Despite the recent advances in percutaneous inter ven-
tion, drug and device therapy, patients with acute myo-
cardial infarction (AMI) and resulting left ventricular
impairment have 13% mortality at 1 year . Following
the loss of over one billion cardiomyocytes in a func-
tionally signifi cant MI, the overloaded surviving cardio-
myocytes undergo abnormal remodelling, eventually
leading to heart failure. Th is condition, a leading cause of
death and disability in the developed world, is associated
with 5-year mortality rates of up to 70% in symptomatic
patients . Current conventional therapies do not correct
underlying defects in cardiac muscle cell number .
Th e only therapeutic option that currently addresses
cardiomyocyte loss is heart transplantation. However,
due to stringent selection criteria and chronic shortage of
donor hearts, the vast majority of patients are deemed
unsuitable or never receive a transplant. Th erefore,
preventing this progression post-MI is a major challenge
requiring novel therapeutic strategies such as stem cell
transplantation to improve the prognosis and quality of
life for these patients.
Th e traditional view that the heart is a terminally
diff erentiated organ has been challenged by the discovery
of diff erentiation of stem cells into cardiomyocytes in
animal and human hearts [4-7]. Th is in turn has led to
the exciting possibility for regenerative therapy for
cardio myocyte loss after a MI. Th e demonstration of
functional recovery of myocardium through cardiomyo-
genesis and neoangiogenesis in AMI in murine models
by Orlic and colleagues  generated tremendous interest
in the potential of bone marrow-derived stem cells. Since
then, the cardiomyogenic ability of these cells has been
challenged. However, studies continue to demon strate
improvement in cardiac function and reduction in infarct
size. It should be noted that progenitor cells also
contribute to cardiac repair by mechanisms beyond the
growth of new cardiomyocytes and as such may off er an
‘indirect’ benefi t.
Animal and human trials
Th e most promising and obvious cell type for the growth
of new cardiomyocytes is the embryonic stem cell;
however, considerable technical and ethical issues exist
with these cells, which must be overcome before their
successful use in humans. Adult stem cells are an
attractive option to explore for transplantation as they
are autologous, but their diff erentiation potential is more
restricted than embryonic stem cells. Currently, the
major sources of adult cells used for basic research and in
clinical trials originate from the bone marrow. Th e bone
marrow mononuclear subset is heterogeneous and com-
prises mesenchymal stem cells, haematopoietic progenitor
cells and endothelial progenitor cells. Th e diff erentiation
capacity of diff erent populations of bone marrow-derived
stem cells into cardiomyocytes has been studied
intensively. Th e results are rather confusing and diffi cult
to compare, since diff erent isolation and identifi cation
Stem cell transplantation is emerging as a potential
therapy to treat heart diseases. Promising results
from early animal studies led to an explosion of
small, non-controlled clinical trials that created
even further excitement by showing that stem cell
transplantation improved left ventricular systolic
function and enhanced remodelling. However, the
specifi c mechanisms by which these cells improve
heart function remain largely unknown. A large variety
of cell types have been considered to possess the
regenerative ability needed to repair the damaged
heart. One of the most studied cell types is the bone
marrow-derived mononuclear cells and these form
the focus of this review. This review article aims to
provide an overview of their use in the setting of acute
myocardial infarction, the challenges it faces and the
future of stem cell therapy in heart disease.
© 2010 BioMed Central Ltd
Bone marrow mononuclear cells and acute
Samer Arnous1, Abdul Mozid1, John Martin1 and Anthony Mathur2*
2Department of Cardiology, London Chest Hospital, Queen Mary University of
London, Barts and the London NHS Trust, Bonner Road, London E2 9JX, UK
Full list of author information is available at the end of the article
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
© 2012 BioMed Central Ltd
methods have been used to determine the cell population
studied. To date, only mesenchymal stem cells seem to
form cardiomyocytes, and only a small percentage of this
population will do so in vitro or in vivo. Pragmatically,
the translation of the basic science into clinical research
has followed a common pathway: injection of bone
marrow-derived mononuclear cells (BMMNCs) as a
source of stem cells into the heart. Table 1 provides a
summary of clinical trials using BMMNCs in patients
with acute MI.
Trials with no sham bone marrow harvest or intracoronary
re-infusion in the control group
In the fi rst human trial, Strauer and colleagues  re-
infused intracoronary BMMNCs 7 days after myocardial
infarction (MI). Th e mean number of mononuclear cells
was 2.8 × 107. Th ere was a signifi cant improvement in
myocardial perfusion and a reduction in the infarct
region in the cell therapy group. Th e Transplantation of
Progenitor Cells and Regeneration Enhancement in
Acute Myocardial Infarction (TOPCARE-AMI) investi-
gators randomised patients into intracoronary infusion of
BMMNCs or ex vivo expanded circulating progenitor
cells 4 days after MI . Th ere was a signifi cant
improve ment in global and regional left ventricular (LV)
function in both groups and a benefi cial eff ect on the
post-infarction remodelling process manifest by a
profound improvement in wall motion abnormalities in
the infarct area and a signifi cant reduction in end-systolic
LV volume at 4 months post-MI. Th e LV ejection fraction
(LVEF) further improved at 12 months, resulting in a
total increase of 9.3% at 1 year . Of interest, there was
no diff erence between the two active treatment groups.
Th e mean number of infused cells was 245 × 106, which
contained haematopoietic progenitor, mesenchymal and
stromal cells. However, a major limitation of both of
these trials was the lack of a control group receiving sham
bone marrow harvest or intracoronary re-infusion.
Another trial in which there was no sham procedure is
the Autologous Stem-Cell Transplantation in Acute
Myocardial Infarction (ASTAMI) trial, which included
only patients with acute anterior MI. Th e intracoronary
re-infusion of BMMNCs 4 to 8 days after infarction did
not have a benefi cial eff ect on LVEF compared to percu-
taneous coronary intervention (PCI) alone at 6 months
. Th is lack of benefi cial eff ect may be explained by the
diff erent cell processing protocols used in this trial. Cell
processing protocols may have a signifi cant impact on
the functional capacity of bone marrow-derived stem
cells . Comparison of diff erent isolation protocols
revealed a vastly reduced recovery of mononuclear cells
and nullifi cation of the neovascularisation capacity when
the ASTAMI cell isolation and storage protocol was used
Th e Bone Marrow Transfer to Enhance ST-Elevation
Infarct Regeneration (BOOST) trial, a slightly larger trial,
included 60 patients that were randomised to receive
intra coronary BMMNCs or standard therapy 4.8 days
after successful PCI following AMI. Th ere was a signi-
fi cant improvement in global LVEF in the cell treatment
group at 6 months without an eff ect on LV remodelling
. However, this improvement was not maintained at
18 months. Th e mean number of bone marrow cells that
were infused contained 9.5 × 106 CD34+ and 3.6 × 106
haematopoietic colony-forming cells. Th e improvement
in LVEF did not correlate with the number of CD34+ cells
or haematopoietic colony forming cells. Again, a major
limitation of the BOOST trial is that the control group
did not undergo a sham bone marrow harvest or
Th e fi rst long-term study involving 62 patients who
underwent intracoronary BMMNC transplantation
7 days post-AMI not only resulted in an early signifi cant
improvement in ejection fraction (EF) and infarct size,
but there was also a signifi cant reduction in mortality
and improvement in exercise capacity compared to
controls at 5 years .
Randomised controlled trials
Th e Transcatheter Transplantation of Stem Cells for
Treat ment of Acute Myocardial Infarction (TCT-STAMI)
trial, which included a control group receiving a placebo
infusion, showed a signifi cant (approximately 5%) improve-
ment in LVEF of patients receiving intracoronary
BMMNCs at 6 months .
Intracoronary bone marrow derived progenitor cells
in acute infarction (REPAIR-AMI), a large random ized
double-blind controlled trial that included over 200
patients, showed an improvement in the primary
endpoint in the treatment group that was an absolute
change in global LVEF from baseline to 4 months, as
measured by quantitative left ventricular angiography
. Furthermore, the pre-specifi ed cumulative end-
point of death, MI, or revascularisation was signifi cantly
reduced, and this benefi t was maintained at one year
follow-up . Th e mean increase in LVEF in the
BMMNC group was 2.5% and there was an inverse
relationship between the baseline EF and the degree of
improvement. For example, patients with a baseline EF
below the median value (48.9%) had an absolute
increase in global EF that was three times higher than
that in the placebo group. In contrast, the improvement
in LVEF in patients with a baseline EF that was above
the median value was non-signifi cant (0.3%). Th e timing
of cell infusion post-PCI also had an eff ect on the
primary endpoint. Patients in whom the cells were
infused ≥5 days post-PCI were the only ones who
derived benefi t.
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
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Cite this article as: Arnous S, et al.: Bone marrow mononuclear cells and
acute myocardial infarction. Stem Cell Research & Therapy 2012, 3:2.
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
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