Nama : Prof. Dr. H. Djanggan Sargowo , dr., SpPD . , SpJP (K),

11

Nama Nama :: Prof. Dr. H. Djanggan SargowoProf. Dr. H. Djanggan Sargowo, dr., , dr., SpPDSpPD..,, SpJP(K), SpJP(K), FIHA, FACCFIHA, FACC, , FESC,FESC, FCAPC, FASCCFCAPC, FASCC

Tempat/Tgl lahirTempat/Tgl lahir :: Sragen, 21 September 1947 Sragen, 21 September 1947AlamatAlamat :: Wilis Indah E-10 Malang, Telp. 0341-552395Wilis Indah E-10 Malang, Telp. 0341-552395Pendidikan Pendidikan :: 1.1. Lulus Dokter dari UGM, tahun 1974Lulus Dokter dari UGM, tahun 19742.2. Lulus Cardiologist dari Univ. Indonesia, tahun 1983Lulus Cardiologist dari Univ. Indonesia, tahun 19833.3. Lulus Internist dari Univ. Airlangga, tahun 1986Lulus Internist dari Univ. Airlangga, tahun 19864.4. Lulus Doktor, Univ. Airlangga, tahun 1996Lulus Doktor, Univ. Airlangga, tahun 19965.5. Advanced Cardiology Course, Univ. Hongkong, tahun 1984Advanced Cardiology Course, Univ. Hongkong, tahun 19846.6. Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 19967.7. Fellow American College of Cardiology (FACC), September 2006.Fellow American College of Cardiology (FACC), September 2006.8.8. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember

200720079.9. Fellow European Sociaty of Cardiology (FESC), 2008Fellow European Sociaty of Cardiology (FESC), 200810.10. Fellow Asean Collage of Cardiology (FASCC), 2008Fellow Asean Collage of Cardiology (FASCC), 2008Jabatan :Jabatan :1.1. Dosen Pengajar Program Pascasarjana Universitas BrawijayaDosen Pengajar Program Pascasarjana Universitas Brawijaya2.2. Ketua MKEK Ikatan Dokter Indonesia Cabang Malang RayaKetua MKEK Ikatan Dokter Indonesia Cabang Malang Raya3.3. Ketua PERKI Cabang Malang RayaKetua PERKI Cabang Malang Raya4.4. Anggota Kolegium Kardiovaskuler IndonesiaAnggota Kolegium Kardiovaskuler Indonesia5.5. Dekan Fak. Kedokteran UDekan Fak. Kedokteran Univ. niv. WWijaya ijaya KKusuma Surabayausuma Surabaya6.6. Ketua Dewan Pengawas Rumah Sakit PendidikanKetua Dewan Pengawas Rumah Sakit Pendidikan7.7. Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. BrawijayaKetua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya

Curriculum VitaeCurriculum Vitae

22

STEM CELL THERAPHY INSTEM CELL THERAPHY INCARDIOVASCULAR DISEASESCARDIOVASCULAR DISEASES

Djanggan SargowoDjanggan Sargowo

Surabaya, 12 Mei 2012Surabaya, 12 Mei 2012

33

O V E R V I E WO V E R V I E W

What’s the problem?What’s the problem?Hype? Hype? Reality?Reality?Hope?Hope?Conclusions Conclusions

44

What’s the Problem ?What’s the Problem ?

55

U N M E T M E D I C A L U N M E T M E D I C A L N E E D N E E D

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

66

DEGENERATIVE DEGENERATIVE DISEASESDISEASES

Other examplesOther examples Alzheimer’s, spinal cord injuries, Amyotrophic Alzheimer’s, spinal cord injuries, Amyotrophic

Lateral Sclerosis, multiple sclerosis, liver Lateral Sclerosis, multiple sclerosis, liver disease etcdisease etc

Restoration of cell or organ functionRestoration of cell or organ functionCurrent drugs don’t treat the causeCurrent drugs don’t treat the causeOrgan transplantsOrgan transplants

Expensive, donor shortages, not applicable to Expensive, donor shortages, not applicable to many diseasesmany diseases


77

Coronary heart disease is Coronary heart disease is the #1 cause of morbidity the #1 cause of morbidity and mortality in the US.and mortality in the US.

CHF is the #1 cause of CHF is the #1 cause of hospitalization for those hospitalization for those age > 65 yo.age > 65 yo.

Annual health care costs Annual health care costs related to cardiovascular related to cardiovascular diseases was ~ $220 diseases was ~ $220 billion last year.billion last year.

Stem cell transplant is a Stem cell transplant is a promising and exciting promising and exciting therapy.therapy.

BackgroundBackground

2004 American Heart Association UpdateOrlic D, et al. Nature 2001

88Boenjamin Setiawan, dr.,PhD

Boenjamin Setiawan, dr.,PhD

Challenge: Knowledge Challenge: Knowledge ExplosionExplosion

““We are drowning in We are drowning in information but starved information but starved for knowledge.”—Naisbitt, for knowledge.”—Naisbitt, ‘82‘82

99

1010

Bone marrow stem cells (BMSC)Bone marrow stem cells (BMSC) Endothelial progenitor cells (EPC)Endothelial progenitor cells (EPC) Mesenchymal stem cells (MSC)Mesenchymal stem cells (MSC) Skeletal myoblasts (SKM)Skeletal myoblasts (SKM) Embryonic stem cells (ESC)Embryonic stem cells (ESC) Cardiac stem cells (CSC)Cardiac stem cells (CSC) Cardiac progenitor cells (isl1+)Cardiac progenitor cells (isl1+)

AVAILABLE STEM AVAILABLE STEM CELLSCELLS

**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]

Shinya Yamanaka & James Thomsonpotential Nobel Prize Winners in the

FutureShinya 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.Boenjamin Setiawan, dr.,PhD

1111

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.,PhD1212

Induced pluripotent stem cells – the science and technology

Chi-Wei Lu, Ph.D.

Assistant Professor, RWJMS/UMDNJ

Director, Human Embryonic Stem Cell Facility

Albert Lasker Basic Medical Research Award, 2009

1313Boenjamin Setiawan, dr.,PhD

1414

EMBRYONIC STEM EMBRYONIC STEM CELLSCELLS

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


1515

EMBRYONIC STEM CELLS EMBRYONIC STEM CELLS SURVEYSURVEY

ES cell therapy is 10-15 years awayWill 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


1616

ADULT STEM CELLSADULT 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


1717

CLINICAL USE OF ADULT STEM CLINICAL USE OF ADULT STEM CELLSCELLS

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


23/05/2010, Seminar Univ Brawijaya 1818


1919

INDUCED INDUCED PLURIPOTENT CELLS PLURIPOTENT CELLS

AND AND TRANSPLANTATION TRANSPLANTATION

THEORYTHEORY Adult cellsAdult cells(skin fibroblasts)(skin fibroblasts)

OCT4OCT4SOX2SOX2KLF4KLF4(Myc)(Myc)

OCT4OCT4SOX2SOX2

NANOGNANOGLin28Lin28

Self Self renewalrenewal

iPS cellsiPS cells

Genetic repair by homo- Genetic repair by homo- logous recombination logous recombination

(if necessary)(if necessary)

DifferentiationDifferentiation

In vitro screening of In vitro screening of drug candidates on drug candidates on

healthy and healthy and diseased cellsdiseased cells

Tranplan-Tranplan-tationtation

Healthy or diseases Healthy or diseases adult human or adult human or mousemouse

Endothelial Progenitor Cells

Hematopoietic SCsMesenchymal SCs

HemangioblastsSP cellsMAPC

Sca-1+ cellsMyoblastsSP cells

Mesenchymal SCsSPcells

Cell Sources for Cardiac Repair

CSC

Acute Chronic

2121

CARDIAC PROGENITOR CARDIAC PROGENITOR CELLS IN THE FETAL CELLS IN THE FETAL AND ADULT HEARTAND ADULT HEART BlastocystBlastocyst Fetal or adult heartFetal or adult heart

ES cellsES cells

Cardiovascular Cardiovascular differentiationdifferentiation

In vitro In vitro differentiationdifferentiation TranplatationTranplatation

In vivo differentiation

Vascular smooth muscle cells, endothelial cells or cardiomyocytes

Vascular smooth muscle cells, endothelial cells or cardiomyocytes

Tissue engineeringMice & other Mice & other

speciesspeciesTranplatationTranplatation

Cardic progenitor cellsCardic progenitor cells(Kit+, SCA1+, SP or MDR1+)(Kit+, SCA1+, SP or MDR1+)

(NKX2 2-5+ or lsl1+) (NKX2 2-5+ or lsl1+)

2222

TRANSPLANTATION TRANSPLANTATION STRATEGY FOR STRATEGY FOR

CARDIAC REPAIRCARDIAC REPAIR

Human ES Human ES cellscells

Differentiating Differentiating human ES cellshuman ES cells

ES-cell-derived ES-cell-derived cardiomyocytescardiomyocytes

Cardiac Cardiac progenitor cellsprogenitor cells

Cell injected into the Cell injected into the myocardium of myocardium of imunodeficient mice after imunodeficient mice after myocardial infarctionmyocardial infarction

Functional analysis by Functional analysis by magnetic resonance magnetic resonance

imaging, ultrasonography imaging, ultrasonography or pressure-volume loopsor pressure-volume loops

Analysis after Analysis after immunostaining of heart immunostaining of heart tissue sectionstissue sections

Adult stem cells Adult stem cells from bone marrowfrom bone marrow

2323

THERAPEUTIC THERAPEUTIC IMPLICATIONS IMPLICATIONS OF CARDIAC OF CARDIAC PROGENITOR PROGENITOR

CELLSCELLS

HumanHuman Mouse

BlastocystBlastocystFetalFetal AdultAdult

Pluripotency Pluripotency genesgenes

Skin

-actinin-actinin PECAMPECAM SMASMA

Models of heart development Models of heart development Models of diseaseModels of disease

Drug testingDrug testingTissue engineering Tissue engineering

CARDIAC THERAPHYCARDIAC THERAPHY

iPS cellsiPS cellsES cellsES cells

CARDIAC PROGENITOR CELLSCARDIAC PROGENITOR CELLS

Tissue Engineered Myocardium

From www.aic.cuhk.edu.hk/web8/Hi%20res/Heart.jpg

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 2424


Decrease in EPCs associated with CV disease

Werner N, Nickenig G. Arterioscler Thromb Vasc Biol. 2006;26:257-66.

Endothelial Progenitor Cells

Atherosclerosis

Improvement of endothelial function

Enhanced re-endothelialization

Reduced plaque size

Improved angiogenesis

Myocardial infarction

Ischemic stroke

Erectile dysfunction

Renal insufficiency

Peripheral artery disease

Disease Regression? Disease Progression

Vasculoprotective agents CV risk factors

EPCs in CV diseasesEPCsEPCs

TherapeuticsTherapeuticsPathophysiologyPathophysiology

AtherosclerosisAtherosclerosis

Heart diseaseHeart disease

Peripheral vascular diseasePeripheral vascular disease

CV risk factorsCV risk factors

Endothelial dysfunctionEndothelial dysfunction

CollateralsCollaterals

RestenosisRestenosis

CV diseaseCV 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 CADHill JM et al. N Engl J Med. 2003;348:593-600.

2828

tPA

EC

SMC

Pal-1

Pal-1

Pal-1

tPA

Pal-1EC

SMC

Normal vessel

Atherosclerotic plaque

Christ et al., Senescent SMCs Increase Vascular Wall PAI-1 ExpressionChrist et al., Senescent SMCs Increase Vascular Wall PAI-1 Expression

2929

Resting endothelial cell Procoagulant, antifibrinolytic matrix-degrading, leukocyte binding endothelial cell

IL-1, TNF

Collagen Elastin

CollagenaseGelatinasesElastolyticenzimesClass II MHC

Antigen

T-cell antigen receptor

T-lymphocyte

IFN TNF

Activatedmatrix-degrading

smooth muscle cell

IL-1TNF

Apoptoticsmooth

muscle cell

Restingsmooth muscle cell

3030

Unstable Unstable Coronary Coronary Artery Artery Disease (II) Disease (II)

Thrombus forms and extends into the lumen

Adventitia

Thrombus

Lipid core

3131

Clinical classification of ACS

Acute Coronary Syndrome (ACS)Acute Coronary Syndrome (ACS)

No ST ElevationNo ST Elevation ST ElevationST Elevation

Unstable Unstable Angina Angina PectorisPectoris

MI (NSTEMI)MI (NSTEMI) MI (STEMI)MI (STEMI)

No Q-waveNo Q-wave Q-waveQ-waveNational Heart Foundation of Australia, Cardiac Society of Australia and New Zealand.Med J Aust 2000;173 (suppl):S65–S88

3232

BACKGROUND ON BACKGROUND ON REMODELLINGREMODELLING

Acute infarctionAcute infarction(hours)(hours)

Infarct expansionInfarct expansion(hours to days)(hours to days)

Global remodellingGlobal remodelling(days to months)(days to months)

Improvement of LV remodelling has been Improvement of LV remodelling has been associated with improvement in mortality and associated with improvement in mortality and morbidity outcomes in CHFmorbidity outcomes in CHF

3333

MANAJEMEN SKA

- Oklusi > 4-6 jam Nekrosis miokard irreversibleIMA dengan gel q (IMA-Q)

- Reperfusi Menurunkan morbiditas - mortalitas

- Fase Pre hospital stageHospital stage : - IGD

- CVCU

3434

23/05/2010, Seminar Univ Brawijaya 3535


3636

CELL-TRANSPLATATION STUDIES IN MODELS OF EXPERIMENTAL CELL-TRANSPLATATION STUDIES IN MODELS OF EXPERIMENTAL MYOCARDIAL INFARCTIONMYOCARDIAL INFARCTION

RC Trials using Intracoronary BMC post MI

LEUVEN-AMI

MI size

ND

ND

P=n.s.

ND

-28%(P=0.03)

(n=60)

(n=84)

(n=184)

(n=67)

FINCELL +7.1% (P=0.05) ND (n=80)

+ 2.8% (P=n.s.)*

* 18-months follow-up

04/21/23

Myocardial Homing and Biodistribution of 18F-FDG-labeled BMC 50 to 75 min after Transfer

Hofmann et al., Circulation 2005; 111: 2198-202

Unselected BMC

CD34-enriched BMC

1.3% to 2.6% in infarct (center)

14% to 39%in infarct (border zone)

3D PET

Schachinger, V. et al. Circulation 2008;118:1425

111In uptake in patient after an anterior AMI (cell administration 5 days after acute PCI)

111In uptake in patient after an anterior AMI (cell administration 5 days after acute PCI)

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

– 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.

Science Push!

4343

EXPEDITED REVIEWEXPEDITED REVIEW

Transplantation of Progenitor Cells Transplantation of Progenitor Cells and Regeneration Enhancement and Regeneration Enhancement

in Acute Myocardial Infarctionin Acute Myocardial Infarction

Final One-Year Results of the Final One-Year Results of the TOPCARE-AMITOPCARE-AMI Trail Trail

4444

ObjectivesObjectives

BackgrouBackgroundnd

MethodMethod

ResultResult

ConclusioConclusionn

The Transplantation of Progenitor Cells And Regeneration Enhancement in Acute The Transplantation of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial investigates both safety, feasibility, Myocardial Infarction (TOPCARE-AMI) trial investigates both safety, feasibility, and potential effect on parameters of myocardial function of intracoronary and potential effect on parameters of myocardial function of intracoronary infusion of either circulating progenitor cells (CPC) or bone marrow-derived infusion of either circulating progenitor cells (CPC) or bone marrow-derived progenitor cells (BMC) in patients with acute myocardial infarction (AMI)progenitor cells (BMC) in patients with acute myocardial infarction (AMI)

A total of 59 patients with AMI were randomly assigned to receive either CPC 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 (n=30) or BMC (n=29) into the infarct artery at 4.9 1.5 days after AMI. 1.5 days after AMI.

Intracoronary infusion of progenitor cells (either BMC or CPC) is safe and Intracoronary infusion of progenitor cells (either BMC or CPC) is safe and feasible in patients after AMI successfully revascularized by stent implantation. feasible in patients after AMI successfully revascularized by stent implantation. Both the excellent safety profile and observed favorable effect on LV Both the excellent safety profile and observed favorable effect on LV remodelling, provide the rationale for larger randimized doble-blind trials. (J Am remodelling, provide the rationale for larger randimized doble-blind trials. (J Am Coll Cardiol 2004;44:1690-9) Coll Cardiol 2004;44:1690-9) 2004 by the American Collage of Cardiology 2004 by the American Collage of Cardiology Foundation. Foundation.

4545

TRIAL DESIGNTRIAL DESIGN59 patients with acute MI undergoing 59 patients with acute MI undergoing

successful PCI / sten revascularizationsuccessful PCI / sten revascularization- LV angigraphy -- LV angigraphy -

CPCCPCIntracoronary infusion of Intracoronary infusion of

circulating progenitor cellscirculating progenitor cells

n = 30n = 30

n = 30n = 30

n = 29n = 29

n = 29n = 29

n = 27n = 27 n = 27n = 27

n = 27n = 27

n = 27n = 27n = 18n = 18

Pregenitor cell theraphyPregenitor cell theraphy3 – 7 days3 – 7 days

Post stent revascularizationPost stent revascularization

BMCBMCIntracoronary infusion of Intracoronary infusion of

bone-marrow cells; n = 29bone-marrow cells; n = 29

4 month clinical follow-up4 month clinical follow-up

12 months clinical follow-up12 months clinical follow-up

Patients excluded from exploratory analysis Patients excluded from exploratory analysis

Addational AMIAddational AMI n = 1 n = 1

< 10< 1055 cells received cells received n = 1 n = 1

*4 months LV angiography*4 months LV angiography

* 4 & 12 months MRI* 4 & 12 months MRI

n = 1 AMI & deathn = 1 AMI & death

4646

Baseline CharacteristicsBaseline Characteristics

4747

4848

PROCEDURAL SAFETY OF PROCEDURAL SAFETY OF INTRACORONARY PROGENITOR INTRACORONARY PROGENITOR

CELL INFUSIONCELL INFUSION Both cellBoth cell

CPCCPC BMCBMC GroupsGroups(n = 30)(n = 30) (n = 29)(n = 29) ( n = 54)( n = 54)

Procedural complications*Procedural complications* 00 00 00CRC (mg/dl)CRC (mg/dl) Before cell theraphyBefore cell theraphy 2.8±2.2 (2.0)2.8±2.2 (2.0) 3.5±2.6 (2.6)3.5±2.6 (2.6) 3.1±2.4 (2.3)3.1±2.4 (2.3) 24 h after cell therapy24 h after cell therapy 2.6±2.3 (1.8)2.6±2.3 (1.8) 3.2±2.0 (2.8)3.2±2.0 (2.8) 2.9±2.2 (2.3) 2.9±2.2 (2.3) 14 d after cell therapy (n=48)14 d after cell therapy (n=48) 0.65±0.54 (0.5)0.65±0.54 (0.5) 1.1±1.3 (0.6)1.1±1.3 (0.6) 0.82±0.97 (0.5)0.82±0.97 (0.5) 4 months follow-up4 months follow-up 0.49±0.38 (0.3)0.49±0.38 (0.3) 0.40±0.18(0.3)0.40±0.18(0.3) 0.44±0.30(0.3)0.44±0.30(0.3)

TroponinTroponin Before cell theraphyBefore cell theraphy 2.3±1.9 (1.7)2.3±1.9 (1.7) 2.5±2.1 (1.9)2.5±2.1 (1.9) 2.4±2.0 (1.85) 2.4±2.0 (1.85) 24 h after cell therapy24 h after cell therapy 1.5±1.4 (1.2)1.5±1.4 (1.2) 1.9±1.8 (1.5)1.9±1.8 (1.5) 1.7±1.6 (1.4) 1.7±1.6 (1.4) 14 d after cell therapy (n=48)14 d after cell therapy (n=48) 0.02±0.03 (0.01) 0.02±0.03 (0.01) 0.03±0.04(0.01)0.03±0.04(0.01) 0.03±0.04 (0.01)0.03±0.04 (0.01)

Value are expressed as mean ± SD (median). Value are expressed as mean ± SD (median). *Thrombosis, embolization, or disection related to cell infusion.*Thrombosis, embolization, or disection related to cell infusion.

4949

CLINICCLINICAL AL

EVENTEVENTSS

5050

EVENTS-FREE SURVIVAL OF DEATH, RECURRENT EVENTS-FREE SURVIVAL OF DEATH, RECURRENT MYOCARDIAL INFARCTION, OR TARGET VESSEL MYOCARDIAL INFARCTION, OR TARGET VESSEL

REVASCULARIZATION REVASCULARIZATION (Kaplan-Meier analysis)(Kaplan-Meier analysis)

0 100 200 300 0 100 200 300 daysdaysnumbernumberexposed 59 57 57 46 45 45 45 45exposed 59 57 57 46 45 45 45 45to riskto risk

76 %76 %

100100

9090

8080

7070

6060

5050

4040

3030

2020

1010

00

Ev

ent-

fre

e s

urv

iva

l (%

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ven

t-fr

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su

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%)

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th,

myo

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infa

rcti

on

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, m

yoca

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l in

farc

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n,

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rct

vess

el r

evas

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t ve

ssel

rev

asc

5151

LEFT VENTRICULAR ANGOGRAPHY: LEFT VENTRICULAR ANGOGRAPHY: QUANTITATIVE GLOBAL AND REGIONAL LEFT QUANTITATIVE GLOBAL AND REGIONAL LEFT

VENTRICULAR FUNCTIONVENTRICULAR FUNCTION

5252

8080

7070

6060

5050

4040

3030

2020

CPCCPC

Qu

an

tita

tiv

e g

lob

al

Qu

an

tita

tiv

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lob

al

left

ve

ntr

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lar

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on

fra

cti

on

(%

) le

ft v

en

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ula

r e

jec

tio

n f

rac

tio

n (

%)

Initial 4 monthsInitial 4 months

p < 0.001p < 0.001AA

5353

8080

7070

6060

5050

4040

3030

2020

BMCBMC

Qu

an

tita

tiv

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al

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n (

%)

Initial 4 monthsInitial 4 months

p < 0.001p < 0.001BB

5454

CONCLUSIONCONCLUSION We still have mountains to We still have mountains to

climbclimb

Alps for adult stem cellsAlps for adult stem cells

Himalayas for embryonic stem Himalayas for embryonic stem cellscells

5555

Nama : Prof. Dr. H. Djanggan Sargowo , dr., SpPD . , SpJP (K),

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