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Stem cell therapy in cardiac practice

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Stem cell therapy in cardiac practice Dr Sajeer K T Senior resident, Department of Cardiology, Govt. Medical College, Kozhikode. * Stem cell therapy in dilated ... – PowerPoint PPT presentation

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Title: Stem cell therapy in cardiac practice


1
Stem cell therapy in cardiac practice
  • Dr Sajeer K T
  • Senior resident,
  • Department of Cardiology,
  • Govt. Medical College,
  • Kozhikode.

2
Background
  • Cardiovascular disease ? leading cause of
    morbidity and mortality
  • worldwide
  • Despite advances in Mx and cath-based therapy
    for AMI
  • 1-year mortality 13
  • 5-year prognosis for patients with HF 50.
  • LV systolic dysfunction
  • major determinant of prognosis
  • associated with significant loss of
    cardiomyocytes
  • (Irreversible ?heart post
    mitotic organ)

Abdul M. Mozid et al. British Medical Bulletin
2011 98 143159
3
Stem cell therapy
  • Clinical trials focused on 3 main situations
  • Acute MI (with the hope of preventing LVSD)
  • Chronic heart failure secondary to previous MI
  • DCM (non ischemic cardiomyopthy)
  • Areas of discussion
  • 1. Stem cell types used in cardiac repair
  • 2. Methods of cell delivery in clinical
    practice
  • 3. Clinical trial evidence to date

4
Stem cell ?
  • Stem cell
  • a cell with a unique capacity to produce
  • unaltered daughter cells (self-renewal) to
  • generate specialized cell types (potency)
  • Self-renewal
  • symmetric division
  • two stem cells
  • two cells destined for differentiation
  • asymmetric division
  • one stem cell and one differentiating cell

5
Signature characteristic of the stem cell
6
Types of stem cells
  • Stem cells 2 types
  • Somatic stem cells
  • BM, brain, liver, skeletal dermal tissue
  • in vitro proliferative ability is limited
  • Pluripotent stem cells
  • Embryonic stem cells, embryonic germ cells
  • embryonic carcinoma cells, induced
    pluripotent stem (iPS)
  • Exhibit pluripotency

7
Traditional view ? Current evidence
  • Traditional view
  • heart is a terminally differentiated post
    mitotic organ
  • Current evidence
  • heart is not a terminally differentiated post
    mitotic organ
  • 4 sources of cells for new cardiomyocytes
    after birth

1. Adult cardiomyocytes (mononucleated) 2. Bone
marrowderived cardiac stem or progenitor
cells 3. Embryonic epicardium derived cells 4.
Niches of cardiac stem or cardiac progenitor
cells (CPCs)
Stem Cells  2007 25589.
Cell 2009 138257270.
8
Different cell types investigated for use in
cardiac repair
Abdul M. Mozid et al. British Medical Bulletin
2011 98 143159
9
Heart - self-renewing organ
  • Myocyte regeneration occurs throughout organism
    lifespan
  • Cardiac niches contain stem cells ? after
    activation
  • ? give rise to
    myocytes and vascular structures

Piero Anversa, Jan Kajstura, Annarosa Leri.
Circulation. 20061131451-1463
10
Cardiac Stem or Progenitor cells (CSC or CPC)
  • niche of primitive cells present in human
    heart
  • possess the ability to form cardiomyocytes,
    endothelial cells
  • (ECs), smooth muscle cells (SMCs)

Different classes of CPCs based on cell surface
markers
  • c-Kit cells
  • 2. Sca-1 cells
  • 3. side population cells (SP)
  • 4. cells expressing the protein Islet-1
    (transcription factor)

11
Cardiac progenitor cell classes
  • c-kit positive cell
  • Sca-1 positive cell
  • SP cells
  • Cardiospheres
  • Epicardial progenitors

12
Hierarchy of CPC growth and differentiation
  • Asymmetrical division of a CSC ? a daughter
  • CSC and a daughter cardiac progenitor (CPg)
  • CPg gives rise to
  • - Myocyte progenitor (MPg ) precursor
    (MPr)
  • - EC progenitor (EPg) precursor (EPr)
  • - SMC progenitor (SMPg) precursor
    (SMPr)
  • Precursors ? transient amplifying cells ?
    divide
  • and differentiate into mature myocytes,
    ECs, and
  • SMCs.
  • CSCs are lineage-negative cells express only
  • c-kit, MDR1, or Sca-1.
  • Progenitors express stem cell antigens and
  • transcription factors of cardiac cells but
    do not
  • exhibit specific cytoplasmic proteins
  • Precursors possess stem cell antigens,
  • transcription factors, membrane
    cytoplasmic
  • proteins typical of myocytes, ECs, and SMCs

13
Hierarchy of CPC growth and differentiation
14
Cardiac Stem Cells and Myocardial Diseases
  • Role of cardiac stem cells in the advanced
    stages of HF
  • - to modulate endogenous CPCs to
    regenerate cardiac muscle
  • and to create new blood vessel
    formation
  • Ventricular remodeling ? progressive chamber
    dilation and thinning of the walls
  • Myocardial regeneration ? reverse this process
  • ?
    transforming a dilated failing heart into a
    normal, functionally


  • competent organ

15
Bone marrow stem cells
  • Bone marrowderived stem cells
  • - best studied cells
  • - used in clinical trials in MI and/or
    idiopathic DCM
  • Bone marrow progenitor cells
  • - hematopoietic stem cells (HSCs)
  • - side population cells (SP cells)
  • (expression of the
    Abcg2 transporter and allowing

  • export of Hoechst dye)
  • - mesenchymal stem cells (MSCs)
  • - multipotential adult progenitor cells (MAPCs)

16
Inducible Pluripotent Stem Cells (iPSCs)
  • Adult stem cells ? successfully reprogrammed
    back to an

  • undifferentiated pluripotent state
  • (by inserting 4 genes Oct3/4, Sox2, KL4
    and c-Myc into differentiated


  • somatic cells)
  • Morphological phenotype of ES cells
  • Same differentiation potential as ES cells (
    in vivo and in vitro)
  • -
    able to form all three germ layers
  • Functioning cardiomyocytes ? produced from iPSCs

17
Inducible Pluripotent Stem Cells (iPSCs)
Generation of iPS cells from somatic cells
  • Reprogramming factors ? introduced in vitro
  • Established iPS cells ? differentiate into
    various cell types

Circulation. 201012280-87
18

iPS demonstrate pluripotent features
Circulation. 2009120408-416
19
Cell types and mode of delivery of cells for
cardiac repair
A Cell types used for cardiovascular
repair B Delivery strategies used in the
clinical setting for cell therapy EPCs
endothelial progenitor cells iPS cells
induced pluripotent SCs MSCs mesenchymal
stem cells SP cells side population cells
20

Summary of cell types used in clinical trials and
future perspective
Circulation. 2010121325-335
21
Method of delivery of stem cells
  • Intracoronary infusion of cells
  • - most popular mode of cell
    delivery - after AMI
  • Intramyocardial injection
  • - performed in patients with
    chronic heart failure
  • secondary to IHD
  • - transendocardial injections
    (catheter-based)
  • - transepicardial injections
    (during open heart surgery)

22
Mechanisms of action
Progenitor cells improve functional recovery of
infarcted or failing myocardium
1. Direct or indirect improvement of
revascularization 2. Paracrine factors released
by progenitor cells may inhibit cardiac
apoptosis, affect remodeling, or enhance
endogenous repair (eg by tissue-resident
PCs) 3. Differentiation into cardiomyocytes may
contribute to cardiac regeneration.
23
Homing of BM-derived stem cells to the
myocardium
  • Homing of BM-derived stem cells to the
    myocardium
  • - fate of bone
    marrow-derived stem cells is determined by the
  • microenvironment that
    they enter

24
Mobilization and homing
  • Homing is mediated by
  • Adhesion
  • Transmigration
  • Invasion

25
Prerequisite for cell-based therapies
Summary of prerequisite for cell-based therapies
Circulation. 2010121325-335
26
Stem cell therapy in acute MI
27
Stem cell therapy in acute myocardial infarction
  • Most of the trials used intracoronary delivery
    of BMSCs following
  • successful stenting of the infarct-related
    artery
  • Surrogate markers used to assess efficacy of
    cell therapy
  • - Improvements in the LVEF
  • - Reduction in size of scar tissue
  • - Reduction in cardiac volume
  • Post infarction heart failure
  • - results from ventricular
    remodeling processes
  • - characterized by progressive
    expansion of the infarct area and
  • dilation of the LV cavity

28
  • Major goal to reverse LV remodeling
  • - enhancement of regeneration of
    cardiac myocytes
  • - stimulation of neovascul.
    within the infarct area
  • 4 main randomized controlled trials (RCTs)
  • - published with positive
    findings
  • 1. TOPCARE-AMI ( Circulation- 2002)
  • 2. BOOST trial ( Lancet - 2004)
  • 3. REPAIR-AMI trial ( EJM - 2006)
  • 4. FINCELL (Eur Heart - 2008)

29
Randomized control trials of intracoronary BMSC
therapy following acute myocardial infarction
30
TOPCARE-AMI Transplantation of Progenitor Cells
and Regeneration Enhancement in AMI
Birgit Assmus et al. Circulation.
20021063009-3017
31
LV Function Assessed by Analysis of LV
Angiography in the Cell Therapy Group
  • Demonstrated potential beneficial effect of BSMC
    therapy following AMI with improvement in the
    LVEF from 51.6 9.6 to 60.18.6 at 4 months

32
TOPCARE-AMI Transplantation of Progenitor Cells
and Regeneration Enhancement in AMI
Left panel (A) LV angiography before
CPC therapy Right panel (B) at
4-month follow-up
Birgit Assmus et al. Circulation.
20021063009-3017
33
TOPCARE-AMI Transplantation of Progenitor Cells
and Regeneration Enhancement in AMI
Echocardiographic wall motion score index at rest
(initial basal) and during low-dose dobutamine
stimulation (initial 10 g dobutamine) at baseline
before progenitor cell therapy and at rest at
4-month follow-up (follow-up basal).
Birgit Assmus et al. Circulation.
20021063009-3017
34
TOPCARE-AMI Transplantation of Progenitor Cells
and Regeneration Enhancement in AMI
Birgit Assmus et al. Circulation.
20021063009-3017
35
BOne marrOw transfer to enhance ST-elevation
infarct regeneration (BOOST trial)
Lancet 2004 364 14148
36
BOne marrOw transfer to enhance ST-elevation
infarct regeneration (BOOST trial)
Lancet 2004 364 14148
37
BOne marrOw transfer to enhance ST-elevation
infarct regeneration (BOOST trial)
Lancet 2004 364 14148
38
BOne marrOw transfer to enhance ST-elevation
infarct regeneration (BOOST trial)
Lancet 2004 364 14148
39
BOne marrOw transfer to enhance ST-elevation
infarct regeneration (BOOST trial)
  • Representative colour-coded
  • images showing systolic wall
  • motion at baseline and 6 months'
  • follow-up in two patients.
  • Both patients had A/C AWMI.
  • Bright colours good systolic
  • wall motion.
  • Dark colours poor wall motion
  • (expressed in mm).
  • Note improved functional recovery
  • in patient treated with BMCs.

Lancet 2004 364 14148
40
Reinfusion of Enriched Progenitor Cellsand
Infarct Remodeling in Acute Myocardial
Infarction(REPAIR-AMI) trial
Enrollment and outcomes
N Engl J Med 20063551210-21.
41
Reinfusion of Enriched Progenitor Cellsand
Infarct Remodeling in Acute Myocardial
Infarction(REPAIR-AMI) trial
N Engl J Med 20063551210-21.
42
Reinfusion of Enriched Progenitor Cellsand
Infarct Remodeling in Acute Myocardial
Infarction(REPAIR-AMI) trial
P value
Placebo n92
BMC n95
N Engl J Med 20063551210-21.
43
Reinfusion of Enriched Progenitor Cellsand
Infarct Remodeling in Acute Myocardial
Infarction(REPAIR-AMI) trial
N Engl J Med 20063551210-21.
44
Reinfusion of Enriched Progenitor Cellsand
Infarct Remodeling in Acute Myocardial
Infarction(REPAIR-AMI) trial
Panel A Interaction between baseline LVEF and
the absolute change in LVEF Panel
B Interaction between the timing of
intracoronary infusion of BMC or placebo after
reperfusion therapy and the absolute change in
LVEF
N Engl J Med 20063551210-21.
45
Reinfusion of Enriched Progenitor Cellsand
Infarct Remodeling in Acute Myocardial
Infarction(REPAIR-AMI) trial
Conclusion
  • Intracoronary administration of BMC is
    associated with improved
  • recovery of left ventricular contractile
    function in patients with acute
  • myocardial infarction

N Engl J Med 20063551210-21.
46
Effects of I/C injection of mononuclear BMCs on
LV function, arrhythmia risk profile, and
restenosis after lytic therapy of AMI
- FINCELL Investigators
Aim To assess the efficacy and safety of bone
marrow cell (BMC) therapy after
thrombolytic therapy of an acute STEMI
Methods Patients with STEMI treated with
thrombolysis followed by PCI
(26 days after STEMI )
Intracoronary BMCs (n 40)
placebo medium (n 40) (collected prepared
36 h prior PCI) Injected
into the infarct artery immediately after stenting
European Heart Journal (2008) 29, 27232732
47
Effects of I/C injection of mononuclear BMCs on
LV function, arrhythmia risk profile, and
restenosis after lytic therapy of AMI
- FINCELL Investigators
  • Efficacy assessed by
  • measurement of global LVEF - LV angiography

  • - 2-D echo
  • Safety by measuring arrhythmia risk variables
  • Restenosis of the stented vessel by IVUS
  • At 6 months
  • BMC group greater absolute increase of
    global LVEF than placebo
  • (measured by
    angiography or 2-D echo)
  • No differences observed between the groups in
  • - adverse clinical
    events
  • - arrhythmia risk
    variables
  • - MLD of stented
    coronary lesion

European Heart Journal (2008) 29, 27232732
48
Effects of I/C injection of mononuclear BMCs on
LV function, arrhythmia risk profile, and
restenosis after lytic therapy of AMI
49
Effects of I/C injection of mononuclear BMCs on
LV function, arrhythmia risk profile, and
restenosis after lytic therapy of AMI
- FINCELL Investigators
Conclusion Intracoronary BMC therapy is
associated with an improvement of global LVEF
and neutral effects on arrhythmia risk profile
and restenosis of the stented coronary lesions
in patients after lytic therapy of STEMI
European Heart Journal (2008) 29, 27232732
50
RCTs with neutral findings
  • LEUVEN-AMI study1
  • - No changes in global LVEF after
    BMSC infusion
  • ASTAMI trial2
  • - No significant effect on the
    LVEF, LV volumes, or infarct size
  • HEBE trial3
  • - No changes in global or regional
    LV systolic function
  • after BMSC therapy

1Janssens et al. Lancet 200636711321
2 Lunde K et al. N Eng J Med 20063551199209
3Alexander Hirsch et al. Eur Heart J 2010
51

Reasons for the inconsistent findings
1. Variations in the number of cells
delivered 2. Timing of delivery after AMI 3.
Differences in the cell isolation protocol
52
Stem cell therapy in chronic ischemic heart
failure
53
Stem cell therapy in chronic ischemic heart
failure
  • Skeletal myoblasts and BMSCs 2 cell types
    investigated in chronic

  • heart failure severely impaired LV
    function

  • secondary to previous MI
  • Skeletal myoblasts transplantation

  • initially investigated in patients undergoing

  • open heart surgery
  • Myoblasts are obtained from culture of a prior
    muscle biopsy
  • Injected in to epicardium at the time of surgery

54

Clinical trials of stem cell therapy for chronic
ischemic heart failure
Clinical trials of stem cell therapy for chronic
ischemic heart failure
55
The Myoblast Autologous Grafting in Ischemic
Cardiomyopathy (MAGIC) Trial
  • 1st randomized placebo-controlled study of
    Myoblast transplantation
  • Patients with LVSD secondary to previous MI and
    who required CABG
  • Cells ? injected into epicardium within scarred
    areas during open heart surgery

Circulation. 20081171189-1200
56
The Myoblast Autologous Grafting in Ischemic
Cardiomyopathy (MAGIC) Trial
Circulation. 20081171189-1200
57
The Myoblast Autologous Grafting in Ischemic
Cardiomyopathy (MAGIC) Trial
A Time to first MACE B Time to first
ventricular arrhythmia
  • study was prematurely stopped
  • no improvement in regional or global

  • LVEF
  • higher number of arrhythmic events

Circulation. 20081171189-1200
58
STAR-heart study
The acute and long-term effects of intracoronary
Stem cell Transplantation in 191 patients with
chronic heARt failure the STAR-heart study
  • only limited data available on the effectiveness
    of BMCs in chronic HF
  • largest study to date of BMSC therapy in chronic
    ischaemic HF
  • investigated ventricular hemodynamics,
    geometry, and contractility as
  • well as the long-term clinical outcome of
    BMC treated patients with
  • reduced LVEF due to chronic ischaemic
    cardiomyopathy

Bodo-Eckehard Strauer et al. European Journal of
Heart Failure (2010) 12, 721729
59
STAR-heart study
60
STAR-heart study
Bodo-Eckehard Strauer et al. European Journal of
Heart Failure (2010) 12, 721729
61
STAR-heart study
EF over time in the BMC group compared with the
control group
Bodo-Eckehard Strauer et al. European Journal of
Heart Failure (2010) 12, 721729
62
STAR-heart study
Effect of BMC therapy on survival in patients
with chronic ischaemic cardiomyopathy
Bodo-Eckehard Strauer et al. European Journal of
Heart Failure (2010) 12, 721729
63
STAR-heart study
64
STAR-heart study-conclusion
  • 5-year follow-up
  • intracoronary BMSC therapy ? associated with
    significant
  • improvement in the LVEF and exercise
    capacity
  • significant decrease in long-term mortality

Bodo-Eckehard Strauer et al. European Journal of
Heart Failure (2010) 12, 721729
65
Stem cell therapy in dilated cardiomyopathy
66
Stem cell therapy in dilated cardiomyopathy
TOPCARE-DCM
Transplantation of Progenitor Cells and
Functional Regeneration Enhancement Pilot Trial
in Patients with Non-ischemic DCM
A Pilot Trial to assess potential effects of
selective intracoronary bone marrow
derived progenitor cell infusion in patients with
non-ischemic DCM
Intracoronary administration of BMCs ? shown to
improve coronary micro
vascular
function in IHD
Coronary micro-vascular dysfunction is implicated
in the pathogenesis and prognosis of noni-schemic
DCM
Ulrich Fischer-Rasokat et al. Circ Heart Fail.
20092417-423
67
TOPCARE-DCM
Individual changes of the extent of hypokinetic
area (A), severity of hypokinesia (B), and
ejection fraction (C) between baseline and
3-month follow-up
68
TOPCARE-DCM
Conclusion Intracoronary administration of
BMC seems to be associated with improvements in
cardiac contractile and micro vascular function
in patients with DCM
Individual changes of the adenosine-induced
minimal vascular resistance index of the
BMC-treated LAD for all 24 patients between
baseline and 3-month follow-up
69
Summary and future directions
  • Past decade has seen an explosion in clinical
    studies investigating the
  • safety and efficacy of stem cell therapy for
    heart diseases.
  • Safety of stem cell therapy has been
    demonstrated uniformly in the
  • vast majority of the studies.
  • Beneficial effects of cell therapy have been
    demonstrated

  • AMI, chronic ischaemic HF and DCM.
  • Need for larger RCTs with longer term follow-up
    assessing morbidity
  • and mortality as primary outcome measures.

70
Thank you
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