bone marrow stem cells in cardiac repair
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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
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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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