Case 1 -
Severe Atherosclerosis of the Left Anterior Descending Coronary Artery with Plaque Erosion, Non-occluding Luminal Thrombus and Acute Anterior Myocardial Infarction
James Stone, Mass General Hosp, Boston, MA
Virtual Slides as well as Still Images are displayed below.
For the fastest viewing of virtual slides, click:
under each thumbnail image below. You must have Aperio ImageScope installed on your PC.
Or, click on slide thumbnail images to view each slide
If you do not already have Aperio ImageScope, Windows users with administrator privileges may download and install a free version in order to view USCAP Virtual Slides. Click the icon on the right to get your free copy: ||
in a Web-based slide viewer, which is somewhat slower.
If you have any difficulties viewing these slides, email or call George Clay at +1.724.449.1137.
The patient was 57 year-old man with a past medical history of hypertension and hypercholesterolemia, which were felt to be well controlled by his primary care provider. He was a former smoker, quitting several years earlier. He died unexpectedly in his sleep, two days after complaining of intermittent pain in his upper back between the shoulder blades.
Case 1 - Slide 1
Case 1 - Figure 7
Left anterior descending coronary artery.
Case 1 - Figure 8
Immunohistochemical stains on left anterior descending coronary artery fibrous cap.
Case 1 - Figure 9
Immunohistochemical stains on left anterior descending coronary artery plaque.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
At autopsy there was an acute myocardial infarction dating approximately 2 days in age, involving the
anterior left ventricle and anterior interventricular septum. In the left anterior descending coronary
artery, there was severe stenosis due to atherosclerosis, with an 80% reduction in cross-sectional area.
There was erosion of the surface of the severe atherosclerotic plaque, associated with non-occluding
luminal thrombus. The atherosclerotic plaque at this location showed marked infiltration by
myeloperoxidase (MPO) positive neutrophils and macrophages. Gram and silver stains were negative for
microorganisms. The other organs showed no significant pathologic changes.
Atherosclerosis with plaque erosion
Severe Atherosclerosis of the Left Anterior Descending Coronary Artery with Plaque Erosion, Non-occluding Luminal Thrombus and Acute Anterior Myocardial Infarction.
Myocardial Ischemia and Infarction
Despite significant advances during the last few decades, cardiovascular disease remains the number
one cause of death in developed countries . Reversible myocardial ischemia and irreversible
myocardial infarction result from insufficient circulatory perfusion of the myocardium. This may occur
as a global hypoperfusion, such as in shock, or as a regional defect due to compromise of a specific
coronary artery segment. The location of the myocardial infarction allows the pathologist to correlate
the myocardial changes with the relevant coronary artery feeding that specific region. In the current
case, the identification of an anterior septal / anterior left ventricular myocardial infarction
implicated specific compromise of the left anterior descending coronary artery or its branches.
Myocardial infarcts heal in a specific temporal fashion, which allows the pathologist to estimate the
time interval from the onset of the infarction to the death of the patient . Necrotic muscle,
characterized by hypereosinophilia and loss of nuclei, becomes apparent within the first day and becomes
maximal by two days. Early infarcts, less than 24 hours old can be very subtle on routine hematoxylin
and eosin stained slides, and are easily overlooked. Trichrome staining and immunohistochemical stains
for complement components, such as C4D, can be helpful in identifying these early infarcts. Neutrophils
begin to infiltrate in many cases by one day, but do not reach maximum levels until 3-5 days.
Infiltration by macrophages and removal of necrotic muscle fibers begins at approximately day 5 and peaks
at around 2-3 weeks, at which time granulation tissue is present. This granulation tissue is then
replaced by dense fibrosis or scar over the subsequent few weeks. This defined temporal pattern requires
live vascularized tissue to be present adjacent to the infarcted muscle. It is important to realize that
large infarcts often heal from the outside in, with the center of the infarcts showing delayed healing
and sometimes mummification of the infarcted myocytes, rather than scar formation. In the current case,
there was a moderate neutrophilic infiltrate, which was not yet maximal, indicating the infarction to be
approximately 2 days in age. Thus the onset of the myocardial infarction likely correlated with the
onset of back pain 2 days prior to death.
Coronary Artery Disease
The vast majority of coronary artery disease leading to myocardial infarction is due to
atherosclerosis. Classic risk factors for atherosclerotic coronary artery disease are male gender,
advancing age, smoking, diabetes, hypertension, and hypercholesterolemia. While the current patient did
not have a known history of coronary artery disease, he displayed multiple risk factors including male
gender, age over 50, hypertension, hypercholesterolemia and a history of smoking. Although he had
previously quit smoking, it is important to note that while former smokers have less risk than active
smokers for myocardial infarction, the risk in former smokers remains elevated more than 20 years
following smoking cessation compared with those who have never smoked
This persistent elevated
risk in former smokers may be due to promotion of a premature atherosclerotic burden in those who smoke
. In addition to classic risk factors, serum inflammatory markers, such as C-reactive protein and
MPO, are becoming increasingly recognized as important aids in assessing risk of atherosclerotic coronary
Due to the success of modern medicine, there is a growing list of conditions associated with
accelerated or premature coronary atherosclerosis. These often involve injury to the coronary arteries.
For example, survivors of Kawsaki coronary arteritis are believed to be at increased risk of coronary
artery disease in young adulthood . The same is true of patients who received thoracic irradiation
for malignancy, particularly Hodgkin's lymphoma
While the vast majority of coronary artery
disease is due to atherosclerosis, much less common forms of non-atherosclerotic coronary artery disease
are encountered, and include congenital anomalies, coronary vasculitis , coronary artery dissection
and coronary vasospasm
, of which the latter two may in some cases be related to cocaine
Atherosclerosis and Coronary Artery Thrombosis
In humans, atherosclerosis proceeds though discrete phases. There is an initial phase of vascular
wall activation, characterized by the formation of intimal hyperplasia or intimal thickening
The intimal hyperplasia is largely composed of intimal smooth muscle cells, and typically forms in an
eccentric fashion, indicating an etiological role for variable shear stress. The formation of intimal
hyperplasia is then followed by the development of true atherosclerosis, with deposition of lipid within
the hyperplastic intima, and the infiltration of inflammatory cells, primarily macrophages, which engulf
the lipid to become foam cells . In a fully-formed atheroma, a necrotic lipid core is present, which
is composed of extracellualr lipid and necrotic cells. The portion of the plaque overlying the necrotic
lipid core is referred to as a fibrous cap. An atherosclerotic plaque with a large necrotic lipid core
and thin fibrous cap is often referred to as a thin cap fibroatheroma (TCFA). In contrast,
atherosclerotic plaques with no or small necrotic lipid cores and thick fibrous caps are commonly
referred to as fibrous plaques or thick cap fibroatheromas, respectively.
A key discovery in the field of atherosclerosis research was the demonstration through careful
pathologic studies that in sudden death cases, coronary artery thrombus is usually associated with
disruption of the atherosclerotic plaque surface
These disruptions most commonly occur at sites
of severe stenoses, ≥75% cross sectional area, but may occur at sites with previously only moderate
stenoses. Full thickness breaks in the fibrous cap that overlies the necrotic lipid core, usually in
TCFAs, are referred to as plaque ruptures, while disruptions of just the surface of the plaque, without
full thickness compromise of the cap are referred to as plaque erosions. Both plaque ruptures and plaque
erosions may be associated with either occluding or non-occluding luminal thrombus. Plaque ruptures
account for approximately two thirds of coronary plaque disruptions with plaque erosions account for
approximately one third. Since plaque ruptures are more common than plaque erosions and are often
associated with TCFAs, the TCFA is often referred to as a vulnerable plaque, or plaque that is
susceptible to disruption and coronary thrombosis.
Identifying the specific morphologic changes in atherosclerotic plaques that may promote plaque
ruptures and erosions is an important and challenging endeavor . The prototypic morphology that is
most often presumed to facilitate rupture is the TCFA, in some cases containing increased amounts of
inflammatory cells, the so-called inflamed TCFA. However, most TCFAs in human coronary arteries probably
never rupture or erode. Likewise, macrophages are a common component of most atherosclerotic plaques,
and quantitative studies have not consistently shown differences in the macrophage levels present in
plaques that have ruptured or eroded compared with the macrophage levels in plaques that have not
ruptured or eroded. Furthermore, fatal coronary artery thrombosis does occur in some patients by erosion
of fibrous plaques containing few to no inflammatory cells. These particular cases support the continued
opinions that in some patients, coronary artery thrombosis may be primarily due to factors other than
inflammation, such as endothelial degeneration, intraplaque hemorrhage, or vasospasm .
One line of investigation that has shown some promise recently has focused on the inflammatory cells
that generate MPO, specifically neutrophils and MPO-expressing macrophages. In 2002, it was reported
that eroded and ruptured plaques contain markedly more neutrophils than plaques that had not ruptured or
eroded . Similarly, it has also been reported that MPO positive cells, including both neutrophils
and MPO-expressing macrophages, are more abundant in plaques that have ruptured than in plaque than have
not ruptured . An important question is whether the increased neutrophils and MPO-expressing
macrophages in disrupted plaques is a cause of the disruption, a result of the disruption, or a
non-causative epiphenomenon. However in a recent large series with quantitative assessment of 355
carotid plaques, the degree of neutrophil infiltration was correlated with features often associated with
an unstable plaque, including a large necrotic lipid core and elevated levels of matrix matalloprotease 9
(MMP-9) within the plaque
, suggesting at least that the neutrophils present in the sudden death
cases are not simply a result of the plaque disruption. In the current case it is hard to ignore the
large numbers of MPO expressing cells, both neutrophils and macrophages, in the plaque underlying the
Like many other inflammatory markers, serum MPO levels have been associated with risk of coronary
artery disease . Serum MPO levels have also been shown to predict adverse outcomes in patients with
confirmed acute coronary syndrome , and it has been suggested that elevated serum MPO levels
correlate closely with the presence of coronary plaque erosion in patients with acute coronary syndrome
. However, a recent large multi-center study has shown that serum MPO levels are not useful in
predicting myocardial infarction in the more general population of patients presenting with suspected
acute coronary syndrome . In fact there are currently no serum biomarkers that can adequately
predict the presence of a vulnerable plaque .
Review of the Literature/Treatment Options:
Quest for the Vulnerable Plaque Certainly a key avenue for future advancement will be prospective
longitudinal studies assessing the value of specific plaque features in predicting future acute coronary
events. Given the inaccessibility of coronary arteries for serial pathologic studies, these longitudinal
studies will largely be based on in vivo plaque imaging. Currently more than two dozen different types
of imaging modalities are being assessed for their abilities to ascertain features of coronary plaques
that may indicate susceptibility to rupture or erosion. The ability of these modalities to accurately
identify pathologic changes in plaques has not in all cases been rigorously assessed, and as these
modalities become more widely utilized, it will be necessary for pathologists to identify the limitations
of these techniques, as pathologists previously did with angiography.
Currently intravascular catheter based modalities hold the most promise for identifying specific
pathologic changes in plaques, due to the close proximity of the imaging probe to the plaque allowing for
enhanced spatial resolution. The three most common intravascular catheter based imaging modalities are
radiofrequency intravascular ultrasound (VH-IVUS), optical coherence tomography (OCT), and near-infrared
spectroscopy. Of these techniques, VH-IVUS is the most widely used currently.
In 2011 two prospective studies were published assessing the value of VH-IVUS in predicting acute
These studies were named PROSPECT (Providing Regional Observations to Study
Predictors of Events in the Coronary Tree) and VIVA (VH-IVUS in Vulnerable Atherosclerosis). Both
studies found that plaque burden (>70% cross-sectional area), small residual lumen, and TCFAs were all
associated with major adverse cardiac events (MACE), confirming earlier observations from pathologic
studies. However, in both studies TCFAs were found to be common, and the event rate for TCFAs was
relatively low, only about ~1% per year. However, it should be considered that both of these
studies focused on acute coronary events in symptomatic coronary artery disease patients. Thus, it is
not unlikely that the rate of events for TCFAs in the general population will be even lower. In the
PROSPECT study, TCFAs combined with >70% cross-sectional stenosis and small lumen area were associated
with an event rate of approximately 5% per year. However, TCFAs were only present in 51% of events, and
only 16% of events were attributed to plaques containing all three features.
Currently the predictive value of plaque imaging, in terms of identifying precisely which plaque will
rupture or erode and in which patients, remains relatively poor. However there is great hope that with
refinement, coronary plaque imaging may become highly sensitive and specific for identifying vulnerable
plaques. It will be essential for pathologists to continue to identify specific features of plaques that
may indicate vulnerability to rupture or erosion, and for these features to be assessed for their
predictive value in prospective longitudinal imaging studies.
- Thiene G, Basso C. Myocardial infarction: a paradigm of success in modern medicine. Cardiovasc. Pathol. 2010;19:1-5.
- Fishbein MC, Maclean D, Maroko PR. Histopathologic evolution of myocardial-infarction. Chest 1978;73:843-849.
- Qiao Q, Tervahauta M, Nissinen A, Tuomilehto J. Mortality from all causes and from coronary heart disease related to smoking and changes in smoking during a 35-year follow-up of middle-aged Finnish men. Eur. Heart J. 2000;21:1621-1626.
- Cook DG, Pocock SJ, Shaper AG, Kussick SJ. Giving up smoking and the risk of heart-attacks: a report from the British-Regional-Heart-Study. Lancet 1986;2:1376-1380.
- Cizek SM, Bedri S, Talusan P, Silva N, Lee H, Stone JR. Risk factors for atherosclerosis and the development of pre-atherosclerotic intimal hyperplasia. Cardiovasc. Pathol. 2007;16: 344-350.
- Senzaki H. Long-term outcome of Kawasaki disease. Circulation 2008;118:2763-2772.
- Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: A surgical and autopsy study of 27 cases. Human Pathol. 1996;27:766-773
- Ng A, Abramson JS, Digumarthy SR, Reingold JS, Stone JR. A 56-year-old woman with a history of childhood Hodgkin's lymphoma and sudden onset of dyspnea and shock. N. Eng. J. Med. 2010;363:664-675.
- Stone JR, Stone JH. Vasculitides. in Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 6th edition, Lippincott Williams & Wilkins 2012, Marder VJ, Aird WC, Bennett JS, Schulman S, White GC, Colman RW eds, (in press).
- Basso C, Morgagni GL, Thiene G. Spontaneous coronary artery dissection: a neglected cause of acute myocardial ischaemia and sudden death. Heart 1996;75:451-454.
- Sabatine MS, Jaffer FA, Staats PN, Stone JR. A woman, 3 weeks post partum, with substernal chest paint: Postpartum coronary artery dissection. N. Eng. J. Med. 2010;363:1164-1173.
- Konidala S, Gutterman DD. Coronary vasospasm and the regulation of coronary blood flow. Prog. Cardiovasc. Dis. 2004;46:349-373.
- Stary HC, Blankenhorn DH, Chandler AB, Glagov S, Insull W, Jr., Richardson M, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW. A definition of the intima of human arteries and of its atherosclerosis-prone regions. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1992; 85:391-405.
- Schwartz SM, deBlois D, O'Brien ER. The intima. Soil for atherosclerosis and restenosis. Circ. Res. 1995; 77:445-465.
- Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W, Jr., Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the committee on vascular lesions of the council on arteriosclerosis, American Heart Association. Circulation 1994; 89:2462-2478.
- Chapman I. Morphogensis of occluding coronary artery thrombosis. Archiv. Pathol. 1965;80:256-261.
- Constantinides P. Plaque fissures in human coronary thrombosis. J. Atherosclerosis Res. 1966;6:1-17.
- Friedmam, M., Van den Bovenkamp, GJ. The pathogenesis of a coronary thrombus. Am. J. Pathol. 1966;48:19-44.
- Fishbein MC. The vulnerable and unstable atherosclerotic plaque. Cardiovasc. Pathol. 2010;19:6-11.
- Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J. Am. Col. Cardiol. 2006;47:C13-C18.
- Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos CM, Itoh A, Komatsu R, Ikura Y, Ogami M, Shimada Y, Ehara S, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation. 2002;106:2894-2900.
- Tavora F, Ripple M, Li L, Burke A. Monocytes and neutrophils expressing myeloperoxidase occur in fibrous caps and thrombi in unstable coronary plaques. BMC Cardiovasc Disord. 2009;9:27.
- Ionita MG, van den Borne P, Catanzariti LM, Moll FL, de Vries JPPM, Pasterkamp G, Vink A, de Kleijn DPV. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler. Thromb. Vasc. Biol. 2010; 30:1842-1848.
- Zhang R, Brennan ML, Fu X, et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 2001;286:2136-42.
- Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 2003;108:1440-1445.
- Ferrante G, Nakano M, Prati F, Niccoli G, Mallus MT, Ramazzotti V, Montone RA, Kolodgie FD, Virmani R, Crea F. High levels of systemic myeloperoxidase are associated with coronary plaque erosion in patients with acute coronary syndromes: a clinicopathological study. Circulation. 2010;122:2505–2513.
- Peacock WF, Nagurney J, Birkhahn R, Singer A, Shapiro N, Hollander J, Glynn T, Nowak R, Safdar B, Miller C, Peberdy M, Counselman F, Chandra A, Kosowsky J, Neuenschwander J, Schrock J, Plantholt S, Lewandrowski E, Wong V, Kupfer K, Diercks D. Myeloperoxidase in the diagnosis of acute coronary syndromes: The importance of spectrum. Am. Heart J., 2011;162:893-899.
- Lindahl B. Are there really biomarkers of vulnerable plaque? Clin. Chem. 2012;58:151-153.
- Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N. Engl. J. Med. 2011;364:226-35.
- Calvert PA, Obaid DR, O'Sullivan M, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) study. J. Am. Coll. Cardiol. Img. 2011;4:894-901.