Stages of Atherosclerotic Plaque Progression: Atheromatous versus Nonatheromatous

The heterogeneity of coronary atherosclerotic plaques is characterized by two major mechanisms of plaque progression: atheromatous, which is the most common, and relatively non–lipid-rich, or nonatheromatous. In most men, and men and women older than 50 years, atheromatous plaques dominate in most coronary lesions. In younger patients, especially women, obstructive coronary disease may occur in the absence of significant cell death and necrotic core formation. The identification of the two types of plaque is crucial if imaging techniques evolve that specifically target the identification of lipid-rich necrotic core.

Atheromatous Plaque Progression

The classic stages of plaque progression, as defined by the American Heart Association (AHA), involve the formation of the necrotic core. A more recent modification of this staging schema³ outlines development of atheroma. The normal human intima contains a small cushion of smooth muscle cells and matrix, which is present from birth and accentuated at branch points; this lesion has been termed adaptive or diffuse intimal thickening. Later in life, with intimal injury, there is influx of lipids, much of which is oxidized; at this stage (pathologic intimal thickening), there is typically influx of small numbers of foamy macrophages, generally luminal in location to the lipid pools. The progression of the pathologic intimal thickening to fibroatheroma (AHA class II-III) is key in the development of lipid-rich plaques that result in symptoms owing to tendency to rupture and thrombose. The features of fibroatheroma include a core of necrotic material (Fig. 51-1), which is composed of apoptotic cell debris–derived smooth muscle cell membranes, macrophages, and red blood cells. Much current imaging technology is focused on the identification of necrotic material because this is the precursor lesion of the most common substrate for coronary atherothrombosis.

FIGURE 51-1 Atheromatous plaque progression. A, Thin cap atheroma, with a necrotic core (NC) characterized by cholesterol clefts (free cholesterol). B, Higher magnification of the thin cap, with numerous foam cells and portions of cholesterol crystals at the top of the image. C, Large necrotic core (NC) with abundant intraplaque hemorrhage and luminal thrombus (Th). D, Higher magnification of the rupture site. CC, cholesterol crystal (cleft); NC, necrotic core; TC, thin cap; Th, thrombus.

Thin Cap Atheroma and the Vulnerable Plaque

The expansion of the atheroma, or necrotic core of the lipid-rich atherosclerotic plaque, results in thinning of the overlying fibrous cap (see Fig. 51-1). An arbitrary fibrous cap thickness of 65 µm has been designated as the criterion for the “vulnerable” plaque or thin cap fibroatheroma.⁴ The characteristics of thin cap atheroma that render it prone to rupture are unknown, but likely involve physical factors, such as size of the necrotic core, and biologic factors, such as proteolytic enzyme activity within the thinned cap. The goal of imaging to detect thin cap fibroatheroma and distinguish it from fibroatheroma with thicker caps remains elusive, but may eventually enable the prophylactic treatment of lesions prone to rupture with the aim of preventing atherothrombosis.

Nonatheromatous Plaque Progression

In autopsy studies, approximately 15% of patients who die of coronary artery disease (CAD) lack lipid-rich atheromatous lesions. Nevertheless, these patients develop significant luminal narrowing, and luminal thrombus may occur by mechanisms other than rupture of the thin fibrous cap. The major alternative mechanism of atherothrombosis (Fig. 51-2), termed plaque erosion, is of unclear etiology.⁵ Erosion may result from endothelial injury that results directly in thrombosis, either via coronary spasm or via interaction with matrix receptors. Because plaque erosion thrombi may be small and nonocclusive, they result in layering of smooth muscle cell–rich plaque that expands without a requisite necrotic core, often with little outward expansion (positive remodeling). Although the goal of imaging remains the detection of lipid-rich plaques, a subset of potentially lethal lesions are not detected by modalities that target lipid.

FIGURE 51-2 Nonatheromatous plaque progression. A, Significant stenosis with areas rich in extracellular lipid (clear areas), which is composed largely of esterified cholesterol and phospholipid, but no necrotic core formation. B, Significant stenosis without abundant lipid (from the same patient). C, Thrombus overlying a smooth muscle cell–rich plaque, with cleared areas indicative of lipid pools (pathologic intimal thickening), but little or no necrotic core formation. D, Higher magnification of the plaque erosion, showing the platelet-rich thrombus in the lumen.

Life Cycling of the Atherosclerotic Plaque

Because coronary imaging seeks to identify lipid-rich plaques, especially plaques with large necrotic cores, mention of the life cycle of lipid-rich lesions and the effect of successive ruptures on plaque composition is relevant. One outcome of plaque rupture, after slowly enlarging core and thinning of the fibrous cap, is occlusive thrombus that organizes as a total occlusion and results in acute coronary syndrome. Much more common after acute rupture is a subocclusive thrombus with healing. The outcome of subocclusive plaque rupture is often plaque enlargement and outward expansion (remodeling) of the arterial wall. The thickening of the fibrous cap that occurs after healed rupture is roughly represented by the AHA class V plaque. Autopsy studies have shown multiple old rupture sites at sites of acute rupture, resulting in compartmentalization of the plaque into areas of lipid core and fibrous healing.⁶ The site of future rupture may not have a single large lipid compartment, but a heterogeneous makeup that includes fibrous tissue. The consequences for imaging are unclear at this time.

Calcification and Coronary Atherosclerosis: Implications for Imaging

Calcification is a reliable marker for the presence of atherosclerotic plaque because there are no other processes in the coronary arteries that result in calcium deposition. Calcium scoring is a reliable marker for atherosclerotic plaque burden, although in younger patients severe obstructive lesions can occur in the absence of any calcification (see Chapter 32). Calcification is not a marker of plaque instability, however. Solid calcification can be the result of diffuse deposition in fibrous tissue in stable plaques, whereas more stippled calcification, reflective of necrotic core calcification in more heterogeneous plaques, may be more suggestive of an unstable plaque.⁷

Clinical Presentation

The major clinical presentations of coronary atherosclerosis are stable angina, acute coronary syndromes (ST segment elevation MI and non–ST segment elevation MI), congestive heart failure, and sudden death. Acute coronary syndromes are discussed Chapter 52. Coronary lesions in sudden death are quite heterogeneous because the mechanisms of ventricular arrhythmias vary. In stable angina, there is generally stable plaque with significant obstruction, whereas unstable syndromes are characterized by intraluminal thrombus. In unstable angina or non–ST segment elevation MI, typically nonocclusive thrombi are present, whereas ST segment elevation MI is associated with larger, often occlusive thrombi. Coronary artery lesions in ischemic cardiomyopathy are typically diffuse and multiple, and there is significant myocardial damage generally with transmural healed MI.

Imaging Indications and Algorithm

Currently, angiography is the gold standard for imaging atherosclerotic coronary disease, and other imaging techniques are investigational. CT scanning for coronary calcium is used as identification for coronary risk (see Chapter 32), and IVUS is indicated for the evaluation of graft vascular disease in heart transplant recipients.

The indication for coronary angiography varies by clinical setting. The AHA has set forth algorithms for coronary angiography that are stratified by specific patient groups.⁸ Patients in whom coronary arteries should be evaluated by angiography include patients with symptoms of stable angina, nonspecific chest pain, unstable angina, recurrence of ischemia after revascularization, and acute MI, and patients undergoing perioperative risk assessment for noncardiac surgery. Patients with valvular heart disease in whom surgery is contemplated, patients undergoing cardiac surgery for other indications including congenital heart disease, and patients with unexplained congestive heart failure may also be candidates for coronary angiography. There are no currently accepted indications for coronary artery imaging other than angiography, although noninvasive modalities, especially multislice CT, are on the brink of being established as a viable option for the identification of coronary artery stenoses (see later).

Imaging Technique and Findings