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Cardiovascular Research
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Review
Healing after myocardial infarction
Georg ErtlT, Stefan Frantz
Medizinische Universitatsklinik Wurzburg, Josef-Schneider-Str. 2, 97080 Wurzburg, Germany
Received 22 November 2004; received in revised form 29 December 2004; accepted 10 January 2005
Time for primary review 22 days
Abstract
Wounding and healing are archaic principles, prerequisite for survival of any biologic material. However, strategies to cope with
wounding may be quite different among organisms, species, or among various organs of one species. Today, myocardial infarction and the
consequent loss of fully functional myocardium is the major aetiology for heart failure. Despite aggressive primary therapy, prognosis
remains serious in patients with large infarction and severe left ventricular dysfunction. Thus, it would be highly desirable to influence
healing of the cardiac wound to maintain structure and function of the heart. Herein, we review different, important factors of cardiac healing
including reperfusion, mechanical stress, gender, and neurohormonal factors as well as specific factors essential for healing which may be
genetic or acquired, emphasizing similarities and discrepancies between different organs and species.
D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Myocardial infarction; Healing; Inflammation; MMP; RAAS
ion Norris M
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Myocardial infarction (MI) and the consequent loss of
contractile myocardium is a frequent cause of chronic heart
failure. Infarct size is a major determinant of prognosis and
depends on the myocardial region supplied by the infarct
related coronary artery [1]. Large infarcts induce a process
of cardiac remodeling which includes gross morphologic,
histological and molecular changes of both the infarcted and
the residual non infarcted myocardium [2]. Remodeling is a
strong prognostic determinant and is closely related to the
incidence of arrhythmias and sudden cardiac death [3].
Myocardial infarct size is dynamic since the loss of viable
myocardium is progressive after coronary artery occlusion
during several hours (infarct extension). In addition, the
infarcted region may further expand or contract [4] during
the first weeks even after the loss of viable myocardium has
terminated. Infarct expansion itself is a critical determinant
of remodeling and thus prognosis [1]. The time window is
too small for many patients to rescue viable myocardium but
0008-6363/$ - see front matter D 2005 European Society of Cardiology. Publish
doi:10.1016/j.cardiores.2005.01.011
* Corresponding author. Tel.: +49 931 201 36301; fax: +49 931 201
36302.
E-mail address: ertl_g@medizin.uni-wuerzburg.de (G. Ertl).
would be sufficiently large for most patients to establish a
therapy to prevent infarct expansion by support of healing.
Support of wound healing is an ancient task of medicine
although mostly directed to wounds of skin, skeletal muscle
and bones. Various remedies have been recommended for
better wound healing. Large experience has gathered since
then by surgeons but knowledge mostly remained empiric.
Actin filaments containing fibroblasts are prominent in skin
wounds and probably contribute to wound contraction [5].
Recently, essential factors for skin wound healing have been
reported and their mechanisms of action have been
identified in part [6]. Their impact on cardiac wound
healing remains unknown.
Attempts were undertaken to stimulate reparative pro-
cesses following experimental MI by the group of Sigmun-
dur Gudbjanarsson and Richard Bing in the sixties of the
last Century but did not reach clinical application [7].
Cardiac wound healing in mammals is hampered by the fact
that regeneration of heart muscle is virtually absent and
damaged myocardium is replaced by scar tissue. In contrast,
zebra fish fully regenerate hearts within 2 months after 20%
ventricular resection (Fig. 1) an enviable capability of
cardiac healing [8]. Moreover, the adult newt has also an
66 (2005) 22–32
ed by Elsevier B.V. All rights reserved.
Fig. 1. Regeneration of ventricular myocardium in the resected zebrafish heart. Hematoxylin and eosin stain of the intact zebrafish heart before (A) and after
about 20% ventricular resection (B). b.a., bulbous arteriosus. (C) An intact ventricular apex at higher magnification, indicating the approximate amputation
plane (dashed line). All images in this and subsequent figures display longitudinal ventricular sections of the amputation plane. (D) 1 dpa. The large clot is filled
with nucleated erythrocytes (arrowheads). (E) 9 dpa. The heart section is stained for the presence of myosin heavy chain to identify cardiac muscle (brown) and
with aniline blue to identify fibrin (blue). The apex is sealed with a large amount of mature fibrin. (F) 14 dpa. The fibrin has diminished, and the heart muscle
has reconstituted. (G) 30 dpa. A new cardiac wall has been created, and only a small amount of internal fibrin remains (arrowhead). (H) 60 dpa. This ventricle
shows no sign of injury [8].
G. Ertl, S. Frantz / Cardiovascular Research 66 (2005) 22–32 23
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extraordinary regenerative capacity being able to regenerate
large sections of its heart in response to tissue damage or
removal dependent on cellular dedifferentiation [9,10]. The
ideal therapy obviously would direct the cardiac healing
process to complete regeneration. The use of various types
of cells for myocardial regeneration is one approach.
Perhaps in future we can learn from zebra fish and the
newt but on our way to such a hopeful fiction, we need to
test other concepts to improve cardiac wound healing.
Time course of morphologic and histological changes of
infarcted myocardial tissue has recently been reviewed in
some detail [11,12]. After cardiomyocyte death and perhaps
with some time overlap, an inflammatory reaction starts
within the first day after MI. Inflammatory cells invade the
infarct and, somewhat later, myofibroblasts appear in the
wound. Alterations of connective tissue are present as early
Fig. 2. Collagen after myocardial infarction in the mouse. Representative examples
weeks after experimental myocardial infarction.
as 40 min after an experimental coronary occlusion and
degradation of collagen is significant at 24 h in the rat. The
normal collagen structure virtually disappears during the
first week after the infarct (Fig. 2). The extent of collagen
damage correlates with the degree of infarct expansion [13].
Increased activities of collagenases and other neutral
proteinases have been made responsible for the rapid
degradation of extracellular matrix collagen in MI. Inflam-
matory cells release proteases and contribute to removal of
necrotic tissue; myofibroblasts to the reconstruction of a
new collagen network. The actions of the myofibroblasts are
admirably systematic and are essential for the organization
of scar formation under the difficult condition of the
rhythmic contraction of the heart. After several weeks, a
solid scar has been formed with a stable collagen structure,
overall little cellularity, but some myofibroblasts remain in
of picrosirius red stained hearts under polarized light 3 days, 1 week, and 6
G. Ertl, S. Frantz / Cardiovascular Research 66 (2005) 22–3224
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the scar tissue [14]. Thus, healing is a complex process of
invasion, transformation and apoptosis of various cell types
which is highly regulated and may well be subject to
disturbances and interventions.
Some factors have been identified which may contribute
to infarct healing. Reperfusion may limit infarct size by
stopping the loss of viable myocardium but also by an
additional beneficial effect on healing [15]. Mechanical
stress may result in infarct expansion [16]. Age, sex,
neurohumoral factors and drugs have also been suggested
to contribute to healing and infarct expansion. More
recently specific factors essential for healing and scar
formation have been analyzed by their specific antagonists
or transgenic mouse models. So far little is known about a
genetic or acquired general healing deficiency which may
contribute to infarct expansion. The purpose of this article
is (1) to review factors which influence infarct healing, (2)
to test the hypothesis that conditions of general healing
deficiency may exist, (3) to discuss complex genetic
diseases as models for the concept of a genetic healing
deficiency.
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1. Factors known to influence healing
Regional wall stress has predicted ventricular remodeling
after anteroseptal MI in man [17]. Physical exercise or
prolonged inotropic stimulation with digoxin started early
after a MI has promoted infarct dilatation and thinning
[16,18]. In contrast, mechanical unloading by vasodilators
prevented infarct expansion and thinning in dog and man
especially if combined with reperfusion [19].
Animal experiments have suggested that late reperfusion
of MI after completion of the extension of cardiomyocyte
death may prevent further infarct expansion and thinning
[15]. Together with observations of benefit of late thrombo-
lytic therapy or mechanical recanalization of occluded
coronary arteries [20], and an open coronary artery in
retrospective observations, these studies generated the
hypothesis of an advantage of an open versus a chronically
occluded coronary artery [21]. A patent infarct related
coronary artery was related to less apoptosis in the associated
myocardium [22]. Reperfusion may activate [23] or inhibit
[24] matrix metalloproteinases, and thrombolytic therapy on
its own may stimulate collagen break down [25]. Infiltrating
neutrophils into reperfused myocardium are an early source
of locally active MMP-9 after reperfusion [26]. Furthermore,
apoptosis may contribute to reperfusion injury [27]. Clinical
data are conflicting and today, clinical evidence is missing for
a beneficial effect of reopening an occluded coronary vessel
in the absence of symptoms.
1.1. Age
Half of the patients admitted to a hospital for acute MI
and 80% of the patients who die are 65 years and older [28].
The exponential, age related increase in the mortality rate
did not appear to be explained by larger infarcts [29].
Aging is associated with reduced deposition of specific
extracellular matrix components, an up regulation of angio-
genesis, an altered inflammatory response in wounds [30],
reduction of vascular NO availability [31], an increased
wound elastase and matrix degeneration [32]. Thus, numer-
ous potential determinants of infarct healing are associated
with age but their actual role has not been studied in detail and
factors like gender, previousMI andMI localization [33] may
have contributed to the age dependent effects.
1.2. Estrogen
Estrogen replacement resulted in an increased infarct size
or infarct expansion and was unable to prevent left
ventricular remodeling in ovariectomized rats [34]. How-
ever, high dose substitution of estrogen to supernormal
levels produced thicker infarct scars and prevented remod-
eling in rats (Beer et al., personal communication). Younger,
but not older women who survive hospitalization for MI
have a higher long-term mortality rate than men [35] and
initiation of hormone replacement therapy after MI is
associated with more cardiac events during follow-up [36].
In cutaneous wounds, estrogen decreases elastase secon-
dary to reduced neutrophil numbers, and decreases fibro-
nectin degradation [37]. In vitro studies have shown that
reproductive hormones influence cellular proliferation and
cytokine production [38]. The rate of cutaneous wound
healing is impaired in ovariectomized female rodents and
post menopausal women but the quality of scarring is
improved. The age related changes in women were reversed
by systemic hormone replacement therapy. Topical estrogen
accelerated cutaneous wound healing is associated with an
increase in TGFh 1 levels in ovariectomized rats [39] and
aged male and female humans [37]. Estrogen activates
endothelial nitric oxide (NO) synthase [40], stimulates
neuronal NO synthase protein expression in human neu-
trophils and mediates NO release [41]. Thus, there are
numerous possible pathways by which estrogen might
influence the inflammatory response and the following
processes of wound healing. However, experimental and
clinical studies are controversial and need further research.
1.3. Neurohumoral systems
1.3.1. The renin–angiotensin–aldosterone system
Angiotensin-converting enzyme inhibition delayed matu-
ration of the infarct scar indicated by reduced collagen
alignment and package (Fig. 3) [42]. Targeted deletion of
angiotensin II type 2 receptor reduced collagen volume
fraction and scar thickness in experimental infarcts and
caused cardiac rupture [43]. Furthermore, Angiotensin II is a
chemoattractant to inflammatory cells [44] and induces
leukocyte-endothelial cell interactions via AT 1 and AT 2
receptor-mediated p-selectin upregulation [45]. Angiotensin
A
B
C WKYSHSH+Q
100
Col
lage
nco
nten
t in
scar
(%
)
80
60
40
20
0
++++
Large MIModerate MI
Fig. 3. Picrosirius red-stained specimen from rat MI scar. (A) bNormalQmature scar of an untreated SHR (spontaneous hypertensive rat). The fibers
are nicely lined up and packed; the scar appears yellow and red. (B)
Specimen from a MI of a rat treated with quinapril. bImmatureQ scar visiblydifferent to that of the untreated animals. (C) Collagen content in the scar of
untreated WKY rats, untreated SHR and quinapril-treated SHR with
moderate and large infarcts. ypb0.05 compared with respective WKY
group; zpb0.05 compared with respective SH group [42].
G. Ertl, S. Frantz / Cardiovascular Research 66 (2005) 22–32 25
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converting enzyme inhibitors and even more angiotensin II
type 1 receptor antagonists reduce the inflammatory
infiltrates into the infarct zone and prevent accumulation
of type I myocardial collagen in the noninfarcted septum
secondary to activation of TGF-beta 1. Redistribution of
macrophages and activated myofibroblasts from the infarct
zone are likely to play a paracrine role in mediating this
inflammatory reaction in surviving myocardium [46].
1.3.2. Endothelin
Sakai et al. [47] and Fracarollo et al. [48] found that
endothelin-A and endothelin-A and -B receptor antagonists
substantially improved survival and left ventricular function
and reduced remodeling and cardiac filling pressures. The
dual endothelin-A and -B receptor antagonist tezosentan
administered during the first day after MI increased long
term survival and hemodynamic conditions [49]. In contrast,
left ventricular dilatation was even aggravated by the use of
endothelin-A receptor antagonists early after MI [50] by
scar expansion and reduction of scar collagen [51]. This was
most likely due to an activation of myocardial tissue
metalloproteinases (Fig. 4). In contrast, others report a
reduction of metalloproteinase activity by the endothelin-A
receptor antagonist sitaxsentan [52]. Thus, the action of
endothelin and its antagonists on myocardial healing remain
controversial. They exemplify the potential of endogenous
systems and their antagonist of ambiguous effects on
healing and remodeling of the heart.
1.3.3. Nitric oxide
eNOS KO mice develop greater left ventricular enddias-
tolic dimensions and lower fractional shortening 28 days
post MI [53]. This suggests a protective role of eNOS. In
contrast, iNOS KO mice had improved contractile function
and higher survival rates after MI without a difference in
infarct size. Yet, as expected, less apoptosis was noted in
iNOS KO mice when compared to matching wildtypes [54].
Effects of NO on cardiac matrix components were not
investigated. However, nitric oxide has profound effects on
cutaneous wound healing: In fact, eNOS [55] as well as
iNOS KO [56] mice have delayed excisional wound
healing. Therefore, direct effects of NO on cardiac wound
healing seem to be very likely, but remain to be defined.
1.4. Cytokines
A variety of cytokines have been implicated in cardiac
remodeling as well as in healing. We will exemplify their
role by interleukin (IL)-1h and tumor necrosis factor (TNF)
in this review.
Blood levels and/or intramyocardial expression levels of
IL-1h are increased in patients with acute MI [57].
However, only little functional data exist about IL-1hfunction in the pathophysiology of heart failure: Indeed,
early administration of inflammatory cytokines decreases
myocardial injury [58]. In contrast, long term activation of
cytokines seems to be detrimental: Mice lacking the active
forms of IL-1h and IL-18 exhibited both improved peri-
infarct survival and a decreased rate of ventricular
dilatation. Interestingly, IL-1h and IL-18 are known to
induce different MMPs and indeed MMP-3 and collagen
content were decreased in animals lacking IL-1h and IL-18
[59]. Thus, long-term effects of cytokines on cardiac
remodeling seem to be dependent on their influence on
the cardiovascular matrix and healing.
The expression of another cytokine, TNF mRNA and
protein can have multiple effects yet extracellular matrix
remodeling seems to be of major importance [60]. Moreover,
mice with overexpression of TNF develop LV dilatation and
changes in collagen content prevented by an MMP inhibitor
[61], further highlighting a potential importance of excessive
Fig. 4. Collagen content (A) and MMP-2/13 (B) expression of the scar, infarct borders, and septum of placebo and LU 135252 treated rats 7 days after
myocardial infarction [51].
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activation of proinflammatory cytokines on matrix remodel-
ing and wound healing in the heart.
1.4.1. TGF (transforming growth factor b1)
TGF plays an important role in collagen production.
Conclusively, animals with targeted deletion of TGF have
reduced age dependent collagen deposition [62]. Over-
expression of TGF in the heart leads to cardiac hypertrophy
and interstitial fibrosis [63]. Somehow surprisingly, after
myocardial injury, increased active TGF-h1 delayed wound
healing [64].
1.5. Leukocytes
The inflammatory reaction appears to be essential to
initiate wound healing. However, adverse wound healing is
accompanied in cutaneous wound models by increased
invasion of inflammatory cells [6]. Leukocyte infiltration
after a cardiac injury is a time dependent phenomenon
regulated by a complex cascade of molecular events
including the activation of selectins and integrins [65].
Leukocytes are mainly attracted by the complement factor
C5a in the first hour, followed by TGF-h1 and monocyte
chemoattractant protein (MCP)-1 in the next 2 h. Infiltration
peaks between 2 and 4 days after MI [65]. Leukocyte
infiltration is mostly restricted to the border zone of the area at
risk and only few neutrophils are found in the center of the
necrotic zone [66]. After invasion into themyocardial wound,
leukocytes lead to more effective healing, regulate extrac-
ellular matrix metabolism through synthesis of MMPs and
their inhibitors and are an important source of cytokines and
growth factors.
1.6. Chemokines
Chemokines [67] are small polypeptides synthesized by
many cells of the immune system as well as by a number of
non-immune cells including, among others, endothelial cells
Table 1
MMP subgroups and their function in healing and heart failure (DCM: dilated cardiomyopathy; ICM: ischemic cardiomyopathy)
Name Number Substrate/function Regulation in CHF Function in CHF (experimental data)
Collagenases
Interstitial collagenase MMP-1 Collagens I, II, III, VII, and basement
membrane components
Reduced [96] Not causative for pathological LV
remodeling [96]
Collagenase 3 MMP-13 Collagens I, II, and III Increased [97]
Gelatinases
Gelatinase A MMP-2 Gelatins, collagens I, IV, V, VII, and
basement membrane components
Increased in DCM, unchanged
in ICM [96]
MMP-2 KO mice have significant
better survival, decreased LV rupture
and decreased LV dilatation after
experimental MI [98]
Gelatinase B MMP-9 Gelatins, collagens IV, V, XIV, and
basement membrane components
Increased [96] MMP-9 KO have improved cardiac
remodeling [70] and decreased left
ventricular rupture [99] after
experimental MI
Stromelysins
Stromelysin 1 MMP-3 Fibronectin, laminin, collagens III,
IV, IX, and MMP activation
Increased in DCM, unchanged
in ICM [96]
LV rupture is unchanged after
experimental MI in MMP-3 KO [99]
Membrane-type MMPs
MT1-MMP MMP-14 Collagens I, II, III, fibronectin,
laminin-1: activates proMMP-2 and
proMMP-13
Increased [96]
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and keratinocytes. Chemokines can be induced by agents
that induce tissue damage. All chemokines are related in
their amino acid sequences and function primarily as
Table 2
Heart failure drugs and their influence on healing (results of animal models unle
Remodeling after MI Cytokines after MI
ACE inhibitor Protective, clinical data Reduced cytokine
expression [100]
AT1 receptor
antagonist
Protective, clinical data Reduced cytokine
expression in AT1
receptor KO mice [101]
Beta-blockers Protective, clinical data Reduced cytokine
expression [104]
Endothelin
antagonists
Protective when started
late after MI [48]. Not
protective when started
early after MI [51]
Not determined
Mineralocorticoid
receptor
antagonism
Protective, clinical data Not determined
Statins Protective, clinical data Reduced cytokines in
human CHF [110]
Glitazones Inconclusive results
Not protective [114]
No effect [115]
Protective [116]
Different results ranging
from depressed [116] to
unchanged [115]
cytokine expression
chemoattractants for phagocytic cells. Generally, CXC
chemokines, such as RANTES, promote neutrophil migra-
tion, while CC chemokines, such as interleukin-8, mediate
ss stated otherwise)
MMPs after MI Fibrosis after MI Leukocytes after MI
Reduced MMP
activation [48]
Reduced collagen
formation [48]
Reduced leukocyte
infiltration [46]
Reduced MMP
activation in AT1
receptor KO mice
[101]
Reduced collagen
formation
[102,103]
Reduced leukocyte
infiltration in AT1
receptor KO mice
[101]. Reduced
leukocyte infiltration
[46]
Not determined Reduced collagen
formation [105]
Reduced infiltration
of leukocytes after
ischemia/reperfusion
[106] and permanent
coronary artery
ligation [107]
Reduced MMP
activation [48]
Reduced collagen
formation [48]
Not determined
Reduced MMP
activation [108]
Reduced collagen
formation [109]
Not determined
Some MMPs are
inhibited after
experimental MI
[111]
Reduced collagen
formation [112]
Reduced infiltration
of leukocytes after
ischemia/reperfusion
[113]
Unchanged [116] Promotes cell
differentiation in
fibroblasts
Reduced infiltration
of leukocytes after
ischemia/reperfusion
[117]
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migration of monocytes and other cell types. Interestingly, a
number of CXC chemokines, including IL-8 and others,
appear to play a role in mediating angiogenesis. However,
the role of chemokines in cardiac wound healing has not
been investigated so far.
1.7. Matrix metalloproteinases
Extracellular matrix is controlled by a system of proteo-
lytic enzymes, the matrix metalloproteinases (MMPs), and
their inhibitors, the tissue inhibitors (TIMPs) of MMPs.
Extracellular matrix degradation may be crucial for the
healing process and MMP activity is increased in MI [68]. A
bbroad spectrumQ MMP inhibitor attenuated early left
ventricular enlargement after experimental MI in mice [69].
Actions of MMPs are interrelated, in the process of wound
healing time dependent, and nomenclature is confusing (see
Table 1). Targeted deletion of MMP 2 or 9 has decreased the
incidence of rupture and attenuated left ventricular enlarge-
ment after MI in mice [70] suggesting importance of one
specific MMP in the early healing process (see Table 1). The
MMP system may be of particular importance since orally
active inhibitors are available for a potential therapy and
drugs may interfere with the MMP system.
1.8. Drugs
Drugs, currently known to influence cardiac remodeling
may also have effects on myocardial healing. Results have
been summarized in Table 2 including different drug effects
on remodeling, cytokines, fibrosis, MMPs, and leukocyte
infiltration after MI. So far, no drug has been developed on
purpose to improve healing of the infarct wound. In fact,
some drugs like ACE inhibitors and endothelin antagonists
may interfere with healing of the infarct in experimental
models [42,51]. The clinical relevance of these findings
Very ear(hours
Early(days)
Late(weeks
Tissue Da
InflammationInflammatory cells, necrosis, apoptosis
Tissue formationEpithelialisation
Granulation tissueNeovascularistation
Tissue remodelingWound contraction
Skin
Fig. 5.
remains obscure. In general, drug effects on healing have not
received adequate attention.
2. General healing factors
It is attractive to compare wounds of various organs to
detect general principles of wound healing. External wound
healing is one of the oldest challenges of medicine and
relatively large experience on healing disturbances is
available in cutaneous wounds. Animals lick their wounds
and saliva contents may support wound healing, e.g. by
growth factors and antibacterial properties [71,72]. However,
discrepancies between skin wounds and myocardial infarcts
are more obvious than similarities. The myocardial infarct
develops during hours, remains ischemic if it is not
reperfused, and faces the stress of rhythmic cardiac contrac-
tion. In addition, the paracrine and autocrine milieu is
probably quite different between cutaneous and cardiac
tissue. Nevertheless, a number of similar steps of healing
may be observed in wounds and appear to be general
characteristics of healing (Fig. 5). For instance, synthesis of
collagen is dysregulated in fibroblasts derived from skin of
subjects with varicose veins [73]. Fibroblasts isolated from
venous ulcers have an impaired ability to synthesize collagen
in vitro, especially under hypoxic conditions [74]. Thus
beside confounding environmental factors, a genetic defect
was assumed to transmit varicose vein pathology, a weakness
of venous wall and, in general, a systemic biochemical defect
of the extracellular matrix affecting the entire body structure
[73]. Holbrook and Byers have defined skin as a window on
heritable disorders of connective tissue [75].
A number of factors meet the requirements of a potential
bgeneral healing factor Q. Secretory leukocyte protease
inhibitor (SLPI) is a constitutively expressed 12 kDa
protein [76]. It was first recognized as a potent inhibitor
ly)
)
mage
InflammationInflammatory cells, necrosis, apoptosis
Early healingFibrosis
Chronic inflammation
Cardiac remodelingScar formation
Heart
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of serine proteases such as neutrophil Elastase and cathepsin
G [77,78]. Furthermore, SLPI controls the synthesis of
intracellular enzymes, and suppresses production and
activity of monocyte matrix metalloproteinase. SLPI KO
mice exhibit wound healing defects, i.e. they have enlarged
wounds with margins that fail to close. This deficiency is
most likely due to unresolved inflammation, a failure of re-
epithelialization, and an inability to generate matrix or to
counter local proteolysis by serine proteases. This effect
seems to be mediated by TGF-h as constitutively active
TGF-h was increased in wounds of SLPI KO mice and
neutralization of TGF-h in vivo reversed impaired healing.
Moreover, our group could detect expression of SLPI in the
heart and in heart failure. However, the function of SLPI in
healing of the infarct wound remains to be defined.
Osteopontin, an extracellular matrix protein interacts
with integrins and the CD44 receptor. It may contribute to
cell adhesion, chemotaxis and signaling [79] and interacts
with fibronectin and collagen [80]. Osteopontin deficiency
leads to disorganization of the collagen matrix and smaller
fibrils in skin wounds [81] suggesting a role in wound
healing. Faint expression is detected in the normal mouse
heart but abundant expression in infarcts during healing
and in chronic cardiac overload [82,83]. Osteopontin
deficiency leads to increased expansion of the infarcted
segment and remote myocardium and decreased collagen
accumulation [82].
Secreted protein acidic and rich in cystein (SPARC) is an
extracellular glycoprotein expressed in proliferating cells. It
belongs to the matricellular proteins and is involved in cell-
extracellular matrix interaction. SPARCs can regulate cell
shape, cell adhesion, proliferation, migration and matrix
turnover [84]. SPARC KO mice have retarded granulation
and impaired fibroblast migration [85]. SPARCs are
expressed in the heart; expression is increased with
isoproterenol treatment [86]. However, the role of SPARCs
in cardiac healing remains to be defined.
Factors of the blood coagulation system, for example
Factor XIII may be involved in numerous cross-link
reactions which form and stabilize the fibrin network.
Factor XIII modulates intestinal epithelial wound healing
in vitro [87], stabilizes bone defects in diabetic rats [88] and
accelerates healing in diabetic food ulcer in man [89].
Inherited lack of factor XIII is rare but several clinical
entities may result in deficiency of factor XIII. The role of
factor XIII in infarct healing is unknown.
3. Complex genetic disorders relevant to healing
Only some examples can be given here. Chronic diabetic
ulcer is a most obvious healing deficiency. Diabetic patients
are at increased risk to develop heart failure after MI [90].
Results on diabetes effects on remodeling are controversial
[91]. Diabetes enhances vascular MMP activity probably by
an increased oxidative stress [92]. Hyperglycemia might be
associated with impaired microvascular function after MI
and thus impair healing [93].
Another model of deficient healing could be osteogenesis
imperfecta which results from alterations of genes encoding
type I collagen pro-a 1 and pro-a 2 chains. In the clinical
situation, diagnosis is made on the basis of bone fragility,
defective skeletal development, small stature, and blue
sclera. Mice deficient of pro-a (2) I collagen have less
and weaker collagen and develop a cardiomyopathy [94].
Aortic dissection, left ventricular rupture, and aortic or
mitral valve incompetence have been observed in humans
with osteogenesis imperfecta [95]. Most likely, this may be
a genetic background which also contributes to deficient
healing post MI. Other genetic disorders of connective
tissue like the Ehlers-Danlos-Syndrome could serve as
clinical models of impaired healing as well.
4. Conclusion
The reaction of the organism to tissue damage is well
preserved throughout evolution. However, cardiac healing
has specific characteristics. The time window for the rescue
of viable myocardium after MIs is only several hours and
often too small, the time window to influence healing of the
scar would be sufficiently large to initiate an adequate
therapy. Therefore, a better understanding of healing and
support of healing mechanisms may help to develop new
therapeutic options.
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