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Abstract
This review article summarizes the results
of histopathological and clinical imaging
studies to assess myocardial necrosis in humans.
Different histopathological features of
myocardial cell necrosis are reviewed.
In
addition, the present role of echocardiographic
techniques in assessing irreversible myocardial
damage is briefly summarized. Heart Views.
2005;6(3): pp?
Introduction
By myocardial cell damage we mean a primary
damage of the myocardial cell. In fact, the
myocardium includes several other structures
as vessels (arteries, veins, lymphatics),
nerves, collagen matrix, interstitium, which
can be primarily altered with subsequent
secondary damage of myocardial cells. In
general, both clinicians and pathologists
believe in a unique pattern of myocardial
necrosis due to ischemia; less frequently to
inflammatory processes or rarely to storage
diseases.
In reality, three types of
myocardial cell necrosis can be
recognized1-4 in relation to contraction
cycle.
The myocardial cell may irreversibly arrest
in: 1. relaxation 2. contraction 3. after
progressive failure.
1. Arrest in relazation
In the first condition the early
histologic pattern is characterized by mild
eosinophilia, increased length of sarcomeres
and elongation of nuclei. This myocellular
stretching is due to the action of
intraventricular pressure on these elements
in flaccid paralysis and visible within 30
minutes.
The lesion is pathognomonic for
myocardial infarct with its sequelae, namely
a polymorphonuclear leukocytic infiltration
which starts after 6-8 hours and disappears
within 5 days, centripetal removal of
necrotic tissue by macrophages and
substitution by collagen ending in acellular
and avascular, dense, scar (Fig.1).
No
repair by granulation tissue is observed. In
humans the infarct is monofocal and its size
ranges from less than 10% to more than 50%
of the total left ventricular mass.
Erroneously named “coagulation necrosis”
(coagulation never occurs), is better
defined as infarct or ischemic necrosis.
In
contrast to the current belief oriented to
reduce or avoid expansion of an infarct,
death due to a myocardial infarct is not
related to its size. About half of these
cases have a size less than 20% of the left
ventricular mass (Table 1).
Table 1: Acute myocardial infarct size (%
left ventricular mass) versus coronary
atherosclerotic obstruction, extensive
myocardial fibrosis (> 20% LVM), occlusive
thrombus, survival and death in 200 selected
cases*
The same table
show that: a) infarct size is not related to
severity of coronary atherosclerotic lumen
reduction and number of main vessels with
sever stenosis; b) long survival (interval
from the beginning to death) prevails in
large infarcts; c) extensive myocardial
fibrosis, as expression of chronic disease,
does not correlate with infarct size; and d)
the frequency of an occlusive thrombus is
significantly higher in the largest infarcts
supporting its secondary formation5.
Fig. 1: Infarct necrosis. The first change
is lost of contraction with stretching of
the myocardium in flaccid paralysis,
resulting in a very early elongation of
sarcomeres and nuclei (A) already visible
within 30 minutes in experimental
infarction. B, polymorphonuclear leukocyte
infiltration from the periphery of the
infarct after 6–8 hours. In the largest
infarcts this infiltration arrests, along a
line (maximal myocardial stretching in
central part of infarct?) with occasional
abscess-like formation (C). This
infiltration disappears by lysis of the
leukocytes, without evidence of myocellular
colliquation or destruction (D). The
myocardial cells maintain they sarcomeric
registered order even in terminal healing
phase. The repair process is carried out by
macrophagic digestion (E) – and not by
granulation tissue – ending in a compact and
dense scar (F).
2. Arrest in contraction
The opposite pattern is seen when the myocytes stop in contraction or
better in hypercontraction (Fig. 2).
Fig. 2: Coagulative myocytolysis or contraction
band necrosis or catecholamine necrosis (CN).
Pancellular lesion involving the whole
myocardial cell. A) histological view of a CN
focus. B) ultrastructural hypercontraction with
extremely short sarcomeres and highly thickened
Z lines and focal myofibrillar rhexis. C)
rupture of a hypercontracted myocell. EM view of
pathological bands (D) formed by segments of
hypercontracted and coagulated sarcomeres
(intravenous infusion of catecholamines in
dogs).
In less
than 10 minutes the hypercontracted
myocardial cells break down forming
hypereosinophilic transverse bands
constituted by hypercontracted, extremely
short sarcomeres with highly thickened Z
lines. This rhexis of the myofibrillar
apparatus ends in coagulation of sarcomeres,
till a total, granular disruption. The
sarcolemmal membrane is preserved and
penetrated by macrophages which digest the
necrotic material leaving empty sarcolemmal
tubes (“alveolar” pattern) which
subsequently collagenized (Fig. 3).
Fig. 3: Repair process of CN. A) early monocytes
infiltration which later, becomes extensive
especially in large necrotic foci (B). It can be
misinterpreted as lymphocytic myocarditis. This
macrophagic reaction results in empty
sarcolemmal tubes with numerous macrophages
often loaded with lipofuscin and normal
intramural vessels (C). The end result is a
focal or plurifocal or confluent fibrosis (D).
Microfocal fibrosis as result of necrosis of few
myocells (E) can be confused with proliferation
of collagen matrix. F) wavyness of normal
myofiber around hypercontracted elements. G) all
stages of CN in human pheochromocytoma.
These
changes suggest that the mechanical
contraction of the normal surrounding
myocardium causes the break of these rigid
elements in tetanic paralysis. This lesion
is plurifocal with foci formed by one or few
cells to thousands and is the typical
necrosis obtained experimentally by
catecholamine infusion and present in the
myocardium of patients with pheochromocytoma.
It must be stressed that in these
experimental and human conditions no infarct
necrosis is seen. Variously called as,
microinfarct, infarct-like, focal
myocytolysis, Zenker necrosis, coagulative
myocytolysis, myofibrillar degeneration,
focal myocarditis and overall contraction
band necrosis, the more appropriate term is
catecholamine necrosis to indicate
cause-effect relationship.
The term “contraction bands” needs a more
precise definition. Apart from the
changeable “physiological bands” in relation
to the normal contraction cycle and beside
catecholamine necrosis, other “pathological
bands” must be considered:
a. Paradiscal bands, part of catecholamine
necrosis as a unique band of 10-15
hypercontracted sarcomeres adjacent to an
intercalated disc, in an otherwise normal
cell. This band does not show any rhexis,
macrophagic reaction or other changes and
may involve two adjacent myocytes from both
sides of the same disc and may appear as a
clear or dark band (Fig. 4).
Already visible
after 5 minutes from catecholamine infusion,
the paradiscal bands correspond to the
“zonal lesion” described in experimental
hemorrhagic shock and prevented by
betablocker. It is unclear if this change is
a reversible one since in our experimental
and human material a reaction of repair
process was never seen. The clear band could
represent a rebuilding of few damaged
sarcomeres in a normally working myocyte.
b. Cutting edge lesion i.e. a 0.5 millimeter
layer of hypercontracted sarcomeres along
the cut margin of living myocardium (biopsy,
surgical sample, heart excised at
transplantation); an artefact not to be
confused with catecholamine necrosis (Fig.
5A,B)
c. Reperfusion injury. From an experimental
model of a) temporary coronary occlusion
followed by reflow or b) long lasting
coronary occlusion, the “wave front
phenomenon” has been proposed6, namely the
expansion of a primary infarct established
within one hour after occlusion of left
circumflex coronary artery and limited to
subendocardial layer and posterior papillary
muscle7. Such an expansion includes the
initial infarct with stretched necrotic
myocytes, surrounded first by a large zone
of “contraction band necrosis” associated
with massive hemorrhage and externally by
macrophagic reaction and reparative process
(Fig. 5C).
This model has been erroneously considered
to mimic human infarct. In 200 fatal, acute
infarct cases, without any attempt of
revascularization, resuscitation and
fibronolytic therapy, the
ischemic/reperfusion changes were never
observed and wavefront expansion was due to
nonhemorrhagic catecholamine necrosis,
always present both in continuity with the
central ischemic necrosis and in normal
surrounding myocardium as well as in
myocardium not related to the occluded
artery. By left circumflex permanent
occlusion for 10,18,40 and 60 minutes and
temporary occlusion far 10 minutes followed
by a 5 minute reperfusion in dog, we tested
location and extent (number of foci and
necrotic myocytes x 100 mm2) of
catecholamine necrosis.
The latter was
present with a similar extent in ischemic
and non ischemic myocardium being
independent from amount of flow calculated
by radioactive microspheres. Both
myonecrosis and frequently associated
ventricular fibrillation were prevented by
beta-blocker.
For a better understanding of the meaning of
catecholamine necrosis in cardiology, its
presence and extent were quantified in
different conditions (Table 2).
Table 2: Catecholamine myocardial necrosis –
Frequency and extent in different conditions
The
catecholamine myotoxicity was significantly
higher in conditions with an adrenergic
overtone than in normal controls dead from
accident. In the latters with a short
survival some damage likely due to an agonal
release of interstitial catecholamines (not
seen in instantaneous death) was found.
The conclusion was that catecholamine
necrosis is an important signal of
adrenergic stress3,4 particularly in in
sudden coronary death, (too often
interpreted as synonymous of infarct), in
which the unique acute lesion found was
catecholamine necrosis in about 80% of cases
while in 20% a “silent” infarct associated
with catecholamine necrosis was detected.
These figures are in agreement with clinical
studies in resuscitated people3.
3. Arrest in progressive failure
The third damage consists in a disappearance
of myofibrils with increasing myocardial
cell vacuolization, edema and small
mitochondria without any reaction
(macrophages, inflammatory elements). This
change (colliquative myocytolysis) was seen
in about 40% of acute infarct cases, around
vessels and in subendocardium in myocardial
layers preserved by ischemic necrosis (Fig.
6).
Its maximal frequency and extent was in
congestive heart failure independently from
the underlying disease (Table 3).
Table 3: Frequency and grade of colliquative
myocytolysis in different conditions
This
damage indicates failure of the myocardium,
when other rare causes of vacuolization are
excluded.
As a matter of fact, the recognition of
different forms of “functional” myonecrosis,
which diverge totally in term of structural
pathology and molecular/ion biology, denies
the assemblage of acute coronary syndromes
as a unique etiopathogenetic entity; and
helps in interpreting the evolutive phase of
each one syndrome as sequence of events and
their own causes and mechanisms. For
example, a recent consensus8 included all
types of necrosis (coagulation necrosis,
contraction band necrosis, apoptosis)
measleading our understanding on what a
myocardial infarct is
Fig. 4: CN. Paradiscal lesion. Always associated
with the pancellular lesion, is already visible
in experimental intravenous infusion of
catecholamines within 5 minutes (pancellular
within 10 minutes). It is formed by a unique
band of hypercontraction involving 10–15
sarcomeres adjacent to an intercalated disc. The
major part of the myocell is normal and this
lesion shows ultrastructurally (A) a clear
aspect without rhexis, thin myofibrils and Z
lines (rebuilding of normal sarcomeres?) or as a
band with different grade of density (B-D),
often involving two myocells (C). The dense band
can be see histologically (E). An
hypercontracted "center" (F) induces wavyness of
normal adjacent myocells seen by EM.
Myocardial Disarray
In discussing the myocardial cause of
cardiac arrest, myocardial disarray is
another pattern to be considered. It
consists of a structural disorganization of
the myocardium in which myocytes, instead of
their usual parallel arrangement for a
correct cardiac pump function, assume a
star-like disposition with elements oriented
obliquely or perpendicular to each other and
joined by short, generally hypertrophic
myobridges with interconnecting myofibrils
and increased interstitial fibrosis (Fig.
7).
This architectonic disorder without
evidence of myocellular primary damage is
visible in some specific zones of normal
hearts at the site of directional change
(apex, interventricular septum) of
myocardial bundles suggesting “junctional
nodes” to help contraction. Furthermore
myocardial disarray has been observed around
scars, in congenital malformed hearts,
lentiginosis, Friedreich’s ataxia, Turner’s
syndrome, hyperthyroidism and overall in
hypertrophic cardiomyopathy. Its correlation
with the adrenergic system has been
suggested by human and experimental data. We
studied frequency, extent of myocardial
disarray in zones normally uninvolved, in
conditions with and without adrenergic
hypertone (Table 4).
A significant increase
in frequency and extent of myocardial
disarray was documented in “adrenergic
overtone” conditions and it correlated with
frequency and extent of catecholamine
necrosis. An interesting observation was the
absence of myocardial disarray in
transplanted hearts of patients dead in the
first week after surgery in contrast to its
presence in longer survivors9. The
conclusion was that myocardial disarray,
more frequent than originally supposed, may
be linked with adrenergic stress and should
be diagnosed in time due to its asynergic
and arrhythmogenic effect leading to
ventricular fibrillation.
Fig.5: Cutting edge lesion which involves a
layer of 0.2–0.5 mm along the cut margin of a
living myocardium (biopsies, surgical samples,
heart excised at transplantation). A)
histological aspect in heart excised at
transplantation and B) ultrastructural pattern
in dog. C) reflow or reperfusion necrosis
characterized by CN plus massive interstitial
hemorrhage never seen in other human and
experimental conditions.
Myocardial Asynergycardiac Arrest
Asynergy or dissinergy means a permanent or
temporary, global or zonal contractile
dysfunction. It may happen in any condition
(coronary heart disease, cardiomyopathies,
myocarditis, congenital malformation, etc)
with the impression, that, no matter what
the underlying disease is, asynergy is
linked mainly with the morphofunctional
damages previously described. Accordingly,
the two apparently opposite patterns of
non-functioning but viable myocardium
secondary one to chronic ischemia
(hibernating myocardium which return to
function following revascularization) and
the other to reperfusion (stunned myocardium
able to refunction after hours, day or
weeks) could be explained as a reversible
form of relaxed or contracted phase; an
assumption derived by experimental permanent
coronary occlusion with flaccid myocyte
paralysis and catecholamine venous infusion
with hypercontraction. Any clinico-pathological
correlation is irrealistic since
reversibility means no damage of structures
which return to function; their temporary
blockage is likely at a molecular/ionic
level difficult to see histologically and
detectable only by immuno-histochemical or
more sophisticated techniques at one
condition: to sample the dysfunctioning
myocardium (serial sections) and
discriminate unrelated terminal changes.
In the previous review on coronary
collaterals we questioned the existence of
chronic ischemia and in the present one we
question the existence of reperfusion
necrosis in human pathology; suggesting
possible alternative etiopathogenetic
mechanisms, in which the autonomic nervous
system may play an essential role. Agreement
exists that in coronary heart disease (CHD),
the starting point is zonal hypokinesis (denervation?).
May the latter aggravate (akinesis-paradoxical
bulging by increased intraventricular
pressure) with consequent block by
compression of vessels within the
non-functioning myocardium, ending in
infarct necrosis? Increased contractility by
nervous reflexes of surrounding, normal
myocardium to compensate the loss of
contractility of infarcted myocardium, may
result in catecholamine necrosis and
ventricular fibrillation (cardiac arrest).
In sudden coronary death catecholamine
necrosis seems the trigger of ventricular
fibrillation. However, in pheochromocytoma
in man and in experimental infusion of
catecholamines with widespread myocardial
lesions ventricular fibrillation does not
occur. Only when injected in one coronary
artery (unpublished data), noradrenaline
produces its typical myocardial necrosis and
ventricular fibrillation. The question,
therefore, is whether medial neuritis (i.e.
lympho-plasmacellular inflammation involving
nerves of the tunica in media in CHD) may be
the trigger of local noradrenaline release.
Similarly in sudden non coronary death in
cases with myocarditis associated with
catecholamine necrosis (as, for instance, in
silent Chagas disease) we should investigate
if myocarditis involves intramyocardial
innervation. Other possibilities exist in
relation to toxic substances or a direct
brain/heart relationship with a release in
excess of noradrenaline within the
myocardium. On the other site, colliquative
myocytolysis, not seen in sudden cardiac
death, may indicate an acute or subacute or
chronic congestive heart failure following
an acute infarct or any other cardiac
disease.
Table 4: Frequency and number of sites with
myocardial disarray in different conditions
Fig.6: Colliquative myocytolysis associated with
acute myocardial infarct. The lesion is confined
in layers of the subendocardial myocardium (A)
or around functioning vessels (B). These layers
are preserved by the infarct necrosis as shown
(C) in a perivascular myocardial layer around a
vessel in an old infarct without congestive
heart failure.
Fig. 7: Myocardial disarray. Different aspects
(A-D) with increased interstitial fibrosis.
Target of Ultrasound Diagnosis:
Present and Future
Information on composition and structure of
myocardial tissue could be of major
importance to better characterize the onset
and progression of several myocardial
diseases in both clinical and research
setting. The use of ultrasounds techniques
for this purpose is not new, since first
applications date back to 40 years ago10.
Its theoretical background is represented by
the fact that ultrasound interacts
differently with abnormal as compared to
normal myocardium. However, an ideal
technique is still far from ready for
clinical use. Different methods, using both
qualitative and quantitative approaches have
been suggested during the last decades.
Qualitative methods
The direct identification of specific
abnormalities by the visual inspection of
both M-mode and B-mode echocardiograms is
the simplest technique used to study the
characteristics of myocardial tissue. An
increased intensity of the echocardiographic
signal has been reported some weeks
following anteroseptal myocardial
infarction10. The same authors were also
able to demonstrate a strong correlation
between intensity of the signal and presence
of scar tissue on surgical or post-mortem
evaluation11,12. Color encoded digital
processing of images proved to further
improve the dynamic range of
echocardiographic information13. In
addition, the simple combination of
increased acoustic reflectance and reduced
end-diastolic thickness has been shown to
represent a simple and reliable predictor of
the scarred, asynergic myocardial segments
which do not improve in function after
revascularization14. In particular, it has
very recently been confirmed that a
diastolic wall thickness of Ť 0.6 cm on
baseline echocardiography can exclude the
presence of significant viability with a
negative predictive accuracy similar to that
of dobutamine stress echocardiography15.
Quantitative methods
The biological basis of quantitative methods
that have been introduced for the ultrasound
tissue characterization is represented by
the possibility that individual structural
components of the myocardium can influence
its acoustic properties in different
physiologic and pathologic conditions16.
These methods are essentially represented by
radiofrequency (integrated backscatter)17,18
and echocardiographic gray level (videodensitometry)
analysis19,20. In particular, integrated
backscatter analyzes the unprocessed
radiofrequency signal returning from the
myocardium, whilst videodensitometry bases
on the conversion of analogic conventional
ultrasonic images into a digitized form
which allowing quantitative analysis of the
ultrasonic myocardial texture. Both
techniques21,22 have been used in
experimental or stress-induced myocardial
ischemia to detect changes in the ultrasound
property of the myocardium. In the setting
of acute myocardial infarction, a dramatic
reduction of the cyclic variation of
integrated backscatter has been demonstrated
in the infarct area23.
Moreover, it was
found that myocardial infarcts show an
increase in integrated backscatter values
and a loss of the cardiac cycle dependent
variation in backscatter24. This
characteristics may be of help in
differentiating them from viable tissue25
that shows preserved cyclic variation of the
backscatter signal despite the reduction in
wall motion26. Differentiation of viable
from nonviable tissue has been recently
attempted using wavelet transform
analysis27,28, a technique based on breaking
up a signal into shifted (translation) and
scaled (stretching or compressing) version
of a mother wavelet signal29, to calculate
texture energy.
Despite promising preliminary remarks, the
pathophysiological background as well as the
effective clinical value of ultrasound
tissue characterization remain to be
defined. In particular, it is expected that
more standardized approaches, that will be
available in the very near future from
digitized technologies, can be of help in
allowing comparison of the results from
different laboratories.
Tissue Doppler Imaging
During a prolonged coronary artery
occlusion, myocardial necrosis progresses
from endocardium toward epicardium as a
wave-front phenomenon30.
Anatomic-pathological studies revealed the
great heterogeneity of the reperfused
myocardium that contains a variable amount
of necrosis surrounded by a viable but
transiently stunned epicardium31. This
structural and functional heterogeneity
complicates the interpretation of wall
motion abnormalities by conventional
echocardiography. Tissue Doppler imaging is
a relatively recent ultrasound technique
enabling quantification of intramural
myocardial velocities by detection of
consecutive phase shifts of the ultrasound
signal reflected from the contracting
myocardium32. Main interest of the technique
for the myocardial tissue characterization
is associated with its ability to
differentiate transmural from nontransmural
myocardial infarction and thus to assess
myocardial viability33.
Further improvements in both qualitative and
quantitative imaging techniques are expected
in the near future. This may provide a
powerful tool to make information on
biochemical composition and physiological
state of the myocardial tissue easily
available in clinical practice. ¨
Competing interests: The author(s) declare
that they have no competing interests.
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* Associate Professor of Pediatrics, George
Washington University; Director of Fetal
Heart Program and
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