1. Heartline Trial sulla terapia cellulare:
end-point strumentali o clinici?
Filippo Crea
Institute of Cardiology
Catholic University of the Sacred Heart
Rome, Italy

2. Evidence that human cardiac myocites divide afte AMI in man
(Beltrami, et al NEJM 2001)

3. VEGF G-CSF MMP-9 C-Kit SDF-1 SCF HGF CXCR4 CD34 KDR CXCR4 C-Met CD34

4. CD 34+ cell mobilization in different coronary syndromes
AMI (n=54)
CSA (n=26)
Controls (n=43) 10 20 30 40
p<0.001
p=0.036
CD34+ cells/ml
(Leone et al, submitted to EHJ)

5. Correlation between improvement
of LV function and CD 34+ cells at 1-yr FU
(Leone et al, EHJ 2005)

6. Which stem cells?

7. Which elivery methods?
Ciononostante, con insolita velocità e comunque sulla base di dati sperimentali ancora in discussione diversi studi clinici empririci sono stati intrapresi nel tentativo di rigenerare il miocardio infartuato. 2 approcci sono prevalsi: l’iniezione i.c.,e quella i.m. per via percutanea o chirurgica.

8. Which patients?
Myocardial infarction
Heart Failure
Refractory angina

10. Back to GISSI 1
(Volpi et al, Circulation 1993)

11. Effects of enalapril on long-term progression of left ventricular dysfunction in patients with heart
(SOLVD, Circulation 1992)

12. Room for improvement Cell type Cell preparation Myocardial homing
Administration timing
Delivery method
Patient selection

13. Human cardiac stem cell
(Urbanek et al, PNAS 2006)

14. Pharmacological BM-SC mobilization
Drugs
Response
ACE-inhibitors
↑ EPC number
AT II antagonists
Statins
PPAR-gamma
↑ EPC functional activity
Insulin
↑ EPC clonogenic properties
Nitroglycerin
Isosorbide-5-dinitrate
↓ EPC migratory capacity
Pentaerythritol tetranitrate
↑ EPC migratory capacity
IGF-1
↑ EPC differentiation
↑ e-CFU
Growth Hormone
↑ EPC proliferation
↑ EPC migration
Erythropoietin
↑ EPC adhesive properties
G-CSF
↑CD34+ cells
CD34+/KDR+ EPCs (n/ml)
(Leone et al IJC 2008)

15. Targeted Migration of Mesenchymal Stem Cells Modified With CXCR4 Gene to Infarcted Myocardium Improves Cardiac Performance
(Cheng et al Mol Ther 2008)

16. Timing of intracoronary injection and LVEF in REPAIR-AMI
(Schachinger et al, NEJM 2006)

17. Comparison of different delivery methods
(Caplice et al, Journal of Nucl. Medicine 2007)

18. Patient selection in REPAIR-AMI
(Schachinger et al, NEJM 2006)

19. Surrogate end-points: negative results
(ASPIRE, EHJ 2011)

20. 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)

21. Time for clinical end-points
BAMI
BMSC
STEM-AMI OUTCOME
G-CSF