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Mechanisms of Hypertrophic Cardiomyopathy Explained
- 1. HypertrohpicCardiomyopathy University Medical Center Groningen Hypertrophic Cardiomyopathy what are the mechanisms? Peter van der Meer, MD PhD cardiologist University Medical Center Groningen The Netherlands
- 2. HypertrohpicCardiomyopathy University Medical Center Groningen Declaration of Interest Consultancy fees: Vifor Pharma, ZS-pharma, Novartis, ResMed, Singulex, Servier
- 3. HypertrohpicCardiomyopathy 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
- 4. HypertrohpicCardiomyopathy University Medical Center Groningen
- 5. HypertrohpicCardiomyopathy University Medical Center Groningen 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?
- 6. HypertrohpicCardiomyopathy University Medical Center Groningen Science 1996 15w 30w control First animal model for HCM α-MHC mutation Homozygous is lethal. Disarray, fibrosis and hypertrophy
- 7. HypertrohpicCardiomyopathy University Medical Center Groningen Use of mouse model to investigate interventions • Effect Tgf-β on non-myocyte proliferation • Effect losartan on non-myocyte proliferation
- 8. HypertrohpicCardiomyopathy University Medical Center Groningen N= 20 Double blind: losartan 2x50mg vs placebo Age: 51 +/- 13 years
- 9. HypertrohpicCardiomyopathy University Medical Center Groningen
- 10. HypertrohpicCardiomyopathy University Medical Center Groningen Is presistent expression of the mutant protein necessary? Double transgenic mouse Cannon et al. JACC 2015
- 11. HypertrohpicCardiomyopathy University Medical Center Groningen
- 12. HypertrohpicCardiomyopathy University Medical Center Groningen • Critical role postnatal period in pathogenesis • Mutation silencing therapies unlike to be effective • Administration very early in life to prevent hypertrophy
- 13. HypertrohpicCardiomyopathy University Medical Center Groningen Rabbit heart predominantly β-MHC (comparable to human)
- 14. HypertrohpicCardiomyopathy University Medical Center Groningen
- 15. HypertrohpicCardiomyopathy University Medical Center Groningen Effects diminish - cell division and -dilution morpholinos
- 16. University Medical Center Groningen Hypertrophihccardiomyopathy Cardiac Lineage Tracing Comparable to the “blood tree” Buikema, Van der Meer et al. Stem Cells 2014
- 17. University Medical Center Groningen Hypertrophihccardiomyopathy
- 18. HypertrohpicCardiomyopathy University Medical Center Groningen Patient specific cell models hiPS technology
- 19. HypertrohpicCardiomyopathy University Medical Center Groningen Patient Specific Cell Model Hoes, …. Van der Meer, unpublished data
- 20. HypertrohpicCardiomyopathy University Medical Center Groningen
- 21. HypertrohpicCardiomyopathy University Medical Center Groningen More arrhytmogenic effects (in single cells)
- 22. HypertrohpicCardiomyopathy University Medical Center Groningen
- 23. HypertrohpicCardiomyopathy 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