Plaque Composition and Virtual Histology


Although grayscale intravascular ultrasound (IVUS) is generally used in clinical practice, using only the amplitude of the reflected ultrasound signals limits the assessment of plaque composition. Virtual histology IVUS is an IVUS-based post-processing modality for spectral analysis of the primary raw backscattered radiofrequency. When the spectral signatures of tissue types are programmed and processed by autoregressive models, the tissues can be color-coded as four major components such as dense calcium (white), necrotic core (red), fibro-fatty (light green), and fibrous tissue (dark green).1,2 Currently, virtual histology IVUS can be performed with either a 20 MHz, 2.9 F phased-array transducer catheter or a 45 MHz 3.2 F rotational catheter.3 Figure 1 shows plaque classification by virtual histology IVUS and definition of virtual histology thin-cap fibroatheroma.6,22

Figure 1

Figure 1
Figure shows plaque classification by virtual histology IVUS.6,23 Fibrotic plaque has mainly fibrous tissue with <10% confluent necrotic core, <10% dense calcium, and <15% fibrofatty plaque. Fibrocalcific plaque has mainly fibrous tissue with >10% dense calcium but <10% confluent necrotic core. Pathologic intimal thickening is a mixture of all plaque components but dominantly fibrofatty plaque with <10% necrotic core and <10% dense calcium. Fibroatheroma is defined as ≥10% confluent necrotic core. If there is >30° of necrotic core abutting to the lumen in three consecutive slices, the fibroatheroma is classified as thin-cap fibroatheroma (virtual histology thin-cap fibroatheroma); otherwise, it is classified as thick-cap fibroatheroma. Reprinted from JACC: Cardiovascular Imaging, 5, Maehara A, Cristea E, Mintz GS, et al. Definitions and methodology for the grayscale and radiofrequency intravascular ultrasound and coronary angiographic analyses, S1-9, 2012, with permission from Elsevier.

Evaluation of Natural History of Coronary Atherosclerosis

The most important mechanism of acute coronary syndrome (ACS) is plaque rupture and subsequent thrombus formation. In previous autopsy studies, the lesion most frequently prone to rupture was a thin-cap fibroatheroma that contained a large necrotic core with an overlying thin fibrous cap (<65 mcm of cap thickness) infiltrated by macrophages and lymphocytes.4,5

The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study evaluated the natural history of deferred coronary lesions in 697 patients with ACS who underwent three-vessel grey scale and virtual histology IVUS imaging after successful percutaneous coronary intervention (PCI) of culprit lesion.6 Both culprit and non-culprit lesions showed similar rates (12.9 and 11.6%, respectively) of 3-year major adverse cardiovascular events including cardiac death, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina. Independent predictors of non-culprit-related events were the presence of virtual histology thin-cap fibroatheroma (hazard ratio 3.35; 95% confidence intervals 1.77-6.36), a plaque burden ≥70% (hazard ratio 5.03; 95% confidence intervals 2.51-10.11), and a minimum lumen area ≤4.0 mm2 (hazard ratio 3.21; 95% confidence intervals 1.61-6.42). In a substudy from the PROSPECT study, patients with (vs. without) virtual-histology-defined fibroatheromas tended to be younger and more often female; non-fibroatheroma lesions were stable and rarely associated with clinical events during 3 years of follow-up.7 The presence of virtual-histology-defined fibroatheroma was more likely associated with a larger plaque burden and a higher rate of 3-year non-culprit-related cardiac events. In addition, minimum luminal areas ≤4.0 mm2, plaque burden ≥70%, and virtual histology thin-cap fibroatheroma were related to high degree of angiographic diameter stenosis, which may partly explain why subsequent clinical events were linked to baseline lesion severity.8 Similarly, the VIVA (VH-IVUS in Vulnerable Atherosclerosis) study prospectively evaluated 170 patients with stable angina or ACS.9 At a median of 1.7 years, morphological predictors of non-culprit-related events were the presence of virtual histology thin-cap fibroatheroma and a plaque burden >70%. The ATHEROREMO-IVUS Study (The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis - Intravascular Ultrasound Study) evaluating 581 patients also demonstrated that virtual histology thin-cap fibroatheroma and a plaque burden of ≥70% were independently associated with a high event rate.10 Those three studies consistently indicated that virtual histology IVUS can identify plaques with a high risk of subsequent events.

Virtual histology IVUS is also useful to assess serial changes in plaque morphology. Kubo et al. evaluated 216 non-culprit lesions to see the dynamic nature of coronary atherosclerosis between baseline and 12-month follow-up.11 Virtual histology thin-cap fibroatheroma at baseline stabilized in 75% of cases, changed into thick-cap fibroatheroma in 65% and fibrotic plaque in 10%, and remain unchanged in 25%. Twelve new virtual histology thin-cap fibroatheromas developed. Conversely, in the setting of ST-segment elevation myocardial infarction, 78% of virtual histology thin-cap fibroatheromas in non-culprit lesions remained unchanged during 13-month follow-up and were accompanied by progressive luminal narrowing and increased necrotic core.12 The data suggested that dynamic features of virtual histology thin-cap fibroatheroma may vary according to the different clinical settings.

Evaluation of Pharmacologic Effect on Coronary Atherosclerosis

In SATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin), which evaluated patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 2 years, atheroma regression was associated with reduced fibrofatty volume and increased dense calcium volume.13 In addition, volumetric changes in necrotic core correlated with on-treatment high-density lipoprotein and C-reactive protein levels. The STABLE (Statin and Atheroma Vulnerability Evaluation) trial was a prospective, double-blind, randomized study to see the effect of rosuvastatin on serial changes in virtual-histology-defined percent compositional volumes within an untreated fibroatheroma-containing target segment.14 In the overall group of 312 patients, percent necrotic core volume within the target segments significantly decreased from 21.3 ± 6.8% at baseline to 18.0 ± 7.5% at 12 months; the frequency of virtual histology thin-cap fibroatheroma also decreased (55 vs. 29%). In this Asian cohort, both high-dose (40 mg) and moderate-dose (10 mg) rosuvastatin similarly reduced percent necrotic core volume. Independent predictors of percent necrotic core volume change were body mass index, high-sensitive C-reactive protein, and baseline percent necrotic core. Furthermore, the correlation between the reduction in percent necrotic core volume and the change in high-sensitive C-reactive protein (not low-density lipoprotein cholesterol) implied that the anti-inflammatory effect of rosuvastatin may be primarily responsible for the plaque modification. In the IBIS-2 (Integrated Biomarker and Imaging Study 2) trial, the darapladib (vs. placebo) group showed a decrease in necrotic core assessed by virtual histology IVUS but was not associated with a decrease in percent atheroma volume.15 Prolonged pharmacological inhibition stabilized plaque vulnerability by reducing the necrotic core, indicating a direct effect on human atheroma.

Virtual Histology IVUS Findings During PCI

Studies have shown the role of virtual histology IVUS in predicting the risk of embolization during PCI.16,17 In a meta-analysis including 11 studies, a larger necrotic core or the presence of virtual histology thin-cap fibroatheroma was associated with a high risk of distal embolization in 9 studies.18 More recent meta-analysis including 16 virtual histology IVUS studies suggested that plaque volume and necrotic core were related to the occurrence of distal embolization.19 Thus, pre-procedural virtual histology IVUS assessment may identify lesions that potentially benefit from the selective use of embolic protection devices.

Virtual histology IVUS is useful in assessing plaque composition of chronic total occlusions (CTO). Guo et al. reported that 84% of CTO lesions had virtual-histology-defined fibroatheromas and that 61% of fibroatheroma-containing lesions had virtual histology thin-cap fibroatheroma, suggesting that the majority of CTOs evolved from ACS and thrombosis.20

Unsolved Issues

The radiofrequency-based method has limitations in assessing plaque in acoustic shadowed areas. The presence of dense calcium induces an artifactual coding of necrotic core in adjacent tissue. Signals behind calcified areas contain noise. There are no signal profiles of stent metal, thrombus, or neointima. Stent struts are colored white (like calcium) surrounded by a peri-stent red halo that does not represent real necrotic core. However, use of virtual histology IVUS may be useful to assess the absorption of bioresorbable vascular scaffolds. Because of poor axial resolution (200-250 mcm), there is a gap between histologic versus virtual-histology-defined thin-cap fibroatheroma. Electrocardiogram gating during virtual histology IVUS acquisition and limits to longitudinal resolution limit an accurate comparison between baseline and follow-up images.

There still remain concerns about the accuracy and external validity of virtual histology IVUS data. In the early ex-vivo validation study including 51 human coronary arteries, the overall diagnostic accuracies were 93.5% for fibrous tissue, 94.1% for fibrofatty tissue, 95.8% for the necrotic core, and 96.7% for dense calcium.1 However, ex vivo studies in a porcine model showed poor accuracies for identifying fibrous, fibrofatty, and necrotic core (58.3, 38.3, and 38.3%, respectively), and there was no significant correlation of necrotic core size between virtual histology IVUS and histology.21 However, in an ex vivo study in humans, the correlation between the absolute necrotic core areas measured by virtual histology IVUS versus histology was modest at the cross-section level (r = 0.50) but was improved at the segment level (r = 0.80).22


In the setting of both clinical practice and research, virtual histology IVUS improves our understanding of coronary atherosclerosis. Despite various methodological limitations, virtual histology IVUS is useful to identify coronary lesions at risk for future cardiovascular events and to assess the effect of medical or interventional treatment. Virtual histology IVUS is also valuable in comparing plaque characteristics between patient groups, even when clinical utility is limited in individual patients.


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Keywords: Acute Coronary Syndrome, Angina, Stable, Atherosclerosis, Benzaldehydes, Biomarkers, Body Mass Index, C-Reactive Protein, Cholesterol, LDL, Constriction, Pathologic, Coronary Angiography, Coronary Artery Disease, Electrocardiography, Embolic Protection Devices, Heart Arrest, Inflammation, Lipoproteins, HDL, Lymphocytes, Macrophages, Methyl Green, Myocardial Infarction, Neointima, Oximes, Percutaneous Coronary Intervention, Plaque, Atherosclerotic, Stents, Thrombosis

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