L8.1 Cardiomyopathies Flashcards Preview

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Flashcards in L8.1 Cardiomyopathies Deck (23):
1

Cardiomyopathy characteristics

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

2

Dilated cardiomyopathy

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

3

Restrictive cardiomyopathy

  • rigid ventricles
  • impaired filling
  • fibrosis and tumor 

4

Familial hypertrophic cardiomyopathy (FHC)

  • disrupted myocyte geometry
  • fibrosis
  • diastolic stiffness & arrhythmias 

5

Inheritence of FHC

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

6

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

  • Actin-myosin interaction blocked by Troponin-tropomyosin interaction

7

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

  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

8

What are the 3 main types of mutation?

  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) 

9

Consequences of mutations

  • ‘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 

10

Structure of a myofilament

MHC = myosin heavy chain

MyBP-C = myosin binding protein C

ELC = essential light chain

RLC = Regulatory light chain

A image thumb
11

Myofilament mutation effects on MHC

  • 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 

12

Myofilament mutation effects on troponin

 

↑ Ca sensitivity

13

Myofilament mutation effects on actin

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

14

Myofilament mutation effects on structure of sarcomere

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

15

Primary functional phenotype of FHC

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

16

Secondary functional phenotype of FHC

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

17

Relationship between hypertrophic impact and risk

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

18

How does gender modify risk

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

19

RAS in FHC

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

20

FHC and sudden cardiac death (SCD)

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

21

SCD mechanism

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

22

Is exercise bad for FHC then?

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

23

Percentage of atheletes having FHC pathologies

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