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Heart Replacement in the Age of Stem Cell Therapy and Biosensors Technology. What we Know and What we can Expect

Heart Replacement in the Age of Stem Cell Therapy and Biosensors Technology. What we Know and What we can Expect. 6 th International Symposium on Stem Cell Therapy & Cardiovascular Innovations Madrid, April 23-24, 2009. Treatment of Severe Heart Failure. Possible Strategies

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Heart Replacement in the Age of Stem Cell Therapy and Biosensors Technology. What we Know and What we can Expect

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  1. Heart Replacement in the Age of Stem Cell Therapy and Biosensors Technology. What we Know and What we can Expect 6th International Symposium on Stem CellTherapy & Cardiovascular Innovations Madrid, April 23-24, 2009

  2. Treatment of Severe Heart Failure • Possible Strategies • To replace key dysfunctional pathways • To replace diseased segments of the left ventricle • To replace the whole left ventricle • To replace the whole heart by a transplant • To replace the whole heart by an artificial device

  3. Interactions Between Cardiac Signalling Pathways MacLennan Nature Reviews Molecular Cell Biology 2008;4:566-77.

  4. Beneficial Effects of SERCA-2 Overexpression in Human Failing Cardiomyocytes del Monte et al. Circulation 1999;100:2308-11.

  5. The CUPID Trial • Intracoronary infusion of AAV1/SERCA2a • 9 pts with advanced HF (NYHA Class III/IV; EF ≤30%; VO2 max  16mL/kg/min) • 3 dose-escalating cohorts (3pts/cohort) • Good safety profile • 6- to 12-month FU : Encouraging hints of efficacy (symptoms, LV function and remodeling, biomarkers)

  6. MicroRNA-Based Therapeutics for Heart Disease Van Rooij et al. Circ Res 2008;103:919-28.

  7. Treatment of Severe Heart Failure • Possible Strategies • To replace key dysfunctional pathways • To replace diseased segments of the left ventricle • To replace the whole left ventricle • To replace the whole heart by a transplant • To replace the whole heart by an artificial device

  8. LV Reconstruction by Patch Plasty Jatene, Dor, Fontan Bockeria et al. Eur J Cardio-thorac Surg 2006;29:S251-8S.

  9. The STICH Trial (1,000 Patients) Kaplan-Meier Estimates of Outcomes Jones R et al. N Engl J Med 2009;10.1056/NEJMoa0900559

  10. The STICH Trial (1,000 Patients) Outcomes Jones R et al. N Engl J Med 2009;10.1056/NEJMoa0900559

  11. The STICH Trial (1,000 Patients) Angina and Heart-Failure Symptoms at Baseline and at the Last FU Visit Jones R et al. N Engl J Med 2009;10.1056/NEJMoa0900559

  12. Treatment of Severe Heart Failure • Possible Strategies • To replace key dysfunctional pathways • To replace diseased segments of the left ventricle • To replace the whole left ventricle • To replace the whole heart by a transplant • To replace the whole heart by an artificial device

  13. Left Ventricular Assist Device

  14. Survival Oucomes of Destination Therapy Lietz & Mille SeminThoracCardiovascSurg 2008;20:225-33.

  15. Survival After LVAD Implantation as DT by the Candidate's Operative Risk Lietz et al. Circulation 2007;116:497-505 .

  16. Long-term Outcomes and Costs of Ventricular Assist Devices Among Medicare Beneficiaries Mean 1-year Medicare payments for inpatient care for patients in the 2000–2005 cohorts were $178 714 (SD, $142 549) in the primary device group and $111 769 (SD, $95 413) in the postcardiotomy group Hernandez et al. JAMA 2008;300:2398–2406.

  17. Ongoing Randomized Trials of DT HeartMateII LVADvs. HeartMateXVE LVAD 260 pts, estimated primary completion date : June, 2009 vs. Medical Tt (180 pts) or LVAD DT device (45 pts) estimated completion date : 2012 VentrAssist

  18. Treatment of Severe Heart Failure • Possible Strategies • To replace key dysfunctional pathways • To replace diseased segments of the left ventricle • To replace the whole left ventricle • To replace the whole heart by a transplant • To replace the whole heart by an artificial device

  19. Adult Heart Transplantation Kaplan-Meier Survival by VAD usage(Transplants: 4/1994-6/2006) VAD vs. no VAD/no inotropes: p < 0.0001 VAD vs. no VAD/inotropes: p < 0.0001 No VAD/no inotropes vs No VAD/inotropes: p = 0.0008 0.0008 ISHLT J Heart Lung Transplant 2008;27: 937-83.

  20. Adult Heart RecipientsEmployment Status of Surviving Recipients (Follow-ups: 1995 - June 2006) Retired Not working Working part time Working full time Retired Last updated based on data as of December 2006 ISHLT J Heart Lung Transplant 2008;27:937-83.

  21. Cumulative Incidence of Leading Causes of Death After Heart Transplantation in Adults (January 1992-June 2005) ISHLT Last updated based on data as of December 2006 J Heart Lung Transplant 2008;27:937-83.

  22. Transplantation for Severe Heart Failure • Areas of Improvement • Improvedmethods of organpreservation • Extension of the donor pool • Prevention of rejection

  23. Transplantation for Severe Heart Failure • Improved Methods of Organ Preservation • Storage solutions • Manipulations of reperfusion conditions (adhesion molecules, postconditioning) • Continous organ perfusion

  24. Cardioprotective Effects of Postconditioning Piot et al. New Engl J Med 2008;359:473-81.

  25. CyPD facilitates a conformational change in the ANT that is triggered by calcium and this creates a channel. CsA inhibit the PTP by preventing this conformational change Javadov & Karmazyn Cell Physiol Biochem 2007;20:1-22

  26. Continous Heart Perfusion : Back in the 30s

  27. Continuous Heart Transplant Perfusion

  28. Transplantation for Severe Heart Failure • Areas of Improvement • Improvedmethods of organpreservation • Extension of the donor pool • Prevention of rejection

  29. Tx Using Hearts From Non-Heart-Beating Donors 38 pts; mean duration of cardiac arrest : 15 min Ali et al. Eur J Cardiothorac Surg 2007;31:929-33.

  30. Transplantation for Severe Heart Failure • Areas of Improvement • Improvedmethods of organpreservation • Extension of the donor pool • Prevention of rejection

  31. Transplantation for Severe Heart Failure • Prevention of Rejection • New immunosuppressive drugs • Induction of tolerance • Pharmacogenomics

  32. T Cell Activation Through Three Signals Signal 1 : Recognition of HLA and peptide antigen by T lymphocyte Signal 2 : Co-stimulation Signal 3 : IL-2-triggered lymphocyte proliferation Halloran PF New Engl J Med 2004;351:2715-29.

  33. Immunosuppressive Drugs : What’s Next in the Pipeline ? Small molecules in clinical trials Biologics in clinical trials Vincenti & Dirk Am J Transplant 2008;1972-81.

  34. Transplantation for Severe Heart Failure • Immunosuppressive Agents Under Evaluation • Extension from Oncology and Autoimmunity • Monoclonal antibodies (anti-CD3, anti-CD52) • B cell-targeted drugs (anti-CD20 & anti-CD22 mAbs, blockers of the B lymphocyte Stimulator [BLyS] pathway) • Inhibitors of cytokine pathways

  35. Transplantation for Severe Heart Failure • Prevention of Rejection • New immunosuppressive drugs • Induction of tolerance • Pharmacogenomics

  36. Conditioning regimen : cyclophosphamide (D-5, D-4); CD2 (D-1, D0, D+1), ciclosporine, thymic irradiation (D-1) New Engl J Med 2008;358:353-61.

  37. Transplantation for Severe Heart Failure • Prevention of Rejection • New immunosuppressive drugs • Induction of tolerance • Pharmacogenomics

  38. Consequences of Genetic Polymorphisms For Sirolimus Requirements Renal transplant in patients on primary sirolimus therapy Anglicheau et al. Am J Transplant 2005;5:595-603.

  39. Treatment of Severe Heart Failure • Possible Strategies • To replace key dysfunctional pathways • To replace diseased segments of the left ventricle • To replace the whole left ventricle • To replace the whole heart by a transplant • To replace the whole heart by an artificial device

  40. CardioWest TAH

  41. AbioCorTAH

  42. Treatment of Severe HF by Mechanical Devices • Expectations • Miniaturization of systems • Better durability • Easier mode of operation • Totally implantable designs

  43. Total Artificial Heart vs. Axial Flow Pumps Jarvik Abiocor TAH DeBakey

  44. Treatment of Severe HF • Conclusions • Patients with severe HF can now be offered a • wide variety of therapeutic interventions • The place of stem cells will depend of how they compete with these treatments with regard to safety, efficacy, but also, practicality of implementation, approvability by regulatory authorities and cost

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