hypertrophic cardiomyopathy
TRANSCRIPT
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University Medical Center Groningen
Hypertrophic Cardiomyopathywhat are the mechanisms?
Peter van der Meer, MD PhD cardiologist
University Medical Center GroningenThe Netherlands
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University Medical Center Groningen
Declaration of Interest
Consultancy fees:
Vifor Pharma, ZS-pharma, Novartis, ResMed, Singulex, Servier
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University Medical Center Groningen
Hypertrophic Cardiomyopathy
• 22 year old woman
• 37 weeks pregnant
• Mutation in MYBPC3-gene
• Gradient LVOT increased to 80mmHg
• Vaginal delivery without complications
• Healthy babyboy was born
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Several questions come up:
-Why is specifically the septum affected in the majority of the cases?
-What’s the implication for the baby-boy
-Are there any models which truly represent the typical HCM phenotype
-Can cell models be of any help; are there any?
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University Medical Center Groningen Science 1996
15w 30w control
First animal model for HCM
α-MHC mutation
Homozygous is lethal.
Disarray, fibrosis and hypertrophy
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Use of mouse model to investigate interventions
• Effect Tgf-β on non-myocyte proliferation
• Effect losartan on non-myocyte proliferation
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University Medical Center Groningen
N= 20Double blind: losartan 2x50mg vs placeboAge: 51 +/- 13 years
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Is presistent expression of the mutant protein necessary?
Double transgenic mouse
Cannon et al. JACC 2015
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• Critical role postnatal period in pathogenesis
• Mutation silencing therapies unlike to be effective
• Administration very early in life to prevent hypertrophy
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University Medical Center Groningen
Rabbit heart predominantly β-MHC (comparable to human)
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University Medical Center Groningen
Effects diminish
- cell division and -dilution morpholinos
University Medical Center Groningen
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Cardiac Lineage TracingComparable to the “blood tree”
Buikema, Van der Meer et al. Stem Cells 2014
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Patient specific cell modelshiPS technology
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University Medical Center Groningen
Patient Specific Cell Model
Hoes, …. Van der Meer, unpublished data
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University Medical Center Groningen
More arrhytmogenic effects (in single cells)
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University Medical Center Groningen
Conclusions• Distribution pattern of hypertrophy in HCM mostly unknown.
• Ca-sensitivity?, energy depletion?, TGF-beta? Developmental disorder?
• Early intervention might be necessary to reverse the phenotype
• Attenuation of progression has been observed with losartan
• Several animal models exist, mouse most commonly used
• Patient specific disease modelling novel tool for understanding HCM