Filippo Crea Institute of Cardiology Catholic University of the Sacred Heart Rome , Italy
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Transcript of Filippo Crea Institute of Cardiology Catholic University of the Sacred Heart Rome , Italy
Filippo CreaInstitute of Cardiology
Catholic University of the Sacred HeartRome, Italy
HeartlineTrial sulla terapia cellulare:
end-point strumentali o clinici?
Evidence that human cardiac myocites divide afte AMI in man
(Beltrami, et al NEJM 2001)
VEGF
G-CSF
C-KitMMP-9
CXCR4 CD133CD34
KDR C-Met
SDF-1
HGFSCF
CXCR4CD
34 KDR
C-Met
C-Kit
C-Kit
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)
Correlation between improvementof LV function and CD 34+ cells at 1-yr FU
(Leone et al, EHJ 2005)
Which stem cells?
Which elivery methods?
Which patients?•Myocardial infarction
•Heart Failure
•Refractory angina
Back to GISSI 1
(Volpi et al, Circulation 1993)
Effects of enalapril on long-term progression of left ventricular dysfunction in patients with heart
(SOLVD, Circulation 1992)
Room for improvement•Cell type •Cell preparation•Myocardial homing•Administration timing•Delivery method •Patient selection
Human cardiac stem cell
(Urbanek et al, PNAS 2006)
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)
Targeted Migration of Mesenchymal Stem Cells Modified With CXCR4 Gene to Infarcted Myocardium Improves Cardiac Performance
(Cheng et al Mol Ther 2008)
Timing of intracoronary injection and LVEF in REPAIR-AMI
(Schachinger et al, NEJM 2006)
Comparison of different delivery methods
(Caplice et al, Journal of Nucl. Medicine 2007)
Patient selection in REPAIR-AMI
(Schachinger et al, NEJM 2006)
Surrogate end-points: negative results
(ASPIRE, EHJ 2011)
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)
Time for clinical end-points• BAMI
– BMSC
• STEM-AMI OUTCOME– G-CSF