“update on stem cells in cardiovascular...
TRANSCRIPT
“Update on stem cells in
cardiovascular disease“
Andreas M. Zeiher, MDDept. of Internal Medicine IIIUniversity of FrankfurtGermany
Disclosure information: Guidant (research support)
t2cure (co-founder, advisor)
Cardiology Forum 2010, Rome, 05 / 2010
Cells for functional cardiac repair
Embyronic-like
stem cells
(iPS)
somatic cells
(skin fibroblasts)
4 genes:Oct4, Klf4,
Sox2, myc
Cardiac
stem cells
Modified from Dimmeler et al, JCI 2005
Cell therapy in cardiovascular diseases
Acute Myocardial Infarction
Refractory Angina
Peripheral arterial occlussive disease
Chronic post-infarction heart failure
Metaanalysis of randomized and
cohort studies of progenitor cell
therapy in ischemic heart disease
N = 976; overall treatment effect
+ 3.7 percentage points increase
in LV-EF ( p < 0.001 )
Abdel-Latif, Arch Intern Med 2007; 167:989
Vascularization
Apoptosis
Paracrine
factors
Cardiac
Regeneration
Acute
Myocardial
Infarction
Chronic
Heart
Failure
chronic
LV- dilatation
infarct
expansion
Adverse LV
Remodeling
Cell Therapy in Acute Myocardial Infarction:
therapeutic targets
0
2
4
6
8
10
EF below median
( 48.9 %)
Baseline LVEF
by QLVA
EF above median
(> 48.9 %)
Ab
so
lute
ch
an
ge i
n g
lob
al
LV
EF
(
%)
Enhanced contractile recovery by BMC is confined to patients with failed initial recovery
2.5 1.1 7.5 1.1 3.7 0.7
p = 0.002 p = 0.81
4.0 0.6
Placebo BMC Placebo BMC
n = 52 41 40 54
p for interaction = 0.020
Schächinger et al.,N Engl J Med 2006
REGENT
Courtesy of M Tendera,
European Heart Journal, 2009
39 39 37 40
Controls
N=20
10
20
30
40
50
60
70
80
BMC
N=46
10
20
30
40
50
60
70
80
p=0.73 p=0.01
0 6 months 0 6 months
REGENT trial
36
31
0 6 months10
20
30
40
50
60
p=0.007
< median
-5
0
5
10
15
20
25
30
FINNCELL trial
< median > median
Ch
an
ge 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 trials
En
dsysto
lic v
olu
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
initial 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
Do beneficial effects of BMC therapy on adverse remodeling translate into clinical benefit ?
?
Therapies preventing
adverse remodelling…
… reduce adverse
cardiovascular events
ACEI , ARB, ß-Blocker, Aldosteron-Ant.
BMC therapy is associated with improved clinical outcome at 2 years
days0 100 200 300 400 500 600 700
0
60
70
80
90
100
p = 0.009
(log rank)
Placebo
BMC
Eve
nt-
fre
es
urv
iva
l(%
)
(de
ath
, m
yo
ca
rdia
lin
farc
tio
n,
reh
osp
ita
lization
f. h
ea
rtfa
ilure
)
# exposed
to risk
Placebo 103 93 90 86 86
BMC 101 99 98 97 95
- Death, MI, Rehospitalization for heart failure -
CirculationHeartFail 2009
Insights into potential
mechanisms of action?
BMC Therapy in Acute Myocardial Infarction
Paracrine Effects
Vasculo-
genesis
Cardio-
myogenesis
FUNCTIONAL CARDIAC
REGENERATION
Cell homing
and tissue integration
Angiogenesis
Arteriogenesis
Scar
Remodelling
Modulation of
Inflammation
Cardiomyocyte
Apoptosis
Cardiomyocyte
Proliferation
Attraction/
Activation
of CSC
EC Differentiation
SMC Differentiation
Cardiac Differentiation
Fusion
Putative mechanisms for cardiac regeneration
Doppler
wireNTG
(epicardial
vessel dilation)
Adenosine
(140 µg/kg i.v.)
Coronary flow reserve CFR = APVadenosine / APVbasal
Infarct artery and Reference vessel
Relative flow reserve rCFR = CFRtarget vessel / CFRreference vessel
APV
Core Lab: Sandra Erbs / Rainer Hambrecht (Herzzentrum Leipzig)
(Flowire®)
3 Centers
(54 patients)
Herzzentrum Leipzig (32),
J. W. Goethe University Frankfurt (20),
Herz- u. Diabeteszentrum Bad Oeynhausen (2)
Assessment of maximum coronary vascular conductance
Mechanistic Insights from Coronary Flow Assessment
0,0
0,5
1,0
1,5
2,0
ab
s.
infa
rct
vessel
CF
R
n = 26 n = 28
Placebo BMC
p = 0.005
Infarct vessel CFR
0.88
0.18
1.8
0.25
0.11
0.060,0
0,2
0,4
0,6
0,8
Placebo BMC
0.49
0.11
n = 26 n = 27
p = 0.021
Relative CFR
(infarct vessel normalized to
reference vessel)
ab
s.
Rela
tive
CF
R
Erbs et al., Circulation 2007
Intracoronary BMC Administration
Normalizes Coronary Flow Reserve
Cell therapy in cardiovascular diseases
Acute Myocardial Infarction
Refractory Angina
Peripheral arterial occlussive disease
Chronic post-infarction heart failure
Cell Therapy for Refractory Angina
JAMA, May 2009
Cell Therapy for Refractory Angina
JAMA, May 2009
1 x 10^5 CD34+ cells/kg
(n = 55)
5 x 10^5 CD34+ cells/kg
(n = 56)
Endomyocardial Mapping and Injection with NOGA
Isolex selected CD34+ cells / Placebo Rx
Cell Mobilization (GCSF 5mcg/kg/d x 5d)
Apheresis on Day 5
Follow-up Safety and Efficacy Assessments:
1 - 7 days, and 1, 3, 6, and 12 months; ETT at 3, 6, 12 months
MRI at 6 months, SPECT at 6 & 12 months
Screening and Baseline Visits
Placebo
(n = 56)
Randomization
Phase II ACT34–CMI Study Design
Subject population
(n=167)
• 21-80 yrs
• CCS class III or IV Angina
• Attempted “best” medical
therapy
• Non-candidate for
Surgical/Perc. revasc.
• Ischemia on SPECT
• 3-10 min. mod. Bruce
protocol with angina or
anginal equivalent at baseline
Courtesy of Doug Losordo
Total ETT Time
Change from baseline at 6 months
0
20
40
60
80
100
120
140
160
Series1 69 138 108
Placebo Low High
Secon
ds
p=0.013
ACT-34 CMI: Increase in Exercise Time
Courtesy of Doug Losordo
-200
-150
-100
-50
0
50
Series1 8.5 -113.2 11.6
Placebo Low High
Total Severity Score - Stress
Change from baseline at 6 months
p=0.002
ACT-34 CMI: SPECT
Courtesy of Doug Losordo
Cell therapy in cardiovascular diseases
Acute Myocardial Infarction
Refractory Angina
Peripheral arterial occlussive disease
Chronic post-infarction heart failure
PROVASA-Study
Vorarbeiten zur TAO-StudieIntraarterial BMC therapy for PAOD:
a randomized-start, placebo-controlled trial
Cell therapy in cardiovascular diseases
Acute Myocardial Infarction
Refractory Angina
Peripheral arterial occlussive disease
Chronic post-infarction heart failure
Vascularization
Apoptosis
Paracrine
factors
Cardiac
Regeneration
Acute Infarction
LV- Dilatation
Chronic Heart Failure
Aims of cell therapy
1. Prevent
post-infarction
heart failure2. Reverse
established
heart failure
?Adverse LV
Remodeling
Reverse LV
Remodeling
Acute Infarction
LV- Dilatation
Chronic Heart Failure
Aims of cell therapy
?Adverse LV
Remodeling
Reverse LV
Remodeling
Vascularization
Apoptosis
Paracrine
factors
Cardiac
Regeneration
1. Prevent
post-infarction
heart failure2. Reverse
established
heart failure
Chronic Post-Infarction Heart Failure- Very modest effects on improvement of LV function- Lack of larger randomized controlled trials- Lack of data on clinical outcome with hard endpoints
Ch
an
ge in
LV
eje
cti
on
fra
cti
on
ab
so
lute
(m
ea
n ±
SE
M,
%)
p = 0.03
p = 0.001
p = 0.38
-2
-1
0
1
2
3
CPC
N=26
Control
N=18
BMC
N=28
Assmus et al., N Engl J Med 2006
Moderate improvement in EF is associated with decreased
NT-proBNP serum levels after BMC therapy in patients with
chronic post-infarction heart failure
Follow-up
(3 months)
Baseline
2.500
2.250
2.000
1.750
1.500
0
NT-p
roB
NP
se
rum
le
ve
ls
Mea
n ±
SE
M [
pg
/ml]
p = 0.033
NT-proBNPLV-EF
Assmus et al., Circ Res 2007
BMC therapy; N=61
Limited data on efficacy is available that suggest
rather small beneficial effects on cardiac function,
but there exists no data on mortality.
Comparison of observed and model-predicted *
mortality in 297 consecutive patients treated with
intracoronary BMC infusion.
Seattle Heart Failure Model (SHFM): multivariable risk model that predicts
all-cause and cause-specific mortality in patients with chronic heart failure,
including contemporary pharmacological and device therapies: (validated in
9942 patients from large clinical trials: ELITE2, Val-HeFT, UW,
RENAISSANCE, IN-CHF)
BMC therapy in CHF –
effects on mortality?
Predicting Prognosis in Chronic Heart Failure
observed
Years of Follow Up
295 202n =
1 2 3
Mo
rtality
(%
)
244
0
5
10
15
20
25
Val-HeFT
model-predicted
Consistently lower observed mortality than
model-predicted mortality throughout 3 years Fup
0.85
0.90
0.95
1.00
0
0 1 2 3
P=0.048
Years of Follow Up
Esti
mate
d c
um
ula
tive s
urv
iva
l [%
]
Single BMC administration
Repeated BMC administration
observed
Model-predicted
Single BMC Administration
Years of Follow Up
Mo
rtality
(%
)
189 132n = 158
1 2 30
5
10
15
20
25
Years of Follow Up
Repeated BMC Administration
1 2 30
10
20
30
106 7086n =
Mo
rtality
(%
)Only repeated intracoronary BMC treatment is associated
with lower mortality than SHFM-model predicted mortality
mean SHFM Score
0.48 ± 0.9
mean SHFM Score
0.45 ± 0.9
Years of Follow Up
05
1015202530
1 2 3
Mo
rtality
(%
)Tertile I (CFU ≤ 17.5)
(n=95)
0
5
10
15
20
25
1 2 3
Mo
rtality
(%
)
Tertile II (17.5 ≤ CFU ≤ 29.5)
(n=96)
0
4
8
12
16
20
1 2 3
Mo
rtality
(%
)
Tertile III (CFU > 29.5)
(n=94)
0 1 2 4
0
0.80
0.90
1.00
0.70
3
P (log rank)=0.02
Years follow-up
Cu
mu
lati
ve s
urv
ival
[%]
I Tertile
II Tertile
III Tertile
Application of functionally competent
BMCs is essential for lower mortality
than predicted
Enhancement strategies for cell therapy
in chronic heart failure
*
** *****
**
*
** **
**
*
**
**
Bone
marrowBlood
Skeletal
muscle
Adipose
tissue
Other
sources
Cell
therapy
genes small
molecules Pretreatment of the
target region
Pretreatment
of progenitor cells
Recruitment
in target tissue
Seeger et al, Nat Clin Pract Cardiovasc Med, 2007
eNOS enhancer
p38 inhibitors
PPARg agonistshock wave pretreatment
nanofiber-based delivery
Stefanie Dimmeler
Birgit Assmus
Volker Schächinger
www.REPAIR-AMI.org
Klinikum der
Johann Wolfgang Goethe Universität
Frankfurt am Main
Dept. of Hematology
H. Martin / W. Hofmann
D. Hoelzer
Dept. of Radiology
N. Abolmaali / J. Schmitt
T. Vogl
Experimental Studies
C. Urbich,
A. Kühbacher
M. Potente
A. Aicher
E. Chavakis, G. Carmona
L. Rössig, D. Scharner
M. Koyanagi, M. Iwasaki
Th. Ziebart, C. Yoon
& technical help (Andrea, Nicole,
Ariane, Marion, Tino)
Red Cross Frankfurt
T. Tonn / Seifried
T. Brühl, M. Vasa,
K. Sasaki, C. Badorff, C. Heeschen
Clinician Scientists:
J. Honold, R. Lehmann
U. Fischer-Rasokat
S. Fichtlscherer
F. Seeger, C.Kissel
S. DeRosa
N. Bellera Gotarda
Kerckhoff Clinic
C. Hamm / T. Dill