Transcript Cell transplantation for cardiac repair and/or inadequate

Bone Marrow Stem Cells in
Cardiac Repair
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Stem cells in cardiac repair:
Proposed mechanisms of action
Cell homing and
tissue integration
EC differentiation
SMC differentiation
Vasculogenesis
Cardiac differentiation
fusion
Paracrine Effects
Angiogenesis
Attraction/
Activation
of CSC
Arteriogenesis
Cardiomyocyte
proliferation
Cardiomyocyte
apoptosis
Modulation of
inflammation
Cardiomyogenesis
Scar remodeling
FUNCTIONAL
IMPROVEMENT
Dimmeler S et al. Arterioscler Thromb Vasc Biol. 2007;Oct. 19 epub.
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Bone marrow cells promote myocardial
regeneration: Postulated mechanism
Infarcted myocardium
Transplanted Cells
Unknown molecular signal(s)
Cell migration to damaged area
Proliferation and differentiation
Cytoplasmic proteins
Cardian myosin
α-Sarcomeric actin
Connexin 43
Nuclear proteins
Csx/Nkx2.5
MEF2
GATA-4
Functional competence
Orlic D et al. Nature. 2001;410:701-5.
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Cardiac stem cells are derived, in part, from
bone marrow
Post-mortem analysis of 4 hearts of female recipients of male BM transplants
Demonstration of
Y-chromosomes in up to
23% of cardiomyocytes
Blue, green arrow = Y chromosome–positive true nucleus of BM
Red = Derived cardiomyocyte cytoplasm (sarcomeric actin) surrounded by basement membrane
laminin (green, arrowhead)
Deb A et al. Circulation. 2003;107:1247-9.
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Communication between heart and bone marrow
signals in repair
Heart
SDF-1
SDF-1 transport
CXCR4
Cell Recruitment
Stem/progenitor cell
Maturing leukocyte
Bone
Bone marrow
Courtesy of Carl J. Pepine, MD
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BMCs regenerate infarcted myocardium in mice
Ventricular function
LVEDP
40
*†
20
mm Hg
mm Hg
100
*
30
10
*
60
40
0
LV +dP/dt
*†
8000
*
4000
SO
MI
MI + BM
LV –dP/dt
12000
mm Hg s-1
12000
mm Hg s-1
*†
80
20
0
0
LVDP
120
8000
*†
*
4000
0
SO
MI
MI + BM
Orlic D et al. Nature. 2001;410:701-5.
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BMCs reduce perfusion defect in ischemic
pig hearts
Kamihata H et al. Circulation. 2001;104:1046-52.
8
BMCs enhance collaterals to infarct region
LAD Ligation
BM-MNC after 3 weeks
Kamihata H et al. Circulation. 2001;104:1046-52.
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BMC therapy increases angiogenesis in ischemic
pig hearts
BM-MNC (Factor-VII)
Control Medium (Factor-VIII)
In part via enhanced synthesis of angiogenic factors in the infarcted region
(ie, VEGF)
Kamihata H et al. Circulation. 2001;104:1046-52.
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Infarcted myocardium repair via autologous
intracoronary mononuclear BMC transplantation
Human model
Strauer BE, et al. Circulation. 2002;106:1913-8.
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BMCs minimize infarcted myocardium region
25
* P = 0.04
20
Infarct region
(%)
15
10
5
0
Cell therapy
Standard therapy
At 3 months:
• SV index 49  56, P = 0.01
• Left ventricular end-systolic volume 8267, P = 0.01
• Thallium scintigraphy, cm2 174128
Strauer BE et al. Circulation. 2002;106:1913-8.
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Assessment of intracoronary cell therapy in AMI
N enrolled
(follow-up)
Cell type
Follow-up
(months)
Study
Design
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-3DES, 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
PMC = peripheral mononuclear cells;
RCT= randomized controlled trial;
WMSI = wall motion score index.
Primary endpoint
Lipinsky MJ et al.
J Am Coll Cardiol. 2007;50:1761-7.
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Effects of intracoronary cell therapy on LVEF
Study
or sub-category
EF change % (random)
95% CI
EF change %
95% CI
ASTAMI, 2005
Bartunek, 2005
BOOST, 2004
Jannsens, 2004
MAGIC-3, 2006
Meluzin, 2006
REPAIR-AM, 2006
Strauer, 2002
TCT-STAMI, 2006
Zhan-Quan, 2006
-1.49 (-2.81, 0.01)
-1.10 (-9.14, 2.94)
-2.83 (-3.00, -0.60)
-1.10 (-2.68, 0.68)
-2.20 (-7.18, 1.23)
-2.03 (-2.94, -1.04)
-2.59 (-1.54, -1.44)
-1.03 (-4.06, 2.04)
-6.70 (-1.89, -3.51)
-5.50 (-3.19, -2.83)
Total
-2.97 (-1.04, -1.22)
-10
-5
Favors cell therapy
0
5
10
Favors control
Test for heterogenicity, Chi2 = 33.62, af = 9 (P = 0.0001), P = 73.2%
Test for overall effect: Z = 5.35 (P = 0.00001)
Lipinsky MJ et al. J Am Coll Cardiol. 2007;50:1761-7.
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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.
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Decrease in angina frequency with CD34+ cell
therapy
10
6.5
5
Angina episodes
per week
(baseline)
Control
CD34+ Cell
0
-3.5
-5
-10
-11.6
-15
-12.6
3
6
Months
Losordo DW et al. Circulation. 2007;115:3165-72.