Stem Cell and Regeneration

Medicine as Breakthrough
Heart Failure Management

Isman Firdaus, MD
FIHA, FAPSIC, FAsCC, FESC, FSCAI
JOHN DOE, MD
SUBTITLE 32 PT ARIAL BOLD ITALICS
Pusat Jantung Nasional - Harapan Kita Hospital
Departement of Cardiology and Vascular Medicine
Faculty of Medicine, Universitas IndonesiaTALICS
 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: 143–159 2

 Stem cell therapy
 Clinical trials focused on 3 main situations:

 Acute MI (with the hope of preventing LVSD)

 Heart failure secondary to previous MI
 DCM (non ischemic cardiomyopthy)
 Highlight:

1. Stem cell types used in cardiac repair

2. Methods of cell delivery in clinical practice

3. Clinical trial evidence to date

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 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

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Signature characteristic of the stem cell

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Sources of stem cells for cardiac regeneration
and potential reparative mechanisms

Sanganalmath S, Bolli R. Circulation Research 2013;113:810-834

Implantation of stem cells
 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
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competent organ
 Bone marrow stem cells

 Bone marrow–derived 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)

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 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

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 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. 2010;122:80-87 12
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 13
Summary of cell types used in clinical trials and future perspective

Circulation. 2010;121:325-335 14
 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)

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 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.
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 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 17
 Mobilization and homing

Homing is mediated by :
 Adhesion
Transmigration
 Invasion

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Prerequisite for cell-based therapies

Summary of prerequisite for

cell-based therapies

Circulation. 2010;121:325-335 19
 Clinical studies using MSCs

342 studies examining the effects of MSCs

160 studies examining the effects of MSCs in heart failure

http://clinicaltrials.gov (September 2013)

Use of various types of stem cell therapies in
patients
with cardiovascular disease

ALCADIA
CADUCEUS
SCIPIO

Sanganalmath S, Bolli R. Circulation Research 2013;113:810-834

 Trials with Negative results:
Late-TIME, Transplantation in Myocardial Infarction Evaluation
Cardiovascular Cell Therapy Research Network [CCTRN]
TIME

Trials with Positive results:

Percutaneous Stem Cell Injection Delivery Effects on
Neomyogenesis (POSEIDON)
Cardiac Stem Cells in Patients with Ischemic Cardiomyopathy
(SCIPIO)
Cardiosphere-derived Autologous Stem Cells to Reverse
Ventricular Dysfunction (CADUCEUS)
 Open label, non-randomized, prospective study

 Intracoronary BMC therapy improves ventricular performance,

quality of life, and survival in patients with heart failure

 These effects were present when BMC were administered in

addition to standard therapeutic regimes

 No side effects were observed

STAR-heart study

Eur J Fail. 2010 Jul;12(7):721-9.

 Phase 1/2 randomized comparison with 13-month follow-up
(n=30)

 Absence of significant alloimmune reactions in patients

receiving allogeneic MSCs

 Cell therapy may not only improve left ventricular structure but
may also improve quality of life and functional capacity
JAMA. 2013 Aug 21;310(7):750
Change in New York Heart Association Classification
Quality of Life

JAMA. 2013 Aug 21;310(7):750

 Circulation. 2012;126:S54–S64

 CSC infusion produces a striking improvement in both

global and regional LV function

 Reduction in infarct size

 Increase in viable tissue that persist at least 1 year and

are consistent with cardiac regeneration
 SCIPIO trial – LVEF
Baseline (27.5 ± 1.6%)
4 months after CSC infusion (35.1 ± 2.4%),
12 months after CSC infusion (41.2 ± 4.5%).

Circulation. 2012;126:S54–S64
 Meta-analysis of 29 studies (1830 patients)

 Intracoronary BMSC therapy post-STEMI improves LVEF beyond

standard medical treatment, in both the short and longer term
Effect of intracoronary BMSC on LVEF at 3–6 months

Zimmet H et al. Eur J Heart Fail 2012;14:91-105

Effect of intracoronary BMSC on LVEF at 12–18 months

Zimmet H et al. Eur J Heart Fail 2012;14:91-105

 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 2006;367:113–21

2 Lunde K et al. N Eng J Med 2006;355:1199–209
3Alexander Hirsch et al. Eur Heart J 2010 32
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

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 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.

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