Circulation. 2000;101:570-580
(Circulation. 2000;101:570.)
© 2000 American Heart Association, Inc.
Recognition of the Importance of Embolization in Atherosclerotic Vascular Disease
Eric J. Topol, MD;
Jay S. Yadav, MD
From the Departments of Cardiology, Neurology, and Molecular Cardiology
and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The
Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Eric Topol, MD, Department of Cardiology, Desk F25, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, Ohio 44195. E-mail topole{at}ccf.org
Key Words: embolization • atherosclerosis • imaging
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Introduction
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It is uncommon in medicine for emerging data to
completely transform
a field, particularly in such a common disease
state as atherosclerotic
vascular disease. New evidence from multiple
fronts has underscored
the frequency and prognostic importance of
atherosclerotic embolization
in the microvasculature. Until recently,
we have had limited
access to diagnose microvascular obstruction in
living patients.
With the availability of imaging technology that
includes magnetic
resonance, myocardial contrast
echocardiography, and transcerebral
or
transcranial Doppler (TCD), microvascular obstruction
has
been documented in a far greater proportion of patients than
ever
conceived. The linkage between microvascular obstruction
and
unfavorable long-term clinical prognosis has been established
in many
series. Furthermore, therapeutics shown to reduce microvascular
obstruction
have improved clinical outcomes. The purpose of this
article
is to present the case for a disturbingly and unexpectedly
high
rate of arterial embolization in certain
atherosclerotic conditions
and to review the promise of newer
therapeutics or devices to
reduce the risk or ameliorate the sequelae
of embolization.
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A Change in the Mind-Set
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Acute myocardial infarction (MI) has been accepted to be related
primarily
to a fissured, eroded, or ruptured plaque.
1 2 3 4 5
This event
leads to exposure of subendothelial matrix,
with attendant platelet
aggregation, thrombus, and occlusion of a
major epicardial vessel.
In a continuum, unstable angina and
non–ST-segment-elevation
MI also are indexed to a breech of the
arterial wall, but the
resultant thrombus is usually mural,
not occlusive. Embolization
of plaque contents of platelet-thrombus
into the microvasculature
has been reported in some patients with these
acute coronary
syndromes, but it has been generally believed to
be uncommon.
1 2 6 7 In some cases of sudden death, the
process of embolization
has been speculated to play an important role.
It is nevertheless
surprising that systematic pathological studies of
the microvasculature
of the postmortem heart infarct territory have not
been performed.
This represents a key deficiency in our
knowledge base with
the use of fibrinolytic therapy or primary
catheter-based myocardial
reperfusion, both interventions capable of
promoting distal
embolization.
Percutaneous coronary intervention began with
balloon angioplasty in 1977, and for >2 decades, we have been under
the impression that embolization is a rare event, confined chiefly to
revascularization of degenerated, aged, saphenous
vein grafts.8 When patients provide informed consent, a
description of the general procedure to patients and their family
members often prompts the question, "What happens to the
cholesterol material during the procedure?" Until quite
recently, the answer was to provide strong reassurance that
embolization is extremely uncommon. Similarly, with the newly
introduced procedure of carotid stenting, it was thought that the
absence of a transient ischemic attack or stroke argued against
the occurrence of embolization.9 In summary, the mind-set
in acute ischemic heart disease and
percutaneous revascularization was
that this process was unlikely and therefore relatively
unimportant.
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Updated Pathophysiology
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The concept of microvascular obstruction, especially by
platelet
emboli, is not new and was pioneered by Willerson, Folts,
and
their colleagues in the 1980s using an experimental model of
endothelial
injury.
10 11 12 13 But the
underappreciation of the actual
incidence of embolization has been
highlighted by several recent
studies, which have also helped to
illuminate the pathophysiology
of microvascular obstruction. In Figure 1
, a histological view
of
an obstructed vessel from a patient with sudden cardiac death
demonstrates
stain for platelet glycoprotein (GP)
IIb/IIIa, confirming platelet-thrombus
as the occlusive material.
Also, atherosclerotic particulate
matter from an elective native
coronary artery percutaneous
coronary
revascularization is shown. In a clinical
investigation
that we have just conducted in >50 patients undergoing
elective
percutaneous
revascularization, all patients had particulate
matter
retrieved via an embolic filter device (vide infra).
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Figure 1. A, Histological specimen of
intramyocardial microvessel filled with platelets, stained positive
for platelet GP IIb/IIIa, from patient who had sudden cardiac
death. (Courtesy of Professor Michael Davies, London, UK.) B,
Atherosclerotic particulate embolic material retrieved from
percutaneous coronary
revascularization with Angioguard guide-wire
filter.
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Two recent studies have been especially noteworthy in focusing on
endothelial cells. In a recent study of patients with
acute coronary syndromes, circulating
endothelial cells were identified at relatively high
frequency (compared with control subjects or patients with effort
angina) in the peripheral blood.14 Using an
experimental canine model, Eguchi et al15 studied the
effect of microvascular obstruction on endothelial
function and demonstrated loss of integrity and adherence of
platelets and leukocytes. The updated pathophysiology of
embolization can be summarized in Figure 2. Atherosclerotic vessels can be
transformed from a stable, quiescent phase to "unstable" when there
is inflammation of the arterial wall or intravascular
iatrogenic manipulation that is part and parcel of
transcoronary revascularization. In both
circumstances, there is disruption of the fibrous cap of the plaque
with exposure of subendothelial matrix elements.
Accordingly, plaque and vessel wall constituents, including lipid,
matrix, and endothelial cells, and
platelet-thrombus, if present, can embolize. As fully
described by Willerson et al,13 this sets up the potential
for microvascular obstruction, with loss of endothelial
integrity, release of vasoactive amines from activated
platelets, increased vascular tone, and potentiation of
platelet-thrombus.
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Figure 2. Schematic of embolization resulting in
microvascular obstruction. Because of inflammation, intervention, or
both, arterial wall is fissured. Small atherosclerotic
(nano) particulate matter, sometimes including adherent
platelet-thrombus, is embolized and can lead to
microvascular obstruction (represented by cross
section).
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New Window to Microvascular Obstruction
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Our awakening to the frequency of microvascular obstruction
was
made possible through an array of newer diagnostic imaging
modalities.
One of the early studies, which took the
cardiovascular community
by surprise, was performed by
Ito and colleagues.
16 Using myocardial
contrast
echocardiography, they showed that
25% of
patients
with what appeared to be brisk epicardial flow (using
conventional
contrast dye angiographic assessment) did not have tissue
level
reperfusion (Figure 3
). Although
microvascular obstruction was
the clear culprit, there was uncertainty
about the veracity
of this finding and whether it might be due to
myocardial edema
and reperfusion injury. Recently, Wu and
colleagues
17 used
MRI of the infarct
myocardium to show that microvascular obstruction
carried a
grave prognosis (Figure 4
). This pattern
of obstruction
could be delineated very early after the onset of MI,
making
inflammation, edema, and reperfusion injury a less likely
explanation
than atherosclerotic and platelet-thrombotic
obstruction.
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Figure 3. Top, Proportion of patients who have perfusion
defect by myocardial contrast echocardiography
(MCE) as function of TIMI grade. Bottom, Example of patient with TIMI
grade 3 flow of infarct vessel with myocardial contrast
echocardiographic defect. (Adapted from data in
Reference 16.)
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Figure 4. Top, Event-free survival (clinical course without
cardiovascular death, reinfarction, congestive heart
failure [CHF], or stroke) for patients with and without MRI
microvascular obstruction. Bottom, MRI from patient with anteroseptal
infarct and extensive subendocardial microvascular obstruction (between
arrows). Figure reprinted with permission from Circulation.
1998;97:765–772. ©1998, American Heart Association.
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Using TCD during carotid stenting procedures, Jordan and
colleagues18 have now demonstrated that virtually every
patient undergoing the procedure has Doppler evidence of
microembolization (Figure 5). With the
use of nuclear scintigraphy with sestamibi in patients
undergoing coronary rotablation, intraprocedural perfusion
defects have been duly noted, despite a lack of enzymatic evidence of
myocardial necrosis (Figure 6).19
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Figure 5. TCD monitoring of middle cerebral artery during
elective carotid artery stent procedure demonstrating high-intensity
transients representing emboli released after balloon
deflation.
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Figure 6. Top, Incidence of patients undergoing rotablation
with perfusion defects according to treatment group. Bottom, SPECT
images obtained before and during rotablation in patient with lesion of
left anterior descending artery and previous inferior MI.
Sagittal long-axis views are displayed, indicating transient apical
perfusion defect. Bottom figure reprinted with permission from
J Am Coll Cardiol. 1999;33:998–1004. ©1999, American
College of Cardiology.
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Besides direct imaging with echocardiography,
magnetic resonance, and scintigraphy, there have been
extensive new insights derived from markers of myocardial necrosis.
Several years ago, the Coronary Angioplasty Versus Excisional
Atherectomy (CAVEAT) investigators demonstrated for the first time in a
large prospective trial that the incidence of periprocedural MI was
much higher than generally accepted.20 By using the
physician-investigator’s recording, they found the infarct
rate to be 3% for PTCA and 6% for atherectomy. By use of a core
laboratory that adjudicated the clinical events with all the creatine
kinase (CK) and myocardial band isoenzyme data that were systematically
collected, the incidence of periprocedural MI (with a 3-fold increase
over baseline value of creatine phosphokinase, CK-MB threshold) was 8%
for balloon angioplasty and 19% for directional
atherectomy.20 In the subsequent CAVEAT-II trial of
saphenous vein graft intervention, the MI rates were considerably
higher at 15% and 24%, respectively.21 This finding set
off a debate as to whether there was any clinical significance of the
"enzyme leaks," "infarctlets," "CK bumps," "CK efflux
events," or "microinfarcts."22 In the long-term
follow-up of CAVEAT, there was a significant excess of mortality for
atherectomy,23 and most patients who died in this group
had experienced a periprocedural non–ST-segment-elevation MI. Several
large series of patients were assessed to determine whether there was a
relationship with periprocedural MI and outcome; indeed, a remarkable
correlation has been established. The higher the CK elevation, the more
risk of death during follow-up was demonstrated by Abdelmeguid et
al,22 24 25 Kong et al,26 and many
others.27 28 29
As shown in Figure 7, there is a striking
relationship of mortality rate as a function of increase in
periprocedural CK-MB elevation in the 3 randomized trials of
percutaneous coronary
revascularization with abciximab or
placebo.30 31 32 33 Of note, the rate of infarction induced by
stenting appeared to be greater than that occurring with balloon
angioplasty. When the risk factors associated with periprocedural MI
were deciphered, the predominant cause was diffuse atherosclerotic
involvement, reflected by long lesions, multiple-vessel disease, or
degenerated saphenous vein bypass grafts.24 25 26 The risk
of periprocedural MI also related to the type of coronary
revascularization, with the highest likelihood
induced by directional atherectomy, followed by rotational atherectomy
and then stenting and least incidence with balloon angioplasty. Thus,
the diffuseness of atherosclerotic disease and invasiveness of the
revascularization technique with respect to vessel
wall injury emerged as 2 dominant risk factors.
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Figure 7. Top, Mortality for patients with 1- to 10-fold
increases in periprocedural CK elevation vs patients without CK
elevation in EPIC trial. Middle, Mortality rates for patients with 1-
to 10-fold increases (within 24 hours) in CK-MB elevation in EPILOG
trial. Bottom, Mortality rates for patients by enzyme level in EPISTENT
trial. Top figure reprinted with permission from JAMA.
1997;278:479–484. ©1997, American Medical Association. Middle figure
reprinted with permission from Circulation.
1999;99:1951–1958. ©1999, American Heart Association.
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Interestingly, little else could be invoked to explain the very high
rate of periprocedural MI besides embolization. The time of
ischemia during balloon inflation, device manipulation, or
stent deployment is generally much too short to result in myocardial
necrosis. Side branch closure is very infrequent, in <3% of recent
trials.33 Transient or abrupt closure occurs only in <1%
of patients, and the actual time of ischemia in such patients
is usually limited to a matter of minutes. Without alternative
explanations, the differential diagnosis leaves embolization with
microvascular obstruction as the leading suspect.
The incidence of myocardial necrosis is even higher if one turns to a
much more sensitive marker, troponin (I or T). With this test, the
incidence of some myocardial necrosis in patients undergoing routine
coronary revascularization is between 30%
and 40%.34 35 36 This suggests that embolization is
extraordinarily common and that a large minority of patients actually
suffer some extent of measurable myocyte damage. Perhaps most patients
still experience some embolization but do not go on to myonecrosis
either because the burden of particulate matter is much less or because
there are adaptive responses to accommodate the process.
Recent data from troponin in patients with unstable angina have been
particularly illuminating. In the Chimeric 7E3 Antiplatelet Therapy
in Unstable Angina Refractory to Standard Treatment (CAPTURE) trial,
abciximab or placebo was administered, and the primary end point of
death or nonfatal MI was assessed in the short term, along with 6-month
follow-up.37 As shown in Figure 8, Hamm et al38
differentiated the response to therapy as a function of troponin T at
baseline. Patients who had an abnormal troponin T level were remarkably
sensitive to therapy with abciximab. It is most likely that the
patients who presented with elevated troponin levels already
had developed microvascular obstruction as a result of embolization. By
virtue of platelet disaggregation with GP IIb/IIIa blockade, the
relief of microvascular obstruction would be anticipated. All along, it
was thought that the predominant explanation for the benefit of GP
IIb/IIIa antagonism in the setting of unstable angina was to reduce
thrombus in the culprit epicardial artery. But this therapeutic tenet
would not provide a foundation for explaining the marked sensitivity
that patients with myocardial necrosis have for GP IIb/IIIa antagonism.
In addition to reducing the propensity for clot formation at the site
of arterial injury, there must be a substantial component
of benefit derived from improving microcirculatory perfusion.
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Figure 8. Top, Rates of cardiac events in initial 72 hours
after randomization among patients (Pts) with serum troponin T levels
above and those with levels below diagnostic cutoff point.
Bottom, Rates of cardiac events during 6-month follow-up after
randomization among patients with serum troponin T levels above and
those with levels below diagnostic cutoff point. Figure
reprinted with permission from N Engl J Med.
1999;340:1623–1629. ©1999, Massachusetts Medical Society.
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Mechanical Approaches
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Besides pharmacological agents capable of dealing with the
response
to embolization, a more direct method of addressing the
problem
would be to prevent the particulate matter from traversing
distally.
Recently, a few devices have been designed to trap embolic
material.
Two devices, the PercuSurge and Angioguard systems, are shown
in
Figure 9
. These devices fall into 2
general types: distal balloons
that occlude the artery during
intervention with aspiration
of debris with a small catheter
(PercuSurge), and filters that
trap debris during intervention and are
then collapsed and withdrawn
from the artery with the trapped debris
(Angioguard). The PercuSurge
and Angioguard devices have had initial
clinical testing and
have provided "smoking gun" evidence that
embolic material is
present in far more patients than was
previously conceived.
PercuSurge has been applied to patients
undergoing saphenous
vein graft and carotid stenting, and in almost all
cases, embolic
material that would have otherwise reached the distal
vasculature
was retrieved.
39 The Angioguard basket
approach has been tested
in patients undergoing
percutaneous coronary, renal, and saphenous
vein
grafts and carotid intervention, with retrieval of atherosclerotic
material
in every patient (Figure 1
).
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Figure 9. Emboli retrieval devices. A, PercuSurge balloon
occlusion device with aspiration catheter. B, Angioguard guide-wire
filter device.
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Some limitations of the devices are important to highlight. The
balloon occlusion-type devices cause distal ischemia that may
not be tolerated by some patients, and an aspiration catheter may not
remove all particles trapped in the artery. In addition, angiography
cannot be performed while the distal balloon is inflated, making
assessment of the artery and stent placement more difficult. The
filter-type devices have a finite lower limit in the size of particles
that can be captured; the practical lower limit for pore size appears
to be 50 µm. Smaller microparticulate matter can still get
through the filter, although particles that small may have no clinical
significance. It is still early in the development of these novel
catheter- and guide-wire–based systems; making them as atraumatic as
possible, with the lowest profile and highest torqueability, will
require further iterative engineering. Without question, there will be
several emboli protection devices that evolve and ultimately are
incorporated into the daily practice of percutaneous
coronary and peripheral
revascularization.
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Pharmacological Therapeutics
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Supporting the importance of microvascular obstruction,
there
are several pharmaceutical agents that have provided strong
evidence
of clinical benefit. While it is likely that some benefit is
mediated
through effects at the epicardial or large artery (eg,
carotid)
level, the microcirculation must play a pivotal role. Several
examples
provide evidence for this assertion.
In a randomized trial by Neumann et al,40 200 patients
with acute MI who were undergoing primary stenting and reperfusion were
randomly assigned to abciximab or heparin. As shown in Figure 10, coronary blood flow was
substantially improved in the infarct zone for abciximab-assigned
patients as assessed by Doppler with adenosine provocation.
Along with this finding, there was a significant improvement in
regional and global ejection fraction compared with control
(conventional) therapy.40 This represents the
first myocardial reperfusion study to show that further augmentation of
microvascular perfusion is associated with improved myocardial
performance. This mechanistic study of abciximab is flanked by
several large-scale clinical trials of the platelet GP IIb/IIIa
inhibitors,41 42 43 44 45 46 47 48 49 all of which show a
reduction in the major events of death or nonfatal MI. The magnitude of
this effect was especially pronounced in the recent Evaluation of
Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT)
trial, which, along with a 55% reduction in large (>5-fold CK-MB)
periprocedural MI, showed a 57% reduction in 1-year mortality (2.4%
for stent-placebo versus 1.0% for stent-abciximab).33
Before this trial, it was noted that a 60% reduction in 3-year
mortality was evident in the original Evaluation of IIb/IIa
Platelet Receptor Antagonist 7E3 in Preventing
Ischemic Complications (EPIC) trial for patients who entered
with an acute coronary syndrome.30 There has been
considerable debate about the mechanism by which a short duration of
platelet IIb/IIIa inhibitor therapy during
percutaneous coronary intervention could
achieve a reduction in long-term mortality.30 An
attractive explanation, in light of the new data showing the likely
ubiquitous nature of emboli induced by percutaneous
coronary revascularization, is protection
of the microvasculature. A watershed zone infarct, albeit small in
terms of myocardial mass damaged, is of critical importance in lowering
the threshold for ventricular arrhythmias. The data
that support the propensity of arrhythmias in patients who have
periprocedural MI show that most of the deaths are sudden, as
demonstrated by Abdelmeguid et al22 and in the recent
EPISTENT trial. Therefore, at least 1 explanation for a durable benefit
of short-term IIb/IIIa blockade invokes the avoidance of
microvasculature obstruction, the attendant myocardial necrosis, and
predicted risk for subsequent malignant arrhythmias. It needs
to be emphasized that abciximab or other IIb/IIIa
inhibitors would not be expected to reduce embolization of
atherosclerotic lipid and matrix constituents. On the other hand, the
putative mechanism of benefit is most likely tied to avoidance of
platelet aggregation in the microcirculatory zone, which has been
the recipient of embolic material.
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Figure 10. A Left, Effect of stroke with and without GP
IIb/IIIa inhibition (GPI) on platelet and fibrin accumulation in
brain. 111In-labeled platelets were administered to
control mice; 24 hours later, brains were harvested, divided into right
and left hemispheres, and counted. Relative platelet accumulation
is expressed as ratio of right/left hemispheric counts per
minute. Right, Immunostaining for fibrin in
contralateral (top right) and ipsilateral (top left) cerebral
hemispheres 24 hours after stroke. Microvessels are indicated with
arrows. Intravascular fibrin formation can be seen as red staining in
postischemic microvasculature. When GPI was administered
before stroke, there was no apparent reduction in microvascular fibrin
accumulation at 24 hours (bottom). B, Plot of differences between
14-day follow-up and initial postinterventional study in basal flow
velocity and in papaverine-induced peak flow velocity at treated
lesion. Columns represent mean difference. Error bars indicate
95% CI; P=0.15 for basal and P=0.024 for
peak. C, Improvement in wall motion index (SD/chord) rejection fraction
with use of abciximab with primary stenting. Figure 10A reprinted with
permission from J Clin Invest. 1998;102:1301–1310.
©1998, American Society for Clinical Investigation. Figures 10B and 10C reprinted with permission from Circulation.
1998;98:2695–2701. ©1998, American Heart Association.
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Other therapeutic agents have shown improvement in microcirculatory
perfusion and may have a role in favorably modulating the response to
embolization. In a randomized trial of intracoronary
verapamil in 40 patients who had catheter-based
reperfusion, there was improved tissue level perfusion, reflected by
myocardial contrast echocardiography, compared with
placebo.50 Besides calcium channel blockade, the agent
nicorandil, an ATP-sensitive K+ channel opener
with vasodilating action, was also recently shown to improve
microcirculatory perfusion in the infarct territory.51 In
a randomized trial of 81 patients with primary PTCA for anterior MI,
the incidence of myocardial contrast echo perfusion defects was reduced
from 34.1% to 15% (P<0.001), and mortality was reduced
from 10% to 0% (P=0.043).51 The benefit
of an agent such as nicorandil may be at the level of improving
endothelial function in the affected microvascular
territory. The platelet-thrombus response to embolization in the
setting of unstable angina may also be diminished by improved
anticoagulation. With the low-molecular-weight heparin dalteparin,
there was a substantial reduction in death or nonfatal MI among
patients in the Fragmin During Instability in Coronary Artery
Disease (FRISC) trial who had abnormal baseline troponin
levels.52 This finding suggests the concept that therapies
directed to either platelets or the coagulation system might be
effective in clinical settings in which embolization is prevalent.
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Profile of "The Embolizer"
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The changed perspective of the prominence of embolization leads
to
a rethinking of our understanding of and approach to several
diseases
and procedures that share atheromatous substrate. We
can
now begin to recognize a certain profile of patients as "the
embolizer,"
individuals who are most apt to shower emboli at
the time of
a revascularization procedure or at
clinical presentation. With
respect to pathological
substrate, the diffuseness of disease,
friability of the
atheromatous lesion, and presence of
platelet-thrombus
would seem to be the most likely predisposing
features once
an artery was manipulated. Disruption of the fibrous cap
of
atherosclerotic plaque, the histopathological basis of acute
coronary
syndromes, surely identifies a patient group quite
prone to
embolize. The friability may well be linked to ongoing
inflammation,
because many recent studies have underscored the
prominent effect
that elevation in C-reactive protein, necrosis
factor-
B, interleukins,
or vascular adhesion
molecules and other inflammatory markers
have on long-term
prognosis.
53 54 55 56 57 Of demographic features,
diabetes
mellitus stands out as 1 with particular risk, such
as increased
mortality after coronary intervention.
58 This
could
be attributed to the diffuseness of atherosclerotic involvement,
extent
of preexisting microvascular disease that reduces the adaptive
capacity
to embolization, or heightened inflammation related to
insulin,
S-glycolation products, or other metabolic
factors. There may
well be genotypic features that will be useful for
identifying
patients who have a propensity to embolize or
cannot accommodate
particulate matter.
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Clinical Conditions
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Percutaneous Coronary Intervention
To reduce the incidence of periprocedural MI, inhibition of
platelet
function more than that achieved with aspirin monotherapy
appears
to be clearly justified. Preprocedural therapy with combination
aspirin
and clopidogrel or ticlopidine should be considered in light
of
new observational data that show a significant reduction
in MI events,
presumably stemmed from modulating the response
to
embolization.
59 A dedicated, prospective trial is ongoing
to
address the specific question of dual preprocedural antiplatelet
therapy.
Although cost issues are significant, intravenous
platelet GP
IIb/IIIa agents would ideally be used in all patients.
This
can be justified on the basis that currently available data
show a
very substantial reduction in death or nonfatal MI, particularly
with
abciximab. Lower-cost strategies need to be developed to
simulate or
surpass the efficacy of this class of agents. Of
note,
platelet-directed strategies are not squarely addressing
the
underlying insult. With the refinement and wide-scale availability
of
emboli protection devices in the future, the need for GP
IIb/IIIa
inhibition may, at some point, be substantially reduced.
One subgroup
of patients demonstrated that even state-of-the-art
therapy is
inadequate to protect against the problem of embolization.
Patients
with degenerated saphenous vein grafts who undergo
percutaneous
intervention are at high risk of
periprocedural MI, and this
risk does not appear to be significantly
reduced with GP IIb/IIIa
inhibition.
60 Whereas saphenous
graft lesions were long thought
to carry an excessive risk of
atherosclerotic gruel dislodgment,
the persistent frequency of MI risk
and resistance to current
therapies point to the need for a better
mechanical approach.
This finding also suggests that when an
embolization mass is
quite large, it can override the benefit of
platelet-directed
therapy.
Another area of concern while more data are garnered is patients who
have a bona fide periprocedural MI and have a risk of death
proportional to the size of MI during extended follow-up. In these
patients, there has been unequivocal myocardial necrosis, but no
current approach has been advocated to reduce the risk. Consideration
of long-term ß-blockade therapy seems appropriate, with the known
risk of sudden death, in abeyance of clinical trials that are necessary
to resolve this critical question of secondary prevention.
Carotid Intervention
Cerebrovascular intervention is still considered an investigation
technique that is being compared with carotid
endarterectomy with respect to safety and efficacy;
however, there are no completed randomized trials. Both strategies
carry an important risk of periprocedural stroke, undoubtedly related
to embolization. With TCD, virtually every patient undergoing either
form of revascularization has acoustic and
Doppler signal evidence of embolization.18 The same
principles discussed for coronary intervention apply, with the
need for improved preprocedural platelet inhibition,
intraprocedural platelet aggregation blockade, and, it is hoped,
imminent availability of emboli protection devices to make both forms
of revascularization safer. Unlike the heart, there
is no readily available enzymatic test of brain necrosis, so the
ability to diagnose watershed damage events is impaired. Laboratory
methods to track brain damage with these procedures are quite important
to develop, because the parallels to the heart for prognosis and
refinement of therapies are obvious.
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CABG Surgery
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It has long been known that a risk of CABG is stroke in 1.5%
to
5.2% of patients in prospective studies and is especially
pronounced
in the elderly. Besides overt stroke, there is a
higher risk of
cognitive defects such as memory impairment,
visuospatial deficits, and
depression. These neurological sequelae
are all believed to result from
emboli.
61 62 63 64 In the past
few years, there has been an
emphasis on the presence of atherosclerosis
in the
aorta as a key risk factor for stroke during open heart
surgery.
65 66 With TCD, cerebrovascular embolization has
been found to
occur in essentially all patients, and there is positive
correlation
between brain injury and embolic burden.
61 62
In a meticulous
study with TEE and TCD, Barbut and
colleagues
64 found that
particle diameter varied from 0.3
to 2.9 mm (mean, 0.8 mm) and
volume varied from 0.01 to
12.5 mm
3 (mean, 0.8
mm
3). Total aortic
embolic load was 0.6 to 11.2
cm
3 (mean, 3.7 cm
3), and
the cerebral
embolic load was 60 to 510 mm
3
(mean, 276 mm
3), with 3.9% to
18.1% of
aortic emboli entering the cerebral circulation. The
field of CABG is
behind other areas of emboli protection, but
this direction needs to be
pursued. The S100 protein may, like
CK-MB or troponin, prove helpful in
tracking brain cell necrosis
and indirectly reflecting microvasculature
obstruction.
67 An
early study suggests that a filter on
the bypass cannula may
reduce the number of emboli and release of S100
protein from
the brain.
63 There should be strong
consideration for clinical
investigation of the use of emboli
protection devices to be
placed in the aorta and for improved
perioperative antiplatelet
therapy. Besides
atherosclerotic debris, small capillary/arteriolar
dilatations are
thought to be lipid-containing emboli that contain
aluminum and
silicon. Small capillary/arteriolar dilatations
are derived from the
cardiopulmonary bypass circuit and its
tubing.
67
|
Unstable Angina and Non–ST-Segment Elevation
|
|---|
The bedside availability of sensitive markers of myocardial
necrosis
such as troponin T or I sets up a new-found ability for the
clinician
to track the likelihood of coronary embolization.
Patients with
unstable angina with a positive troponin have likely
suffered
microvascular obstruction and clearly derive pronounced
benefit
from the use of platelet GP IIb/IIIa
inhibitors. We are only
in the early phase of revamping our
therapies for such patients;
a patient who has developed an embolic
event may also have significant
inflammation of the diseased
coronary artery. In fact, a recent
study showed the prognostic
interdependence and additivity of
troponin and C-reactive
protein.
56 Thus, such patients may
require improved
anti-inflammatory strategies that have yet
to be tested in clinical
trials. Furthermore, long-term augmentation
of antiplatelet therapy
such as the addition of an ADP receptor
antagonist or oral
GP IIb/III inhibitor may be necessary.
|
Stroke
|
|---|
Only a small proportion of patients with evolving stroke are
eligible
for intravenous fibrinolytic therapy with tissue
plasminogen
activator.
68 However,
the prothrombotic deficiencies of tissue
plasminogen
activator, along with an inability of any
plasminogen
activator to address the
platelet-rich white thrombus, undermine
the therapeutic efficacy.
Indeed, the data have been mixed or
marginal for the fibrinolytic
approach.
69 Perhaps a key further
explanation is the lack
of attention to relieving microvascular
obstruction, which would
potentially be exacerbated by fibrinolytic
therapy alone. In a recent
experimental stroke model, Choudhri
et al
70 showed marked
sparing of brain infarction and relief
of microvascular obstruction
using a platelet GP IIb/IIIa inhibitor.
Initial
experience with GP IIb/IIIa blockade in acute stroke
management had
indeed been quite favorable.
71 It is likely
that a
combined low-dose fibrinolytic, full–GP IIb/IIIa
blockade strategy
will be useful in achieving brain salvage
in acute cerebrovascular
thrombosis.
|
Acute MI
|
|---|
A major problem in the treatment of acute MI is the potentiation
of
bulk fibrin emboli, which is promoted by either fibrinolytic
therapy
or catheter-based reperfusion therapy. Interestingly,
a recent trial of
stenting compared with balloon angioplasty
showed no improvement in
flow achieved and actually a decrease
for stenting.
72 With
the increased use of stenting as the mainstay
of catheter-based
reperfusion, the problem of emboli of atherosclerotic
gruel in addition
to platelet-thrombus is exacerbated. Use of
improved
antiplatelet therapy, such as that shown with GP IIb/IIIa
inhibition,
40 44 and ultimately the application of emboli
entrapment devices
in this setting can be anticipated. Another
alternative or adjunct
to emboli entrapment may be the use of
ultrasound fibrinolysis
catheters, which can fully
dissolve the coronary thrombus and
reduce the potential of bulk
emboli.
73 Initial results in clinical
trials for improving
myocardial perfusion and regional wall
motion of the infarct zone
beyond conventional therapy are encouraging.
73
With pharmacological strategies, there are intrinsic obstacles that
need to be surmounted. The paradoxical prothrombotic effects of
plasminogen activators set up the potential for
more accumulation of thrombus,74 particularly in the
lower-flow watershed zone of the infarct. The current approaches do not
include any acute platelet- directed strategy except for the modest
effects of chewable or orally administered aspirin. For this reason, we
and others have embarked on a new reperfusion strategy that is
primarily platelet directed75 76 using fibrinolytic
therapy in lower doses as an adjunct. The Global Utilization of
Streptokinase and Tissue Plasminogen Activator
for Occluded arteries (GUSTO-4) 16 600-patient acute MI trial is
currently testing the hypothesis that GP IIb/IIIa inhibition with
abciximab and low-dose reteplase will be superior for survival compared
with conventional reteplase dosing. Pilot studies of the combined
approach are all promising with respect to this revamped approach to
myocardial reperfusion.74 75 76 77 The low-dose fibrinolytic
component may be especially helpful in catheter-based reperfusion to
more directly address the red, fibrin-rich clot component that
otherwise may be part of the embolic burden to the
microvasculature.
Conclusions
Through the development of new imaging modalities and specific
therapeutics that serve as probes, microvascular obstruction, owing to
embolization, has become increasingly recognized as an important
sequelae of atherosclerotic vascular disease. It is likely that all
patients undergoing revascularization, be it
surgical or percutaneous, experience embolization.
Furthermore, clinical presentation of patients with acute
vascular occlusion or ischemia may be the signal that there has
already been embolization. Certain therapies routinely used to achieve
reperfusion, such as fibrinolytics or transcatheter
recanalization, have the potential to induce or
augment microvascular obstruction. Underlying inflammation and
friability of the diseased arterial segment undoubtedly
play a key triggering role. Although recent data have propelled
embolization to the pathophysiological forefront in
atherosclerotic acute ischemic disease states, considerable
investigative work is necessary to prevent or favorably modulate this
process. Recognition of the pivotal importance of microvascular
obstruction should facilitate integrated fundamental and clinical
science to enhance the therapeutic armamentarium in the next century of
managing atherosclerotic vascular disease.
|
Footnotes
|
|---|
Dr Yadav is an inventor of one of the emboli retrieval devices,
and both authors had an equity position in the company (Angioguard)
before its acquisition by Johnson & Johnson.
|
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Introduction
A Change in the...