HEARTLINE 2013 Genova 15/11/2013
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Transcript of HEARTLINE 2013 Genova 15/11/2013
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HEARTLINE 2013 Genova 15/11/2013
Dr Felice Achilli
Le cellule staminali ripareranno il cuore del Paziente infartuato?
Lo studio STEMAMI OUTCOME
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20 years ago ….Ejection Fraction in GISSI 1
(Volpi et al, Circulation 1993)
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10 years ago ….not only EF!
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Zhang Y, et al. Am Heart J 2008;156:1124-32.
Cardiac Remodeling Post AMI
ESV, end systolic volume; Ts-SD: Standard deviation of time to peak myocardial contraction Te-SD: Standard deviation of time to peak early relaxation
Characteristic Normal LV Gp Remodeled Gpearly Post MI (n = 31) (n=16) P value
Q waves 24/31 13/16 NS
Anterior wall 11/31 14/16 .007
Peak CK (u/L) 1910 ± 1046 4098 ± 2081 .006
ESV mL 40.6 ± 8.5 47.6 ± 8.4 .006
Ts-SD 33.7 ± 7.5 50.9 ± 10.8 <.0005
Te-SD 36.2 ± 20.2 45.2 ± 23.2 .048
EF% 53.1 ± 11.7 40.8 ± 7.6 <.0005
Infarct size 10.7 ± 5.9 26.4 ± 10.2 <.0005
Transmurality % 73.6 ± 17.3 85.7 ± 19.6 .039
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Data from BLITZ 4Mortality rates vs "ischemic time" and AMI location
4,2
7,26,9
2,9
5,75,1
3,5
4,4
1,9
0
1
2
3
4
5
6
7
8
<3h >3h tot
30d M
orta
lity R
ates
(%) Anterio
Non Anterior
All
< 3 h > 3 h ALL
r
Today…..
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Tomorrow….: “Reverse Remodeling” or….
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Myocardial Recovery!
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“CARDIOMYOCITE RENEW”
(MI) results in the loss of 1 billion functional cardiomyocytes, which are replaced with a fibrous scar, frequently leading to heart failure. Experimental data demonstrate that the mitotic renewal in the human myocardium exists but at a very low rate: 1% annually at the age of 25 and 0.45% at the age of 75. With this turnover rate, most cardiomyocytes will never be exchanged during a normal life span. Although the renewal rate may increase somewhat after injury, the heart itself is not able to effect large-scale cardiac regeneration.
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Dimmler S., 2012 (with permission)
Cell Therapy of Cardiovascular Disease: start of CT
Bone Marrow derived Cells
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CELL SOURCES TARGETED for CARDIAC REGENERATION
Evolution of the cell types used:
1) Myoblasts
2) Bone Marrow Derived Cells:
• Hematopoetic stem cells
• Mesenchymal stem cells
• Endothelial progenitor cells
• Side population cells
FOURTH GENERATION :
Cardiac Progenitors Cells (CPC)
MORE THAN 2000 PATIENTS
TREATED IN 10 YEARS!
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European Heart Journal (2012) Zimmet et Al.
CELL THERAPHY AND ACUTE CORONARY DISEASES
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J.Tongers,D.W. Losordo, U.Landmesser EHJ 2011 Review (modif)
“EXOGENOUS CELL THERAPY” FOR CARDIAC REPAIR
C. Direct Endomyocardial cell injection
Chronic ICM
Acute MI
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FGF familyEPO
FLT-3 ligand
VEGF family(PIGF)
Angiopoietin-1
HGF/IGF-1/GH
Growth
Factors
G-CSF/GM-CSF
SDF
“ENDOGENOUS CELL THERAPY” FOR CARDIAC REPAIR
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Sanganalmat SK, et al., Basic Res Cardiol 2011
CLINICAL BENEFIT
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CELLS THERAPY IN AMI: SAFETY
Zimmet et Al. EHJ 2012
NO DIFFERENCE ABOUT : IN STENT RESTENOSIS
THROMBOSIS
Re-AMI
DEATH
HOSPITALIZATION
ARRYTHMIA
SURGICAL REVASCULARIZATION
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META-ANALYSIS OF BMSC IN AMI PTS
Follow-up 6mFollow-up 18m
Zimmet et Al. EHJ 2012
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Postgrad Med J 2011; 87:558
Changes in LVEF in Clinical Trial that have changed clinical practice
based on effect on clinical outcome
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Mc Alister et al JAMA 2007
CRT for Patients With LV Dysfunction: A Systematic Review
4420 PtsBasal mean LVEF range, 21%-30%
QRS duration (mean range, 155-209 milliseconds)NYHA 3 or 4 despite optimal pharmacotherapy.
CRT improved LVEF 3.0%;
(95% CI: 0.9%-5.1%),
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TARGET ?
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• Smalls and monocentric studies
• No randomization
• Heterogeneous populations
• No blinded study
• Similar surrogate end-points but measured with
different methods (ECHO / MRI / SPECT )
PHASE 2 TRIALS IN CELL THERAPY: LIMITS
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PHASE III CT aiming for approval of Cell Therapy
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Cell Therapy with CARDIAC stem cells
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Meta-analysis of G-CSF Trials in AMI Pts
Effect on EF at 6m of follow-up
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Hill J et al., Circulation, 2006Hill J et al., Circulation, 2006Abdel-Latif A, Am Heart J 2008 Abdel-Latif A, Am Heart J 2008
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Achilli F. et Al. Heart 2013 (submitted)
STEM-AMI Trial 3 YEARS FOLLOW-UP
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STEM-AMI Trial: 3 YEARS FOLLOW-UP
European Heart Journal (2012) Zimmet et Al.
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Time has come for hard clinical endpoints:
GISSI Outliers STEM-AMI OUTCOME TRIAL
Large Phase III, open, randomized, multicenter nationwide Trial.
1502 patients; 65 centres involved.
Anterior STEMI with low ejection fraction post PCI (<45%).
Symptoms-to-baloon time >3 h and <24 h
G-CSF (n=751) vs. saline (n=751) within 12 h from reperfusion.
Primary endpoint: Death, Recurrence of MI, Rehospitalisation for heart failure
(accrural=2y; follow-up=3 y).
E.C. APPROVAL
MAY,8, 2013!
FIRST PATIENT NOV,8,2013
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SWISS-AMI Trial
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TIME Trial
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EPO & G-CSF: dual protective mechanism after AMI
ADAPTED FROM: NAGAI T, AM J PHYSIOL HEART CIRC PHYSIOL 2012
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Which growth factor for AMI?
Growth Factor Safety in humans
Preclinical studies(large animal models)
Preliminary data in patients
Dual mode of action
G-CSF (swine,
primates)
EPO (1 study on
swine)
GM-CSF (concerns
after MI: worsens outcome?)
- (chronic HF)
-
FLT-3 - - - (combined with G-CSF)
SDF - - - (combined with G-CSF)
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Large EPO clinical trials on STEMI TRIAL POPULATION DESIGN ENDPOINTS
Voors et al.Eur Heart J, 2010
HEBE IIII
STEMI after successfull PCIN=529 (1:1)
- Phase II, prospective, randomized, open-label. placebo-controlled.
- Single bolus EPO
- powered to detect differences in EF
Infarct size/EF = negative (MR)
Event-free survival = positive (at 6 weeks)
Najjar SS et al.JAMA, 2011
REVEAL
STEMI after successfull PCIN=222 (1:1)
Phase II prospective, randomized, placebo-controlled.
- Single bolus EPO (i.v.)
- powered to detect differences in infarct size
Infarct size = negative (MR)
Event-free survival = higher rates of CV events in EPO group(at 12 weeks)
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Which determinants of success after AMI for the “dream growth factor”?
Extent of BMCs mobilization and homing
Characteristics of mobilized cells
Timing of therapy
Mobilization-independent effects
Patients characteristics
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Timing?
Martin_Rendon E et al., Eur Heart J 2008Bartunek J et al. Nat Clin Pract Cardiovasc Med 2006
Exp
ressio
n (
fold
in
cre
ase
esti
mate
) Adhesion
Migration
ROS
Inflammatory cytokines
Matrix SupportCollagen
Mobilization
0
1
2
3
4
5
6
BL
Day 3
Day 7
Day 14
Day 21-28
Optimal timingOptimal timingOptimal timingOptimal timing
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Timing?
Kuhlmann MT, et al. JEM 2006.