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Stem Cell Therapy inAcute Myocardial Infarction:
hype or reality?Stefan Janssens, MD, PhDDepartment of Cardiology
Gasthuisberg University HospitalLeuven, Belgium
Brussels, 08-12-2007No disclosures
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30 years later: VALIANT study(14,703 post-MI pts EF<35%, clin CHF)
1 ymortality
1 y death, re-MI, CHF rehospPfeffer et al . NEJM 2003
Cardiac Regeneration in 2007: the stem cell approach
Premise: myocyte deficit contributes to dysfunctional phenotype?
Caulfield et al . Circ 1976
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Infarct size(% LV mass)
Shock, Death CHF
48% 28%
13%
26%
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Full Regeneration ofMyocardium in Zebrafish
Poss et al., Science 2002;298; 2188Poss et al., Science 2002;298; 2188
Cardiac Regeneration: how it all started in 2001
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Cytokine/Growth Factor Response and BMC Mobilization after Myocardial Infarction
Mobilization: • CD34+/CxCR4+/CD117+, c-met+
(Wojakowski, Circ 2004)• CD133+ (Ott, EHJ 2006)• CD34+ (Crea, EHJ 2005)• Mes SC (Kastrup, EHJ 2006)• EPC (Shintani, Circ 2001, George EHJ 2004,
Massa, Blood 2005, Penn, Circ Res 2007,….)
Early peak post-AMI
Systemic:- EPO- CRP, IL-6, IL-8, - FGF2, - VEGF, SCF- ….
- HIF1-a- VEGF- SDF-1
Local:
?
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(Engelmann et al. J Am Coll Cardiol 2006; 48: 1712)
Stem Cell Mobilisation by G-CSF after Subacute STEMI(44 Pts > 6 h and < 7 d after Primary PCI)
1. Kuethe et al. (Am Heart J 2005;150:115)2. Ince et al. (FIRSTLINE-AMI, Circ 2005;112: 3097)3. Valgimigli et al. (Eur Heart J 2005;26:1838)4. Ripa et al. (STEMMI, Circ 2006;113:1983)5. Zohlnhofer et al. (Revival 2, JAMA 2006;295:1003)
----> reassuring safety profile-----> not superior to placebo for LV function recovery-----> timing, dose, direct cellular effects?
G-CSF RCT Trials in Acute Myocardial Infarction
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BOOST: LV-Ejection Fraction after 6 and 18 Months
(Circulation 2006;113:1287-94)
BMC-TransferControls
LVEF
[%]
0.7% 6.7%2.4% -0.8%
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AMI: ST-↑ 6 mm, t >2h+ LV dysfunction post PCI
BMSC or placebo transfer in open IRA
• Informed consent• TTE & PET• Bone marrow aspiration
+ randomization
24 hours
Admission (4 d)
- cine MRI - LE- TTE
Follow-up (4 mo)
- cine MRI – LE- TTE & PET
Follow-up (1 y)
- cine MRI – LE- TTE
LEUVEN STEM CELL TRIAL DESIGN
1 week 4 months
LAD occlusionCx occlusion
Myocardial Infarction Imaging
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EDV EF Mass WTh WM Area at MPI CE-IR-MRI Risk IS IT MVO Hem BOOST Y Y Y - Y - - Y - - - Repair-AMI Y Y Y Y Y - - Y - - - Janssens Y Y Y Y Y Y (Y) Y Y Y (Y) ASTAMI Y Y (Y) - - - - (SPECT) - - - STEMMI Y Y Y Y - - - Y - - - MAGIC-3 Y Y (Y) - - - - Y - - - REVIVAL-2 Y Y - - - - - (SPECT) - - G-CSF-STEMI Y Y Y Y - - Y Y - Y -
CMR in Stem Cell Therapy (RCTs)
Leuven-AMI
Y
Bone Marrow Cell Transfer Post-AMI(randomized controlled trials 2006)
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LVEF - MRI (%)
BMSCCON
Leuven AMI (n=67)
+ 2.2% + 3.4%
Δ = +1.2% (P=NS)
4-mo4-mo
(Lancet 2006; 367:113-121)
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LVEF - MRI (%)
REPAIR-AMI (n=187) ASTAMI (n=87)
+ 3.0% + 5.5%
Δ = +2.5% (P<0.05)
+ 4.2% + 1.2%
Δ = -3% (P=NS)
CON CON BMSCBMSC
4-mo 4-mo 6-mo 6-mo
LVEF - angio (%)
(NEJM 2006; 355:1199-1221)
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Mixed Results of Early RCT using BMC to be Expected in Absence of Gold Standard
BMC effect varies with timing, infarct severity, and cell preparation.
1. Boost Gelatine-polysucc 4.8 6 mo - MRI =(n=60) 24.6x108 (9.5 CD34+) +6%→ +2.8%
2. Leuven-AMI Ficoll 1 4 mo - MRI =(n=67) 304x106 (2.8 CD34+) +1.2%
3. Repair-AMI Ficoll 3-7 4 mo - angio = (n=187) 280x106 (2.5 CD34+) +2.5%
4. AST-AMI Lymphoprep 5 6 mo - MRI = (n=87) 68x106 (0.7 CD34+) -3%
Cell preparation LVEF(prim EP)
Timing(days)
LVEDV
Bone Marrow Cell Transfer Post-AMIInfarct size and Timing of Cell Transfer
BMCPlac
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<48.9% >48.9%
P=0.002
P=0.81
(52) (41) (40) (54)
Time after PCI (days)
(Schachinger et al., NEJM 2006; 355:1210-21)
Baseline EF (%)
Multi-center (n=18)
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MVO impairs LV Functional Recovery
• Early: present in 64% pts– Vol: 7.5 g / transmurality 51% / MVO-infarct ratio: 36%
20 min3 min 20 min
Acute phase FU (4 months)
Bogaert et al. Eur J Rad 2007
47 (9)
4 mo
46 (8)
LV-EF (%)
P=NS
3-4 dLV-EDV
(mL)
P=0.014162 (33) 175 (43)
3-4 d 4 mo
How to Optimize Stem Cell Transfer? Homing and Engraftment
Hofmann, Circ 2005
IC injection18F-FDG labeled BMSC:1.3 - 2.6% homing infarct region
IV injection18F-FDG labeled BMSC:background
IC injection 18F-FDG labeled CD34+SC:14 - 39% activity
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BMSC (n=17)
CON (n=19)
MVO
Global LV Function Recovery in AMI Patientswith and without Microvascular Obstruction
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1 week 4 months
P = 0.63
P = 0.60
LV-EF (%)
BMSC (n=11)
CON (n=9)
No MVOP = 0.05
P = 0.36
+3.5%
+5.5%
Global versus Regional LV Function Analysis for Risk Stratification after AMI
Predictors of mortality(forward Cox PHA)
HR P
Age (per 10y) 1.65 <.0001
Kilip Class 1.44 <.0001(per 1 increase)
WMSI 1.15 <.0001(per 0.2 increase)
(Moller et al. Am Heart J 2006;151:419-25)
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Powerful Technology to Detect Biological Signals:MRI and TDI Analysis
Infarct Transmurality & Segmental Contraction
Coronary occlusion
20 min 60 min 3h >6h
LV
apexapexmidmidbasebase
Time (ms)
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-10
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0 200 400 600 800 1000
Strain Septum 4 months (%)
-30
AVCAVCAVOAVO
-20
-10
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200 400 600 800
-30
AVCAVCAVOAVOBaseline Strain Septum (%)
Improved contraction (%)
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CONTROL BMC
(29 of 53)
(33 of 63)
(14 of 32)
(25 of 83)
(6 of 13)
(9 of 18)
(9 of 25)
(10 of 87)
Improved Regional Contraction in Dysfunctional Segments indicates BMC Functional Repair
Lancet 2006; 367:113-121
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0Baseline 5 d 2 mo 4 mo 1 yr
(n=232)Infarcted segments
*** ***
ES Strain(%)
BMSC
Control
0-25
%26
-50%
51-7
5%76
-100
%
0-25
%26
-50%
51-7
5%76
-100
%
P<0.05 for interaction
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BMSC Treatment Effect* on Infarct Size
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CONTROL BMSC
BASELINE4 Months
Infarct size (g) P=0.036
* Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI.
28% treatment effect*
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**
Lancet 2006; 367:113-121
BMSC Treatment Effect* on Infarct Size
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CONTROL BMSC
BASELINE4 Months1 Year
Infarct size (g) P=0.036
* Expressed as ratio’s of adjusted squares means (ANCOVA) with 95% CI.
28% treatment effect*
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23%
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Copyright restrictions may apply. Abdel-Latif, A. et al. Arch Intern Med 2007;167:989-997.
Meta-Analysis: LV Ejection Fraction (n=499 BMC, n=477 Controls)
Pooled difference3.66%
95% CI [1.93% to 5.40%]P<0.001
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Clinical Trials of Bone Marrow Cell Therapywhere are we?
• Growing consensus that improvement in cardiac function is largely independent of cardiac muscle regeneration.
• The mixed results in the 4 RCTs of BMC transfer post MI, should not defer from cell transfer studies.
- need for preclinical parallel mechanistic studies- focus on informative clinical trials
Limitations of Bone Marrow Cell-mediated Repair after Myocardial Infarction
In situ:- no cardiac differentiation- impaired microcirculation (NO low) and angiogenesis- death of cardiac progenitor cells- cellular senescence (oxidative damage, telomere shortening,..
Systemic:- insufficient number and function of progenitor cells- defective homing
Enhancement strategies for BMChoming and survival?
Cardiac protection vs regeneration
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Stem Cells: from Bench to BedsideCell Enhancement Strategies
Priming ofProgenitor cells
• statins• p38 inhibitors• PPARγ• eNOS enhancers• Integrin activators• Cardiac specification….
(gene transduction)
• Mechanical activation• Cytokines / Growth
factors:– IGF-1, HGF, SDF-1, PDGF,….
• NO
Priming ofTarget Tissue
Impaired EPC phenotype & non-responders ~ CV Risk factors~ post MI cell modification
Hostile target milieu ~ oxidant stress~ microvascular obstruction~ transmigration - residency
90 min balloonocclusion Cx
EPC/MSC/Plac IC Transfer
Lenti-GFP MSC(n=11)
Placebo (n=10)
HemodynamicsTTE
Trop, CK-MB
HemodynamicsTTE - MRI
Trop, CK-MB
T=0 T=1w
T=7wEuthanasia
HemodynamicsTTE MRI
Trop, CK-MBHistology
Labeled EPC(n=10)
Comparison of Different Progenitor Cell Populations in the Infarcted Porcine Heart
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Progenitor Cell-type Specific Biological Effects in Infarcted Porcine Heart
MRI: 15 min after iv Gd-PTPA
MSCCon EPCSham
LVEF (%)
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+5.2% +6.4% +3.0%
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30Δ LV-EDV (%)
Con EPC MSC**
TTC: 6w after Cell Transfer
Conclusions
• IC transfer of autologous BMSCs is safe and does not cause delayed major adverse clinical events.
• In early reperfused MI with moderate reduction in global LV function, BMSC transfer has variable effects on global function recovery, but significantly improves recovery of regional function.
• The challenge for future BMSC studies is to investigate whether observed paracrine effects translate in clinical benefit in AMI patients with greater baseline impairment in systolic function .
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• Large, multicenter, clinical outcome study in large AMI (?)- Centralized hematology core - SOPs cell preparation - Q-control, financial support,….
Future Directions:Optimizing Stem Cell Transfer?
• Focused clinical studies and parallel preclinical studies- Boost 2 (dose comparison)- NL interuniversity study - Poland (cell comparison)- Leuven/Frankfurt/Rome/Madrid/London: FP7- Leuven homing studies & differentiation studies (SCIL)
Stem Cell Therapy: Fountain of Eternal Youth?
Lucas Cranach (oil on canvas 1546)