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. 2023 Nov 1;30(11):1715-1726.
doi: 10.5551/jat.64098. Epub 2023 Apr 19.

Cholesterol Crystals as the Main Trigger of Interleukin-6 Production through Innate Inflammatory Response in Human Spontaneously Ruptured Aortic Plaques

Sei Komatsu  1 , Chikao Yutani  2   3 , Satoru Takahashi  1 , Mitsuhiko Takewa  1 , Nobuzo Iwa  2 , Tomoki Ohara  1 , Kazuhisa Kodama  1
Affiliations

Cholesterol Crystals as the Main Trigger of Interleukin-6 Production through Innate Inflammatory Response in Human Spontaneously Ruptured Aortic Plaques

Sei Komatsu et al. J Atheroscler Thromb. .

Abstract

Aim: This study aimed to clarify whether cholesterol crystals (CCs) are the main trigger of innate inflammation in human spontaneously ruptured aortic plaques (SRAPs).

Methods: This study included 260 SRAPs collected during nonobstructive general angioscopy (NOGA) from 126 patients with confirmed or suspected coronary artery disease. Interleukin (IL)-6 levels in SRAPs were measured. IL-6 levels in the Valsalva sinus and femoral or brachial arteries were measured. IL-6 ratios (the IL-6 level in SRAPs and arteries divided by the IL-6 level at the Valsalva sinus at the beginning of the aorta) were calculated. Quantitative analysis of CCs was performed from SRAPs. The correlation between the count of CCs and IL-6 levels in SRAPs and that between the counts of CCs and IL-6 ratios in SRAPs were analyzed.

Results: The IL-6 levels in SRAPs were 3.4 [2.1, 7.2] pg/mL, and the IL-6 ratio (median [interquartile range]) in SRAPs was 1.10 [1.00, 1.26]. CCs were detected in 94 of 260 SRAPs (36%). The count of CCs was 11,590 (95% confidence interval, 2,386-30,113) per 10 mL in CC-positive samples. There was a moderate correlation between the counts of CCs and IL-6 ratios in SRAPs (r=0.49, r＜0.0001), whereas there was no correlation between the count of CCs and IL-6 levels in SRAPs. The IL-6 ratios of the brachial and femoral arteries were 1.06 (95% CI, 0.99-1.20) and 1.11 (95% CI, 1.04-1.20), respectively.

Conclusions: CC is the main trigger of IL-6 production through innate inflammatory response in human SRAPs in situ.

Keywords: Aorta; Cholesterol crystals; Nonobstructive general angioscopy; Spontaneously ruptured aortic plaque.

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Conflict of interest statement

Sei Komatsu is a technical consultant for Nemoto Kyorin-do Co. Ltd. A part of IL-6 measurements was provided by SRL Co., ltd. All other authors have no conflicts of interest to declare.

Figures

Supplementary Fig.1. Schema of sampling blood for interleukin-6 ratio
Supplementary Fig.1. Schema of sampling blood for interleukin-6 ratio
＊1: the Valsalva sinus, ＊2: the left brachial artery, ＊3: the femoral artery, ＊4: spontaneously ruptured aortic plaques.
Fig.1. Representative images of cholesterol crystal count
Fig.1. Representative images of cholesterol crystal count
Polarized microscopic images (A, B) and schema. (C) The count of the multilayered cholesterol crystals is four.
Supplementary Fig.2. Interobserver and intraobserver agreements on the quantitative analysis of CCs
Supplementary Fig.2. Interobserver and intraobserver agreements on the quantitative analysis of CCs
A. Interobserver agreement on the quantitative analysis of CCs. Bland–Altman plots showing the comparison between CC counts by an expert pathologist and an expert cardiologist. Bias is indicated by the mean difference between two observers, and precision is indicated by the 95% limits of agreement represented by the mean±1.96 standard deviations (SD). B. Intraobserver agreement on the quantitative analysis of CCs. Bland–Altman plots showing the intraobserver agreement on CC counts by an expert pathologist. Bias is indicated by the mean difference between two independent CC counts, and precision is indicated by the 95% limits of agreement represented by the mean±1.96 standard deviations (SD).
Fig.2. Correlation between the IL-6 levels in the Valsalva sinus and IL-6 levels in the femoral/brachial arteries or in SRAPs
Fig.2. Correlation between the IL-6 levels in the Valsalva sinus and IL-6 levels in the femoral/brachial arteries or in SRAPs
A. Strong correlation between the IL-6 levels in the Valsalva sinus and IL-6 levels in the femoral/brachial arteries (r=0.998, r＜0.0001) B. Strong correlation between the IL-6 levels in the Valsalva sinus and IL-6 levels in SRAPs (r=0.997, r＜0.0001)
Fig.3. Correlation between the number of SRAPs and the sum of CCs from SRAPs and IL-6 levels
Fig.3. Correlation between the number of SRAPs and the sum of CCs from SRAPs and IL-6 levels
A. Weak correlation between the number of SRAPs and the sum of CCs from SRAPs (r=0.32, p=0.0003) B. Weak correlation between the number of SRAPs and IL-6 levels in the Valsalva sinus (r=0.34, p=0.0004) C. Weak correlation between the number of SRAPs and IL-6 levels in the femoral/brachial arteries (r=0.35, p=0.0002)
Fig.4. Correlation between the count of cholesterol crystals and IL-6 levels in SRAPs
Fig.4. Correlation between the count of cholesterol crystals and IL-6 levels in SRAPs
A. No correlation between the count of cholesterol crystals and IL-6 levels in all SRAPs (p=0.2704). B. No correlation between the count of CCs and IL-6 levels in SRAPs in samples with a positive count of CCs (p=0.5471).
Fig.5. Correlation between the count of cholesterol crystals and IL-6 ratio in SRAPs
Fig.5. Correlation between the count of cholesterol crystals and IL-6 ratio in SRAPs
A. Correlation between the count of CCs and IL-6 levels/ratios in all SRAPs. There is a significant correlation between the counts of cholesterol crystals and IL-6 ratios in SRAPs (r=0.496, p＜0.0001). B. Correlation between the count of CCs and IL-6 levels/ratios in samples with a positive count of CCs. There was a moderate correlation between the counts of CCs and IL-6 ratios in SRAPs (r=0.472, r＜0.0001) (Fig. 4B).
See this image and copyright information in PMC

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