Gray-Scale Intravascular Ultrasound

Gray-scale intravascular ultrasound (IVUS) utilizes one or more miniaturized transducers secured at the end of a flexible catheter that is inserted into arteries for in vivo tomographic visualization of vascular anatomy. Intracoronary ultrasound has become the most commonly used form of intravascular imaging and is regularly employed to delineate plaque morphology and distribution, to assess angiographically ambiguous lesions, to assess atherosclerosis progression and regression, to guide transcatheter coronary intervention, and to assess mechanisms of restenosis (Fig. 7-1).^1–2 The IVUS catheter is attached to either a portable or installed ultrasound machine through an interface that ensures sterility of the catheter and allows for motorized pullback. Motorized pullback of the IVUS catheter (or of the transducer within the catheter) at 0.5 mm/s or 1.0 mm/s allows calculation of lesion length and plaque volumes (necessary for progression/regression studies), ensures adequate time to visualize the lesion, and allows comparison between IVUS “runs” done at different times but with similar pullback speeds.

Figure 7-1 A, Pictorial representation of an intravascular ultrasound catheter inserted into a coronary artery after stent deployment. B, Actual intravascular ultrasound image of a well-deployed coronary stent.

There are two types of transducers used in IVUS catheters: mechanical and phased array. The mechanical catheter uses a single transducer that is mounted at the tip of the catheter and rotated quickly (at 1800 rotations per minute [rpm]). Because the IVUS transducer is oriented at a 90° angle to the length of the catheter, the images are displayed as cross-sectional views of the artery. The mechanical transducer has the advantage of a simple design and a greater signal-to-noise ratio. These properties account for its high image quality with an overall resolution (with current 40- to 45-MHz transducers) of approximately 100 to 120 µm. The primary disadvantage of mechanical transducers is that they require a central drive shaft to rotate the transducer on the tip of the catheter. This drive shaft decreases catheter flexibility. If a mechanical transducer is placed within a tortuous vessel, the drive shaft may be constricted, resulting in nonuniform rotation of the distal transducer, thus creating an artifact of the image termed nonuniform rotational distortion.

The phased array transducer uses multiple, tiny transducer elements. Each transducer element is permanently mounted around the circumference of the catheter tip and sends and receives ultrasound from a small sector. The multiple imaging sectors are then “added together” to produce a cross-sectional image of the artery. Because the phased array transducer is permanently fixed with no moving parts, it is more flexible and transverses torturous vessels more easily. These transducers do not produce nonuniform rotational distortion artifacts. However, the 20-MHz phased array transducer does require more complex programming to add the sectors together and thus has a lower temporal resolution (a function of computational speed) and lower spatial resolution.

Image Formation

An IVUS image is formed when ultrasound bounces off the multiple layers of the artery and returns to the transducer.³ The coronary artery is a muscular vessel composed of three basic layers: intima, media, and adventitia (Fig. 7-2). The intima, only a few cells thick at birth, is the site of atherosclerotic plaque accumulation. The intima is directly surrounded by the media, a layer of predominately homogeneous smooth muscle cells that provides the artery with its vascular tone. The outermost layer is the adventitia. Each of these layers tends to have a different acoustic property, allowing each to be visualized separately. When ultrasound encounters the intima, there is a large change in acoustic impedance; and much of it is bounced back to the transducer and displayed as a single concentric echo. Unless the intima becomes extremely hard, such as with the formation of a calcified plaque, some ultrasound penetrates through to the media. Because the media is composed of homogeneous smooth muscle cells, it passes through with minimal reflection; thus the media appears as a dark zone devoid of echoes. The adventitia has numerous layers of collagen fibers and therefore is a highly reflective structure that appears bright. As a result of the different acoustic properties of each layer, the normal coronary artery has a three-layered appearance, which includes (1) a bright echo from the intima, (2) a dark zone from the media, and (3) bright echoes from the adventitia. Because the resolution of IVUS is approximately 100 to 120 µm, the intima has to be at least this thick to be visualized as a distinct structure. In Western society, most patients presenting to the cardiac catheterization laboratory have some diffuse thickening of the intima. But if the intima is truly disease free, as in a newborn, child, or adolescent, then the intima will be much thinner and below the resolution of IVUS so that the artery will appear as a monolayer (see Fig. 7-2).

Figure 7-2 Center image was magnified and displayed at right and left. (Right) Typical “three-layered” appearance indicating intima, media (dark band), and adventitia. (Left) “Mono-layered” appearance indicating very thin intima below intravascular ultrasound resolution, media (not visible), and adventitia.

Image Interpretation

The interpretation of an IVUS image involves only a few simple steps: (1) identify the IVUS catheter in the center of the screen, keeping in mind that the IVUS catheter is traveling down the blood-filled lumen; (2) identify the dark stripe of the media that tells the size of the artery in the absence atherosclerotic disease; (3) remember that all of the echoes within the media stripe represent intima or intimal (atherosclerotic) disease and (4) all of the echoes outside the media are adventitia (see Fig. 7-2).

The amount of ultrasound that reflects off of tissue depends on the acoustic impedance (density) of the tissue. This property provides IVUS with some ability to differentiate plaque of different compositions. Hard material (calcium or fibrotic plaque) will reflect more ultrasound and appear brighter, whereas soft plaque (fat) will not reflect the ultrasound and will appear dark. Calcium is so dense that no ultrasound penetrates to the deeper tissues and, thus, produces acoustic shadows; shadowing, along with the bright echoes is the hallmark of calcification. A conventional approach is to compare the overall brightness of the plaque to the surrounding adventitia. Plaque is typically characterized as hypoechoic if less dense than the adventitia, hyperechoic if more dense than the adventitia, calcified if bright with acoustic shadowing, or mixed. IVUS can detect dense calcium with high sensitivity and specificity,^4–6 but its accuracy in identifying high-risk lipid rich plaque or even thrombus formation is poor.⁷ As shown in Figure 7-3, gray-scale IVUS can also detect two other types of high-risk plaques: (1) noncalcified attenuated plaque (which correlates with fibroatheroma) and (2) calcium nodules (calcium with a convex shape and irregular surface).^8–10

Figure 7-3 Both intravascular ultrasound (IVUS) and corresponding histology (Russell-Movat’s pentachrome staining) are shown. (Top) IVUS image shows typical “attenuated plaque”—non-hyperechoic plaque with attenuation. Corresponding histology shows advanced fibroatheroma (black arrows). Intravascular ultrasound image (bottom) shows “calcified nodule,” which has convex irregular surface with acoustic shadow. Corresponding histology shows cluster of calcified nodules (black arrows).

Radiofrequency Ivus

Standard gray-scale IVUS is limited, in part, because it uses only the amplitude of reflected ultrasound to formulate the image. In an effort to improve on the qualitative assessment of the reflected ultrasound signal, Kawasaki and coworkers developed a plaque characterization algorithm called integrated backscatter IVUS using time domain information directly from the radiofrequency signal. This process has resulted in improved plaque characterization with a reported in vitro sensitivity of 90% and specificity or 92% for lipid-rich plaque.¹¹

In a similar effort to improve plaque characterization, spectral analysis (virtual histology [VH]-IVUS) combines signal frequency and amplitude analysis to create an algorithm that detects fibrous tissue (dark green), fibrofatty (light green), necrotic core (red), and dense calcium (white). Reported sensitivity and specificity of VH-IVUS are 91.7% and 96.6% for identification of the lipid-rich necrotic core.^12–14 However, VH-IVUS cannot detect thrombus (in fact, thrombus appears as either fibrotic or fibrofatty plaque depending on the age of the thrombus) and has not been validated for assessment of stent metal or intimal hyperplasia. VH-IVUS lesion phenotype has been classified as (1) VH thin-cap fibroatheroma, (2) thick-cap fibroatheroma, (3) pathologic intimal thickening, (4) fibrotic plaque, and (5) fibrocalcific plaque (Fig. 7-4). Fibrotic plaque has mainly fibrous tissue with less than 10% confluent necrotic core, less than 10% confluent dense calcium, less than 15% fibrofatty. Fibrocalcific plaque has mainly fibrous tissue with greater than 10% confluent dense calcium, but less than 10% confluent necrotic core. Pathologic intimal thickening has a mixture of all plaque components, but dominantly fibrofatty with less than 10% confluent necrotic core and less than 10% confluent dense calcium. Fibroatheroma (both VH thin-cap fibroatheroma and thick-cap fibroatheroma) has greater than 10% confluent necrotic core. Because the resolution of VH-IVUS is 150 to 250 µm, it is not possible to detect fibrous cap thickness less than 65 µm (the typical pathologic definition of a thin fibrous cap). Therefore, if there is greater than 30° of necrotic core abutting to the lumen in three consecutive slices, the fibroatheroma is classified as VH thin-cap fibroatheroma; otherwise, it is classified as thick-cap fibroatheroma.¹⁵

Figure 7-4 Virtual histology (VH) IVUS classification.

(red, necrotic core; white, dense calcium; light green, fibrofatty; dark green, fibrous tissue) VH-TCFA, VH thin-cap fibroatheroma; ThCFA, thick-cap fibroatheroma; PIT, pathologic intimal thickening; fibrotic plaque; and fibrocalcific plaque.

Ivus Versus Angiography

Angiography permits the measurement of only luminal diameters and typically in only two or three views. Because of its tomographic presentation and high resolution, IVUS is far more accurate than angiography in assessing atherosclerotic plaque extent, morphology, and distribution.

To appreciate and apply IVUS in clinical practice, one needs to have a full understanding of how IVUS and angiography differ. Angiography is often referred to as a “shadowogram” of the lumen because a silhouette of the arterial lumen is obtained by injecting radiopaque dye into the lumen and projecting the shadow from the dye on to cineangiographic film. The shadow-o-gram is then used to extrapolate a luminal narrowing to a plaque accumulation. It is common to detect atherosclerosis in an artery that appears “normal” by angiography. Although it may appear to be a discrepancy at first, it is not, and both the angiography and the IVUS studies are providing complementary and accurate information. The primary difference is that angiography is visualizing just the lumen, whereas IVUS visualizes both the lumen and arterial walls. If the assumption is that all angiographic stenoses are from plaque, then it would make sense to conclude that an angiogram displaying a lumen without any narrowing is free of plaque. However, that may not be true (and usually is not). Conversely, an angiogram of an artery can be free of any stenosis, but that artery can still have many areas of plaque. This is true because of three phenomena: (1) atherosclerotic plaque is often diffusely distributed, (2) arteries can undergo vascular remodeling, and (3) complex atherosclerotic plaques are not appreciated by the two-dimensional silhouette.

It has been verified in autopsy studies and other IVUS studies of healthy donors that most people have diffuse atherosclerotic disease throughout their arteries by midlife, and this disease often remains angiographically silent because of its diffuse nature. In addition to diffuse plaque, vascular remodeling is also responsible for the high prevalence of angiographically silent disease. Both pathology and IVUS studies have documented that coronary arteries will enlarge to accommodate focal plaque deposition in an attempt to maintain luminal integrity. Compensatory dilation of the arterial wall occurs in direct response to the accumulation of atherosclerotic plaque. An absolute reduction in lumen dimensions typically does not occur until the lesion occupies approximately 40% to 50% of the area within the internal elastic membrane (40% to 50% cross-sectional narrowing).¹⁶ As a result, most of the atherosclerotic burden is contained within angiographically normal reference segments.¹⁷

Complex luminal shapes can result from irregular plaques or the disruption of a plaque (from balloon angioplasty). Although such a lesion may appear hazy, it may not demonstrate a luminal stenosis when viewed from only one or two views and projected as a silhouette. This may be similar to an eccentric lesion, which can fool inexperienced angiographers, unless a large number and variety of views are obtained, each displaying a different severity. However, a lumen with highly irregular borders may not be fully appreciated, even in multiple views. The tomographic images of IVUS are necessary to appreciate the true luminal shape. Therefore, diffuse plaque, vascular remodeling, and irregular plaque can all lead to an inability of angiography to appreciate the plaque that is seen on IVUS. This is predominately because angiography only visualizes the lumen and does so in limited views using silhouettes of the dye.

Finally, angiography may contain areas that are hazy or lesions that are ambiguous. These hazy or ambiguous lesions may result from irregular plaque, a focal area of calcium, a dissection, or an intraluminal thrombus. IVUS is particularly useful for ambiguous lesions because each of the causes (plaque irregularities, calcium, dissection, or thrombus) appear different on IVUS.

Integration Into Practice

Many practical aspects of IVUS imaging are facilitated by designating specific IVUS technologists who become responsible for all practical aspects of IVUS imaging: (1) equipment and catheter setup, (2) image optimization, (3) proper recording of IVUS imaging runs, (4) accurate voice and onscreen alphanumeric documentation, (5) patient and procedure logs, and (6) equipment maintenance. With time, technologists can be trained to interpret images accurately, to provide the iterative feedback necessary for IVUS-based decision making, and to answer questions posed by the primary operators. Measurements should be made offline (from hard drive after the imaging run is complete), not when the catheter is in the vessel; this saves procedure time and minimizes patient ischemia.

The angiographic (i.e., “road-map”) monitors can be “wired” to display IVUS images. Angiographic monitors offer superior resolution, are convenient and readily visible to the operator, and allow the IVUS machine to be placed in a position away from the patient table and out of the way of the nurses providing patient care.

In a busy laboratory with multiple operators, it is important to standardize image acquisition and analysis. The use of a motorized transducer pullback device aids (in fact, enforces) discipline and acquisition standards; there is no question whether the transducer is being advanced or withdrawn. The preferred pullback speed is 0.5 mm/s; this is the fastest rate at which the trained eye can assimilate the information. Standardization of image acquisition facilitates offline image analysis and comparison of serial (preintervention versus postintervention or postintervention versus follow-up) studies; it is essential for multicenter studies.

Standard Ivus Acquisition Protocol

IVUS imaging should include careful uninterrupted imaging of (1) at least 10 mm of distal reference, (2) the lesion site(s), and (3) the entire proximal reference back to the aorta. Advantages of motorized pullback are (1) controlled catheter withdrawal so no segment of the vessel is skipped or imaged too quickly by pulling the catheter back too rapidly, (2) the ability to concentrate on the images without having to simultaneously pay attention to catheter manipulation, (3) the ability to make length and volumetric measurements, and (4) uniform and reproducible image acquisition for multicenter and serial studies. Disadvantages of motorized pullback are the following: (1) even at slow pullback speeds, it is possible to skip over focal lesions; (2) not enough attention may be paid to important regions of interest; and (3) it is not possible to have the transducer “sit” at one specific site in the vessel.

However, motorized transducer pullback does not preclude the addition of careful, manually controlled interrogation of the lesion. Manual transducer pullback should be at a slow rate similar to motorized pullback. Advantages are that it is possible to concentrate on specific regions of interest by having the transducer sit at a specific site in the vessel. Disadvantages include the following: (1) it is easy to skip over significant pathology by pulling the transducer back too quickly or unevenly, (2) length and volume measurements cannot be performed, and (3) antegrade and retrograde manual catheter movement can be confusing when the study is reviewed at a later date.

When interrogating ostial lesions, it is important that the guiding catheter be disengaged from the ostium. If not, the true ostial lumen dimensions may not be identified. In all cases, at least one continuous uninterrupted imaging run should be performed from approximately 10 mm beyond the target lesion to the ostial junction of the ostium with the aorta.

Safety

Three large studies have evaluated the safety of IVUS. Other than transient spasm, complications appear to be rare (Table 7-1).^18–20

Assessment Of Stenosis Severity

Coronary angiography underestimates stenosis severity most markedly in vessels with 50% to 75% plaque burden (plaque area divided by arterial area) at necropsy and in patients with multivessel disease.^21–25 Clinical events are determined by lumen size, not by the amount of plaque. Therefore, it is important to focus on accurate measurement of lumen dimensions and not to be distracted by the plaque burden. Plaque burden in patients with atherosclerosis tends to be large even in the absence of lumen compromise.

Studies performed more than 10 years ago suggested that an IVUS minimum lumen area (MLA) greater than 4 mm² was a valid criterion for deferring an intervention based both on comparisons to physiologic measures and on follow-up data.^26–29 This cutoff only applied to major epicardial vessels excluding the LMCA and excluding saphenous vein grafts. However, it was necessary to interrogate the lesion carefully to identify the image slice with the smallest lumen, especially in very focal stenoses. Once the smallest lumen is identified, careful measurement was required. Recently this cutoff has come under criticism for a number of reasons including the size of the vessels (studies were done mostly in large 3.5-mm vessels), the average MLA of the intermediate lesions studied (4 mm²), and the fact that these studies have been misinterpreted to suggest that lesions with an MLA below 4 mm² justify stent implantation. For this reason, it is recommended that for major epicardial vessels excluding the LMCA, physiologic lesion assessment (using an intracoronary pressure wire and maximum hyperemia with intravenous adenosine to measure the fractional flow reserve) is a complementary approach to assess lesion severity.³⁰

Assessment Of Lmca Disease

A high percentage of patients with angiographically “normal” LMCA with only nonsignificant stenosis have substantial disease by IVUS.^31–34 Reasons for the discrepancy between angiography and necropsy or IVUS assessment of LMCA disease include the following: (1) diffuse atherosclerotic involvement affects the angiographic diameter stenosis (DS) calculation because of the lack of a normal reference segment; (2) a short LMCA also makes identification of a normal reference segment difficult; (3) unique geometric issues exist in LMCA disease (the correlation between angiography and necropsy or IVUS appears to be somewhat better in non-LMCA stenoses); and (4) there is significant interobserver and intraobserver variability in the angiographic assessment of LMCA disease.^35–42 In fact, the LMCA is the coronary arterial segment with the greatest variability in angiographic assessment.