filippo crea institute of cardiology catholic university of the sacred heart rome , italy
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Heartline. Trial sulla terapia cellulare : end-point strumentali o clinici ?. Filippo Crea Institute of Cardiology Catholic University of the Sacred Heart Rome , Italy. Evidence that human cardiac myocites divide afte AMI in man. (Beltrami, et al NEJM 2001). VEGF. G-CSF. C-Kit. - PowerPoint PPT PresentationTRANSCRIPT
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Filippo CreaInstitute of Cardiology
Catholic University of the Sacred HeartRome, Italy
HeartlineTrial sulla terapia cellulare:
end-point strumentali o clinici?
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Evidence that human cardiac myocites divide afte AMI in man
(Beltrami, et al NEJM 2001)
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VEGF
G-CSF
C-KitMMP-9
CXCR4 CD133CD34
KDR C-Met
SDF-1
HGFSCF
CXCR4CD
34 KDR
C-Met
C-Kit
C-Kit
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CD 34+ cell mobilization in different coronary syndromes
AMI (n=54) CSA (n=26) Controls (n=43)0
10
20
30
40
p<0.001
p=0.036
p<0.001
CD
34+
cells
/ml
(Leone et al, submitted to EHJ)
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Correlation between improvementof LV function and CD 34+ cells at 1-yr FU
(Leone et al, EHJ 2005)
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Which stem cells?
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Which elivery methods?
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Which patients?•Myocardial infarction
•Heart Failure
•Refractory angina
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Back to GISSI 1
(Volpi et al, Circulation 1993)
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Effects of enalapril on long-term progression of left ventricular dysfunction in patients with heart
(SOLVD, Circulation 1992)
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Room for improvement•Cell type •Cell preparation•Myocardial homing•Administration timing•Delivery method •Patient selection
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Human cardiac stem cell
(Urbanek et al, PNAS 2006)
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Pharmacological BM-SC mobilizationDrugs Response
ACE-inhibitors ↑ EPC number
AT II antagonists ↑ EPC number
Statins ↑ EPC number
PPAR-gamma ↑ EPC number↑ EPC functional activity
Insulin ↑ EPC number↑ EPC clonogenic properties
Nitroglycerin Isosorbide-5-dinitrate
↑ EPC number↓ EPC migratory capacity
Pentaerythritol tetranitrate ↑ EPC number↑ EPC migratory capacity
IGF-1↑ EPC number↑ EPC differentiation↑ EPC migratory capacity↑ e-CFU
Growth Hormone ↑ EPC number↑ EPC proliferation↑ EPC migration
Erythropoietin ↑ EPC number↑ EPC proliferation↑ EPC adhesive properties
G-CSF ↑CD34+ cells↑ EPC number
Acute phase 5 days 4 months0
1
2
3
4
5
6
7
8Aggressive arm
Conservative arm
CD
34+/
KD
R+
EPC
s (n
/ml)
(Leone et al IJC 2008)
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Targeted Migration of Mesenchymal Stem Cells Modified With CXCR4 Gene to Infarcted Myocardium Improves Cardiac Performance
(Cheng et al Mol Ther 2008)
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Timing of intracoronary injection and LVEF in REPAIR-AMI
(Schachinger et al, NEJM 2006)
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Comparison of different delivery methods
(Caplice et al, Journal of Nucl. Medicine 2007)
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Patient selection in REPAIR-AMI
(Schachinger et al, NEJM 2006)
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Surrogate end-points: negative results
(ASPIRE, EHJ 2011)
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Surrogate end-points: positive results• Flecainide in post-AMI
– Reduces ventricular ectopic beats– Increases mortality (CAST trial, NEJM 1991)
• Ibopamine in severe HF– Improves cardiac function– Increases mortality (PRIME II trial, Lancet 1997)
• Torcetrapib in dyslipedemia– Improves lipid profile– Increases mortality (ILLUMINATE, NEJM 2007)
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Time for clinical end-points• BAMI
– BMSC
• STEM-AMI OUTCOME– G-CSF