Clinical perspectives in assessment of high-risk atherosclerotic plaques

University Heart Center
Department of Cardiology
University Hospital Zurich

Clinical perspectives in assessment of high-risk atherosclerotic plaques

by R. Klingenberg, O. Gaemperli and T. F. Lüscher, Switzerland

This short review discusses the implications of findings from recent clinical studies on the use of invasive and noninvasive imaging modalities in the detection of high-risk coronary lesions. Based on findings from autopsy studies, a short summary of the morphological features of coronary plaques responsible for acute coronary events is provided, and the concept of the “vulnerable plaque” is outlined. With regard to invasive imaging of the coronary vasculature, a focus is given to intravascular ultrasound, with discussion of recent prospective data on the morphology and progression of coronary plaques and their correlation with plaque rupture. Advances in optical coherence tomography are also illustrated in relation to defining the features of unstable plaques. Among the noninvasive imaging modalities, a focus is placed on computed tomography coronary angiography for identification of the morphological characteristics of coronary plaques that correlate with future coronary events. In addition, the prospects for magnetic resonance imaging and molecular hybrid imaging are outlined. Among the latter, combined positron emission tomography/computed tomography angiography is emerging as a prominent modality that enables characterization of both the morphology and biology of coronary plaques in patients. Finally, the place of imaging modalities alongside the currently available clinical risk scores and biomarkers for identification of individuals at risk for future coronary events is discussed, in addition to how these may guide therapeutic management.

Medicographia. 2014;36:103-109 (see French abstract on page 109)

Plaque rupture or erosion (or more rarely, calcific nodules) with ensuing atherothrombosis constitutes the underlying pathophysiology of acute coronary syndromes (ACS). The pathomorphological features of ruptured plaques comprise a thin fibrous cap, a large lipid core, outward (positive) remodeling, angiogenesis, and an abundance of inflammatory cells.1 Thin-cap fibroatheroma (TCFA) by definition comprises a large necrotic core covered by a thin fibrous cap of <65 μm. It is typically found in the proximal segments of coronary arteries with less than 50% diameter stenosis, and represents the most frequent type of lesion found in patients dying of coronary plaque rupture.2

By inference, when plaque composition is characteristic of a ruptured plaque, but there is an intact fibrous cap remaining, it is considered to predispose the “vulnerable plaque” to rupture.1 The natural course of coronary plaques with features of vulnerable plaque is not unidirectional, and it does not always involve a move toward plaque rupture manifesting as ACS, but rather it often remains asymptomatic, with ruptured plaques healing.3 The advent of novel imaging modalities has enabled detailed analysis of the natural course of vulnerable plaques and its correlation with clinical events.

Invasive imaging modalities for assessment of high-risk coronary laques

For decades, coronary angiography constituted the primary invasive imaging modality for assessment of the presence and degree of luminal stenosis (quantitative coronary angiography; QCA). Particularly when combined with pressure wire measurements, the modality enables quantitative evaluation of the functional relevance of myocardial perfusion and the risk for future cardiovascular events.4,5 Although QCA improved the quantification of coronary lesions, the fact that it is based on only 2 projections of a 3-dimensional structure means that it nevertheless has limitations. On the other hand, the assessment of fractional flow reserve has made it possible to precisely quantify the hemodynamic relevance of coronary lesions (for a review see reference 6).

Grayscale intravascular ultrasound (IVUS) enables visualization of vessel size, plaque burden, and morphology at a resolution of 100 μm to 120 μm by means of amplitude analysis of backscattered sound waves.7 In contrast to IVUS, coronary angiography grossly underestimates the extent of plaque burden and outward expansion of the atheromatous arterial wall (positive remodeling).8 Radiofrequency IVUS (RF-IVUS, virtual histology) allows for enhanced assessment of plaque composition, and results correlate well with histology findings.9 The prospective multicenter PROSPECT study (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), an imaging study in patients with unstable atherosclerotic lesions, evaluated the morphological characteristics of nonculprit lesions and their progression over time, as well as their association with future cardiovascular events, using grayscale IVUS and RF-IVUS versus coronary angiography. After 3 years, cardiovascular events were reported in 20.4% of patients, and were associated in equal measure with nonculprit lesions and culprit lesions that had previously been treated by percutaneous coronary intervention (PCI) at the time of ACS.10 Nonculprit lesions associated with cardiovascular events were characterized by a plaque burden of ≥70%, a minimal lumen area of ≤4 mm2, and TCFA, the latter defined by RF-IVUS. Interestingly, nonculprit lesions associated with future events were classified angiographically at baseline as mild stenotic lesions, indicating that identification of patients at risk for future events using coronary angiography alone is limited. In turn, nonculprit lesions with angiographically mild stenosis, but a high plaque burden (≥70%), were found in one-third of patients and were more frequent in patients with diffuse coronary artery disease (CAD) (3-vessel disease) and a prior history of PCI,11 demonstrating the systemic nature of atherosclerosis as the underlying disease. However, it should be noted that of the 74 events that occurred in nonculprit vessels, 67 were related to revascularization procedures for progressive or unstable angina. There were no deaths or cardiac arrests and only 6 myocardial infarctions in nonculprit vessels during follow- up, highlighting the overall low event rates achieved with current medical prevention strategies. Grayscale IVUS has consistently been used to demonstrate slowing of coronary plaque progression, and even regression following statin therapy.12-15 Thus, IVUS is a useful tool to assess the effects of pharmacotherapy on plaque stabilization. Recently, a pooled analysis was carried out of 7 trials involving performance of serial IVUS measurements at baseline and after 21 months to assess the effects of various pharmacotherapies. The analysis identified smaller minimal lumen area, greater plaque burden at baseline, and greater progression of atheroma volume and constrictive arterial remodeling in the left main coronary artery (LMCA) as predictors of cardiovascular events.16 Interestingly, the response to treatment in the LMCA was opposite that in other vascular territories of the coronary tree, and it remains unclear as to how this impacts on risk prediction for future events. Furthermore, in a recent prospective multicenter trial, IVUS-based identification of a minimum lumen area of 6 mm2 as a cutoff value to guide revascularization of intermediate LMCA plaques did not translate into a difference in the rate of future events within 2 years.17

Figure 1
Figure 1. Intravascular imaging modalities for the assessment of coronary plaque.

(A) Grayscale intravascular ultrasound (IVUS), (B) radiofrequency IVUS, and (C) frequency domain optical coherence tomography are shown.
After reference 18: Klingenberg et al. Clinical manifestations of atherosclerosis. In: Wick G, Grundtman C, eds.
Inflammation and Atherosclerosis, Vol I. New York: Springer Wien New York; 2012:69-58. © 2012, Springer Science and Business Media.

Figure 2
Figure 2. Thrombus in a venous bypass graft adjacent to atherosclerotic plaque.

(A) Coronary angiogram with thrombus in saphenous vein graft (arrowhead). (B) Frequency domain optical coherence tomography (OCT) with thrombus (arrowhead) and graft atherosclerotic plaque with a large lipid core (white arrows). (C-E) Frequency domain OCT with thrombus (arrowheads). (F) Coronary angiogram after stent deployment.

Optical coherence tomography (OCT) is based on infrared light emitted from a catheter-based light source, and has better resolution (10 μm to 15 μm), but less penetration than IVUS (Figure 1),18 enabling clear visualization of the intima and differentiation of the intima/media.19 Frequency domain (FD) OCT constitutes a refinement of the time-domain technology of OCT, enabling a faster pull-back during imaging, reducing the time needed for flushing of blood from the lumen and thus providing better image quality and improved handling of this technique.20 Due to its excellent imaging quality in the near field, the main application of this technique is currently visualization of stent coverage and assessment of stent apposition and intimal dissection in the evaluation of the vascular response to stent implantation in interventional cardiology.21 Furthermore, FD OCT can be used to visualize plaque morphology such as fibrous cap thickness, the lipid core, calcium, plaque rupture, and thrombus apposition (including atherosclerotic plaques in bypass grafts, as shown in Figure 2),19 and even macrophage density22 and collagen composition of fibrous caps.23 Early reports indicate that OCT provides better detection of plaque rupture and thrombus in patients with ACS than IVUS and coronary angiography, in addition to defining TCFAs.24 The ability to detect TCFA was found to be better in patients with acute myocardial infarction/ACS than in those with symptomatic stable CAD.25 Unlike IVUS, OCT is a rather novel technique, and standards for characterization of plaque composition and useful data interpretation need to be defined.26,27 In this respect, a recent study involving a systematic comparison of computed tomography (CT) angiography, IVUS, and OCT against histopathological examination ex vivo may set the stage for future studies. For discriminating between early and advanced coronary plaques, diagnostic accuracy was found to be best with OCT, followed by CT angiography and IVUS.28 Furthermore, by using both OCT (high spatial resolution) and IVUS (high penetration), thus combining the strengths of both methods, it was recently demonstrated that statin therapy increased fibrous cap thickness and decreased plaque and lipid volume indices in patients with CAD.29

Figure 3
Figure 3. Coronary plaque assessment in a 68-year-old asymptomatic patient prior to liver transplant.

(A) On invasive angiography, a nonsignificant stenosis of the proximal left anterior descending artery can be seen. (B) However, angiography fails to reveal the total plaque burden hidden beyond the lumen. (C) Computed tomography coronary angiography reveals a very large eccentric plaque with noncalcified and calcified components and a typical “napkin-ring”–like hyperenhancement in the proximal portion of the plaque.

Noninvasive imaging modalities for assessment of high-risk coronary laques

Multidetector CT technology enables determination of the coronary artery calcium (CAC) score, which is a measure of total plaque burden in the coronary vasculature. The CAC score is a powerful tool for risk prediction in asymptomatic individuals.30,31 However, a high CAC score does not rule out significant coronary stenosis and does not exclude the presence of noncalcified plaques. CT coronary angiography (CTCA) permits delineation of coronary plaque morphology, plaque volume, eccentric remodeling, and the presence of calcifications, and allows a crude assessment of plaque composition based on increasing amounts of calcium (noncalcified, mixed, and calcified plaques).32 A large plaque area, a high remodeling index, and a relatively large proportion of noncalcified and mixed plaque components on CTCA is found more often in culprit plaques of ACS patients than in patients with stable angina.33-36 Moreover, in 1 study, patients who had plaques with signs of positive remodeling and lower CT density had a higher likelihood of developing an ACS during a 2-year follow-up period.33 Furthermore, addition of plaque composition (≥2 segments with noncalcified plaque) to stenosis severity (≥50%) provided incremental prognostic information to reduced myocardial perfusion in patients with suspected CAD who were evaluated prospectively by CTCA and single-photon emission CT myocardial perfusion imaging.37 In addition, CTCA enables assessment of the progression of coronary plaques38 and statin-induced changes in plaque morphology.39 However, current CTCA analysis of coronary plaques is still limited by the spatial resolution of CTCA, which precludes depiction of TCFA (<65 μm cap thickness), the presumable precursor to plaque rupture. Furthermore, subclassification of noncalcified plaques into predominantly lipid-rich/necrotic versus fibrous plaque based on CT density is still unreliable.40 A “napkin- ring”–like enhancement of the plaque border surrounding the hypodense core seen on intravascular imaging with OCT and on histopathology examination41 was recently found to be associated with TCFAs (Figure 3) and is thought to represent a sign of plaque vulnerability.

Magnetic resonance imaging (MRI) of the coronary vasculature is an emerging modality driven forward by technological advances that have translated into better temporal resolution, improved signal-to-noise ratio, and reduced scan times.42 Recent MRI studies have demonstrated positive remodeling of the vascular wall in patients with CAD,43 and a positive correlation between coronary wall thickness and cardiovascular risk factors and intima-media thickness, but not CAC score.44 Combining MRI with use of ultra-small superparamagnetic iron oxide particles allows for visualization of macrophage-rich areas, and thus plaque inflammation, in carotid arteries. A recent study using ultrasmall superparamagnetic iron oxide particles showed that administration of statin therapy was associated with a significant reduction in carotid plaque inflammation.45 Several additional contrast agents have been developed, and multimodality positron emission tomography (PET) and MRI hold great promise for visualization of plaque morphology and biology, although they are not yet ready for clinical use.46,47

Molecular imaging combines imaging modalities to assess plaque morphology, perfusion, and metabolism/inflammation. From a clinical standpoint, the combination of PET, which uses a radiolabeled tracer capable of visualizing molecular targets in the picomolar range, and CT angiography, which has excellent spatial and temporal resolution, figures prominently among the current most advanced modalities.47,48 Promising tracers for detecting macrophage-driven inflammation in atherosclerotic plaque comprise 18F-NaF fluorodeoxyglucose (FDG),49-51 11C-PK11195,52 and 68Ga-DOTATATE.53 Two recent FDG-PET/CT angiography studies demonstrated the feasibility of the tracer approach, with a markedly higher FDG uptake found in culprit lesions from patients with an ACS compared with target lesions in patients with stable angina.50,51

The place of imaging in the diagnostic work-up of individuals at risk for future adverse events

In primary prevention, risk calculators such as the Framingham Risk Score54 or the Systematic COronary Risk Evaluation (SCORE) model55 are widely used. These scores integrate established cardiovascular risk factors to identify high-risk individuals, defined as those with a >20% absolute risk of experiencing a fatal coronary event or a nonfatal myocardial infarction within a 10-year period (Framingham Risk Score) or those with a ≥5% risk of death within a 10-year period (SCORE).

The challenge for the clinician concerning whether to initiate lifestyle changes and/or therapy lies in the identification of individuals in the intermediate-risk group. A recent analysis of a large cohort of asymptomatic individuals identified CAC as an independent predictor of future cardiovascular events in intermediate- risk individuals, as measured by CT. CAC provided superior discrimination and risk reclassification compared with other risk markers, including C-reactive protein.30 At present, it is unclear whether imaging of plaque morphology and biology that goes beyond the determination of CAC can translate into even better discrimination of individuals at risk and, most importantly, help guide the decision as to when to initiate therapy in asymptomatic individuals.

In the setting of ACS, commonly-used risk scores are the Thrombolysis in Myocardial Infarction (TIMI) risk score for patients with unstable angina/non–ST-segment elevation myocardial infarction (NSTEMI)56 and ST-segment elevation myocardial infarction (STEMI),57 and the Global Registry of Acute Coronary Events (GRACE) risk score, which covers the whole spectrum of ACS.58 Compared with the clinical TIMI risk score alone, addition of a highly sensitive troponin test to the TIMI risk score resulted in improved risk stratification of patients with NSTEMI.59

Despite the impact of PROSPECT in defining with the use of RF-IVUS morphological characteristics of coronary plaques that are associated with future cardiovascular events, the study did not provide any answers concerning lesions that are not TCFAs, but that also cause ACS in the absence of plaque rupture, ie, in the presence of plaque erosion and calcific nodules. Future studies are needed to address whether RF-IVUS–based identification of nonculprit lesions in patients with ACS can guide interventional/pharmacological strategies to prevent future events. Furthermore, prospective studies assessing the morphological characteristics and progression over time of nonculprit lesions and their association with future cardiovascular events with the use of OCT versus coronary angiography are lacking. Moreover, studies that address the impact of interventions on outcome after OCT identification of vulnerable plaques are clearly needed. Among the noninvasive imaging modalities, CT angiography appears the most clinically advanced, but identification of the most appropriate population to screen for coronary plaque morphology in order to prevent future ACS remains to be addressed in future studies. Similarly, following successful proof-of-concept studies using FDGPET/ CT angiography, prospective studies are needed to evaluate whether vulnerable plaques can therefore be identified prior to any clinical manifestation, and there is also a need to minimize radiation exposure with these modalities.

In summary, despite having a prominent place in the identification of coronary plaques that show characteristics of vulnerability, prospective data are only now beginning to emerge regarding the value of these imaging modalities in helping to guide therapies. ■

Acknowledgments. The authors received support by the Swiss National Research Foundation (Sonderprogramm Universitäre Medizin SPUM 33CM30-124112) the Swiss Heart Foundation; the Fondation Leducq, and the Zurich Heart House – Foundation for Cardiovascular Research, Zurich.

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Keywords: coronary artery disease; high-risk coronary lesion; invasive imaging; noninvasive imaging; risk stratification

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