Atherosclerosis Pathology

Definition

The term atherosclerosis is derived from the Greek "athero," meaning gruel, or wax, corresponding to the necrotic core area at the base of the atherosclerotic plaque, and "sclerosis" for hardening, or induration, referring to the fibrous cap of the plaque's luminal edge.

The earliest pathologic descriptions of atherosclerotic lesions focused on morphologies of fatty streaks to fibroatheromas (FAs) and advanced plaques complicated by hemorrhage, calcification, ulceration, and thrombosis. In the mid 1990s the terminology used to define atheromatous plaques was refined by the American Heart Association (AHA) Consensus Group headed by Dr. Stary.{{Ref2}

The classification consists of 6 different numeric categories to include early lesions of initial type I, adaptive intimal thickening; type II, fatty streak; and type III, transitional or intermediate lesions; and advanced plaques characterized as type IV, atheroma; type V, fibroatheroma or atheroma with thick fibrous cap; and type VI, complicated plaques with surface defects, and/or hematoma-hemorrhage, and/or thrombosis.

A modified version of the AHA classification was developed by our laboratory to include important pathologic lesions responsible for luminal thrombosis other than plaque rupture, such as plaque erosion and calcified nodule.[1] In this modified classification, numeric AHA lesions types I to IV are replaced by descriptive terminology to include adaptive intimal thickening, intimal xanthoma, pathologic intimal thickening (PIT), and fibroatheroma, as shown in the table below.

Lesion reference to AHA types V and VI was discarded, because it failed to account for the 3 different morphologies (rupture, erosion, and calcified nodule) that give rise to acute coronary thrombosis.

Epidemiology

Coronary artery disease remains the leading cause of death in the Western world. A new or recurrent myocardial infarction afflicts approximately 1.1 million people in the USA per year, of which 40% are fatal. Sudden cardiac death as a first manifestation of the atherosclerotic process occurs in >450,000 individuals annually. The vast majority of acute myocardial infarctions (approximately 75%) occur from plaque rupture; other causes of coronary thrombosis include erosion and calcified nodules.[3]

Although lesions with rupture occur in men of all ages (this is consistent for all plaque morphologies with thrombi), the frequency of sudden coronary death decreases with advancing age. The incidence of rupture varies with each decade, and the highest incidence of plaque rupture is seen in the 40s in men, whereas in women the incidence increases beyond age 50 years. Approximately 80% of coronary thrombi in women older than 50 years occur from plaque rupture, and there is a strong association with circulating cholesterol. In acute myocardial infarction or sudden coronary death, plaque erosion occurs primarily in patients younger than 50 years and represents the majority of acute coronary thrombi in premenopausal women. Furthermore, 20-25% of acute myocardial infarcts occurring in hospitalized patients are due to plaque erosion.

The etiology of atherosclerosis is unknown, but there are multiple factors that contribute to atherosclerotic plaque progression. These include genetic and acquired factors. Processes involved in atherosclerosis include coagulation, inflammation, lipid metabolism, intimal injury, and smooth muscle cell proliferation (see the image below).

Factors that affect these processes may inhibit or accelerate atherosclerosis. The most common risk factors are family history, hyperlipidemia, diabetes mellitus, cigarette smoking, hypertension, and dietary deficiencies of antioxidants.[4] Early lesion development is marked by lipid retention with activation of endothelial adhesion molecules. Inflammatory macrophages play a significant role throughout all phases of atherosclerotic progression; hyperlipidemia-induced macrophage infiltration of the arterial intima is one of the earliest pathologic changes.

A major event in atherosclerotic plaque progression is thrombosis, which may occur in any arterial bed (coronary, aorta, carotid, etc.) Three different morphologies (rupture, erosion and calcified nodule) may give rise to acute coronary thrombosis. Plaque rupture is defined by fibrous cap disruption or fracture, whereby the overlying thrombus is in continuity with the underlying necrotic core. Plaque erosion is identified when serial sectioning through a thrombus fails to show communication with a necrotic core or deep intima; the endothelium is absent, and the thrombus is superimposed on a plaque substrate primarily composed of smooth muscle cells and proteoglycans. Calcified nodules are characterized by eruptive dense calcified bodies protruding into the luminal space and represent the least frequent morphology associated with luminal thrombosis. See the following diagram.
Atherosclerosis occurs in elastic and muscular arteries and may occur iatrogenically in vein grafts interposed in the arterial circulation. The aorta is affected earliest, followed by the carotid arteries, coronary arteries, and iliofemoral arteries. Initially, lesions are most common at branch points, at sites of low shear, where a predilection to plaque formation has been observed. Coronary lesions, including thrombi occuring at atherosclerotic sites, are most prevalent in the proximal coronary arteries: the proximal left anterior descending coronary artery, followed by the right and left circumflex coronary arteries.

Atherosclerosis causes symptoms by arterial obstruction, embolization of plaque material, and weakening with rupture of the arterial wall. Obstruction with or without embolization causes ischemia of the circulation supplied by the vessel. Ischemic strokes result from atherosclerosis of the carotid arteries and aortic arch, which embolize thrombi and atherosclerotic material, as well as local atherosclerosis of the cerebral vessels.

Obstruction of coronary arteries causes myocardial ischemia. Myocardial ischemia may present as acute coronary syndromes (acute ST elevation infarct, non-ST elevation infarct, and unstable angina), sudden death, or chronic congestive heart failure. Obstruction of iliac vessels results in ischemia of the lower extremities (claudication). Atherosclerotic aneurysms show a predilection for the aorta, especially the abdominal aorta. Aortic aneurysms may rupture and cause death by hemorrhage into the retroperitoneal space or pleural cavities, depending on the location.

The gold standard for imaging atherosclerotic lesions of the coronary circulation is angiography. Newer imaging modalities, such as cardiac magnetic resonance imaging (MRI), are being developed that may provide less invasive methods of determining sites of stenosis. Imaging of atherosclerotic lesions of the carotid circulation include carotid ultrasonography, a noninvasive technique.


Gross Findings

In the aorta, atherosclerotic lesions have been classified largely on gross findings. Fatty streaks are yellow, minimally raised lesions that demonstrate abundant lipid when stained with oil red O. Fibrous plaques are raised, white, firmer areas that are relatively well demarcated. Ulcerated plaques demonstrate surface thrombosis and represent ruptured fibroatheromas.

Coronary lesions, when cut on cross-section, show bright yellow cores when there is abundant extracellular lipid, as in fibroatheromas. Ruptured or eroded plaques demonstrate a luminal thrombus, which is pale red or tan in the unfixed state, depending on the proportion of fibrin, platelets, and entrapped red blood cells. Calcified plaques are hard and brittle, are difficult to cute with a scalpel blade, and must be decalcified during or after fixation so that sections for microscopy may be performed.

The gross findings of carotid plaques are similar to those of the coronary arteries. There is often calcification, which can be seen and felt as mineral deposits. Atheromas are bright yellow on cross-section, and atheromas with intraplaque hemorrhage show a more variegated yellow-red cut surface. Fibrous plaques are homogeneous, firm and white, and often show areas of calcification.