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HEARTLINE 2013 Genova 15/11/2013. Le cellule staminali ripareranno il cuore del Paziente infartuato? Lo studio STEMAMI OUTCOME. Dr Felice Achilli. 20 years ago ….Ejection Fraction in GISSI 1. (Volpi et al, Circulation 1993). 10 years ago ….not only EF!. Cardiac Remodeling Post AMI.
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HEARTLINE 2013 Genova 15/11/2013 Le cellule staminali ripareranno il cuore del Paziente infartuato? Lo studio STEMAMI OUTCOME Dr Felice Achilli
20 years ago ….Ejection Fraction in GISSI 1 (Volpi et al, Circulation 1993)
Cardiac Remodeling Post AMI Characteristic Normal LV Gp Remodeled Gp early Post MI (n = 31) (n=16) P value Q waves 24/31 13/16 NS Anterior wall 11/31 14/16 .007 Peak CK (u/L) 1910 ± 1046 4098 ± 2081 .006 ESV mL 40.6 ± 8.5 47.6 ± 8.4 .006 Ts-SD 33.7 ± 7.5 50.9 ± 10.8 <.0005 Te-SD 36.2 ± 20.2 45.2 ± 23.2 .048 EF% 53.1 ± 11.7 40.8 ± 7.6 <.0005 Infarct size 10.7 ± 5.9 26.4 ± 10.2 <.0005 Transmurality % 73.6 ± 17.3 85.7 ± 19.6 .039 ESV, end systolic volume; Ts-SD: Standard deviation of time to peak myocardial contraction Te-SD: Standard deviation of time to peak early relaxation Zhang Y, et al. Am Heart J 2008;156:1124-32.
Today….. r < 3 h > 3 h ALL
“CARDIOMYOCITE RENEW” (MI) results in the loss of 1 billion functional cardiomyocytes, which are replaced with a fibrous scar, frequently leading to heart failure. Experimental data demonstrate that the mitotic renewal in the human myocardium exists but at a very low rate: 1% annually at the age of 25 and 0.45% at the age of 75. With this turnover rate, most cardiomyocytes will never be exchanged during a normal life span. Although the renewal rate may increase somewhat after injury, the heart itself is not able to effect large-scale cardiac regeneration.
Cell Therapy of Cardiovascular Disease: start of CT Bone Marrow derived Cells Dimmler S., 2012 (with permission)
CELL SOURCES TARGETED for CARDIAC REGENERATION • Evolution of the cell types used: • 1) Myoblasts • 2) Bone Marrow Derived Cells: • Hematopoetic stem cells • Mesenchymal stem cells • Endothelial progenitor cells • Side population cells FOURTH GENERATION : Cardiac Progenitors Cells (CPC) MORE THAN 2000 PATIENTS TREATED IN 10 YEARS!
CELL THERAPHY AND ACUTE CORONARY DISEASES European Heart Journal (2012) Zimmet et Al.
“EXOGENOUS CELL THERAPY” FOR CARDIAC REPAIR J.Tongers,D.W. Losordo, U.Landmesser EHJ 2011 Review (modif) Acute MI Chronic ICM C. Direct Endomyocardial cell injection
“ENDOGENOUS CELL THERAPY” FOR CARDIAC REPAIR FGF family VEGF family (PIGF) EPO G-CSF/ GM-CSF SDF Growth Factors FLT-3 ligand Angiopoietin-1 HGF/IGF-1/GH
CLINICAL BENEFIT Sanganalmat SK, et al., Basic Res Cardiol 2011
CELLS THERAPY IN AMI: SAFETY NO DIFFERENCE ABOUT : IN STENT RESTENOSIS THROMBOSIS Re-AMI DEATH HOSPITALIZATION ARRYTHMIA SURGICAL REVASCULARIZATION Zimmet et Al. EHJ 2012
META-ANALYSIS OF BMSC IN AMI PTS Follow-up 18m Follow-up 6m Zimmet et Al. EHJ 2012
Changes in LVEF in Clinical Trial that have changed clinical practice based on effect on clinical outcome Postgrad Med J 2011; 87:558
CRT for Patients With LV Dysfunction: A Systematic Review 4420 Pts Basal mean LVEF range, 21%-30% QRS duration (mean range, 155-209 milliseconds) NYHA 3 or 4 despite optimal pharmacotherapy. CRT improved LVEF 3.0%; (95% CI: 0.9%-5.1%), Mc Alister et al JAMA 2007
PHASE 2 TRIALS IN CELL THERAPY: LIMITS • Smalls and monocentric studies • No randomization • Heterogeneous populations • No blinded study • Similar surrogate end-points but measured with • different methods (ECHO / MRI / SPECT )
Meta-analysis of G-CSF Trialsin AMI Pts Effect on EF at 6m of follow-up
Hill J et al., Circulation, 2006 Abdel-Latif A, Am Heart J 2008
STEM-AMI Trial 3 YEARS FOLLOW-UP Achilli F. et Al. Heart 2013 (submitted)
STEM-AMI Trial: 3 YEARSFOLLOW-UP European Heart Journal (2012) Zimmet et Al.
Time has come for hard clinical endpoints: GISSI Outliers STEM-AMI OUTCOME TRIAL • Large Phase III, open, randomized, multicenter nationwide Trial. • 1502 patients; 65 centres involved. • Anterior STEMI with low ejection fraction post PCI (<45%). • Symptoms-to-baloon time >3 h and <24 h • G-CSF (n=751) vs. saline (n=751) within 12 h from reperfusion. • Primary endpoint: Death, Recurrence of MI, Rehospitalisation for heart failure (accrural=2y; follow-up=3 y). E.C. APPROVAL MAY,8, 2013! FIRST PATIENT NOV,8,2013
EPO & G-CSF: dual protective mechanism after AMI ADAPTED FROM: NAGAI T, AM J PHYSIOL HEART CIRC PHYSIOL 2012
Which determinants of success after AMI for the “dream growth factor”? • Extent of BMCs mobilization and homing • Characteristics of mobilized cells • Timing of therapy • Mobilization-independent effects • Patients characteristics
Matrix Support Collagen Optimal timing ROS Inflammatory cytokines Adhesion Mobilization Migration Timing? 6 Optimal timing 5 4 Expression (fold increase estimate) 3 2 1 0 BL Day 3 Day 7 Day 14 Day 21-28 Martin_Rendon E et al., Eur Heart J 2008 Bartunek J et al. Nat Clin Pract Cardiovasc Med 2006
Timing? Kuhlmann MT, et al. JEM 2006.