L8.1 Cardiomyopathies Flashcards
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
Dilated cardiomyopathy
- chamber enlargement (walls becomes thinner)
- Associated with viral, alcohol toxicity
- genetic metabolic abnormality
Restrictive cardiomyopathy
- rigid ventricles
- impaired filling
- fibrosis and tumor
Familial hypertrophic cardiomyopathy (FHC)
- disrupted myocyte geometry
- fibrosis
- diastolic stiffness & arrhythmias
Inheritence of FHC
- A genetic ‘disease of the sarcomere’, incidence 1/500
- variable symptoms, onset, severity
- Malignant or benign
- autosomal dominant (50/50 inheritance)
What occurs during low Ca (resting/diastole) levels in the sarcomere
- Actin-myosin interaction blocked by Troponin-tropomyosin interaction
What occurs during high Ca (Activation/systole) levels with sarcomere?
- Ca binds to TnC (Tn = troponin)
- Pulls TnI away from actin
- Tropomyosin moves out of actin groove
- Actin free to form cross-bridge with myosin
What are the 3 main types of mutation?
- point missense – different codon (one aa change in protein)
- point nonsense – premature stop -> no aa coded
- frameshift – base insertion/deletion (very diff protein)
- occur in exons or introns (diff consequences)
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
Structure of a myofilament
MHC = myosin heavy chain
MyBP-C = myosin binding protein C
ELC = essential light chain
RLC = Regulatory light chain
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
Myofilament mutation effects on troponin
↑ Ca sensitivity
Myofilament mutation effects on actin
- ↓ myosin affinity, myofilament sliding velocity
- Reduce myosin swing
Myofilament mutation effects on structure of sarcomere
- MBP-C, titin, etc affected
- altered sarcomere mechanical integrity
- defective localization of sarcomere associated
Primary functional phenotype of FHC
- ↑ Ca sensitivity
- ↑ systolic function -> mechanical stress
- ↓ distolic function -> incomplete relaxation
- ↑ ATP utilization at submax [Ca]
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
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)
How does gender modify risk
- sex: female FHC low (reduced myocyte Ca load?)
- polymorphisms in growth genes speculated (ET1, TNF)
RAS in FHC
- ACE polymorphism increases ACE levels -> leads to LV hypertrophy
- amplified growth response, or gene co-inheritance?
FHC and sudden cardiac death (SCD)
- FHC most common cause death < 35 yr
- 70% SCD in FHC ocurs during or immediately after exercise
SCD mechanism
- ventricular triggered arrhythmia (Ca handling)
- conduction arrhythmia (fibrosis, myocyte loss)
Is exercise bad for FHC then?
- no systematic human studies
- in mouse gene models moderate exercise delays and strenuous exercise accelerates hypertrophy development
Percentage of atheletes having FHC pathologies
- LV wall thickness: 2% trained will have FHC pathology
- LV cavity: 15% trained have FHC dilated pathology
