HEARTLINE 2013 Genova 15/11/2013

Dr Felice Achilli

Le 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 AMI

ESV, end systolic volume; Ts-SD: Standard deviation of time to peak myocardial contraction Te-SD: Standard deviation of time to peak early relaxation

Characteristic Normal LV Gp Remodeled Gpearly 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

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

4,2

7,26,9

2,9

5,75,1

3,5

4,4

1,9

0

1

2

3

4

5

6

7

8

<3h >3h tot

30d M

orta

lity R

ates

(%) Anterio

Non Anterior

All

< 3 h > 3 h ALL

r

Today…..

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 cells

• Endothelial progenitor cells

• Side population cells

FOURTH 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 ICM

Acute MI

FGF familyEPO

FLT-3 ligand

VEGF family(PIGF)

Angiopoietin-1

HGF/IGF-1/GH

Growth

Factors

G-CSF/GM-CSF

SDF

“ENDOGENOUS CELL THERAPY” FOR CARDIAC REPAIR

Sanganalmat SK, et al., Basic Res Cardiol 2011

CLINICAL BENEFIT

CELLS THERAPY IN AMI: SAFETY

Zimmet et Al. EHJ 2012

NO DIFFERENCE ABOUT : IN STENT RESTENOSIS

THROMBOSIS

Re-AMI

DEATH

HOSPITALIZATION

ARRYTHMIA

SURGICAL REVASCULARIZATION

META-ANALYSIS OF BMSC IN AMI PTS

Follow-up 6mFollow-up 18m

Zimmet 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 2007

CRT for Patients With LV Dysfunction: A Systematic Review

4420 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, 2006Hill J et al., Circulation, 2006Abdel-Latif A, Am Heart J 2008 Abdel-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 (<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

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 Factor Safety in humans

Preclinical studies(large animal models)

Preliminary data in patients

Dual mode of action

G-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 TRIAL POPULATION DESIGN ENDPOINTS

Voors et al.Eur Heart J, 2010

HEBE IIII

STEMI 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 2006

Exp

ressio

n (

fold

in

cre

ase

esti

mate

) Adhesion

Migration

ROS

Inflammatory cytokines

Matrix SupportCollagen

Mobilization

0

1

2

3

4

5

6

BL

Day 3

Day 7

Day 14

Day 21-28

Optimal timingOptimal timingOptimal timingOptimal timing

Timing?

Kuhlmann MT, et al. JEM 2006.