A 60 year old white male, 5'11", 180 lbs., complained of chest pain one day prior to being found
unresponsive on the ground in front of his home. He had a history of thyroid problems, asthma, and
recent sinus infection. He was taking anti-allergy medicines [Advair Discus (fluticasone/salmeterol),
Allegra-D (fexofenadine & pseudoephedrine), Atrovent (ipratropium bromide), Nasonex (mometasone
furoate), and Singulair (montelukast)], an antibiotic [Cefzil (cefprozil)], and Synthroid
(levothyroxine). At autopsy, his heart weighed 400 grams; the foramen ovale was probe patent; left
ventricular chamber dimensions were normal; there was mild right ventricular hypertrophy (6 mm thick at
posterior wall); and there were focal myocardial scarring and hyperemia in the posteroseptal left
ventricle and posterior right ventricle. A section of the proximal right coronary artery is available
The myocardial sections demonstrated acute myocardial infarction (Figure 1). The coronary artery section
(proximal right coronary artery) demonstrated a large lipid-rich plaque with necrotic core and
intraplaque hemorrhage and occlusive luminal thrombus (Figure 2). The cross sectional area luminal
narrowing was approximately 75%. At the site of plaque rupture, there was marked thinning of the fibrous
cap with foam cell macrophage infiltrates (Figure 3).
Slide 1 - Acute myocardial infarct, posterior left ventricle
Slide 2 - Proximal right coronary artery, low magnification (Movat pentachrome stain)
Slide 3 - Higher magnification, demonstrating disruption of thinned fibrous cap, infiltrated by foamy macrophages.
Fatal plaque rupture was first described in 1844 in a Danish newspaper and subsequently that year in the
Journal of the Danish Medical Association1. A famous sculptor, Bertel Thorvaldsen, died
suddenly at the age of 73 years. He was autopsied at his home, with the finding of "several atheromatous
lesions, of which a rather significant one was ulcerated and the atheromatous mass extruded into the
arterial lumen."2 After this case report, in the first half of the twentieth century, the
importance of plaque rupture as a cause of coronary thrombosis was emphasized by Herrick3 and
subsequently Leary4. Currently, plaque rupture is generally regarded as the most important
substrate for occlusive coronary thrombosis and an important cause of atherosclerotic sudden
death5. In large series of sudden coronary death, plaque rupture accounts for approximately
65-75% of mural thrombi, and at least 50% of cases of sudden coronary death6, 7.
Because of the importance of plaque rupture, triggers of plaque disruption have been extensively
studied. Humoral triggers may include stress-related conditions and sympathetic activity, circulating
inflammatory substances, exertion, and activated circulating inflammatory cells. Factors related to the
plaque itself are generally divided into two categories. Structural features, such as core size,
positive remodeling, relation to branch points and other determinants of shear stress, and cap thickness
have been studied in relation to plaque disruption and biomechanical forces. The other feature, which
will be emphasized in this discussion, is the presence of inflammatory cells in the fibrous cap.
Inflammation has been recognized since the descriptions of Virchow as an important histologic feature
of atherosclerosis. The term "Grutzbalg", akin to a cutaneous abscess, was used by Virchow to describe
plaques with imminent rupture8. Recently, Ridker emphasized the historical human requirements
of enhanced inflammatory function to ward of epidemics and cellular metabolism in times of famine, and
how glucose intolerance and inflammation as risk factors for atherosclerosis have an evolutionary
basis9. To this may be added a pro-thrombotic tendency, another pillar of atherosclerotic
etiology, as trauma was an important cause of mortality in evolutionary times. There is a complex
interplay between inflammation, thrombosis, intimal smooth muscle cell proliferation, and endothelial
activation and atherogenesis. The role of inflammation in this process has been reviewed extensively by
Russell Ross10 and Peter Libby11, among other investigators.
Virtually all types of inflammatory cells have been described in the atherosclerotic plaque.
T-lymphocytes and macrophages have been most extensively studied as elaborators of inflammatory cytokines
and smooth muscle cell mitogens. Mast cells are present both in the adventitia as well as intima, and
may be associated with vasospasm. The roles of antigen-presenting cells and B-cells are only beginning
to be investigated, and the importance of neutrophils and plasma cells, historically ignored or
overlooked, have yet to be elucidated. The presence of infectious agents or their proteins, especially
Chlamydia pneumoniae, has been extensively reported within atherosclerotic
plaque12, although the alterations of the immune atherosclerotic response and their
relationship, if any, to chronic infection is far from clear.
In the case of plaque rupture, several features of the local immune response are important in thinning
of the fibrous cap and ultimate rupture and thrombosis. A common mechanism of disruption of the fibrous
cap atheroma occurs via the thinning and weakening, of the fibrous cap, resulting in breaks exposing
tissue factor to the lumen, luminal thrombosis, vasospasm, and embolization. A definition of thin
fibrous cap, or "vulnerable plaque," was published in 1997 and was quantitated as 65 microns or
thinner6. Computerized reconstruction of simulated and histologic sections of real plaques
suggest that stress may be concentrated at critical points in the cap, and that computed high-stress
points in the shoulder region of the cap correlate with sites of rupture found at autopsy13.
Local changes in the amount of collagen, including the thinning of the cap's collagen may occur due to an
imbalance between its synthesis and its breakdown. Zorina Galis has extensively studied the role of
matrix metalloproteases (MMPs) in collagenolysis within the fibrous cap14, 15.
Over-expression of several MMPs has been detected in the vulnerable shoulders of human atheroma.
Furthermore, in situ matrix degrading activity was demonstrated within the plaque shoulders, providing
mechanistic support for the idea that MMPs may precipitate plaque destabilization through matrix
weakening. Discovery of MMP activity also suggested the local imbalance between the levels of active
MMPs and those of their natural inhibitors, TIMPs, which characterize non-diseased arterial tissue. The
breakdown of collagen in the fibrous caps of human atheroma in ex vivo conditions has been attributed to
MMP activity associated with macrophage-derived foam cells. Due to their multiple modes of involvement,
macrophage foam cells, a major characteristic of unstable plaques, have emerged as a key element in
MMP-dependent degradation of plaque matrix. These cells have the capacity to produce several MMPs,
including MMP-1, MMP-3, MMP-7, and MMP-9, specifically associated with unstable angina in coronary
In addition to MMPs, there are other potential mediators of collagen breakdown within the fibrous.
Myeloperoxidase-expressing monocytes are present within the fibrous caps of plaques that have ruptured,
and may be etiologically important16. Increased numbers of MPO containing monocytes are also
present within the thrombi overlying disrupted plaques, and serum levels of MPO are altered in acute
The fate of plaque rupture is not always occlusive thrombus and sudden death or myocardial
infarction17. It has been appreciated for some time that not all plaque disruptions result in
clinical symptoms or myocardial necrosis. Detailed studies of the coronary tree in patients with severe
atherosclerosis will frequently demonstrate incidental fissures and small ruptures. Morphometric studies
of acute and healed plaque ruptures, together with cell proliferation markers, have demonstrated that
plaque rupture with healing is a mechanism of plaque enlargement18. Plaque ruptures are
identified morphologically by the presence of a break in the fibrous cap, surrounded by granulation
tissue with overlying organized thrombus. Special stains for collagen, such as picrosirius red viewed
with polarized light, are helpful to identify the prior break in the fibrous cap. Although healed plaque
ruptures are a form of stable plaque and do not result in acute coronary syndromes, they are associated
with similar risk factors as are acute ruptures, and are important for the autopsy pathologist to
The second most common form of coronary plaque thrombosis is the plaque erosion19. More
recently described than plaque rupture, plaque erosion is an often-overlooked cause of sudden death in
young men and women accounting for about 35% of fatal coronary thrombi6, 7. Because the
protective effects of the pre-menopausal state apply only to plaque rupture and its variants, and not to
plaque erosion, a high proportion of sudden coronary death in young women are due to plaque erosion.
There are several features of plaque erosion that are distinct from plaque rupture. Plaque erosion is
uncommon after age 50 and typically does not have a prominent necrotic core, in contrast to plaque
rupture. Plaque erosion is characterized by lesser degrees of calcification and overall plaque burden.
Histologically, plaque erosion shows a denuded endothelial surface with luminal thrombus. The plaque
underlying the thrombus is rich is proteoglycans and smooth muscle cells; there is often a small lipid
core near the internal elastic lamina, but prominent cholesterol crystals and hemorrhage into plaque are
absent. In contrast to plaque rupture, plaque erosion does not have a strong association with
hypercholesterolemia. It is likely that pro-thrombotic states and vasospasm play a more important role
in the pathogenesis of erosion as compared to rupture, although the etiology is still unknown.
Acute plaque rupture, right coronary artery, with occlusive luminal
thrombosis, acute myocardial infarction, and sudden death
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- Falk E. Why do plaques rupture? Circulation 1992; 86:III30-42.
- Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA 1912; 59:214-18.
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- Burke AP, Farb A, Malcom GT, Liang Y-H, Smialek J, Virmani R. Coronary risk factors and plaque
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- Kol A, Bourcier T, Lichtman AH, Libby P. Chlamydial and human heat shock protein 60s activate human
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- Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured
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- Galis ZS. Atheroma morphology and mechanical strength: looks are important, after all--lose the
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- Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, Libby P. Macrophage myeloperoxidase
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- Burke A, Farb A, Kolodgie FD, Malcom GT, Virmani R. Healed plaque ruptures are frequent in men with
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