“ “ Progenitor Cell Therapy in AMI Progenitor Cell Therapy in AMI After Meta-Analyses Results ? Pro“ After Meta-Analyses Results ? Pro“ Andreas M. Zeiher, MD Dept. of Internal Medicine III University of Frankfurt Germany Disclosure information: Guidant (research support) t2cure (co-founder, advisor)
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““Progenitor Cell Therapy in AMIProgenitor Cell Therapy in AMIAfter Meta-Analyses Results ? Pro“After Meta-Analyses Results ? Pro“
““Progenitor Cell Therapy in AMIProgenitor Cell Therapy in AMIAfter Meta-Analyses Results ? Pro“After Meta-Analyses Results ? Pro“
Andreas M. Zeiher, MDDept. of Internal Medicine IIIUniversity of FrankfurtGermany
Andreas M. Zeiher, MDDept. of Internal Medicine IIIUniversity of FrankfurtGermany
Cell Therapy in Ischemic Heart Failure: Cell Therapy in Ischemic Heart Failure: therapeutic targetstherapeutic targets
Cell Therapy in Ischemic Heart Failure: Cell Therapy in Ischemic Heart Failure: therapeutic targetstherapeutic targets
Cell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart Failure
The patient population at risk post-AMIThe patient population at risk post-AMI
Effects of cell therapy in patients at riskEffects of cell therapy in patients at risk
Derivation of the clinical benefitDerivation of the clinical benefit
Volpi et al., Circulation 1993; 88: 416-429
LV contractile recovery within 1 week after successful LV contractile recovery within 1 week after successful reperfusion determines clinical outcome in STEMIreperfusion determines clinical outcome in STEMIThere is no linear correlation between mortality and ejection fraction after AMI !
p for interaction = p for interaction = 0.0200.020p for interaction = p for interaction = 0.0200.020
Schächinger et al., N Engl J Med 2006
REGENTREGENT
Courtesy of M Tendera, ESC Congress Munich, 9/2008
39 39 37 40
Controls N=20
10
20
30
40
50
60
70
80
BMCN=46
10
20
30
40
50
60
70
80
p=0.73 p=0.01
0 6 months 0 6 months
REGENT trialREGENT trial
36
31
0 6 months10
20
30
40
50
60
p=0.007
< median
-5
0
5
10
15
20
25
30
FINNCELL trialFINNCELL trial
< median > median
Ch
ang
e in
EF
(%
)
BMC
Placebo
Courtesy of H. Huikuri, European Heart Journal, 2008
p = 0.04
Enhanced contractile recovery by BMC in patients with failed initial recovery – results of recent controlled trialsEnhanced contractile recovery by BMC in patients with failed initial recovery – results of recent controlled trials
En
dsy
sto
lic
volu
me
(ml)
EF < median
Baseline 4 months 12 months
EF > median
BMC
Placebo
Baseline EF: 39 + 1.9 % Baseline EF: 56 + 2.3 %
Adverse remodeling is confined to patients with failed Adverse remodeling is confined to patients with failed initial recovery of EF and abrogated by BMC therapyinitial recovery of EF and abrogated by BMC therapy
Dill et al., AHJ 2009
Change of endsystolic volumes over time (MRI)
0
20
40
60
80
100
120
140
Baseline 4 months 12 months
p = 0.7
p = 0.06
p = 0.01
p = 0.9 p = 0.7 p = 0.5
Change in endsystolic volume (ml)Change in endsystolic volume (ml)
- Death, MI, Rehospitalization for heart failure -- Death, MI, Rehospitalization for heart failure -
Do potential effects persist ?Do potential effects persist ?
Cell Therapy for Ischemic Heart FailureCell Therapy for Ischemic Heart Failure
Sustained benefit after 2 years – MRI subgroup analysis -
P = 0.98 #
0
70
90
110
130
150
170
190
Abs
olu
te e
nddi
asto
lic v
olum
e[m
l]; (
mea
n ±
SE
M)
P = 0.049 *
0
2
4
6
8
10
12
14
16
Re
lati
ve
in
farc
t s
ize
[%
]; (
me
an
± S
EM
)
0
10
20
30
40
50P = 0.009
Wa
ll t
hic
ke
nin
g o
f in
farc
ted
se
gm
en
ts [
%];
(m
ea
n ±
SE
M)
Placebo
BMC
P = 0.16 #
0
60
70
80
90
100
110
Abs
olu
te e
ndsy
stol
ic v
olu
me
[ml];
(m
ean
± S
EM
)
P = 0.009 #
0
35
40
45
50
55
Ab
so
lute
LV
eje
cti
on
fra
cti
on
[%
]; (
me
an
± S
EM
)
N = 58 patients; ANCOVA model# adjusted for baseline value (LVA)* Adjusted for baseline value (MRI)
LVEF EDV ESV
Infarct Size Infarct Wall ThickeningA.Rolf, Bad Nauheim
90
80
70
60
50
40
30
Baseline 4 months 1 year
MR
I L
VE
F (
%)
2 years
p < 0.001 p = 0.008 p = 0.04
5 years
p < 0.001
p = 0.03
Improvement of MRI - determined LVEF isImprovement of MRI - determined LVEF issustained 5 years after progenitor cell therapysustained 5 years after progenitor cell therapy
Mean ± SDN
46 ± 10N = 31
52 ± 11N = 30
57 ± 13N = 30
62 ± 11N = 28
59 ± 8N = 31
Persistently low NT-pro BNP serum levels at 5 years Persistently low NT-pro BNP serum levels at 5 years indicate absence of adverse LV remodelingindicate absence of adverse LV remodeling
1.000
500
0
Baseline 4 months 1 year 2 years 5 years
Mean ± SDN
917 ± 920N = 39
283 ± 283N = 34
285 ± 346N = 25
304 ± 602N = 19
213 ± 308N = 39
NT
-pro
BN
P s
eru
m l
evel
s[p
g/m
l]
p < 0.001 p = 0.20 p = 0.97
p = 0.03
p = 0.97
2.500
Bone Marrow Cell Therapy for Post-Infarction Heart Failure
Bone Marrow Cell Therapy for Post-Infarction Heart Failure
Intracoronary administration of BMC …Intracoronary administration of BMC …
abrogates adverse left ventricular remodeling abrogates adverse left ventricular remodeling in patients at risk in patients at risk - - failure of initial contractile recovery after reperfusionfailure of initial contractile recovery after reperfusion- persistently elevated NT-proBNP acutely- persistently elevated NT-proBNP acutely
abrogates adverse left ventricular remodeling abrogates adverse left ventricular remodeling in patients at risk in patients at risk - - failure of initial contractile recovery after reperfusionfailure of initial contractile recovery after reperfusion- persistently elevated NT-proBNP acutely- persistently elevated NT-proBNP acutely
is associated with enhanced LV contractile is associated with enhanced LV contractile recovery and improved coronary flow reserverecovery and improved coronary flow reserveis associated with enhanced LV contractile is associated with enhanced LV contractile recovery and improved coronary flow reserverecovery and improved coronary flow reserve
is associated with improved clinical is associated with improved clinical outcome at 2 yearsoutcome at 2 yearsis associated with improved clinical is associated with improved clinical outcome at 2 yearsoutcome at 2 years
demonstrates a cell bioactivity - contractile demonstrates a cell bioactivity - contractile recovery response relationship recovery response relationship demonstrates a cell bioactivity - contractile demonstrates a cell bioactivity - contractile recovery response relationship recovery response relationship
prevents adverse remodelling over 5 yearsprevents adverse remodelling over 5 yearsprevents adverse remodelling over 5 yearsprevents adverse remodelling over 5 years
ConclusionConclusion
In patients with acute post-infarction heart failure In patients with acute post-infarction heart failure despite successful reperfusion therapydespite successful reperfusion therapy
a large-scale clinical endpoint trial is a large-scale clinical endpoint trial is warranted to document the effects on warranted to document the effects on mortality and morbiditymortality and morbidity
a large-scale clinical endpoint trial is a large-scale clinical endpoint trial is warranted to document the effects on warranted to document the effects on mortality and morbiditymortality and morbidity
Study Centers and Core FacilitiesStudy Centers and Core Facilities
S. Erbs / R. HambrechtS. Erbs / R. Hambrecht
V. Schächinger /V. Schächinger /B. Assmus / S. DimmelerB. Assmus / S. Dimmeler
A. M. Zeiher (PI)A. M. Zeiher (PI)
A. Elsässer / M. Stanisch /A. Elsässer / M. Stanisch /T. Dill / Ch. HammT. Dill / Ch. Hamm
W. HaberboschW. Haberbosch
H. Hölschermann /H. Hölschermann /H. TillmannsH. Tillmanns
J. Yu / B. LauerJ. Yu / B. Lauer
R. Corti / T. LüscherR. Corti / T. Lüscher
D. Mathey / T. TüblerD. Mathey / T. Tübler
T. Süselbeck / M. Brückmann /T. Süselbeck / M. Brückmann /K. HaaseK. Haase
G. Nickenig / N. Werner /G. Nickenig / N. Werner /M. BöhmM. Böhm
J. HaaseJ. Haase
C. Hansen / J. NeuznerC. Hansen / J. Neuzner
A. Germing / A. MüggeA. Germing / A. Mügge
B. Mark / J. SengesB. Mark / J. Senges
C. Hoffmann / M. Farr /C. Hoffmann / M. Farr /D. HorstkotteD. Horstkotte
A. Cuneo / U. TebbeA. Cuneo / U. Tebbe
S. Genth-Zotz /S. Genth-Zotz /T. MünzelT. Münzel
BochumBochum
Cell Processing CenterCell Processing Center
T. Tonn / N. Krzossok/T. Tonn / N. Krzossok/E. SeifriedE. Seifried
Safety CommitteeSafety CommitteeT. Bonzel / W. KasperT. Bonzel / W. Kasper
Coordinating CenterCoordinating Center
H. BraunH. Braun
MRI Core LabMRI Core Lab
Doppler Core LabDoppler Core Lab
Echo Core LabEcho Core Lab
Angio Core LabAngio Core Lab
www.REPAIR-AMI.orgwww.REPAIR-AMI.org400 km400 km
Klinikum derKlinikum derJohann Wolfgang Goethe UniversitätJohann Wolfgang Goethe Universität
Frankfurt am MainFrankfurt am Main
Dept. of HematologyDept. of Hematology
H. Martin / W. HofmannH. Martin / W. HofmannD. HoelzerD. Hoelzer
Dept. of RadiologyDept. of Radiology
N. Abolmaali / J. SchmittN. Abolmaali / J. SchmittT. VoglT. Vogl
Experimental StudiesExperimental StudiesC. Urbich, C. Urbich, A. KühbacherA. KühbacherM. Potente M. Potente A. AicherA. Aicher E. Chavakis, G. CarmonaE. Chavakis, G. CarmonaL. Rössig, D. Scharner L. Rössig, D. Scharner M. Koyanagi, M. IwasakiM. Koyanagi, M. IwasakiTh. Ziebart, C. YoonTh. Ziebart, C. Yoon
& technical help (Andrea, Nicole,& technical help (Andrea, Nicole,Ariane, Marion, Tino)Ariane, Marion, Tino)
Red Cross FrankfurtRed Cross Frankfurt
T. Tonn / SeifriedT. Tonn / SeifriedT. Brühl, M. Vasa,T. Brühl, M. Vasa,K. Sasaki, C. Badorff, C. HeeschenK. Sasaki, C. Badorff, C. Heeschen
Clinician Scientists:Clinician Scientists:J. Honold, R. Lehmann J. Honold, R. Lehmann U. Fischer-RasokatU. Fischer-RasokatS. Fichtlscherer S. Fichtlscherer F. Seeger, C.KisselF. Seeger, C.KisselK.SpyridopoulosK.SpyridopoulosN. Bellera GotardaN. Bellera Gotarda