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Eur J Nucl Med Mol Imaging (2009) 36:587–593
DOI 10.1007/s00259-008-0988-6
ORIGINAL ARTICLE
Impact of intracoronary injection of mononuclear
bone marrow cells in acute myocardial infarction on left
ventricular perfusion and function: a 6-month follow-up
gated 99mTc-MIBI single-photon emission computed
tomography study
Piotr Lipiec & Maria Krzemińska-Pakuła &
Michał Plewka & Jacek Kuśmierek & Anna Płachcińska &
Remigiusz Szumiński & Tadeusz Robak &
Anna Korycka & Jarosław D. Kasprzak
Received: 15 July 2008 / Accepted: 9 October 2008 / Published online: 29 November 2008
# Springer-Verlag 2008
Abstract
Purpose We investigated the impact of intracoronary injection of autologous mononuclear bone marrow cells (BMC)
in patients with acute ST elevation myocardial infarction
(STEMI) on left ventricular volumes, global and regional
systolic function and myocardial perfusion.
Methods The study included 39 patients with first anterior
STEMI treated successfully with primary percutaneous coronary intervention. They were randomly assigned to the treatment group or the control group in a 2:1 ratio. The patients
underwent baseline gated single-photon emission computed
tomography (G-SPECT) 3–10 days after STEMI with
quantitative and qualitative analysis of left ventricular
perfusion and systolic function. On the following day, patients
from the BMC treatment group were subjected to bone marP. Lipiec : M. Krzemińska-Pakuła : M. Plewka : J. D. Kasprzak
2nd Department of Cardiology, Medical University of Łódź,
Łódź, Poland
J. Kuśmierek : A. Płachcińska : R. Szumiński
Department of Nuclear Medicine, Medical University of Łódź,
Łódź, Poland
T. Robak : A. Korycka
Department of Hematology, Medical University of Łódź,
Łódź, Poland
P. Lipiec (*)
2nd Department of Cardiology, Bieganski Hospital,
Medical University of Łódź,
Kniaziewicza 1/5,
91-347 Łódź, Poland
e-mail: [email protected]
row aspiration, mononuclear BMC isolation and intracoronary injection. No placebo procedure was performed in the
control group. G-SPECT was repeated 6 months after STEMI.
Results Baseline and follow-up G-SPECT studies were
available for 36 patients. At 6 months in the BMC group
we observed a significantly enhanced improvement in the
mean extent of the perfusion defect, the left ventricular
perfusion score index, the infarct area perfusion score and
the infarct area wall motion score index compared to the
control group (p=0.01–0.04). However, the changes in left
ventricular volume, ejection fraction and the left ventricular
wall motion score index as well as the relative changes in
the infarct area wall motion score index did not differ
significantly between the groups.
Conclusion Intracoronary injection of autologous mononuclear BMC in patients with STEMI improves myocardial
perfusion at 6 months. The benefit in infarct area systolic
function is less pronounced and there is no apparent
improvement of global left ventricular systolic function.
Keywords Myocardial infarction . Mononuclear bone
marrow cells . Gated single-photon emission computed
tomography . Left ventricular systolic function .
Myocardial perfusion
Introduction
Despite the widespread use of state-of-the-art invasive and
pharmacological treatment, myocardial infarction with
588
resulting left ventricular dysfunction remains one of the
major causes of chronic heart failure [1]. Experimental and
clinical studies have shown that intracoronary injection of
mononuclear bone marrow cells (BMC) in patients with
acute myocardial infarction may improve left ventricular
perfusion and function more than conventional therapy.
However, the evidence remains conflicting and the underlying mechanisms as well as the optimal treatment protocols are still disputed [2–4].
Different imaging modalities have been employed for
the assessment of the effect of BMC treatment on cardiac
performance, including: left ventricular angiography, echocardiography, magnetic resonance imaging and gated
single-photon emission computed tomography (G-SPECT)
[2, 3]. G-SPECT is widely considered a reference method
for the assessment of myocardial perfusion [5]. Quantitative
G-SPECT (QGS) is also a well-validated tool that allows
the computation of left ventricular volumes and ejection
fraction as well as the evaluation of regional wall motion
abnormalities based on data acquired during perfusion
studies [6–9].
We sought to determine the impact of intracoronary
injection of autologous mononuclear BMC in patients with
acute myocardial infarction treated successfully with
primary percutaneous coronary intervention (PCI) on left
ventricular volume, global and regional systolic function
and myocardial perfusion assessed by G-SPECT over a
6-month follow-up period.
Eur J Nucl Med Mol Imaging (2009) 36:587–593
patients in the BMC treatment group were subjected to
intracoronary cell therapy. No placebo procedure (sham
bone marrow aspiration or injection) was performed in the
control group. The patients’ pharmacological treatment
during hospitalization and follow-up was administered in
accordance with current guidelines and was not influenced
by their study group assignment. The patients underwent
repeated G-SPECT and clinical evaluation 6 months after
STEMI. The study protocol was approved by the Ethics
Committee of our institution and written consent was
obtained from all participants.
Intracoronary cell therapy
Material and methods
A total of 100 ml of bone marrow was aspirated from the
iliac crest under local anaesthesia. The cell preparation
procedure and administration protocol have been described
in detail previously [10, 11]. In brief, bone marrow
aspirates were diluted with 20 ml 0.9% NaCl and filtered,
and mononuclear cells (CD34+ and CD133+) were isolated
by density gradient centrifugation (Ficoll-Paque Plus, 15°C,
20 min). The mononuclear cells were then washed twice
with 0.9% NaCl, suspended in 30 ml 0.9% NaCl, filtered
and subjected to quality and quantity control. Subsequently,
2–3 h after bone marrow harvest, 20.3 ± 2.2 ml of
mononuclear cell suspension was infused in four portions
into the infarct-related artery with a stop-flow balloon
catheter technique through an over-the-wire balloon catheter (Ninja, Cordis) positioned within the culprit-lesion stent.
Intermittent balloon inflation was used to ensure the
absence of flow distal to the segment containing the stent.
Patient population
G-SPECT
Included in the study were 39 patients with first ST
elevation anterior myocardial infarction (STEMI) treated
successfully with primary PCI of the infarct-related artery
within 12 h of the onset of symptoms and demonstrating
significant left ventricular systolic dysfunction (ejection
fraction ≤40%) on echocardiographic examination performed within 48 h of PCI. The exclusion criteria were:
previous myocardial infarction, presence of multivessel
coronary artery disease, clinical and haemodynamic instability, current infection, neoplasm and other severe coexisting conditions that could have influenced compliance
with the protocol or the 1-year prognosis.
G-SPECT studies (eight gates per cycle) were obtained at
rest with datasets acquired approximately 1 h after injection
of a weight-adjusted dose (555–1100 MBq) of 99mTcmethoxyisobutylisonitrile. A total of 64 projections, each
lasting 25 s, were acquired over a 180° arc from the 45°
right anterior oblique to the 45° left posterior oblique
position using a Varicam dual head camera (GE Medical
Systems, Milwaukee, WI). Data were reconstructed by
filtered back projection (Butterworth filter order 2.5, cut-off
frequency 0.36 of the Nyquist frequency) using a commercially available Xpert workstation (GE Medical Systems).
Perfusion data were analysed quantitatively (CEqual
software, Cedars Sinai Medical Center, CA) yielding leftventricular perfusion defect extent (PDE). Perfusion images
were also analysed qualitatively by a single investigator
blinded to all other data using the Cedars-Sinai 20-segment
model of the left ventricle (including six segments each of
the basal, midventricular and distal short-axis slices and
two apical segments in a midventricular vertical long-axis
Study protocol
Patients were randomly assigned to a BMC treatment group
or a control group in a 2:1 ratio (26:13). Patients underwent
baseline ECG-gated 99m Tc-methoxyisobutylisonitrile
SPECT 3–10 days after STEMI. On the following day,
Eur J Nucl Med Mol Imaging (2009) 36:587–593
Table 1 Study population
characteristics. Data are presented as the means±SD
(range) or number (%) of
patients
589
Age (years)
Gender (M/F)
Stent use
Maximum troponin T (ng/ml)
Days to baseline G-SPECT
CD133+ (×106 cells)
CD 34+ (×106 cells)
Treatment group (n=26)
Control group (n=10)
p value
57±9 (36–73)
18/8
26 (100%)
24±16 (2–69)
6.3±1.7 (3–10)
0.33±0.17 (0.08–0.78)
3.36±1.87 (0.85–8.00)
59±9 (45–74)
7/3
9 (90%)
21±15 (2–50)
6.7±1.9 (4–10)
NA
NA
0.66
0.73
0.62
0.49
0.55
NA
NA
NA not applicable.
slice) [12]. Radiopharmaceutical uptake in each of the 20
segments was scored using four-point scale: normal (0),
mildly reduced (1), moderately reduced (2), and severely
reduced/no uptake (3). Thereafter, the left ventricular
perfusion score index (LV PSI) was calculated by dividing
the sum of scores for all segments by 20. The segments
demonstrating reduced tracer uptake during the baseline
study were considered to belong to the infarct area. For
each patient the infarct area perfusion score index (IA PSI)
was calculated by dividing the sum of scores for all
segments from the infarct area by the number of these
segments.
Left ventricular end-diastolic volume (LV EDV), endsystolic volumes (LV ESV) and ejection fraction (LV EF)
were assessed with the commercially available automated
software – QGS (Cedars-Sinai Medical Center, Los
Angeles, CA). Regional wall motion abnormalities were
assessed qualitatively using the eight-segment model of the
left ventricle (including five segments in a midventricular
vertical long-axis slice and three segments in the midventricular short-axis slice). Wall motion was scored in each of
the eight segments as normal (1), hypokinetic (2), akinetic
(3), or dyskinetic (4). The left-ventricular wall motion score
index (LV WMSI) was then calculated by dividing the sum
of scores for all segments by 8. The segments demonstrating wall motion abnormality during the baseline study were
considered to belong to the infarct area. In patients who
exhibited no wall motion abnormalities in the eight
analysed segments during the baseline study, the segments
belonging to the vascular territory of the infarct-related
artery were considered to belong to the infarct area. For
each patient the infarct area wall motion score index (IA
WMSI) was calculated by dividing the sum of scores for all
segments from the infarct area by the number of these
segments.
Statistical analysis
Continuous variables that approximated a normal distribution (as assessed by Kolmogorov-Smirnov test) and
categorical variables are expressed as means±SD and as
percentages, respectively, unless otherwise stated. The
unpaired t test was used to compare continuous variables
between study groups. However, first the F test was used to
compare the variances of the analysed samples. If the p
value was low (p<0.05) the variances of the two samples
Table 2 LV EDV, LV ESV, LV EF, LV WMSI and IA WMSI at baseline and at 6 months, and their absolute change from baseline to 6 months in
the BMC treatment group and the control group
Baselinea
p value 6 monthsa
Treatment group Control group
(n=26)
(n=10)
LV EDV (ml) 147.0±46.3
(68.0–226.0)
LV ESV (ml) 89.8±38.2
(26.0–152.0)
LV EF (%)
41.2±10.1
(26.0–61.0)
LV WMSI
1.65±0.37
(1.00–2.50)
IA WMSI
2.30±0.45
(1.00–3.33)
a
b
169.1±91.5
(57.0–354.0)
110.0±75.9
(20.0–261.0)
40.0±14.2
(26.0–64.0)
1.51±0.41
(1.00–2.00)
1.85±0.59
(1.00–2.40)
Means±SD (range).
Means±SD (95% confidence interval).
0.48
0.44
0.79
0.33
0.02
Changeb
p value
Treatment group Control group Treatment group
(n=26)
(n=10)
(n=26)
Control group
(n=10)
156.7±65.2
(64.0–292.0)
94.8±57.2
(22.0–214.0)
44.2±13.7
(26.0–68.0)
1.43±0.40
(1.00–2.13)
1.70±0.55
(1.00–2.50)
9.9±37.1
(−16.7 to 36.5)
3.4±28.0
(−16.6 to 23.4)
3.8±4.6
(0.5 to 7.1)
−0.10±0.17
(−0.23 to 0.03)
−0.25±0.33
(−0.49 to −0.01)
178.4±106.3
(49.0–336.0)
113.4±86.4
(15.0–247.0)
43.8±15.3
(26.0–69.0)
1.41±0.41
(1.00–2.00)
1.60±0.55
(1.00–2.40)
9.7±40.4
(−6.6 to 26.0)
5.0±34.3
(−8.9 to 18.8)
3.0±7.3
(0.1 to 6.0)
−0.22±0.33
(−0.36 to −0.09)
−0.61±0.64
(−0.87 to −0.35)
0.99
0.90
0.76
0.17
0.04
590
Eur J Nucl Med Mol Imaging (2009) 36:587–593
were assumed to be unequal; we used the t test with a
correction for unequal variances (Welch test). Statistical
significance was assumed for p values less than 0.05.
Results
All patients had myocardial infarction related to the left
anterior descending coronary artery. In the treatment group
there were no deaths during the follow-up period. In
the control group there was one death, which occurred in the
5th month of the follow-up period. Furthermore, in the
control group two patients failed to attend for follow-up GSPECT. Therefore, the results of baseline and follow-up GSPECT studies were available for 26 patients from the
treatment group and 10 patients from the control group.
These 36 patients were the subject of further analysis; their
characteristics are summarized in Table 1.
Left ventricular volumes and function
LV EDV, LV ESV and LV EF assessed by QGS at baseline
and after 6 months, as well as their change from baseline to
follow-up, are presented in Table 2. There were no
statistically significant differences between the BMC
treatment group and the control group in the baseline
values of LV EDV, LV ESV and LV EF (p=0.48–0.79). In
the follow-up G-SPECT study increases in LV EDV, LV
ESV and LV EF were seen in both groups. These changes
did not differ between the treatment group and the control
group (p=0.76–0.99; Fig. 1a).
Table 2 presents the values of LV WMSI and IA WMSI
at baseline and at 6 months. There was no statistically
significant difference between the treatment group and the
control group in baseline LV WMSI (p = 0.33). The
decrease in LV WMSI over 6 months did not differ
significantly between the two groups (p=0.17), even
though the mean improvement in the treatment group was
twofold that observed in the control group (Fig. 1b). There
was a statistically significant difference between the groups
in baseline IA WMSI with the treatment group demonstrating higher values (2.30±0.45 vs 1.85±0.59, p=0.02). The
absolute change in IA WMSI over 6 months also differed
significantly between the treatment group and the control
group (−0.61±0.64 vs −0.25±0.33, p=0.04; Fig. 1c).
Because of significant differences in baseline IA WMSI
values between the groups, the relative changes in IA
WMSI (ratios of the absolute changes to the baseline
values) were calculated. Despite the mean values of the
relative changes of IA WMSI differing twofold in favour of
the treatment group, there was a trend towards more
pronounced improvement in the treatment group, but no
statistically significant difference between the treatment
Fig. 1 Absolute changes in LV EF (a), LV WMSI (b) and IA WMSI
(c) between baseline and 6 months in the BMC treatment group and
the control group. The bars indicate the mean changes and the
whiskers indicate 95% confidence intervals for the mean changes
group and the control group (−0.24±0.24 vs −0.11±0.16,
p=0.14).
In the treatment group there were no statistically
significant correlations between changes in indices of
systolic function from baseline to follow-up and volume
of injected cells, numbers of CD133+ or CD34+ cells.
Myocardial perfusion
The results of quantitative and qualitative analysis of GSPECT perfusion images at baseline and at 6 months are
summarized in Table 3. There were no statistically significant
differences in baseline PDE, LV PSI and IA PSI between the
treatment group and the control group (p=0.68–0.90). At
Eur J Nucl Med Mol Imaging (2009) 36:587–593
591
Table 3 PDE, LV PSI and IA PSI at baseline and at 6 months, and their absolute changes from baseline to 6 months in the treatment group and
the control group
Baselinea
PDE (%)
LV PSI
IA PSI
a
b
p value
Treatment group
(n=26)
Control group
(n=10)
25.8±14.8
(6.0–49.0)
1.14±0.45
(0.35–1.80)
1.83±0.42
(1.00–2.57)
23.4±16.4
(0.0–44.0)
1.17±0.73
(0.05–2.15)
1.85±0.61
(1.00–2.53)
0.68
0.90
0.90
6 monthsa
Changeb
p value
Treatment group
(n=26)
Control group
(n=10)
Treatment group
(n=26)
Control group
(n=10)
20.3±15.1
(0.0–42.0)
0.95±0.49
(0.10–1.70)
1.42±0.61
(0.29–2.43)
22.3±16.3
(1.0–43.0)
1.22±0.67
(0.05–2.00)
1.86±0.68
(0.50–2.69)
−5.4±4.8
(−7.4 to −3.5)
−0.18±0.27
(−0.30 to −0.07)
−0.41±0.38
(−0.56 to −0.26)
−1.1±4.5
(−4.3 to 2.1)
0.05±0.27
(−0.14 to 0.24)
0.01±0.51
(−0.35 to 0.37)
0.02
0.03
0.01
Means±SD (range).
Means±SD (95% confidence interval).
6 months a decrease in mean PDE was seen in both groups,
but the absolute change from the baseline value was
significantly enhanced in the treatment group compared to
the control group (−5.4±4.8 vs −1.1±4.5, p=0.02; Fig. 2a).
Moreover, in the treatment group there were decreases in the
mean values of LV PSI and IA PSI (−0.18±0.27 and −0.41±
0.38, respectively), whereas in the control group there was a
slight increase in mean LV PSI and IA PSI (0.05±0.27 and
0.01±0.51, respectively). The changes in LV PSI and IA PSI
differed significantly between the two groups (p=0.01–0.03;
Fig. 2b,c).
In the treatment group there were no statistically significant correlations between changes in indices of myocardial perfusion from baseline to follow-up and patients’
baseline characteristics, volume of injected cells, numbers
of CD133+ or CD34+ cells.
Discussion
Our study demonstrated that in patients with large STEMI
of anterior wall, intracoronary injection of autologous
mononuclear BMC 4–11 days after successful primary
PCI significantly improves myocardial perfusion at
6 months compared to patients treated conventionally.
Furthermore, the IA WMSI was significantly more improved at 6 months in the BMC treatment group than in the
control group. Nevertheless, in the BMC treatment group
no significant improvement in LV EF or a significant
reduction in left ventricular volumes as compared with the
control group was observed at 6 months. The LV WMSI
showed a trend towards more pronounced improvement in
the BMC treatment group. Similarly, the difference between
groups in the relative changes in IA WMSI from baseline to
6 months failed to reach statistical significance. Changes in
indices of myocardial perfusion and function did not
correlate with volume or number of injected cells.
Fig. 2 Absolute changes in PDE (a), LV PSI (b) and IA PSI (c)
between baseline and 6 months in the treatment group and the control
group. The bars indicate the mean changes and the whiskers indicate
95% confidence intervals for the mean changes
592
Eur J Nucl Med Mol Imaging (2009) 36:587–593
As mentioned above, the evidence in the literature concerning the effect of BMC therapy on myocardial perfusion
and function is conflicting, with some studies showing no
improvement of left ventricular function or perfusion [13, 14]
and others indicating significant benefit [15–18]. Not
surprisingly, at first glance our findings seem to be consistent
with observations of certain investigators, and at the same
time to be contradictory to the findings of other investigators. These discrepancies can be best explained by the
heterogeneity of study protocols. It has been clearly shown
that the choice of cell preparation protocol has a major
impact on the functional activity of BMC [19]. Furthermore,
meta-analysis by Lipinski et al. of controlled clinical trials
demonstrated that the effect on the change in LV EF may be
related to the injected cell volume (p=0.066; in our study no
significant correlation, probably due to the low number of
patients) [3]. Baseline LV EF and time from the reperfusion
therapy to intracoronary cell therapy have also been shown to
significantly influence the degree of functional improvement
after BMC treatment [16]. Since the study protocols differed
also with regard to other inclusion criteria, cell populations
used for therapy, cell administration protocols and imaging
modalities used to assess functional change [2, 3], such
conflicting results in the literature come as no surprise.
Similarly, the underlying mechanisms of BMC treatment
are still disputed [4]. Putative mechanisms of action of stem
cells include a paracrine effect (secretion of cardioprotective factors and angiogenic cytokines), transdifferentiation
into endothelium and myocardial tissue, and cell fusion
[20–23]. The significant improvement in myocardial perfusion with less apparent benefit on myocardial systolic
function observed in our study in the BMC treatment group
support the hypothesis of vasculogenesis as a major mechanism of the BMC treatment.
One of the inclusion criteria in our study was significant
left ventricular systolic dysfunction (LV EF ≤40%) on
echocardiographic examination performed within 48 h of
primary PCI, whereas the mean baseline value of LV EF
assessed by G-SPECT and further used for analysis was
41.2±10.1% and 40.0±14.2% for the BMC treatment
group and the control group, respectively. There are two
possible reasons for this discrepancy: first, there was a time
interval between study enrolment echocardiographic examination (first 48 h after PCI) and baseline G-SPECT (3–
10 days after PCI); second, as described previously LV EF
can be overestimated by G-SPECT compared to echocardiography in patients with a small heart due to underestimation of volumes, particularly in end-systolic phase [24, 25].
a well-validated technique, the strength of the evidence
obtained would undoubtedly benefit from confirmation of
the results by other imaging modalities.
Currently, the 17-segment model of the left ventricle is
recommended for the interpretation of SPECT images [26].
In this study, for perfusion assessment we used the stillwidespread Cedars-Sinai 20-segment model, whereas for
wall motion analysis we used an eight-segment model,
which was a modification of the nine-segment model
employed by some investigators [9].
In the control group no placebo procedure (sham bone
marrow aspiration or injection) was performed. This fact
should not have influenced the results of the G-SPECT
analysis, because the G-SPECT data were analysed by an
investigator blinded to all other data, including the treatment
assignment. However, the lack of a placebo procedure could
have influenced the patients’ behaviour and may partially
explain the poorer patient compliance with the study protocol
in the control group, in which two patients failed to attend
follow-up G-SPECT.
The number of patients included in our study is insufficient
for drawing definite conclusions regarding both clinical endpoints and the safety of mononuclear BMC intracoronary
transfer. Therefore, even though we realize that the data
regarding the effect of intracoronary injection of autologous
mononuclear BMC on clinical end-points would be of great
interest, we focused our analysis on the procedure’s influence
on the parameters of myocardial perfusion and function. One
may also hypothesize that the relatively small number of
patients in this study prevented the benefit on WMSI in the
BMC treatment group from reaching statistical significance.
Limitations
References
In this study left ventricular volumes, perfusion and
function were assessed using G-SPECT. Even though it is
Conclusion
Intracoronary injection of autologous mononuclear BMC in
patients with acute myocardial infarction improves myocardial perfusion at 6 months. The benefit in systolic
function of the infarct area is less pronounced and there is
no apparent improvement of global left ventricular systolic
function. Further experimental studies and large-scale
randomized clinical trials are needed to fully establish the
mechanisms and the efficacy of BMC therapy in patients
with myocardial infarction.
Acknowledgments The study was financially supported by a grant
from the Polish Ministry of Science and Higher Education (no. 2
P05B 178 28).
Conflicts of interest None.
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