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 MMP-9 C-Kit SDF-1 SCF HGF CXCR4 CD34 KDR CXCR4 C-Met CD34

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)

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

Which stem cells?

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.

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 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)

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