““Next steps in stem cell therapy for heart repair:Next steps in stem cell therapy for heart repair:The clinical view – a (very) personal view !“The clinical view – a (very) personal view !“

““Next steps in stem cell therapy for heart repair:Next steps in stem cell therapy for heart repair:The clinical view – a (very) personal view !“The clinical view – a (very) personal view !“

Andreas M. Zeiher, MDDept. of Internal Medicine IIIUniversity of FrankfurtGermany

Andreas M. Zeiher, MDDept. of Internal Medicine IIIUniversity of FrankfurtGermany

Disclosure information: Guidant (research support)t2cure (co-founder, advisor)

7th International Symposium on Stem Cell Therapy & CV Innovations, Madrid, 05 / 2010

Cells for functional cardiac repairCells for functional cardiac repair

Embyronic-likestem cells

(iPS)

somatic cells(skin fibroblasts)

4 genes:Oct4, Klf4, Sox2, myc

Cardiacstem cellsCardiacstem cells

Modified from Dimmeler et al, JCI 2005

Cell therapy in cardiovascular diseasesCell therapy in cardiovascular diseasesCell therapy in cardiovascular diseasesCell therapy in cardiovascular diseases

Acute Myocardial InfarctionAcute Myocardial Infarction

Refractory AnginaRefractory Angina

Peripheral arterial occlussive diseasePeripheral arterial occlussive disease

Chronic post-infarction heart failureChronic post-infarction heart failure

Volpi et al., Circulation 1993; 88: 416-429

LV contractile recovery within 1 week after successful LV contractile recovery within 1 week after successful reperfusion determines clinical outcome in STEMIreperfusion determines clinical outcome in STEMIThere is no linear correlation between mortality and ejection fraction after AMI !

VALIANTVALIANTValValsartan sartan iin n AAcute Myocardial Icute Myocardial Innfarction farction TTrialrial

• 14703 patients14703 patients• STEMISTEMI • 0.5 - 10 days0.5 - 10 days• EF < 40%EF < 40%• Killlip I-III Killlip I-III • Diuretics 60%, Diuretics 60%, • Beta-Blocker 71%Beta-Blocker 71%

Pro

bab

ility

of

ca

rdia

c d

eath

, re

-MI

reh

os

pit

alis

atio

n f

or

hea

rt f

ailu

re

NEJM 2003, 349: 1893-1906

23% in23% in 1 year1 year23% in23% in 1 year1 year

30 % in30 % in 2 years2 years30 % in30 % in 2 years2 years

0

2

4

6

8

10

EF below medianEF below median(( 48.9 %) 48.9 %)

Baseline LVEFBaseline LVEFby QLVAby QLVA

EF above medianEF above median((>> 48.9 %) 48.9 %)

Ab

solu

te c

han

ge

in g

lob

al L

VE

F (%

)A

bso

lute

ch

ang

e in

glo

bal

LV

EF

(%

)

Enhanced contractile recovery by BMC is confined to patients with failed initial recovery

Enhanced contractile recovery by BMC is confined to patients with failed initial recovery

2.52.5 1.11.1 7.5 1.17.5 1.1 3.73.7 0.70.7

p = 0.002p = 0.002p = 0.002p = 0.002 p = 0.81p = 0.81p = 0.81p = 0.81

4.0 0.64.0 0.6

PlaceboPlacebo BMCBMC PlaceboPlacebo BMCBMCn =n = 5252 4141 4040 5454

p for interaction = p for interaction = 0.0200.020p for interaction = p for interaction = 0.0200.020

Schächinger et al., N Engl J Med 2006

REGENTREGENT

Courtesy of M Tendera, European Heart Journal, 2009

39 39 37 40

Controls N=20

10

20

30

40

50

60

70

80

BMCN=46

10

20

30

40

50

60

70

80

p=0.73 p=0.01

0 6 months 0 6 months

REGENT trialREGENT trial

36

31

0 6 months10

20

30

40

50

60

p=0.007

< median

-5

0

5

10

15

20

25

30

FINNCELL trialFINNCELL trial

< median > median

Ch

ang

e in

EF

(%

)

BMC

Placebo

Courtesy of H. Huikuri, European Heart Journal, 2008

p = 0.04

Enhanced contractile recovery by BMC in patients with failed initial recovery – results of recent controlled trialsEnhanced contractile recovery by BMC in patients with failed initial recovery – results of recent controlled trials

BMC therapy is associated with improved clinical outcome at 2 years

BMC therapy is associated with improved clinical outcome at 2 years

daysdays00 100100 200200 300300 400400 500500 600600 7007000

60

70

80

90

100

p = 0.009p = 0.009(log rank)

PlaceboPlacebo

BMCBMC

Eve

nt-

free

su

rviv

al (

%)

Eve

nt-

free

su

rviv

al (

%)

(dea

th,

myo

card

ial i

nfar

ctio

n,(d

eath

, m

yoca

rdia

l inf

arct

ion,

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osp

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atio

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. h

eart

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italiz

atio

n f

. h

eart

fai

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)

# exposedto risk

Placebo 103 93 90 86 86

BMC 101 99 98 97 95

- Death, MI, Rehospitalization for heart failure -- Death, MI, Rehospitalization for heart failure -

CirculationHeartFail 2009

Next step in cell therapy of AMINext step in cell therapy of AMI

In patients with acute post-infarction heart failure In patients with acute post-infarction heart failure despite successful reperfusion therapydespite successful reperfusion therapy

a large-scale clinical endpoint trial is a large-scale clinical endpoint trial is warranted to document the effects on warranted to document the effects on mortality and morbiditymortality and morbidity

a large-scale clinical endpoint trial is a large-scale clinical endpoint trial is warranted to document the effects on warranted to document the effects on mortality and morbiditymortality and morbidity

Cell therapy in cardiovascular diseasesCell therapy in cardiovascular diseasesCell therapy in cardiovascular diseasesCell therapy in cardiovascular diseases

Acute Myocardial InfarctionAcute Myocardial Infarction

Refractory AnginaRefractory Angina

Peripheral arterial occlussive diseasePeripheral arterial occlussive disease

Chronic post-infarction heart failureChronic post-infarction heart failure

Cell Therapy for Refractory AnginaCell Therapy for Refractory Angina

JAMA, May 2009

Cell Therapy for Refractory AnginaCell Therapy for Refractory Angina

JAMA, May 2009

1 x 10^5 CD34+ cells/kg (n = 55)

5 x 10^5 CD34+ cells/kg (n = 56)

Endomyocardial Mapping and Injection with NOGAIsolex selected CD34+ cells / Placebo Rx

Cell Mobilization (GCSF 5mcg/kg/d x 5d)Apheresis on Day 5

Follow-up Safety and Efficacy Assessments:1 - 7 days, and 1, 3, 6, and 12 months; ETT at 3, 6, 12 months

MRI at 6 months, SPECT at 6 & 12 months

Screening and Baseline Visits

Placebo (n = 56)

Randomization

Phase II ACT34–CMI Study Design

Subject population (n=167)

• 21-80 yrs• CCS class III or IV Angina• Attempted “best” medical

therapy• Non-candidate for

Surgical/Perc. revasc.• Ischemia on SPECT• 3-10 min. mod. Bruce

protocol with angina or anginal equivalent at baseline

Courtesy of Doug LosordoCourtesy of Doug Losordo

Total ETT TimeTotal ETT TimeChange from baseline at 6 monthsChange from baseline at 6 months

Sec

onds

p=0.013

ACT-34 CMI: Increase in Exercise ACT-34 CMI: Increase in Exercise TimeTime

Courtesy of Doug LosordoCourtesy of Doug Losordo

Next step in cell therapy of refractory anginaNext step in cell therapy of refractory angina

a phase III clinical trial aiming at a phase III clinical trial aiming at approval of NOGA-guided injection of approval of NOGA-guided injection of BMC or CD34+ cells for treatment of BMC or CD34+ cells for treatment of stable refractory angina, e.g. like stable refractory angina, e.g. like ranolazineranolazine

a phase III clinical trial aiming at a phase III clinical trial aiming at approval of NOGA-guided injection of approval of NOGA-guided injection of BMC or CD34+ cells for treatment of BMC or CD34+ cells for treatment of stable refractory angina, e.g. like stable refractory angina, e.g. like ranolazineranolazine

Cell therapy in cardiovascular diseasesCell therapy in cardiovascular diseasesCell therapy in cardiovascular diseasesCell therapy in cardiovascular diseases

Acute Myocardial InfarctionAcute Myocardial Infarction

Refractory AnginaRefractory Angina

Peripheral arterial occlussive diseasePeripheral arterial occlussive disease

Chronic post-infarction heart failureChronic post-infarction heart failure

Acute Infarction

LV- Dilatation

Chronic Heart Failure

Aims of cell therapy

??Adverse LV RemodelingAdverse LV Remodeling

Reverse LV RemodelingReverse LV Remodeling

Vascularization Apoptosis

Paracrine factorsParacrine factors

CardiacRegenerationCardiacRegeneration

1. Prevent post-infarction

heart failure

1. Prevent post-infarction

heart failure2. Reverse establishedheart failure

2. Reverse establishedheart failure

Chronic Post-Infarction Heart FailureChronic Post-Infarction Heart Failure- Very modest effects on improvement of LV function- Lack of larger randomized controlled trials- Lack of data on clinical outcome with hard endpoints

Limited data on efficacy is available that suggest Limited data on efficacy is available that suggest rather small beneficial effects on cardiac function, rather small beneficial effects on cardiac function, but there exists no data on mortality.but there exists no data on mortality.

Comparison of observed and model-predicted * Comparison of observed and model-predicted * mortality in 297 consecutive patients treated with mortality in 297 consecutive patients treated with intracoronary BMC infusion.intracoronary BMC infusion.

Seattle Heart Failure Model (SHFM):Seattle Heart Failure Model (SHFM): multivariable risk model that predicts multivariable risk model that predicts all-cause and cause-specific mortality in patients with chronic heart failure, all-cause and cause-specific mortality in patients with chronic heart failure, including contemporary pharmacological and device therapies: (validated in including contemporary pharmacological and device therapies: (validated in 9942 patients from large clinical trials: ELITE2, Val-HeFT, UW, 9942 patients from large clinical trials: ELITE2, Val-HeFT, UW, RENAISSANCE, IN-CHF)RENAISSANCE, IN-CHF)

BMC therapy in CHF –effects on mortality?

observed

Years of Follow Up

295 202n =

1 2 3

Mo

rtal

ity

(%)

244

0

5

10

15

20

25

Val-HeFT

model-predicted

Consistently lower observed mortality than model-predicted mortality throughout 3 years Fup

0.85

0.90

0.95

1.00

0

0 1 2 3

P=0.048

Years of Follow Up

Est

imat

ed c

um

ula

tive

su

rviv

al [

%]

Single BMC administration

Repeated BMC administration

observed

Model-predicted

Single BMC Administration

Years of Follow Up

Mo

rtal

ity

(%)

189 132n = 158

1 2 30

5

10

15

20

25

Years of Follow Up

Repeated BMC Administration

1 2 30

10

20

30

106 7086n =

Mo

rtal

ity

(%)

Only repeated intracoronary BMC treatment is associated with lower mortality than SHFM-model predicted mortality

mean SHFM Score

0.48 ± 0.9

mean SHFM Score

0.45 ± 0.9

Years of Follow Up

05

1015202530

1 2 3

Mo

rtal

ity

(%)

Tertile I (CFU ≤ 17.5)(n=95)

05

10152025

1 2 3

Mo

rtal

ity

(%)

Tertile II (17.5 ≤ CFU ≤ 29.5)(n=96)

0

4

8

12

16

20

1 2 3

Mo

rtal

ity

(%)

Tertile III (CFU > 29.5)(n=94)

0 1 2 4

0

0.80

0.90

1.00

0.70

3

P (log rank)=0.02

Years follow-up

Cu

mu

lati

ve s

urv

ival

[%

]

I Tertile

II Tertile

III Tertile

Application of functionally competent BMCs is essential for lower mortality than

predicted

Enhancement strategies for cell therapy as next steps in chronic heart failure

*

** *****

**

*

** **

**

*

**

**

Bone marrow

BloodSkeletal muscle

Adipose tissue

Other sources

Cell therapy

genes small molecules Pretreatment of the

target region

Pretreatment of cells

Recruitment in target tissue

Seeger et al, Nat Clin Pract Cardiovasc Med, 2007

eNOS enhancereNOS enhancerp38 inhibitorsp38 inhibitorsPPARPPAR agonist agonist

eNOS enhancereNOS enhancerp38 inhibitorsp38 inhibitorsPPARPPAR agonist agonist shock wave pretreatmentshock wave pretreatment

nanofiber-based deliverynanofiber-based deliveryshock wave pretreatmentshock wave pretreatmentnanofiber-based deliverynanofiber-based delivery

Stefanie DimmelerStefanie DimmelerBirgit AssmusBirgit AssmusVolker SchächingerVolker Schächingerwww.REPAIR-AMI.org

Klinikum derKlinikum derJohann Wolfgang Goethe UniversitätJohann Wolfgang Goethe Universität

Frankfurt am MainFrankfurt am Main

Dept. of HematologyDept. of Hematology

H. Martin / W. HofmannH. Martin / W. HofmannD. HoelzerD. Hoelzer

Dept. of RadiologyDept. of Radiology

N. Abolmaali / J. SchmittN. Abolmaali / J. SchmittT. VoglT. Vogl

Experimental StudiesExperimental StudiesC. Urbich, C. Urbich, A. KühbacherA. KühbacherM. Potente M. Potente A. AicherA. Aicher E. Chavakis, G. CarmonaE. Chavakis, G. CarmonaL. Rössig, D. Scharner L. Rössig, D. Scharner M. Koyanagi, M. IwasakiM. Koyanagi, M. IwasakiTh. Ziebart, C. YoonTh. Ziebart, C. Yoon

& technical help (Andrea, Nicole,& technical help (Andrea, Nicole,Ariane, Marion, Tino)Ariane, Marion, Tino)

Red Cross FrankfurtRed Cross Frankfurt

T. Tonn / SeifriedT. Tonn / SeifriedT. Brühl, M. Vasa,T. Brühl, M. Vasa,K. Sasaki, C. Badorff, C. HeeschenK. Sasaki, C. Badorff, C. Heeschen

Clinician Scientists:Clinician Scientists:J. Honold, R. Lehmann J. Honold, R. Lehmann U. Fischer-RasokatU. Fischer-RasokatS. Fichtlscherer S. Fichtlscherer F. Seeger, C.KisselF. Seeger, C.KisselS. DeRosaS. DeRosaN. Bellera GotardaN. Bellera Gotarda

Kerckhoff ClinicKerckhoff Clinic

C. Hamm / T. DillC. Hamm / T. Dill