Evaluating Carotid Plaque and Carotid Intima-Media Thickness

Introduction

The ultrasound evaluation of carotid artery atherosclerosis has evolved over the years. At the start, B-mode (gray-scale) images were used to evaluate the severity of carotid artery disease in the hope of supplementing traditional arteriography. Unfortunately, it became apparent that at higher degrees of stenosis the diagnostic accuracy of B-mode images was insufficient to estimate fully the severity of carotid artery stenosis. This held true when B-mode images were correlated against arteriographic examinations and pathology specimens. The major problem was the inability to visualize fully the echolucent (hypoechoic or low echo intensity) components of plaque. Continuous wave Doppler and duplex ultrasound were better at estimating high degrees of stenosis severity than B-mode images alone. Since then, technological innovations and the use of higher frequency transducers have improved visualization of the echolucent components of plaque. In addition, color Doppler, power Doppler images, and B-flow images have helped outline the echolucent components of plaques ( Fig. 6.1 ).

FIG. 6.1, (A) This gray-scale image shows a solitary echogenic plaque ( large arrow ). (B) Color Doppler image with spectral Doppler sampling distal to the echogenic plaque shows the large echolucent component to the plaque causing a 50% to 69% stenosis with peak systolic velocity of 218 cm/s ( small arrows ). (C) B-flow image confirms the extent of the hypoechoic component of this plaque.

While researchers were concentrating on characterizing plaques by ultrasound, another ultrasound manifestation of carotid atherosclerosis was discovered. In 1986, Pignoli et al. reported that a diffuse form of wall thickening, the intima-media thickness (IMT) of the aortic and the common carotid artery walls, was linked to atherosclerosis. With this discovery came the realization that B-mode ultrasound images showed the combined wall layers from the lumen to the external elastic lamina (intima and media) and that a separate measurement of the intima thickness, the site of plaque on pathology specimens, was not being made.

This chapter reviews these two aspects of carotid artery atherosclerosis: (1) carotid artery plaque characterization, and (2) the IMT of the common and internal carotid arteries.

Pathogenesis of Carotid Atherosclerosis

Mechanisms of plaque formation and intima-media thickening

Current theory holds that early atherosclerosis occurs in multiple stages and is driven by inflammatory responses. The process begins with the penetration of lipids, mostly low-density lipoprotein (LDL) cholesterol particles, into the subendothelial lining of the artery wall. LDL cholesterol is then oxidized, promotes an inflammatory response, and attracts monocytes ( Fig. 6.2 ). Penetration of lipid into the artery wall is more likely to occur at artery branch points where slow flow or cyclical flow reversal occurs. A similar process also occurs in straight arterial segments.

FIG. 6.2, This diagram summarizes the early stages of the atherosclerotic process. Low-density lipoprotein ( LDL ) cholesterol particles enter through the endothelium and reach the intima. Local factors are then released and promote the migration of monocytes from the blood into the intima where they transform into macrophages.

In the early stages, the response to the penetrating lipid particles is essentially the same in the common and internal carotid arteries. The lipid material is ingested by macrophages, forming foam cells, so named because of their foamy appearance on microscopic examination ( Fig. 6.3 ). Small pools of extracellular lipid form, and smooth muscle cells proliferate. Here the pathologic processes diverge.

FIG. 6.3, Macrophages incorporate the oxidized low-density lipoprotein particles and serve as lipid reservoirs (foam cells) while promoting a more intense inflammatory response.

On microscopic examination, foam cells and extracellular lipid pooling are commonly seen in the straight segment of the common carotid. Infrequently, more advanced lesions with confluent areas of extracellular lipid called a lipid core form in the intima.

The formation of a large aggregate of extracellular cholesterol, the lipid core, typically occurs at the carotid bifurcation and in the proximal internal carotid arteries ( Fig. 6.4 ). With time, this is associated with microcalcification that can lead to larger calcium aggregates as the plaque increases in size. The subendothelium thickens to become a fibrous cap of varying thickness covering the lipid core ( Fig. 6.5A ). As this is happening, plaque neovascularization takes place when small arteries of the vasa vasorum extend from the adventitia through the media into the now evolving plaque. The fibrous cap can also be subject to a separate inflammatory response when metalloproteinases, enzymes capable of digesting the fibrous cap, preferentially accumulate at the plaque shoulders and weaken the protective fibrous cap that has developed around the lipid core (see Fig. 6.5B ).

FIG. 6.4, The macrophages (foam cells) continue to accumulate lipid content and elicit an inflammatory response. Dying foam cells accumulate in the intima and form an aggregate called a lipid core.

FIG. 6.5, (A) A typical lipid-laden plaque ( P = lipid core) below the fibrous cap ( FC ). The media lies next to the intima (here composed of both P and FC ). In (B), the plaque ( P ) has become complex with a mixture of dense tissue as well as lipid. The arrows identify the site of rupture of the fibrous cap. The histologic stains used in A and B are different.

Atherosclerotic plaques that develop in the coronary and carotid arteries have similar morphologies. Their evolution and ultimate fate are different, depending on their location, local flow dynamics, and artery size ( Table 6.1 ). In the coronaries, plaque rupture because of disruption of the fibrous cap will lead to occlusion of the artery and potentially cause an acute coronary syndrome or sudden cardiac death. In the carotids, disruption of the fibrous cap will not typically occlude the artery. It will either be contained and cause a rapid expansion of the plaque or, if it is not contained, lead to embolization of thrombus and plaque material.

TABLE 6.1

Comparison of the Hemodynamic Environment of Coronary and Carotid Artery Plaques and Artery Morphology.

Variable	Carotid Artery	Coronary Artery
Number of branch points	One	Multiple
Blood flow pattern	Higher velocities with flow mostly during systole	Lower velocities with flow mostly during diastole
Size	5 to 6 mm and stays constant	3 to 4 mm and tapers
Shear rates	Complex with reversing eddies at only one branch point	Complex at each of multiple branch points
Ulcerated plaque	Common	Uncommon
Erosions	Uncommon	Common
Acute occlusions	Uncommon	Common
Nonocclusive plaque hemorrhage	Common	Common
Calcification	Common with high-grade stenosis	Common with high-grade stenosis

Plaque rupture is not only due to a primary dissolution of the fibrous cap. Plaque rupture can also occur from intraplaque hemorrhage caused by rupturing vessels of the neovascular supply. This can lead to a rapid increase in plaque volume and fibrous cap disruption. Repeated intraplaque hemorrhages can be contained and simply lead to incremental plaque expansion. Such a mechanism was inferred when pathologic specimens of large carotid artery plaques showed pathologic evidence of multiple prior episodes of intraplaque hemorrhage.

Plaque histopathology: limitations

It is well recognized that severity of internal carotid stenosis is the major risk factor for neurologic events. Interventions aimed at preventing strokes such as carotid endarterectomy or stenting therefore target large plaques. What we know of the histopathology of atherosclerotic plaque has relied heavily on endarterectomy specimens from advanced carotid lesions. The histopathology studies of the 1980s emphasized the qualitative detection of intraplaque hemorrhage, not an unexpected finding given what we now know of the evolution of atherosclerotic plaque. Although plaque thrombus and intraplaque hemorrhage are still being studied, for example in the Oxford Plaque Study, recent histopathology studies increasingly use quantitative measurements to focus on associations of plaque contents with future cardiovascular events. This shift in emphasis is typical of plaque specimens used in the atherosclerotic plaque expression (Athero-Express) study.

Vulnerable and unstable plaques

The existence of a vulnerable plaque is based on observations made on coronary artery plaques. Large lipid cores, thin fibrous caps, and markers of inflammation are associated with acute coronary syndromes, whereas fibrous plaques tend to be stable and are associated with chronic angina. The key features of the vulnerable coronary plaque are the development of a necrotic core, the presence of inflammation that leads to a thin fibrous cap, increased enzymatic activity at the shoulders of the plaque, and active neovascularization from the adventitia into the plaque. The carotid artery vulnerable plaque is typically echolucent (lipid cores are mainly echolucent) and large in size. Ultrasound cannot directly grade the level of inflammation but can detect evidence that an active inflammatory process is taking place. Plaque neovascularization, a marker of the vulnerable plaque, can be detected by the presence of intraplaque microbubbles ( Fig. 6.6 ) after ultrasound contrast injection. These vulnerable plaques are unlikely to cause symptoms until they rupture.

FIG. 6.6, This echolucent plaque is imaged early and shortly later during an ultrasound contrast study. On image (A), the echolucent component ( arrows ) is homogeneous. Later in the study (B), small echogenic foci of contrast ( arrows ) appear within the substance of the plaque indicating the presence of neovascularization.

The plaques associated with clinical neurologic events are often “active” and have irregular surfaces and a heterogeneous composition. Transcranial Doppler (TCD) ultrasound studies have shown that symptomatic plaques are associated with increased numbers of high-intensity transient signals (HITS), a marker of intracranial embolization. These plaques tend to be large and cause a significant narrowing of at least 50% in the lumen diameter of the artery and frequently greater than 70% stenosis.

The concept of an “unstable” carotid plaque is somewhat broad. It can include an intact homogeneous plaque with a thin cap and large lipid core or a plaque with an irregular surface and mixed histology.

What to expect from imaging

High-grade carotid stenoses are in essence large plaques. These lesions are apt to have a heterogeneous histologic composition and will often have a discontinuous endothelial lining. They are likely the source of cerebral emboli either by being susceptible to rupture or because of the exposed subintimal plaque matrix. Plaque matrix is thrombogenic and serves as the nidus for platelet aggregates and thrombus formation. On ultrasound, these lesions have a heterogeneous composition of echodense and echolucent elements as well as mural irregularities. The ultrasound correlates of echodense areas include fibrous tissue and various levels of calcium deposition that can cause shadowing, whereas echolucent areas represent either areas of recent hemorrhage or lipid deposition. The heterogeneity of these large plaques makes them more susceptible to suffer mechanical damage especially when local inflammation and increased enzymatic activity are present.

Ultrasound is well suited for the evaluation of plaque compared with other modalities. The geometry of the carotid bifurcation as it turns into the internal carotid artery sinus may mask early plaque formation on traditional angiography. Computed tomographic arteriography and magnetic resonance imaging offer additional capabilities for imaging plaque components but at additional cost. On computed tomography, the echolucent elements tend to be low density within the plaque and the echodense and calcified elements are high density. On magnetic resonance imaging, enhancement of the plaque indicates the presence of hypervascularity, a sign of active inflammation.

Practical Tips

The carotid artery responds differently to LDL cholesterol deposition in straight arterial segments from that seen at the bifurcation: diffuse thickening of the wall compared with the creation of a plaque with a lipid core.
Atherosclerosis is a dynamic process. Once early plaque forms, the inflammatory responses within the intima and subendothelium lead to the development of complex histologic structures.
Histopathology studies are limited by selection bias toward high-grade symptomatic carotid artery plaques.
“Vulnerable” plaques tend to be homogeneous with a large lipid core, have a thin fibrous cap, and show evidence of neovascularity.
“Active” plaques are a source of emboli and tend to have irregular surfaces and a heterogeneous appearance.

Imaging Protocol: IMT and Plaque

Distal common carotid artery

A B-mode image is taken at the distal common carotid artery. The head of the patient is rotated 45 degrees away from the side being imaged and the probe is held parallel to the artery ( Fig. 6.7A ). The probe is kept parallel to the artery so that the double lines of the lumen-intima and media-adventitia interfaces are clearly visible on both near and far walls. The location of the common carotid IMT measurement is always below the bulb extending to the right over a distance of approximately 1 cm (by convention, the patient's head is to the left of the image and the legs to the right). The point where the measurement is taken is protocol-dependent ( Fig. 6.7B and C ) but it should start at or below the point where the outer wall of the common carotid artery (the adventitia) starts to diverge. Image size, as determined by pixels/cm, should be at least 140 pixels/cm and ideally around 180 pixels/cm. Some protocols exclude plaques (local increase in IMT of 50% or IMT ≥1.5 mm) from the measurement.

Common carotid artery bulb/internal carotid artery

Because plaque is eccentric, full visualization of any carotid plaque will require multiple longitudinal planes to be sampled ( Fig. 6.8 ). We start with a transverse sweep along the carotid artery into the bifurcation and then into the proximal internal carotid artery. We then focus on the flow divider (the junction between the internal and the external carotid artery) from an anterior ( Fig. 6.8B ), lateral ( Fig. 6.8C ), and posterior projection ( Fig. 6.8D ), finding the one projection that best displays the full extent of the plaque ( Fig. 6.8B ). The probe can be placed lower or higher in the neck depending on plaque location. Because of eccentricity, plaques require sampling in multiple projections until the best two-dimensional (2D) B-mode image is selected ( Figs. 6.8 and 6.9 ). On some projections, the plaque looks disconnected from the artery wall ( Fig. 6.10A ), and appears as a “floater” ( Fig. 6.10B and C ). These images are avoided and images where the plaque is anchored to either the near or far wall over a long distance are selected for plaque characterization. Beam steering can be judiciously used to emphasize the blood-plaque (lumen-intima) interface ( Fig. 6.11 ). The imaging plane that best displays a plaque is also used for color Doppler imaging and Doppler waveform analysis. Plaque area measurements can also be performed on the selected image because they have been shown to be predictive of future cardiovascular events.