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Kristin Lewis, DVM Pathology Resident/Graduate Research Associate

Structural and functional remodeling following pharmacologic intervention in 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.

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Kristin Lewis, DVM Pathology Resident/Graduate Research Associate

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  1. Structural and functional remodeling following pharmacologic intervention in 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. Why are we interested in heart failure? • ~5 million Americans currently have CHF • ~550,000 new cases diagnosed annually • Contributes to ~300,000 deaths each year • Sudden death is 6-9x more likely in CHF patients than in the general population • HF is responsible for >11 million physician visits annually and more hospitalizations than all forms of cancer combined http://www.emoryhealthcare.org/heart-failure/learn-about-heart-failure/statistics.html

  3. 2 types of hemodynamic overload  HF Volume Overload Pressure Overload • Increased afterload • Concentric hypertrophy • Fibrosis • Examples: • Hypertension • Aortic stenosis • Increased preload • Eccentric hypertrophy • ECM degradation • Examples: • Aortic/Mitral regurgitation • Area opposite infarct • Ventricular septal defect

  4. Systolic Dysfunction Diastolic Dysfunction Progression of Volume Overload (VO) to Heart Failure Reversible Irreversible • ValvularDysfunction • Aortic regurgitation • Mitral regurgitation Volume Overload Septal Defects HF Death Myocardial Infarct LV Remodeling LV Dysfunction Overt HF Time (months to years) Time (months)

  5. Overall hypothesis: Early intervention will result in return of LV structure and function to baseline levels

  6. Volume overload-induced HF with aortocaval fistula (ACF) in the rat 18g Aorta

  7. ACF progressive increase in LVDd Sham 4 wk ACF LVDd LVDs 8 wk ACF 15 wk ACF

  8. VO is accompanied by functional deterioration % FS * * *= P < 0.05 vs. Sham

  9. Will reversal of ACF improve LV structure and function? Stent graft Suture

  10. LV chamber geometry is normalized 4wks post-reversal *= P < 0.05 vs. Sham †= P < 0.05 vs. ACF Hutchinson KR, et al. J Appl Physiol. 2011 Sep 1

  11. ACF reversal  decreased LV contractility @ 4 weeks & normalization of LV contractility @ 11 weeks Sham ACF Only ACF + Reversal * * 4 wk ACF ± 4 wk Rev Pressure (mmHg) † * 4 wk ACF ± 11 wk Rev *= P < 0.05 vs. Sham Volume (µL) †= P < 0.05 vs. ACF Hutchinson KR, et al. J Appl Physiol. 2011 Sep 1

  12. AIM 1 In a rat model of ACF-induced volume overload: Determine the optimal time to initiate medical therapy by comparing the temporal efficacy of β-blocker (metoprolol) or myofilament Ca2+ sensitizer (levosimendan) therapy

  13. Beta-blocker: Metoprolol • Preferentially binds to β1-AR in the heart & blocks NE binding • Clinical mechanism of action poorly understood: • Theoretically: •  HR, contractility, conduction velocity, relaxation rate • Clinically: •  contractility • Benefit may be 2o to blockade of excess Epi/NE stimulation http://www.cvpharmacology.com/cardioinhibitory/beta-blockers.htm

  14. Levosimendan (and OR-1896) act through multiple cardiovascular targets Papp Z, et al. Int J Cardiol. 2011 Jul 23.

  15. Study Design • Sprague dawley rats, 210-260 g • Treatment: • Vehicle: water • Metoprolol: 30 mg/kg x 4 wk, 50 mg/kg x 4 wk, 80 mg/kg x 3 wk • Levosimendan: 1 mg/kg ECHO (q2w) Hemodynamics Necropsy Treatment start SHAM VEH (n=10) (n=8) ACF VEH (n=9) MET ACF (n=9) ACF LEVO 0 wk 4 wk 15 wk

  16. Body weight gain unaffected by surgery or treatment

  17. Met enhanced progression to HF

  18. Levo & Met  delayed and enhanced increases in LVDd, respectively

  19. Levo early reversal of eccentric dilation index

  20. %FS is consistent with treatment

  21. Summary • In our model of volume overload: • Metoprolol accelerates the progression to HF • Levosimendan delays the progression to HF • Treatment started at lower LVDd • 1) return to pre-surgical LVDd • 2) maintenance of LVDd

  22. Next steps • Current study: • Structure: • ECHO • Routine histology, organ weights • Collagen content, TGF-β • MMPs/TIMPs • α-MHC, β-MHC • Function: • ECHO • PV Loops • ANP, BNP, Connexin 43 • Future studies: • Repeat current study + myocyte isolation • ACF + earlier treatment • ACF + reversal + treatment

  23. Next steps • Current study: • In vivo: • ECHO • PV loops • Ex vivo: • Organ weights/ratios • Routine histology: heart, liver, lungs, kidney • Picrosirius red • qPCR: Col1a1, Col3a1, elastin, α-MHC, β-MHC, ANP, BNP, TGF-β • Immunoblot: MMP-13, MT1-MMP, MMP-7, MMP-9, TIMP-2 • Future studies: • Repeat current study + myocyte isolation • ACF + earlier treatment • ACF + reversal + treatment

  24. Acknowledgements Nationwide Childrens The Ohio State University Veterinary Biosciences Funding Sources ACVP/STP Coalition Fellowship NIH HL056046 Nationwide Children’s Hospital • Lucchesi lab • Pam Lucchesi • AnuGuggilam • Maarten Galanctowicz • Aaron Trask • Kathryn Halleck • Kirk Hutchinson • Aaron West • Mary Cismowski • Jean Zhang • Vivarium • Natalie Snyder

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