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STEM CELL THERAPY IN HEART FAILURE

Yudi Her Oktaviono


Department of Cardiology and Vascular Medicine
DR. Soetomo Teaching Hospital
Faculty of Medicine-Airlangga University,
Surabaya, Indonesia
The Hype
The Hype
New paradigm for CV disease
• Human heart can regenerate
– Bone marrow derived stem cells (BMCs)
– Circulating progenitor cells (CEPCs)
– Circulating hematopoietic stem cells
– Resident stem cells

• With certain risk conditions (eg, hypertension,


diabetes, hypercholesterolemia, aging) and diseases
(eg, ischemic heart disease) stem cells are inadequate
(number/quality/time)
The Background
STEM CELL IN HEART FAILURE
HEART FAILURE
Cause
Ischemic
Nonischemic

Pathogenesis
cell death/inflammation/scar/loss of contractility

Natural history
5-year mortality of approximately 50% .

Financial Burdon
HF creates a heavy burden on health care resources

Medical Rx
improve symptoms and can prolong life
but are unable to replace scar tissue or awaken hibernating myocardium via
angiogenesis.
Peranan EPC pada pemeliharaan endotel

Jonathan Hill, 2004


Damaged Myocardium Repair

Grounds MD et al. J Histochem Cytochem. 2002;50:589-610.


HYPOTHESIS

• Increase number of
effective myocardial cells

• Increase number of blood


vessels Improve cardiac
function
THE STEM CELL
CONUNDRUM
ISCHEMIC HEART
FAILURE
Stem Cell Science: Achievement Todate?

• Much biological
information from the first
study in 2001

• Can stem cell therapy


correct/regenerate blood
vessels and/or
myocardium?
Some Unresolved Issues
• Which cells type?
• Which mode of delivery
• Tailored administration in clinical scenarios
• What dose?
• Adjunctive therapyImmunogenecity
• How effective / How risky
• Optimal timing of therapy
• Ethical timing of therapy
• Durability of therapy
Stem Cells
• The most important component in
regenerative medicine
• Cell that has ability to asymmetrical
division, self renewal and differentiation to
another cells
• Type:
• Haematopoitic stem cells (HSCs)
• Mesenchymal stem cells (MSCs)

• Classification:
• Embryonal stem cells
• Adult stem cells

• Differentiation (plasticity): Totipotent,


Pluripotent, Multipotent, Unipotent
Stem Cell Therapy in PAD and CAD
Neo-Revascularization
Role of The Stem Cells
in Cardiac Regeneration Therapy
• As a cell, As a factory, As a courier
Stem Cell Mechanism

Gnecchi et al; Circ Res. 2008;103:1204–1219


Neuseux et al :2011 Stem Cells in Clinic and Research
Nygren et al :Nat Med. 2004;10:494–501.
Reinecke et al : Circ Res. 2008;103:1058–1071
Stem Cells
Source of cell
• Embryonal stem cells
• Totipotent, pluripotent
• Teratogenic formation
• IVF (in vitro fertilization)
• Controversy (ethic and religion)
• Forbidden in Indonesia
Embryonic Stem Cell
• Embryonic stem cells = derived
from embryonic and fetal
tissue
– Totipotent: capable of
developing into any cell of an
organism eg. Zygote
– Pluripotent: capable of
developing into most tissues
except the placenta eg.
Embryonic stem cell
– Multipotent: capable of
developing into limited number
of tissues eg. Adult stem cells
Adult Stem Cells
• Bone marrow stem cells
(BMSC)
• Adipose stem cells (ADS)
• Umbilical cord stem cells
(UCS)
• From each organs
• Biology:
• Multipotent, unipotent
• Transdifferentiation
• Less risk to
tumorogenesis
Why Use Adult Stem Cell?
• Readily available
• Easy to isolate
• Autologous
• No ethical concerns
Transplantasi Stem Cell
Routes of Delivery in Stem Cell Theraphy

Strauer BE. Kornowski R. Circulation 2003;107:929-34


The Limitations
27
Conduction
• After the MSCs undergo differentiation it is
essential that they also acquire the electrical
properties of cardiac myocytes
– Electrical conduction through the differentiated MSCs
is attributed to the development of gap junctions,
which are seen at the interfaces between the MSCs
themselves and between the MSCs and cardiac
myocytes.
30
The Effects Of Garlic Extract (Allicin) On Endothelial Progenitor Cell (EPC)
Proliferation In Patients with Stable Coronary Artery Disease
0.3 0.5

0.25
0.375 p < 0.05

Cell Proliferation
P=

Sel (0.D)
Cell Proliferation
(O.D)Sel (0.D)

0.2
0.000 p < 0.05 10 μg/ml

(O.D)
0.15 Kontrol 0.25 p = 0.000

Proliferasi
50 μg/ml
Proliferasi

Control
p = 0.005
Allicin
0.1
0.281 0.39 100 μg/ml
0.194 Allicin
0.125
0.267 0.281
0.05

0 0
Allicin
KONTROL
Control ALLICIN
Allicin Allicin

There is a significant increase of EPC proliferation There is a significant difference of EPC proliferation
in stable coronary artery disease patients within in stable coronary artery disease patients whose
garlic extract (Allicin) group compared to control treated low, medium, and high dose of garlic
group extract (Allicin) and the increment shows dose-
dependently.
EPC proliferation in Statin vs Control Group
0.000 0.3 0.25 0.000
0.25 0.000
0.25
0.2

Cell Proliferation (O.D)


0.2

Cell Proliferation (O.D)


Cell Proliferation (O.D)

0.2
0.15 Control Control 0.15 Control
0.15
0.1 Simvastatin Atorvastatin 0.1 Rosuvastatin
0.1
0.1 µmol/L 0.1 µmol/L 0.1 µmol/L
0.05 0.05 0.05

0, 0, 0, 0,
0 0 24 0 0, 0,2
23 31
7 8
†Analyzed with Independent T test
Simvastatin, atorvastatin, and rosuvastatin increase EPC
proliferation from peripheral blood of stable coronary artery
disease patient compared with control
EPC Proliferation between Statin Groups
Result

0.25 0.000 0.000


There are differences between the
0.245
effect of simvastatin, atorvastatin,
Cell Proliferation (O.D)

0.24 0.025
and rosuvastatin on EPC proliferation
Rosuvastatin
0.235
Simvastatin from peripheral blood of stable
Atorvastatin
0.23 coronary artery disease patient.
0.225 Atorvastatin has the highest effect,
0.22
0.231 0.237 0.248
followed by simvastatin, and
†Analyzed with ANOVA, LSD test rosuvastatin
Effect of Captopril, Ramipril, and Lisinopril on Endothelial Progenitor Cell (EPC)
Proliferation in Patients with Stable Coronary Artery Disease
Captopr Ramipri Ramipri
Captopr il 50 l 10 l 50
il 10 µmol/L, Ramipri µmol/L µmol/L
µmol/L, 0.2605 l2 2, 2, 0.264
Captopr
0.24375 µmol/L, 0.253…
il 2
0.2362
µmol/L,
5
0.23088

Lisinopril 50
Lisinopril 10 µmol/L, 0.28288
Lisinopril 2 µmol/L, µmol/L, 0.26475
0.24625
ON GOING CLINICAL TRIAL
• INTRA CORONARY INJECTION EPC FOR NO OTHER OPTION TREATMENT
CORONARY ARTERY DISEASE .

• INTRA ARTERY INJECTION ENDOTELIAL PROGENITOR CELL FOR CRONIC


LIMB ISCHAEMIA
Cell Therapy in Failing Heart
• GOAL
– Transfer of functional myocytes to heart – improve its function
– The DEALS “Homing of grafted cells”
– Engraft into non functional scar
– Electromechanical coupling and synchronisation
– Neo angiogenesis and myogenesis
– Good craft survival
– Low immunogenecity
– Ethical acceptance
– Low oncogenicity
– Case of application
Cell Therapy in Failing Heart
Risks vs Benefits
Risks Benefits
• Highly invasive procedures except • Clinical trials have shown
for IV infusion improvement of both systolic and
diastolic function after transplant of
• Susceptible to re-entrant
MSC
arrythmias
• Increase in left ventricular ejection
• Risk of propagating genetic fraction (LVEF)
defects • Decrease in the area of functional
• Tumors defect
• Increase in the wall movement
velocity of the infarcted area
Current status:
Provacel
• FDA has approved Phase 1 clinical trial for
Provacel an interventional therapy using
product of an adult MSC
MSCs to prevent heart failure resulting • Control group
from an acute myocardial infarction,
sponsored by Osiris Therapeutics Inc.
• 53 patients are admitted in this double-
blind, placebo-controlled, dose escalating,
multicenter, randomized trial and were
treated using allogenic MSCs which were
• Experimental group treated using
delivered through a standard IV line within
7 days of suffering from a first MI. Provacel
• These patients are going to be followed
for a period of 2 years to demonstrate the
safety of the products and to evaluate
preliminary efficacy data.
Conclusion
• Preclinical and human trials have showed short term benefits of
using EPCs,MSCs

• Further studies are warranted to help design treatments that are


best suited for heaert failure

• Thus although EPCs, MSCs transplants have a long way to go from


the laboratory to the patient’s bedside, they do show promise, that
their use will help improve the quality of life of the patients and
reduce progression to heart failure
DIFFICULT ROAD OFTEN CARRIES
TO A BEAUTIFUL DESTINATION