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 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)

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+

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)

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