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Efficacy of existing heart failure drugs in preventing/delaying Lmna related DCM

Efficacy of existing heart failure drugs in preventing/delaying Lmna related DCM. A. Beqqali, MSc PhD I. Van Rijsingen , MD PI: Y. Pinto , MD Ph. Research area 3: Animal models WP7: Lmna KO mice. Experimental setup.

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Efficacy of existing heart failure drugs in preventing/delaying Lmna related DCM

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  1. Efficacy of existing heart failure drugs in preventing/delaying Lmna related DCM A. Beqqali, MSc PhD I. Van Rijsingen, MD PI: Y. Pinto, MD Ph Research area 3: AnimalmodelsWP7: Lmna KO mice

  2. Experimental setup • Metoprolol (beta-blocker) and Enalapril (ACE-inhibitor) (n=20 per group): • WT : no treatment • Lmna+/- : no treatment • Lmna+/- : Metoprolol 30mg/kg/day • Lmna+/- : Enalapril 10mg/kg/day • Treatment started at 10 weeks of age and will continue for at least 30 weeks • Heart function will be monitored at week 10, 25, 40, 50, 60 of age • Sacrifice at endpoint: morphology, histology, molecular characterization of hearts hearts (“-omics”?)

  3. No effect on heart function after 15 weeks of treatment n=20 per group Age: 25 weeks 15 weeks treatment

  4. No effect on heart function after 15 weeks of treatment n=20 per group Age: 25 weeks 15 weeks treatment

  5. No significant changes in cardiac performance at 30 weeks of treatment N=20 per group Age: 40 weeks 30 weeks treatment

  6. Enalapril affects wall thickness after 30 weeks of treatment P=0.005 N=20 per group Age: 40 weeks 30 weeks treatment

  7. Enalapril treatment leads to better cardiac performance at 40 weeks of treatment P=0.0009 P=0.0007 P=0.01 P=0.01 N=15 per group Age: 50 weeks 40 weeks treatment

  8. Enalapril prevents dilation after 40 weeks of treatment P=0.017 P=0.05 N=15 per group Age: 50 weeks 40 weeks treatment

  9. Summary • ACE inhibitor Enalapril leads to better cardiac performance • Beta blocker Metoprolol has no significant effect on heart function • Lmna+/- mice did not develop sufficient DCM yet at the age of 50 weeks : continue experiment up to 80 weeks of age. (January 2013) • Concern: is it true that regular chow in our lab contains 10% more antioxidants, hence delaying onset of DCM? • Fact: Enalapril has strong anti-oxidant effect

  10. RBM20 Heterozygous missense mutations in exon 9 of RBM20 were found in 3% of all DCM cases tested, and in over 13% of those with a history of sudden death

  11. 1 1199 AA Zf RRM Zf RS RNA binding motif protein 20 • Member of RNA binding motif “protein family “ • Well conserved amongst vertebrates • RRM containing proteins play role in splicing, miR processing, apoptosis, RNA stability, translation • Mutations in RBM20 cause familial DCM (Brauchet al 2009 and Li et al 2010) • Function is unknown • AIM: investigate the role of Rbm20 in normal and diseased heart

  12. RBM20 is localized in nuclear speckles (spliceosome) RBM20 DAPI Human ES cell derived cardiomyocytes

  13. RBM20 is localized in the Golgi of cardiomyocytes RBM20 GM130 DAPI Human ES cell derived cardiomyocytes

  14. INHERITANCE and RBM20 • RBM20 mutations found in the consortium? • In vitro mutation analysis: • Subcellular localization • RNA target binding/splicing (titin) • Exon arrays/RNA seq on patient material • Keratinocytes/leukocytes for generation of induced Pluripotent Stem Cells

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