Transcript Cardiac progenitor cells - Cardiology

Curriculum Vitae
Nama
: Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K),
FIHA, FACC, FESC, FCAPC, FASCC
Tempat/Tgl lahir : Sragen, 21 September 1947
Alamat
: Wilis Indah E-10 Malang, Telp. 0341-552395
Pendidikan
:
1. Lulus Dokter dari UGM, tahun 1974
2. Lulus Cardiologist dari Univ. Indonesia, tahun 1983
3. Lulus Internist dari Univ. Airlangga, tahun 1986
4. Lulus Doktor, Univ. Airlangga, tahun 1996
5. Advanced Cardiology Course, Univ. Hongkong, tahun 1984
6. Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996
7. Fellow American College of Cardiology (FACC), September 2006.
8. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007
9. Fellow European Sociaty of Cardiology (FESC), 2008
10. Fellow Asean Collage of Cardiology (FASCC), 2008
Jabatan :
1. Dosen Pengajar Program Pascasarjana Universitas Brawijaya
2. Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya
3. Ketua PERKI Cabang Malang Raya
4. Anggota Kolegium Kardiovaskuler Indonesia
5. Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya
6. Ketua Dewan Pengawas Rumah Sakit Pendidikan
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STEM CELL THERAPHY IN
CARDIOVASCULAR DISEASES
Djanggan Sargowo
Surabaya, 12 Mei 2012
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OVERVIEW
What’s the problem?
Hype?
Reality?
Hope?
Conclusions
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What’s the Problem ?
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UNMET MEDICAL NEED
Diabetes
 12.1 million sufferers in US (2002)
 Costs $132 billion p.a. (2002) rising to $156 billion
p.a. (2010)
Cardiovascular disease
 64.4 million cases in US (2004)
 Costs $368.4 billion p.a. (2004)
Parkinson’s Disease
 100,000 sufferers in UK
 Treatment costs £600 million p.a. (1998)
Paul Rodgers, 2006, Ithaka Lifesciences
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DEGENERATIVE DISEASES
Other examples
 Alzheimer’s, spinal cord injuries, Amyotrophic
Lateral Sclerosis, multiple sclerosis, liver
disease etc
Restoration of cell or organ function
Current drugs don’t treat the cause
Organ transplants
 Expensive, donor shortages, not applicable to
many diseases
Paul Rodgers, 2006, Ithaka Lifesciences
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Background
 Coronary heart disease is
the #1 cause of morbidity
and mortality in the US.
 CHF is the #1 cause of
hospitalization for those
age > 65 yo.
 Annual health care costs
related to cardiovascular
diseases was ~ $220
billion last year.
 Stem cell transplant is a
promising and exciting
therapy.
Orlic D, et al. Nature 2001
2004 American Heart Association Update
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Boenjamin Setiawan, dr.,PhD
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Challenge: Knowledge
Explosion
“We are drowning in
information but starved
for knowledge.”—Naisbitt, ‘82
Boenjamin Setiawan, dr.,PhD
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AVAILABLE STEM CELLS

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Bone marrow stem cells (BMSC)
Endothelial progenitor cells (EPC)
Mesenchymal stem cells (MSC)
Skeletal myoblasts (SKM)
Embryonic stem cells (ESC)
Cardiac stem cells (CSC)
Cardiac progenitor cells (isl1+)
**Stem cells are capable of self-renewal, transformation into dedicated
progenitor cells, and differentiation into specialized progeny
Joseph Wu, MD, PhD; Department of Medicine/Cardiology; Department of Radiology/Nuclear Medicine; Email: [email protected]
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Shinya Yamanaka & James Thomson
potential Nobel Prize Winners in the
Future
Boenjamin Setiawan, dr.,PhD
Shinya Yamanaka,45,
working in Japan's Kyoto
University with mouse cells,
made the iPS breakthrough.
He screened 24 candidate
proteins before finding four
that were able to reprogram
adult cells, reverting them to
their embryonic state. He
and others then showed that
these factors are also
effective in human cells.
Developmental biologist
James Thomson,49, of the
University of Wisconsin
was the first to identify a
slightly different group of
factors that do the same
.
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VANCOUVER, BRITISH COLUMBIA, MAY 3, 2010 – The March
of Dimes awarded Shinya Yamanaka, MD, PhD, (third from left)
its 2010 Prize in Developmental Biology at a gala event.
23/05/2010, Seminar
Univ Brawijaya
Boenjamin Setiawan, dr.,PhD
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Induced pluripotent stem cells –
the science and technology
Albert Lasker Basic Medical Research Award, 2009
Chi-Wei Lu, Ph.D.
Assistant Professor, RWJMS/UMDNJ
Director, Human Embryonic Stem Cell Facility
Boenjamin Setiawan, dr.,PhD
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EMBRYONIC STEM CELLS
Immortal
 A single cell line is all you need
Precursors of all cell types
 Can produce any cell you need
Can divide without limit
 Unlimited supply
Paul Rodgers, 2006, Ithaka Lifesciences
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EMBRYONIC STEM CELLS SURVEY
ES cell therapy is 10-15 years away
Will be used to treat certain diseases
 Diabetes, cardiovascular, single gene
defects, MS, Alzheimer’s, Parkinson’s, liver
disease, spinal cord injury, retinal disease
Schering and Merck are the only pharma
companies to say they are interested at
this stage
Paul Rodgers, 2006, Ithaka Lifesciences
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ADULT STEM CELLS
Can be isolated from most tissues
 e.g. bone marrow, cord blood, fat, skin etc
Generate cell types of tissue of origin
 Produce useful cells for therapies
Plasticity
 Can be coaxed into forming cells of
completely different tissues
 e.g. neurons from blood cells
Paul Rodgers, 2006, Ithaka Lifesciences
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CLINICAL USE OF ADULT STEM CELLS
Bone marrow transplants
 Replace blood cells ablated by cancer therapies
~ 300 clinical studies on haematopoietic stem
cells
 Cell expansion is a key issue
Haematopoietic stem cells may be able to
restore function to damaged cardiac tissue (3
trials so far)
Neural stem cell trial started in 2006
 Batten’s disease (Stem Cells Inc.)
Developments in China and Korea
Paul Rodgers, 2006, Ithaka Lifesciences
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23/05/2010, Seminar
Univ Brawijaya
Boenjamin Setiawan, dr.,PhD
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INDUCED PLURIPOTENT
CELLS AND
TRANSPLANTATION
THEORY
Healthy or diseases
adult human or
mouse
Adult cells
(skin fibroblasts)
OCT4
SOX2
NANOG
Lin28
OCT4
SOX2
KLF4
(Myc)
Self
renewal
iPS cells
Genetic repair by homologous recombination
(if necessary)
Differentiation
In vitro screening of
drug candidates on
healthy and
diseased cells
Tranplantation
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Cell Sources for Cardiac Repair
Endothelial
Progenitor Cells
Hematopoietic SCs
Mesenchymal SCs
Hemangioblasts
SP cells
MAPC
Sca-1+ cells
Myoblasts
SP cells
Mesenchymal SCs
SPcells
CSC
Acute
Chronic
CARDIAC PROGENITOR CELLS IN
THE FETAL AND ADULT HEART
Blastocyst
Fetal or adult heart
ES cells
Cardiovascular
differentiation
Cardic progenitor cells
(Kit+, SCA1+, SP or MDR1+)
(NKX2 2-5+ or lsl1+)
In vitro
differentiation
Tranplatation
In vivo
differentiation
Vascular smooth muscle cells,
endothelial cells or cardiomyocytes
Vascular smooth muscle cells,
endothelial cells or cardiomyocytes
Tissue engineering
Tranplatation
Mice & other
species
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TRANSPLANTATION STRATEGY
FOR CARDIAC REPAIR
Human ES
cells
Differentiating
human ES cells
ES-cell-derived
cardiomyocytes
Adult stem cells
from bone marrow
Cell injected into the
myocardium of
imunodeficient mice after
myocardial infarction
Cardiac
progenitor cells
Functional analysis by
magnetic resonance
imaging, ultrasonography
or pressure-volume loops
Analysis after
immunostaining of heart
tissue sections
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THERAPEUTIC
IMPLICATIONS OF
CARDIAC
PROGENITOR CELLS
Human
Fetal
Mouse
Pluripotency
genes
Skin
Adult
Blastocyst
ES cells
iPS cells
CARDIAC PROGENITOR CELLS
-actinin
PECAM
SMA
Models of heart development
Models of disease
Drug testing
Tissue engineering
CARDIAC THERAPHY
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Tissue Engineered Myocardium
Ischemic heart disease is one of the
leading causes of morbidity and mortality in
Western societies with 7,100,000 cases of
myocardial infarction (MI) reported in 2002
in the United States alone
Within 6 years of MI, 22% of men and
46% of women develop CHF
MI and CHF will account for $29 billion of
medical care costs this year in the US alone
Cardiac transplantation remains the
best solution, but there is an inadequate
supply of donor organs coupled with the
need for life-long immunosuppression
following transplantation
From www.aic.cuhk.edu.hk/web8/Hi%20res/Heart.jpg
Boenjamin Setiawan, dr.,PhD
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Decrease in EPCs associated
with CV disease
Endothelial Progenitor Cells
Vasculoprotective agents
CV risk factors
Atherosclerosis
Disease Regression?
Disease Progression
Improvement of endothelial function
Myocardial infarction
Enhanced re-endothelialization
Ischemic stroke
Reduced plaque size
Erectile dysfunction
Improved angiogenesis
Renal insufficiency
Peripheral artery disease
Werner N, Nickenig G. Arterioscler Thromb Vasc Biol. 2006;26:257-66.
EPCs in CV diseases
EPCs
Pathophysiology
Therapeutics
CV risk factors
Atherosclerosis
Endothelial dysfunction
Heart disease
Collaterals
Peripheral vascular disease
Restenosis
CV disease
Courtesy of Arshed A. Quyyumi, MD.
EPC physiology
• Originate in bone marrow
• Circulate in blood stream
• Number and function (proliferation, migration, homing)
modulated by age, CV risk factors, and disease
• Release stimulated by organ and vascular injury
• Participate in vascular repair (collateralization) and
re-endothelialization, partly by paracrine effects
• Circulating numbers by exercise and drugs (statins and
ACE inhibitors)
• Independent predictors of endothelial dysfunction and
long-term prognosis in patients with CAD
Hill JM et al. N Engl J Med. 2003;348:593-600.
Normal vessel
Pal-1
EC
Pal-1
SMC
tPA
Atherosclerotic
plaque
Pal-1
EC
Pal-1
tPA
SMC
Christ et al., Senescent SMCs Increase Vascular Wall PAI-1 Expression
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Resting endothelial cell
Resting
smooth
muscle cell
Procoagulant, antifibrinolytic matrixdegrading, leukocyte binding endothelial cell
IL-1, TNF
Collagen Elastin
IL-1
TNF
Activated
matrix-degrading
smooth muscle cell
Class II MHC
Collagenase
Gelatinases
Elastolytic
enzimes
Antigen
Apoptotic
smooth
muscle cell
IFN 
TNF
T-lymphocyte
T-cell antigen
receptor
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Unstable Coronary
Artery Disease (II)
Thrombus forms and
extends into the lumen
Thrombus
Lipid core
Adventitia
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Clinical classification of ACS
Acute Coronary Syndrome (ACS)
No ST Elevation
Unstable
Angina
Pectoris
MI (NSTEMI)
No Q-wave
ST Elevation
MI (STEMI)
Q-wave
National Heart Foundation of Australia, Cardiac Society of Australia and New Zealand.
Med J Aust 2000;173 (suppl):S65–S88
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BACKGROUND ON REMODELLING
Acute infarction
(hours)
Infarct expansion
(hours to days)
Global remodelling
(days to months)
Improvement of LV remodelling has been
associated with improvement in mortality and
morbidity outcomes in CHF
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MANAJEMEN SKA
- Oklusi > 4-6 jam
- Reperfusi
- Fase
Nekrosis miokard irreversible
IMA dengan gel q (IMA-Q)
Menurunkan morbiditas - mortalitas
Pre hospital stage
Hospital stage : - IGD
- CVCU
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23/05/2010, Seminar
Univ Brawijaya
Boenjamin Setiawan, dr.,PhD
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CELL-TRANSPLATATION STUDIES IN MODELS OF EXPERIMENTAL MYOCARDIAL INFARCTION
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RC Trials using Intracoronary BMC post MI
MI size
ND
ND
(n=60)
+ 2.8% (P=n.s.)*
P=n.s.
(n=84)
ND
(n=184)
-28%
(P=0.03)
LEUVEN-AMI
(n=67)
FINCELL
+7.1% (P=0.05)
ND
(n=80)
* 18-months follow-up
Myocardial Homing and Biodistribution of
18F-FDG-labeled BMC 50 to 75 min after Transfer
3D PET
Unselected BMC
1.3% to 2.6% in
infarct (center)
CD34-enriched
BMC
14% to 39%
in infarct (border
zone)
Hofmann et al.,
Circulation 2005; 111:
2198-202
4/7/2016
111In
uptake in patient after an anterior AMI
(cell administration 5 days after acute PCI)
Schachinger, V. et al. Circulation 2008;118:1425
Ischemic Cardiomyopathy Therapy
Anno 2010: from drugs to cells?
• Clinical outcome in ischemic cardiomyopathy patients
with LV dysfunction remains unacceptable with
combined event rates of 25% despite state-of-the art
treatment.
• Modest improvement in cardiac function in RCTs of
BMC transfer is attributable to:
– limited homing, engraftment, and survival of BMCs
– lack of cardiac muscle regeneration
– (differences in cell infusate)
Conclusions:
Cell Therapy for Heart Failure 2010
• Mixed bone marrow-derived progenitor cells have
paracrine trophic effects in the dysfunctional ischemic
heart. Whether they can affect clinical outcome in patients
with large MI, at risk for maladaptive remodeling and heart
failure, remains to be determined in prospective RCT.
• Identification of cell-specific effects and enhancement of
progenitor cell functionality warrant focused trials.
• Major breakthrough requires a better understanding of
post-natal cardiomyogenesis and strategies to stimulate
endoge-nous regeneration, paralleled by effective
neovascularisation.
Conclusions:
Cell Therapy for the Dysfunctional Heart 2010
• Modest improvement in cardiac function in 6 RCTs of
BMC transfer is attributable to:
– limited homing, engraftment, and survival of cells
– lack of cardiac muscle regeneration
Science Push!
– differences in cell infusate
• Progenitor cell transfer is best reserved for patients
with large MI, at risk for heart failure.
• Identification of best cell type, enhancement of cell
functionality and stimulation of endogenous cardiac
repair warrant focused translational trials.
EXPEDITED REVIEW
Transplantation of Progenitor Cells
and Regeneration Enhancement
in Acute Myocardial Infarction
Final One-Year Results of the TOPCARE-AMI Trail
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Objectives
The Transplantation of Progenitor Cells And Regeneration Enhancement in Acute
Myocardial Infarction (TOPCARE-AMI) trial investigates both safety, feasibility,
and potential effect on parameters of myocardial function of intracoronary
infusion of either circulating progenitor cells (CPC) or bone marrow-derived
progenitor cells (BMC) in patients with acute myocardial infarction (AMI)
Background
Method
A total of 59 patients with AMI were randomly assigned to receive either CPC
(n=30) or BMC (n=29) into the infarct artery at 4.9  1.5 days after AMI.
Result
Conclusion
Intracoronary infusion of progenitor cells (either BMC or CPC) is safe and
feasible in patients after AMI successfully revascularized by stent implantation.
Both the excellent safety profile and observed favorable effect on LV remodelling,
provide the rationale for larger randimized doble-blind trials. (J Am Coll Cardiol
2004;44:1690-9)  2004 by the American Collage of Cardiology Foundation. 44
TRIAL DESIGN
59 patients with acute MI undergoing
successful PCI / sten revascularization
- LV angigraphy -
CPC
Intracoronary infusion of
circulating progenitor cells
Pregenitor cell theraphy
3 – 7 days
Post stent revascularization
BMC
Intracoronary infusion of
bone-marrow cells; n = 29
4 month clinical follow-up
n = 30
n = 29
12 months clinical follow-up
n = 30
n = 29
Patients excluded from exploratory analysis
Addational AMI
n=1
< 105 cells received
n=1
n=1
AMI & death
n = 27
*4 months LV angiography
n = 27
n = 27
* 4 & 12 months MRI
n = 18
n = 27
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Baseline Characteristics
46
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PROCEDURAL SAFETY OF INTRACORONARY
PROGENITOR CELL INFUSION
Procedural complications*
CRC (mg/dl)
Before cell theraphy
24 h after cell therapy
14 d after cell therapy (n=48)
4 months follow-up
Troponin
Before cell theraphy
24 h after cell therapy
14 d after cell therapy (n=48)
CPC
(n = 30)
0
BMC
(n = 29)
0
Both cell
Groups
( n = 54)
0
2.8±2.2 (2.0)
2.6±2.3 (1.8)
0.65±0.54 (0.5)
0.49±0.38 (0.3)
3.5±2.6 (2.6)
3.2±2.0 (2.8)
1.1±1.3 (0.6)
0.40±0.18(0.3)
3.1±2.4 (2.3)
2.9±2.2 (2.3)
0.82±0.97 (0.5)
0.44±0.30(0.3)
2.3±1.9 (1.7)
2.5±2.1 (1.9)
2.4±2.0 (1.85)
1.5±1.4 (1.2)
1.9±1.8 (1.5)
1.7±1.6 (1.4)
0.02±0.03 (0.01) 0.03±0.04(0.01) 0.03±0.04 (0.01)
Value are expressed as mean ± SD (median).
*Thrombosis, embolization, or disection related to cell infusion.
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CLINICAL
EVENTS
49
EVENTS-FREE SURVIVAL OF DEATH, RECURRENT MYOCARDIAL INFARCTION,
OR TARGET VESSEL REVASCULARIZATION (Kaplan-Meier analysis)
100
Infarct vessel revasc
Death, myocardial infarction,
Event-free survival (%)
90
80
70
76 %
60
50
40
30
20
10
0
number
exposed
to risk
0
59
100
57
57
200
46
45
300
45
45
days
45
50
LEFT VENTRICULAR ANGOGRAPHY: QUANTITATIVE GLOBAL AND
REGIONAL LEFT VENTRICULAR FUNCTION
51
Quantitative global
left ventricular ejection fraction (%)
A
p < 0.001
80
70
60
50
40
30
20
CPC
Initial
4 months
52
Quantitative global
left ventricular ejection fraction (%)
B
p < 0.001
80
70
60
50
40
30
20
BMC
Initial
4 months
53
CONCLUSION
 We still have mountains to
climb
 Alps for adult stem cells
 Himalayas for embryonic stem
cells
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