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  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

MacLennan Nature Reviews Molecular Cell Biology 2008;4: Interactions Between Cardiac Signalling Pathways

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

The CUPID Trial  Intracoronary infusion of AAV1/SERCA2a  9 pts with advanced HF (NYHA Class III/IV; EF ≤30%; VO 2 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)

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

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

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

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

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

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

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

Left Ventricular Assist Device

Lietz & Mille Semin Thorac Cardiovasc Surg 2008;20: Survival Oucomes of Destination Therapy

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

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

Ongoing Randomized Trials of DT HeartMateII LVAD vs. 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

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

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

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

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

Transplantation for Severe Heart Failure Areas of Improvement  Improved methods of organ preservation  Extension of the donor pool  Prevention of rejection

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

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

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

Continous Heart Perfusion : Back in the 30s

Continuous Heart Transplant Perfusion

Transplantation for Severe Heart Failure Areas of Improvement  Improved methods of organ preservation  Extension of the donor pool  Prevention of rejection

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

Transplantation for Severe Heart Failure Areas of Improvement  Improved methods of organ preservation  Extension of the donor pool  Prevention of rejection

Transplantation for Severe Heart Failure Prevention of Rejection  New immunosuppressive drugs  Induction of tolerance  Pharmacogenomics

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:

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

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

Transplantation for Severe Heart Failure Prevention of Rejection  New immunosuppressive drugs  Induction of tolerance  Pharmacogenomics

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

Transplantation for Severe Heart Failure Prevention of Rejection  New immunosuppressive drugs  Induction of tolerance  Pharmacogenomics

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

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

CardioWest TAH

AbioCorTAH

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

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

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