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Stem cell therapy for myocardial repair
Birgit Assmus
The heart is regenerating !
Undisputable Evidence from DNA Integration of C-14– generated during nuclear bomb testing during cold war -
Bergmann O et al., Science 2009; 324:98-102
expected
observed
The heart muscle is younger than the body!
Cells for functional cardiac repairCells for functional cardiac repair
Embyronic-likestem cells
(iPS)
somatic cells(skin fibroblasts)
4 genes:Oct4, Klf4, Sox2, myc
Cardiacstem cells
Modified from Dimmeler et al, JCI 2005
Phase I/II clinical trials
2001/2002
2008
Adipose tissue-derived
cells
Cardiac stem cells
c-kit+ cellsCardiospheres
Bone marrow-derived cells
2006 2009
CD34+CXCR4+Bone marrow mononuclear cells (BMC)
CD34+
CD133+
Cell enhancement,target region preconditioning
Mesenchymal Stromal Cells
2013
Phase III trials
Clinical evolution of BMC therapy for cardiovascular diseases
- Factors to enhance cardiac
differentiation
- Repeated administration
- Shock waves for enhancing cell engraftment
stopped end 2013
Cell therapy in cardiovascular diseases
Acute Myocardial InfarctionAcute Myocardial Infarction
Refractory AnginaRefractory Angina
Peripheral arterial occlusive diseasePeripheral arterial occlusive disease
Chronic postChronic post--infarction heart failureinfarction heart failure
Vascularization
Apoptosis
AcuteMyocardialInfarction
AcuteAcuteMyocardialMyocardialInfarctionInfarction
ChronicHeart Failure
ChronicChronicHeart Heart FailureFailure
chronicchronicLVLV-- dilatationdilatation
infarctinfarctexpansionexpansion
Adverse LV RemodelingAdverse LV Remodeling
Cell Therapy in Acute Myocardial Infarction: therapeutic targets
Paracrine factors
CardiacRegeneration
BMC/CPCBMC/CPC
Cytokines, e.g.
VEGF, SDF-1
Ischemia
Cell Therapy for STEMI
The patient population at risk postThe patient population at risk post--AMIAMI
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 reperfusion determines clinical outcome in STEMI
There is no linear correlation between mortality and ejection fraction after AMI !
Enhanced contractile recovery by BMC is confined to patients with failed initial recovery
4 months data LV angiography 12 months data MRI
N Engl J Med 2006
Repair-AMI: n= 204 patients; 1:1 multicentre double-blind randomized intracoronary placebo or BMC infusion 3 -7 days after successful acute reperfusion therapy
Do beneficial effects of BMC therapy on adverse remodeling translate into clinical benefit ?
??
Therapies preventingadverse remodelling…Therapies preventingadverse remodelling…
… reduce adverse cardiovascular events… reduce adverse cardiovascular events
ACEI , ARB, ß-Blocker, Aldosteron-Ant., CRT
Jeevanantham et al, Circulation, 2012
BMC therapy post-AMI Improved clinical outcome in meta-analysis
N = 2625 patients from 50 studies
Baseline LVEF determines
5-year survival in Repair-AMI
5-year survival
Assmus et al; Eur Heart J 2014
Factors influencing function of autologous BMC
Study Number of pts.
Cells Heparin in Final Cell Product
Primary Endpoint
Effects
ASTAMI 100 i.c.; BM-MNC vs. standard therapy
5 U/ml LVEF (SPECT) (-) after 6 / 12 months
BONAMI 101 i.c.; BM-MNC vs. standard therapy
No heparin Vitality (SPECT)
(+) vitality after 3 months
(-) LVEF
FINCELL 80 i.c.; BM-MNC vs. medium
heparinized serum LVEF (QLVA, echo)
(+) LVEF after months
HEBE 200 i.c.; BM-MNC vs. peripheral MNC vs. standard therapy
20 U/ml reg. LV-function (MRI)
(-) after 4 months
Janssens-Trial 67 i.c.; BM-MNC vs. NaCl + serum
No heparin LVEF (MRI) (+) reduction infarct size
(+) regional LV function
Plewka et al 60 i.c.; BM-MNC vs. standard therapy
? LVEF (echo) (+) LVEF after 6 months
REGENT 200 i.c.; BM-MNC vs. CXCR4+ BM-MNC vs. standard therapy
No heparin LVEF (MRI) ((+)) LVEF after 6 months in cell treated groups
REPAIR-AMI 204 i.c.; BM-MNC vs. medium
No heparin LVEF (QLVA) (+) LVEF after 4 months
(+) after 12 & 24 months
Selection of clinical BMC Trials in AMIEU- Ficoll isolated BMC trials
Migratory / Invasion Capacity of BMC: Effects of Heparin
BMC/CPCBMC/CPC
Cytokines, e.g.
VEGF, SDF-1
Ischemia
24 hours
SDF-1
in-vitro migration assay
MigrationHoming of BMC inear wound model
Functional capacity of the applied BMC predicts clinical outcome at 5 years
Eur Heart J 2014
BAMI Clinical Trial Design (ESC Cell Therapy Trial Consortium)
‚The effect of intracoronary reinfusion of bone marrow-derived mononuclear cells
on all-cause mortality in STEMI‘
- 1:1 randomized, controlled, no placebo group- intracoronary BMC administration vs. standard care- approx. 3000 patients, event-driven trial design- primary endpoint: all-cause mortality- Inclusion criterion: LVEF < 45% 3-6 days after successful
reperfusion by quantitative echo core lab analysis- Aim: to reduce 2-year mortality by 25%- anticipated mortality in control group: 11.5% at 2 years- 11 participating European countries- 6 core cell processing facilities across Europe- first patient in: Q3 / 2013
Visit planPatients with acute myocardial infarction post primary PCI
Randomisation 1:1
N = 3000 eligible AMI patients 3-6 days post primary PCICentral reading of echocardiography (EF ≤ 45%)
Intracoronary infusion of BMCs 4-8 days post PCI
Day 30 ± 7 days: Site visit follow-up
Month 3: Telephone follow-up
Every 3 months: Telephone follow-up
Following observation of full no. of events:End of study visit (on site)
Group 1: Control, n= 1500No intervention
Group 2: BM-MNC, n= 1500Bone marrow aspiration
Day 30 ± 7 days: Site visit follow-up
Month 3: Telephone follow-up
Every 3 months: Telephone follow-up
Following observation of full no. of events:End of study visit (on site)
Study flowchart
Cell processing centers and patient distribution
- The Royal London Hospital,London, UK- Hospital Gregorio Maranon,Madrid, Spain- Rigshospitalet University Hospital, Copenhagen, Denmark- Universitaire Ziekenhuizen,Leuven, Belgium- BSD, Institute for Transfusion Medicine, Frankfurt, Germany
potentially eligible patients@ day 4-5 post AMI (EF≤45)
Start Sept 2013, 8 Sept 2014: n = 51 patients
Cell therapy in cardiovascular diseases
Acute Myocardial InfarctionAcute Myocardial Infarction
Refractory AnginaRefractory Angina
Peripheral arterial occlusive diseasePeripheral arterial occlusive disease
Chronic postChronic post--infarction heart failureinfarction heart failure
Acute Infarction
LV- Dilatation
ChronicHeart Failure
Challenges in Cell Therapy of Chronic Heart Failure
-- ‘‘healedhealed‘‘ infarctioninfarction-- established scarestablished scar-- lack of inflammationlack of inflammation-- remodeled LVremodeled LV-- chronically ill patientchronically ill patient
Reverse LV RemodelingReverse LV Remodeling
?
Impaired homing of progenitor cells in chronic heart failure
Effects of i.c. administration of progenitor cells in CHF
Acute MI MI > 1 year0
2
4
6
8
10
Mean
In
diu
m a
cti
vit
y(%
; A
UC
/tim
e)
Schächinger et al, Circ 2008
Assmus et al, NEJM 2006Kang et al, Circ 2006
0
1
2
3
4
5
6
7
Ab
s. d
elt
a L
VE
F(b
aselin
e –
FU
; %
)
Pooled analysis (N=70)
Need for novel cell sources or enhancement strategies for cell therapy in chronic heart failure
Bone marrow
BloodSkeletal muscle
Adipose tissue
Cardiac stem cells
genes small molecules
Pretreatment of progenitor cells
*
** *****
**
*
** **
**
*
**
**
Celltherapy
Pretreatment of the target region
Recruitmentin target tissue
Seeger et al, Nat Clin Pract Cardiovasc Med, 2007
shock wave pretreatmentshock wave pretreatmentnanofibernanofiber--based deliverybased delivery
Repetitiveapplications
Vrtovec B,…,Wu JC; Circ Res 2013
Shock Wave Application may Improve Cell Homing to Target Area
Shock WavePretreatment
1.
(Aicher et al, Circulation 2006)
Injection of cells3.
Homing 0
200
400
600
800
Untreatedlimb
500 1000 2000
6876N =
P<0.05
Nu
mb
er o
f C
ells
(% o
f co
ntr
ol)
Number of pulses
0.05 mJ/mm2
Release of chemoattractant factorsin target tissue
after 24 h
VEGF & SDF-1 (attraction & retention of BMC)
2.GAPDH
0 500 1000 2000 HLI H20
SDF-1
SDF-1 SDF-1
VEGF VEGF
Target tissue
Flat coil
Membrane
Acoustic lens
Bellow
Shockwave path
Shockwave Source
Shockwave generator
• Coil High Voltage pulse
• Membrane (Magnetic field)
• Rapid membrane movement
• Shock wave produced in water bellow
• Shockwave focused by acoustic lens
Live 2D integratedUltrasound Imaging
ECG Trigger
Patient
SW target area
Power generator with Energy level control unit and ECG synchronization
2-D-Echo-guided cardiac shockwave application
Custom build byDornier Med Tech Systems
Wessling, GermanyAssmus et al., JAMA 2013
p=0.01
0
1
2
3
4
SW & PlaceboN=33
SW & BMCN=37
- pooled groups -
Primary endpoint:absolute change in LVEF at 4 months
Assmus et al., JAMA 2013
5
4
3
2
1
0
SW & Placebo
SW & BMC
Placebo-SW & BMC
N=11 N=7 N=15
P for trend =0.01
7.5
5.0
2.5
0
-2.5
SW & Placebo
SW & BMC
Placebo-SW & BMC
N=12 N=6 N=13
P for trend =0.002
Mechanistic Insights by MRI substudy
Increased infarct wall thickening Decreased infarct size
Abs
olut
e D
elta
Wal
l Thi
cken
ing
Infa
rct (
%)
Abs
olut
e D
elta
Infa
rct S
ize
(% L
V m
ass)
Assmus et al., JAMA 2013
SW & Placebo betterSW & BMC better
Cardiac death and rehospitalisationfor heart failure
Cardiac Death
Re-MI
Rehospitalization for CHF
Ventricular Tachycardia
All-cause death
Cardiac death, rehospitalisationfor heart failure, and re-AMI
Cardiac death, rehospitalisationfor heart failure, re-AMI and VT
Hazard ratios for MACE at 3-year follow-up
0.2 10.5 2 5
Assmus et al., JAMA 2013
Conclusions
Cell therapy with autologous BMC is a realistic option in
patients with large acute myocardial infarction
EU-sponsored mortality trial
Cell therapy with autologous BMC in patients with chronic post-infarction heart
failure: application and single therapy are safe, but have minor efficacy ;
Enhancement stragies are under way
- different cell types (cardiomyocyte progenitor cells)
- pretreatment of target tissue (shockwave)
- repeated applications (Repeat trial)
Support:
DFG (SFB 834, TR-SFB23)Excellence Cluster ECCPSLOEWE Leducq Foundation: Transatlantik Network of ExcellenceEuropean Union: ERC Advanced Grant, Endostem
Institute of Cardiovascular RegenerationCentre for molecular medicine
Med. Klinik III, Kardiologie, Goethe University
Andreas Zeiher & Stefanie DimmelerFlorian Seeger, Stephan Fichtlscherer, Jörg Honold, Brigitte Luu
Cardiology Studies Coordinating Centre (CSCC): Stephanie Estel, Daniela Höhl, Carmelo Smorta, Anne Krämer, Marga Müller-Ardogan
Former contributers:Volker Schächinger, Salvatore de Rosa,David Leistner, Ulrich Fischer-RasokatRalf Lehmann
Need for novel cell sources or enhancement strategies for cell therapy in chronic heart failure
Bone marrow
BloodSkeletal muscle
Adipose tissue
Other sources
genes small molecules
Pretreatment of progenitor cells
*
** *****
**
*
** **
**
*
**
**
Celltherapy
Pretreatment of the target region
Recruitmentin target tissue
Seeger et al, Nat Clin Pract Cardiovasc Med, 2007
shock wave pretreatmentshock wave pretreatmentnanofibernanofiber--based deliverybased delivery
Repetitiveapplications
Comparison of observed and model-predicted * mortality in 297 consecutive patients treated with intracoronary BMC infusion.
Seattle Heart Failure Model (SHFM):Seattle Heart Failure Model (SHFM):
•• multivariable risk model that predicts allmultivariable risk model that predicts all--cause and causecause and cause--specific mortality in CHFspecific mortality in CHF
• age, gender, etiology of cardiomyopathy, hemodynamics, LVEF, treatment incl. devices, lab values
•• validated in 9942 patients from large validated in 9942 patients from large clinical trials: ELITE2, Valclinical trials: ELITE2, Val--HeFT, UW, HeFT, UW, RENAISSANCE, INRENAISSANCE, IN--CHF)CHF)
RE
PE
AT
BMC therapy in CHF – effects on mortality?
Small but significant effects on LV function
• initiation of an ongoing registry in 2005 • open to all patients presenting with CHF
at our centre• patients were offered repeated treatment
at 4 months at time of first treatment (not to long-distance travellers)
Only repeated intracoronary BMC treatment is associated with lower mortality than SHFM-model predicted mortality
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
ival [%
]
Single BMC administration
Repeated BMC administration
observed
Model-predicted
RE
PE
AT
Only repeated intracoronary BMC treatment is associated with lower mortality than SHFM-model predicted mortality
De Rosa, … Zeiher, Assmusunder revision
N = 297 patients; repeated treatment offered at 4 months FUSingle BMC Administration (n=186)
Repeated BMC Administration (n=111)
RE
PE
AT
Only repeated intracoronary BMC treatment is associated with lower mortality than SHFM-model predicted mortality
repeated BMC administration
single BMC administration
Es
tim
ate
d c
um
ula
tiv
e s
urv
iva
l
MortalityTotal cohort analysis Landmark analysis
P=0.02 P=0.07
Es
tim
ate
d e
ve
nt-
fre
e s
urv
iva
l
Death and rehospitalizationTotal cohort analysis Landmark analysis
repeated BMC administration
single BMC administration
P=0.02 P=0.06
Design REPEAT trial
RE
PE
AT
N = 668 patients with post-infarction heart failureOpen infarct vessel / bypass
1. intracoronary infusion of BMCN=334
1. intracoronary infusion of BMCN=334
2. intracoronary infusion of BMC4 monthsVisit
Randomisation 1:1
8 months
24 months; primary endpoint
Visit
Visit
Group 1 Group 2
60 months; end of studyVisit
Visit
Visit
Visit
Trial Flowchart
Primary endpoint: Mortality at 2 years
Secondary endpoint: Rehospitalization for CHF, cardiac death,
HTX/LVAD
Started Dec. 2013
Need for novel cell sources or enhancement strategies for cell therapy in chronic heart failure
Bone marrow
BloodSkeletal muscle
Adipose tissue
Other sources
genes small molecules
Pretreatment of progenitor cells
*
** *****
**
*
** **
**
*
**
**
Celltherapy
Pretreatment of the target region
Recruitmentin target tissue
Seeger et al, Nat Clin Pract Cardiovasc Med, 2007
- shock wave pretreatment- nanofiber-based delivery
Repetitiveapplications
Beltrami et al, Cell 114(6):763-76, 2003
•c-kit (mouse, dog, human)
•Sca-1 (mouse)Sca-1-like (dog, human)
•Cardiospheres (murine, human)
•Islet (postnatal mouse, human)
(Beltrami, Cell 2003)
(Oh et al, PNAS 2003)
(Laugwitz et al, Nature 2005)
(Messina et al, Circ Res 2004)
Cardiac stem cells: the heart´s little helperCardiac stem cells: the heart´s little helper
Cell therapy with cardiac stem cellsCell therapy with cardiac stem cells
Cardiospheres (Caduceus trial)
Ejection Fraction at 4 Months After CSCs
N=17N=17 N=8
• No difference in EF or volumes
2009 2011First patient
treatedPhase I data: presented AHA 2011
c-kit+ CSC (Scipio trial)(Makkar et al Lancet 2012)(Bolli et al Lancet 2011)
Infarct size reduction at 6 and 12 months after Cardiospheres
Cells expanded from endomyocardial biopsiesCells expanded from atrial samples obtained during CABG