Imaging Biomarkers for Vulnerable Plaques

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Multiple diagnostic imaging modalities have been developed and applied to detect atherosclerotic plaques. Table 1 summarizes key features of each modality, including advantages and limitations of their applications in atherosclerosis [12-27]. While earlier methods provided anatomical information, the field is currently shifting toward imaging techniques that provide information on plaque and vessel composition as well. The imaging modalities are summarized as invasive and noninvasive categories, of which the invasive methodologies include angiography, intravascular ultrasound (IVUS), angioscopy, optical coherence tomography (OCT), and noninvasive methodologies include ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical imaging [24, 25, 27, 28]. This review will focus on noninvasive imaging methodologies and their applications in atherosclerosis. In addition, molecular imaging has been rapidly advancing and there is great interest and potential for its application in the molecular and functional aspects of atherosclerosis such as inflammation, protease activity, and angiogenesis. Some potential applications of molecular imaging in atherosclerosis are also reviewed/highlighted in the following sections along with each imaging modalities.

4.1. Ultrasound

Surface ultrasound has been successfully used to noninvasively assess plaques in the carotid artery because of its high sensitivity and the proximity of this artery to the body surface, thus allowing for excellent penetration

Advantages and Disadvantages of Various Imaging Modalities for Vulnerable Plaque Assessment

Modality

Advantages

Limitations

References

Invasive Angiography

Angioscopy IVUS

Intravascular MRI

Noninvasive Ultrasound

PET/SPECT MRI

Optical imaging

Standard for stenotic lesions/luminal diameter Clinical experience

Excellent visual of lipid component in plaques and lumen surface Direct imaging of vessel wall and plaques

Excellent for vessel wall penetration High resolution

High resolution and morphological characterization of plaques

Excellent for wall and plaques

Reproducible

Quick

Clinical trial experience Calcified plaque detection

Molecular imaging High sensitivity

Anatomic and functional characterization of plaques High resolution Molecular imaging Versatile, high sensitivity

Provides only lumen dimensions [12]

Poor penetration [13]

Poor for lipids [14] Noncoronary assessment

Clinical applications to be developed [15]

Invasive [16, 17]

Time-consuming

Potential heat buildup inside vessel wall

Poor for lipids [18, 19]

Technically demanding Noncoronary assessment

Lack of clinical experience for plaques [20, 21]

Radiation exposure

Low resolution [22, 23]

Lack of clinical experience for plaques

Lack of clinical experience for plaques [24, 25]

Lack of clinical experience [26, 27]

IVUS, intravascular ultrasound; OCT, optical coherence tomography; MRI, magnetic resonance imaging; CT, computed tomography; PET, positron emission tomography; SPECT, single photon emission computed tomography.

through the tissues. Measurements of carotid wall thickness and quantitative analysis of plaque are usually taken at B-mode and evaluated as carotid intima-media thickness (CIMT) [29, 30], and is the most common use of this methodology. On a more experimental nature, ultrasound has been used to identify intraplaque hemorrhage and lipids (as hypoechoic heterogeneous plaque) versus mostly fibrous (as hyperechoic homogenous plaque) [31, 32]. A variety of studies have shown that there is a correlation between CIMT and CV risk factors [33-35]. Ultrasound technology is reproducible and suitable for large, multicenter trials; low cost; and quick. CIMT imaging has been frequently used in clinical trials as a surrogate end point for determining the effectiveness of interventions that lower risk factors for atherosclerosis, such as the following: the Kuopio Ischaemic Heart Disease Risk Factor (KIDH) Study [36], Atherosclerosis Risk in Community (ARIC) Study [37], the effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP) [38], Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2, (ARBITER 2) [39], Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin (METEOR) [40], and Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression study (ENHANCE) [41]. The resolution of ultrasound for lipids and plaque composition is limited, however, unless contrast agents are applied. It is also technically challenging, especially to assess plaques in the coronary artery. Other limitations are illustrated in a recent study which showed that ultrasound measurement may underestimate the vessel wall thickness and plaques compared to MRI [42], and that CIMT represents mainly hypertensive medial hypertrophy, which is more predictive of stroke than of myocar-dial infarction (MI) [28-30]. In addition to CIMT, carotid artery plaque ulceration can be reliably detected by three-dimensional ultrasound [43]. Likewise, microemboli can be detected by transcranial Doppler in patients at higher risk of stroke [44,45]. In a new emerging application, ultrasound-based molecular imaging of atherosclerotic plaques and CV disease with contrast-enhanced ultrasonography, which relies on the detection of the acoustic signal produced by microbubble or nanoparticle agents that are targeted to the specific molecules at the sites of disease [46], has also been developed.

4.2. Computed Tomography (CT)

CT provides high sensitivity to noninvasively detected calcified plaques due to its substantially higher density over noncalcified tissues. CT is reliable and widely used in the clinic, especially with the replacement by helical CT of electron bean CT for the detection of calcified coronary artery plaques. The disadvantages of CT include radiation exposure and its inability to differentiate the compositional changes in the noncalcified plaque areas. One study performed by multislice detector CT showed that statin therapy led to a significant reduction of noncalcified plaque burden that was not reflected in calcium scoring or total plaque burden [47], suggesting the potential to monitor medical treatment in patients with coronary atherosclerosis. Recent advances in CT are aided by contrast enhancement (CT angi-ography or CTA) and the use of multidetector row CT (MDCT) with submillimeter collimation and retrospective ECG gating, that permit high-resolution imaging of coronary artery stenosis and atherosclerotic plaques. However, the recent study of CTA using MDCT failed to reliably identify the functional significance of coronary lesions in patients with stable angina and atypical chest pain, suggesting that at this time a diagnostic strategy relying on CTA alone should not be used for making revasculariza-tion decisions [48].

4.3. Positron Emission Tomography (PET)

PET is the study of human physiology by electronic detection of positron-emitting radiopharmaceuticals. The simultaneous detection of these photons (two high-energy photons emitted in opposite directions) is the basis of PET imaging [49]. PET provides a measure of metabolic and functional activity of living tissue based on the retention of positron-emitting tracers. Current approaches in PET imaging for atherosclerosis use 18F-fluorodeoxyglucose (FDG), as a radiolabeled tracer, which is taken up by metabolically active cells and has been frequently used in cancer diagnosis. Two studies in particular support the use of this ligand for atherosclerosis as a noninvasive measure of carotid plaque inflammation. Rudd et al. reported a greater uptake in symptomatic carotids versus asymptomatic vessels and that this uptake was located near macrophages in endarterectomy samples [50]. In another report, FDG uptake was shown to correlate with the CD68 (macrophage) count in histological examination carotid endarterectomy samples from patients [22]. PET is very sensitive, noninvasive, and provides molecular and functional imaging of plaques. Further development of PET could allow detection of the molecular and cellular events in atherosclerotic plaques by the development of imaging probes that target MMPs [51] or annexin A5 (99mTc), a marker of ongoing apoptosis [52]. Limitations of PET are its poor resolution, which also requires then a coregistration with CT or MRI, and the requirement of specific radioactive tracers that usually require a reactor/cyclotron, which are limited in scope of applications. The clinical application of PET in atherosclerosis is still in its exploratory phase.

4.4. Magnetic Resonance Imaging (MRI)

MRI has several advantages. It is noninvasive, has high resolution, and provides a quantitative characterization of a full range of pathologic features that could represent plaque rupture, including a lipid core and fibrous cap, calcification, intima/media/adventitia dimensions as well as intraplaque hemorrhage and acute thrombosis [24]. Therefore, MRI has shown great promise to study atherosclerosis in the carotid and coronary arteries, as demonstrated in several clinical studies such as a longitudinal MRI study of atherosclerotic patients in response to statin treatment [53] and a case-control subgroup from the Familial Atherosclerosis Treatment Study (FATS) [54]. Exploration of MRI applications is still evolving, especially with the development of various contrast agents for the assessment of cellular and molecular components of atherosclerosis progression and plaque rupture [24, 28]. For example, the use of ultrasmall particles of iron oxide (USPIO) allows the detection of macrophage-rich atheroma by MRI [55, 56]. The development of contrast agents that target specific molecular and cellular components of high-risk plaques such as macrophage scavenger receptor (for macrophages) [57] and endothelial adhesion molecules (for vascular inflammation) [58] will provide excellent tools of MRI biomarkers to monitor atherosclerotic plaque vulnerability. However, the clinical applications of MRI for atherosclerosis burden assessment and detection of vulnerable plaque remain to be further explored.

4.5. Optical Imaging

Optical imaging, in particular, near-infrared fluorescence (NIRF) imaging (excitation 650-900 nm), provides a new and highly versatile platform for noninvasive in vivo molecular imaging [27]. Optical imaging is extremely sensitive (picomolar range), utilizes a variety of target platforms (peptide, protein, antibody, nanoparticles, etc.), thereby providing further versatility, and is flexible on the detection system needed and range of detection. Optical imaging provides the ability to visualize atheroma inflammation, calcification, and angiogenesis [27]. For example, the application of a fluorescent VINP-28 for VCAM-1 internalizing nanoparticle-28 was demonstrated to be a sensitive method of optical imaging to noninvasively detect atherosclerotic plaques in apo-E deficient mice [26].

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