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Kristin Lewis, DVM Pathology Resident/Graduate Research Associate

The Myofilament Ca 2+ Sensitizer Levosimendan Preserves Systolic Function in Rats with Volume Overload Heart Failure. Kristin Lewis, DVM Pathology Resident/Graduate Research Associate The Ohio State University, Columbus, OH

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Kristin Lewis, DVM Pathology Resident/Graduate Research Associate

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  1. The Myofilament Ca2+ Sensitizer Levosimendan Preserves Systolic Function in Rats with Volume Overload Heart Failure Kristin Lewis, DVM Pathology Resident/Graduate Research Associate The Ohio State University, Columbus, OH The Research Institute, Nationwide Children’s Hospital, Columbus, OH

  2. 2 types of hemodynamic overload  HF Volume Overload Pressure Overload • Increased preload • Eccentric hypertrophy • ECM degradation • Examples: • Aortic/Mitral regurgitation • Myocardial infarct • Ventricular septal defect • Arterio-venous fistulae • Increased afterload • Concentric hypertrophy • Fibrosis • Examples: • Hypertension • Aortic stenosis

  3. Systolic Dysfunction Diastolic Dysfunction Progression of Volume Overload (VO) to Heart Failure Reversible Irreversible Mitral regurgitation Volume Overload HF Death Arterio-venous Fistulae LV Remodeling LV Dysfunction Overt HF Time (months to years) Time (months)

  4. MR treatment options • Surgical repair/replacement • Optimal timing for patients with symptoms or decreased function is defined • Optimal timing for asymptomatic patients is controversial • Intervene early or “watch and wait”? • Post-operative dysfunction • Pharmacologic therapy • Can these agents delay surgery or improve function post-operatively? • Optimal agents?

  5. VO-induced HF with aortocaval fistula (ACF) in the rat 18g Aorta

  6. ACF progressive increase in LVEDd, LVEDs Chest wall “Anterior” Sham 4 wk ACF LVEDd LVEDs “Posterior” Time 8 wk ACF 15 wk ACF

  7. VO is accompanied by functional deterioration % Fractional Shortening * * LVEDd LVEDs *= P < 0.05 vs. Sham

  8. ACF Altered Ca2+ responsiveness and handling 8 wk ACF 8 wk ACF Sham ACF SERCA2a PLB pPLB *** p<0.001 vs. Sham

  9. Hypothesis Therapeutic strategies targeting myofilament Ca2+ sensitivity will preserve/improve LV function in valvular heart disease

  10. Myofilament Ca2+ sensitizer: Levosimendan Hemodymanics Myocyte isolation Tissue collection ECHO (q2w) SHAM (n=28) (n=22) ACF (n=23) ACF Levo, 1 mg/kg 8 wk 0 wk Adapted from Papp Z, et al. Int J Cardiol. 2011 Jul 23.

  11. Levomay attenuate the increase in LVEDD Sham ACF-Veh ACF-Levo LVEDd LVEDs **** p<0.0001 vsSham-Veh; ^ p<0.05, ^^ p<0.01 vs ACF-Veh

  12. Levoimproved LV systolic function * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001 vs Sham-Veh ^ p<0.05, ^^^^ p<0.0001 vsACF-Veh

  13. Levo ↑myofilament Ca2+ sensitivity & ↑ maximal force without ↑ Ca2+ transient * p<0.05, ** p<0.01 vs Sham-Veh ^ p<0.05, ^^^ p<0.001, ^^^^ p<0.0001 vs ACF-Veh

  14. Levo does not result in vasodilation

  15. Levoimproved LV diastolic function **** p<0.0001 vs Sham-Veh ^ p<0.05, ^^^ p<0.001 vsACF-Veh

  16. cMyBP-C and cTnI • Cardiac Myosin Binding Protein-C (cMyBP-C) • Thick filament associated protein • Phosphorylation ↑ contraction and relaxation & ↓Ca2+ sensitivity • Cardiac Troponin I (cTnI) • Thin filament associated protein • Phosphorylation  ↓Ca2+ sensitivity  earlier onset of relaxation Adapted from Landstrom AP, et al. Circulation. 2010 Dec 7;122(23):2441-9 Colson BA et al. J Mol Cell Cardiol. 2012 Nov; 53(5):609-16 Michalek AJ et al. Biophys J. 2013 Jan 22;104(2):442-52.

  17. Phosphorylation at cMyBP-C Ser273, Ser302 and cTnI Ser23/24 may drive functional improvement ACF Sham ACF Sham ACF+L ACF+L ACF Sham ACF+L pSer302 pSer273 pSer23/24 Total cMyBP-C Total cMyBP-C Total cTnI

  18. Summary • Myofilament Ca2+ sensitizer therapy  improved systolic and diastolic function • Improved systolic function is due to increased myofilament Ca2+ sensitivity • Improved diastolic function may be due to cMyBP-C and/or cTnI phosphorylation • Myofilament Ca2+ sensitizer therapy mildly attenuated increase in LVEDD • Therapeutic strategies targeting myofilament Ca2+ sensitivity may improve function prior to load reduction surgery

  19. Acknowledgements Nationwide Children’s Hospital • Lucchesi lab • Pam Lucchesi • Aaron Trask • Aaron West • Jean Zhang • Anu Guggilam • Kirk Hutchinson • Mary Cismowski • Vivarium • Natalie Snyder • Brenna Barbour • Erin Grove The Ohio State University • Veterinary Biosciences Funding Sources • ACVP/STP Coalition Fellowship & Genentech • NIH R01-HL056046 • Nationwide Children’s

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