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Am J Physiol Heart Circ Physiol 288: H981–H983, 2005;
doi:10.1152/ajpheart.00977.2004.
Special Medical Editorial
Wound model of myocardial infarction
Georg Ertl and Stefan Frantz
Medizinische Klinik, Universität Würzburg, Germany
Address for reprint requests and other correspondence: G. Ertl, Medizinische Klinik, Universität Würzburg, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany (E-mail: [email protected]).
http://www.ajpheart.org
istics of the infarct wound as “a living tissue,” which may be
even more important for healing, infarct expansion, and the
development of arrhythmias, so far have been more or less
neglected. The time course of morphologic and histological
changes of infarcted myocardial tissue was recently reviewed
in some detail (4). Inflammatory cells invade the infarct and,
somewhat later, myofibroblasts appear in the wound. Inflammatory cells release proteases and contribute to removal of
necrotic tissue; myofibroblasts participate in the reconstruction
of a new collagen network. The actions of the myofibroblasts
are admirably systematic and are essential for the organization
of scar formation.
Obviously, it would be highly desirable to influence healing
of the cardiac wound by more targeted interventions. While
research to improve traumatic and surgical wound healing has
quite a tradition back to ancient medicine, current research on
myocardial infarction is limited to cell transplantation into the
infarct wound. It is attractive to compare wounds of various
organs to detect general principles of wound healing. However,
discrepancies are more obvious than similarities between skin
wounds and myocardial infarcts. The myocardial infarct develops during hours, remains ischemic if it is not reperfused, and
faces the stress of rhythmic cardiac contraction. In addition, the
paracrine and autocrine milieu is probably quite different
between cutaneous and cardiac tissue even when wounded.
Nevertheless, a number of similar steps of healing may be
observed in wounds and appear to be general characteristics of
healing, like the influence of gender, age, diabetes, and certain
factors perhaps essential for wound healing (Table 1). Indeed,
some cutaneous phenomena are related to cardiovascular abnormalities: 1) the occurrence of keloid and certain types of
hypertension; 2) synthesis of collagen in skin fibroblasts and
the occurrence of varicose veins in patients; and 3) an impaired
ability to synthesize collagen in vitro of fibroblasts isolated
from venous ulcers. Thus 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. Holbrook and
Byers (13) defined skin as a window on heritable disorders of
connective tissue. A single factor, “secretory leukocyte inhibitory protein,” was recently identified by Ashcroft et al. (2) to
be essential for cutaneous wound healing. So far, no such
factor has been related to infarct healing. In humans, deficient
wound healing is observed in certain hereditary diseases.
Osteogenesis imperfecta, Ehlers-Danlos syndrome, and other
genetically transmitted deficiencies in connective tissue could
be rare but representative models for general states of deficient
wound healing.
Attempts were undertaken to stimulate reparative processes
following experimental myocardial infarction by the group of
Sigmundur Gudbjanarsson and Richard Bing (10) in the 1960s
but did not reach clinical application. Their limitation was a
lack of methods for a detailed analysis of cellular and molecular biology. Some indirect evidence about a potential modification of healing of the myocardial infarct wound may be
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is the major etiology for heart failure
today (3). The initial event is frequently a large or recurrent
myocardial infarction. Acute myocardial infarction starts with
thrombotic occlusion of a coronary artery, develops during
several hours, and terminates when necrosis has reached its
ultimate extension, which is defined by the boundary of the
infarct-associated vascular bed and potential collateral flow.
Therapy of acute myocardial infarction is reasonably standardized and consists of prevention of fatal arrhythmias and early
reperfusion, for instance, by vessel dilatation and stent implantation, to limit infarct size. If reperfusion is established too late,
large transmural infarction may develop that results in a reduction of left ventricular function and is followed by “remodeling” of the heart (Fig. 1). Remodeling is closely related to
“infarct expansion,” which may continue after the necrosis has
extended to its ultimate size; the left ventricle dilates, probably
because of increased wall stress on the basis of La Place’s law
(1). The increase in global left ventricular volume indicates and
quantifies remodeling of the heart, which may ultimately result
in heart failure, arrhythmias, and sudden death (8). Standard
therapy today tries to prevent remodeling and its prognostic
consequences by reducing cardiac preload and afterload and
preventing hypertrophy and fibrosis in residual surviving myocardium with the use of angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists. Thus clinical
research has focused on strategies for an optimal reperfusion
therapy during the first hours of developing myocardial infarction or long-term prevention of remodeling. However, despite
standard therapy, prognosis remains serious in patients with
large infarctions and severe left ventricular dysfunction (20).
This may be due to the fact that the “first hours” have mostly
elapsed before patients receive reperfusion therapy, and a large
myocardial defect or cardiac aneurysm (Fig. 1) may not respond well to therapy.
Infarct expansion occurs after the first hours of developing
myocardial infarction and precedes remodeling, hypertrophy,
and fibrosis of residual myocardium. In fact, it occurs predominantly during healing of the “cardiac wound” when the normal
collagen structure has been destroyed and the scar is formed. If
the infarct heals without expansion, the heart maintains its
shape and prognosis is good. Infarct expansion has been
studied in some detail, and mechanical determinants have been
defined. Physical exercise begun early after a myocardial
infarction has promoted left ventricular dilatation and thinning
of the infarct in animal experiments (9). In contrast, mechanical unloading by nitroglycerin or captopril has prevented
infarct expansion and thinning in dogs and humans, especially
when combined with reperfusion (17, 18). Thus the infarct scar
mostly has been considered from a biophysical point of view.
However, the cellular, biochemical, and molecular character-
ISCHEMIC HEART DISEASE
Special Medical Editorial
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deducted from available data. Animal experiments have suggested that late reperfusion of myocardial infarction after
completion of cardiomyocyte death may prevent further infarct
expansion and thinning (5, 6, 11, 12, 16), possibly by an
interference with collagen and matrix metalloproteinase metabolism. Angiotensin-converting enzyme inhibition delayed
maturation of the infarct scar as indicated by reduced collagen
content (23). Targeted deletion of angiotensin II type 2 receptor reduced collagen volume fraction and scar thickness in
experimental infarcts and caused cardiac rupture (15). Angiotensin-converting enzyme inhibitors and even more angiotensin II type 1 receptor antagonists reduced the inflammatory
infiltrates into the infarct zone and prevented accumulation of
type I myocardial collagen in noninfarcted myocardium (22).
Left ventricular dilatation was aggravated by the use of endothelin A receptor antagonists early after myocardial infarction.
Early initiation of the selective endothelin A receptor blocker
LU 135252 resulted in scar expansion, reduction of scar
collagen, and a particular unfavorable outcome. This was most
likely caused by an activation of myocardial tissue metalloproTable 1. Factors that may influence infarct healing
Factors
Reperfusion
Mechanical load
Neurohumoral factors, zytokines, and growth factors
Drugs
AJP-Heart Circ Physiol • VOL
teinases (7, 14, 19, 21). However, others reported a reduction
of metalloproteinase activity by another endothelin A receptor
antagonist (21). Nevertheless, principles inhibiting the reninangiotensin system have been used successfully in patients
with myocardial infarction. However, a large trial in which an
angiotensin converting enzyme inhibitor was used intravenously early after myocardial infarction failed and was stopped
because of a tendency toward increased mortality in a subgroup
of patients. Thus, today, clinically established or developing
therapeutic approaches already have the potential to interfere
with cellular, biochemical, and molecular processes during
healing of the infarct wound. These processes, therefore, urgently need to be analyzed with modern techniques of cell and
molecular biology and genetics. They may offer new therapeutic options. However, they have to avoid weakening of the scar
and an eventual aneurysm and rupture.
In conclusion, while the current conventional concepts of
pathophysiology and myocardial infarction therapy consider
coronary occlusion, development of necrosis, and remodeling
of residual myocardium, the concept of wound healing focuses
on the cellular, biochemical, and molecular changes of the
myocardial wound after ultimate extension of necrosis and
before scarring. Reperfusion, mechanical factors, hormones,
and neurohumoral and other factors may influence wound
healing. General acquired or inherited deficiency of wound
healing may be important for infarct healing but has not been
defined in depth, so far. Interventions to improve wound
healing may open a new time window between the few hours
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Fig. 1. A large anterior myocardial infarction (MI) followed by deficient wound healing, infarct expansion, and a large apical aneurysm was the sequence of
events leading to heart failure and terminal arrhythmia in the patient from whom this tissue was taken.
Special Medical Editorial
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EDITORIAL FOCUS
that may be used to limit necrosis by reperfusion and an
irreversible cardiac scar or aneurysm. It is conceivable that
therapeutic concepts to improve wound healing (collagen generation, hypertrophy) differ fundamentally from the therapy of
remodeling (prevention of fibrosis and hypertrophy). Because
healing and remodeling are closely related but have a different
time course, differential therapy may be designed.
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