Transcript TERAPIA CELLULARE CARDIACA : A CHE PUNTO SIAMO

HEARTLINE 2013
Genova 15/11/2013
Le cellule staminali ripareranno il cuore del Paziente
infartuato?
Lo studio STEMAMI OUTCOME
Dr Felice Achilli
20 years ago ….Ejection Fraction in GISSI 1
(Volpi et al, Circulation 1993)
10 years ago ….not only EF!
Cardiac Remodeling Post AMI
Characteristic
early Post MI
Normal LV Gp
(n = 31)
Remodeled Gp
(n=16)
P value
Q waves
24/31
13/16
NS
Anterior wall
11/31
14/16
.007
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
Peak CK (u/L)
ESV, end systolic volume; Ts-SD: Standard deviation of time to peak myocardial contraction
Te-SD: Standard deviation of time to peak early relaxation
Zhang Y, et al. Am Heart J 2008;156:1124-32.
Today…..
Data from BLITZ 4
Mortality rates vs "ischemic time" and AMI location
30d Mortality Rates (%)
8
7,2
6,9
7
5,7
6
5
5,1
4,4
4,2
4
3,5
2,9
3
2
Non Anterior
All
1,9
1
0
Anterio r
<3h
>3h
ALL
<3h
>3h
tot
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.
Cell Therapy of Cardiovascular Disease: start of CT
Bone Marrow
derived Cells
Dimmler S., 2012 (with permission)
CELL SOURCES TARGETED for CARDIAC REGENERATION
Evolution of the
cell types
used:
FOURTH GENERATION :
Cardiac Progenitors Cells (CPC)
MORE THAN 2000
2) Bone Marrow
PATIENTS
TREATED
Derived
Cells:
• Hematopoetic
stem cells IN 10 YEARS!
1) Myoblasts
• Mesenchymal
stem cells
• Endothelial
progenitor cells
• Side population
cells
CELL THERAPHY AND ACUTE CORONARY DISEASES
European Heart Journal (2012) Zimmet et Al.
“EXOGENOUS CELL THERAPY” FOR CARDIAC REPAIR
Acute MI
Chronic ICM
C. Direct
Endomyocardial
cell injection
J.Tongers,D.W. Losordo, U.Landmesser EHJ 2011 Review (modif)
“ENDOGENOUS CELL THERAPY” FOR CARDIAC REPAIR
VEGF family
(PIGF)
G-CSF/
GM-CSF
FGF family
Growth
EPO
SDF
Factors
FLT-3 ligand
Angiopoietin-1
HGF/IGF-1/GH
CLINICAL BENEFIT
Sanganalmat SK, et al., Basic Res Cardiol 2011
CELLS THERAPY IN AMI:
SAFETY
NO DIFFERENCE ABOUT :
IN STENT RESTENOSIS
THROMBOSIS
Re-AMI
DEATH
HOSPITALIZATION
ARRYTHMIA
SURGICAL REVASCULARIZATION
Zimmet et Al. EHJ 2012
META-ANALYSIS OF BMSC IN AMI PTS
Follow-up18m
6m
Follow-up
Zimmet et Al. EHJ 2012
Changes in LVEF
in Clinical Trial that have changed clinical practice
based on effect on clinical outcome
Postgrad Med J 2011; 87:558
CRT for Patients With LV Dysfunction: A Systematic Review
4420 Pts
Basal 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%),
Mc Alister et al JAMA 2007
TARGET ?
PHASE 2 TRIALS IN CELL THERAPY: LIMITS
• Smalls and monocentric studies
• No randomization
• Heterogeneous populations
• No blinded study
• Similar surrogate end-points but measured with
different methods (ECHO / MRI / SPECT )
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, 2006
Abdel-Latif A, Am Heart J 2008
STEM-AMI Trial 3 YEARS FOLLOW-UP
Achilli F. et Al. Heart 2013 (submitted)
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
E.C.involved.
APPROVAL
 Anterior STEMI with low ejection fraction post PCI (<45%).
MAY,8, 2013!
 Symptoms-to-baloon time >3 h and <24 h
FIRST PATIENT NOV,8,2013
 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).
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)
G-CSF

 (swine, primates) 

EPO

 (1 study on swine) 

GM-CSF

SDF
Dual mode
of action
-
 (chronic -
-
-
-

(combined
-
-
-

(combined
(concerns
after MI: worsens
outcome?)
FLT-3
Preliminary
data in
patients
HF)
with G-CSF)
with G-CSF)
Large EPO clinical trials on STEMI
TRIAL
Voors et al.
Eur Heart J, 2010
POPULATION
STEMI after
successfull PCI
N=529 (1:1)
HEBE IIII
DESIGN
- Phase II, prospective,
randomized, open-label.
placebo-controlled.
- Single bolus EPO
- powered to detect
differences in EF
Najjar SS et al.
JAMA, 2011
REVEAL
STEMI after
successfull PCI
N=222 (1:1)
Phase II prospective,
randomized, placebocontrolled.
- Single bolus EPO (i.v.)
- powered to detect
differences in infarct
size
ENDPOINTS
Infarct size/EF
= negative (MR)
Event-free
survival =
positive (at 6
weeks)
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?
Matrix Support
Collagen
Expression (fold increase estimate)
6
Optimal timing
Optimal timing
5
4
ROS
3
Inflammatory
cytokines
2
Adhesion
Mobilization
1
Migration
0
BL
Day 3
Day 7
Martin_Rendon E et al., Eur Heart J 2008
Bartunek J et al. Nat Clin Pract Cardiovasc Med 2006
Day 14
Day 21-28
Timing?
Kuhlmann MT, et al. JEM 2006.