—  SPECIALTY CONFERENCE  —

Cardiovascular Pathology

Case 1 - Acute Plaque Rupture, Right Coronary Artery, with Occlusive Luminal Thrombosis and Acute Myocardial Infarction

Allen P. Burke
Armed Forces Institute of Pathology
Washington, D.C.


Click on each slide thumbnail image for an enlarged view
Clinical History:
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 for review.

Histologic Findings
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.

Discussion
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 atherectomy specimens.

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 coronary syndromes.

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 identify.

Differential Diagnosis
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.

Diagnosis
Acute plaque rupture, right coronary artery, with occlusive luminal thrombosis, acute myocardial infarction, and sudden death

References

  1. MØdet den 26de Marts. Ugeskr Loeg 1844; 10:214-218.
  2. Falk E. Why do plaques rupture? Circulation 1992; 86:III30-42.
  3. Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA 1912; 59:214-18.
  4. Leary T. Pathology of coronary sclerosis. Am Heart J 1934; 10:328-337.
  5. Davies MJ. Anatomic features in victims of sudden coronary death. Coronary artery pathology. Circulation 1992; 85:I19-24.
  6. Burke AP, Farb A, Malcom GT, Liang Y-H, Smialek J, Virmani R. Coronary risk factors and plaque morphology in patients with coronary disease dying suddenly. N Engl J Med 1997; 336:1276-82.
  7. Farb A, Burke AP, Tang A, Liang Y-H, Mannan P, Smialek J, Virmani R. Coronary plaque erosion without rupture into a lipid core: A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996; 93:1354-63.
  8. Virchow R. Die Cellularpathologie in ihrer Begrundung auf physiologische und pathologische Gewebelehre. Berlin: Verlag August Hirschwald, 1858:p. 318.
  9. Ridker P. On evolutionary biology, inflammation, infection, and the causes of atherosclerosis. Circulation 2002; 105:2-4.
  10. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340:115-26.
  11. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105:1135-43.
  12. Kol A, Bourcier T, Lichtman AH, Libby P. Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Invest 1999; 103:571-7.
  13. Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation. Circulation 1993; 87:1179-87.
  14. Galis Z. Molecular mechanisms of plaque weakening and disruption. Cardiovascular Plaque Rupture. New York, N.Y: Marcel Dekker, Inc, 2002:79-121.
  15. Galis ZS. Atheroma morphology and mechanical strength: looks are important, after all--lose the fat. Circ Res 2000; 86:1-3.
  16. Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol 2001; 158:879-91.
  17. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death : A comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20:1262-75.
  18. Burke A, Farb A, Kolodgie FD, Malcom GT, Virmani R. Healed plaque ruptures are frequent in men with severe coronary disease and are associated with elevated total/high density lipoprotein (HDL) cholesterol. Circulation 1997; 96:SI-235.
  19. Burke AP, Farb A, Virmani R. Coronary thrombosis: What's new. Pathol Case Rev 2001; 6:244-252.