CHAPTER 21: CORONARY INTRAVASCULAR IMAGING

Intravascular imaging continues to play a vital role in advancing our understanding of the pathophysiology of coronary artery disease (CAD) and in the development of novel cardiovascular drugs and device therapies.^{1,2,3,4,5,6,7} Grayscale intravascular ultrasound (IVUS) was introduced more than 25 years ago and has been an integral component of the clinical decision-making process in the catheterization laboratory. Contemporary percutaneous coronary intervention (PCI) techniques mostly derived from initial IVUS observations showing that high-pressure balloon inflation was required to adequately appose metallic stents to the vessel wall and prevent thrombosis. Intravascular imaging has also evolved with time. IVUS technologies have added features such as tissue characterization by means of radiofrequency data analysis to facilitate evaluation of the atherosclerotic plaque. This technique allows a more sophisticated assessment of changes in plaque characteristics over time beyond simplistic measurements of plaque dimensions.⁸ However, the relative poor image resolution of IVUS and physical limitations of sound have hampered a broader clinical and research application of intravascular imaging. The introduction of infrared light-based imaging technologies such as optical coherence tomography (OCT), which offers image resolution 10 times greater than that of IVUS, has allowed interventional cardiologists to explore the vascular microenvironment for the first time, whereas near-infrared spectroscopy (NIRS) has enabled more reliable assessment of plaque composition and detection of the lipid component.⁹ Other emerging invasive imaging techniques, such as Raman spectroscopy photoacoustic imaging, near-infrared fluorescence imaging, and time-resolved fluorescence spectroscopy, are currently undergoing preclinical evaluation; they are expected to have clinical applications in the near future and provide additional information about plaque morphology and pathophysiology (Fig. 21–1). These intravascular imaging technologies and their clinical and research applications are discussed in more detail below.

Coronary x-ray angiography has retained the gold standard status in coronary imaging for more than four decades. Angiography depicts arteries as a planar silhouette of the contrast-filled lumen and provides a quick road map of the coronary circulation. Importantly, angiography does not provide visualization of the vessel wall and is not suitable for assessment of atherosclerosis. Essentially, angiography provides assessment of lumen dimensions and is used to localize and estimate the severity of obstructive coronary disease. Angiographic disease assessment is based on the comparison of the stenotic segment with the adjacent, “normal-appearing” coronary, which is often an incorrect assumption because of the diffuse nature of atherosclerosis. Angiography image interpretation is flawed by large inter- and intraobserver variability and usually underestimates the severity of the disease and vessel dimensions. Although quantitative coronary analysis (QCA) has reduced visual errors, the ability of arteries to enlarge to compensate for plaque growth makes angiography an unreliable method of assessing atherosclerosis burden.¹⁰ Vessel foreshortening and overlapping side branches, particularly in disease involving bifurcations, are important practical limitations of angiography and QCA. Despite the use of multiple views, characterization of eccentric lesions by angiography remains a challenge. Finally, angiographic assessment of balloon angioplasty results is hampered by the presence of contrast-filled dissection and intraplaque channels, and determination of proper stent apposition is not possible. Three-dimensional angiography at the time of the contrast injection may provide an accurate and precise assessment of the luminogram. This may address some of the limitations of conventional angiography but still does not allow visualization of the arterial wall and plaque burden. These limitations of angiography can be minimized by the intravascular tomographic visualization of lumen and vessel wall architecture. Intravascular imaging plays an essential complementary role in the catheterization laboratory, enabling more definitive assessment of angiographically intermediate disease, of vessels with aneurysmal dilatation, ostial stenoses, or disease located at branching points or in the left main (LM) artery, as well as tortuous or calcified segments and eccentric plaques, complex disease morphology, intraluminal filling defects, thrombus, dissection, and lumen dimensions after coronary intervention.

Intravascular Ultrasound

Basic Principles

The final graphic image display is a result of reflected ultrasound waves that are converted to electrical signals and sent to an external processing system for amplification, filtering, and scan conversion. After leaving the transducer, the beam remains parallel for a short distance (near field; better image quality) and then begins to diverge (far field). The length of the near field is expressed by the equation L = r²/λ, where L is the length of the near field, r is the radius of the transducer, and λ is the wavelength. After encountering a transition between different materials (eg, the interface between blood and the intimal arterial layer), the beam will be partially reflected and partially transmitted, depending on tissue composition and differences in mechanical impedance between materials. Calcium produces nearly complete backscattering of the signal and is displayed as a bright image with a characteristic acoustic shadowing. Ultimately, grayscale IVUS imaging is formed by the envelope (amplitude) of the radiofrequency signal (Fig. 21–2).

The quality of ultrasound images can be described by spatial resolution and contrast resolution. Spatial resolution is the ability to discriminate small objects and is determined in axial (parallel to the beam; primarily a function of wavelength) or lateral (perpendicular to the beam; a function of wavelength and aperture). Axial resolution is approximately 100 μm, and lateral resolution reaches 200 to 250 μm in conventional IVUS systems (20-45 MHz) (Table 21–1). Contrast resolution is the distribution of the gray scale of the reflected signal and is often referred to as dynamic range. An image of low dynamic range appears as black and white with a few levels of gray; images at high dynamic range are often softer.

Catheter Designs

The IVUS equipment consists of a catheter incorporating a miniaturized transducer and a console to reconstruct and display the image. Lately, IVUS consoles have been incorporated into the catheterization laboratory equipment for easier operation. Current catheters range from 2.6 to 3.2 French (Fr) in size and can be introduced through conventional 6-Fr guide catheters. The Opticross catheter (Boston Scientific) is the only mechanical system that is compatible with a 5-Fr guiding catheter; Eagle Eye Platinum electronic phased-array IVUS catheters (Volcano Corporation) are also 5-Fr guide catheter compatible. Rotational, mechanical IVUS catheters operate at frequencies between 30 and 45 MHz, and electronic phased-array systems operate at a center frequency of approximately 20 MHz. Higher ultrasound frequencies are associated with better image resolution. At 30 MHz, the wavelength is 50 μm, yielding a practical axial resolution of approximately 150 μm. But increasing the frequency beyond 60 MHz has been limited because of decreased tissue penetration.¹¹ The mechanical probes rotate a single piezoelectric transducer at 1800 rpm, yielding 30 images per second. Electronic systems have up to 64 transducer elements in an annular array that are activated sequentially to generate the cross-sectional image.¹¹ In general, whereas electronic catheter designs are slightly easier to set up and use, mechanical probes offer superior image quality and have a better crossing profile. Images may be recorded on videotape or digitally with both systems. Electronic IVUS catheters have the ability to display blood flow in color to facilitate distinction between lumen and wall boundaries.

Autoregressive spectral analysis of IVUS backscattered data has been incorporated into conventional IVUS systems to facilitate image interpretation of different tissue components (see Fig. 21–2). This function displays different plaque components in a color-coded scheme according to tissue signal properties (necrotic core in red, dense calcium in white, fibrous in dark green, and fibrofatty in light green).¹² In a postmortem validation study, radiofrequency analysis demonstrated sensitivity and specificity for detection of necrotic core of 92% and 97%, respectively.¹² The initial algorithm was validated using the mechanical rotating single-element IVUS system, but the first commercially available IVUS backscattering image analysis, named virtual histology (IVUS-VH), was built on the electronic 20-MHz IVUS platform. Lately, rotational mechanical IVUS systems have also integrated a backscattering regression algorithm.¹³

IVUS-VH imaging has been extensively used in clinical trials to monitor progression of atherosclerosis and to predict plaque growth, providing for the first time evidence that plaque composition carries significant prognostic information.^{14,15,16,17,18} Nevertheless, reports have raised concerns about the efficacy of this approach to characterize plaque composition, especially in complex calcified lesions and in stented segments, highlighting the need to develop alternative imaging modalities for more reliable assessment of the composition of the plaque.^19,20

IVUS-based imaging has been used to assess the mechanical properties of the plaque and in particular its deformability using the analysis of radiofrequency signals at different diastolic pressure levels, normalized to a pressure difference of 2.5 mm Hg per frame. This allows the construction of a “strain” image, in which harder (low strain) and softer (high strain) regions of the coronary arteries can be identified, with radial strain values ranging between 0% and 2%²¹ (see Fig. 21–2). Postmortem coronary arteries were investigated with histology and IVUS palpography. The sensitivity and specificity of palpography to detect vulnerable plaques was reported to be 88% and 89%, respectively.²¹ Although preliminary studies have provided evidence about the ability of palpography in detecting high-risk plaque, a substudy of the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study, which investigated the value of IVUS in identifying lesions that will progress and cause cardiovascular events, showed that palpography did not provide additional prognostic information.²² This technology has currently limited applications in the research arena.

Examination Technique

The IVUS procedure is performed using standard guide catheters (≥ 5 Fr) under full anticoagulation with an activated clotting time of more than 250 seconds. After intracoronary infusion of nitroglycerin (100-200 μg) to minimize vasospasm, the rapid-exchange IVUS catheters are introduced in the coronary over a standard 0.014-in guidewire. Mechanical IVUS systems require infusion of heparinized saline through a dedicated port to clear air bubbles inside the sheath covering the transducer before inserting the catheter in the guide catheter. The IVUS catheter should be advanced under fluoroscopic guidance approximately 10 mm distal to the segment of interest. The operator should realize that the distal marker in mechanical systems at the tip of the catheter is a radiopaque marker and not the ultrasound probe. If possible, the catheter should be advanced beyond 10 mm and retracted slowly to straighten the catheter shaft, which may have built up some slack during insertion, to minimize nonuniform rotation distortion (NURD) artifacts. Motorized pullback devices should be used to withdraw the catheter at a constant speed (most frequently at 0.5 mm/s) to allow proper examination of the entire coronary artery and calculation of distances. During pullback, the record function should be activated to allow storage of images with concomitant voice narration of interesting findings for off-line detailed analysis. Unless coronary ischemia ensues, the catheter should be withdrawn up to the aortic coronary junction and the guide catheter should be retracted slightly to allow imaging of the coronary ostium. Side branches visualized by angiography or ultrasonography are useful landmarks to facilitate interpretation and comparisons in sequential examinations.

Safety

IVUS has been performed safely in a large number of subjects enrolled in research studies with no apparent increase in the incidence of adverse effects. The rate of complications associated with IVUS images was investigated in 2207 patients from 28 centers (including 915 patients studied for diagnostic purposes).²³ A total of 87 patients (3.9%) had complications judged to be unrelated to IVUS imaging, and 63 patients (2.9%) had transient vasospasm. In nine patients (0.4%), complications were judged to be related to the IVUS procedure, including five acute vessel occlusions, three dissections, and one embolism. In 14 patients (0.6%), complications were judged to have an “uncertain” relationship to IVUS. Major events (acute myocardial infarction [MI] or emergency bypass surgery) occurred in 3 of 9 and 5 of 14 of these patients, respectively. The complication rate was higher in patients with unstable angina or acute MI and in patients undergoing intervention compared with diagnostic IVUS.

Another report comprising 718 IVUS “examinations” performed at 12 centers reported a 1.1% rate of complications without adverse clinical consequences. There were four cases of transient vasospasm; two dissections; and two guidewire entrapments. All complications occurred in patients with unstable angina undergoing PCI. In 7085 IVUS studies from 51 centers, vasospasm occurred in 3% of patients.²⁴ Major complications (dissection, thrombosis, ventricular fibrillation, and refractory spasm) occurred in 10 (0.14%). There was only one major event.

The safety of multivessel IVUS imaging has been investigated in the PROSPECT and the Prediction of Progression of Coronary Artery Disease and Clinical Outcome Using Vascular Profiling of Shear Stress and Wall Morphology (PREDICTION) studies. These studies utilized three-vessel IVUS imaging to assess plaque characteristics and predict atherosclerotic disease progression and future cardiovascular events in patients admitted with an acute coronary syndrome (ACS). In these high-risk populations, the complications caused by IVUS imaging were 1.6% in the PROSPECT study and only 0.6% in the PREDICTION study.^15,25

Limitations and Image Artifacts

The echogenicity and texture of different tissue components may exhibit comparable acoustic properties. The similar appearance of different materials represents an inherent limitation of all gray-scale IVUS systems. For example, an echolucent intraluminal image may represent thrombus, atheroma with a high lipid content, retained contrast, or an air bubble.

Most mechanical limitations of IVUS imaging are specific to the construct of each system. NURD is specific to mechanical catheters and arises from friction of the transducer in the coronary or guiding catheter or from a poor connection of the IVUS catheter in the motor drive unit, which causes a typical “onion skin” image appearance. Common causes of NURD are tortuosity; severely stenotic segments; small guide lumen size; and guide catheters with sharp secondary curves, slack in the catheter shaft, or tightened hemostatic valve. The ring-down artifact, however, is specific to electronic systems and is caused by transducer oscillations that obscure the near-field image.²⁶ The side lobe artifact is an intense reflection that comes from strong reflectors, such as calcium and stent struts. This usually follows the circumferential sweep of the beam. The presence of the side lobes may mask the actual lumen edge or may also be taken as tissue prolapse or dissection flaps. Reverberation is another artifact that comes from strong reflectors and is concentric repetitions at equidistant locations of the same image.

An eccentric or nonperpendicular position of the IVUS catheter produces geometric distortions and an artificially elliptical appearance of the cross-sectional image, leading to overestimation of the lumen area.²⁶ The speed of catheter pullback is also prone to errors, which may lead to incorrect assessment of the length of the segment of interest. In non–sheath-based catheters (electronic system), the pitfalls of automatic pullback are greater and include the presence of catheter slack outside the patient and friction in the coronary artery and guiding catheter during pullback. Sheath-based, mechanical catheter systems allow more uniform pullbacks during image acquisition and more precise length measurements.²⁷ The accuracy of four IVUS pullback systems was evaluated in 180 patients (45 in each group) who had been treated with a single stent of known length ranging from 8 to 33 mm. The correlation between the actual versus IVUS-measured stent lengths was 0.92 for Cardiovascular Imaging Systems (CVIS), 0.83 for Galaxy (both from Boston Scientific Corporation, IVUS Technology Center, Fremont, CA), 0.63 for Endosonics Track-Back, and 0.69 for Volcano Model R-100 (both from Volcano Corporation, Rancho Cordova, CA) pullback devices.²⁷ The pullback speed is least accurate at the beginning of an imaging run (in the distal artery) and most accurate in the proximal artery. In battery-powered pullback devices, the battery charge should be verified at the beginning of the procedure to ensure uniform pullback speed. Ideally, the same pullback device and catheter should be used in repeated longitudinal studies. Finally, one should realize that intravascular imaging only assesses a single coronary segment at a time.

Optical Coherence Tomography

Basic Principles

OCT evolved from optical one-dimensional, low-coherence reflectometry, which uses a Michelson interferometer and a broadband light source. The addition of transverse B-scans by James Fujimoto in 1991 enabled a two-dimensional imaging of the retina.²⁸ Intravascular OCT uses a single optical fiber that both emits and records light reflection. The image is formed by the backscattering of light from the vessel wall based on “echo time delay” with measurable signal intensity. The speed of light (3 × 10⁸ m/s) is much faster than that of sound (1500 m/s), thus requiring interferometry techniques because direct signal quantification cannot be achieved on such a time scale. The interferometer uses a fiberoptic coupler similar to a beam splitter, which directs half of the beam to the tissue and the other half to the reference arm. The reference arm of the first-generation, time-domain OCT system (TD-OCT), consists of a mirror that moves to produce variable, yet known echo delays. The second-generation intravascular OCT systems use a fixed mirror with a variable frequency light source or “swept laser.” This method, termed Fourier-domain OCT (FD-OCT), allows the simultaneous detection of reflections from all echo time delays, making the system significantly faster. There are two types of FD-OCT systems that differ in their method of data extraction from the interferometer: optical frequency domain imaging (OFDI), also known as swept-source OCT, and spectral domain OCT. OCT images are formed by the reflected signal returning from the tissue and reference arms “interferes” in the fiber coupler and are detected by a photodetector.

As the fiberoptic rotates, multiple axial scans (A-lines) are continuously acquired to generate the cross-sectional vascular image. Bandwidths in the near-infrared spectrum with central wavelengths ranging from 1250 to 1350 nm are used for intravascular applications. Longer wavelengths would provide deeper tissue penetration but would be limited by absorption and the refractive index caused by protein, water, hemoglobin, and lipids. Thus, the image depth of current OCT systems ranges from 1 to 3 mm into the vessel wall. The axial resolution, which is determined by the light wavelength, ranges from 12 to 20 μm. The lateral resolution in catheter-based OCT is typically 20 to 90 μm (see Table 21–1).

Catheter Designs

The first clinically available OCT systems used time-domain (TD) technology (M2 and M3 OCT Imaging Systems, LightLab Imaging Inc., Westford, MA). The newer systems are based on frequency domain technology. TD-OCT system consists of a single-mode fiberoptic wire (ImageWire), which is able to rotate inside a fluid-filled polymer sheath. An over-the-wire low-pressure occlusion balloon catheter (Helios Goodman, Advantec Vascular Corp.) with distal flush ports is used to infuse saline or Ringer’s lactate at approximately 0.5 mL/s to displace blood during imaging acquisition.

The St. Jude C7XR (FD-OCT) was the first OFDI-OCT system and is approved for clinical use in most countries, including the United States. It is equipped with a tunable laser light source, with the fiber encapsulated within a rotating torque wire built in a rapid exchange 2.6-Fr catheter compatible with 6-Fr guides. Recently, St. Jude introduced an updated version Optis that is able to acquire 180 frames per second, enabling more accurate axial imaging resolution. Lunawave (Terumo Corporation, Tokyo, Japan) has also developed an FD-OCT system, which has a 2.6-Fr shaft.

Examination Technique

General principles of intravascular imaging also apply to OCT. Standard guide catheters (≥ 6 Fr) are used, patients must receive full anticoagulation, the image wire or catheter should be advanced under fluoroscopy guidance approximately 10 mm distal to the segment of interest, and the image is acquired after intracoronary infusion of intracoronary nitroglycerin. Despite its guidewire-like profile, the OCT ImageWire is not designed to be advanced into the coronary artery as a stand-alone device. Thus, a conventional angioplasty guidewire (0.014 in) should be inserted first and exchanged to the ImageWire using the Helios or a microcatheter with an inner diameter larger than 0.019 in. Proper OCT imaging requires a blood-free environment because any amount of residual red blood cells causes signal attenuation. In TD-OCT, this is achieved by the inflation of the occlusion balloon proximal to the segment of interest. After advancing the ImageWire into the distal coronary segment, the occlusion balloon is pulled back and repositioned in a healthy proximal segment. Before inflating the Helios balloon at 0.4 to 0.7 atm using a dedicated inflator, injection of Ringer’s lactate at 0.5 mL/s should be started using an injector pump with a warming cuff. Infusion rates can be increased to up to 1.0 mL/s until blood is completely cleared. In TD-OCT systems, the pullback speed can be adjusted from 0.5 to 3.0 mm/s.

FD-OCT is built in rapid-exchange, 6-Fr–compatible, catheter-based systems that are advanced into the coronary segment over a standard 0.014-in guidewire. These systems can acquire 100 to 180 image frames per second, reaching pullback speeds up to 18 to 40 mm/s with the potential to scan epicardial coronary vessels that are 4 to 6 cm long in less than 3 seconds, with the use of a single, high-rate (~ 4 mL/s) bolus injection of contrast (see Table 21–1).²⁹ For nonocclusion techniques, iodinated contrast media are preferred over saline or Ringer’s lactate because of the advantage of high-viscosity solutions in completely removing blood. Before introducing the catheter, a small amount of iodine contrast must be purged into the covering sheath to clear air bubbles and prevent blood entry. The activation of the pullback is automatic as the blood is cleared from the lumen and triggers recording of images, which are stored electronically. The pullback system also has a function to readvance the fiber within its cover sheath. The fast pullback speed does not allow voice recording during imaging acquisition of FD-OCT systems.

Safety

The OCT imaging technique has been adopted in many centers across Europe and Japan, and various centers have presented large series of patients imaged by OCT without major complications. The applied energy in intravascular OCT is relatively low (output power in the range of 5.0-8.0 mW) and is not considered to cause functional or structural damage to the tissue. Safety concerns thus seem mainly dependent on the mechanical properties and need for blood clearance for image acquisition. Studies comparing OCT with IVUS suggest that TD-OCT is safe and can be performed with success rates at least comparable to those of IVUS. The most frequent complication in 76 patients imaged with TD-OCT using the occlusive OCT technique were transient chest discomfort, bradycardia or tachycardia, and ST-T changes on electrocardiography (ECG), all of which resolved immediately after the procedure. Similar transient events were also seen during IVUS imaging procedures. Neither hemodynamic instability nor ventricular tachyarrhythmia was observed.³⁰ In addition, in a multicenter registry, the acute complications associated with OCT were assessed in 468 patients. TD-OCT was performed using a nonocclusive flush technique in 45.3% of the patients with a mean contrast volume of 36.6 ± 9.4 mL (M2 and M3). Transient chest pain and QRS widening or ST-segment depression or elevation were observed in 47.6% and 45.5% of patients, respectively. Major complications were rare; they included five (1.1%) cases of ventricular fibrillation caused by balloon occlusion or deep guide catheter intubation, three (0.6%) cases of air embolism, and one (0.2%) case of vessel dissection. There were no cases of coronary spasm or major adverse cardiovascular events (MACE) during or within the 24-hour period after OCT examination.³¹ The more recent nonocclusive FD-OCT technique has led to an important reduction in the image acquisition time (3-4 seconds) and in the rate of chest pain and ECG changes during image acquisition. The safety and feasibility of the larger catheter-based FD-OCT systems has been examined in numerous small scale studies, which demonstrated that FD-OCT is safer than TD-OCT, as it is associated with a low risk of complications.^32,33 In the study of Lehtinen and colleagues, the procedural success of FD-OCT was 87.4%, whereas the complication rate was 17.4% (chest pain in 10.9% of the cases, myocardial ischemia in 2.6%, and minor bleeding in 4.8%). In contrast, in the study of Imola and coworkers, which included 90 patients who underwent FD-OCT to assess lesion severity and the final results poststent implantation, none of the studied patients experienced major complications (ie, death, MI, emergency revascularization, embolization, life-threatening arrhythmia, coronary dissection, prolonged and severe vessel spasm, or contrast-induced nephropathy).^32,33

Recently, Taniwaki and colleagues reported the safety and feasibility of multimodality three-vessel intravascular imaging in the Integrated Biomarkers Imaging Study (IBIS) 4.³⁴ This study included 103 patients admitted with a ST-segment elevation MI who had serial OCT and IVUS-VH imaging at baseline and 13 months follow-up. OCT and IVUS-VH were feasible in the vast majority of the cases at both baseline (OCT: 89.9%; IVUS-VH: 85.7%) and follow-up (OCT: 86.6%; IVUS-VH: 84.8%). Failure of OCT imaging was mainly caused by poor vessel flushing and difficulty of advancing the OCT catheter to the distal vessel; IVUS-VH imaging failure was mainly caused by the inability to gate the ECG or to advance the catheter into the distal vessel. A low complication rate was reported (1.9% at baseline; 1.1% at follow-up); all the events (one ventricular fibrillation, and one dissection at baseline and one ventricular fibrillation at 13 months follow-up) were caused by OCT imaging. There were no differences in the MACE between patients who had PCI with and without multimodality intravascular imaging at 2 years follow-up (16.7% vs 13.3%, P = .39). These findings suggest that multimodality intravascular imaging is feasible and safe, even in high-risk patients.

Limitations and Image Artifacts

Some image artifacts are common to both OCT and IVUS. NURD can result in focal image loss or shape distortion, but this seems to occur less frequently in OCT than in IVUS imaging, perhaps as a result of the smaller profile and simplified rotational mechanics of OCT wires. Sew-up artifact is the result of rapid artery or imaging wire movement in one frame’s imaging formation, leading to misalignment of the lumen border. Eccentricity intraluminal position of the ImageWire may lead to wider distances between A-lines and consequently decrease lateral resolution. This effect has been dubbed the “merry-go-round.” Some catheters have reflecting surface; the reflections may bounce off of multiple facets of the catheter, resulting in one or more circular lines; this artifact is called a multiple reflection artifact. Similarly, one can notice the reflection from metallic stent struts aligning toward an eccentrically positioned ImageWire (“sunflower” effect). The saturation artifact occurs when light reflected from a highly specular surface (usually stent struts) produces signals with amplitudes that exceed the dynamic range of the data acquisition system. Although these artifacts are common to all intravascular imaging technologies, others are specific to OCT imaging. The attenuation artifact occurs when the catheter is against the vessel wall. In this case, the light beam is attenuated as it passes along the surface of the artery wall, and thus the vessel wall may appear as a signal poor region below the luminal surface.³⁵ The foldover artifact is seen when the vessel is larger than the ranging depth; in this occasion the vessel may appear to fold over in the image. Residual blood produces light attenuation and may defocus the beam if the red blood cell density is high. This reduces the brightness of the vessel wall. Residual blood does not appear to affect area measurements in OCT images with a clearly defined lumen-wall interface.³⁵ The operator should be aware that residual blood can mimic the OCT appearance of thrombus. Foldover artifact is specific to the new generation of FD-OCT systems and is the consequence of the “phase wrapping” or “alias” along the Fourier transformation when structure signals are reflected beyond the field of view. This can occur at the site of bifurcations or in large vessels. Air bubbles can form within the silicon lubricant used to reduce friction between the sheath and the optic fiber in TD-OCT systems, causing light attenuation (Fig. 21–3).

Other Intervascular Imaging Modalities

Near-Infrared Spectroscopy

Another imaging modality able to detect necrotic core invasively is NIRS. To this aim, the 3.2-Fr NIRS catheter approved by the US Food and Drug Administration is used. This catheter is compatible with a conventional 0.014-in guidewire, contains a rotating (240 Hz) NIRS light source at its tip, and is pulled back by a motor drive unit at 0.5 mm/s. The catheter’s ability to detect lipid core plaques (LCPs) has been validated successfully in a human autopsy study in which the device algorithm prospectively identified LCP with a receiver operator characteristic area of 0.80 (95% confidence interval [CI], 0.76-0.85).³⁶ Nevertheless, a more extensive validation suggested that NIRS may be superior to IVUS in detecting lipid-rich plaques, but it has limited accuracy in characterizing their phenotype and detecting fibroatheroma (FA) and thin-cap fibroatheroma (TCFA).⁹ Other significant limitations of NIRS that have considerably reduced its application in the clinical arena are its inability to quantify plaque burden; visualize lumen and outer vessel wall; and assess plaque characteristics associated with increased vulnerability, such as plaque erosion, neovascularization, and microcalcification.

To overcome these limitations, combined NIRS-IVUS imaging has been proposed. Recently, a combined NIRS-IVUS catheter has been designed that enables simultaneous acquisition and coregistration of the NIRS and IVUS data. The TVC imaging system (InfraReDx, Burlington, MA) incorporates a monorail catheter that can be inserted through a 6-Fr guide and over a 0.014-in guidewire. The catheter has an entry profile of 2.4 Fr and a shaft profile of 3.6 Fr, and includes a mechanical rotating IVUS probe operating at 40 MHz that is pulled back at a speed of 0.5 mm/s using an automated pullback device. NIRS imaging is performed by a NIRS probe located at the tip of the catheter that acquires 30,000 chemical measurements per 100 mm. Each measurement interrogates 1 to 2 mm² of a tissue at a depth of 1 mm. The output of NIRS is the chemogram that is a map of the measured probability of the presence of lipid-rich tissue presented as a two-dimensional image with pullback position on the x-axis, rotation on the y-axis (as if the artery were cut longitudinally and laid flat). Yellow color indicates regions with a high probability of lipid-rich tissue, whereas red regions suggest a low probability. A measure of the lipid burden is the lipid core burden index, which ranges from 0 to 1000, and gives a semiquantitative summary of the lipid core within the scanned segment. The block chemogram is the summary of the chemogram that display the presence of the lipid tissue in 2-mm intervals. The TVC system also provides a composite view of the coregistered NIRS and IVUS data, allowing comprehensive assessment of the association between plaque burden and composition (Fig. 21–4).

Histology-based studies have shown that combined NIRS-IVUS imaging allows more accurate characterization of the composition of the plaque,^9,37 while several in vivo studies have examined the reproducibility of NIRS imaging and provided robust data that this enables a consistent assessment of plaque compositional characteristics. Over the past years, numerous studies have implemented this technology to assess the implications of lipid-lowering therapies on the compositional characteristics of the plaque and its role in identifying high-risk plaques and culprit lesions.^{18,38,39,40,41,42,43}

Emerging Imaging Modalities

Raman Spectroscopy

Raman spectroscopy relies on the spectral analysis of the Raman scattering by a tissue after being illuminated with a laser beam. The laser light is scattered between molecules, and finally the energy of the photons is changed, resulting in a different frequency of the backscattered light. The Raman spectra is unique for a given molecule and, therefore, it can be used to assess the chemical composition of the plaque and differentiate esterified from nonesterified cholesterol (see Fig. 21–1A). A significant limitation of Raman spectroscopy is the increased noise, generated within the fibers of the imaging catheters, which interferes with the Raman spectra. Modification of the initial prototypes and utilization of high-wave number Raman spectroscopy can potentially overcome this limitation and enable its application in the study of atherosclerosis.^44,45

Intravascular Photoacoustic Imaging

Intravascular photoacoustic (IVPA) imaging involves irradiation of the vessel wall by short laser pulses with a length of several nanoseconds. The absorbed laser light transfers the optical energy to the tissue, which causes a transient pressure rise⁴⁶ that propagates through the tissue as an acoustic wave and can be detected with an ultrasound transducer. The time interval between tissue irradiation and acoustic wave detection enables localization of the source and depth-resolved imaging. Studies have demonstrated that IVPA can detect the composition of the plaque and, in particular, lipid component as well as plaque features associated with increased vulnerability, such as intraplaque hemorrhage and inflammation (see Fig. 21–1B).⁴⁷

Limitations of IVPA include its inability to assess the luminal, outer vessel wall and plaque dimensions; the vessel geometry the distribution of the plaque; and the fact that optimal image quality requires blood clearance and prolonged timing. With the advent of high-speed lasers, the time for imaging is becoming compatible with clinical application.

Near-Infrared Fluorescence Imaging

Near-infrared fluorescence (NIRF) imaging caries a great potential for the study of vascular inflammation. It relies on the use of activatable markers that have the ability to bind molecules associated with plaque vulnerability and fluorescence when they irradiated by near-infrared light (see Fig. 21–1C). Advances in molecular biology have enabled detection of fibrin, of plaque’s inflammation, and identification of neovascularization.⁴⁸ Recently, a two-dimensional rotational NIRF catheter has been designed that is pulled back by an automated pullback device at a constant speed, enabling generation of a spread out plots of the coronary plaque inflammation and assessment of vessel wall biology.⁴⁹ This design enables in vivo detection of different molecules, such as thrombin, matrix metalloproteinases 2 and 9, and cathepsin K, D, and S, and permits assessment of plaque biology, inflammation, and neorevascularization.

Significant limitations of this modality are (1) that it requires injection of an activatable agent; (2) that it cannot provide depth-resolved information, and (3) assess the lumen, outer vessel wall, and plaque dimensions and composition.

Time-Resolved Fluorescence Spectroscopy

Time-resolved (lifetime) fluorescence spectroscopic (TRFS) imaging using pulsed ultraviolet light appears able to provide information about the compositional characteristics of the plaque. It relies on the assessment of the time required to resolve the fluorescence emitted after molecules being excited by light. The compositional characteristics of the plaque (ie, the lipid component, macrophages, elastin, and collagen) have different fluorescence properties; thus TRFS has a value in assessing plaque composition and inflammation (see Fig. 21–1D).⁵⁰

Recent technological advances in fluorescence lifetime imaging have enabled adaptation of these techniques for intravascular scanning.^51,52 Experimental studies have shown that TRFS measurements enable detection of diseased segments, visualization of pathological changes in the superficial plaque (~ 250-300 μm depth), and characterization of the phenotype of the plaque and differentiation of TCFA from FA.

Normal Coronary Artery Structure

Understanding of the structure of a normal coronary artery is essential to identify its pathologic conditions. The arterial wall of coronary arteries is composed of three layers. The innermost tunica intima is in direct contact with the blood and is constituted by an endothelial cell monolayer resting on a basement membrane. Aging of human arteries is associated with the presence of smooth muscle cells in the tunica intima. These cells produce extracellular matrix molecules, leading to intimal layer thickening. This process is not necessarily associated with pathologic lipid accumulation and atherosclerosis formation. The second layer, the tunica media, is separated from the tunica intima by the internal elastic membrane (IEM) and is formed by concentric layers of smooth muscle cells. The adventitia is the outermost arterial layer, which is separated from the media by the external elastic membrane (EEM) and contains fibroblasts and mast cells, collagen fibrils, vasa vasorum, and nerve endings. At the take-off from the aorta of the right and LM coronary arteries, the media and the adventitia show multiple layers of elastic lamellae as the artery transitions into a muscular artery.

The normal coronary architecture can be assessed using intravascular imaging. The circulating blood elements may assist IVUS image interpretation and differentiate the lumen from the vessel wall because these produce characteristic speckles in the image. However, the appearance of blood speckles depends on the flow velocity and may have increased intensity in case of slow blood flow, causing it to have a similar appearance as the vessel wall. The reported normal value for intimal thickness in young subjects is typically 0.15 ± 0.07 mm. Thus, the thin tunica intima poorly reflects ultrasound and is not visualized as a separate layer. The media is typically less echogenic than the intima, but it may appear thick because of signal attenuation and weak reflectivity of the IEM. A monolayer appearance is a common finding in normal coronary arteries, but a trilayered appearance by IVUS suggests the presence of intimal thickening.⁵³ A trilaminar appearance depends not only on the age but also on the histologic characteristics of the vessel. The adventitia has the strongest echo signal, which is used as a reference to determine plaque components. Importantly, the IVUS beam penetrates beyond the adventitial layer, allowing visualization of the perivascular structures, including the cardiac veins and the pericardium.

In contrast, the normal coronary artery wall (< 1.5 mm thick) appears as a three-layer structure on OCT, but imaging beyond the adventitial layer is not possible. The normal thickness of the tunica intima is approximately 4 μm, which is beyond the resolution capacity of current OCT systems. The first visualized layer is indeed the internal elastic lamina (IEL) (not seen by IVUS), which despite its less than 3-μm thickness, generates a 20-μm signal-rich band. The relatively thick media (> 100 μm) can be visualized easily by OCT,³⁵ which is depicted as a low-intensity band between the IEL and external elastic lamina (EEL). Whereas the EEL produces a signal-rich band, the adventitia produces a signal-rich band with heterogeneous texture on OCT images.

Atheroma

A number of studies have demonstrated the ability of IVUS and OCT to differentiate coronary atheroma components (Figs. 21–5 and 21–6). However, it should be stressed that in vivo intravascular imaging is fundamentally different from ex vivo histology and that specific histologic plaque components cannot be assessed by conventional clinical imaging. A detailed description of atherosclerosis development and composition is beyond the scope of this chapter (see Chap. 32). In brief, an atheroma is formed by an intricate sequence of events, not necessarily in a linear chronologic order, that involves extracellular lipid accumulation, endothelial dysfunction, leukocyte recruitment, intracellular lipid accumulation (foam cells), smooth muscle cell migration and proliferation, expansion of extracellular matrix, neoangiogenesis, tissue necrosis, and mineralization at later stages. The ultimate characteristic of an atherosclerotic plaque at any given time depends on the relative contribution of each of these features.⁵⁴ Thus, the pathologic intimal thickening (PIT) is rich in proteoglycans and lipid pools, but no trace of necrotic core is seen. The earliest lesion with a necrotic core is the FA, and this is the precursor lesion that may give rise to symptomatic heart disease. TCFA is a lesion characterized by a large necrotic core containing cholesterol clefts. The overlying fibrous cap is thin and rich in inflammatory cells, macrophages, and T lymphocytes, with few smooth muscle cells. A cutoff value for cap thickness of less than 65 μm has been suggested by histology studies to define a thin cap vulnerable coronary plaque.⁵⁵

Based on tissue echogenicity, not necessarily histologic composition, atheromas have been classified into four categories by grayscale IVUS: (1) soft plaque (lesion echogenicity less than the surrounding adventitia), (2) fibrous plaque (intermediate echogenicity between soft [echolucent] atheromas and highly echogenic calcified plaques), (3) calcified plaque (echogenicity higher than the adventitia with acoustic shadowing), and (4) mixed plaques (no single acoustical subtype represents > 80% of the plaque)²⁶ (see Fig. 21–5).

IVUS-VH can potentially identify all of the previously mentioned plaque types.⁵⁶ Figure 21–7 outlines the VH plaque and lesion types that are proposed based on the histological data.

Intravascular ultrasound-derived thin-cap fibroatheroma (IDTCFA) using IVUS-VH has been defined as a lesion fulfilling the following criteria in at least three consecutive frames: (1) necrotic core of 10% or more (2) without evident overlying fibrous tissue, and (3) plaque burden of 40% or more. Here, thin cap is defined as all fibrous caps of less than 200 microns, which is the limit of IVUS resolution. In this study, 62% of patients had at least one IDTCFA in the interrogated vessels. Patients with ACS had a significantly higher incidence of IDTCFA than did stable patients (P = .018). Finally, a clear clustering pattern was seen along the coronaries, with 66.7% of all IDTCFAs located in the first 20 mm. This distribution of IDTCFAs is consistent with previous clinical studies, with a clear clustering pattern from the ostium demonstrating a nonuniform distribution of vulnerable plaques along the coronary tree.⁵⁷ Rioufol and colleagues reported that patients presenting with ACS had a significantly higher prevalence of plaque ruptures even in nonculprit vessels, supporting the concept that atherosclerosis is a multifocal process.⁵⁸ Of note, the plaque burden and the mean necrotic core areas of the IDTCFAs detected by IVUS-VH were also similar to previously reported histopathologic data (55.9% vs 59.6% and 19% vs 23%, respectively).⁵⁹

The frequency and distribution of IDTCFA identified in patients with ACS (n = 105) and stable angina pectoris (SAP; n = 107) in a three-vessel IVUS-VH study have been reported by Hong and coworkers.⁶⁰ There were 2.5 ± 1.5 in ACS and 1.7 ± 1.1 in SAP TCFAs per patient (P < .001). A total of 76 patients with ACS and 58 with SAP had multiple ID TCFA (P = .009). Presentation of ACS was the only independent predictor for multiple IDTCFA (P = .011). A total of 83% of IDTCFA were located within the first 40 mm of the coronary.

Although a 2-mm depth might be sufficient to image the entire plaque in most diseased vessels, OCT cannot serve as a routine method to assess deeper arterial wall structures such as the adventitia. Ex vivo validations have also shown that OCT is superior to conventional and integrated backscatter IVUS for characterization of coronary atherosclerotic plaque composition.^19,61 In vivo, OCT is able to identify most of the architectural features identified by IVUS and may be superior for the identification of lipid pools, calcification, and thrombus.⁶² A study comparing OCT with histopathology reported 41% plaque misclassification mostly caused by a combination of incomplete image penetration and the inability to distinguish calcium deposits from lipid pools.⁶³ An ex vivo OCT investigation classified 357 diseased carotid and coronary segments as fibrous, fibrocalcific, and lipid-rich plaques. Fibrous plaques were characterized as homogeneous, signal-rich regions; fibrocalcific plaques as signal-poor regions with sharp borders; and lipid-rich plaques as signal-poor regions with diffuse borders (see Figs. 21–5 and 21–6). The comparison with histology showed a sensitivity and specificity ranging from 71% to 79% and 97% to 98% for fibrous plaques; 95% to 96% and 97% for fibrocalcific plaques; and 90% to 94% and 90% to 92% for lipid-rich plaques, respectively.⁶⁴

Numerous OCT-based studies confirmed the findings of IVUS-based imaging reports, demonstrating a higher prevalence of lipid-rich plaques in the proximal segment of the coronary arteries^65,66 and in patients with ACS than in patients with SAP.^62,67,68 Patients with renal impairment, diabetic patients, and patients with metabolic syndrome appear to have coronary plaques with an increased lipid component compared to patients without a metabolic syndrome/renal failure. In addition, patients with renal failure also had an increase in calcific tissue component.^69,70,71

Detection of Calcification

The presence, depth, and circumferential distribution of calcification are important factors for selecting the type of interventional device and estimating the risk of vessel dissection and perforation during PCI. On IVUS, calcium appears as bright echoes that obstruct the penetration of ultrasound (acoustic shadowing) (see Fig. 21–5A). IVUS detects only the leading edge of calcium and cannot determine its thickness. Thus, calcification on IVUS is usually described based on its circumferential angle (arc), longitudinal length, and depth. Calcification can be located deeper in the arterial wall or in the surface of the plaque in close contact with the lumen wall interface. As mentioned above, calcium can produce reverberations or repeated reflections at reproducible distances. IVUS has shown significantly higher sensitivity than fluoroscopy in the detection of coronary calcification.⁷² Virtual histology, compared with histology, has a predictive accuracy of 96.7% for detection of dense calcium.¹²

In contrast to ultrasonography, light penetrates calcium well, and OCT can depict calcification within plaques as well-delineated, low-backscattering heterogeneous regions (see Figs. 21–5 and 21–6). In addition to circumferential angulation, depth, and longitudinal length, OCT can quantify calcium burden. A histology-based study, that compared the accuracy of IVUS and OCT in assessing the calcific burden, has demonstrated that OCT allows more accurate estimation of the calcium component than IVUS, which significantly underestimates its extent.⁷³

Superficial microcalcifications can also be identified on OCT images as small calcific deposits separated from the lumen by a thin tissue layer. A sensitivity of 96% and a specificity of 97% to detect calcified nodules by OCT compared with histology have been reported.⁶⁴

Arterial Remodeling

Arterial remodeling refers to a continuous process involving positive or negative changes in vessel size measured by the EEM cross-sectional area (CSA). Positive remodeling occurs when there is an outward increase in EEM. Negative remodeling occurs when the EEM decreases in size (shrinkage of the vessel).²⁶ The magnitude and direction of remodeling can be expressed by the following index: EEM CSA at the plaque site divided by EEM CSA at the reference “nondiseased” vessel. Whereas positive remodeling demonstrates an index above 1.0, negative remodeling has an index below 1.0. Direct evidence of remodeling can only be demonstrated in serial studies showing changes in the EEM CSA over time because remodeling may also be encountered at the “normal-appearing” reference coronary segment.²⁶

Whether this phenomenon, which was first described by Glagov,⁷⁴ is an independent process or an adaptive response to compensate for plaque growth is still debated. The limitation of angiography in determining disease burden and stenosis severity is largely caused by vessel remodeling. Detection of remodeling is extremely important during PCI to define plaque burden and the appropriate size of devices. The limited penetration of light into tissue poses significant limitations for appropriate assessment of remodeling by OCT.

Pathologic studies have also suggested a relationship between positive vessel remodeling and plaque vulnerability. Vessels with positive remodeling showed increased inflammatory marker concentrations, larger lipid cores, a paucity of smooth muscle cells, and medial thinning.^75,76 Several IVUS studies have linked positive vessel remodeling with culprit and ruptured coronary plaques.⁷⁷ Positive remodeling has been observed more often in patients with an ACS than in those with stable CAD,⁷⁸ and it has been identified as an independent predictor of MACE in patients with unstable angina. Plaques exhibiting positive remodeling also more often demonstrate thrombus and signs of rupture.⁷⁹ The pattern of remodeling has also been correlated with plaque composition; soft plaques exhibit often positive remodeling, whereas fibrocalcific plaques have more often negative or constrictive remodeling.⁸⁰ Similar findings have been observed in studies using IVUS-VH analysis, a technique developed specifically for tissue characterization. Positive remodeling was directly correlated with the presence and size of the necrotic core and inversely associated with fibrotic tissue. NIRS-IVUS imaging based studies have also revealed a direct association between positive remodeling and lipid component.^37,81 A recent meta-analysis of the PROSPECT study has shown that not only positive remodeling, but also negative remodeling, predicted lesions that cause cardiovascular events at follow-up.⁸²

Vulnerable Plaque and Thrombi

ACS are often the first manifestation of coronary atherosclerosis, making the identification of plaques at high risk for complication an important component of strategies to reduce deaths associated with atherosclerosis. Our current understanding of plaque biology suggests that approximately 60% to 80% of clinically evident plaque rupture originates within an inflamed TCFA.^2,83 Plaque ruptures occur at sites of significant plaque accumulation but are often not highly stenotic by coronary angiography because of positive vascular remodeling.^84,85,86 The transition to plaque rupture has been characterized by the presence of active inflammation (monocyte or macrophage infiltration), thinning of the fibrous cap (< 80 μm), development of large lipid necrotic core, endothelial denudation with superficial platelet aggregation, and intraplaque hemorrhage.⁸⁷ The remaining plaques that cause ACS contain calcium nodules (~ 10%) or have none of the pathologic features described (~ 20%). Superficial plaque erosion explains at least a portion of the latter events, particularly in women and individuals with diabetes, and occurs in plaques that are rich in proteoglycans and smooth muscle cells, as well as in individuals with a PIT or a FA phenotype.⁸⁸

In addition, most plaque ruptures are silent without clinical manifestations, and repetitive healed ruptures may contribute to stable progression into obstructive disease.^89,90 Although plaque characteristics do not yet influence current therapeutic guidelines, the available clinical imaging modalities, IVUS and OCT, have the ability to identify some of the pathologic atheroma features described above (see Figs. 21–5 and 21–6). The clinical implications of plaque rupture appear to depend on the anatomical characteristics of the plaque. A recently published analysis demonstrated that OCT plaque characteristics enable detection of the lesions that are likely to rupture, whereas IVUS imaging appears able to predict which of the ruptured plaque will cause cardiovascular events.^91,92 Ruptured TCFA have more thrombus and a thinner fibrous cap compared to the nonruptured TCFA. IVUS analysis demonstrated that the ruptured plaques causing events have smaller lumen area and increased plaque burden compared to the plaques having a silent rupture.

The preferential localization of atherosclerosis is somewhat puzzling. The entire vasculature is exposed to systemic injury from insults such as high lipoproteins, hypertension, cigarette-smoking metabolites, inflammation, high insulin and glucose levels, and oxidative stress. Nevertheless, pathologic, angiographic and, more recently, IVUS and OCT studies have shown that plaque rupture occurs more often in the proximal 40-mm segment of the left coronary arteries.^66,93,94 In the LM coronary artery, plaque ruptures are more often observed in the distal segment or at the bifurcation.⁹⁵ Several IVUS and OCT studies revealed that up to 79% of the patients with ACS also have a ruptured plaque in another nonculprit lesion.^58,90,91

IVUS has also been used to assess the natural evolution of ruptured plaques. IVUS studies have suggested that up to 50% of the ruptured plaques detected in a first ACS event heal with medical therapy without significant change in plaque size.⁹⁶ One study revealed complete healing of plaque rupture in 29% of patients treated with statins and incomplete healing in untreated patients.⁹⁷

Thrombus represents the ultimate pathologic feature leading to ACS. Thrombus is usually recognized as an echolucent intraluminal mass, often with a layered or pedunculated appearance by IVUS.²⁶ Whereas fresh or acute thrombus may appear as an echodense intraluminal tissue that does not follow the circular appearance of the vessel wall, older, more organized thrombus has a darker ultrasound appearance. However, none of these IVUS features is a hallmark for thrombus, and one should consider slow flow (fresh thrombus), air, stagnant contrast or black hole, an echolucent neointimal tissue observed after drug-eluting stents (DES), and radiation therapy as differential diagnoses.²⁶

Although OCT images do not currently have the tissue penetration to quantify large lipid cores and evaluate remodeling, their high resolution allows precise visualization and quantification of the thin fibrous cap, allowing accurate detection of ruptured plaques.^35,98 As already discussed, OCT is highly sensitive and specific for characterizing different types of atherosclerotic plaques. In particular, studies have shown the ability of OCT to detect macrophage infiltrate (at least in vitro), detect plaque erosion, and not only identify but also characterize thrombus composition.^35,99 These findings position OCT as the ideal tool for unraveling the complex pathophysiology of atherosclerosis progression and plaque rupture.

The prevailing hypothesis that ruptured fibrous caps have less than a 65-μm thickness⁵⁵ derives from seminal postmortem investigations. OCT has revealed that patterns of fibrous cap thickness in ruptured plaques vary widely in vivo. The average cap thickness was 90 μm in patients presenting with ST-segment elevation myocardial infarction (STEMI) triggered by exertion. In contrast, ruptured fibrous cap thickness averaged 50 μm in 57% of STEMI patients who experienced symptoms at rest²⁷ (Fig. 21–8). The incidence of TCFA was 83% in a clinical study comparing OCT, IVUS, and angioscopy, and only OCT was able to estimate the fibrous cap thickness (mean, 49 ± 21 μm).^100,101 OCT has also been used to monitor the thickness of the fibrous cap over time, with several studies showing an increase in cap thickness in patients taking lipid-lowering medications.^3,102,103

The large size of macrophages and the high lipid content of foam cells yield strong optical signals, allowing OCT to detect macrophage infiltration in the fibrous cap as bright spots.³⁵ Histology-based studies have showed that OCT allows accurate detection of the macrophages in the fibrous cap, but it has a low sensitivity and specificity in the remaining plaque.¹⁰⁴ In vivo OCT studies have suggested higher macrophage density in unstable versus stable patients and at sites of plaque rupture versus nonruptured sites.¹⁰⁵

The interface between lipid and fibrous tissue causes a high superficial backscattering border, allowing OCT to accurately identify the presence of a necrotic core. However, light is highly absorbed by lipids, leading to low or no signal beyond the necrotic core, making determination of the extent of the lipid pool difficult to quantify.

Overall, OCT possesses diagnostic advantages compared with both IVUS and angioscopy in the assessment of thrombus in culprit lesions, but previous studies were conducted in a selected population with a high pretest probability of thrombosis.^98,106,107 OCT was compared with IVUS and angioscopy for the assessment of the culprit lesion morphology in patients with ACS. Plaque rupture, detected by OCT in 73% of patients, was significantly higher than that detected by both angioscopy (47%; P = .035) and IVUS (40%; P = .009). Intracoronary thrombus was observed in all cases by OCT and angioscopy but was identified in only 33% by IVUS.⁹⁸ Furthermore, the ability of OCT to distinguish between white, low-backscattering thrombus from red, high-backscattering thrombus, has been demonstrated in a postmortem study (Fig. 21–9).⁹⁹

Determination of the Severity and Extent of Atherosclerosis

The estimation of the severity and extent of atherosclerosis remains one of the main diagnostic clinical applications of intravascular imaging because angiography and noninvasive methods lack spatial and temporal resolution for accurate coronary disease assessment. Standards for acquisition, measurement, and reporting of IVUS have been proposed in a clinical expert consensus document.²⁶ Similarly, a recent expert opinion report proposed standards for diagnostic assessment of atherosclerosis by OCT.³² Cross-sectional measurements are essentially the same for both IVUS and OCT. Luminal area stenosis describes the relative decrease in luminal CSA at the site of disease, in percentage, compared with lumen CSA in a “normal-appearing” reference segment in the same coronary. The lumen area relative to the reference lumen area is analogous to the angiographic definition of diameter stenosis. Proximal and distal reference lumen areas are calculated at sites with the largest lumen located before large side branches and within 10 mm proximal and distal to the plaque, respectively. The image analyst should be aware of potential poststenotic dilatation of the vessel wall when using these measurements to guide clinical decisions. The minimal lumen area (MLA) describes the smallest lumen CSA along the length of the target lesion. Because most vessels depict an oval rather than a perfect circular shape, maximum lumen diameter and minimal lumen diameters are calculated along a vector passing through the lumen center at the reference segments. Reference vessel lumen diameter is essential to guide section of interventional devices. Measurements of distances (length) are based on the automated pullback speed during image acquisition. Disease length can be calculated based on the number of seconds or frames between the first and last image frames depicting the atherosclerotic plaque.

Calibration represents an essential step in any image quantification. Current IVUS digital systems provide automated calibration without the need for manual adjustments. Older mechanical IVUS systems required manual calibration, which was based on a predefined calibration grid displayed in the cross-sectional image. The imperatives of accurate image calibration remain valid for OCT images. The size of the OCT image is calibrated by adjusting the feature called the z-offset, which represents the zero-point setting of the system. Given the high resolution of OCT images, z-offset must be fine-tuned before image quantification, particularly when performing strut-level analysis. In the current LightLab TD-OCT system, the catheter diameter acts as a reference for optimal z-offset determination within an image frame. The four marks or fiduciaries should align to fit the outer surface of the catheter. If the catheter is not well visualized, calibration is performed in a frame where the catheter is in contact with the vascular surface by adjusting the fiduciaries to align the vessel wall. Corrections are typically made in the first 10 mm of the pullback image. The operator should monitor these patterns throughout the entire pullback because additional adjustments may be necessary. In the C7-XR LightLab FD-OCT catheters, calibration is adjusted automatically and the semitransparent catheter around the optic fiber facilitates manual calibration when needed.

Quantification of Luminal Dimensions

Comparisons of luminal geometry at the site of disease versus a reference “nondiseased” segment remain the cornerstone of clinical decision making in the catheterization laboratory. Clinical IVUS units have integrated automated contour detection algorithms to facilitate online measurements, which should be performed at the leading edge of luminal boundaries (Fig. 21–10).²⁶ Measurements are determined by planimetry in cross-sectional images, and longitudinal views may help orient the operator. The similar ultrasound appearance of blood and soft plaques may render lumen detection in single-image frames inaccurate, requiring evaluation of dynamic images to properly differentiate moving blood speckles from the arterial wall.

Blood is displaced by saline or iodine contrast during OCT imaging acquisition, leading to a clear, well-characterized interface between the lumen and the vessel wall. This allows fully automated and real-time lumen contour detection with high precision, requiring minimal, if any, operator interference.

Assessment of Atheroma Burden

Quantification of atheroma or plaque area in IVUS images is performed by subtracting the lumen area from the EEL area. Hence, the IVUS-defined atheroma area is a combination of plaque plus the media area. The atheroma area can be calculated in each frame (cross-sectional image), and total atheroma volume (TAV) can be calculated based on the pullback speed during image acquisition. The atheroma volume can be reported as the percent of the volume of the EEM occupied by atheroma, namely the percent atheroma volume (PAV). Parameters commonly used to report the extent of the coronary atherosclerosis in research protocols are shown in Fig. 21–11.

In the presence of a large plaque burden (> 1.5-mm thick), OCT may fail to visualize the entire circumference of the IEL. Consequently, the plaque burden cannot be measured in many lesions. Unlike IVUS, OCT can visualize the IEL and, therefore, can distinguish the atherosclerotic plaque from the muscular media. Measurements are performed between the inner lumen border and the media, which corresponds to the “true” histologic area of the atheroma.

Assessment of Ambiguous Anatomy on Angiography

The three-dimensional and dynamic nature of the coronary vasculature cannot be fully appreciated by planar angiography. Frequently, defining the proper angiographic angulation that provides a straight, nonforeshortened view of the target coronary segment without overlapping of other vessels may be a challenge in the catheterization laboratory. As discussed previously, determination of disease severity by angiography is hampered by the diffuse nature of atherosclerosis and its most common eccentric growth in the vessel wall. Hence, lesions may appear more stenotic in one orthogonal view than in the other, making clinical decisions difficult. The so-called “intermediate lesion” is the more prevalent phenotype in the coronary tree. The American Heart Association/American College of Cardiology/Society for Angiography and Interventions (AHA/ACC/SCAI) guidelines define an intermediate coronary lesion as a plaque producing a 30% to 70% stenosis on angiography.¹⁰⁸ These plaques represent a heterogeneous group of coronary lesions, which can be hemodynamically flow limiting or not. The IVUS minimum luminal cross-sectional area (MLA) proved to be a good morphometric surrogate of coronary physiology. In 73 patients studied preintervention, an MLA of 4.0 mm² or more had a diagnostic accuracy of 89% in predicting a coronary flow reserve above 2.0. Likewise, IVUS has been correlated with noninvasive single-photon emission computed tomography (SPECT).¹⁰⁹ A 4-mm² MLA by IVUS had 88% sensitivity and 90% specificity to discriminate the SPECT (+) group from the SPECT (–) group. Over the past years, several studies have examined the value of IVUS in detecting hemodynamic significant lesions using fractional flow reserve (FFR) as a gold standard and demonstrated that IVUS has a moderate accuracy in identifying obstructive stenoses.^{110,111,112,113} Reports have recently explored the accuracy of OCT-derived metrics in detecting flow-limiting stenoses and showed that OCT had also a moderate—although a slightly better than IVUS—accuracy in detecting hemodynamic significant lesions.^110,114,115

The limited value of intravascular imaging in detecting flow-limiting lesions should be attributed to the fact that the hemodynamic implications of a stenosis depends not only on the MLA but also on the length of the stenosis and the physiology of the microvascular bed, which cannot be assessed by imaging techniques.

Intravascular imaging can have a role, however, in assessing hazy lesions,^116,117 detecting spontaneous dissection,¹¹⁸ identifying the causes of stent failure (ie, stent fracture, in-stent restenosis, stent underexpansion, neoatherosclerosis, stent malapposition), and planning further treatment.^119,120,121

Aneurysmal and Large Vessels

A true aneurysm cannot be determined by angiography because its definition requires expansion of all three layers of the vessel wall with an increased in EEM and lumen area more than 50% larger than the proximal reference segment. Pseudoaneurysm is characterized by disruption of the EEM, usually observed after PCI or plaque rupture. IVUS is extremely useful not only to differentiate between true and pseudoaneurysmal formation but also to evaluate vessel sizes and the presence of lumen stenosis, which is often masked by the aneurysm.¹²² On the other hand, OCT is not suitable to evaluate aneurysmal disease in vessels larger than 3 mm in diameter, given its limited imaging depth.

There is robust evidence that intravascular imaging can provide useful information in patients with an intermediate LM obstruction. Abizaid and colleagues followed 122 patients with moderate LM stenosis for 1 year and found that a smaller minimal lumen diameter (MLD) measured by IVUS was associated with a worse outcomes (event rate 60% for patients with MLD < 2.0 mm, 24% for MLD 2.0-2.5mm, 16% for MLD 2.5-3.0 and 3% for MLD > 3 mm). In contrast to angiographic indices, IVUS-derived MLD was an independent predictor of cardiac events in multivariable model (odds ratio [OR] 0.17, 95% CI: 0.05-0.59; P = .005).¹²³ In another study, an IVUS-determined MLD of 2.8 mm and an MLA of 5.9 mm² had the highest sensitivity and specificity (93% and 98% for MLD; 93% and 95% for MLA, respectively) for detecting hemodynamically significant LM stenosis compared with FFR.¹²⁴ Based on this study, the recently conducted LITRO study examined the value of IVUS in deferring PCI in patients with an intermediate LM stenosis. Three hundred fifty-four patients with an intermediate LM disease were included in the study; patients underwent PCI if they had a MLA of 6 mm² or less while those with a MLA of greater than 6 mm² were left untreated. At 2 years follow-up, there was no differences in the event rate in the patients who underwent LM revascularization and those who were left untreated (87.3 vs 94.3; P = 0.3).¹²⁵ Of note, this study was conducted in a Caucasian population and it is unclear whether this criterion can be applied in other ethnicities. Recently, a Korean report that included 55 patients with isolated LM disease who had IVUS and FFR imaging has shown that the IVUS-derived MLA that predicted hemodynamic significant stenosis was considerably smaller in this population (4.8 mm² for FFR < 0.80).¹²⁶

Data about the role of OCT in assessing LM disease are limited. A. Erglis (personal communication, 2009) compared FD-OCT with IVUS to visualize the LM and showed that OCT may have a value in this setting. However, future studies are required to determine the role of OCT to determine lesion severity and guide LM PCI.

Ostial and Bifurcation Disease

The continuous dynamic variation in the three-dimensional anatomical configurations of coronary bifurcations poses significant challenges to planar coronary imaging modalities. Intravascular imaging plays an important role in evaluating the severity and distribution of atheroma in the bifurcation segment. IVUS has been used to identify and characterize aorto-ostial disease, but OCT remains limited for this anatomical indication because of the difficulty to clear the blood. The concept of “plaque shift” to explain side-branch occlusion during intervention in the main branch is not supported by IVUS and necropsy studies that have shown plaques most commonly located in the opposite side of side branches.¹²⁷ Three-dimensional OCT has recently attracted attention for the evaluation of the bifurcation lesions because it appears able to provide a comprehensive assessment of the coronary anatomy. Thus, it can facilitate rewiring and procedural planning and assessment of the final results, detect carina shift, and evaluate the extent of the stenosis at the ostium of the side branch.^128,129,130

Diffuse and Cardiac Allograft Disease

Most clinical adverse events in transplant patients occur after 1 year. The cumulative incidence of cardiac events per patient year is 0.9% within the first year, increasing to 1.9% by 5 years. Cardiac events account for 3.8% of the deaths by the end of the first year, increasing to 18% of total mortality by 7 years after heart transplantation. After the first year of transplantation, 36% (20 of 55) of the patients die because of CAD.¹³¹ MI is usually silent because the heart is denervated. Therefore, there is a need for screening for early detection of coronary atherosclerosis. The presence of obstructive coronary disease in angiography is a predictor of any cardiac event (OR 3.44; P < .05), as well as a predictor of cardiac death (OR 4.6; P < .05). A pathologic study reported on 10 patients who died or underwent retransplantation within 2 months of coronary angiography. One-fourth of the patients had intermediate lesions or atheromatous plaques. Fresh or organizing thrombus was most often associated with discrete lesions and accounted for all complete occlusions. The authors concluded that transplant CAD has a heterogeneous histologic and angiographic appearance, with angiographic underestimation of disease in some patients. Numerous reports have demonstrated that IVUS-derived plaque characteristics provide useful prognostic information in this vulnerable population.^132,133 In a study that included 143 patients who underwent three-vessel IVUS investigation at 1 and 12 months after transplantation, rapid change in intimal thickness (≥ 0.5 mm was defined as rapidly progressive vasculopathy) was found at 1 year in 37% of the patients, and a new lesion was found in 47% of them. At 5.9 years, patients with rapid progression had a higher mortality than their counterparts (26% vs 11%; P = .03). The combined end point of death and MI was also more frequently seen in patients with rapid progression (51% vs 16%; P < .0001).¹³³ In a more recent report, an increase in the media-intima thickness greater than 0.35 mm and not of 0.5 mm was an independent predictor of MACE.¹³² Accordingly, many active transplant centers have incorporated IVUS imaging into their post-transplant surveillance to estimate prognosis, but there is no consensus on how frequently IVUS should be performed. IVUS has been also used to assess novel therapies in heart transplantation recipients. Eisen and colleagues randomized 634 patients to receive 1.5 mg/d of everolimus (209 patients), 3.0 mg/d of everolimus (211 patients), or 1.0 to 3.0 mg/d of azathioprine (214 patients) per kilogram of body weight in combination with cyclosporine, corticosteroids, and statins. The primary efficacy end point was a composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proven acute rejection of grade 3A, or rejection with hemodynamic compromise. At 1 year, IVUS showed that the average increase in maximal intimal thickness was significantly smaller in the two everolimus groups than in the azathioprine group.¹³⁴ The value of OCT to assess allograft disease has been recently investigated in small-scale studies. Ichibori and coworkers assessed with OCT coronary plaque characteristics in 45 patients (155 vessels) who had undergone heart transplantation and demonstrated that neovessels are seen more often in segments with an increased intima-media thickness, suggesting that neovessels may play a role in transplant coronary artery vasculopathy.¹³⁵ In addition, Dong and colleagues used OCT to study the coronary anatomy of 48 patients and showed that patients with transplant coronary artery vasculopathy have an increased intima-medial thickness and macrophage accumulation.¹³⁶ Finally, Cassar and coworkers used OCT to demonstrate that patients with coronary artery vasculopathy have lesions with vulnerable plaque characteristics (ie, TCFA phenotype, microchannels, macrophages, thrombus, and intimal laceration).¹³⁷

The use of intravascular imaging to guide PCI is heterogeneously distributed across the world, varying from more than 60% of use in Japan to less than 20% in Europe and United States. The explanation for such disparity is multifactorial but likely involves local reimbursement practices for the procedure, differences in clinical practice and training, and a relative lack of scientific evidence.

Preinterventional Imaging

Intravascular imaging provides the only means (1) to accurately determine the vessel size, disease severity, character, extent, as well as location and (2) to guide therapeutic decision making in the cardiac catheterization laboratory. The main limitation of intravascular imaging is that despite the extreme miniaturization of IVUS and FD-OCT catheters, these probes may occlude vessels with severe stenoses, which may disturb image acquisition and interpretation. The additional information provided by IVUS on lesion composition, eccentricity, and length may change treatment strategies in up to 20% of cases.¹³⁸ As discussed previously, the presence, depth, and circumferential distribution of calcification are very important factors for selecting the type of interventional device.¹³⁹

Non–Stent-Based Percutaneous Coronary Interventions

Contemporary PCI techniques are essentially based on stents, but balloon angioplasty remains an integral step of the procedure. In addition, atherectomy and plaque modification strategies remain necessary in some procedures. Thus, understanding the mechanisms and the proper utilization of these techniques remains important in the modern era. The importance of intravascular imaging is likely amplified in non–stent-based interventions with the goal of maximal luminal gain and minimal risk of dissection and vessel perforation. Selection of the device size can be based on measurements of the total vessel (EEM) diameter, although a more conservative approach matching the balloon size to that of lumen diameter of the distal reference segments is most routinely performed in practice. The landmark Clinical Outcomes with Ultrasound Trial (CLOUT) study showed that mid-wall dimensions measured by IVUS can be safely used for balloon sizing.¹⁴⁰ In this study, angioplasty was initially performed using angiography-defined balloon sizes; then repeat angioplasty was performed guided by IVUS imaging. This study showed that 73% of the lesions needed larger balloons even after achieving an “optimal” angiographic result and a success rate of IVUS-guided angioplasty of 99% without increased rates of dissections or ischemic complications. These findings have been confirmed in other studies.

Modifications of the dilatation strategy based on IVUS results include changes in balloon diameter, length, type, and inflation pressure. IVUS is also critical to define circumferential and longitudinal extension of plaque fracture or dissection and to guide the need for further intervention. Dissections can be classified into five categories: (1) intimal, (2) medial, (3) adventitial, (4) intramural hematoma (an accumulation of blood within the medial space, displacing the IEM inward and EEM outward), and (5) intrastent.²⁶ The severity of a dissection can be quantified according to depth, circumferential extent (in degrees of arc), length, size of residual lumen (CSA), and CSA of the luminal dissection.¹⁴¹ Additional descriptors of a dissection may include the presence of a false lumen, the identification of mobile flap(s), the presence of calcium at the dissection border, and dissections in close proximity to stent edges. In a minority of patients, the dissection may not be apparent by IVUS because of scaffolding by the imaging catheter or because the dissection is located behind calcium.

IVUS studies have also been performed to define predictors of restenosis after balloon angioplasty. One of the main contributions of intravascular imaging to this field was the realization that negative remodeling, not neointimal hyperplasia, was the most important mechanism of long-term failures of nonstented coronary interventions, namely restenosis. This was initially demonstrated in the peripheral vessels and later reported in the coronary circulation.¹⁴² These studies revealed that more than 70% of lumen loss was attributable to the decrease in EEM area; the neointima accounted for only 23% of the loss.

Although stand-alone atherectomy coronary intervention is not used in modern practice, these techniques still play a role in plaque modification and facilitate stent deployment. The use of IVUS during atherectomy results in a more aggressive strategy, leading to a greater plaque removal and a larger lumen diameter.¹⁴³ The adjunctive use of IVUS-guided directional coronary atherectomy (DCA) before stenting was proposed in the Stenting after Optimal Lesion Debulking (SOLD) registry¹⁴⁴ but the Atherectomy before Multilink Improves Lumen Gain Outcome (AMIGO) randomized trial failed to show a benefit in terms of angiographic restenosis of DCA followed by coronary stenting compared with coronary stenting alone.¹⁴⁵ Although DCA technologies have been removed from the US market, rotational atherectomy remains a niche technique to facilitate stent delivery in patients with severe coronary lesion calcification. IVUS can detect calcification, define the location and extent of calcification, and help define the need for the use of rotational atherectomy in clinical practice.^146,147 However, vessel calcification impacts delivery of the IVUS catheter and the quality of images, which hinders preintervention IVUS utilization in many cases.

Stent-Based Percutaneous Coronary Interventions

Stents have become standard in virtually every PCI. IVUS has played a critical role in the establishment of modern stent deployment techniques. IVUS provides cross-sectional views of the stent, enabling unique assessment of expansion, apposition, vessel dissection, and residual untreated disease that cannot be properly defined by angiography. The pioneer report of Colombo and coworkers revealing a mean residual stenosis of 51% after angiography-guided stent deployment and a high prevalence of incomplete stent apposition significantly altered the understanding of optimal stent deployment and prevention of subacute thrombosis. After balloon inflations at higher pressures (typically 18-20 atm), use of a larger balloon, or both, the operators were able to reduce the residual stenosis to 34%, which likely led to a 0.3% rate of subacute thrombosis without the need for systemic postprocedure anticoagulation.¹⁴⁸ However, restenosis remained an important limitation of the bare metal stent (BMS), affecting approximately 20% to 40% of patients.

“The bigger the better” adage that has dominated the interventional cardiology approach for decades¹²⁵ derived from angiography assessment of lumen gain and late loss, but it also suggests the importance of IVUS to optimize stent expansion and maximize lumen gain without the risk of vascular complication. The landmark Multicenter Ultrasound Stenting in Coronaries (MUSIC) registry helped defined IVUS criteria for optimal stenting and was based on three variables: (1) complete apposition of the stent over its entire length, (2) symmetric stent expansion defined by the ratio of minimal to maximal lumen diameter of 0.7 or above, and (3) in-stent MLA 90% or greater of the average area of distal and proximal references or 100% or greater of the lumen area of the reference segment with the smallest lumen area.¹⁴⁹ The subgroup of patients that met the criteria had a record 8% rate of restenosis after BMS implantation. However, the criteria are difficult to achieve in real practice. In the Optimal Stent Implantation Trial, stents were postdilatated at 18 atm, and only 60% reached the MUSIC criteria. In the Angiography Versus Intravascular Ultrasound Directed (AVID) stent placement trial, the more liberal goal of in-stent lumen CSA 90% or larger of the distal reference area was not achieved in more than 70% of 225 patients.¹⁵⁰ Other adaptations to the criteria have been suggested, including (1) an 80% average reference area and a 90% lumen area of the reference segment with the smallest area, (2) a minimal in-stent lumen area of 9 mm² or larger, and (3) a ratio of stent area to reference EEM area of 0.55 or above. However, these commonly used IVUS end points based on a predefined stent-to-reference ratio are also difficult to achieve.

Several prospective clinical studies have been conducted to test the hypothesis that IVUS guidance of stent deployment improves outcomes, but the results were conflicting. Can Routine Ultrasound Influence Stent Expansion? (CRUISE) was a large observational substudy involving 538 patients from the Stent Anticoagulation Regimen Study (STARS), a randomized, multicenter trial testing different antithrombotic regimens that compared angiographic versus ultrasound guidance on a center-by-center basis. The study showed improvement in the rates of target vessel revascularization after 9 months in patients treated at centers using the IVUS-guided approach.¹⁵¹ In the Optimization with ICUS (OPTICUS) study, IVUS- and angiography-guided approaches resulted in similar rates of both angiographic restenosis and need for target vessel revascularization.¹⁵² The Thrombocyte Activity Evaluation and Effects of Ultrasound Guidance in Long Intracoronary Stent Placement (TULIP) study suggested that routine IVUS guidance for stent deployment was likely to be of benefit only in patients at high risk for restenosis.¹⁵³ A large retrospective study including 884 patients compared outcomes of IVUS-guided versus a propensity-score matched population undergoing DES implantation with angiographic guidance alone.¹⁵⁴ The study showed that IVUS guidance during DES implantation reduced both DES thrombosis and the need for repeat revascularization.

However, the focus of contemporary interventional cardiology has shifted toward improving the safety rather than efficacy of DES, because these devices have virtually eliminated the problem of restenosis but have been associated with late in-stent thrombosis. IVUS studies were important to provide a morphologic analysis of the local biologic effects of the implantation of DES. Initial IVUS studies were essentially to confirm suppression of neointimal hyperplasia by DES.^155,156 These studies also revealed the occurrence of new late, incomplete stent apposition, which has been anecdotally associated with in-stent thrombosis. The first randomized control studies investigating the prognostic implications of IVUS-guided PCI in the DES era failed to demonstrate improved outcomes in the IVUS-guided group.^157,158 The Angiography Versus IVUS Optimization (AVIO) study was the first well-designed clinical study that examined the role and prognostic value of IVUS-guided PCI. In this study, prespecified criteria were suggested to define optimal stent deployment in the IVUS guided group. According to the AVIO criteria, the average EEM diameter at the proximal and distal reference segment was used to select the diameter of the noncompliant balloon for postdilation and optimal stent deployment was defined as a greater than 80% minimum lumen area of the predicted area of the noncompliant balloon. Two hundred eighty-four patients with complex lesions (long lesions, chronic total occlusions, bifurcations, small vessels ≤ 2.5 mm) were randomized to IVUS and conventional PCI and were followed for 2 years. Although at postprocedure, the MLD was higher in the IVUS-guided group (2.70 ± 0.46 vs 2.51 ± 0.46mm; P = .0002), there were no differences in the clinical outcomes at 2 years follow-up.¹⁵⁷ The results of the study conducted by Kim and colleagues, who focused on long lesions, were similar. 543 patients with lesions greater than 28 mm were randomized to IVUS and angiography-guided PCI. At 1 year of follow-up, there was no difference in the MACE rate between the two groups (4.5% vs 7.3%; P = .16).¹⁵⁸

Nevertheless, the results of meta-analyses and of the large-scale Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents (ADAPT-DES) registry have provided cumulative evidence that IVUS guidance is related to better clinical outcomes in the DES era.^{159,160,161,162,163} Possible explanation of this controversy was the small number of patients included in the first studies, which were not sufficiently powered to demonstrate the prognostic benefit of IVUS guidance. Indeed, the recently published IVUS Guidance on Outcomes of Xience Prime Stents in Long Lesions (IVUS-XPL)—the first appropriately sized randomized study—confirmed this hypothesis. In this study, 1400 patients with long lesions (> 28 mm) were randomized to IVUS and angiography-guided PCI.¹⁶⁴ IVUS guidance was associated with a lower incidence of MACE at 1 year of follow-up (2.9% vs 5.8%; P = .007), which was attributed to a lower incidence of target lesion revascularization (2.5% vs 5.0%; P = .02).

IVUS-guidance seems also to be useful in the treatment of chronic total occlusions. IVUS can be used to identify the entry site in stumpless chronic total occlusions and optimize stent deployment. A recent report has shown that IVUS-guided stent implantation in chronic total occlusion is associated with a lower incidence of late lumen loss (0.28 ± 0.48 mm vs 0.46 ± 0.68 mm; P = .025) and in-stent restenosis (3.9% vs 13.7%; P = .021) compared to angiography-guided PCI,¹⁶⁵ while another study that included 402 patients with chronic total occlusions who were randomized to IVUS- or angiography-guided treatment has demonstrated a lower MACE rate in the IVUS-guided group (2.6% vs 7.1%; P = .035).¹⁶⁶ On the other hand, the Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) MI registry has shown that IVUS-guided PCI in patients admitted with a STEMI is not associated with better clinical outcomes compared to angiography-guided PCI.¹⁶⁷

The use of IVUS to guide stent implantation in LM PCI has been evaluated in two propensity matched analyses.^168,169 Park and colleagues compared clinical outcomes in 402 propensity matched patients who had LM PCI under angiographic or under IVUS guidance with BMS or DES. At 3 years of follow-up, the patients who had IVUS-guided PCI had lower mortality (4.7% vs 16%; P = .048) compared to those having angiography-guided PCI.¹⁶⁸ In the study of Hernandez and coworkers, 1010 propensity matched patients who had LM PCI under IVUS or angiographic guidance were followed for 3 years. A lower event rate was noted in the IVUS-guided group (death-MI-revascularization: 14.4% vs 22.2%; P = .006; cardiac death-MI-revascularization: 11.7% vs 16%, P = .04).¹⁶⁹ The benefit of the IVUS guidance can be attributed to the optimal stent deployment in the IVUS group. Indeed, Kang and colleagues have recently demonstrated that stent underexpansion in LM PCI is associated with an increased incidence of restenosis and cardiovascular events at 2 years follow-up.¹⁷⁰

The concept of OCT-guided PCI has been tested prospectively in the ILUMIEN I study.¹⁷¹ In this study, 418 patients with stable angina and non-STEMI underwent OCT and FFR-guided PCI. The use of OCT changed procedural planning in 55% of the cases. At the end of the procedure, OCT imaging indicated further intervention in 25% of the patients. OCT guidance resulted in a low event rate at 30 days (death: 0.25%; MI: 7.7%; repeat PCI: 1.7%). In the ILUMIEN II study, the clinical outcomes were compared in patients undergoing OCT- and IVUS-guided PCI.¹⁷² This matched pair analysis of the patients included in the ILUMIEN I and ADAPT-DES study compared stent expansion, stent malapposition, and edge dissection and demonstrated no significant differences in the two groups. The clinical benefit of OCT-guided over angiography-guided PCI has been examined in a small propensity matched analysis including 670 patients.¹⁷³ Although OCT guidance appeared to be associated with a better clinical outcomes in this study, further research and convincing data from randomized control trials are required before advocating the prognostic value of OCT-guided PCI.

Small-scale studies have demonstrated that the combined NIRS-IVUS catheter allows accurate prediction of lesions associated with an increased incidence of periprocedural MI caused by distal embolization and that an embolic protection device may reduce this risk.¹⁷⁴ Recently, Erlinge and coworkers have shown that thrombus aspiration devices reduce the lipid content at the culprit lesion site. They aspirate not only thrombus but also calcium, macrophages, and lipids; thus they can potentially reduce the risk of no reflow.¹⁷⁵ However, the recently published Coronary Assessment by Near-infrared of Atherosclerotic Rupture prone Yellow (CANARY) did not demonstrate a prognostic benefit of an embolic protection device in lipid-rich plaques, and therefore the role of NIRS-IVUS imaging in guiding PCI is under question.¹⁷⁶

Diseased bypass grafts have been a challenge for both interventionists and cardiac surgeons. Intravascular imaging is important to guide stent size selection and define the extent of disease. IVUS has also been used to monitor outcomes after treatment of vein grafts with DES. The Compassionate Use of Sirolimus-Eluting Stent (SECURE) study included 76 patients (94 lesions) with graft disease treated with a sirolimus-eluting stent (SES), and 14 patients had IVUS follow-up performed at 8 months. Overall, the percentage of intimal hyperplasia was 11.8 ± 16.5%, and 50% of the patients with graft SES had less than 1% intimal hyperplasia.¹⁷⁷ In the setting of a randomized trial, 75 patients with graft disease (96 lesions) who received either SES or BMS (Reduction of Restenosis In Saphenous Vein Grafts with Cypher Sirolimus-Eluting Stent [RRISC] study), were assessed by IVUS at 6 months. The SES showed smaller neointimal hyperplasia volume compared with the BMS (1.3 vs 24.5 mm³; P < .001). In the SES group, there was greater intimal hyperplasia at overlapping sites compared with nonoverlapping segments.¹⁷⁸

Assessment of Complications after Percutaneous Coronary Interventions

Dissection

Many interventional cardiologists prefer to use angiography alone to manage intraprocedural complications. However, IVUS can be instrumental in many unanticipated circumstances. The presence of significant persistent flow-limiting lesions or dissections has been linked to higher likelihood of stent thrombosis.¹⁷⁹ These findings are often angiographically occult or appear as areas of indistinct haziness at the vessel border. In this scenario, IVUS distinguishes patients who require further intervention to treat uncovered dissections from those who have minimal lumen compromise and a short dissected segment and can be managed conservatively. In 201 stent patients, IVUS detected 31 segments with persistent angiographic haziness; 15 of them had significant lumen obstruction, and 14 had significant wall injury. IVUS is useful to detect the extent of post-PCI dissection, often revealing a greater length than is evident from angiography, which may be helpful in guiding vessel salvage and ensuring that the full length of dissection is covered by the stent. Finally, during treatment of dissections, IVUS may be very helpful in differentiating between the true and false lumen. OCT represents an optimal imaging tool to evaluate coronary dissection and in a recent report Radu and colleagues explored the natural history of edge dissections in 57 patients (63 lesions) undergoing PCI.¹⁸⁰ Twenty-two non–flow-limiting edge dissections were identified immediately after stent implantation. At 1 year of follow-up, most of the dissections were completely healed. No stent thrombosis or target lesion revascularization was reported, indicating that non–flow-limited edge dissections are associated with good prognosis. On the other hand, in the Centro per la Lotta contro l’Infarto-Optimisation of Percutaneous Coronary Intervention (CLI-OPCI II) study, the presence of a dissection more than 200 μm at the distal edge of the stent was an independent predictor of stent failure and MACE.¹⁸¹

Thrombosis

Intravascular imaging can play an important role in both prevention and diagnosis of stent thrombosis. Stent underexpansion, incomplete wall apposition, and vessel dissection—features easily identified by intravascular imaging—have been associated with an increased risk of stent thrombosis.¹⁸² The minimum stent CSA (4.3 ± 1.6 mm² vs 6.2 ± 1.9 mm²; P < .001) and the degree of stent expansion (0.65 ± 0.18 vs 0.85 ± 0.14; P < .001) were significantly smaller in patients with versus those without DES thrombosis. The same study also showed that residual edge disease—defined as edge lumen CSA smaller than 4 mm² and a plaque burden greater than 70%—was associated with a risk of thrombosis.¹⁸³

OCT studies have been proven useful in understanding the mechanisms of stent thrombosis and reports have shown that suboptimal stent expansion, stent fracture, neoatherosclerosis, and delayed arterial healing and stent malapposition are common causes of stent thrombosis in the DES era.^{119,120,121,184}

Restenosis

Unlike restenosis after balloon angioplasty or atherectomy, IVUS studies have shown that in-stent restenosis is essentially a result of neointimal hyperplasia. Predictors of stent restenosis have been identified by multivariate analyses and include a small reference vessel and lumen size, a larger plaque burden, and a small in-stent lumen area. Although the prevalence of restenosis has decreased dramatically with DES, maximizing luminal gain remains an important approach in preventing restenosis. The receiver operating characteristic curve identified a poststenting minimum stent CSA of 5 mm² for the SES and 6.5 mm² for the BMS, which were associated with lumen CSA larger than 4 mm² at 8 months of follow-up.¹⁸⁵ Others have shown that the highest restenosis rate was observed in lesions with a stent area smaller than 5.5 mm² and a stent length larger than 40 mm after deployment of an SES.¹⁸⁶

Intravascular imaging is also essential to guide therapy of in-stent restenosis because mechanical problems related to stent deployment procedures contribute to approximately 25% of in-stent restenosis.¹⁸⁷ Stent fracture has been reported as a cause of stent restenosis in the modern era of long stent implantation, which may be identified by intravascular imaging.¹⁸⁸ Intravascular imaging has shown that characteristics of neointimal hyperplasia may differ between BMS and DES. Neointimal hyperplasia in the DES may have a more echolucent nonhomogeneous appearance compared to that in the BMS.¹⁸⁹ In addition, diffuse in-stent restenosis is common after the use of the BMS, but the pattern of restenosis associated with the DES is most frequently focal. One of the most common variables used to report restenosis is percentage of intimal hyperplasia volume in the stent segment.¹⁹⁰ This variable normalizes the intimal hyperplasia to the stent length, allowing a comparison of different stent types (BMS vs DES), as well as different drug types (ie, SES vs paclitaxel-eluting stents [PES]). The percentage of intimal hyperplasia, however, minimizes the impact of focal restenosis. The use of IVUS-VH to assess in-stent restenosis in metal stents is hampered by the following factors: lack of validation of the technique in this context, misclassification of the stent struts as “dense calcium” surrounded by necrotic core, and the potential interference of the superficial stent struts on the backscattering of the tissue behind them.

OCT has been used to evaluate the restenotic tissue based on structure, lumen shape, and the presence of microvessels and intraluminal material, with low inter- and intraobserver variability. The qualitative definition of tissue backscatter is influenced by the position of the OCT catheter relative to the vessel wall.¹⁹¹ Tissue with low and high backscatter and variable optical properties are often observed in the same vessel, suggesting that “restenosis” after DES might have a heterogeneous composition. Histologic analysis of human atherectomy specimens has also shown heterogeneous tissue components, including proteoglycan-rich tissue, organized thrombus, atheroma, inflammation, and fibrin.^191,192 Restenosis presenting with unstable angina symptoms was more frequently associated with an irregular lumen shape and intraluminal material suggestive of thrombus.¹⁹¹

Neoatherosclerosis is a common cause of very late stent failure and is characterized by the accumulation of lipid-laden foamy macrophages with or without necrotic core or calcification formation. Histology studies have showed that OCT allows reliable detection of neoatherosclerotic lesion characteristics and is regarded today as the gold standard for the in vivo identification of these lesions.^119,193 The exact mechanisms that regulate neoatherosclerotic lesion formation are yet unclear. However, it appears that endothelial dysfunction, delayed vascular healing, the local endothelial shear stress patterns, and a chronic inflammatory response to the DES polymer contribute to the generation of the neoatherosclerotic lesions.¹¹⁹ Several OCT-based studies have explored the neoatherosclerotic lesion distribution in different stent types,^194,195 and in different study populations,^196,197 and investigated the association between neointima characteristics and neoatherosclerotic lesion formation.¹⁹⁸ Nakazawa and colleagues¹⁹⁹ have shown that in-stent neoatherosclerosis occurs early in the first generation of DES as compared to BMS and that no differences in the prevalence of neoatherosclerosis were seen between the first and second generation (Fig. 21–12).²⁰⁰ A recent meta-analysis of the Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX) study has shown that neoatherosclerotic lesion formation is related to atherosclerotic disease progression in the native coronary arteries, suggesting that these processes are regulated by the same pathophysiological mechanisms.²⁰¹

Intravascular imaging has played an important role in the understanding of atherosclerosis disease in humans and translation of novel therapies to the clinical arena.

Drug Effects on Atherosclerosis

The initial observations about a positive continuous relationship between coronary heart disease and cholesterol levels led to the conduction of a number of IVUS-based studies that evaluated the effect of different lipid-lowering drugs on atheroma size. Changes in plaque characteristics may be a more relevant end point to predict the risk of vascular thrombosis than plaque progression or regression of mild to moderate disease, but imaging tools to accurately evaluate plaque characteristics were not available until recently. Other limitations of using conventional grayscale IVUS to assess the natural history of atherosclerosis should be enumerated, including (1) use of catheterization, an invasive procedure, which is required for serial imaging; (2) only a segment of the coronary tree can be studied; (3) plaque composition is not obtained; and (4) there is no direct evidence linking changes in coronary plaques and clinical events.

The efficacy of lowering low-density lipoprotein cholesterol (LDL-C) with inhibitors of hydroxymethylglutaryl coenzyme A reductase (statins) is unequivocal; however, the change in atheroma size by statins is not constant across all IVUS studies. There are many potential explanations for these discrepancies in IVUS studies, such as drug properties, dose, and duration of treatment. In early studies such as the German Atorvastatin Intravascular Ultrasound (GAIN) study, atheroma volume was not reduced by atorvastatin despite the reduction in LDL-C (86 vs 140 mg/dL) at 12 months. In contrast, the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study showed that LDL-C levels were further lowered by atorvastatin versus pravastatin (110 vs 79 mg/dL), which was associated with an increase of 2.7% of atheroma volume in pravastatin-treated patients and in a 0.4% reduction in atheroma volume in atorvastatin-treated patients.²⁰² The clinical significance and the accuracy of IVUS for such measurements are still debatable, but these results were statistically significant. The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study showed that the lower the LDL-C and C-reactive protein values, the greater the reduction in clinical events and atheroma progression.²⁰³

The first study showing regression of plaque size was the A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) trial.²⁰⁴ At 24 months, treatment with 40 mg/d of rosuvastatin resulted in lowering of LDL-C to 60.8 mg/dL and elevation of high-density lipoprotein cholesterol (HDL-C) by 14.7%. These lipid effects were associated with statistically significant, albeit small, reductions in PAV (0.79%) and TAV (6.8%).

OCT has also been used to evaluate the effect of statin therapy on coronary fibrous cap thickness in patients with ACS.²⁰⁵ This pilot study showed that lipid-lowering therapy for 9 months after STEMI increases the fibrous cap thickness. Although fibrous cap thickness increased in both the statin treatment group (151 ± 110 to 280 ± 120 μm) and the control group (153 ± 116 to 179 ± 124 μm), the magnitude was greater in the statin treatment group. The EASY-FIT (Effect of AtorvaStatin therapy on FIbrous cap Thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography) study that recently compared aggressive treatment with 20 vs 5 mg of atorvastatin has also shown that the patients on the higher dose of atorvastatin exhibited an statistical significant increase in the thickness of the fibrous cap at 12 months follow-up (69% vs 17%; P < .001).³

IVUS studies have also demonstrated coronary plaque modification in HDL-treated patients. The infusion of synthetic HDL-C particles containing the variant apolipoprotein, apoA-I Milano, complexed with phospholipids (ETC-216) reduced the PAV by –1.06% (3.17%; P = .02 compared with baseline) in the combined ETC-216 group at 5 weeks. On the contrary, in the placebo group, PAV increased by 0.14% (3.09%; P = .97 compared with baseline).²⁰⁶ In the Effect of Reconstituted High-Density Lipoprotein on Atherosclerosis: Safety and Efficacy (ERASE) study, 60 patients were randomly assigned to receive four weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111), and 12 to receive 80 mg/kg of CSL-111. The latter was discontinued because of liver function test abnormalities. Within the treated group, the percentage change in atheroma volume was –3.4% with CSL-111 (P < .001 vs baseline) and was –1.6% (P = .48 between groups) for the placebo group. It is still unclear what the future holds for these therapeutic agents.²⁰⁷

Patients with human deficiency of cholesteryl ester transfer protein (CETP) have elevated circulating levels of HDL-C. This has led to investigation of CETP inhibition as a novel and potentially effective approach to elevate HDL-C. In the Investigation of Lipid Level Management Using Coronary Ultrasound To Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE) trial, the PAV (primary efficacy measure) increase was similarly low in patients receiving atorvastatin monotherapy compared with those receiving the combined torcetrapib–atorvastatin therapy after 24 months (0.19% vs 0.12%, respectively).²⁰⁸

The enzyme acyl–coenzyme A:cholesterolacyltransferase (ACAT) esterifies cholesterol in a variety of cells and tissues. Inhibition of ACAT1 by blocking the esterification of cholesterol could prevent the transformation of macrophages into foam cells and slow the progression of atherosclerosis, and inhibition of ACAT2 would be expected to decrease serum lipid levels. In the ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) study, the change in PAV was similar in the pactimibe (100 mg/d) and placebo groups (0.69% and 0.59%, respectively; P = .77).²⁰⁹

Systolic blood pressure has been shown to be an independent predictor of plaque progression by IVUS.²¹⁰ A randomized study of patients with CAD and a diastolic blood pressure below 100 mm Hg treated with placebo or antihypertensive therapy, using either 10 mg/d daily of amlodipine or 20 mg/d of enalapril, showed that patients treated with amlodipine had a reduction in plaque size and a reduction in cardiovascular events at 24 months compared with those given placebo.²¹⁰ The PERindopril’s Prospective Effect on Coronary aTherosclerosis by IntraVascular ultrasound Evaluation (PERSPECTIVE) study, a substudy of the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) trial, evaluated the effect of perindopril on coronary plaque progression in 244 patients. There were no differences in changes in IVUS plaque measurements detected between the perindopril and placebo groups, indicating that this treatment had no effect on the plaque burden.²¹¹

Several recent reports have shown serial changes of plaque composition in patients treated with various statin treatments. In one of them, patients with SAP (n = 80) treated with fluvastatin for 1 year had significant regression of plaque volume and changes in atherosclerotic plaque composition with a significant reduction of fibrofatty volume (P < .0001). This change in fibrofatty volume had a significant correlation with the change in LDL-C level (r = 0.703; P < .0001) and change in high-sensitivity C-reactive protein (hsCRP) level (r = .357; P = .006).²¹² Of note, the necrotic core did not change significantly. In a second study, Hong and colleagues randomized 100 patients with stable angina and ACS to either rosuvastatin 10 mg or simvastatin 20 mg for 1 year. Overall, necrotic core volume significantly decreased (P = .010), and fibrofatty plaque volume increased (P = .006) after statin treatments. Particularly, there was a significant decrease in necrotic core volume (P = .015) in the rosuvastatin-treated subgroup. By multiple stepwise logistic regression analysis, the researchers showed that the only independent clinical predictor of decrease in necrotic core volume was baseline HDL-C level (P = .040; OR, 1.044; 95% CI, 1.002-1.089).²¹³

The Integrated Biomarkers and Imaging Study-2 (IBIS-2) compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA2 inhibitor, 160 mg/d) or placebo in 330 patients.¹⁴ End points included changes in necrotic core size (IVUS-VH) and atheroma size (grayscale IVUS). Background therapy was comparable between groups, with no difference in LDL-C at 12 months (placebo, 88 ± 34; darapladib, 84 ± 31 mg/dL; P = .37) In the placebo-treated group, however, the necrotic core volume increased significantly, but darapladib halted this increase, resulting in a significant treatment difference of –5.2 mm³ (P = .012). These intraplaque compositional changes occurred without a significant treatment difference in TAV.

NIRS and NIRS-IVUS have also been used to investigate the effect of statins on the compositional characteristics of the plaque. In the Reduction in Yellow Plaque by Intensive Lipid Lowering Therapy (YELLOW) study, NIRS and IVUS imaging were used to assess the effect of aggressive lipid lowering treatment on plaque burden and composition in flow limiting lesions.³⁹ In this study, NIRS and IVUS imaging were performed at baseline and at 7 weeks follow-up in lesions with a FFR of less than 0.80 in 87 patients who were randomized to aggressive lipid therapy with rosuvastatin 40 mg/d or standard of care lipid therapy. A significant reduction (by 24%) in the lipid component and an increase (by 9%) in the elastic membrane area in the intensive treatment group was noted at 2 months follow-up, whereas in the standard of care group, the change in the lipid component was increased by 5.4% and the external elastic membrane by 3%.

On the other hand, the Integrated Biomarkers Imaging Study 3 (IBIS-3) that included 103 patients who underwent coronary angiography for clinical purposes and had serial single vessel NIRS-IVUS imaging at baseline and at 12 months of follow-up failed to demonstrate an effect of the treatment with rosuvastatin on the lipid component (lipid core burden index, 44.9 at baseline vs at 12 months 46.1, P = .80; max 4 mm lipid core burden index, 201.9 vs 206.8, P = .72) at 1 year of follow-up.¹⁸

Predictive Value of Intracoronary Imaging

The potential value of IVUS in the prediction of adverse coronary events was evaluated in an international multicenter prospective study, the PROSPECT study. The PROSPECT trial was a multicenter, natural history study of patients with ACS. All patients underwent PCI in their culprit lesion at baseline followed by angiography and IVUS-VH of the three major coronary arteries. Within a follow-up period of 3.4 years, 104 new lesions were developed in the nontreated vessels (11.6%). Interestingly, most of the nontarget lesion–related cardiovascular events were unstable, progressive angina (92%) and only 8% were acute thrombotic cardiovascular events. Of the 104 new lesions, 55 were studied by IVUS-VH at baseline.¹⁵ An IDTCFA with a minimum lumen area of 4 mm² or less and a large plaque burden (≥ 70%) had a 18.2% likelihood of causing an event within 3 years. Similar were the results of the VH-IVUS in Vulnerable Atherosclerosis (VIVA) study, which included 170 patients admitted with stable angina or an ACS who had IVUS-VH imaging in the nonculprit vessel at baseline during the index procedure and were followed for 2 years.¹⁶ During follow-up, 16 cardiovascular events occurs in the nontreated vessels. Similarly to what it has been shown in the PROSPECT study, IDTCFA (hazard ratio [HR] 8.16; P = .007), plaque burden > 70% (HR 7.48; P < .001), and MLA less than 4 mm² (HR 2.91; P = .036) were associated with cardiovascular events.

IVUS-based imaging has also been used to assess the implication of the local hemodynamic forces on atherosclerotic evolution. Fusion of conventional angiography and IVUS has been used to reconstruct coronary anatomy, perform blood flow simulation, and assess the endothelial shear stress (ESS) and its effect on plaque phenotype morphology and evolution.^214,215,216 Several OCT-based and IVUS-based reconstruction studies have shown that low ESS promotes atherosclerotic evolution and the formation of vulnerable high-risk lesions in native arteries and stented vessels.^{217,218,219,220} The recently reported PREDICTION study is the largest prospective large-scale trial that examined the implications of ESS on plaque growth and future cardiovascular events.²²¹ This study included 509 patients who were admitted for an ACS and underwent three-vessel IVUS examination at baseline and at 6 months follow-up. The baseline IVUS and angiographic data were used to reconstruct the coronary anatomy and evaluate the ESS distribution. Low ESS, which appeared to promote plaque growth, and baseline plaque burden were the only independent predictors of future revascularizations, with a positive predictive value of 41%.

The efficacy of OCT in predicting lesions that are prone to progress and cause cardiovascular events has been assessed in a small-scale study that included 53 patients with CAD who had PCI and OCT imaging at baseline and repeat coronary angiography at 7 months follow-up. During this time interval 13 non–flow-limiting lesions showed disease progression at follow-up. Compared to lesions that did not progress, those that progressed had a higher incidence of intima laceration (61.5% vs 8.9%; P < .01), thrombi (30.8 vs 1.8%; P < .01) microchannels (76.9% vs 14.3%; P < .01), macrophages (61.5% vs 14.3%; P < .02) and an increased lipid component (100% vs 60.7%; P < .01). This study provided, for the first time, evidence that plaque microfeatures and the presence of inflammation, indicated by the presence of macrophages, may facilitate prediction of lesions that will progress and cause cardiovascular events.²²²

Vascular Response to Endovascular Devices

Metallic Stents

IVUS has been extensively used as a surrogate end point in stent trials, primarily to assess the effectiveness of devices as it relates to neointimal proliferation. IVUS was an essential investigational tool during initial clinical testing of the DES,^155,156 confirming the dramatic suppression of neointimal proliferation, revealing new patterns of restenosis, and establishing intravascular imaging metrics of stent optimization as described above.

Intravascular imaging is now focused on the evaluation of surrogate safety end points. “Vascular healing” represents a complex array of vascular responses to DES implantation, including reendothelialization, tissue coverage, thrombus and fibrin deposition, and strut apposition. In particular, stent-strut coverage and apposition have been linked to the risk of stent thrombosis.¹²⁰ Histology has revealed that IVUS does not have the adequate resolution to detect small amounts of tissue coverage.²²³ Contemporary DES clinical trials such as OCT for DES Safety (ODESSA), Optical Coherence Tomography in Acute Myocardial Infarction (OCTAMI), and Optical Coherence Tomography Drug Eluting Stent Investigation (OCTDESI) trials have selected these variables as their primary end point, and larger studies such as Limus Eluted from A Durable versus ERodable Stent coating (LEADERS) and Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) have integrated OCT substudies. Light, in a manner similar to ultrasound, reflects from the metal surface and hides the abluminal stent face. For the quantification of strut malapposition, the distance between the luminal surface of the strut and the vessel wall needs to be measured, accounting for the additional thickness of the polymer and drug coating.²²⁴ Malapposition is then declared if the measured distance is longer than the strut-polymer thickness. Some images of struts protruding in the lumen are obviously related to malapposition; others may represent a well-apposed, but not embedded, strut. This is particularly critical in the research environment, where a “quantitative strut-level analysis” should be performed for accurate data evaluation (Fig. 21–13).

Bioresorbable Scaffolds

Bioresorbable scaffolds (BRS) constitute a novel approach for the treatment of CAD. These devices have the ability to provide a transient support to the vessel wall, deliver the antiproliferative drug, and then disappear, allowing the vessel to return to its natural state. The unique advantages of these devices have been appreciated from their first applications in the clinical and research arena and attracted the attention of the industry and scientific communality.^225,226 Today, numerous BRS with different properties and design have been developed and are available in the clinical arena or undergoing clinical or preclinical evaluation.

Intravascular imaging has played a pivotal role in understanding the properties, advantages, and limitations of these devices.²²⁷ Serial IVUS imaging has provided unique insights about the resorption process in the first-generation BRS (ie, the ABSORB BVS 1.0, the AMS 1.0, and DREAMS) and the causes of the high late lumen loss noted in the first clinical trials (ie, late vessel recoil caused by inadequate lumen support by the BRS and neointima formation).²²⁸ To address these limitations, the second-generation BRS with delayed resorption were introduced; they provided prolonged radial support and incorporated a drug elution that reduced the neointima response.^229,230

Apart from IVUS, OCT with its high imaging resolution has been used to study the vessel wall response to BRS. In the ABSORB BVS, struts appear as black central cores framed by light-scattering borders that permit complete imaging of their distribution and their position with regard to the vessel wall. OCT has been used to assess the resorption process, understand the mechanisms of scaffold expansion²³⁰ and the vascular edge response following device implantation;²³¹ and identify acute strut fractures caused by excessive postdilation of the scaffold, which constitute one of the causes of early scaffold failure.²³² Moreover, OCT has allowed us to appreciate the healing response following BRS implantation and assess the neointima burden and its composition. Serial OCT studies have demonstrated that, following ABSORB BVS implantation, a thick layer of fibromuscular tissue develops that shield the underlying potential high-risk plaque, leading to its passivation (Fig. 21–14).^233,234 The long-term—5-year follow-up—OCT imaging data have shown complete scaffold resorption and plaque sealing, while IVUS analysis has showed plaque regression.^235,236

Computational fluid dynamic studies performed in models reconstructed from OCT and x-ray imaging data have demonstrated that BRS implantation affects the local hemodynamic forces, as the protruded struts disturb flow, creating flow disturbances and recirculation zones behind the struts.²³⁷ This creates a low ESS environment that promotes neointima proliferation, which seals the underlying high risk plaques.²³⁸ The developed neotissue appears to create a smooth luminal surface that normalizes the ESS. Therefore, the treated segment at long-term follow-up has a low-risk plaque phenotype (as all the high-risk lesions are covered by the developed neointima) and is exposed to a normal atheroprotective ESS environment.^239,240 These favourable imaging findings have attracted attention and the recently commenced PROSPECT ABSORB study (NCT02171065) aims to investigate the potential role of ASBORB BVS in sealing future culprit lesions.

The future of intravascular imaging relies on the development of hybrid intravascular imaging modalities that would enable complete and comprehensive evaluation of plaque pathology and physiology. Advances in signal processing and the miniaturization of medical devices have enabled the design of hybrid-dual probe catheters that combine two imaging modalities with complementary strengths and permit simultaneous visualization of plaque morphology and bioogy.²⁴¹ Apart from the NIRS-IVUS catheter that has already been presented in previous sections and has applications in the clinical setting, several other prototypes have been recently introduced and are currently undergoing preclinical evaluation. These include the combined IVUS-OCT,^242,243,244 OCT-NIRS,²⁴⁵ IVUS-IVPA,^246,247 OCT-NIRF,^{248,249,250,251} IVUS-NIRF,^252,253 TRFS-IVUS,^51,52 and the combined three-probe NIRS-OCT-IVUS catheters (Fig. 21–15).²⁵⁴ These modalities are anticipated to allow detailed evaluation of plaque characteristics and, thus, more precise assessment of the effect of new treatment on the compositional characteristics of the plaque, detection of high-risk vulnerable lesions that are prone to progress and cause cardiovascular events, and evaluation of lesion severity and procedural planning. For example, the combined IVUS-OCT catheter carries a great clinical potential because IVUS can be used to plan stent implantation and OCT to evaluate the final results poststent implantation, and there is hope that it will constitute the ideal modality for guiding PCI in the future in complex cases. Whether these modalities will improve clinical outcomes especially in the BRS era is expected to be investigated by future studies.

We would like to thank Dr. Marco A. Costa and Dr. Hector M. Garcia-Garcia, who contributed to the previous version of this chapter in the 13th edition.