“Update on stem cells in

cardiovascular disease“

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

Disclosure information: Guidant (research support)

t2cure (co-founder, advisor)

Cardiology Forum 2010, Rome, 05 / 2010

Cells for functional cardiac repair

Embyronic-like

stem cells

(iPS)

somatic cells

(skin fibroblasts)

4 genes:Oct4, Klf4,

Sox2, myc

Cardiac

stem cells

Modified from Dimmeler et al, JCI 2005

Cell therapy in cardiovascular diseases

Acute Myocardial Infarction

Refractory Angina

Peripheral arterial occlussive disease

Chronic post-infarction heart failure

Metaanalysis of randomized and

cohort studies of progenitor cell

therapy in ischemic heart disease

N = 976; overall treatment effect

+ 3.7 percentage points increase

in LV-EF ( p < 0.001 )

Abdel-Latif, Arch Intern Med 2007; 167:989

Vascularization

Apoptosis

Paracrine

factors

Cardiac

Regeneration

Acute

Myocardial

Infarction

Chronic

Heart

Failure

chronic

LV- dilatation

infarct

expansion

Adverse LV

Remodeling

Cell Therapy in Acute Myocardial Infarction:

therapeutic targets

0

2

4

6

8

10

EF below median

( 48.9 %)

Baseline LVEF

by QLVA

EF above median

(> 48.9 %)

Ab

so

lute

ch

an

ge i

n g

lob

al

LV

EF

(

%)

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

2.5 1.1 7.5 1.1 3.7 0.7

p = 0.002 p = 0.81

4.0 0.6

Placebo BMC Placebo BMC

n = 52 41 40 54

p for interaction = 0.020

Schächinger et al.,N Engl J Med 2006

REGENT

Courtesy of M Tendera,

European Heart Journal, 2009

39 39 37 40

Controls

N=20

10

20

30

40

50

60

70

80

BMC

N=46

10

20

30

40

50

60

70

80

p=0.73 p=0.01

0 6 months 0 6 months

REGENT trial

36

31

0 6 months10

20

30

40

50

60

p=0.007

< median

-5

0

5

10

15

20

25

30

FINNCELL trial

< median > median

Ch

an

ge 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 trials

En

dsysto

lic v

olu

me (

ml)

EF < median

Baseline 4 months 12 months

EF > median

BMC

Placebo

Baseline EF: 39 + 1.9 % Baseline EF: 56 + 2.3 %

Adverse remodeling is confined to patients with failed

initial recovery of EF and abrogated by BMC therapy

Dill et al., AHJ 2009

Change of endsystolic volumes over time (MRI)

0

20

40

60

80

100

120

140

Baseline 4 months 12 months

p = 0.7

p = 0.06

p = 0.01

p = 0.9 p = 0.7 p = 0.5

Do beneficial effects of BMC therapy on adverse remodeling translate into clinical benefit ?

?

Therapies preventing

adverse remodelling…

… reduce adverse

cardiovascular events

ACEI , ARB, ß-Blocker, Aldosteron-Ant.

BMC therapy is associated with improved clinical outcome at 2 years

days0 100 200 300 400 500 600 700

0

60

70

80

90

100

p = 0.009

(log rank)

Placebo

BMC

Eve

nt-

fre

es

urv

iva

l(%

)

(de

ath

, m

yo

ca

rdia

lin

farc

tio

n,

reh

osp

ita

lization

f. h

ea

rtfa

ilure

)

# exposed

to risk

Placebo 103 93 90 86 86

BMC 101 99 98 97 95

- Death, MI, Rehospitalization for heart failure -

CirculationHeartFail 2009

Insights into potential

mechanisms of action?

BMC Therapy in Acute Myocardial Infarction

Paracrine Effects

Vasculo-

genesis

Cardio-

myogenesis

FUNCTIONAL CARDIAC

REGENERATION

Cell homing

and tissue integration

Angiogenesis

Arteriogenesis

Scar

Remodelling

Modulation of

Inflammation

Cardiomyocyte

Apoptosis

Cardiomyocyte

Proliferation

Attraction/

Activation

of CSC

EC Differentiation

SMC Differentiation

Cardiac Differentiation

Fusion

Putative mechanisms for cardiac regeneration

Doppler

wireNTG

(epicardial

vessel dilation)

Adenosine

(140 µg/kg i.v.)

Coronary flow reserve CFR = APVadenosine / APVbasal

Infarct artery and Reference vessel

Relative flow reserve rCFR = CFRtarget vessel / CFRreference vessel

APV

Core Lab: Sandra Erbs / Rainer Hambrecht (Herzzentrum Leipzig)

(Flowire®)

3 Centers

(54 patients)

Herzzentrum Leipzig (32),

J. W. Goethe University Frankfurt (20),

Herz- u. Diabeteszentrum Bad Oeynhausen (2)

Assessment of maximum coronary vascular conductance

Mechanistic Insights from Coronary Flow Assessment

0,0

0,5

1,0

1,5

2,0

ab

s.

infa

rct

vessel

CF

R

n = 26 n = 28

Placebo BMC

p = 0.005

Infarct vessel CFR

0.88

0.18

1.8

0.25

0.11

0.060,0

0,2

0,4

0,6

0,8

Placebo BMC

0.49

0.11

n = 26 n = 27

p = 0.021

Relative CFR

(infarct vessel normalized to

reference vessel)

ab

s.

Rela

tive

CF

R

Erbs et al., Circulation 2007

Intracoronary BMC Administration

Normalizes Coronary Flow Reserve

Cell therapy in cardiovascular diseases

Acute Myocardial Infarction

Refractory Angina

Peripheral arterial occlussive disease

Chronic post-infarction heart failure

Cell Therapy for Refractory Angina

JAMA, May 2009

Cell 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 NOGA

Isolex 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 Losordo

Total ETT Time

Change from baseline at 6 months

0

20

40

60

80

100

120

140

160

Series1 69 138 108

Placebo Low High

Secon

ds

p=0.013

ACT-34 CMI: Increase in Exercise Time

Courtesy of Doug Losordo

-200

-150

-100

-50

0

50

Series1 8.5 -113.2 11.6

Placebo Low High

Total Severity Score - Stress

Change from baseline at 6 months

p=0.002

ACT-34 CMI: SPECT

Courtesy of Doug Losordo

Cell therapy in cardiovascular diseases

Acute Myocardial Infarction

Refractory Angina

Peripheral arterial occlussive disease

Chronic post-infarction heart failure

PROVASA-Study

Vorarbeiten zur TAO-StudieIntraarterial BMC therapy for PAOD:

a randomized-start, placebo-controlled trial

Cell therapy in cardiovascular diseases

Acute Myocardial Infarction

Refractory Angina

Peripheral arterial occlussive disease

Chronic post-infarction heart failure

Vascularization

Apoptosis

Paracrine

factors

Cardiac

Regeneration

Acute Infarction

LV- Dilatation

Chronic Heart Failure

Aims of cell therapy

1. Prevent

post-infarction

heart failure2. Reverse

established

heart failure

?Adverse LV

Remodeling

Reverse LV

Remodeling

Acute Infarction

LV- Dilatation

Chronic Heart Failure

Aims of cell therapy

?Adverse LV

Remodeling

Reverse LV

Remodeling

Vascularization

Apoptosis

Paracrine

factors

Cardiac

Regeneration

1. Prevent

post-infarction

heart failure2. Reverse

established

heart failure

Chronic 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

Ch

an

ge in

LV

eje

cti

on

fra

cti

on

ab

so

lute

(m

ea

n ±

SE

M,

%)

p = 0.03

p = 0.001

p = 0.38

-2

-1

0

1

2

3

CPC

N=26

Control

N=18

BMC

N=28

Assmus et al., N Engl J Med 2006

Moderate improvement in EF is associated with decreased

NT-proBNP serum levels after BMC therapy in patients with

chronic post-infarction heart failure

Follow-up

(3 months)

Baseline

2.500

2.250

2.000

1.750

1.500

0

NT-p

roB

NP

se

rum

le

ve

ls

Mea

n ±

SE

M [

pg

/ml]

p = 0.033

NT-proBNPLV-EF

Assmus et al., Circ Res 2007

BMC therapy; N=61

Limited data on efficacy is available that suggest

rather small beneficial effects on cardiac function,

but there exists no data on mortality.

Comparison of observed and model-predicted *

mortality in 297 consecutive patients treated with

intracoronary BMC infusion.

Seattle Heart Failure Model (SHFM): multivariable risk model that predicts

all-cause and cause-specific mortality in patients with chronic heart failure,

including contemporary pharmacological and device therapies: (validated in

9942 patients from large clinical trials: ELITE2, Val-HeFT, UW,

RENAISSANCE, IN-CHF)

BMC therapy in CHF –

effects on mortality?

Predicting Prognosis in Chronic Heart Failure

observed

Years of Follow Up

295 202n =

1 2 3

Mo

rtality

(%

)

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

Esti

mate

d c

um

ula

tive s

urv

iva

l [%

]

Single BMC administration

Repeated BMC administration

observed

Model-predicted

Single BMC Administration

Years of Follow Up

Mo

rtality

(%

)

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

rtality

(%

)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

rtality

(%

)Tertile I (CFU ≤ 17.5)

(n=95)

0

5

10

15

20

25

1 2 3

Mo

rtality

(%

)

Tertile II (17.5 ≤ CFU ≤ 29.5)

(n=96)

0

4

8

12

16

20

1 2 3

Mo

rtality

(%

)

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

in chronic heart failure

*

** *****

**

*

** **

**

*

**

**

Bone

marrowBlood

Skeletal

muscle

Adipose

tissue

Other

sources

Cell

therapy

genes small

molecules Pretreatment of the

target region

Pretreatment

of progenitor cells

Recruitment

in target tissue

Seeger et al, Nat Clin Pract Cardiovasc Med, 2007

eNOS enhancer

p38 inhibitors

PPARg agonistshock wave pretreatment

nanofiber-based delivery

Stefanie Dimmeler

Birgit Assmus

Volker Schächinger

www.REPAIR-AMI.org

Klinikum der

Johann Wolfgang Goethe Universität

Frankfurt am Main

Dept. of Hematology

H. Martin / W. Hofmann

D. Hoelzer

Dept. of Radiology

N. Abolmaali / J. Schmitt

T. Vogl

Experimental Studies

C. Urbich,

A. Kühbacher

M. Potente

A. Aicher

E. Chavakis, G. Carmona

L. Rössig, D. Scharner

M. Koyanagi, M. Iwasaki

Th. Ziebart, C. Yoon

& technical help (Andrea, Nicole,

Ariane, Marion, Tino)

Red Cross Frankfurt

T. Tonn / Seifried

T. Brühl, M. Vasa,

K. Sasaki, C. Badorff, C. Heeschen

Clinician Scientists:

J. Honold, R. Lehmann

U. Fischer-Rasokat

S. Fichtlscherer

F. Seeger, C.Kissel

S. DeRosa

N. Bellera Gotarda

Kerckhoff Clinic

C. Hamm / T. Dill