Journal of the American College of Cardiology Vol. 58, No.

23, 2011
© 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2011.08.034

STATE-OF-THE-ART PAPER

Repair After Myocardial Infarction,

Between Fantasy and Reality
The Role of Chemokines

Elisa A. Liehn, MD, PHD,*† Otilia Postea, PHD,* Adelina Curaj, MD,*‡§ Nikolaus Marx, MD†
Aachen, Germany; and Bucharest, Romania

Despite considerable progress over the last decades, acute myocardial infarction continues to remain the major
cause of morbidity and mortality worldwide. The present therapies include only cause-dependent interventions,
which are not able to reduce myocardial necrosis and optimize cardiac repair following infarction. This review
highlights the cellular and molecular processes after myocardial injury and focuses on chemokines, the main
modulators of the inflammatory and reparatory events, as the most valuable drug targets. (J Am Coll Cardiol
2011;58:2357–62) © 2011 by the American College of Cardiology Foundation

Modern cardiology has made considerable advances in the
diagnosis and management of acute myocardial infarction
(MI), but there still remains the need to design strategies to
regain the affected tissue and to re-establish the organ
function entirely.
To accomplish this, sustained effort must be made to
understand the cellular and molecular mechanisms follow-
ing MI (1). It is known that hypoxia induces death of
cardiomyocytes and triggers an inflammatory response (1,2).
The recruited inflammatory cells clean the wound of tissue
debris, whereas fibroblasts and endothelial cells infiltrate,
proliferate, remodel the extracellular matrix, and determine
scar formation (1).
Beyond their crucial role in coordinating leukocyte re-
cruitment (3), chemokines interfere with all phases of MI
(4) (Fig. 1, Online Appendix, Online Table 1), contributing
to inflammatory and reparatory processes.
Heart: the “motor” of life. Myocardium is built from long
chains of striated muscle, and because of its increased
mitochondrial content, exhibits remarkable resistance to
fatigue, sustaining all vital functions of the organism.
Despite what was hitherto believed, new evidence dem-
onstrates the regeneration of heart muscle cells after birth
(5). But how is that possible? Although several studies have
reported a possible fusion of stem cells with cardiomyocytes
From the *Institute for Molecular Cardiovascular Research (IMCAR), RWTH
Aachen University, Aachen, Germany; †Department of Cardiology, Pneumology,
Angiology and Internal Medicine Intensive Care (Internal Medicine I), University
Hospital, RWTH Aachen University, Aachen, Germany; ‡Department of Experi-
mental Molecular Imaging, RWTH Aachen University, Aachen, Germany; and the
§Victor Babes National Institute of Pathology, Bucharest, Romania. All authors have
reported that they have no relationships relevant to the contents of this paper to
disclose.
Manuscript received April 20, 2011; revised manuscript received July 26, 2011,
accepted August 2, 2011.
followed by mitochondria and genetic material transfer (6),
discussion regarding this subject is purely speculative.
However, it is generally accepted that Lin⫺/c-kit⫹ car-
diac progenitor cells must exist (7) and could be localized
beneath epicardium, or near the origin of the coronary
arteries and aorta, in a so-called cardiac stem cell niche (8).
On the other hand, mesenchymal stem cells (MSCs) were
also described as cardiac precursors and are mostly found in
bone marrow (9). We do not know their role in physiolog-
ical cardiac renewal; however, they have an important role in
cardiac regeneration after injury (10) and were broadly used
as a source for stem cell therapy after MI (9).
Recently, a network of interstitial cells with exceptionally
long cellular processes, called telocytes, which assure the
long-distance signaling in myocardium, has been described
(8). These cells seem to play a significant role in cardiac
development, physiology, renewal, and repair (11).
A dramatic scenario occurs when, for various reasons, the
blood supply to the heart cells is interrupted. Without
oxygen, most of the cardiomyocytes will die. Therefore, a
rapid repair and renewal of the injured area is of critical
importance.
Inflammatory phase: danger or necessity. Despite the
cardioprotective effects of some secreted cytokines (TNF␣, HIF)
and chemokines (CCL2, CXCL12, macrophage inhibitory
factor) (12–17), along with permanent damaging of the
cardiomyocyte, the local repair capacity of the heart is
limited, and prompt external cellular help at this moment
becomes essential.
The initial inflammation is modulated through several
molecular steps involving selectins, integrins, cell adhesion
molecules (1), and various endogenous ligands, called danger-
associated molecular patterns (DAMPs) or “danger signals”
(18). Moreover, several Toll-like receptors (TLRs) recog-
2358 Liehn et al.
Chemokines in Cardiac Repair
Abbreviations nize pathogen-associated molec-
and Acronyms ular patterns (PAMPs), the basis
of the innate immune system (19),
EPC ⴝ endothelial
progenitor cell but are also endogenous markers
MI ⴝ myocardial infarction
of tissue damage (20).
The first cells recruited within
MSC ⴝ mesenchymal stem
cell
hours for a short time to the in-
jured site are neutrophils. When
arriving, they release proteolytic
enzymes and reactive oxygen species, and directly injure
surrounding cells (1,21). Neutrophil depletion in animals
undergoing MI led to a marked decrease in infarct size
(22,23). All successful experimental interventions of block-
ing complement (24), reactive oxygen species (25),
or NF-kB pathway (26) reduce neutrophil infiltration.
CXCR2-binding chemokines, including CXCL8, CXCL2,
CXCL1 and CXCL6, as well as CCL3 and CCL5 (23,27),
are also critical for neutrophil recruitment (4). Blocking
these chemokines and their receptors dramatically reduces
infarction size and preserves cardiac function.
On the other hand, neutrophils release chemotactic
factors (28) and induce accumulation of splenic monocytes
in injured tissue (29). Blocking this splenic monocytes
exodus by angiotensin-converting enzyme inhibition has a
beneficial effect on cardiac function (30). Two monocyte
populations have been identified, the inflammatory mono-
cytes: Gr1(⫹)CCR2(⫹)CX3CR1(lo)(Gr1high), and the
resident monocytes: Gr1(⫺)CCR2(⫺)CX3CR1(hi)(Gr1low)
(31). The first population of murine monocytes shares the
same characteristics with the classical human CD14hiCD16⫺
monocytes, dominates the early phase of MI, and exhibits
phagocytic, proteolytic, and inflammatory functions. They
digest damaged tissue and clear the wound of cellular debris.
The murine resident monocytes correspond to human
CD14loCD16⫹ nonclassical monocytes (32) and dominate the
later phase, have attenuated inflammatory properties, and
promote healing via myofibroblast accumulation, angiogenesis,
and deposition of collagen (33). Neutrophils seem to sustain
the extravasation of inflammatory monocytes, in a CCR2-
dependent manner, but not the recruitment of resident mono-
cytes (34).
Recent data have shown that Ly-6C(hi) monocytosis
(35), as well as CD14hiCD16⫺, but not resident mono-
cytes, negatively correlated with preservation of left ventric-
ular function (36). Indeed, inhibiting CCL2 with a neutral-
izing antibody or competitive peptide leads to pathological
defects in infarcted mice, such as decreased macrophage
infiltration, delayed replacement of dead cardiomyocytes
with granulation tissue, and decreased myofibroblasts accu-
mulation (37,38). However, delayed phagocytosis of injured
cardiomyocytes may increase the arrhythmogenic potential
or predisposition to mechanical complications, such as heart
rupture (37). Therefore, the potential use of CCL2 as a
clinical therapeutic target should be carefully scrutinized.
In conclusion, until proven otherwise, short and limited
presence of neutrophils is needed to initiate inflammatory
JACC Vol. 58, No. 23, 2011
November 29, 2011:2357–62
reaction and pave the way for monocytes. However, the
explosion of inflammatory mediators leads to a self-
maintaining cycle, increasing myocardial damage. There-
fore, specific reduction of neutrophil infiltration could have
a favorable clinical impact on the evolution of an MI.
Besides the cellular external help, the inflammatory re-
sponse can also have another important task: preparing the
surrounding unaffected cardiomyocytes for stress conditions.
It is known that chemokines and cytokines are synthesized,
not only in infarcted tissue, but also in unaffected regions
(4), triggering initiation of defending mechanisms, such as
activating HIF (39) and NF-kB (40), and place cardio-
myocytes in a “pre-conditioning” state, increasing resistance
to a new hypoxic event. HIF induces specific synthesis of
some chemokines, such as CXCL12 (41) and MIF (42),
with demonstrated cardioprotective effects. Impairing HIF
activation by hypoxic condition, as in diabetic hearts,
interferes with ATP production and induces metabolic,
energetic abnormalities, disturbing vessel development (43).
In conclusion, the inflammatory response after MI de-
serves special attention and may provide therapeutic key
targets to control the entire wound healing and scar forma-
tion (33).
Proliferation phase: when it starts and why it stops. The
transition between the inflammatory and proliferation
phases is decisive. The heart wall, cleaned of dead cardio-
myocytes and matrix debris, without new supporting struc-
tures, will inevitably break under the high blood pressure
and high mechanical force. The incidence of experimental
heart rupture occurs at a later time, after a hypoxic insult
(44), and coincides with the passage between the 2 phases.
As soon as the necrotic cells and matrix debris are removed,
the rapid inhibition of inflammation by TGF-␤ and IL10 (45)
is essential for the optimal infarct healing. Inflammatory cells
are replaced by resident or recruited Gr1low monocytes, lym-
phocytes, and mast cells that initiate healing.
Resident monocytes, a heterogenic group of cells, patrol
between the cardiomyocytes using CX3CR1 receptors (34),
maturate into macrophages, and maintain the homeostasis
of the normal tissue. After MI, they are recruited to the site
of injury by CX3CR1-dependent (46) or CCR5-dependent
(47) mechanisms. Recent studies demonstrate the existence
of 2 distinct types of macrophages, M1 and M2, with
similar behavior as Gr1high and Gr1low monocytes, respec-
tively (48). However, it is not known whether the differen-
tiation is determined by monocyte maturation or later
macrophage polarization.
Because the appropriate blood supply is crucial for heart
survival and function, angiogenesis is considered an optimal
therapeutic target. VEGF and CXCL12 control and mod-
ulate the recruitment of endothelial progenitor cells (EPCs)
and proper formation of blood vessels (49). Although this
occurs continuously, EPCs are not continuously recruited.
Earlier transplantation of EPCs seems to have maximal
beneficial effects, whereas later systemic transplantation of
EPCs failed to influence cardiac remodeling and function.
JACC Vol. 58, No. 23, 2011 Liehn et al. 2359
November 29, 2011:2357–62 Chemokines in Cardiac Repair

Figure 1 Cellular and Molecular Events After MI

The healing after myocardial infarction involves 3 overlapping phases: inflammatory, proliferative, and healing phases. Each is characterized by specific events (red),
implicating different cells, controlled by specific chemokines (blue). Extracellular matrix (ECM) evolves to mature scar (dark blue), which ensures the stability and the
function of the heart. HIF ⫽ hypoxic inducible factor; IL ⫽ interleukin; MCP ⫽ monocyte chemotactic protein; MI ⫽ myocardial infarction; MIF ⫽ macrophage inhibitory
factor; MSC ⫽ mesenchymal stem cell; NF-kB ⫽ nuclear factor kappa B; SDF ⫽ stromal-derived factor; TGF ⫽ transforming growth factor; TNF ⫽ tumor necrosis factor.

Therefore, angiogenesis should be supported by the survival
and proliferation of EPCs shortly recruited after infarction
and of local stem cells, differentiated towards an endothelial
phenotype. A recent study highlights the important role of
MI-induced epicardium-derived cells in angiogenesis by
secreting paracrine factors (50). However, these cells are not
able to differentiate into endothelial cells or cardiomyocytes,
but into MSCs, and seem to offer cardiac protection.
After infarction, angiostatic factors, such as CXCL10, are
up-regulated, inhibiting angiogenesis until the myocardium
is cleaned of cell debris and a provisional matrix is formed
(1,51). Along with suppressing cytokines and chemokines of
the inflammatory phase, TGF-␤ suppresses the expression
of CXCL10 and allows angiogenic factors, such as
CXCL12, CXCL1 (52), CXCL2 (53), MIF (54,55), and
even CCL2 (56), to exert their function (1,51).
2360 Liehn et al.
Chemokines in Cardiac Repair
Another player is recruited lymphocytes, which synthe-
size IL-10 and tissue inhibitor of metalloproteinase (TIMP)-1,
modulating the mononuclear cell phenotype and T helper 2
polarization, in a CCL2-dependent manner (57). Recently,
it was shown that CCR5-mediated regulatory T cell recruit-
ment reduced post-infarction inflammation, preventing ex-
cessive matrix degradation and attenuating adverse remod-
eling (58). Although lymphocytes seem to have important
roles during healing after MI, there are still many unknowns
that have to be clarified.
Fibroblasts produce extracellular matrix and provide me-
chanical support for the newly formed structures (1,51).
Resident, as well as recruited, fibroblast progenitors (59)
activate and differentiate into myofibroblasts under TGF-␤
(60) and CCL2 (61) stimulation, developing morphological
and contractile characteristics of smooth muscle cells. The
synthesized collagen together with proteoglycans and glyco-
proteins constitute the extracellular matrix (62). CD44,
expressed on all implicated cells, is critically involved in the
regulation of the fibroblast function (63).
Although the original cardiac matrix network is degraded
by metalloproteinases and cleared together with cellular
debris, extravasation of plasma proteins results in a complex
and dynamic matrix network based on fibrin and fibronec-
tin, serving as a scaffold for migration and proliferation of
the cells (64). Once the inflammatory phase is repressed,
and myofibroblasts proliferate, this fibrin-based provisional
matrix is gradually replaced by collagen. Specific proteins,
such as thrombospondin-1 and -2, osteopontin, tenascin C,
periostin, and SPARC, regulate the cellular interaction,
induce cross-linking, and organize the mature matrix (64).
Another important aspect of the proliferative phase is
cardiomyocyte regeneration after injury. The major goal of
cellular therapies is to restore the initial integrity of the heart
tissue. Transplanted fetal cardiomyocytes integrate between
the existent cells and improve contractile heart function
(65). However, it would be a real challenge, not only
methodically, but also ethically, to obtain these cells for a
future clinical application. Therefore, other cells, such as
MSCs, are broadly used as a source for stem cell therapy
after MI (9,66). It seems that CXCL12 (67) and CCL7
(68) chemokines control myocardial homing of MSC after
injury, which engraft and differentiate into cardiomyocytes,
or fuse partially/permanently with neighbor cells, transfer-
ring genetic and mitochondrial material (6). Unfortunately,
despite extensive research in the last few years, the cell-
mediated regenerative mechanisms remain elusive, making
their clinical implementation difficult.
Healing phase: “dead” or “living” scar? In the last stage,
the scar contains a dense collagen-based extracellular matrix,
myofibroblasts, stem cells, and newly formed vessels. Un-
known mechanisms activate apoptotic pathways in myofi-
broblasts and vascular cells, and determine the loss of most
cellular components (64). The mature infarction scar was for
a long time considered inert, incapable of biological func-
tion. Since increased collagen content was associated with
JACC Vol. 58, No. 23, 2011
November 29, 2011:2357–62
decreased ventricular function (69), inhibition of myofibro-
blast is considered an appropriate therapeutic goal. Our data
have shown that increased collagen content even supports
contractility and preserves heart function (23,70). However,
using noninvasive methods to visualize the interstitial
changes in vivo (71) should enable us to monitor the
remodeling and signal specific changes.
To date, we know that mature scar is a dynamic tissue,
vascularized and metabolically active. Experimental cell
transplantation in mature scar induces cell-specific changes,
improving ventricular function (65,70,72,73), the same
effect being observed also by biologically inactive glass
microsphere transplantation. This leads to the conclusion
that the underlying mechanisms might be based on inflam-
matory processes induced by transplantation (73). This
could represent a potential therapeutic strategy in patients
with extended scar tissue, for whom all current clinical
treatment alternatives have been exhausted.
Strategies for clinical settings of the new therapies. Be-
side cell therapy, manipulation of different biological pathways
in the heart by gene therapy, antibodies, peptides, silencing
RNA, or microRNA seems to represent other promising
approaches to heart failure treatment. However, despite the
evident effects in experimental models, the clinical application
requires extensive research and intensive discussion.
Since the systemic application of drugs would have
uncontrolled adverse effects, local delivery is necessary. For
example, the intracoronary transfer of viral vectors (74) or
Hemagglutinating Virus of Japan liposome (75) carrying a
gene proved to be very simple and less invasive. Likewise,
intracoronary gene-containing microbubbles followed by
ultrasonic destruction at the desired position may represent
a feasible clinic setting (76). The same strategies can be
applied when using stimulating or blocking peptides, anti-
bodies, or other control tools for gene transcription, such as
silencing RNA or microRNA. On the other hand, due to
the unpredictable progress of the events, it is not possible to
implement these strategies in any clinical settings.
Supreme control: fine-tuning the chemokine. Despite
extensive research, our current knowledge regarding the
control of molecular and cellular events after MI is still
limited. Therefore, to be able to create efficient therapies,
we need to understand how all these processes are modu-
lated and controlled. Chemokines and chemokine receptors
have the most precise functions in leukocyte trafficking,
angiogenesis, collagen synthesis, and cardiac repairing. Ma-
nipulating them, by interfering with receptor–ligand inter-
action, chemokine– glycosaminoglycan interaction, hetero-
merization, or signaling pathways induced upon receptor
activation (77), should enable us to control and modify
molecular and cellular events (Table 1, Online Table 1).
Conclusions
Understanding the basic mechanisms involved in MI is crucial
for the development of new strategies to reduce injury and
JACC Vol. 58, No. 23, 2011 Liehn et al. 2361
November 29, 2011:2357–62 Chemokines in Cardiac Repair

ischemic-induced apoptosis in a murine model of acute myocardial

Potential
Disadvantages
Potential Advantages Advantages
of Targeting
and and
Chemokines
Table 1
Disadvantages of Targeting Chemokines
Advantages Disadvantages
Precise and differentiated actions on
leukocyte subsets and stem cells
Precise and differentiated actions on Concomitant actions are
angiogenesis, collagen synthesis, poorly studied
and cardiac remodeling
Specific and selective agonists and Price
antagonists available
Local or systemic applications Interference with other organs
by systemic applications
(partly disadvantageous)
Very short action: side effects rapidly reversible Sometimes repetitive
application is needed
Easy combination with other carrying systems
(liposomes, microbubbles, nanoparticles)
promote repair, which together with the classical interventions
should improve the left ventricular remodeling, the function of
the heart, and the prognosis of a patient after MI.
Acknowledgment
The authors want to thank Dr. O. Bucur for critical review
of the manuscript.
Reprint requests and correspondence: Dr. Elisa A. Liehn,
Department of Cardiology, Pneumology, Angiology and Internal
Medicine Intensive Care (Internal Medicine I), University Hos-
pital Aachen, RWTH Aachen, Pauwelsstrasse 30, D-52074
Aachen, Germany. E-mail: eliehn@ukaachen.de.
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Key Words: chemokine y inflammation y myocardial infarction y
remodeling.
APPENDIX
For supplementary material and a table,
please see the online version of this paper.