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Editorial
Meta-Analysis of Preclinical Data Reveals Efficacy of
Cardiac Stem Cell Therapy for Heart Repair
Anweshan Samanta, Buddhadeb Dawn
C
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early successes of CSC therapy in humans, efficacy has been
questioned. In view of this raging controversy, it is both important and useful to critically evaluate the preclinical evidence underlying clinical translation.
In this issue of Circulation Research, Zwetsloot et al6 present the first systematic review and meta-analysis of placebocontrolled animal studies of CSC therapy for cardiac repair
after MI. The authors must be commended for painstakingly
compiling detailed information from 80 eligible studies and
generating valuable insights. In the combined analysis, CSCs
improved LVEF by 10.7% compared with controls, indicating
a robust positive impact on cardiac function. The improvement in LVEF was largely independent of cell source, although CDCs produced greater improvement compared with
Sca-1+ cells in small animals. The benefits on cardiac function
were not significantly influenced by cell source, comorbidities, use of immunosuppression, cell culture methodologies,
and disease models. Overall, the results of this meta-analysis
of cumulative data from diverse experimental conditions provide strong and consistent preclinical evidence in support of
the efficacy of cardiac progenitors for heart repair.
These results also unravel several translationally relevant
findings. The comparable ability of allogeneic cells to improve
LVEF is particularly encouraging. One of the fundamental
challenges to widespread CSC use in humans is the mandatory
waiting period required for expansion of autologous CSCs,
the frequency of which is low in cardiac tissue. For example, CSCs were injected at a mean of 113 days after harvest
in SCIPIO and at 1.5 to 3 months after MI in CADUCEUS.
This unavoidable delay also precludes autologous CSC injection at earlier time points after acute MI. However, several
animal studies have tested the efficacy of allogeneic or even
xenogeneic CSCs in immunocompetent recipients without immunosuppression. In the study by Malliaras et al, injection of
syngeneic and allogeneic CDCs both reduced infarct size and
improved EF in rats after MI.7 The current observations by
Zwetsloot et al are consistent with these findings. Importantly,
meta-analysis of pooled data revealed that improvements in
LVEF with xenogeneic cells were also similar to those with
syngeneic and allogeneic CSCs. These results bode well for
potential use of off-the-shelf CSC products with minimal delay after MI in humans.
Another important finding is the comparable improvement
in LVEF with CSC therapy in models of permanent coronary
occlusion and ischemia/reperfusion. Although most patients
with acute MI currently undergo prompt revascularization,
healthcare access varies widely across the globe. Moreover,
many patients experience clinically unrecognized MIs. If CSCs
are able to restore cardiac function in patients with chronically
occluded arteries and ischemic cardiomyopathy, larger number
ell therapy has rapidly emerged as a potential option for
cardiac repair in patients with ischemic heart disease.
Since the turn of the century, several forms of cell therapy
have been evaluated in clinical trials, including skeletal myoblasts, bone marrow mononuclear cells, mesenchymal stem
cells, and cardiac stem cells (CSCs). Cell therapy, in its various forms, has generally been efficacious, providing modest
improvements in cardiac structure and function in patients
with acute myocardial infarction (MI), as well as chronic ischemic heart disease.1 Although bone marrow cells are relatively
easy to harvest and deliver, these are not natural residents of
cardiac tissue, and their ability to regenerate lost myocardium
remains controversial. In the absence of an obvious choice,
the search for newer cellular substrates has continued.
Article, see p 1223
In 2003, Beltrami et al2 described the existence of c-kit+
cells in the heart, which were reported to be self-replicating,
clonogenic, and multipotent, giving rise to cardiomyocytes,
smooth muscle cells, and new blood vessels in ischemic rat
hearts. Subsequent demonstration of heart repair with intravascular delivery of c-kit+ CSCs paved the way for clinical
translation using intracoronary delivery.3 Intense research
in this area quickly resulted in the discovery of several additional types of cardiac progenitors, including cardiospherederived cells (CDCs), Sca-1+ cells, cardiac side population
cells, Isl1+ cells, and epicardial progenitors, among others.
Of these, c-kit+ CSCs and CDCs have already been tested in
randomized controlled trials in humans. Intracoronary injection of culture-expanded autologous c-kit+ CSCs into hearts
of ischemic cardiomyopathy patients improved left ventricular ejection fraction (LVEF) and reduced infarct size in the
Stem Cell Infusion in Patients With Ischemic cardiomyopathy (SCIPIO) trial.4 Injection of autologous CDCs into the
infarct-related artery reduced scar mass and increased regional contractility with a nonsignificant increase in LVEF in
the Cardiosphere-Derived Autologous Stem Cells to reverse
Ventricular Dysfunction (CADUCEUS) trial.5 Despite these
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Division of Cardiovascular Diseases, Cardiovascular
Research Institute, and the Midwest Stem Cell Therapy Center, University
of Kansas Medical Center and Hospital, Kansas City.
Correspondence to Buddhadeb Dawn, MD, Division of Cardiovascular
Diseases, University of Kansas Medical Center, 3901 Rainbow Blvd,
1001 Eaton, MS 3006, Kansas City, KS 66160. E-mail [email protected]
(Circ Res. 2016;118:1186-1188.
DOI: 10.1161/CIRCRESAHA.116.308620.)
© 2016 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.116.308620
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of patients may potentially benefit. However, nearly all large
animal studies of CSC therapy thus far have used ischemia/
reperfusion, although cells were injected after several weeks
in most studies. The efficacy of CSCs to improve cardiac parameters in patients with cardiomyopathies resulting from
reperfused as well as nonreperfused MIs at various stages of
remodeling remains to be further examined in clinical trials.
The differences in outcomes of CSC therapy between
small and large animal studies identified by Zwetsloot et al6
are also important from a translational viewpoint. The improvement in LVEF with CSC therapy was significantly
greater in small animals (11.5%) compared with large animals (5.2%). The reduction in infarct size expressed as percentage of LV was also significantly different between small
and large animal studies. CSC therapy led to ≈10% reduction
in infarct size in small animals, whereas large animal studies
documented small and nonsignificant decrease compared with
controls. Infarct size expressed as percentage of area at risk
was provided only in small animal studies, and the 10.85%
reduction with CSC therapy mirrored the above data on infarct size as percentage of LV. Intriguingly, these infarct size
data from large animals do not corroborate the results from
SCIPIO and CADUCEUS. The SCIPIO trial reported a 22.7%
reduction in infarct size at 4 months and a 30.2% reduction at
12 months.8 The CADUCEUS trial showed an 11.1% reduction in scar size at 1 year after CDC injection.9 Together, these
data from well-conducted separate clinical trials underscore,
on a positive note, that even large animal preclinical data may
not always accurately predict the outcomes in clinical trials.
How do we explain these differences in observations
based on animal size? In their extensive analysis, Zwetsloot
et al6 highlighted a significant difference between the qualities
of large and small animal studies, with large animal studies
emerging superior to their counterparts. There was also evidence of potential publication bias in small animal studies,
although the overall effect size was reduced only by 0.1% in
EF difference, following correction. The numerically smaller
effect size in large animal studies offers another potential explanation for this difference. However, the likely influence
of study quality was further supported by the indication of
attrition bias, particularly evident in small animal studies.
Although 8 of 9 large animal studies were considered low risk
for attrition bias, only 21 of 71 studies in small animals appeared to be at low risk. In the majority of the small animal
studies, the authors failed to report the number of animals excluded from the study and the reasons behind their exclusion.
This attrition bias in small animal studies might have a sizable
impact on the measured outcomes and could possibly explain
the differences in observations between small and large animal studies. Collectively, these observations emphasize the
critical importance of honest and accurate reporting of all experimental data in preclinical research.
Although meta-analyses of animal studies are considerably less frequent compared with clinical ones, the importance
of such endeavors is paramount, especially in this era of rapid
translation of basic discoveries. Although CSC therapy has
shown tremendous promise in early clinical trials, many questions remain unanswered with regard to mechanisms as well
as the ideal cell type, timing, route, cell number, and other
relevant details of study design, some of which are addressed
in this meta-analysis by Zwetsloot et al.6 Meta-analysis of
preclinical data can also be helpful to identify the influence
of bias in the published literature. In this regard, when the
authors stratified the analysis after removing the heterogeneity introduced by cell types, the publication bias became extensive with the majority of cell types. This is a key finding
that can be unmasked only by careful meta-analysis of pooled
preclinical data.
In closing, it is reassuring to find that infarct repair with
CSC therapy has actually been better in humans than in large
animals. This is consistent with the notion that as bona fide tissue-resident cardiac precursors, CSCs are able to reconstitute
functional myocardium that was once considered lost forever.
However, these early benefits of CSC therapy from smaller
trials need to be tested and further substantiated in the current
multicenter randomized controlled trials that are being performed using the most stringent methodologies. The cumulative preclinical data demonstrate that these ongoing clinical
trials with cardiac progenitors are based on solid foundations,
and provide reason for much optimism in the field of cardiac
cell therapy.
Acknowledgments
This publication was supported in part by the National Institutes of
Health grant R01 HL-117730.
Disclosures
None.
References
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Key Words: Editorial ■ cardiac progenitor cells ■ cardiomyopathy
■ meta-analysis ■ myocardial infarction ■ ventricular dysfunction
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
Meta-Analysis of Preclinical Data Reveals Efficacy of Cardiac Stem Cell Therapy for
Heart Repair
Anweshan Samanta and Buddhadeb Dawn
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
Circ Res. 2016;118:1186-1188
doi: 10.1161/CIRCRESAHA.116.308620
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