Correspondence *Department of Medicine, Division of Cardiology, Medizinische Klinik und Poliklinik—Campus Innenstadt, Ludwig-Maximilians-Universität, Ziemssenstrae 1, 80336 Munich, Germany

Email andreas.koenig@med.uni-muenchen.de

Introduction

Acute coronary syndromes (ACS) and sudden cardiac death are the main causes of morbidity and mortality in the western world.¹ ACS are often the first manifestation of coronary artery disease and the rupture of a coronary plaque is the main cause of ACS. Histopathological studies have revealed that the majority of thrombi result from plaque rupture. Plaque rupture of high-risk lesions, thus, has a central role in the pathogenesis of acute coronary events.²

The importance of nonstenotic coronary lesions has been highlighted by increased knowledge of the role of inflammation in the progression of atherosclerosis at every stage of development up to thrombotic occlusion as seen in patients with ACS, and the appreciation of remodeling processes such as compensatory vessel-wall enlargement.^{3, 4} In vivo lesion analysis of plaque classification in coronary atherosclerosis is necessary to determine the natural history of these high-risk lesions. Histopathological plaque classification on the basis of post-mortem data uses descriptive morphology, highlighting the specific morphological aspects of lesions such as in plaque rupture and plaque erosion. Emphasis is placed on the amount of necrotic core, macrophage infiltration and calcification, and the thickness or presence of a fibrous cap.⁵

Grayscale intravascular ultrasonography (IVUS), a tomographic imaging tool, can visualize coronary atherosclerosis in vivo, elucidating plaque area, plaque distribution, lesion length and coronary remodeling. IVUS has demonstrated the discrepancies between the extent of atherosclerosis seen by coronary angiography and the actual extent of atherosclerotic disease.⁶ Quantitative assessment of plaque composition has, however, not been possible with grayscale IVUS analysis, until now.⁷

IVUS-derived virtual histology (VH-IVUS) uses advanced radiofrequency analysis of ultrasound signals and is able to overcome the main limitation of grayscale IVUS by providing a more detailed analysis of plaque morphology.⁸ In addition, VH-IVUS has the potential to provide patient-specific plaque analysis and, therefore, eliminates the bias introduced by studying a selective autopsy population. In this Review we attempt to outline the utility of radiofrequency-based plaque composition analysis in the context of clinical and pathohistological atherosclerotic studies.

Plaque composition and pathology

As the majority of acute events are triggered by plaque rupture,^{9, 10} defining the anatomic features that lead to plaque rupture should be of central importance during lesion imaging. Post-mortem analyses have shown that thin-cap fibroatheroma (TCFA) is probably the main precursor lesion for plaque rupture.² TCFAs are characterized by a large necrotic core separated from the coronary lumen by a thin fibrous cap. According to pathohistological studies, the size of the necrotic core and the thickness of the fibrous cap have a critical influence on plaque stability. In addition to a large necrotic core and a thin fibrous cap, other characteristics of vulnerable lesions include localized expansive enlargement of the vessel wall—so-called 'positive remodeling'—and microcalcification within the lesion. The location of the lesion within the coronary tree, the length of the lesion, and the narrowing of the artery relative to healthy reference lumen size are also important parameters for the evaluation of plaque vulnerability. Coronary dimensions and elements of plaque composition such as the presence and amount of necrotic core, the thickness of the fibrous cap, degree of calcification and coronary remodeling are all anatomic features visualized by IVUS and VH-IVUS, but not by traditional angiography.

IVUS versus ivus-derived virtual histology

IVUS enables real-time, high-resolution tomographic visualization of the coronary arteries. Both lumen and vessel dimensions and the distribution of plaques can be analyzed. In addition, grayscale IVUS can be used to assess the presence of intraluminal thrombus and plaque rupture.¹¹

Grayscale IVUS has demonstrated the multiplicity of plaque ruptures seen in patients with ACS.^{12, 13, 14} A recent study demonstrated that the number of vulnerable plaques with less than 75% luminal obstruction identified by IVUS had a positive correlation with future cardiovascular events.¹⁵ Of note, serial IVUS analysis of a small patient cohort showed that 50% of ruptured coronary plaques detected on first ACS event had spontaneously healed at 22 months' follow-up.¹⁶

Grayscale IVUS imaging is, however, limited with regards to analysis of plaque composition. Both calcified and dense fibrotic tissues, such as those found in plaques, have strong echoreflections with lateral shadowing and are, therefore, not easy to differentiate. As a consequence, the extent of calcification is often overestimated. Areas with low echoreflections comprise foam cells or necrotic core, fibrotic tissue, intraplaque hemorrhage and fresh or 'still-organizing' intraluminal thrombus. Currently, VH-IVUS can better distinguish between areas with low echoreflections than can grayscale IVUS. Nevertheless, quantification of hypoechogenicity is promising, as it has been related to adverse event rate.^{17, 18}

A more detailed analysis of plaque composition is achieved by VH-IVUS. This technique is based on advanced radiofrequency analysis of reflected ultrasound signals in a frequency domain analysis, and displays a reconstructed color-coded tissue map of plaque composition superimposed on cross-sectional images of the coronary artery obtained by grayscale IVUS.⁸ Recent imaging technology now allows the reconstruction of VH-IVUS images in a longitudinal view, enabling a more comprehensive analysis of the total length of the plaque, its spatial orientation and its relation to the rest of the coronary tree (Figure 1). Of note, Volcano Corporation (Rancho Cordova, CA) is, at the moment, the sole manufacturer of VH-IVUS equipment.

Figure 1 Real-time intravascular-ultrasonography-derived virtual histology images in (A) tomographic and (B) longitudinal views.

Intravascular ultrasonography provides a quantitative measure of the cross-section of the vessel and a quantitative measure of lesion length and tissue characterization. Tissue characterization automatically identifies fibrous (dark green), fibrofatty (light green), dense calcium (white) and necrotic core (red). Permission obtained from BMJ Publishing Group Ltd © König A and Klauss V (2007) Heart 93: 977–982.

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Plaque components

As outlined previously, many different cell and tissue types are commonly found in atherosclerotic plaques. To simplify image interpretation and because of the fundamental resolution limitations of the underlying ultrasound signal, plaque components are grouped into four basic tissue types during VH-IVUS imaging. These components are displayed on VH-IVUS as different color pixels.

Fibrous tissue

Fibrous tissue is represented as dark green pixels. Histologically, this tissue type is characterized by bundles of collagen fibers with little to no lipid accumulation in or around the fibrous area.^{19, 20} On grayscale IVUS, these tissues tend to be bright to medium-bright regions and generally have no acoustic shadow behind. Occasionally—depending on catheter power level, console settings, catheter position within the artery and other variables—dense fibrous tissue can cause a subtle shadowing behind the plaque (Figure 2).

Figure 2 Intravascular ultrasonographic images of an eccentric plaque.

(A) Grayscale intravascular ultrasonographic (IVUS) image shows the echodense areas on the lumen surface of the plaque and lateral shadowing over the vessel circumference. (B) The virtual histology IVUS image shows predominantly fibrous (dark green) and fibrofatty (light green) tissue.

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Necrotic core

In VH-IVUS, the necrotic core is represented by red pixels (Figure 3). In histology, this tissue type is characterized by a high concentration of extracellular lipid within a necrotic core that is made up of remnants of dead, lipid-filled smooth muscle cells, foam cells, trapped red blood cells and fibrin.^{2, 19} Little to no collagen is present and a matrix-like cellular structure is absent. The loss of tissue matrix means that these 'necrotic cores' are rich in lipid, consisting predominantly of cholesterol monohydrate, cholesterol ester and phospholipids. This tissue, therefore, has poor mechanical stability. Microcalcification, areas of solid calcification and calcification of collagenous tissue are often observed as a byproduct of the dead and dying cells. On grayscale IVUS, these microcalcifications tend to reflect the ultrasound signal more strongly than other components, and as a result areas of necrotic core can appear moderately bright white, with or without shadow.

Figure 3 Intravascular ultrasonographic images and histologic specimen of the same thin-cap fibroatheroma.

(A) Grayscale intravascular ultrasonographic (IVUS) image shows an echodense confluent plaque area. Lateral shadowing indicates a high amount of calcified plaque. (B) The correlating virtual histology IVUS image and (C) the ex vivo pathohistologic section show the thin-cap fibroatheroma and a large necrotic area, respectively.

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Cross-section lesion analysis

In vivo plaque classification with VH-IVUS is based on a histopathological classification system developed by Virmani et al. in 2000.⁵ According to this system, coronary lesions can be classified as adaptive intimal thickening, pathologic intimal thickening, fibroatheroma, TCFA and fibrocalcific plaques (Figure 4 and Table 1). For risk stratification or the assessment of the likelihood of lesion rupture, it is important to distinguish between the above-mentioned plaque types, and especially between pathologic intimal thickening and TCFAs. This classification system represents the different stages of development of atherosclerosis, from early intimal thickening to vulnerable lesions such as TCFA. According to pathologic studies TCFA represent precursor lesions for plaque rupture.²

Figure 4 Current coronary plaque classification according to virtual histology intravascular ultrasonography.

Plaque classification distinguishes between (A and B) intimal thickening and (C, D, E and F) more vulnerable lesions, such as fibroatheroma. (D) In a thin-cap fibroatheroma, the necrotic core is proximal to the surface of the plaque. The fibrous cap is not visible in this plaque type. (E) Thin-cap fibroatheroma presenting with several layers of necrotic cores suggests previous ruptures.

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Table 1 Histological characterization and corresponding VH-IVUS representation of different plaque types.

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Fibroatheroma

Fibroatheromata are plaques with a true necrotic core containing cholesterol, phospholipids and triglycerides (Figure 5). The fibrous cap that protects the coronary lumen from the necrotic core consists of smooth muscle cells in a proteoglycan-rich collagen matrix. The degree of inflammatory cell infiltration within the fibrous cap can vary. The thickness of the fibrous cap and the amount of necrotic core are part of further classification. As lesions progress, the fibrous cap overlying the necrotic core is assumed to become thinner and when the thickness is less than 65 m for lesions in coronary arteries the lesion is classified as a TCFA. In light of the limited axial resolution of VH-IVUS—approximately 150 m—the cap can be measured only if greater than 150 m thick. VH-IVUS defines fibroatheromata as having a confluent necrotic core of more than 10% of the total plaque volume in mainly fibrous and/or fibrofatty tissue. The amount of calcium can vary—a fibroatheroma is defined as having less than 10% dense confluent calcium (i.e. a minor amount of calcium); if a lesion has more than 10% dense confluent calcium, it is defined as a calcified fibroatheroma. The longitudinal distribution of the necrotic core can be either focal or diffuse. These features seen on VH-IVUS are believed to contribute to the increased vulnerability of fibroatheromata and represent a decrease in the mechanical integrity of the coronary plaque.

Figure 5 Current classification for plaque type.

Virtual histology images of (A) a fibrotic plaque, and (B and C) fibroatheroma in the left panel, with corresponding histopathological images on the right.

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Classification of IVUS-derived thin-cap fibroatheroma

A new vulnerability index is under development for improved classification and stratification of TCFAs (Figure 6). Of note, TCFAs identified by VH-IVUS (termed 'ID TCFAs') can be further subclassified on the basis of certain characteristics that increase the risk of sudden cardiac death, as determined by analyses of post-mortem data. ID TCFA have a confluent necrotic core (>10%) without any evidence of a fibrous cap and a minor amount of calcium (<10%). The presence of ID TCFA confers a first step increase in vulnerability (vulnerability index 1).

Figure 6 A new vulnerability index currently under development for improved classification and stratification of thin-cap fibroatheroma.

Amount of dense calcium influences vulnerability index. (A) Lesions with less than 10% dense calcium are classified as being in vulnerability index 1, (B) while those with more than 10% are classified as vulnerability index 2. (C) Vulnerability index 3 lesions have multiple layers of calcium, and (D) lesions classified as vulnerability index 4 have more than 20% confluent necrotic core, no fibrous cap and more than 10% dense calcium, with a 'speckled' appearance.

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Within the classification of ID TCFA, additional degrees of presumed vulnerability based on pathohistologic data can be derived. Generally, a focal necrotic core that has less surface contact with the lumen is distinct from a diffuse necrotic core that has more contact. It is hypothesized that the higher the extent of surface contact the necrotic core has with the lumen—in the presence of increased amounts of calcium—the higher the risk for rupture (i.e. diffuse necrotic core with at least 2 mm contact with the lumen = vulnerability index 2).

The occurrence of multiple, confluent necrotic cores and at least one necrotic core without evidence of a fibrous cap indicates underlying, previously healed plaque ruptures.²² In terms of risk, this feature is additive and increases lesion vulnerability (vulnerability index 3). The concomitant occurrence of the above features is thought to increase the risk of rupture in the interrogated TCFA. On the basis of post-mortem data, a TCFA with a confluent necrotic core greater than 20%, no evidence of a fibrous cap, calcium content higher than 10% with a speckled appearance, a positive remodeling index and a high amount of plaque burden with significant cross-sectional luminal area narrowing confers the most-vulnerable plaque type (vulnerability index 4). Post-mortem data and in vivo studies have also shown a close correlation between positive remodeling and plaque vulnerability.^{19, 23}

Longitudinal view and serial analysis

The longitudinal VH-IVUS view of the target segment provides information about the length of the plaque and its composition. According to post-mortem data, plaque composition is a better predictor of ACS events than the degree of coronary stenosis.²⁵ The formation of intraluminal thrombus after plaque rupture or erosion has a central role in the clinical course of ACS. Coronary thrombosis is a dynamic process and the culprit thrombus can assume different degrees of organization. With repeated thrombosis, the imaging of lesions becomes increasingly difficult. As the plaque ruptures, the lesion site is covered with thrombus and the underlying plaque and necrotic core is filled by intramural hemorrhage.²⁶ An intraluminal thrombus tail rich in red blood cells can form proximal to the site of plaque rupture, especially in the presence of slow blood flow. This thrombotic tissue can be organized as fibrotic tissue, causing luminal narrowing further to that at the rupture site.

Post-mortem studies have clearly shown that repeated plaque ruptures have a key role in plaque progression. Pathologic studies have detected complex plaques with previous ruptures concentrating at one site, suggesting that certain sites are chronically vulnerable.²² Subclinical episodes of plaque disruption followed by healing is considered a mechanism by which plaque burden increases and leads to inward remodeling processes and finally luminal narrowing.²² The site of the TCFA is often the site of the minimum lumen cross-sectional area within the lesion. The origin or focus of the plaque rupture can be proximal or distal to the minimum lumen area of the lesion.²⁷ Hence, assessment of atherosclerotic lesions should include the whole length of the lesion to ensure detection of the site of plaque rupture, which might not necessarily be the site of the minimum lumen cross-sectional area. This phenomenon has been seen earlier by IVUS (Figure 7).²⁷

Figure 7 The relation between the site of plaque rupture and the site of the MLD of the interrogated lesion, as suggested by post-mortem studies.

(A) The site of plaque rupture can be distant from the MLD or, in case of several healed plaque ruptures, can be the reason for progressive luminal narrowing. (B) Examples of the MLD and site of vulnerable plaque as represented by virtual histology and grayscale intravascular ultrasonography. Abbreviation: MLD, minimum lumen diameter.

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The change of atheroma dimensions documented by serial IVUS analyses was used as a surrogate end point in atherosclerotic progression and regression trials.^{28, 29, 30} According to these trials, the plaque compositional changes, as observed by VH-IVUS could also serve as a possible serial end point in the assessment of novel antiatherosclerotic medications. Regarding plaque geometry and plaque composition, recent studies have demonstrated an acceptable reproducibility of serial VH-IVUS analyses.³¹ As a result of the lower longitudinal resolution of VH-IVUS imaging based on electrocardiography-triggered cross-sectional analysis than of real-time analysis by grayscale IVUS, whole lesion segments should be compared side by side. A volumetric analysis of plaque components is also possible.

Present studies with VH-IVUS

In a recent study, VH-IVUS backscatter data from 51 ex vivo left anterior descending coronary arteries were recorded and compared with histological interpretation of the same sites.²⁰ The overall predictive accuracies for VH-IVUS were 93.5% for fibrotic tissue, 94.1% for fibrofatty tissue, 95.8% for necrotic core and 96.7% for dense calcium—demonstrating the potential of this imaging tool for analyzing plaque vulnerability. In the Carotid Artery Plaque Virtual Histology Evaluation (CAPITAL) study there was a strong correlation between VH-IVUS plaque characterization and characterization following true histological examination of the plaque following endarterectomy.³² The predictive accuracy for TCFA was 99.4% and 96.1% for calcified TCFA.

In vivo studies using VH-IVUS have shown that presumed vulnerable plaques (ID TCFAs according to IVUS criteria) occur more often in patients with ACS than in patients with stable angina.³³ Patients who are stable at clinical presentation show intimal thickening and plaque composition with considerably more fibrotic tissue than that typically seen in vulnerable plaques.

Angiographic studies have shown that acute coronary occlusions that lead to ST-segment elevation myocardial infarction tend to cluster in predictable hot spots—the proximal third of the coronary arteries, in particular. For each 10 mm increase in distance from the ostium, the risk of a coronary occlusion decreases significantly; by 13% in the right coronary artery, 30% in the left anterior descending artery and 26% in the circumflex artery.³⁴ Recent VH-IVUS studies have also confirmed that plaque composition has a nonuniform distribution along the coronary arteries.³³ The lower incidence of ID TCFA as the distance from the ostium increases—as seen in vivo by VH-IVUS—supports previous data.³⁴ Depending on the distance from the coronary ostium, the proximal segments show a significantly larger necrotic core, but no change in other plaque components.³⁵ As the proportion of necrotic core is related to lesion vulnerability, these findings could explain the higher incidence of plaque ruptures in the proximal segments of the coronary tree.

The tomographic imaging technique enables the presentation of the whole coronary artery cross section, clearly demonstrating the expansive vessel area changes that occur with positive remodeling.³⁶ According to recent studies, VH-IVUS analysis could confirm the relation of outward and inward remodeling processes to plaque composition.³⁷ In a small, in vivo study, plaque composition and morphology assessed using IVUS radiofrequency analysis were shown to relate to coronary remodeling, supporting a role of plaque composition in vessel remodeling.²³ The size of necrotic core is significantly larger in lesions with positive remodeling; fibrous plaque burden, however, has a significant inverse relationship with remodeling index. Positive remodeling is, therefore, associated with presumed high-risk lesions such as fibroatheromata and TCFAs, while negative remodeling is associated with less-vulnerable lesion types such as those with pathologic intimal thickening and fibrotic plaques.²³ As vasa vasorum correlate with the degree of infiltration of inflammatory cells³⁸ and are associated with intraplaque hemorrhage and plaque rupture,³⁹ it should be of interest that recent studies showed the feasibility of vasa vasorum imaging by contrast harmonic IVUS.^{40, 41} The ongoing Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) trial is a natural history study designed to assess the relationship between unexpected acute coronary events and plaque burden, composition and type in intermediate lesions. PROSPECT is the first prospective study aimed at detecting high-risk lesions that could rupture using both grayscale and VH-IVUS technologies.

Potential clinical strategies

In terms of secondary prevention, the detection of plaque progression and the identification of coronary lesions at significant risk for ACS are of great clinical importance. Angiographic studies have demonstrated clinically relevant progression of nonculprit lesions in a large cohort of consecutive patients following percutaneous coronary intervention (PCI). The rate of non-target-lesion PCI during 1-year follow-up is also strongly dependent on the overall severity of coronary artery disease.⁴² The annual reintervention rate of patients with three-vessel disease is approximately 13% and the majority of these patients (70%) present with ACS. In addition, earlier angiographic studies showed a distinctive kind of stenosis progression for nonculprit lesions with differing angiographic lesion morphology; either slight or marked progression of stenosis,⁴³ complex lesion morphology and unstable presentation were all features associated with rapid stenosis progression.⁴⁴ Coronary angiography and clinical parameters are, however, poor surrogates for predicting future events in a broad cohort of patients who have undergone PCI. With regards to noninvasive imaging techniques, MRI is seen as a potential approach for lesion composition analysis, but at present is limited by cardiac and respiratory motion artifacts.⁴⁵ All these findings highlight the clinical need to identify potentially vulnerable lesions in vivo for early risk stratification and treatment in order to reduce coronary mortality.

Catheter-based invasive diagnosis of plaque composition with VH-IVUS can identify the features of different plaque types that are important predictors of plaque vulnerability. The in vivo predictive power and accuracy of VH-IVUS and the assumptions we have made from post-mortem data are currently being assessed in a clinical trial that aims to identify lesions at high risk of plaque rupture leading to either plaque progression (silent plaque progression) or a clinically symptomatic event. The current characteristics being examined as possible indicators of increased lesion vulnerability are the presence and the extent of confluent necrotic core, the absence of fibrotic cap, the pattern of calcification, positive remodeling, degree of luminal stenosis and the location of the interrogated lesion.

In the presence of a vulnerable plaque, aggressive risk factor modification is needed. At present, prophylactic treatment of angiographically assessed intermediate-risk lesions with balloon dilation or stent implantation is not recommended. A recent meta-analysis found the restenosis risk after revascularization with bare-metal stents to be unacceptably high.⁴⁶ With improved diagnostic accuracy and the reduced restenosis rates (<5%) with drug-eluting stents,⁴⁷ prophylactic therapy of potentially vulnerable lesions to avoid plaque rupture and ACS could be re-evaluated. Ongoing clinical studies could, however, demonstrate the efficacy of optimum medical therapy to prevent coronary intervention in patients with stable coronary artery disease.⁴⁸ We need prospective randomized studies to determine whether prophylactic treatment with coronary stent implantation confers a higher benefit than does optimized medical therapy in patients with high-risk vulnerable lesions.

As post-mortem data have demonstrated, longitudinal analysis of the target lesion using VH-IVUS also shows the site of plaque rupture, mainly the TCFA or calcified TCFA, which are often proximal to the site of the minimal lumen cross section. As a consequence, just covering the minimum lumen site might not be sufficient to fully treat the lesion. If proximal to the site of the minimal lumen cross section, full coverage of the lesion, including the site of the problem (i.e. TCFA or calcified TCFA) could reduce the rate of future events related to reoccurring ruptures of the uncovered lesion. This concept is also being evaluated in ongoing clinical studies.

Discussion

Compared with other diagnostic tools, VH-IVUS provides improved in vivo diagnostic accuracy of atherosclerotic plaques. As an in vivo diagnostic tool with online, on-screen data display, it has the potential to bypass the most important bias of post-mortem data—that analyzed patients have already died from acute cardiac death—and accurately assess plaque progression on an individual basis.

Of all currently available diagnostic tools, the pathology-based criteria for plaque vulnerability regarding plaque composition and plaque type can be most comprehensively assessed by grayscale IVUS and VH-IVUS. This evaluation enables more comprehensive risk assessment and stratification on an individual basis for secondary prevention.

Grayscale IVUS has established some 'niche' interventional applications, for example, the characterization and quantitative analysis of left main disease and transplant vasculopathy in heart transplant patients.^{49, 50} The additional benefit of plaque composition analysis for these clinical indications is under investigation at present.

IVUS has a role in the assessment of stent underexpansion and stent malapposition; however, it is not recommended for routine use during stent implantation. VH-IVUS guidance of coronary interventions could achieve complete coverage of virtual histologically defined high-risk lesions, in addition to treatment of minimum lumen area, and, therefore, reduce the risk of restenosis or progression of atherosclerosis in the reference segments. The efficacy of this application, in comparison with that of optimum medical therapy, is also yet to be determined.

Until now we have had no diagnostic tools and no evidence to support the treatment of vulnerable lesions with a preventive strategy other than risk factor modification. There is uncertainty regarding the restenosis risk after preventative stent treatment of a vulnerable lesion in comparison with the spontaneous rupture rate of high-risk lesions that have not been treated with stenting. The duration of the possible vulnerable stage is also unknown, as is the time of the progression or regression of coronary artery disease. Given that the vulnerability of high-risk lesions could be only temporary owing to the possibility of changes in plaque structure, prospective, serial VH-IVUS studies should be performed to clarify the natural history of these vulnerable lesions.

Our knowledge of the natural history of atherosclerosis including lesion classification relies on post-mortem histology data. As VH-IVUS enables in vivo identification of four different plaque characteristics and their location, this technique may enable a more accurate classification of lesions with regard to progression and regression. With time, we may even be able to determine with high accuracy which lesions should be treated with intervention and which with systemic medical therapy.

Limitations

The limitations of this technique have been previously described.⁵¹ Accurate border detection is critically important, as the virtual histology software characterizes the entire plaque area along with the main tissue types, and requires experience in grayscale IVUS imaging and analysis.

The axial resolution of VH-IVUS (i.e. 150 m) is too low to detect critical fibrous cap thickness, which is currently defined as 65 m. This threshold for critical cap thickness has, however, been established for ruptured plaques and not TCFAs. Histopathological studies demonstrated a higher critical thickness for caps in TCFAs.⁵² In addition, dehydration processes used during histological fixation can induce considerable tissue shrinkage (particularly of collagen, the main component of the fibrous cap), thereby underestimating the real threshold of thin caps.

Despite better differentiation of low echogenic reflexes with VH-IVUS, a differential diagnosis between soft plaque material and intraluminal organizing thrombus is currently not possible by radiofrequency analysis. Thrombus detection could help localize the extent and also origin of the plaque rupture in patients with ACS. Thrombus as the primary surrogate for acute coronary thrombosis cannot yet be detected and, therefore, has to be excluded from current VH-IVUS analyses. It should be noted that the inflammatory activity of the plaque representing the actual vulnerability of the interrogated lesion cannot be directly visualized by VH-IVUS.

Conclusions

In comparison with other clinically available catheter-based intracoronary diagnostic tools, VH-IVUS provides the most comprehensive imaging method for detailed assessment of plaque components in both cross-sectional and longitudinal views of the coronary artery. As grayscale IVUS increased our knowledge of coronary atherosclerosis, VH-IVUS is likely to provide even more detailed information by imaging the vessel dimensions and the components of the coronary plaque. The present plaque classification by VH-IVUS represents the current translation of histopathological knowledge into in vivo intracoronary diagnosis. Using the virtual histology derived plaque classification and lesion analysis guidelines, we now have the ability to modify coronary interventions using lesion specific strategies.

Acknowledgments

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Imaging and other investigations | Vascular disease