Growth-factor-induced mobilisation of stem cells after acute infarction: which growth factors and when?

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1 Growth-factor-induced mobilisation of stem cells after acute infarction: which growth factors and when? Giulio Pompilio MD PhD DEPT. OF CARDIOVASCULAR SURGERY LABORATORY OF VASCULAR BIOLOGY AND REGENERATIVE MEDICINE CENTRO CARDIOLOGICO MONZINO IRCCS UNIVERSITA DEGLI STUDI DI MILANO NOTHING TO DISCLOSE

2 what is a growth factor? what has it to do with MI? A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Hematopoietic growth factors (cytokines) influence cellular proliferation, differentiation, maturation, and lineage commitment in the bone marrow. Growth factors are pleiotropic, specifically they have been found to exert a direct beneficial effect on the myocardium after ischemic injury.

3 The fantastic world of growth-factors VEGF family (PIGF) FGF family EPO G-CSF/ GM-CSF Growth Factors SDF Angiopoietin-1 HGF/IGF-1/GH FLT-3 ligand

4 Why are we interested to citokynes for MI? ISCHEMIC INJURY TNF-alpha Interleukin-6 G-CSF, VEGF, SDF-1 Adapted from Frangogiannis et al., Circ Res 2004

5 Which determinants of success after AMI for the dream growth factor? Extent of BMCs mobilization and homing Characteristics of mobilized cells (EPCs) Timing of therapy Mobilization-independent effects Patients characteristics

6 Growth Factor G-CSF EPO GM-CSF FLT-3 SDF Safety in humans Which growth factor? Preclinical studies (large animal models) Preliminary data in patients (swine, primates) (swine) (concerns after MI: worsens outcome?) - (chronic HF) Dual mode of action (combined - with G-CSF) (combined with G-CSF)

7 EPO & G-CSF: dual protective mechanism after AMI Adapted from: Nagai T, Am J Physiol Heart Circ Physiol 2012 Sanganalmat SK, et al., Basic Res Cardiol 2011

8 Large EPO clinical trials on STEMI TRIAL POPULATION DESIGN ENDPOINTS Voors et al. Eur Heart J, 2010 HEBE IIII STEMI after successfull PCI N=529. Doseescalation phases (3, ratio 2:1) and an efficacy phase (ratio 1:1, 131 patients). - Prospective, randomized, open-label. placebocontrolled. - Single bolus of IU i.v. of epoetin-alfa. - powered to detect differences in EF. Infarct size/ef = negative (MR 130vs.124 pts) Higher rates of CV events in placebo group (at 6 weeks) Najjar SS et al. JAMA, 2011 REVEAL STEMI after successfull PCI N=222 (1:1) Prospective, randomized, placebo-controlled. - Efficacy Phase: single bolus of IU i.v. of epoetin-alfa. - powered to detect differences in infarct size Infarct size = negative (MR) Higher rates of CV events in EPO group (at 12 weeks)

9 Valgimigli Ince et al. Ripa et al. Zohlhofer Engelmann Leone et Randomized trials with G-CSF in STEMI et al. N=20 (1:1) FIRSTLINE N=50 (1:1) STEMMI N=78 (1:1) et al. REVIVAL- 2 N=114 (1:1) et al. G-CSF STEMI N=44 (1:1) al. RIGENERA N=41 (2:1) Achlli et al. STEM- AMI N=50 (1:1) G-CSF DOSAGE 5 µg/kg/da y 10 µg/kg/day 10 µg/kg/day 10 µg/kg/day 10 µg/kg/day 10 µg/kg/day 10 µg/kg/da y TIMING G-CSF administration 4 days beginning h after symtoms onset 6 days beginning 85±30 Min after symtoms onset 6 days beginning 1-2 Days after AMI (85%<48 h) 5 days beginning 5 Days after AMI 5 days beginning 6 h to 7 days after symtoms onset 5 days beginning 5 days after AMI 5 days beginning 9 h after symtoms onset Mean EF Baseline (GCSF/C) 40% (Echo) 48/47% (Echo) 51/55% (MR) 51/49% (MR) 41/44% (MR) Subacute STEMI 40/38% (Echo) 39/38% (MR) EF/ ± LVVol Kang S et al. Clinical Therapeutics 2007

10 Hill J et al., Circulation, 2006 Abdel-Latif A, Am Heart J 2008

11 Early: G-CSF immediately after MI Delayed= G- CSF 5 days after MI Beohar N et al., Cath Cardiovasc Int 2007

12 Expression (fold increase estimate) 6 5 Timing? Optimal timing Optimal timing Matrix Support Collagen 4 ROS 3 2 Inflammatory cytokines Adhesion Mobilization 1 Migration 0 BL Day 3 Day 7 Day 14 Day Bartunek J et al. Nat Clin Pract Cardiovasc Med 2006 Martin_Rendon E et al., Eur Heart J 2008

13 Timing? Kuhlmann MT, et al. JEM 2006.

14 Phase II, single-blind, randomized, placebo-controlled. Anterior STEMI with low ejection fraction post PCI (<45%). Symptoms-to-baloon time >2 h and <12 h G-CSF (n=25) vs. saline (n=25) within 12 h from reperfusion. Achilli F, et al. Eur J Heart Fail 2010.

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17 STEM-AMI: 2 years follow-up

18 Placebo Day 5 There is no rose without a thorn DAPI Ac-LDLDiI Lectin G-CSF Day um DAPI Ac-LDLDiI Lectin 100 um Honold J et al., ATVB 2006 Tilling L, BJCP 2009

19 better if the thorn is short cell-mediated effects Sumi S et al., Am J Physiol Heart Circ Physiol 2006

20 Adapted from Theiss HD, Stem Cell Res 2011 Theiss HD et al. Int J Cardiol 2010

21 Growth-factor-induced mobilisation of stem cells after acute infarction: which growth factors and when? Which? Let s give a second chance to G-CSG (alone or in dual therapy) When? Use G-CSF ASAP

22 Time has come for hard clinical endpoints: STEM-AMI OUTCOME Large Phase III, single-blind, randomized, placebo-controlled, multicenter nationwide trial (PIs: Felice Achilli, Giulio Pompilio) patients; 60 centres involved. Anterior STEMI with low ejection fraction post PCI (<45%). Symptoms-to-baloon time >3 h and <24 h G-CSF within 12 h from reperfusion vs. saline, 1:1 ratio Primary endpoint: Death, Recurrence of MI, Rehospitalisation for heart failure (accrural time=2y; follow-up=3 y).