Stem cell therapy for cardiac dysfunction
Amer A Matar
1
James JH Chong
0
1
0
Department of Cardiology, Westmead Hospital
,
Sydney, NSW, Australia
1
Sydney Medical School, University of Sydney
,
Sydney, NSW, Australia
Following significant injury, the heart undergoes induced compensation and gradually deteriorates towards impending heart failure. Current therapy slows but does not halt the resultant adverse remodeling. Stem cell therapy, however, has the potential to regenerate or repair infarcted heart tissue and therefore is a promising therapeutic strategy undergoing intensive investigation. Due to the wide range of stem cells investigated, it is difficult to navigate this field. This review aims to summarize the main types of stem cells (both of cardiac and extra-cardiac origin) that possess promising therapeutic potential. Particular focus is placed on clinical trials supporting this therapeutic strategy.
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Introduction
Myocardial infarction (MI) remains a leading cause of
death and disability worldwide. In the United States
alone, approximately 1 million cases of MI occur
annually (Roger et al. 2011). The implementation of
cardiovascular prevention strategies continues to reduce the
incidence of MI. Concurrently, however, evolution of
pharmacological approaches and coronary reperfusion
interventions has led to an increased post-MI survival
rate, which in turn has raised MI disease morbidity.
Previous estimates indicate that approximately 9095% of
patients survive their first MI (Rosamond et al. 2012),
contributing to a current epidemic of heart failure and
imposing an enormous health burden on individuals and
the community.
After MI, local cardiac compensatory mechanisms are
activated giving rise to a vicious cycle of cardiac metabolic
insufficiency, leading to heart failure and potentially
sudden death (Orn et al. 2007). Timely reperfusion together
with optimal drug and device-based interventions has
improved MI management by reducing the initial burden of
injury and slowing progression of resultant adverse
remodeling (White et al. 2005). Nevertheless, no current
therapy is able to reverse the inexorable decline in cardiac
function. Therefore, new strategies investigating cardiac
regeneration have demanded considerable interest. These
involve either 1) the implantation of stem cells or their
derivatives directly into the heart or 2) the activation of
endogenous cardiac repair mechanisms in order to replace
damaged cardiomyocytes and promote vascular
reconstruction (Laflamme and Murry 2011).
This review provides physicians with a concise
overview of the major types of stem cells, both from cardiac
or extra-cardiac origins, being investigated for post-MI
treatment. For further detail and information on
endogenous cardiac regeneration, the interested reader is
directed to the following detailed reviews (Laflamme and
Murry 2011; Choi and Poss 2012; Rasmussen et al.
2011).
Extra-cardiac stem cells
Skeletal myoblasts
Skeletal myoblasts (SKM) are the progenitor cells of
skeletal muscle. Initial observations that SKMs could be
harvested from an autologous origin, easily expanded ex vivo
and undergo spontaneous differentiation into contractile
muscle sparked interest in SKMs for cardiac myoplasty
(Taylor et al. 1998). Early uncontrolled clinical studies
reported that SKMs could engraft in the injured heart with
remarkable efficiency and enable significant improvement
in cardiac function (Menasche et al. 2003). These findings
were not reproduced in a subsequent prospective
randomized placebo-controlled trial (Menasche et al. 2008), where
97 participants with severe left ventricular (LV)
dysfunction underwent transepicardial autologous SKM injection
at the time of coronary artery bypass grafting. Six months
following the procedure, no improvement in LV function
was found when compared to placebo. Importantly, a high
prevalence of ventricular tachyarrhythmias was observed
leading to premature discontinuation of the trial. Similar
results were observed in the SEISMIC trial which used
transendocardial injection of autologous SKMs (Veltman
et al. 2008). A follow-up study conducted four years later
reported no significant change in LV function compared
to the placebo group.
The general consensus amongst clinicians now is that
SKMs do not electrically couple to host cardiomyocytes
(Leobon et al. 2003). Notably, it is now understood that
the gap-junction protein, connexin 43, can augment
intracellular coupling of cardiomyocytes and confers a
protective effect against ventricular tachyarrhythmias
following cell transplantation (Roell et al. 2007).
Bone marrow mononuclear cells
The major stem cell type in the bone marrow (BM) is
the hematopoietic stem cell (HSC). HSCs comprise less
than 0.1% of unfractionated bone marrow mononuclear
cell (BMMNC) samples (Challen et al. 2010). Although
the vast majority of BMMNCs are not stem cells, they
are still considered a significant source of hematopoietic
progenitors which may be useful for cardiac repair. In
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