L8.1 Cardiomyopathies

Question 1

Cardiomyopathy characteristics

Answer 1

• A heterogeneous group of dysfunctional conditions
• Cardiac structural abnormalities
• Generally identified on basis of anatomical characteristics
• Variety of etiologies:
  
  • disease, drug-induced, genetic, unknown

Question 2

Dilated cardiomyopathy

Answer 2

• chamber enlargement (walls becomes thinner)
• Associated with viral, alcohol toxicity
• genetic metabolic abnormality

Question 3

Restrictive cardiomyopathy

Answer 3

• rigid ventricles
• impaired filling
• fibrosis and tumor

Question 4

Familial hypertrophic cardiomyopathy (FHC)

Answer 4

• disrupted myocyte geometry
• fibrosis
• diastolic stiffness & arrhythmias

Question 5

Inheritence of FHC

Answer 5

• A genetic ‘disease of the sarcomere’, incidence 1/500
• variable symptoms, onset, severity
  
  • Malignant or benign
• autosomal dominant (50/50 inheritance)

Question 6

What occurs during low Ca (resting/diastole) levels in the sarcomere

Answer 6

• Actin-myosin interaction blocked by Troponin-tropomyosin interaction

Question 7

What occurs during high Ca (Activation/systole) levels with sarcomere?

Answer 7

1. Ca binds to TnC (Tn = troponin)
2. Pulls TnI away from actin
3. Tropomyosin moves out of actin groove
4. Actin free to form cross-bridge with myosin

Question 8

What are the 3 main types of mutation?

Answer 8

1. point missense – different codon (one aa change in protein)
2. point nonsense – premature stop -> no aa coded
3. frameshift – base insertion/deletion (very diff protein)

• occur in exons or introns (diff consequences)

Question 9

Consequences of mutations

Answer 9

• ‘poison peptide’ (‘dominant negative’):
  
  • affected allele makes defective protein, interferes with wildtype allele protein
• ‘haploinsufficiency’:
  
  • normal allele doesn’t produce enough protein for sarcomere stoichiometry imbalance.
• splice error:
  
  • the exons are not assembled normally

Question 10

Structure of a myofilament

Answer 10

MHC = myosin heavy chain

MyBP-C = myosin binding protein C

ELC = essential light chain

RLC = Regulatory light chain

Question 11

Myofilament mutation effects on MHC

Answer 11

• heart expresses α (MYH6) & β (MYH7) isoforms
  
  • β form expressed more marked early dev & failure
  • mutations in β form more common
• mutations in α and β forms hyper-contractile

Question 12

Myofilament mutation effects on troponin

Answer 12

↑ Ca sensitivity

Question 13

Myofilament mutation effects on actin

Answer 13

• ↓ myosin affinity, myofilament sliding velocity
• Reduce myosin swing

Question 14

Myofilament mutation effects on structure of sarcomere

Answer 14

• MBP-C, titin, etc affected
  
  • altered sarcomere mechanical integrity
  • defective localization of sarcomere associated

Question 15

Primary functional phenotype of FHC

Answer 15

• ↑ Ca sensitivity
• ↑ systolic function -> mechanical stress
• ↓ distolic function -> incomplete relaxation
• ↑ ATP utilization at submax [Ca]

Question 16

Secondary functional phenotype of FHC

Answer 16

• inefficient oxygen consumption
• hypertrophy gene induction: sarcomere mechano-receptors & oncogenes ( Ca, H switch?)
• reduced SR Ca loading
• Sarcomere/myocyte mechanical trauma & necrosis

Question 17

Relationship between hypertrophic impact and risk

Answer 17

• hypertrophic impact & risk not necessarily linked
  
  • ie moderate hypertrophy can be associated with high death risk (other moderating factors)

Question 18

How does gender modify risk

Answer 18

• sex: female FHC low (reduced myocyte Ca load?)
• polymorphisms in growth genes speculated (ET1, TNF)

Question 19

RAS in FHC

Answer 19

• ACE polymorphism increases ACE levels -> leads to LV hypertrophy
• amplified growth response, or gene co-inheritance?

Question 20

FHC and sudden cardiac death (SCD)

Answer 20

• FHC most common cause death < 35 yr
• 70% SCD in FHC ocurs during or immediately after exercise

Question 21

SCD mechanism

Answer 21

• ventricular triggered arrhythmia (Ca handling)
• conduction arrhythmia (fibrosis, myocyte loss)

Question 22

Is exercise bad for FHC then?

Answer 22

• no systematic human studies
• in mouse gene models moderate exercise delays and strenuous exercise accelerates hypertrophy development

Question 23

Percentage of atheletes having FHC pathologies

Answer 23

• LV wall thickness: 2% trained will have FHC pathology
• LV cavity: 15% trained have FHC dilated pathology