Transcript 6 th International Symposium on Stem Cell Therapy

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 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
Interactions Between Cardiac Signalling Pathways
MacLennan Nature Reviews Molecular Cell Biology 2008;4:566-77.
Beneficial Effects of SERCA-2 Overexpression in
Human Failing Cardiomyocytes
del Monte et al. Circulation 1999;100:2308-11.
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)
MicroRNA-Based Therapeutics for
Heart Disease
Van Rooij et al. Circ Res 2008;103:919-28.
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
LV Reconstruction by Patch Plasty
Jatene, Dor, Fontan
Bockeria et al. Eur J Cardio-thorac Surg
2006;29:S251-8S.
The STICH Trial (1,000 Patients)
Kaplan-Meier Estimates of Outcomes
Jones R et al. N Engl J Med 2009;10.1056/NEJMoa0900559
The STICH Trial (1,000 Patients)
Outcomes
Jones R et al. N Engl J Med 2009;10.1056/NEJMoa0900559
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
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
Survival Oucomes of Destination Therapy
Lietz & Mille Semin Thorac Cardiovasc Surg 2008;20:225-33.
Survival After LVAD Implantation as DT by the
Candidate's Operative Risk
Lietz et al. Circulation 2007;116:497-505 .
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.
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)
100
VAD (N=3,757)
No VAD / Inotropes (N=11,576)
No VAD / No Inotropes (N=9,435)
Survival (%)
90
80
70
60
VAD vs.
inotropes:
p < 0.0001
VAD
vs.no
noVAD/no
VAD/no
inotropes:
p < 0.0001
VAD vs.
p < 0.0001
VAD
vs.no
noVAD/inotropes:
VAD/inotropes:
p < 0.0001
No
VAD/no
inotropes
vs
No
VAD/inotropes:
p = 0.0008
No VAD/no inotropes vs No VAD/inotropes:
p = 0.0008
0.0008
50
40
0
1
ISHLT
2
3
4
5
6
7
8
9
10
Years
J Heart Lung Transplant 2008;27: 937-83.
Adult Heart Recipients
Employment 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.
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.
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;359:473-81.
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
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.
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;351:2715-29.
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.
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;358:353-61.
Transplantation for Severe Heart Failure
Prevention of Rejection
 New immunosuppressive drugs
 Induction of tolerance
 Pharmacogenomics
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.
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
Jarvik
Abiocor TAH
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