ORIGINAL ARTICLE

The effect of bone marrow mononuclear stem

cell therapy on left ventricular function
and myocardial perfusion
Kamel Sadat, MD,a Sameer Ather, MD, PhD,a Wael Aljaroudi, MD, FACC,b
Jaekyeong Heo, MD, FACC,a Ami E. Iskandrian, MD, MACC,a
and Fadi G. Hage, MD, FASH, FACCa,c
a
Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
b
Division of Cardiovascular Disease, American University of Beirut Medical Center, Beirut,
Lebanon
c
Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, AL

Received Jul 10, 2013; accepted Dec 8, 2013

doi:10.1007/s12350-013-9846-4

Background. Bone morrow stem cell (BMC) transfer is an emerging therapy with potential
to salvage cardiomyocytes during acute myocardial infarction and promote regeneration and
endogenous repair of damaged myocardium in patients with left ventricular (LV) dysfunction.
We performed a meta-analysis to examine the association between administration of BMC and
LV functional recovery as assessed by imaging.
Methods and Results. Our meta-analysis included data from 32 trials comprising infor-
mation on 1,300 patients in the treatment arm and 1,006 patients in the control arm. Overall,
BMC therapy was associated with a significant increase in LV ejection fraction by 4.6% 0.7%
(P < .001) (control-adjusted increase of 2.8% 0.9%, P 5 .001), and a significant decrease in
perfusion defect size by 9.5% 1.4% (P < .001) (control-adjusted decrease of 3.8% 1.2%,
P 5 .002). The effect of BMC therapy was similar whether the cells were administered via
intra-coronary or intra-myocardial routes and was not influenced by baseline ejection fraction
or perfusion defect size.
Conclusions. BMC transfer appears to have a positive impact on LV recovery in patients
with acute coronary syndrome and those with stable coronary disease with or without heart
failure. Most studies were small and a minority used a core laboratory for image analysis. (J
Nucl Cardiol 2013)
Key Words: Bone marrow stem cell myocardial perfusion imaging single-photon
emission computed tomography cardiac magnetic resonance imaging echocardiography
myocardial infarction stable coronary artery disease heart failure

INTRODUCTION tissue, with a limited ability to regenerate the lost cells.

Myocardial infarction results in necrosis and perma-
nent loss of cardiomyocytes and the formation of scar
Electronic supplementary material The online version of this
article (doi:10.1007/s12350-013-9846-4) contains supplementary
material, which is available to authorized users.
Reprint requests: K. Sadat, MD, Division of Cardiovascular Disease,
University of Alabama at Birmingham, Lyons-Harrison Research
Building 314, 1900 University Blvd, Birmingham, AL 35294;
ksadat01@gmail.com
1071-3581/$34.00
Copyright 2013 American Society of Nuclear Cardiology.
Despite the advances in therapy on the quality of life and
longevity, coronary artery disease (CAD) remains the
number one cause of death worldwide.1 The ideal therapy
for myocardial infarction and ischemic heart failure (HF),
in which the primary mechanism is cardiomyocyte loss, is
to recuperate injured myocytes or regenerate new ones. The
rationale for bone morrow stem cell (BMC) transfer is
based on the assumption that the transplanted cells may
have the potential to either transform into cardiomyocytes,
hence replacing lost tissue, or repair the injured vascular
and cardiac cells through paracrine effects.2-5 The benefits
 Sadat et al
The effect of stem cell on LV function and perfusion
of BMC therapy have been modest though variable and
occasionally conflicting.6,7 Cardiovascular imaging has
played an essential role in the assessment of left ventricular
(LV) functional recovery as an endpoint in these trials.
Prior meta-analyses have examined the effect of BMC
therapy on LV function, remodeling, and change in infarct
size. In a meta-analysis of ten studies, BMC therapy was
associated with an improvement of LV ejection fraction
(EF) of 3.0% (95% confidence interval (CI) 1.9%-4.1%)
and a reduction in infarct size of 5.6% (95% CI 2.5%-8.7%)
compared with controls in the setting of acute myocardial
infarction.6 In patients with chronic ischemic cardiomy-
opathy, a meta-analysis of ten studies showed an increase in
LVEF of 4.5% (95% CI 2.4%-6.5%). These studies
combined results from different imaging modalities in
order to present an overall assessment of effect.8 We here
review the trials that have studied BMCs for the treatment
of acute coronary syndrome (ACS) and for stable CAD
with or without HF with particular attention to the role of
imaging parameters and the choice of the endpoints. The
results show a wide variability in the methods used as well
as the endpoints. The differences could conceivably have
an impact on the conclusions of these studies, which often
involved small number of patients.
METHODS
Literature Search Strategy
We used Cochrane, Pub Med, Ovids MEDLINE search of
English literature through June 2012 to identify eligible trials;
complex search strategies were formulated using the following
medical subject heading terms and text words: bone morrow,
stem cell progenitor cells, cell transplantation, cell therapy,
intra-coronary transfusion, ACS, CAD, HF, myocardial perfu-
sion, LVEF, single-photon emission computed tomography
(SPECT), myocardial perfusion imaging (MPI), and magnetic
resonance imaging (MRI). The search was supplemented by
review of references listed for all relevant studies.
Selection Criteria
Clinical trials investigating the effects of intra-coronary
and intra-myocardial autologous BMC transfer for patients
with ACS or stable CAD/HF were considered whether they
involved a control group or not. Trials were excluded if they
did not include human participants, involved less than 20
participants in the treatment group, or if the transferred cells
were other than autologous BMCs. Duplicate reports and
ongoing or unpublished studies were excluded.
Study Enrollment and Data Extraction
From each trial included in the current review,9-50 we
extracted information regarding study information (first
authors name, year of publication), baseline characteristics
Journal of Nuclear Cardiology
(age, sex, number of patients), follow-up period, imaging
modalities used to assess the endpoints, mode of cell transfu-
sion, type of cell transfused, time from the chest pain or
percutaneous coronary intervention (PCI) to cell transfusion,
and the success of reperfusion therapy. The endpoints for each
study were also extracted and tabulated with particular
attention to LVEF and myocardial perfusion, the modalities
used for their assessment and the methods of assessment. In
studies that reported the endpoints at multiple time points, we
used the values provided at the latest available follow-up.
Cardiac MRI was used to quantify infarct size in eight
studies,13-16,19,21,22,29-31,34-36,43 but the results were expressed
in different units in the included studies (%LV, g and mL).
Thus, our primary analysis for perfusion defect size (PDS)
includes data exclusively by SPECT MPI. In a secondary
analysis, we combined data from studies that assessed PDS by
MRI and PDS. In studies that used multiple methods to
measure LVEF and/or PDS, we used cardiac MRI if available.
Statistical Analyses
Primary analyses were performed for control-adjusted
changes in LVEF and PDS with BMC therapy. We also report
the unadjusted change in LVEF or PDS with BMC therapy in
all the trials (whether or not a control group is included).
To assess risk of bias, methodological quality was
assessed by reported allocation generation, allocation conceal-
ment, blinding, documentation of withdrawal, selective
reporting, and intention to treat analysis, in line with the
recommendation by the Cochrane Collaboration.51
Statistical analyses were done in accordance with the
PRISMA statement.52 Mean difference was chosen as the
principal measure of effect as the unit of measurement was
same across all studies. Data were analyzed for heterogeneity
by I2 statistic proposed by Higgins and Thompson.53 In the
presence of significant heterogeneity, a random effects model
(DerSimonian and Laird approach) was used to pool the data;
otherwise, a fixed effects model (inverse-variance) was used.
Publication bias was assessed and quantified using Eggers
regression intercept.54 Metaregression was performed using
fixed effects model in the absence of heterogeneity and method
of moments in the presence of significant heterogeneity. To
evaluate the effect of BMC therapy on PDS using data from
studies that used either MRI or PDS, we used standardized
means since the included studies used different units of
measurement of PDS. Outlier was defined as a data point more
than 1.5 interquartile range below the first quartile or above the
third quartile. The results are reported as mean standard
error of the mean (SEM). A P value \.05 was considered
statistically significant. All analyses were conducted using
Comprehensive Meta Analysis Version 2.2.046.
RESULTS
Search Results
Of 70 human trials identified by the electronic
database search, 38 were excluded; 25 had less than 20
Journal of Nuclear Cardiology
patients in the treatment arm, four used cells other than
BMCs in the treatment arm (peripheral blood cells or
myocytes), three used subgroups from other trials
already included in the review, four did not specifically
assess the change in LVEF or PDS after BMC therapy,
one study was prematurely stopped secondary to patient
safety issues, and one study did not distinguish between
patients with ACS and those with stable CAD/HF. Thus,
32 trials were included. Figure 1 shows our search and
study selection strategy.
Study Characteristics
These trials9-50 included a total of 1,300 patients in
the treatment arm (range 20-191 per study) and 1,006
patients in the control arm (range 10-200 per study),
predominately men, with a mean age of 50-65 years,
and a mean follow-up 3-61 months. The baseline
Figure 1. Flow chart showing our strategies for literature search and study selection. ACS, Acute
coronary syndrome; CAD, coronary artery disease; EF, ejection fraction; HF, heart failure; LV, left
ventricle; PDS, perfusion defect size.
Sadat et al
The effect of stem cell on LV function and perfusion
characteristics and design features of the included
studies based on the acuity of presentation (ACS vs
CAD/HF) are shown in Table 1. Table S1 (in the online
supplement) summarizes the features of the studies
used for quality assessment. The BMCs were introduced
via the intra-coronary route in 24 studies9-37,43,46,48,50
and via the intra-myocardial route in eight
studies.38-42,44,45,47,49
Most of the studies included in our analysis were
randomized, some in a 1:1,9-11,13-17,19-27,29-31,35,37,43,44,46
1:2,18,32,34,36,45,47,48 or 1:333 ratio to control vs treatment
with the exception of some studies that were not
randomized.12,28,50 Three studies did not have a control
group,38-42,49 and were used only for comparison before
and after stem cell therapy. Four studies involved two
active treatment arms in addition to the control group;
one study9,10 compared low vs high dose bone morrow
mononuclear cells; one study32 compared CD34?
Table 1. Study characteristics

Patients Time to
numbers Mean cell PDS by MPI Other
First author, age Men F/U Cell number therapy Reperfusion visual/ imaging
Sadat et al

Study year, Ref# T C (years) (%) (M) (3106) (days) success (%) automated modality
ACS
1 Meluzn, 2008,9,10 20 20 54 95 12 10100 7 100 V and A PET, 2DE, LVG
2 Kaminek, 2008,11 31 31 54 90 3 100 7 100 V and A PET, 2DE, LVG
3 Lipiec, 2008,12 26 10 57 70 6 NR 5 100 V and A
4 Lunde, 2009,13-16 50 50 58 84 36 54130 5 94 A 2DE, MRI
5 Cao, 2009,17 41 45 51 95 48 50 7 100 A 2DE, LVG
6 Grajek, 2010,18 31 14 50 87 12 410 5 100 V 2DE, LVG
7 Roncalli, 2011,19 52 49 56 81 3 98.3 9 100 A 2DE, MRI, LVG
8 Chen, 2004,20 34 35 58 94 6 48,00060,000 18 100 2DE, LVG
9 Janssens, 2006,21,22 33 34 56 82 4 BMNC:304, 1 100 MRI, 2DE, LVG
The effect of stem cell on LV function and perfusion

BMMNC:172
10 Li, 2006,23 35 35 60 80 6 NR 6 100 2DE
11 Huikuri, 2008,24 40 40 60 90 6 402 2 98 2DE, LVG
12 Wollert, 2009,25-27 30 30 53 67 61 2,460 5 100 MRI
13 Youcef, 2009,28 62 62 51 87 60 61 7 100 2DE, LVG
14 Schachinger, 2009,29-31 101 103 55 82 24 236 4 100 MRI, LVG
15 Tendera, 2009,32 80 40 55 71 6 178 7 100 MRI, LVG
16 Traverse, 2010,33 30 10 53 83 6 100 5 100 MRI
17 Wohrle, 2010,34 29 13 61 90 6 381 7 100 MRI, LVG
18 Hirsch, 2011,35 69 65 56 84 4 296 6 100 MRI
19 Traverse, 2011,36 58 29 58 79 6 147 17 100 MRI, 2DE
CAD/HF
20 Chen, 2006,37 24 24 59 88 12 30 289 100 NR 2DE
21 Fuchs, 2006,38 27 58 82 12 28 NR V 2DE
22 Beeres, 2006,39,40 25 64 84 12 84 NR A
23 Beeres, 2006,41 20 63 80 6 82 NR V MRI
24 Beeres, 2007,42 30 64 87 12 94 NR A MRI
25 Yao, 2008,43 24 23 55 96 6 190 390 100 A 2DE, MRI, LVG
26 Van ramshort, 2009,44 25 25 64 92 6 98 NR A MRI
27 Perin, 2011,45 20 10 61 80 6 30 NR A 2DE, LVG
28 Hu, 2011,46 31 29 57 93 6 132 NR 100 A 2DE, MRI
29 Perin, 2012,47 61 31 64 87 6 100 NR NR 2DE, LVG
30 Assmus, 2006,48 35 23 60 89 3 205 2,430 100 MRI, LVG
Journal of Nuclear Cardiology
Journal of Nuclear Cardiology Sadat et al
The effect of stem cell on LV function and perfusion

HF, coronary artery disease/heart failure; D, day; F/U, follow-up; LVG, left ventriculogram; M, month; MPI, myocardial perfusion imaging; MRI, magnetic resonance imaging;
2DE, Two-dimensional echocardiography; A, automated; ACS, acute coronary syndrome; BMMNC, bone morrow mononuclear cell; BMNC, bone morrow nucleated cell; CAD/
modality
CXCR4? cells and non-selected BMCs; and two stud-

imaging

MRI, 2DE
Other
ies35,48 compared peripheral blood cells and BMCs, both
introduced via the intra-coronary route. The primary

LVG
intervention was PCI in 21 studies,9-23,25-37,43,50 fibrino-
lysis followed by PCI in two studies,13-16,24 coronary
artery bypass grafting in one study,46 and no interven-
PDS by MPI

automated

tion in nine studies.38-42,44,45,47-49 Time to BMC transfer

visual/

from onset of chest pain or PCI to cell therapy ranged

from 1 to 18 days in the ACS trials and was not reported

in most CAD/HF trials (Table 1). The BMCs were
administered via the intra-coronary route in all the ACS
trials and in five of the CAD/HF trials.37,43,46,48,50 The
Reperfusion
success (%)

remaining eight studies administered BMCs via the

intra-myocardial route.38-42,44,45,47,49
100

Table 2 details the endpoints used in each study with

special emphasis on the imaging endpoints, especially
LVEF and PDS. A core laboratory was used to analyze the
imaging data in only 6 of the 32 trials.19,24,29-31,35,38,43 Of
therapy
Time to

the 19 trials studying patients with ACS, seven used MPI

(days)

3,111
cell

for assessment of PDS9-19 while the other 12 studies did

NR

not.20-36 Of the 1337-50 trials studying patients with stable

NR, none-reported; PCI, percutaneous coronary intervention; PDS, perfusion defect size; V, visual; Y, year.

CAD/HF, ten used MPI for the assessment of PDS37-47

while the other three did not.48-50 Cardiac MRI was
Cell number

used to quantify infarct size in eight stud-

(3106)

ies.13-16,19,21,22,29-31,34-36,43 Quantitation of PDS with

85
66

MPI was either supervised automated (n = 3), automated

alone (n = 9), visual assessment alone (n = 3), or
unspecified (n = 2). While the readers were generally
blinded to patients history, it is not clear if the readers
F/U
(M)

read the pre- and post-BMC transfusion studies side-by-

60
3

side and hence were also blinded to treatment effect. In

addition, the number of readers for each imaging modality
Men
(%)

was unknown in many studies. There was heterogeneity in

79
90

the modalities used to measure LVEF as well. Cardiac

MRI, MPI, two-dimensional echocardiography (2DE),
(years)
Mean

and left ventriculography were used, and some studies

age

65
59

used more than one modality.

The Effect of BMC Therapy on LVEF and PDS

200
numbers
Patients

Overall in 32 studies, BMC therapy was associated

with a significant increase in LVEF by 4.6% 0.7%
24
191

(P \ .001). In the 27 studies that had a control arm, there

T

was a significant increase in LVEF by 2.0% 0.8%

(P = .008) in the control group. BMC therapy was
Strauer, 2010,50
Beeres, 2008,49
First author,
year, Ref#

associated with a control-adjusted significant increase in

Table 1. Continued

LVEF by 2.8% 0.9% (P = .001; Figure 2, right panel).

Overall, in 15 studies, BMC therapy was associated
with a significant decrease in PDS by 9.5% 1.4%
(P \ .001). In the 12 studies that had a control arm, there
was a significant decrease in PDS by 3.6% 1.5%
(P = .01) in the control group. BMC therapy was associated
Study

with a control-adjusted significant decrease in PDS by

31
32

3.8% 1.2% (P = .002; Figure 3, right panel). The

Table 2. Study endpoints

Primary end Secondary end

point/modality point/modality Other end points/modality
First author,
Sadat et al

Study year, Ref# LVEF PDSMPI LVEF PDS/MPI Primary Secondary

ACS
1 Meluzn, 2008,9,10 - - ?/MPI ? Regional systolic LVV/MPI
function/2DE
2 Kaminek, 2008,11 ?/MPI ? - - Regional systolic
function/2DE
3 Lipiec, 2008,12 ?/MPI ? - -
4 Lunde, 2009,13-16 ?/MPI - - - Infarct size/MRI, quality
of life, exercise capacity
5 Cao, 2009,17 ?/2DE - - - Efficacy
6 Grajek, 2010,18 ?/LVG ? - - Exercise capacity, side effect,
The effect of stem cell on LV function and perfusion

wall motion score

7 Roncalli, 2011,19 - ? ?/LVG, MRI, 2DE - LVV/MRI, infarct size/MRI,
restenosis/Ccath
8 Chen, 2004,20 - - - - Cardiac death
9 Janssens, 2006,21,22 ?/MRI, 2DE - - - Regional function/ Infarct size/MRI
strain imaging
10 Li, 2006,23 - - - - Safety, feasibility,
initial outcome
11 Huikuri, 2008,24 ?/LVG, 2DE - - - Arrhythmia risk,
restenosis
12 Wollert, 2009,25-27 ?/MRI - - - LVV, Infarct size/MRI,
wall motion score
13 Youcef, 2009,28 ?/LVG - - - Long-term outcome,
LV geometry
14 Schachinger, 2009,29-31 ?/LVG - - - Infarct size/MRI wall
motion score
15 Tendera, 2009,32 ?/MRI - ?/LVG - LVV/MRI
16 Traverse, 2010,33 ?/MRI - - - Safety LVV/MRI
17 Wohrle, 2010,34 ?/MRI - - - Infarct size/MRI
18 Hirsch, 2011,35 - - ?/MRI - Regional systolic Infarct size/MRI, LVV/MRI
function/MRI
19 Traverse, 2011,36 ?/MRI - - - Safety, regional LVV/MRI
function/MRI
Journal of Nuclear Cardiology
Table 2. Continued

Primary end Secondary end

point/modality point/modality Other end points/modality
First author,
Study year, Ref# LVEF PDSMPI LVEF PDS/MPI Primary Secondary
CAD/HF
20 Chen, 2006,37 - - - - -
Journal of Nuclear Cardiology

21 Fuchs, 2006,38 - - - - Safety, efficacy -

22 Beeres, 2006, 39,40 - - - - Mechanism of -
benefit
23 Beeres, 2006,41 ?/MRI ? - - Decrease in angina symptoms -
24 Beeres, 2007,42 - - - - Restenosis/Ccath -
25 Yao, 2008,43 ?/MRI, MPI, 2DE - - - -
26 Van ramshort, 2009,44 - ? ?/MRI - CCS, quality of life
27 Perin, 2011,45 - - - - Safety Efficacy
28 Hu, 2011,46 ?/MRI - - ? LVV/MRI, wall motion score,
BNP, 6MWT
29 Perin, 2012,47 ?/2DE ? - - Oxygen consumption CCS, angina score, NYHA,
30 Assmus, 2006,48 ?/LVG - - - LVV, Regional systolic
function/LVG
31 Beeres, 2008,49 - - - - LV diastolic function/MRI, TDI -
32 Strauer, 2010,50 ?/LVG - - - Long-term outcome, LV geometry -

2DE, Two-dimensional echocardiography; 6MWT, 6-minute walking test; ACS, acute coronary syndrome; BNP, brain natriuretic peptide; CAD/HF, coronary artery disease/
heart failure; Ccath, cardiac catheterization; CCS, Canadian Cardiovascular Society Angina Grading Scale; EF, ejection fraction; LVV, left ventricle volume; LVG, left ventric-
ulogram; MPI, myocardial perfusion imaging; MRI, magnetic resonance imaging; NYHA, New York Heart Association Functional Classification; PDS, perfusion defect size; TDI,
tissue Doppler imaging.
Sadat et al
The effect of stem cell on LV function and perfusion
 Sadat et al Journal of Nuclear Cardiology
The effect of stem cell on LV function and perfusion

Figure 2. Effect of bone marrow cell therapy on left ventricular ejection fraction (LVEF). The
change in LVEF with active treatment, control, and the difference between treatment and control is
shown for studies that recruited patients with acute coronary syndrome (ACS, left), stable coronary
artery disease or heart failure (CAD/HF, middle), and acute coronary syndrome plus stable coronary
artery disease or heart failure (ACS ? CAD/HF, right) . The number of studies in each analysis is
indicated in parenthesis and the P value is shown above the bars.

Figure 3. Effect of bone marrow cell therapy on left ventricular perfusion defect size. The change
in perfusion defect with active treatment, control, and the difference between treatment and control
is shown for studies that recruited patients with acute coronary syndrome (ACS, left), stable
coronary artery disease or heart failure (CAD/HF, middle), and acute coronary syndrome plus stable
coronary artery disease or heart failure (ACS ? CAD/HF, right). The number of studies in each
analysis is indicated in parenthesis and the P value is shown above the bars.

association between BMC therapy and control-adjusted There was significant heterogeneity between studies
improvement in PDS was also significant when results of for the effect of BMC therapy on LVEF and PDS
studies that used MRI were added to the analysis (Figure S1). (P \ .001 for heterogeneity for both).
Journal of Nuclear Cardiology
Publication Bias and Effect of Study Quality
There was no evidence of publication bias for the
primary analyses of control-adjusted change in LVEF
and PDS with BMC therapy (P = .13 and .17, respec-
tively; Figures S2 and S3). Effect of study quality on
results was assessed by metaregression. There was no
significant association between the study quality and
effect of BMC therapy on LVEF or on PDS (P = .10
and .18, respectively).
Effect of Baseline LVEF and PDS
On metaregression, baseline LVEF did not affect
the control-adjusted LVEF response to BMC therapy
(P = .99). Similarly, baseline PDS did not affect the
control-adjusted PDS response to BMC therapy
(P = .13).
Effect of Number of Cells Injected
We assessed the effect of number of cells injected
on magnitude of response. The number of cells injected
was reported in 26 studies that evaluated the effect of
BMC therapy on LVEF.9-11,13-22,24-38,43-48,50 Among
these, there were 2 outliers that injected 54,000 and
2,460 million cells, respectively.20,25 In the rest of the
studies, a median of 100 million cells (IQR: 68-201
million cells) was injected. In these 24 studies, there was
no association between number of cells injected and
change in LVEF (b = -0.006, P = .39).
The number of cells injected was reported in 12
studies9-11,13-19,37,43-47 that evaluated the effect of BMC
therapy on PDS. These studies injected a median of 98
million cells (IQR: 56-100 million cells). Unexpectedly,
a higher number of injected cells was associated with
reduced response (b = 0.067, P = .01; Figure S4A).
There was significant heterogeneity that was attributed to
a study by Chen et al.37 On excluding this study from the
analyses, there was no significant heterogeneity between
studies and the association became less robust although a
trend toward reduced response remained (Figure S4B).
BMC Therapy in ACS Patients
The effect of BMC therapy on LVEF was compared
with a control group in ACS patients in 19 studies.9-37 In
these studies, BMC therapy was associated with a
control-adjusted significant increase in LVEF by
2.8% 1.0% (P = .005) (Figures 2, left panel, 4A).
The effect of BMC therapy on PDS was compared with
a control group in ACS patients in six studies.9-17,19 In
these studies, BMC therapy was associated with a
Sadat et al
The effect of stem cell on LV function and perfusion
control-adjusted significant decrease in PDS by
3.3% 0.8% (P \ .001) (Figures 3, left panel, 5A).
BMC Therapy in CAD/HF Patients
The effect of BMC therapy on LVEF was compared
with a control group in CAD/HF patients in eight
studies.37,43-48,50 In these studies, BMC therapy was
associated with a trend toward control-adjusted increase
in LVEF by 3.0% 1.7% (P = .09) (Figures 2, middle
panel, 4B). On comparing the effect of BMC therapy
between studies in CAD/HF and ACS patients there was
no statistically significant difference based on significant
overlap of 95% CIs (P = .58).
The effect of BMC therapy on PDS was compared
with a control group in CAD/HF patients in six stud-
ies.37,43-47 In these studies, BMC therapy was significantly
associated with a control-adjusted decrease in PDS by
4.8% 2.4% (P = .04) (Figures 3, middle panel, 5B).
These results were not significantly different from the
effect of BMC therapy in ACS patients (P = .64).
BMC Therapy Via Intra-coronary Route
The effect of BMC therapy (vs control) adminis-
tered via intra-coronary route on LVEF was assessed in
24 studies.9-37,43,46,48,50 In these studies, BMC therapy
was associated with a significant control-adjusted
increase in LVEF by 3.0% 0.9% (P = .002). The
effect of BMC therapy (vs control) administered via
intra-coronary route on PDS was assessed in nine
studies.9-17,19,37,43,46 In these studies, BMC therapy
was associated with a control-adjusted significant
decrease in PDS by 4.4% 1.6% (P = .006).
BMC Therapy Via Intra-myocardial Route
The effect of BMC therapy (vs control) adminis-
tered via intra-myocardial route on LVEF was assessed
in only three studies.44,45,47 In these studies, BMC
therapy was associated with a control-adjusted signifi-
cant increase in LVEF by 2.8% 0.9% (P = .002). On
comparing the effect of BMC therapy administered via
the intra-myocardial vs intra-coronary routes, there was
no statistically significant difference based on significant
overlap of 95% CIs (P = .92).
The effect of intra-myocardial BMC therapy (vs
control) administered via intra-myocardial route on PDS
was assessed in only three studies.44,45,47 In these studies,
BMC therapy was associated with a significant control-
adjusted decrease in PDS by 2.8% 1.2% (P = .02).
These results were not significantly different from the
effect of BMC therapy in ACS patients (P = .42).
 Sadat et al Journal of Nuclear Cardiology
The effect of stem cell on LV function and perfusion

Figure 4. Change in left ventricular ejection fraction (LVEF) with bone marrow cell therapy in
individual studies. The change in LVEF from pre- to post-bone morrow cell therapy and control
therapy for individual studies that recruited patients with (A) acute coronary syndrome and (B)
stable coronary artery disease or heart failure are displayed. The imaging modality used, follow-up
time in months (F/U), and the baseline LVEF are shown for each study. LVG, Left ventriculogram;
M, months; MPI, myocardial perfusion imaging; MRI, magnetic resonance imaging; 2DE, two-
dimensional echocardiography.

Core Laboratory Analysis increase in LVEF by 3.0% 1.0% (P = .003) in studies

using on-site image analysis. These results were not
The effect of BMC therapy on LVEF was compared
significantly different from the effect of BMC therapy
with a control group using a core laboratory for image
using core laboratory for image analysis based on signif-
analysis in five studies.19,24,29,30,35,43 In these studies, BMC
icant overlap of 95% CIs (P = .42). Since only two studies
therapy was associated with a control-adjusted significant
used a core laboratory to assess the change in PDS,19,43 we
increase in LVEF by 1.5% 0.6% (P = .008). BMC
did not perform a subgroup analysis for this variable.
therapy was associated with a control-adjusted significant
Journal of Nuclear Cardiology Sadat et al
The effect of stem cell on LV function and perfusion

Figure 5. Change in perfusion defect size (PDS) with bone marrow cell therapy in individual
studies. The change in PDS from pre- to post-bone morrow cell therapy and control therapy for
individual studies that recruited patients with (A) acute coronary syndrome and (B) stable coronary
artery disease or heart failure are displayed. The follow-up time in months (F/U) and the baseline
PDS are shown for each study. LV, left ventricle; M, months.

Modality for Assessment of LVEF
There was significant heterogeneity in our primary
analysis for the assessment of LVEF change with BMC
therapy vs control wherein we combined the results of
all imaging modalities (I2 = 89, P \ .001). Thus, we
performed a sensitivity analysis by the modality used
for LVEF assessment. BMC therapy was associated
with a significant control-adjusted increase in LVEF
in studies that used 2DE13-18,20-24,36,43,45,47 (n = 11,
2.9% 0.9%, P = .002; I2 = 75, P \ .001 for hetero-
geneity) or left ventriculography18-20,24,28-31,45,48,50
(n = 9, 5.7% 1.7%, P = .001; I2 = 83, P \ .001 for
heterogeneity) and a trend toward significant increase
in studies that used MRI13-16,19,21,22,25-27,29-36,43,44,46
(n = 13, 1.1% 0.7%, P = .08; I2 = 56, P = .007
for heterogeneity) or SPECT MPI9-16,43 (n = 5,
2.0% 1.9%, P = .28; I2 = 56, P = .06 for heteroge-
neity). Thus, the type of modality used did not affect the
heterogeneity between the studies.
DISCUSSION
In this meta-analysis, by pooling the results of
multiple trials, BMC therapy appears to be associated
with an increase in LVEF and reduction in PDS. The
effect of BMC therapy was found to be similar whether
the cells were administered via the intra-coronary or
intra-myocardial routes and was not influenced by
baseline LVEF or PDS. We did not find evidence of a
 Sadat et al
The effect of stem cell on LV function and perfusion
dose-response relationship between BMC therapy and
change in LVEF or PDS. There was significant vari-
ability between studies in the effect of BMC therapy on
the change in LVEF, however, this variability was not
dependent on the modality used to assess LVEF.
In our meta-analysis, BMC therapy was associated
with a modest control-adjusted increase in LVEF.
Although this effect was statistically significant only in
patients with ACS, the effect had a similar trend in those
with stable CAD/HF and the overall results were not
statistically different between the two sets of studies
(ACS vs CAD/HF). Most studies in patients with ACS
have demonstrated a greater increase in LVEF with
BMC than control.9-11,17,18,20-24,28-32 Some studies
showed discordant results with a decrease in LVEF
with treatment or a more robust increase in LVEF in the
control group.12-16,19,25-27,33-36 This may be due to: (1)
late timing of PCI and BMC transfusion; (2) the
dynamic nature of LVEF (for example, in the study by
Wollert et al25-27 LVEF increased by 6.7% at 6-month in
the treatment group but the effect was lost at 18 months)
raising the issue of possible time-limited benefit; (3)
discrepancy in the measurements of LVEF when multi-
ple modalities were used for the same patient; or (4)
BMC therapy is not associated with benefit in this
population or the benefit is modest compared to the
effect of revascularization and is therefore not detect-
able. In the CAD/HF studies, an improvement in LVEF
with BMCs was evident in all the studies. When a
control group was available, this improvement was more
marked with active treatment vs control except in the
study by Chen et al37 which showed initial benefit at 3,
6, and 9 months but that was subsequently lost at
12 months, again indicating the possibility of time-
limited benefit. Thus, the effect of BMC therapy is
similar irrespective of the acuity of presentation and the
lack of statistical significance in the CAD/HF group may
be related to the lower number of studies in this group.
BMC therapy was also associated with a control-
adjusted decrease in PDS (assessed by MPI). Unlike
with LVEF, the change in PDS was statistically signif-
icant in patients with ACS as well as in those with stable
CAD/HF and the results in the 2 sets of studies were
again not statistically different. In the ACS studies,
BMC administration was associated with an improve-
ment in PDS in all studies and this improvement was
greater than that seen with controls except in one
study.11 In this study, patients with radionuclide tracer
uptake in the range of 31%-50% of maximum in the
infracted area responded to BMC therapy while those
with less than 30% uptake did not. In the CAD/HF
studies, BMC treatment was associated with an
improvement in PDS in all studies. When a control
group was used, the improvement in PDS was greater
Journal of Nuclear Cardiology
with active treatment in all the studies except one.46 We
have not included the study by Fuchs et al38 in our
analysis since the stress score was reported separately
for injected and remote territories. The stress score
improved in the segments within the injected territories
but not in the segments within remote territories.
Cell-based therapy for CAD is a novel technique
that has the potential to improve myocardial function
and act as adjunctive therapy to medical and reperfusion
strategies.55 In experimental mechanistic studies, both
in vitro and in vivo, administration of BMCs has been
shown to regenerate areas of infracted myocardium and
coronary capillaries through differentiation into new
cardiomyocytes and vascular endothelial cells.56-59
However, data suggest that the main effect of BMCs
may be mediated through their paracrine effects via
secretion of cytokines, fibroblast growth factors, and
vascular endothelial growth factors that are involved in
angiogenesis,2-5 inhibition of cardiomyocyte apopto-
sis,60 and cell-cell transaction.61-63 The end-result of
these effects is the replacement of lost myocardial tissue
and rescue of ischemic and hibernating tissue and
improvement of LV function.
There was significant heterogeneity in the efficacy
of BMC administration in our analyses. This heteroge-
neity may be linked to multiple factors including cell
type, origin, number of injected cells, method of
preparation and injection, and patient selection. It has
been suggested that mononuclear BMCs enriched with
CD34? and CD133? cells may represent the ideal cell
source because of their ability to induce angiogenesis.56
Cells from older individuals64 or from those with
multiple comorbidities such as diabetes and hyperten-
sion2,65,66 may have reduced cellular function and thus
when injected in subjects may induce less favorable
results. In addition, the method of cell isolation and
processing may impact the viability of BMCs and the
expression of surface receptors and/or adhesion mole-
cules that are important for the success of cell therapy.63
Many studies have used the Ficoll method that isolates
predominantly mononuclear cells with few granulo-
cytes, while the point-of-care system isolates nucleated
cells with mononuclear and specific stem cell popula-
tions (CD34? and CD133?) and platelets, with higher
yield of isolated BMCs compared to the Ficoll system.67
Another factor that should be taken into account when
evaluating the efficacy of therapy is cell number68
(varied from 106 to 109 in the reviewed studies,
Table 1). Since only a small fraction of the injected
cells is retained in the myocardium, while the majority is
lost via cell death due to the hostile inflammatory
milieu, it has been proposed that injecting a larger
number of cells will help achieve greater benefit.
However, successful myocardial repair depends also
Journal of Nuclear Cardiology
on other factors like the specific BMC type, the timing,
and the route of injection.6,56,68 In our analysis, the
number of administered BMCs was not associated with
the change in LVEF but the administration of a higher
number of cells was associated with less decrease in
PDS. As discussed, this was influenced by the results of
a single study but also highlights the complexity of
combining data from multiple studies that use different
protocols. Thus, we do not see any signal in our meta-
analysis that a higher number of cells injected is
associated with greater improvement in either PDS or
LVEF. One of the studies included in our analysis9,10
compared the administration of a high cells dose
(100 million) with lower dose (10 million) BMCs via
the intra-coronary route in patients with a first acute MI.
The increase in LVEF at 12 months was dose dependent
(0% 2% for control, 4% 1% for low dose, 7% 2%
for high dose, ANOVA P = .027) whereas there was no
statistically significant change in PDS (-6% 2% for
control, -9% 3% for low dose, and -10% 2% for
high dose, ANOVA P = .3). The role of cell delivery is
crucial; intravenous administration results in a small
fraction of the infused cells reaching the target region,69
while intra-coronary and intra-myocardial injections are
more efficient but also more invasive. One method that
has promise for future applications is the targeting of
cells administered systemically to the region of
interest.70
Determining the ideal time for cell transfer is
complicated. While delayed treatment may decrease the
efficacy of therapy due to scar formation, very early
treatment can negatively influence the transplanted cells
due to local inflammation, tissue edema, and toxic
reperfusion products. Thus, the golden period may be
around 6-7 days after ACS when the inflammatory
process cools down and the healing process starts, and
the chance of a successful BMC transfer is most
optimal.64-67,71,72 Another factor that has important
implications on the result of BMC transfer is the time
between the onset of symptoms and the initial coronary
revascularization therapy. With prompt revasculariza-
tion, the myocardium is injured rather than dead and
thus its recuperation is more likely. Finally, careful
recipient selection is paramount with recent data show-
ing that those with more myocardial damage and lower
LVEF are, not surprisingly, set to derive the greatest
benefit with treatment.21,27
On-site reading has a tendency to overcall PDS and
the change in perfusion pattern, and to underestimate
LVEF compared to core laboratory analysis.73,74 Based
on the utilization of core laboratory for image analysis,
our results show that the change in LVEF with active
therapy vs control was similar between centers that used
core laboratory vs on-site analysis but the magnitude of
Sadat et al
The effect of stem cell on LV function and perfusion
the effect was lower when a core laboratory was used
(1.5% 0.6%, P = .008) compared to on-site analysis
(3.0% 1.0%, P = .003). We did not perform a similar
analysis for PDS since only two studies used a core
laboratory to assess the change in PDS.19,43
Most of the studies included in this review did not
compare perfusion images of the pre- and post-BMC
treatment side-by-side in a manner that allows the reader
to adjudicate the contribution of extraneous factors on
image interpretation and better assess the effect of
therapy. If such an approach is considered the reader(s)
should obviously be blinded to which image is pre- or
post-therapy. Such an approach has been extensively
used in trials assessing the effects of medical therapy on
myocardial perfusion75-77 and should be considered in
future BMC trials.
Strengths and Limitations
The absolute changes in LVEF and PDS were small
and fall within the error margin of the measuring
techniques. Further, some studies used multiple imaging
modalities and showed discrepant findings based on
which modality was used for analysis.13-16,33 Another
aspect for variation between studies in the effect on PDS
is that the results could vary based on the methodology
used for quantitation (automated vs visual), method of
quantitation (summed stress score, summed rest score,
vs polar maps), the change in PDS vs change in size and
severity of the defect, and the use of rest only vs rest and
stress images. It should be stated that the PDS was not
always considered as the primary endpoint of these
studies and the rest PDS does not always represent scar
as in some patients it might represent hibernating
myocardium. Even when automated measurements are
used, the results could still vary based on the software
used for analysis.78 Lack of a core laboratory in the
majority of studies (26 out of the 32 studies), the lack of
side-by-side interpretation, unclear methodology in
some studies, and the small sample size per study are
other important limitations. Cardiac MRI was used in a
minority of the studies. The follow-up time varied
among studies and there might be time-dependent
effects on LVEF as evidenced in some studies that
showed initial improvement followed by subsequent
worsening. Both LVEF and PDS improve in the early
phase after injury. These BMC-independent changes
although accounted for in the control-adjusted analyses
make it harder to see a true effect of BMC therapy on
LVEF and PDS especially in the ACS group. The
studies included in our meta-analysis are relatively small
therefore limiting the conclusions that can be derived
from the analysis. Currently, larger studies are being
conducted that will shed lights on the benefits of BMC
 Sadat et al
The effect of stem cell on LV function and perfusion
therapy. For example, the repetitive progenitor cell
therapy in advanced chronic heart failure (REPEAT trial),
a multi-center trial currently being conducted in Europe,
plans to randomize 676 patients with chronic post-
myocardial infarction HF treated with optimal medica-
tions according to the evidence-based guidelines with
open vessel/bypass supplying the previously infarcted
area to receive single vs repeated intra-coronary applica-
tion of autologous BMCs. The primary endpoint of this
trial is overall mortality with a multitude of secondary
endpoints and it will also compare the observed mortality
in both arms to the Seattle Heart Failure Model predicted
mortality (https://www.clinicaltrialsregister.eu/ctr-search/
trial/2011-000595-33/DE#C assessed on September 22,
2013).
NEW KNOWLEDGE GAINED
This meta-analysis of 32 trials showed that bone
marrow cell therapy is associated with modest improve-
ment in left ventricular ejection fraction and myocardial
perfusion defect size in patients with acute coronary
syndrome and those with stable coronary disease with or
without heart failure. The heterogeneity in effect between
studies suggests that adjustments in cell selection and
administration and more robust image analysis in future
trials may be associated with more pronounced effects.
CONCLUSION
Autologous BMC transfusion appears to have
positive impact on LV recovery in patients with ACS
and those with stable CAD/HF. Future advancements in
BMC harvest and transfer techniques and proper timing
of therapy might improve the magnitude of benefit to
patients. While large randomized double-blinded pro-
spective studies with long-term follow-up and cost-
effectiveness analysis are needed and are being per-
formed, it is important for future studies to pay attention
to the imaging aspects of the trial and to consider
utilization of automated analysis of extent and severity
of perfusion abnormality in core laboratories with
blinded readers.
Disclosures
None.
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