HEARTLINE 2013 Genova 15/11/2013

Dr Felice AchilliLe cellule staminali ripareranno il cuore del Paziente infartuato?Lo studio STEMAMI OUTCOME

20 years ago .Ejection Fraction in GISSI 1 (Volpi et al, Circulation 1993)

10 years ago .not only EF!

Zhang Y, et al. Am Heart J 2008;156:1124-32.Cardiac Remodeling Post AMIESV, end systolic volume; Ts-SD: Standard deviation of time to peak myocardial contraction Te-SD: Standard deviation of time to peak early relaxationCharacteristicNormal LV GpRemodeled Gpearly Post MI(n = 31)(n=16)P valueQ waves24/3113/16NSAnterior wall11/3114/16.007Peak CK (u/L)1910 10464098 2081.006ESV mL40.6 8.547.6 8.4.006Ts-SD33.7 7.550.9 10.8

< 3 h> 3 hALLrToday..

Chart1

4.21.92.9

7.24.45.7

6.93.55.1

Anterio

Non Anterior

All

30d Mortality Rates (%)

Data from BLITZ 4Mortality rates vs "ischemic time" and AMI location

Foglio1

AnterioNon AnteriorAll

3h7.24.45.7

tot6.93.55.1

Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

Tomorrow.: Reverse Remodeling or.

Myocardial Recovery!

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.

Dimmler S., 2012 (with permission)Cell Therapy of Cardiovascular Disease: start of CT

Bone Marrow derived Cells

CELL SOURCES TARGETED for CARDIAC REGENERATION Evolution of the cell types used: 1) Myoblasts 2) Bone Marrow Derived Cells:Hematopoetic stem cells Mesenchymal stem cellsEndothelial progenitor cells Side population cellsFOURTH GENERATION : Cardiac Progenitors Cells (CPC) MORE THAN 2000 PATIENTS TREATED IN 10 YEARS!

European Heart Journal (2012) Zimmet et Al. CELL THERAPHY AND ACUTE CORONARY DISEASES

J.Tongers,D.W. Losordo, U.Landmesser EHJ 2011 Review (modif)EXOGENOUS CELL THERAPY FOR CARDIAC REPAIR C. Direct Endomyocardial cell injection Chronic ICMAcute MI

FGF familyEPOFLT-3 ligandVEGF family(PIGF)Angiopoietin-1HGF/IGF-1/GHGrowth

FactorsG-CSF/GM-CSFSDFENDOGENOUS CELL THERAPY FOR CARDIAC REPAIR

Sanganalmat SK, et al., Basic Res Cardiol 2011 CLINICAL BENEFIT

CELLS THERAPY IN AMI: SAFETYZimmet et Al. EHJ 2012NO DIFFERENCE ABOUT : IN STENT RESTENOSIS THROMBOSIS Re-AMIDEATHHOSPITALIZATIONARRYTHMIASURGICAL REVASCULARIZATION

META-ANALYSIS OF BMSC IN AMI PTS

Follow-up 6mFollow-up 18mZimmet et Al. EHJ 2012

Postgrad Med J 2011; 87:558 Changes in LVEF in Clinical Trial that have changed clinical practice based on effect on clinical outcome

Mc Alister et al JAMA 2007CRT for Patients With LV Dysfunction: A Systematic Review4420 PtsBasal 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%),

TARGET ?

Smalls and monocentric studies No randomization Heterogeneous populations No blinded study Similar surrogate end-points but measured with different methods (ECHO / MRI / SPECT )

PHASE 2 TRIALS IN CELL THERAPY: LIMITS

PHASE III CT aiming for approval of Cell Therapy

Cell Therapy with CARDIAC stem cells

Meta-analysis of G-CSF Trials in AMI Pts

Effect on EF at 6m of follow-up

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

Achilli F. et Al. Heart 2013 (submitted) STEM-AMI Trial 3 YEARS FOLLOW-UP

STEM-AMI Trial: 3 YEARS FOLLOW-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 (3 h and

SWISS-AMI Trial

TIME Trial

EPO & G-CSF: dual protective mechanism after AMI ADAPTED FROM: NAGAI T, AM J PHYSIOL HEART CIRC PHYSIOL 2012

Which growth factor for AMI?

Growth FactorSafety in humansPreclinical studies(large animal models)Preliminary data in patientsDual mode of actionG-CSF (swine, primates) EPO (1 study on swine) GM-CSF (concerns after MI: worsens outcome?)- (chronic HF) - FLT-3- - - (combined with G-CSF)SDF- - - (combined with G-CSF)

Large EPO clinical trials on STEMI

TRIALPOPULATIONDESIGNENDPOINTSVoors et al.Eur Heart J, 2010

HEBE IIIISTEMI after successfull PCIN=529 (1:1)- Phase II, prospective, randomized, open-label. placebo-controlled.

- Single bolus EPO

- powered to detect differences in EF Infarct size/EF = negative (MR)

Event-free survival = positive (at 6 weeks)Najjar SS et al.JAMA, 2011

REVEAL STEMI after successfull PCIN=222 (1:1)Phase II prospective, randomized, placebo-controlled.

- Single bolus EPO (i.v.)

- powered to detect differences in infarct size Infarct size = negative (MR)

Event-free survival = higher rates of CV events in EPO group(at 12 weeks)

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

Timing?Martin_Rendon E et al., Eur Heart J 2008Bartunek J et al. Nat Clin Pract Cardiovasc Med 2006Expression (fold increase estimate)0123456BLDay 3Day 7Day 14Day 21-28

Timing?Kuhlmann MT, et al. JEM 2006.

*La difficolt nello svolgere il compito assegnatomi legata al grande numero di lavori pubblicati in letteratura negli ultimi anni (il primo lavoro sullutilizzo di staminali nelluomo stato pubblicato nel 2002. oggi c.a 250), alla diversit dei contesti clinici, delle modalit di somministrazione e dei materiali biologici e farmacologici utilizzati nei diversi studi.Per fornire un quadro di insieme sufficientemente chiaro, stato necessario innanzitutto distinguere i diversi contesti patologici in cui si sono realizzati i trials clinici, cercare di riassumerne i risultati in termini sia di efficacia che di sicurezza, ed infine cercare di ordinare da un lato le domande che gli studi hanno aperto, e le prospettive che hanno contribuito a delineare.This recent work pubished on Am H J shows that the clinical determinants of post MI LV remodelling are: the infarction of anterior wall, the extent of CK release, the low EF, and the infarc size area. ***La ricerca clinica e sperimentale in ambito di medicina rigenerativa ha definitivamente minato il dogma per cui il cuore non abbia possibilit di riparazione nella vita post-natale.Oggi definitivamente riconosciuto che poco pi del 50% dei cardiomiociti venga cambiato durante la vita. *Jo rn Tongers1*, Douglas W. Losordo2, and Ulf Landmesser3* European Heart Journal (2011) 32, 11971206Cariosfere: Il cuore umano, infatti, contiene cellule staminali cardiache/progenitrici endogene che si possono isolare ed espandere a partire da campioni di biopsie atriali e/o ventricolari. Queste cellule crescono sottoforma di aggregati multicellulari detti Cardiosfere (CS), che possono essere isolate ed espanse da biopsie endomiocardiache (Messina E. et al. 2004; Circ. Res. 95:911-21). Sebbene scarsamente differenziate, le cellule staminali cardiache vanno incontro a maturazione spontanea. Le CS esprimono marcatori di staminalit nella porzione centrale, e marcatori di differenziamento cardiaco, endoteliale, vascolare e mesenchimale in periferia. Le CS sono capaci di prolungato autorinnovamento e sono dotate di alto potenziale cardiogenico. Tali caratteristiche rendono queste cellule particolarmente appropriate per la terapia cellulare autologa Cardiospheres: Another type of cardiac resident stem cell has been identified by growing self-adherent clusters (termed cardiospheres) from subcultures of murine or human biopsy specimens. Others have generated cardiac SP-cell ( side population-cells) derived cardiospheres by adapting a method used for creating neuro-spheres suggesting that cardiac neural crest cells may contribute to cardiac SP cellsCardiosphere-derived cardiac stem cells as well as c-Kit cardiac stem cells are capable of long-term self-renewal and can differentiate into the major specialized cell types of the heart: myocytes and vascular cells expressing both endothelial or smooth muscle cell markers. The exact origin of these c-Kit, Sca-1, SP, Islet-1, or cardiosphere-derived cardiac stem cells and the mechanisms maintaining the cardiac stem cell pool are unclear. Two recent studies suggest that c-Kit and cardiac SP cells may arise from the bone marrow,26,27 however these studies cannot entirely exclude that specific subpopulations of cardiac stem cells originate from the heart and these cardiac stem cells may represent remnants from embryonic development in selected niches within the heart. In summary, although several different types of adult stems.Come fare ad ottenere le cellule? Bone marrow is, at present, the most frequent source used clinically for cardiac repair.29 The rapid tr