Healing after myocardial infarction

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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

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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: [email protected] (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

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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

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scar

(%

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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].



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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]


of leukocytes after


[113]

Unchanged [116] Promotes cell

differentiation in

fibroblasts


of leukocytes after


[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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Healing after myocardial infarction