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

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.

Different Characteristics and Interleukin-6 Ratios of Scattering-Type Aortic Plaques

“…Previously, we reported the presence of various types of SRAPs [ 4 , 8 ] and the diversity of their constituent elements [ 9 , 13 ]. The contribution of SRAPs to embolism and inflammation may vary, and the degree of CCs in the SRAPs may lead to varying levels of inflammation.…”

“…Additionally, puff-chandelier ruptures may cause embolisms in larger arteries and end organs because puff-chandelier segments are longer than puff ruptures. The higher IL-6 ratio in puff-chandelier ruptures indicates that the innate inflammation triggered mainly by CCs is responsible for IL-6 production [ 13 ]. Anti-inflammatory agents are expected to be more effective against puff-chandelier ruptures than puff ruptures.…”

“…However, stopping blood flow for measurement is life-threatening, so this is currently the optimal method available for evaluating the inflammatory level in plaque by sampling. Training may be necessary for diagnosing CCs using polarized light microscopy [ 13 ]. Two methods for direct CC direction and H&E staining may improve CC detection, but they require more effort than conventional HE staining.…”

“…Serum IL-6 levels were measured with a commercially available assay reported previously [ 13 ]. We defined the IL-6 ratio as the ratio of the serum IL-6 level in SRAPs to the IL-6 level at the beginning of the aorta, that at the sinus of Valsalva was defined as the baseline value.…”

“…We defined the IL-6 ratio as the ratio of the serum IL-6 level in SRAPs to the IL-6 level at the beginning of the aorta, that at the sinus of Valsalva was defined as the baseline value. The IL-6 ratio was calculated in 100 randomly selected puff-chandelier ruptures and 100 puff ruptures in the same manner [ 13 ]. The IL-6 levels and ratios between puff-chandelier and puff ruptures were compared.…”