Morphology of the Coronary Arteries After Combined

Thrombolysisand PercutaneousTransluminalCoronary
Angioplastyfor Acute Myocardial Infarction
CHRISTOPH DijBER, MD, ACHIM JUNGBLUTH, MD, HANS-JOACHIM
RUMPELT, MD,
RAIMUND ERBEL, MD, JURGEN MEYER, MD, and WOLFGANG THOENES, MD

Autopsy findings are reported for 6 patients who

died early (8, 9, 12, 13 and 14 days) or late (52
days) after combined thrombolysis and percutaneous transluminal coronary angioplasty (PTCA) for
acute myocardial infarction. Morphologic changes in
the coronary arteries at the site of revascularization
included injury to the inner portion of the arterial
wall (intimal splitting, subintimal dissection, medial
tears and submedial dissection) and necrosis of medial smooth muscle cells. Residual mural thrombi
and thrombotic reocclusion were noted within the
arterial lumen. There was a beginning neointima formation in all patients who died early and a reobstrutting neointima proliferation in the patient who

died late after PTCA. The results of this study support the suggestion that both rupture and dissection
of the inner arterial wall and necrosis of the tunica
media resulting from irreversible dilatation of the
grossly intact outer layers are the most important
mechanisms of PTCA. Response to arterial wall injury after PTCA is a neointima formation leading to
covering of mural thrombi and thrombogenic
intimal,
medial and adventitial substances and smoothing of
the luminal surface. Large residual mural thrombi
and excessive neointimal proliferation may cause
restenosis within a few weeks.
(Am J Cardiol

espite increasing clinical and angiographic experience, knowledge of the morphologic

changes during
and after percutaneous transluminal
coronary angioplasty (PTCA] is limited. Postmortem findings in 19
patients with previous PTCA were reported-l-l1 Most
information about postdilatation morphologic characteristics is derived from observations at noncoronary
sites,2,12.13 in vitro studies14-l8 and experimental
animal work with normal or diseased vessels.14.1g-26Coronary morphologic changes after interventional
catheter treatment of acute myocardial infarction (AMI]
have not been reported previously.
In this autopsy investigation
immediate
changes
and the subsequent healing mechanism of the coro-

nary arteries after combined

are described in 6 patients.

1986;58:698-703)

thrombolysis

and PTCA

Patients
From September 1983 through June 1984 thrombolysis with or without subsequent PTCA was performed in 72 patients with AMI. Thrombolysis
included systemic and intracoronary administration
of
250,000 IU of streptokinase. PTCA of residual highgrade coronary stenosis was performed immediately
after successful thrombolysis. Gruentzig 4Fr balloon or
3Fr recanalization
catheters (Schneider) were used.
Fifteen patients died in hospital [within 4 weeks) and 3
died during the follow-up period. This autopsy study
was conducted in 6 patients who died 8, 9, 12, 13, 14
and 52 days after combined thrombolysis and PTCA.
Details of the revascularization
procedure in the 6 patients are listed in Table I. The cause of death was
cardiogenic shock in 4 cases (patients 1, 2, 5 and 6).
Patient 3 died from refractory dysrhythmia and patient
4 from multiple organ failure after cardiac surgery for
rupture of the left ventricle and mitral regurgitation.

From the Institute of Pathology and the II Medical Clinic, Johannes Gutenberg University, Mainz, Federal Republic of Germany. Manuscript received March 13, 1986; revised manuscript
received May 21,1986, accepted May 24,1986.
Address for reprints: Christoph Diiber, MD, Institut fur klinische Strahlenkunde,
Universitatskliniken,
Langenbeckstrasse
1, D-65 Mainz, Federal Republic of Germany.
696

October

TABLE

Clinical

Pt
Age (Yr)
Sex
Stenosis
(%)
before
thrombolysis
Interval
(min)
symptomsthrombolysis
Stenosis
(% )
after
thrombolysis
Interval
(days)
thrombolysisPTCA
Balloon
diameter
(mm)
No. of
dilatations
Stenosis
(%)
after
PTCA
A second
stenosis
lated in patient
4.
PTCA = percutaneous

and Angiographic

1, 1986

Data

69
M
86

70
M
100

46
M
100

65
M
100

54
M
100

50
F
100

84

212

210

240

95

269

86

74

07

80

70

80

34

2.0
3.7
3
4
25

2.0

3.0

3.0

3.0

3.0

15

17

20

3.0
3.7
4
3
16

artery

was di-

in the distal
transluminal

part

of the infarct-relateci
coronary

5
50

angioplasty.

Methods
At autopsy the epicardial coronary arteries were
carefully excised, fixed in formalin, decalcified, cut
into 2- to 3-mm-long segments and processed for light
microscopy. Histologic sections were prepared from
each segment and interesting segments were step-sectioned. The slides were stained with hematoxylineosin, elastica van Gieson, Goldner trichrome and
Ladewig stains. In 1 case, the fixed segment of the
coronary artery containing the site of angioplasty was
cut longitudinally
and prepared for scanning electron
microscopy.
The heart was sectioned transversely from apex to
base at l-cm intervals for complete gross inspection.
Sections from normal myocardium,
the junction of

FIGURE

1. intimai

changes-a,

circumferentiaiiy

orientated
intimai tear with thin fibrin deposits
on
the newly created
iuminai
surface.
Congestion
of
adventitiai
blood vessels. b, intraintimai
dissecting
hematoma
resulting
from proximal
intimai
tear
with compression
of arterial lumen. A = adventitia;
I = intima; M = media. Goidner
trichrome
stain;
original magnification
X100.

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699

normal and infarcted tissue and the central portion of

the infarct were prepared for light microscopy. Extension and type of infarction were defined both macroscopically and histologically.

Results
Coronary pathology at the site of angioplasty: The
left anterior descending artery (LAD] was the infarctrelated vessel in all patients. Fibrous lesions (n = 3) or
complex intimal plaques with large amounts of calcific
deposits (n = 3) resulting in eccentric (n = 5) or concentric (n = 11 stenosis were present in the proximal (within 3 cm from the ostiumj previously occluded, reopened and dilated part of the artery. A fibrous
concentric intimal lesion was noted in the distal part of
the LAD in 1 patient, in whom PTCA of a second
stenosis had been performed.
In all instances, PTCA caused arterial wall injury of
varying degree. Neointimal
formation was an important healing mechanism. Residual mural thrombi and
thrombotic reocclusion were observed within the arterial lumen.
Arterial wall injury during angioplasty:
Intima:
Intimal tears ranging from small fissures in the inner
portion of the intima to complete splitting extending to
the internal elastic lamina were a consistent finding
(Fig. la and 2a). The tears occurred within the plaque
(Fig. 2a] or at the junction of normal and diseased
intima (Fig. la]. Their orientation was always longitudinal On cross section the tears were either radial or,
more frequently, circumferential
along preexisting
layers within the plaque [Fig. la and 2aj. Splitting of
the fibrous cap of a mixed atheromatous lesion with
release of lipid debris into the arterial lumen was noted in 1 patient [Fig. 3a). An intraintimal
dissecting
hematoma
resulting from a proximal
intimal tear
caused considerable compression of the arterial lumen
in another case (Fig. lb).
Subintimal dissection, i.e., separation of the intima
from the media along the internal elastic lamina, was
seen in 4 cases, with complete rupture of the intima

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THROMBOLYSWANGIOPLASTY

FIGURE 2. Medial changes-a,

complete
rupture of intima (I) and media (M) with submedial
dissection.
Strand of medial tissue (arrow)
crossing the new arterial lumen. Small intimal tears with fibrin desposits
(arrowheads).
b, submedlal
dissection
channel covered
by a thin
fibrin layer. Beginning
formation
of a neointima
by small aggregates
of fibromyoblasts.
A = adventitia.
Goldner trlchrome
stain; original
magnification
a, X50, b, X200.

(Fig. 3). Dissection was associated with stretching of

the media and adventitia indicated by small gaps between the intimal flaps, redundancy of the outer arterial wall and necrosis of smooth muscle cells within
the tunica media.
Media: Complete rupture of the tunica media was
observed in 4 cases with overlying intimal splits (Fig.
4a). Medial tears were also noted without histologic
changes of the adjacent intima (Fig. 4b).
In 2 cases, complete splitting of the intima and media was associated with extensive submedial dissection and distention of the adventitia, resulting in extraanatomic enlargement of luminal cross-sectional area
(Fig. 2 and 5). In 1 patient, a small cholesterol fragment
was seen within a submedial dissection channel.
Structural alterations of the media, with focal necrosis of smooth muscle cells involving not only the site

of intimal or medial tears but also the whole circumference of the arterial wall, were present in all patients, in addition to preexisting fibrosis, sclerosis and
localized thinning (Fig. 2b and 4).
Adventitia: Congestion of adventitial blood vessels
[Fig. la] and a slight inflammatory
reaction were noted
in all cases. Bleeding within the connective tissue
around the dilated part of the artery was seen both
macroscopically
and histologically
in 2 patients with
submedial dissection. Disruption of the adventitia was
not present in any case.
Intraluminal
findings: Small platelet thrombi and
thin fibrin deposits were observed on the original or
the newly created intimal surface in 3 cases (Fig. la, 2
and 4a). A large residual mural thrombus covered by a
neointima proliferation was present in the patient who
died 52 days after PTCA (Fig. 5a). Three patients had

FIGURE
3. a, extensive
splitting
of fibrous cap of
mixed intimal plaque with release
of lipld debris
into the arterial
lumen. b, complete
rupture of intlma with interruption
of internal elastic membrane.
a and b, thrombotic
reocclusion.
A = adventltla;
I
= intima;
M = medla. Goldner
trichrome
stain;
original magnification
a, X50, b, X100.

October

FIGURE
4. Medial changes-a,
complete
(A). Platelet thrombus
(T) in the arterial
underlying
intimal splitting.
Proliferation
grossly intact media. Disruption
of elastic
a, X100, band c, X200.

rupture of intima
lumen. Combined
of fibromyoblasts
fibers. Interruption

1, 1986

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701

(I) and media (M) with dehiscence

of medial flaps. Redundancy
of adveniitia
fibrin and platelet thrombus
in the medial gap. f~, rupture
of media without
within the medial defect. c, patchy
necrosis
of smooth
muscle cells within
of internal elastic membrane.
Goldner trichrome
stain; original magnification

thrombotic reocclusion of the infarct artery (Fig. 3a

and 5a).
Response to arterial wall injury after angioplasty:
Beginning fieointimal formation was apparent in the 5
patients, who died 8,9,12,13 and 14 days after PTCA.
A thin interrupted lamina or small aggregates of fibromyoblasts covered the rough, irregular, thrombogenic
surface within intimal and medial tears and subintima1 and submedial dissection clefts (Fig. 2 and 3b).
The patient who died 52 days after angioplasty showed
extensive neointimal
proliferation,
leading to considerable restenosis (Fig. 5). The whole luminal surface,
consisting of the original intimal plaque, a large mural
thrombus, the torn ends of the intimal and medial flaps
and the media [outer aspect) and adventitia (inner aspect] in the region of submedial dissection, was coated
by a thick layer of fibromyoblasts within a loose intercellular matrix.
Morphologic
changes of the coronary arteries during and after PTCA as seen in this study [excluding
thrombosis] are summarized in Figure 6.
Mvocardial
uatholoe;v: Large transmural mvocardial iifarcts in he anterTlatera7 part of the left ientri-

FIGURE
5. Neointimal
proliferation-a,
complete
rupture of intima (I) and media (M) with submedial
dissection.
Thrombotic
reocclusion
(artificle
shrinking
of thrombus
during histologic
processing). Neointima
(N) of fibromyoblasts
within
a
loose intercellular
matrix covering
the whole surface of the newly created lumen and a large mural
thrombus
(T), with considerable
reobstruction.
b,
neointima
proliferation
within a submedial
dissectlon channel.
Compare
with Figure 4. A = adventitia. Goldner trichrome
stain; original magnification
a, X50, b, X200.

THE AMERICAN

cle, including the ventral portion of the ventricular

septum, were present in all cases. Hemorrhagic type of
infarction was seen in 3 patients. Myocardial hemorrhage was limited to the infarct area.

Discussion
Arterial wall injury, including
intimal splitting,
subintimal dissection, medial tears and submedial dissection, was the predominant
finding in the dilated
part of the coronary arteries in this histologic investigation. This observation confirms previous results from
postmortem studies after PTCA2-gJ1 and dilatation of
peripheral arteries,2J2J3 in vitro studies,13-l8 and experimental animal investigations.14J5Jg-z6 Thus, rupture of the inner portion of the arterial wall appears to
be an inevitable and necessary event during successful PTCA.
However, widening of the arterial lumen cannot be
achieved by intimal and medial splitting alone. Plastic
deformation of the media and adventitia with enlargement of the outer arterial diameter (i.e., formation of
an aneurvsml is necessafi to obtain Dermanent luminal extension after PTCA. In the present study, this

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THROMBOLYSWANGIOPLASTY

FIGURE
6. Proposed
mechanism
of angioplasty.
A, status before
angioplasty.
Eccentric
stenosis,
intact
media.
B, early changes
after angioplasty.
Injury of the inner portion
of the arterial
wall
(upper Iine, intimal splitting
with sublntimal
dissection;
lower line,
intimal and medial rupture with submedial
dissection).
Dilatation
of
outer portion
of the arterial
wall with patchy
necrosis
of medial
smooth muscle cells. C, late changes after angioplasty.
Smoothing
of the surface
and reobstruction
of the newly created
lumen by
neointima
formation.

mechanism was evident from gaps between the ruptured intimal and medial flaps and, most important,
from irreversible structural changes of the media with
patchy necrosis of smooth muscle cells along the whole
circumference
of the arterial wall. Medial necrosis
may result from disruption of individual
cells during
angioplasty or ischemia of the vessel wall after PTCA
caused by damage to adventitial vasa vasorum. Similar
findings within the media were reported by Baumgartner et alz7 in the description in 1963 of a new experimental method for the production of thrombi by
overdilatation
of the rabbit aorta using a balloon catheter. Loss of constrictive response to vasopressin in
dilated arteries further supports the notion that medial
smooth muscle cells are damaged during angioplasty.z8 The important role of medial changes during
therapeutic angioplasty has already been stressed in
but has not been &sanimal experiments, 15SW1,23,25,26
cussed in postmortem studies after PTCA in patients.
Retraction of ruptured intimal flaps and partial dissolution of atheromatous material has been considered
a possible healing mechanism after PTCA with further
enlargement of luminal cross-sectional area.14Jg There
is no evidence to support this suggestion in the present
study. Early response after angioplasty was a neointima formation covering the rough and thrombogenic
surface of the newly created lumen. A proliferating
neointima and a large residual mural thrombus caused
reobstruction of the arterial neolumen in the patient
who died 2 months after PTCA. Similar findings have
been reported in animal experiments,20,21,25,27 and in 4
cases after PTCA in patients.lt3r5x8 We conclude from
findings of the present study that neointimal formation
as a response to arterial wall injury is the pathologic
basis for both smoothing of the luminal surface and
restenosis after PTCA. Factors that determine neointi-

ma1 growth remain unclear from this investigation.

Proliferation
of fibromyoblasts
upon platelet and fibrin thrombi seen in this study [Fig. 2b and 5a] and
reported in experimental animal studies21gZ5suggests a
stimulating
role of thrombotic
material. Moreover,
prevention of restenosis has been demonstrated with
anticoagulation
therapy after angioplasty.22
Early and late changes of the coronary arteries after
combined thrombolysis and PTCA as seen in this study
do not differ from histologic findings after PTCA
alone.l-l1
Thrombotic
reocclusion of the infarct artery occurred in 3 of 6 patients in the present study despite
successful thrombolysis and angioplasty in the acute
phase of myocardial infarction. Inadequate coronary
blood flow due to low cardiac output and, possibly,
increase of peripheral coronary vascular resistance
caused by damage to the small vessels within the infarct area are believed to cause rethrombosis. An intraintimal dissecting hematoma with compression of
the arterial lumen in 1 instance and cardiac surgery
with prior reversal of thrombolytic activity in another
may have induced thrombosis in these 2 patients.
Transmural rather than subendocardial
AMI, was
present in all patients. Myocardial hemorrhage demonstrating reperfusion of necrotic tissue and irreversibly injured small vessels was noted in 3 cases.
However, as reported in experimental
studies,2g hemorrhage was not seen outside the infarct zone and did
not cause extension of myocardial damage.
Acknowledgment:
We gratefully acknowledge
technical assistance of R. Baumann.

the

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