Atherosclerosis: Practical Implications for Pathologists
Section 3 -
The Vulnerable Atherosclerotic Plaque - Plaque Complications
Case 2 - The Vulnerable Atherosclerotic Plaque - Plaque Complications
This 74-year-old man presented to emergency with an acute myocardial infarct. He was given
intravenous thrombolytic therapy. Reperfusion changes were noted on subsequent EKG. On the day of
admission he developed back pain and leg weakness. ECHO showed severe left ventricular (LV)
dysfunction. He had worsening pulmonary edema, acute renal failure and his legs became mottled. He
developed paralysis of his legs. Shortly after he had a cardiac arrest.
Findings at complete autopsy: ruptured atherosclerotic plaque
Atherosclerotic Plaque Complications
- Old subendocardial anterolateral left ventricular myocardial infarct (MI)
- Recent transmural inferoseptal left ventricular myocardial infarct
- Reperfusion hemorrhage of infarct identified
- Coronary atherosclerosis - severe stenosis of LAD, Circumflex, and RCA
- Recent plaque rupture and hemorrhage of the proximal RCA
- Severe aortic atherosclerosis with complicated plaques
- Iliac artery aneurysms with thrombosis
- Spinal cord microinfarcts secondary to atheroemboli
Plaque Constituents and Growth
The largest cause of mortality and morbidity in the developed world is ischemic heart disease and this
is mostly due to coronary atherosclerosis. Atherosclerosis also contributes to stroke and peripheral
Atherosclerotic plaques have several major constituents with lipid, extracellular matrix proteins,
including collagen produced by smooth muscle cells, and calcium. The lipid may be extracellular or
intracellular. Mononuclear inflammatory cells including macrophages, lymphocytes, and mast cells are
also present in the plaques. 
The progression of atherosclerosis from the initial fatty streak stage to the well-developed
atheromatous plaque is associated with the appearance and accumulation of extracellular lipid. 
Smooth muscle proliferation also occurs. The lipid core of advanced plaques is separated from the lumen
of the artery by a fibrous or collagenous cap containing smooth muscle cells. The lipid core also
contains mononuclear inflammatory cells and foam cells, which represent lipid-filled macrophages. Some
of the extracellular necrotic debris may result from cell apoptosis including death of the foam cells.
The lipid core is highly thrombogenic containing collagen fragments and tissue factor produced by the
macrophages. Loss of small areas of endothelial covering and small thrombi are very common over plaques
and most of the resultant thrombi probably are asymptomatic, but may contribute to plaque growth.
Intraplaque hemorrhage may also stimulate plaque progression. Erythrocyte membranes from extravasated
erythrocytes may activate macrophages and also may be a source of free cholesterol derived from their
cell membranes. Glycophorin A and iron have been found in necrotic cores and plaques. Iron may cause
free radical damage.
Adverse plaque events are associated with plaques with high amounts of
neovascularization.  This is one of the characteristics of a so called vulnerable plaque, as will be
Plaques vary in morphology with "soft" plaques containing an abundant lipid core and other "hard"
plaques, which are fibrous or fibrocalcific plaques with abundant fibrous tissue and calcium and little
lipid. The plaques with large lipid cores and thin fibrous caps are now being termed vulnerable plaques.
Calcium may occur either as nodular masses within the extracellular lipid or as laminar masses of calcium
or even bone within the plaque connective tissue. The degree of calcification does not appear to relate
to the degree of stenosis. If one looks closely, one can note the presence of osteoclast like giant
cells at the periphery of these laminar calcium deposits. Even osteoblast like cells are noted. The
process of calcification in plaques is now realized to be active, having much in common with bone
Coronary arteries contain plaques at all stages of development. High grade stenotic and occlusive
lesions may develop in arteries previously thought to be normal. It is postulated that plaque
complications may be responsible for disease progression. Plaque progression may be slow with gradual
lipid, smooth muscle cell and extracellular matrix accumulation. Sudden increases in plaque mass are
usually due to plaque hemorrhage, thrombosis or rupture. After plaque complication, vascular healing
occurs with myofibroblast infiltration and subsequent production of collagen.
Underneath the atherosclerotic plaque, the vessel wall adapts to preserve the lumen diameter by
expansion of the blood vessel diameter with medial atrophy. This process, originally described by
Glagov, has been termed positive remodeling.  Glagov demonstrated that the intima had to be
increased by more than 40 % of the original cross sectional area of the vessel before the capacity of the
arterial wall to accommodate the plaque was overcome. The media undergoes atrophy and thinning with loss
of cells. The plaque may even be extruded outward to the adventitia. Grossly, this is reflected by the
vessel appearing to be focally variable in external diameter. As pathologists we note this phenomenon
when we see an enlarged artery in external diameter with no significant stenosis when we look at the cut
cross sections. This remodeling preserves the lumen, and accounts for the fact that angiography may
underestimate the severity of disease. There may be considerable plaque with what appears to be a normal
lumen by the angiogram.
Remodeling may not be totally beneficial, as it appears that the process may weaken the fibrous cap of
the atheroma and weaken the lesion making it more prone to complication, as discussed.  Remodeling
involves reorganization and degradation of the plaque matrix with changes in the activity of matrix
Plaques commonly become symptomatic in two ways: (a) chronic plaque growth with stenosis and
limitation of the heart's blood supply leading to heart failure or chronic stable angina (this may be
accommodated by remodeling), and (b) plaque erosion or rupture with thrombosis leading to an acute
coronary syndrome (coronary insufficiency or unstable angina), sudden death or myocardial infarction.
The Vulnerable Plaque
A plaque may have little luminal stenosis and still be vulnerable to rupture causing an acute coronary
event. Paradoxically many coronary events are associated with complications of an angiographically mild
stenosis. Plaque composition, not size, determines the risk of plaque rupture.
Plaque rupture or deep plaque injury with resulting overlying luminal thrombus is a complication of an
advanced plaque with a lipid core. The plaque fibrous cap tears allowing blood from the lumen to enter
the plaque. The plaque atheromatous material is thrombogenic with lipid, tissue factor, macrophages and
exposed collagen. The exposure of the atheroma contents leads to platelet and coagulation system
activation causing thrombosis. 
The underlying morphology of plaques that have disrupted is "soft plaque" which has a large amount of
extracellular lipid, a thin fibrous cap, decreased number of smooth muscle cells and an increased number
of macrophages in the cap. Thinning of the fibrous cap overlying the lipid core probably precedes its
rupture. Virmani's group has termed these coronary lesions "thin cap atheromas".
probably develop at the junction of the cap with the normal vessel. Eccentric lipid pools are commonly
associated with fissure.
(Modified from reference  )
Features of a vulnerable plaque
- Large lipid core
- Thin fibrous cap
- Low collagen content
- Decreased number of smooth muscle cells
- Chronic inflammation abundant
- Macrophage rich and active
- Mast cells present and active
- T cells at cap
- Increased expression of pro-inflammatory cytokines and procoagulant mediators
- Increased matrix metalloproteinase expression
What Causes Plaques to Rupture?
The exact factors leading to plaque rupture are not known, but external factors including shear
stress, changes in coronary artery pressure and inflammation are postulated. The large lipid pool
underlying a soft plaque may cause poor collagenous support of the overlying cap. 
Inflammation in the plaques is recognized as an important contributing factor for the development and
complications of atherosclerosis.
A marked inflammatory cell infiltrate is a marker of plaque
vulnerability. Factors including lipoproteins, oxidized lipoproteins, infectious agents, and heat shock
proteins may incite a chronic inflammatory reaction in the atherosclerotic plaque.
C reactive protein, an acute phase reactant, has been of recent interest as a marker of risk of
cardiac events, as well as a direct participant in plaque inflammation and instability. Its role as a
serum marker of cardiac event risk seems better established.  Its direct role in the plaque may be
through its effects on complement activation and neutrophilic cytokine mediators.
animal models and using transgenic animal models are contradictory and the verdict is still not decided
on the role of this interesting molecule.
An influx of activated macrophages (which may become foam cells) and T-cells into the plaque follows
with elaboration of cytokines and matrix degrading proteins termed metalloproteinases (MMPs) leading to
weakness of the connective tissue network of the plaque.  Activated T cells may produce interferon
gamma, which inhibits the proliferation of smooth muscle cells and collagen synthesis thus contributing
to plaque vulnerability. Metalloproteinases are a family of proteolytic enzymes that degrade various
components of the extracellular matrix. Inflammatory cells may also release mediators such as tissue
factor that are thrombogenic. The inflammatory cells promote the atherosclerotic process and the
development of a lesion that is prone to complication.
Mechanical stress may also play a role in plaque rupture. The irregularity of plaque shape and the
presence of a lipid core may result in uneven distribution of wall tension along the arterial wall, with
areas of increased stress at certain points.  The thinner the cap, the less able it is to withstand
chronic or progressive wall stress. Sudden accentuation of stress may cause plaque rupture. The
shoulder of the plaque has been found to have the highest concentration of stress and it is this region
of the plaque cap where the cap tears and plaque rupture commonly are noted at autopsy.
Rupture may occur spontaneously or be triggered by certain events including emotional stress or
physical activity. A rise in sympathetic activity with an increase in blood pressure, heart rate, force
of cardiac contraction and coronary blood flow may contribute to plaque disruption. Coronary vasospasm
may also contribute.
Fate and Course of Plaques that Rupture
Rupture or ulceration of the luminal surface of a plaque may expose thrombogenic substances inducing
thrombus, or discharge debris into the bloodstream producing cholesterol or atheroemboli. Hemorrhage
into the plaque may occur from rupture of the fibrous cap or from rupture of the thin walled capillaries
in the plaque. Intra-plaque hemorrhage may lead to plaque rupture, but not necessarily so. With rupture
and thrombosis the media may also spasm due to vasoconstrictor stimuli. This may be especially important
in eccentric coronary plaques where there is a segment of the arterial circumference that has no plaque
and thus can spasm. 
The repair process following plaque disruption is complex with a wide range of outcomes. Spontaneous
lysis of the thrombus may restore the lumen. The thrombus may be invaded by endothelial cells and smooth
muscle cells converting the thrombus into collagenous tissue. The plaque mass may increase or the vessel
may recanalize. Plaques may contain fibrin, fibrinogen and fibrin degradation products. Regardless of
whether there is clinical ischemia or not, organization of the thrombus may lead to plaque growth.
The presence of a residual thrombus increases the chance of recurrent thrombosis as the residual
thrombus may encroach on the lumen resulting in an increased shear, thus activating platelets. Thrombus
material is also a potent thrombogenic surface. 
Plaque Erosion and Calcified Nodules - The Other Vulnerable Plaques
Coronary thrombosis may occur without plaque rupture, although this is less common.
Plaque erosion or calcified protruding vascular nodules have been described in individuals with sudden
death.  Plaque erosion is caused by thrombus deposition on what morphologically appears to be an
intact plaque. The endothelium may be denuded or dysfunctional causing platelet adhesion on the surface
of the plaque. Plaque erosion has been mainly described in young female smokers with sudden death. 
Farb and colleagues have shown that erosions and thrombus can develop in plaques that are relatively rich
in proteoglycan matrix and smooth muscle cells and that lack a superficial lipid core. These plaques
often have little calcium and inflammation.
It has been postulated that severe endothelial
apoptosis with cell death and thrombotic tendency or repetitive vasospasm (exacerbated by smoking) may
explain plaque erosion.  To diagnose plaque erosion it is important to cut levels through the
lesion so as not to miss an adjacent plaque rupture with luminal thrombus.
Calcified nodules with non-occlusive thrombi that protrude into the vascular lumen have also been
described as a coronary lesion associated with sudden death.  These have little lipid core and occur
in the absence of an erosion or ruptured plaque. Their clinical onset is not well understood yet.
Clinical consequences of plaque rupture
Plaque rupture and thrombosis may lead to unstable angina, myocardial infarction or sudden death. If
flow is adequate and thrombolysis active, a small thrombus may be clinically silent. Indeed, small
plaque disruptions are noted in about 8 % of patients dying of non-cardiac causes. The incidence is
higher in patients with diabetes or systemic arterial hypertension. 
The resolving thrombus may lead to a reduction in perfusion causing myocardial infarction or the
development of unstable coronary syndrome (also termed an acute coronary syndrome - ACS). The extent of
organ injury depends on the size of the artery, the duration of occlusion, the presence of collateral
flow and the integrity of the fibrinolytic system. In unstable angina and non-Q wave infarcts (now
termed NSTEMI - non-ST elevated myocardial infarctions), the disrupted plaque leads to a labile thrombus
and platelet activation with transient vessel stenosis. In Q wave myocardial infarcts (now termed
STEMIs) the plaque disruption results in deep arterial injury and the formation of a fixed persistent
thrombus resulting in cessation of blood flow thus resulting in myocardial necrosis.  The underlying
coronary lesion is often only mildly stenotic and there is thus little collateral flow - hence the
Fate of the Vulnerable Plaque
(Modified from reference 
Practical Considerations for the Pathologist
At autopsy or with a surgical specimen it is recommended the arteries be decalcified and the vessels
cross cut. Opening the vessels along the long axis cannot be recommended. The vessels should be cross
cut at 2-3 mm intervals and "red" lesions and significantly stenotic lesions should be examined by
microscopy. Plaque erosions and ruptures should be sampled by this method.
The myocardium should also be carefully examined for microemboli of fibrin platelet thrombus material
and atheromatous plaque constituents such as cholesterol and calcium. Occasionally the clinicians refer
to a "no reflow" state after they have successfully opened an artery with thrombolytics or by a catheter
procedure. In these cases the pathologists should assess the small vessels of the myocardium for
displaced plaque constituents and thrombus that has fragmented and ended up in the intramyocardial
vessels. Capture devices are now used to minimize this.
Does the Coronary Angiogram Reflect Plaque Risk? Imaging Considerations
Evidence challenges the notion that the number of severely stenotic lesion on an angiogram
is a predictor of future cardiac events. Unfortunately plaques that are noted to be only mild to
moderately stenotic on angiography are frequently those that undergo abrupt disruption leading to angina
or myocardial infarct. Severely stenotic plaque lesions often have collaterals, whereas an acute plaque
complication in what was only a mildly stenotic plaque may have little collateral development and thus
the event may be serious.
In a study of patients with unstable angina who underwent sequential angiograms, 72 % of the lesions
that progressed had stenosis of less than 50 % on the first angiogram.  Little and colleagues
studied 42 patients who underwent coronary angiography before and up to a month after having myocardial
infarction. They concluded that most of the infarcts resulted from coronary occlusions that had
previously shown less than 50 % stenosis at angiography. 
Angiography is still considered to be a useful modality for the evaluation of the degree of coronary
atherosclerosis, but has many apparent limitations:
Angiography cannot accurately predict the site of future coronary plaque events as these events are
highly unpredictable and many complications result from disruption of only mildly stenotic plaques. The
number of plaques may be more important as far as risk of future events and prognosis, than the severity
of stenosis demonstrated on angiogram.
- A lesion with less than 50 % stenosis is capable of progression with
severe clinical consequences;
- Parts of the coronary arteries that appear normal may be used as a
reference for assessment of the severity of coronary lesions, but this may underestimate the disease if
the plaques are diffuse;
- The physiological effect of coronary artery obstructions cannot be
- Vascular remodeling with plaque enlargement preserves the luminal
area despite extensive atheroma. This can cause under-estimation of the disease.
We are moving from a question of how tight are the stenoses we see? To how active and how many
plaques are there that we do not see?  Imaging studies are evolving to reflect this and better
predict the risk of events. Functional studies and morphology imaging for prediction of potential
vulnerability are being studied for their utility.
Intravascular ultrasound (IVUS) is now
available to image the plaques from within the coronary artery at the time of catheterization. It is
accurate for determining the degree of stenosis and also characterizing the plaque and stratifying its
risk of rupture or complication.
Multislice CT scan may image the arteries and provide a calcium score, which may be prognostic. 
Bypass grafts are very well imaged. Myocardial function and ventricle wall abnormalities may be studied
with CT or MRI. Dense calcified plaques and stents are poorly imaged. In a patient being evaluated or
screened for the possibility of coronary disease, a negative examination is probably the most valuable
information that can be established. 
Other potentially interesting imaging modalities include MRI scan, direct angioscopy with optical
coherence tomography, thermography (more inflamed plaques = higher temperature), Raman spectroscopy for
determining plaque composition, intravascular MRI (regular MRI with an intravascular coil or a MRI
catheter with magnet and coil together).
Metabolic imaging with detection of plaques by detecting metabolic activity is a novel area. Such
studies could detection of high risk plaques, allow personalized molecular based therapy and also act as
an imaging endpoint to assess other medical therapy.  Imaging of protease activity, cell surface
receptors, oxidative stress, and other metabolic activities have been investigated. Nanoparticles of
iron labeled with dextran are taken up by macrophages and can be imaged. FDG and PET can detect glucose
uptake in macrophages. Iodine labeling of MMPs is possible. Technetium labeled LDL can be utilized and
Annexin V can detect apoptosis. VCAM and beta integrins have been attached to nanoparticles to assess
In the future we may screen individuals with serum endothelium cell activation markers and markers of
inflammation and then later identify vulnerable plaques by imaging. This will include a hybrid of more
conventional imaging modalities to provide an anatomical index of plaque burden and ventricular function,
followed by metabolic imaging to detect plaque vulnerability.
The question is what to do with the information? If we detect these local non-critical stenotic
lesions, some of which will show "vulnerable morphology", it is not clear what should be done with these
plaques. At the Ottawa Heart Institute many clinicians faced with these findings are aggressively
lowering the patient's lipids, but it is recognized there is no supporting data for this.
Primary and secondary prevention are important for prevention of the initial plaque masses and
subsequent stabilization of plaques. Clearly primary prevention is preferable.  In utero factors
may actually influence future adult atherogenesis. Maternal hypercholesterolemia and being an infant of
low birth weight both have been found to be predictive of future atherosclerosis.  Systemic
inflammation may have an effect on the plaque vulnerability by mediators such as C reactive protein
(CRP). Infectious agents such as Chlamydia may be present in the plaque foam cells or may
non-specifically activate a stable plaque via the systemic inflammatory process associated with the
infection.  Coagulation abnormalities may contribute to plaque complications, and obesity and
diabetes are pro-inflammatory states.
We should be thinking in terms of the vulnerable individual rather than
just a vulnerable plaque. Individuals at risk may have many vulnerable lesions that are prone to
activation.  Studies have demonstrated that individuals suffering an acute coronary event may have
widespread multifocal coronary arterial inflammation. 
The "vulnerable patient" may have multiple vulnerabilities including:
Lipid lowering therapy with statin medications (3-hydroxy-3-methylglutaryl-coenzyme A
reductase inhibitors) has many effects thought to stabilize a plaque.
 These include reduction in
the proteolytic activity of macrophages, increased plaque collagen content, reduction of the size of the
lipid core, reduction in the degree of inflammation, decreased C-reactive protein, restoration of
endothelial function (increased nitric oxide and decreased thromboxane), and a decrease in tissue factor
expression thus decreasing propensity for thrombosis.
Repression of MHC-II expression,
blockage of LFA-1 / ICAM-1 (leukocyte function antigen -1) / ICAM-1 (intercellular adhesion molecule 1)
interaction and inhibition of CD40-CD40L signaling are all molecular mechanisms that have been described
to explain the pleiotropic effects of the statins 
- vulnerable plaques/ arteries,
- vulnerable blood (prone to thrombosis), and
- vulnerable myocardium (prone to arrhythmia).
Plaques may be stabilized by these medications and thus it is not surprising that in the clinical
trials designed for lipid lowering, one of the unexpected observations was the occurrence of less
coronary events in the treated patients. Statins may slow plaque progression and may promote regression.
After statin treatment carotid plaques studied had less lipid, less macrophages, less
oxidized LDL, decreased number of T lymphocytes, more collagen and decreased matrix metalloproteinase
activity.  More aggressive cholesterol lowering using statin drugs in appropriate at risk patient
populations is now recommended.  Whether statins will be used for individuals with normal
cholesterol levels remains to be seen. Stains also have beneficial effects in multiple sclerosis, stroke
and in reducing the risk of colon carcinomas.
Future possible strategies to stabilize plaques include over-expression of inhibitors of MMPs,
anti-sense strategies to block pro-inflammatory molecules, over-expression of nitric oxide or
prostacyclin synthetase to help with endothelial dysfunction and the associated pro-coagulant state.
 Some have proposed a controlled disruption of vulnerable plaques by angioplasty, well controlled
with thrombolytics. Heat, ultrasound and cryoablation could also disrupt plaques. It is postulated that
the healed plaque would be more stable than a lipid rich thin cap one. Photodynamic sealing using a
photosensitizing agent attached to macrophages could be used to decrease the macrophage load in plaques.
 Such interventions are still theoretical.
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