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
20 years ago ….Ejection Fraction in GISSI 1
(Volpi et al, Circulation 1993)
10 years ago ….not only EF!
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
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…..
Tomorrow….: “Reverse Remodeling” or….
Myocardial Recovery!
“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.
Dimmler S., 2012 (with permission)
Cell Therapy of Cardiovascular Disease: start of CT
Bone Marrow derived Cells
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!
European Heart Journal (2012) Zimmet et Al.
CELL THERAPHY AND ACUTE CORONARY DISEASES
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
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
Sanganalmat SK, et al., Basic Res Cardiol 2011
CLINICAL BENEFIT
CELLS THERAPY IN AMI: SAFETY
Zimmet et Al. EHJ 2012
NO DIFFERENCE ABOUT : IN STENT RESTENOSIS
THROMBOSIS
Re-AMI
DEATH
HOSPITALIZATION
ARRYTHMIA
SURGICAL REVASCULARIZATION
META-ANALYSIS OF BMSC IN AMI PTS
Follow-up 6mFollow-up 18m
Zimmet et Al. EHJ 2012
Postgrad Med J 2011; 87:558
Changes in LVEF in Clinical Trial that have changed clinical practice
based on effect on clinical outcome
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%),
TARGET ?
• 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
PHASE III CT aiming for approval of Cell Therapy
Cell Therapy with CARDIAC stem cells
Meta-analysis of G-CSF Trials in AMI Pts
Effect on EF at 6m of follow-up
Hill J et al., Circulation, 2006Hill J et al., Circulation, 2006Abdel-Latif A, Am Heart J 2008 Abdel-Latif A, Am Heart J 2008
Achilli F. et Al. Heart 2013 (submitted)
STEM-AMI Trial 3 YEARS FOLLOW-UP
STEM-AMI Trial: 3 YEARS FOLLOW-UP
European Heart Journal (2012) Zimmet et Al.
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
SWISS-AMI Trial
TIME Trial
EPO & G-CSF: dual protective mechanism after AMI
ADAPTED FROM: NAGAI T, AM J PHYSIOL HEART CIRC PHYSIOL 2012
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)
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)
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
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
Timing?
Kuhlmann MT, et al. JEM 2006.
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