Bone Marrow Stem Cells in Cardiac Repair

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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
Cardiac differentiation fusion
Paracrine Effects
Attraction/ Activation of CSC
Angiogenesis
Arteriogenesis
Cardiomyocyte proliferation
Vasculo-genesis
Cardio-myogenesis
Cardiomyocyte apoptosis
Scar remodeling
Modulation of inflammation
FUNCTIONAL IMPROVEMENT
Dimmeler S et al. Arterioscler Thromb Vasc Biol.
2007Oct. 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
Nuclear proteins
Cardian myosin a-Sarcomeric actin Connexin 43
Csx/Nkx2.5 MEF2 GATA-4
Functional competence
Orlic D et al. Nature. 2001410701-5.
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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 chromosomepositive true
nucleus of BM Red Derived cardiomyocyte
cytoplasm (sarcomeric actin) surrounded by
basement membrane laminin (green, arrowhead)
Deb A et al. Circulation. 20031071247-9.
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Communication between heart and bone marrow
signals in repair
Heart
endosteum
Blood vessel endothelium
SDF-1 SDF-1 transport CXCR4 Cell
Recruitment Stem/progenitor cell Maturing
leukocyte
Blood vessel endothelium
Bone marrow
Bone
Courtesy of Carl J. Pepine, MD
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BMCs regenerate infarcted myocardium in mice
Ventricular function
LVEDP
LVDP
40 30 20 10 0
120 100 80 60 40 20 0



mm Hg
mm Hg

LV dP/dt
LV dP/dt
12000 8000 4000 0
12000 8000 4000 0


mm Hg s-1
mm Hg s-1


SO
MI BM
MI
SO
MI BM
MI
Orlic D et al. Nature. 2001410701-5.
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BMCs reduce perfusion defect in ischemic pig
hearts
Kamihata H et al. Circulation. 20011041046-52.
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BMCs enhance collaterals to infarct region
LAD Ligation
BM-MNC after 3 weeks
Kamihata H et al. Circulation. 20011041046-52.
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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. 20011041046-52.
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Infarcted myocardium repair via autologous
intracoronary mononuclear BMC transplantation
Human model
Strauer BE, et al. Circulation. 20021061913-8.
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BMCs minimize infarcted myocardium region
25 20 15 10 5 0
P 0.04
Infarct region ()
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. 20021061913-8.
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Assessment of intracoronary cell therapy in AMI
PMC peripheral mononuclear cells RCT
randomized controlled trial WMSI wall motion
score index.
Lipinsky MJ et al. J Am Coll Cardiol.
2007501761-7.
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Effects of intracoronary cell therapy on LVEF

• 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)

-10 -5 0 5 10
Favors cell therapy Favors control
Test for heterogenicity, Chi2 33.62, af 9 (P
0.0001), P 73.2Test for overall effect Z
5.35 (P 0.00001)
Lipinsky MJ et al. J Am Coll Cardiol.
2007501761-7.
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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, 31 randomization, with
  crossover of placebo patients using frozen cells

Losordo DW et al. Circulation. 20071153165-72.
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Decrease in angina frequency with CD34 cell
therapy
3
6
Months
Losordo DW et al. Circulation. 20071153165-72.