25

What happens when troponin is mutated?

Answer 25

Increased calcium sensitivity

Question 26

What happens when actin is mutated?

Answer 26

Reduced sliding velocity and myosin affinity

Question 27

What happens when there is a structural mutation in the myofilaments?

Answer 27

Altered mechanical integrity, problems with energy production

Question 28

What are the four regions of myosin mutation?

Answer 28

ATP binding site, actin binding pocket, hinge and lever, filament backbone

Question 29

What happens in the FHC primary phenotype?

Answer 29

Increased calcium sensitivity, systolic function and ATP utilisation at low calcium levels. Decreased diastolic function.

Question 30

What happens in the FHC secondary phenotype?

Answer 30

Inefficient oxygen consumption, hypertrophy gene induction, reduced SR calcium loading, sarcomere trauma and necrosis

Question 31

What gene in myosin leads to 70-80% function loss?

Answer 31

ArgGln

Question 32

What gene in FHC is linked with increased LV hypertrophy?

Answer 32

ACE DD

Question 33

Under what age is FHC the most common cause of death?

Answer 33

35

Question 34

When does 70% of SCD in FHC occur?

Answer 34

During or immediately after exercise

Question 35

What is SCD due to?

Answer 35

Ventricular triggered arrhythmia or conduction arrhythmia

Question 36

What effect does exercise have on SCD?

Answer 36

Moderate exercise delays and strenuous exercise accelerates

Question 37

What percentage of SCD does FHC account for?

Answer 37

33%

Question 38

What is the male to female ratio of SCD?

Answer 38

M 9: F 1

Question 39

What % of athletes have LV wall thickness as seen in FHC?

Answer 39

2%

Question 40

What % of athletes have LV cavity size as seen in FHC?

Answer 40

15%