Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques

Abstract

Objectives: The goal of this study was to identify histomorphologic characteristics of atherosclerotic plaques and to determine the amenability of some of these components to be used as markers for invasive and noninvasive imaging.

Background: Rupture of the atherosclerotic plaques is responsible for the majority of acute coronary events, and the culprit lesions demonstrate distinct histopathologic features. It has been tacitly believed that plaque rupture (PR) is associated with angiographically minimally occlusive lesions.

Methods: We obtained 295 coronary atherosclerotic plaques, including stable (fibroatheroma [FA]; n = 105), vulnerable (thin-cap fibroatheroma [TCFA]; n = 88), and disrupted plaques (plaque rupture [PR]; n = 102) from the hearts of 181 men and 32 women who had died suddenly. The hierarchical importance of fibrous cap thickness, percent luminal stenosis, macrophage area, necrotic core area, and calcified plaque area was evaluated by using recursive partitioning analysis. Because clinical assessment of fibrous cap thickness is not possible by noninvasive imaging, it was excluded from the second set of partitioning analysis.

Results: Thickness of the fibrous cap emerged as the best discriminator of plaque type; the cap thickness measured <55 μm in ruptured plaques, and all FA were associated with >84-μm cap thickness. Although the majority of TCFA were found in the 54- to 84-μm thickness group, those with <54-μm thickness were more likely to show <74% luminal stenosis (area under the curve: FA, 1.0; TCFA, 0.89; PR, 0.90). After exclusion of cap thickness, analysis of the plaque characteristics revealed macrophage infiltration and necrotic core to be the 2 best discriminators of plaque types (area under the curve: FA, 0.82; TCFA, 0.58; PR, 0.72). More than 75% cross-section area stenosis was seen in 70% of PR and 40% of TCFA; only 5% PR and 10% TCFA were <50% narrowed.

Conclusions: This postmortem study defines histomorphologic characteristics of vulnerable plaques, which may help develop imaging strategies for identification of such plaques in patients at a high risk of sustaining acute coronary events.

Figure 1. Gross Morphology of Human Coronary Artery With Disrupted, Vulnerable (TCFA), and Stable (FA) Plaques

(Left) Plaque rupture (PR), showing disruption of fibrous cap at the shoulder region of the plaque (red arrowhead) and thrombus (Thr) superimposed. (Middle) An example of thin- cap fibroatheroma (TCFA). A large hemorrhagic necrotic core (NC) is observed within the plaque. White arrows are pointing to the thinnest portion of the fibrous cap. (Right) Stable plaque. The plaque mainly consists of fibrous tissue with calcification (black arrows). FA = fibroatheroma.

Figure 2. Photomicrographic Cross-Section of Human Coronary PR, TCFA, and FA With Varying Degree of Luminal Stenosis

(A to C) Plaque rupture with mild, moderate, and severe luminal stenosis, respectively. Nonocclusive Thr is observed in the microphotograph A whereas occlusive Thr is occupying the lumen in the image B and C. (D to F) TCFA with mild, moderate, and severe luminal stenosis, respectively. NC is covered by a thin fibrous cap, and Thr is not present in the lumen. (G to I) Stable plaque or FA with mild, moderate, and severe luminal stenosis, respectively. The size of necrotic core is relatively small when present, and calcification (Ca⁺⁺) is frequently seen. Abbreviations as in Figure 1.

Figure 3. Luminal Obstruction in FA, TCFA, and PR

(A) Bar graph and (B) boxplot show >50% cross-sectional vascular area stenosis in a majority of PR and TCFA. The distribution indicates that TCFA may further enlarge before plaque rupture. Boxplot shows numerical data through the lower quartile, median, and upper quartile, and the whiskers represent the sample minimum and sample maximum observations. Abbreviations as in Figure 1.

Figure 4. Multivariate RPA Model Including All Cases and All Candidate Variables

Cap thickness was the key plaque characteristic in its ability to discriminate between the 3 plaque types, with all stable FA (green) separated into a subgroup of >84 μm. TCAP in PR measured <54 μm (red). Blue represents TCFA. The receiver-operating characteristic curve generated from the analysis suggested the following area under the curve: FA, 0.82; TCFA, 0.58; and PR, 0.72. G^2 statistic is a likelihood-ratio chi-square test on which the candidate variables are evaluated for inclusion in the partitioning process. Similar to the Pearson chi-square test (and asymptotically equal), G^2 is a goodness-of-fit test and considered more appropriate for smaller samples and for nested models. RPA = recursive partitioning analysis; other abbreviations as in Figure 1.

Figure 5. Multivariate RPA Model Including All Cases But Excluding Cap Thickness as the Candidate Variable

Predominance of macrophage infiltration identified a majority of PR (red) and TCFA (blue). TCFA and PR in the less-inflamed group (contaminating the FA group) showed larger NC. The few remaining less inflamed and small core PR and TCFA could be isolated from FA (green) once again by the degree of inflammation. The receiver-operating characteristic curve generated from the analysis suggested the following area under the curve: FA, 0.82; TCFA, 0.58; and PR, 0.72. Essentially, similar results were observed in re-analysis including only the lesions showing 50% to 75% luminal diameter stenosis; area under the curve: FA, 0.81; TCFA, 0.70; and PR, 0.85. The results were similar for those with >75% diameter stenosis; area under the curve: FA, 0.86; TCFA, 0.59; and PR, 0.82. Abbreviations as in Figures 1 and 4.