Download Infarct scar: a dynamic tissue

Cardiovascular Research 46 (2000) 250–256
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Review
Infarct scar: a dynamic tissue
Yao Sun, Karl T. Weber*
Division of Cardiovascular Diseases, Department of Internal Medicine, University of Tennessee, Memphis College of Medicine,
Rm. 353 Dobbs Research Institute, 951 Court Avenue, Memphis, TN 38163, USA
Received 23 November 1999; accepted 21 January 2000
Abstract
Infarct scar, a requisite to the rebuilding of necrotic myocardium following myocardial infarction (MI), has long been considered inert.
Earlier morphologic studies suggested healing at the infarct site was complete within 6–8 weeks following MI and resultant scar tissue,
albeit necessary, was acellular and simply fibrillar collagen. Utilizing molecular and cellular biologic technologies, recent studies indicate
otherwise. Infarct scar is composed of phenotypically transformed fibroblast-like cells, termed myofibroblasts (myoFb) because they
express alpha-smooth muscle actin (a-SMA) and these microfilaments confer contractile behavior in response to various peptides and
amines. These cells are nourished by a neovasculature and are persistent at the MI site, where they are metabolically active expressing
components requisite to angiotensin (Ang) peptide generation, including converting enzyme, receptors for AngII and transforming growth
factor (TGF)-b1. They continue to elaborate fibrillar type I collagen. Their generation of these peptides contribute to ongoing scar tissue
collagen turnover and to fibrous tissue formation of noninfarcted myocardium. Infarct scar contraction accounts for its thinning and its
tonus may contribute to abnormal ventricular chamber stiffness with diastolic dysfunction. Infarct scar is a dynamic tissue: cellular,
vascularized, metabolically active and contractile. Pharmacologic interventions with angiotensin converting enzyme inhibitor or AT1
receptor antagonist has proven effective in attenuating scar tissue metabolic activity and minimizing adverse accumulation of fibrous
tissue in noninfarcted myocardium.  2000 Elsevier Science B.V. All rights reserved.
Keywords: Angiotensin; Fibrosis; Growth factors; Infarction
1. Introduction
Following MI with loss of necrotic cardiac myocytes, a
reparative process is quickly initiated to rebuild infarcted
myocardium and maintain structural integrity of the ventricle. A series of cellular responses are called into play
driven largely by cell–cell signaling that serves to regulate
tissue repair. Initially, inflammatory cells are attracted to
and invade the site of injury, regulatory peptides are
activated and elaborated, new blood vessels are formed
(angiogenesis), and fibroblast-like cells appear and replicate. This early inflammatory phase of healing with
resultant granulation tissue formation is followed by a
fibrogenic phase that eventuates in scar tissue — a
rebuilding of infarcted myocardium. In the case of a large
transmural MI, the entire heart is involved in the repair
*Corresponding author. Tel.: 11-901-448-5759; fax: 11-901-4488084.
E-mail address: [email protected] (K.T. Weber)
process with unwanted fibrous tissue appearing at sites
remote to the MI and contributing to a remodeling of
noninfarcted myocardium.
Postinfarction healing has been considered complete
6–8 weeks following MI. Moreover, the infarct scar is
viewed as inert tissue — simply fibrillar, cross-linked
collagen whose tensile strength resists deformation and
rupture. Accordingly, there has been little interest in scar
tissue and any active role it may play in the failing heart of
ischemic origins. Jugdutt et al. [1,2] have systematically
examined the topography and temporal response in the
architectural remodeling of infarct scar following MI of the
canine heart. Scar thinning was observed at 6–8 weeks [1].
This would suggest an active process of scar tissue
contraction had occurred.
In recent years and using technologies of molecular and
cellular biology, a new perspective of the infarct scar has
emerged. One that reveals a cellularity based on a populaTime for primary review 27 days.
0008-6363 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 00 )00032-8
Y. Sun, K.T. Weber / Cardiovascular Research 46 (2000) 250 – 256
tion of fibroblast-like cells, termed myofibroblasts
(myoFb), nourished by a neovasculature and whose metabolic activity includes generating peptides that regulate
ongoing type I collagen synthesis in an autocrine manner
and whose a-SMA microfilaments and attachments to
extracellular matrix confers contractile behavior to scar
tissue [3–5]. This review focuses on these features of
infarct scar tissue and its dynamic nature.
2. Rebuilding and remodeling myocardium following
infarction
2.1. Collagen turnover in infarct scar
Cardiac tissue consists of a muscular compartment
composed of large cardiac myocytes and an interstitial
compartment that contains extracellular matrix and vasculature, each having their own distinctive cellular composition. Transmural MI involves a segmental loss of
cardiac myocytes. Tissue repair must follow to rebuild and
restore structural integrity at the infarct site. The balance
between collagen synthesis and degradation are primary
determinants of tissue fibrosis.
Collagen degradation involves proteolytic enzymes (or
matrix metalloproteinases, MMPs). MMP-1 (or collagenase) and MMP-8 (a gelatinase) degrade fibrillar collagen
into fragments, which are further degraded into amino
acids and oligopeptides by MMP-2, 3, and 9 [6]. During
the very early phase of repair that follows MI in rats,
degradation predominates represented as an initial increase
in MMP-1 activity and its subsequent mRNA expression
[7,8]. This early proteolytic activity accounts for fibrillar
collagen degradation at the site of MI. Tissue inhibitors of
MMPs (TIMPs) neutralize this collagenolytic activity and
function as a regulatory brake on the activity of MMPs.
TIMPs directly inhibit the activated form of MMPs. TIMP
synthesis at the infarct site is elevated during week 1 and
in subsequent weeks [7], which suppresses the activity of
MMPs in the infarcted rat myocardium and promotes
progressive collagen accumulation.
Scar tissue is composed predominantly of type I and III
fibrillar collagens. Temporal response of cardiac collagen
turnover has been examined in rats with MI created by left
coronary artery ligation. By northern blot and in situ
hybridization analyses, type I procollagen mRNA at infarction site increases soon after MI and remains elevated over
the course of 3 months (Fig. 1) [9]. This is an extended
period of time based on the normal 2–3 year life-span of
rats. Microscopic evidence of collagen fiber accumulation
appears at the border zone to the infarct as early as day 7.
An organized assembly of fibers in the form of scar tissue
becomes evident by day 14 and continues to accumulate
for many weeks [10,11]. Hydroxyproline concentration at
the site of scarring increases progressively for over 6
weeks [1]. These findings lend support to the concept that
251
collagen is continuously synthesized and deposited in the
infarct scar. Unlike traditional concepts, fibrous tissue
formation in the infarcted heart is not a transient process
but rather an ongoing one.
2.2. Collagen turnover at remote sites
Following large anterior transmural MI in rats, fibrous
tissue also appears in noninfarcted myocardium, but to a
lesser extent than seen at the site of MI [12–15]. Expression of procollagen I and III mRNAs by fibroblast-like
cells is increased in the noninfarcted interventricular
septum and right ventricle on days 4 and 7, respectively. In
the septum closest to the anterior MI, type I collagen
mRNA remains elevated until day 28. In the right ventricle, more distant to the infarct site, message for these
collagens is attenuated after day 7. Interstitial collagen
appears at each of these remote sites to create a remodeling
of noninfarcted myocardium by day 14 and continues to
accumulate for weeks. Fibroblast-like cells are involved in
collagen turnover at these sites. Right ventricle stiffness is
significantly increased 8 weeks following anterior MI in
rats.
3. Myofibroblasts and infarct scar
The growth and activity of extracellular matrix producing cells are integral to tissue fibrosis. Interstitial fibroblasts are responsible for collagen synthesis in the normal
myocardium, while phenotypically transformed fibroblasts,
termed myoFb, are central to fibrogenesis at sites of
rebuilding and remodeling following MI [16,17]. MyoFb
are not residents of normal cardiac tissue (except heart
valve leaflets). They appear at the infarct site. A hallmark
of myoFb is their expression of a-SMA microfilaments.
MyoFb appear to arise from interstitial fibroblasts and / or
adventitial fibroblasts [18,19], however, progenitor cells
are presently uncertain. Signals that determine the appearance of myoFb are not fully understood. In vivo and in
vitro studies reveal that transforming growth factor-beta
(TGF-b1) contributes to fibroblast differentiation into
myoFb [20]. Activated macrophages appear at the site of
MI on days 1 and 2, where they elaborate TGF-b1. MyoFb
appear at the site of infarction thereafter. In experimental
MI in rats, myoFb first appear at the site of MI as early as
day 3, become evident at week 1 and remain abundant for
months thereafter. These cells are colocalized with accumulated collagen. They persist in the infarct scar for
prolonged periods of time (many months in rats, years in
man) (Fig. 1) [16,21], where they continue to generate
fibrogenic signals that perpetuate tissue repair and promote
fibrosis. By in situ hybridization, myoFb are responsible
for increased expression of genes encoding for fibrillar
type I / III procollagens [9,22]. Why myoFb persist in the
infarct heart has not been elucidated. This contrasts to skin,
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Y. Sun, K.T. Weber / Cardiovascular Research 46 (2000) 250 – 256
Fig. 1. Eight weeks following MI, the infarct scar still contains abundant myofibroblasts (MF) (panel A, a-SMA labeling) and remains vascularized (panel
B, a-SMA labeling at vessels labeled with arrowheads); type I collagen and TGF-b1 mRNA (panels, C and D, in situ hybridization) expressions are still
elevated at the site of MI; and binding density of ACE and AngII receptors (panels E and F, autoradiography) continues to be increased at this site. RV,
right ventricle.
where they disappear (via apoptosis) once healing is
complete [23]. Their persistence in other injured organs is
associated with a progressive fibrosis and predicts organ
failure. In an experimental model of toxic nephritis,
progressive renal fibrosis is seen only in those kidneys in
which myoFb fail to disappear [24]. In humans with
Y. Sun, K.T. Weber / Cardiovascular Research 46 (2000) 250 – 256
immunoglobulin A nephropathy, the evidence of a-SMA
labeling on renal biopsy tissue is a predictor of poor renal
function and correlates with progressive renal fibrosis [25].
The importance of persistent fibrogenic signals that perpetuate tissue repair and an unwanted fibrosis is emphasized not only within a particular organ, but could take on
even broader implications for multiple tissues when such
signals are chronically elevated and not neutralized.
4. Neovasculature and infarct scar
Angiogenesis is a major feature of tissue repair. Following MI, angiogenesis begins in the infarcted myocardium
at 3 days and becomes more apparent in the following 2
weeks. Detected by a-SMA labeling, infarcted myocardium remains vascularized over 8 weeks (Fig. 1). Newly
formed blood vessels accompany and nourish myoFb at the
site of MI.
5. Myofibroblast activity and regulatory signals for
tissue repair
5.1. Angiotensin II
In addition to its well-described circulating endocrine
properties, there is now accumulating evidence that AngII
has important autocrine / paracrine functions in a variety of
tissues [26,27]. The involvement of local AngII in tissue
repair and fibrogenesis that follows inflammation has been
inferred from experimental studies of MI.
Local AngII peptide generation requires: the presence of
requisite AngII peptide precursor, angiotensinogen (Ao);
renin or cathepsin D that converts Ao to AngI; ACE, a
membrane-bound ectoenzyme that provides extracellular
hydrolysis of AngI to AngII.
Ao is the only known precursor to Ang peptides and it is
obligatory to tissue Ang generation and requires demonstration of Ao synthesis. Ao synthesis is present in rat and
human cardiac tissue. In situ hybridization localizes Ao
mRNA within fibroblasts and brown adipocytes [28,29].
Ao mRNA expression is found enhanced in the infarcted
rat heart on day 5 after coronary artery ligation [30]. This
precedes the morphologic appearance of fibrillar collagen
in the form of fibrous tissue at this remote site.
Renin synthesis is demonstrated in cultured fibroblasts
and myocytes in neonatal rat hearts, but is very low in
adult rat cardiac tissue. In situ hybridization reveals several
fold increases in renin mRNA in the infarcted area [31].
Renin activity is also significantly increased in the infarcted myocardium 10 days after MI [32]. Various proteases,
produced by the cell or procured from its environment,
may also be involved in the generation of Ang peptides.
These include cathepsin D and G, and other serine
proteases that generate AngII directly from Ao [33,34].
253
ACE mRNA and activity have been demonstrated in the
heart of different species [35,36]. Localization and binding
density of ACE in the normal and infarcted heart has been
determined by in vitro quantitative autoradiography. ACE
is heterogeneously distributed in the normal rat heart.
Low-density ACE binding is found throughout ventricular
myocardium and atria, whereas high-density binding is
present at sites of high collagen turnover, including heart
valve leaflets and the adventitia of intramyocardial coronary arteries [37]. Immunolabeling with a monoclonal
ACE antibody identified cells expressing ACE. They
include: endothelial cells on the surface of each valve
leaflet; valvular interstitial cells residing within leaflet
matrix; and fibroblast-like cells in the adventitia of intramural vessels, where they are responsible for collagen
formation. High-density autoradiographic ACE binding is
found at the site of MI at week 1 and increases progressively over the course of 8 weeks (Fig. 1) in parallel
with morphological evidence of fibrillar collagen accumulation [10]. Increased ACE binding density in the infarct
scar remains for at least 6 months, suggesting continued
AngII generation at this site. ACE activity, as measured by
substrate conversion, is increased in the infarcted myocardium, as is also the case for ACE activity at sites remote
from the MI [10,38]. The concentration of AngII at the MI
site is enhanced several fold [39]. Several cell types have
been demonstrated to express ACE at the site of infarction.
These include macrophages, endothelial cells, and myoFb
[16]. Endothelial ACE is well positioned for circulating
AngII generation, while ACE in macrophages and myoFb
contributes to local AngII generation. Circulating renin–
angiotensin–aldosterone system (RAAS) is, however, not
activated in rats with MI [36,40], implicating the rise in
AngII generation in the repairing myocardium is independent of circulating RAAS.
Receptor–ligand binding is a requisite if locally generated AngII is to influence fibrogenesis. AngII receptors can
be divided into two subtypes, AT1 and AT2. By autoradiography, atria and ventricles have been demonstrated
to express low AngII receptors, while heart valve leaflets
and aorta contain higher amounts of AngII receptors [41].
In the infarcted rat heart, high density AngII receptor
binding is present at sites of repair over the course of 8
weeks following MI (Fig. 1) [42]. The specific AngII
receptor subtype in the repairing rat myocardium is
predominantly AT1. MyoFb are the primary contributor to
AT1 receptor expression in the infarct scar [43]. These
autoradiographic findings are consistent with the increase
in mRNA and protein expression of the AT1 receptor
found in homogenized tissue of the infarcted rat heart. The
anatomic association between ACE and AT1 receptors at
infarct scar raises the prospect that local concentration of
AngII contributes to fibrous tissue formation. Campbell
and Katwa [44] have reported AngII induced expression
(mRNA and protein) of TGF-b1 by cultured myoFb
mediated primarily by AT1 receptor-binding tissue. In vivo
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studies further reveal that AngII is correlated with TGF-b1
expression in repairing tissues, including infarcted heart
and injured kidneys [22,44,45], suggesting AngII stimulates fibrous tissue formation by promoting TGF-b1 synthesis via AT1 receptor binding. Studies have demonstrated that in addition to collagen synthesis, AngII may
regulate collagen degradation by attenuating MMP-1 activity [46] and enhancing TIMP-1 production [47], which
further serve to promote collagen accumulation [48–50].
AT1 receptors are the predominant subtype expressed in
the infarcted rat heart [43]. In the failing human heart, AT2
receptors are upregulated and fibroblast-like cells are
responsible for their expression. AT2 receptors have
therefore been linked to fibrosis, but this remains unclear at
present.
High-density ACE binding is also observed in endocardial and pericardial fibrosis that appear in the infarcted rat
heart, as well as the pericardial fibrosis following sham
operation (without MI). It also holds true for the foreign
body fibrosis that surrounds the silk ligature placed around
the left coronary artery and the infarcted rat kidney [51].
These findings strongly suggest AngII is involved in tissue
repair irrespective of the etiologic basis of injury or the
tissue involved. It further sheds light on why tissue ACE
activity is increased in the infarcted heart and why AngII
concentration is markedly increased at the site of MI. Both
are a result of fibrous tissue and its cellular population.
soon after induction of MI in rats or dogs, infarct size,
hydroxyproline concentration of scar tissue, and myocardium bordering on the infarct were each reduced by these
agents [53–57]. They likewise attenuated fibrous tissue
formation at remote sites, e.g. interventricular septum and
right ventricle, endocardium and visceral pericardium. In
association with these interventions has been the attenuation in infarct tissue AngII concentration and TGF-b
expression. Elevations in circulating renin, AngII and ACE
are not observed in rats following MI, suggesting that
locally produced AngII contributes to fibrogenesis in the
repairing heart.
The ability of these agents to protect an injured organ
against unwanted fibrosis, mediated by the expression and
elaboration of AngII and TGF-b1, has now been demonstrated in multiple organs after diverse forms of injury,
including kidney, lung, liver and skin. Findings from
multiple laboratories whose research is focused on addressing the regulation of unwanted fibrous tissue formation
have underscored the importance of de novo generation of
AngII by myoFb and autocrine induction of the fibrogenic
cytokine TGF-b1 by this peptide in mediating tissue
repair. This is now recognized as a common paradigm of
repair in many injured organs.
6. Contractile behavior of infarct scar
5.2. Transforming growth factor-beta 1
TGF-b1 is an important regulatory peptide in fibrous
tissue formation and has numerous actions on extracellular
matrix. It stimulates fibroblast-like cell growth, enhances
collagen synthesis, and suppresses collagen degradation
[52]. By in situ hybridization, transcription of TGF-b1
mRNA increases at the site of MI soon after MI and
remains elevated for many weeks (Fig. 1) [22]. The
concentration of TGF-b1 is also increased in the infarcted
rat myocardium week 4 following MI, implicating TGF-b1
synthesis in the infarct scar [22]. Cells accountable for
TGF-b1 synthesis in the infarcted heart are primarily
macrophages in the early phase of repair and myoFb in the
fibrogenic phase of healing. The cellular actions of TGFb1 are mediated by its specific membrane-bound receptors.
By in vitro autoradiography, TGF-b receptor binding
density is found upregulated in the infarcted heart and
remains so for weeks [22].
5.3. Pharmacologic interventions
Pharmacologic interventions with either an ACE inhibitor or an AT1 receptor antagonist have further underscored the importance of locally generated AngII and
TGF-b1 in promoting tissue remodeling. Introduced at or
MyoFb contain a-SMA and have cell–cell connections
via gap junctions and cell–matrix connections via a
fibronexus. This provides for a contractile assembly that
contributes to scar tissue remodeling [3]. Contractile
myoFb remain abundant in the infarct scar for months
(Fig. 1) and progressive infarct thinning occurs over the
course of 8 weeks. Such fibrous tissue contraction is
stimulated by various substances, including AngII,
catecholamines and endothelin-1 [58].
7. Summary
Infarct scar, long considered inert, is a dynamic tissue:
cellular, vascularized, metabolically active, and contractile.
It is composed of myoFb, which express components
requisite to Ang peptide generation, including ACE, AT1
receptors with regulating fibrogenic cytokine TGF-b1.
MyoFb, nourished by a neovasculature are persistent in
infarct scar, where they continue to elaborate fibrillar type
I collagen. Their generation of these peptides contribute to
ongoing scar tissue collagen turnover and to fibrous tissue
formation with structural remodeling of noninfarcted sites
remote to MI. Infarct scar contraction accounts for its
thinning and its tonus may contribute to abnormal ventricular chamber stiffness and diastolic dysfunction.
Y. Sun, K.T. Weber / Cardiovascular Research 46 (2000) 250 – 256
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