Bone Marrow Stem Cells in Cardiac Repair

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Dimmeler S et al. Arterioscler Thromb Vasc Biol. 2007;Oct. 19 epub.

EC differentiationSMC differentiation Paracrine Effects

Cardiac differentiation fusion

Angiogenesis

Attraction/Activation

of CSC

ArteriogenesisCardiomyocyte

proliferation

Cardiomyocyte apoptosis

Scar remodelingModulation of inflammation

FUNCTIONAL IMPROVEMENT

Vasculo-genesis

Cardio-myogenesis

Cell homing andtissue integration

Stem cells in cardiac repair: Proposed mechanisms of action

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Bone marrow cells promote myocardial regeneration: Postulated mechanism

Orlic D et al. Nature. 2001;410:701-5.

Transplanted Cells

Infarcted myocardium

Cell migration to damaged area

Proliferation and differentiation

Cytoplasmic proteins Nuclear proteins

Functional competence

Unknown molecular signal(s)

Cardian myosinα-Sarcomeric actin

Connexin 43

Csx/Nkx2.5MEF2

GATA-4

4

Deb A et al. Circulation. 2003;107:1247-9.

Blue, green arrow = Y chromosome–positive true nucleus of BM

Red = Derived cardiomyocyte cytoplasm (sarcomeric actin) surrounded by basement membrane laminin (green, arrowhead)

Post-mortem analysis of 4 hearts of female recipients of male BM transplants

Demonstration of Y-chromosomes in up to 23% of cardiomyocytes

Cardiac stem cells are derived, in part, from bone marrow

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Communication between heart and bone marrow signals in repair

Courtesy of Carl J. Pepine, MD

SDF-1

SDF-1 transport

CXCR4

Cell Recruitment

Stem/progenitor cell

Maturing leukocyte

Heart

Blood vessel endothelium

Bone Bone marrow

end

osteu

m

Blood vessel endothelium

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Orlic D et al. Nature. 2001;410:701-5.

mm

Hg

40

30

20

10

0

*

* †

LVEDP

mm

Hg

120

100

80

60

40

20

0

*

* †

LVDP

mm

Hg

s-1

12000

8000

4000

0

*

* †

LV +dP/dt

*

* †

LV –dP/dt

mm

Hg

s-1

12000

8000

4000

0SO MI + BMMI SO MI + BMMI

Ventricular function

BMCs regenerate infarcted myocardium in mice

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Kamihata H et al. Circulation. 2001;104:1046-52.

BMCs reduce perfusion defect in ischemic pig hearts

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Kamihata H et al. Circulation. 2001;104:1046-52.

LAD Ligation BM-MNC after 3 weeks

BMCs enhance collaterals to infarct region

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BMC therapy increases angiogenesis in ischemic pig hearts

In part via enhanced synthesis of angiogenic factors in the infarcted region (ie, VEGF)

Kamihata H et al. Circulation. 2001;104:1046-52.

BM-MNC (Factor-VII) Control Medium (Factor-VIII)

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Infarcted myocardium repair via autologous intracoronary mononuclear BMC transplantation

Strauer BE, et al. Circulation. 2002;106:1913-8.

Human model

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BMCs minimize infarcted myocardium region

At 3 months:

• SV index 49 56, P = 0.01

• Left ventricular end-systolic volume 8267, P = 0.01

• Thallium scintigraphy, cm2 174128

Strauer BE et al. Circulation. 2002;106:1913-8.

Cell therapy Standard therapy

25

20

15

10

5

0

Infarct region (%)

* P = 0.04

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Assessment of intracoronary cell therapy in AMI

Study DesignN enrolled (follow-up)

Cell type

Follow-up (months) Primary endpoint

Strauer, 2002 Non-RCT 20(20) BMC 3 LVEF

Bartunek, 2005 Non-RCT 35 (35) BMC 4 Safety, LVEF

Jannsens, 2006 RCT 67 (66) BMC 4 LVEF

BOOST, 2006 RCT 60 (60) BMC 18 LVEF, safety

Zhan-Quang, 2006 Non-RCT 70 (58) PMC 6 LVEF, LV vol, WMSI

MAGIC CELL-3-DES, 2006

RCT 56 (50) PMC 6 LVEF

TCT-STAMI, 2006 RCT 20 (20) BMC 6 LVEF

ASTAMI, 2006 RCT 100 (97) BMC 6 LVEF, EDV, infarct size

REPAIR-AMI, 2006 RCT 204 (197) BMC 12 LVEF

Meluzin, 2006 RCT 66 (66) BMC 3 Infarct zone systolic function

Lipinsky MJ et al. J Am Coll Cardiol. 2007;50:1761-7.

PMC = peripheral mononuclear cells; RCT= randomized controlled trial; WMSI = wall motion score index.

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Effects of intracoronary cell therapy on LVEF

Lipinsky MJ et al. J Am Coll Cardiol. 2007;50:1761-7.

Test for heterogenicity, Chi2 = 33.62, f = 9 (P = 0.0001), P = 73.2%Test for overall effect: Z = 5.35 (P = 0.00001)

Study EF change % (random) EF change %or sub-category 95% CI 95% CI

ASTAMI, 2005 -1.49 (-2.81, 0.01)Bartunek, 2005 -1.10 (-9.14, 2.94)BOOST, 2004 -2.83 (-3.00, -0.60)Jannsens, 2004 -1.10 (-2.68, 0.68)MAGIC-3, 2006 -2.20 (-7.18, 1.23)Meluzin, 2006 -2.03 (-2.94, -1.04)REPAIR-AM, 2006 -2.59 (-1.54, -1.44)Strauer, 2002 -1.03 (-4.06, 2.04)TCT-STAMI, 2006 -6.70 (-1.89, -3.51)Zhan-Quan, 2006 -5.50 (-3.19, -2.83)

Total -2.97 (-1.04, -1.22)

Favors cell therapy Favors control

-10 -5 0 510

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Autologous CD34+ cells for intractable angina

• N = 24 patients with CCS class 3/4 angina

• G-CSF 5 μg/kg/day x 5 days

• Leukapheresis performed on Day 5

• CD34+ cell selection

• NOGA-guided transplantation to zones of myocardial ischemia

• Phase I/IIa double-blind, 3:1 randomization, with crossover of placebo patients using frozen cells

Losordo DW et al. Circulation. 2007;115:3165-72.

15

6.5

-3.5

-11.6-12.6

-15

-10

-5

0

5

10

Angina episodes per week(baseline)

ControlCD34+ Cell

Decrease in angina frequency with CD34+ cell therapy

Months

Losordo DW et al. Circulation. 2007;115:3165-72.

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