—  SPECIALTY CONFERENCE  —

Cardiovascular Pathology

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





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Clinical History
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
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Case 1 - Figure 1
Anterior view of the heart.
Case 1 - Figure 2
Cross section of the formalin-fixed heart.
Case 1 - Figure 3
Anterior interventricular septum.

Case 1 - Figure 4
Anterior interventricular septum.
Case 1 - Figure 5
Left anterior descending coronary artery.
Case 1 - Figure 6
Left anterior descending coronary artery.

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.

Differential Diagnoses:
Atherosclerosis with plaque erosion

Final Diagnosis:
Severe Atherosclerosis of the Left Anterior Descending Coronary Artery with Plaque Erosion, Non-occluding Luminal Thrombus and Acute Anterior Myocardial Infarction.

Case Discussion:

Myocardial Ischemia and Infarction
Despite significant advances during the last few decades, cardiovascular disease remains the number one cause of death in developed countries [1]. 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 [2]. 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 [3, 4]. This persistent elevated risk in former smokers may be due to promotion of a premature atherosclerotic burden in those who smoke [5]. 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 artery disease.

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 [6]. The same is true of patients who received thoracic irradiation for malignancy, particularly Hodgkin's lymphoma [7, 8]. 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 [9], coronary artery dissection [10, 11], and coronary vasospasm [12], of which the latter two may in some cases be related to cocaine use.

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 [5, 13, 14]. 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 [15]. 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 [16, 17, 18]. 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 [19]. 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 [20].

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 [21]. 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 [22]. 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 [23], 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 erosion.

Like many other inflammatory markers, serum MPO levels have been associated with risk of coronary artery disease [24]. Serum MPO levels have also been shown to predict adverse outcomes in patients with confirmed acute coronary syndrome [25], 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 [26]. 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 [27]. In fact there are currently no serum biomarkers that can adequately predict the presence of a vulnerable plaque [28].

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 coronary events [29, 30]. 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.

Conclusion(s):
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.

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