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Filippo CreaInstitute of Cardiology
Catholic University of the Sacred HeartRome, Italy
HeartlineTrial sulla terapia cellulare:
end-point strumentali o clinici?
VEGF
G-CSF
C-KitMMP-9
CXCR4 CD
133CD
34
KDR C-Met
SD
F-1
HGFSCF
CXCR4
CD
34 KD
R
C-Met
C-K
it
C-K
it
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+
cel
ls/m
l
(Leone et al, submitted to EHJ)
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
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+
EP
Cs
(n/m
l)
(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)
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)