Author + information
- Yu Kataoka, MD,
- Rishi Puri, MBBS, PhD,
- Muhammad Hammadah, MD,
- Bhanu Duggal, MD,
- Kiyoko Uno, MD, PhD,
- Samir R. Kapadia, MD,
- E. Murat Tuzcu, MD,
- Steven E. Nissen, MD and
- Stephen J. Nicholls, MBBS, PhD∗ ()
- ↵∗South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia
The high local concentration of cholesterol in foam cells has been reported to formulate cholesterol crystals, which trigger a local inflammatory response (1). Intracellular crystals also induce apoptosis of foam cells, leading to further attraction of macrophages and development of a lipid-rich necrotic core (2). These effects may suggest a potential contribution of cholesterol crystals to plaque destabilization. Frequency-domain optical coherence tomography (FD-OCT) enables visualization of cholesterol crystals in vivo (3). We investigated the impact of cholesterol crystals on plaque vulnerability in stable patients with coronary artery disease.
We analyzed 250 patients with stable coronary artery disease in whom FD-OCT imaging was performed for the culprit vessel before percutaneous coronary intervention. The Cleveland Clinic’s Institutional Review Board Committee approved this study, and all patients gave written informed consent. A cholesterol crystal was defined as a thin, linear region of high-signal intensity within the lipid plaque (Figure 1) (3). Continuous variables are expressed as mean ± SD, and categorical variables are expressed as percentages. The chi-square test was used to test for differences in categorical variables between groups, and continuous data were compared by using unpaired Student t tests. A kappa coefficient was used to estimate intraobserver and interobserver reliability. The generalized estimating equations approach was used to take into account the intraclass correlation due to the multiple plaques analyzed within a single patient’s data. SAS software version 9.1.3 (SAS Institute, Cary, North Carolina) was used to conduct all statistical analyses.
Ninety-nine patients (39.6%) had at least 1 cholesterol crystal within the culprit vessel. In the 250 patients, we identified 263 nonculprit and 113 culprit lipid plaques within 330 target vessels. Nonculprit plaques with cholesterol crystals had a larger average lipid arc, a smaller fibrous cap thickness, and a higher prevalence of thin-cap fibroatheroma, microchannel, and plaque rupture (Figure 1). Culprit plaques with cholesterol crystals also exhibited a larger lipid arc (179.8 ± 72.1° vs. 111.1 ± 65.6°; p = 0.001) and a greater frequency of thin-cap fibroatheroma (30.3% vs. 2.1%, p = 0.01). Intraobserver and interobserver variabilities yielded acceptable concordance for cholesterol crystals (kappa = 0.88 and 0.85, respectively).
Plaques with cholesterol crystals were predominantly located in the proximal segment of left anterior descending artery and right coronary artery, whereas their even distribution was observed within the left circumflex artery.
During the 2-year follow-up, the incidence of major adverse cardiovascular events was similar between nonculprit lipid plaques with and without cholesterol crystals (12.0% vs. 12.8%, p = 0.80).
Plaques containing cholesterol crystals exhibited distinct FD-OCT–derived microstructures associated with plaque instability. This finding supports histological observations linking cholesterol crystals with local inflammation and apoptosis within foam cells. Cholesterol crystals have been reported to activate members of the interleukin-1 family via triggering of the inflammasome (1). Given the contribution of inflammatory cytokines to thinning fibrous cap and plaque neovascularization, these effects would account for FD-OCT–derived vulnerable features within plaques having cholesterol crystals.
The distribution pattern of plaques with cholesterol crystals in the left anterior descending artery and right coronary artery is similar to recent observations showing proximally located “hot spots” of vulnerable plaques in major coronary arteries (4,5). Our finding provides further evidence linking cholesterol crystals with plaque vulnerability.
A number of caveats should be noted. The possibility of selection bias cannot be excluded. Due to the shallow imaging depth of FD-OCT, we cannot assess the plaque composition of the whole plaque area. Cholesterol crystals on FD-OCT are not histopathologically validated. Because of the relatively small study population, a larger study is required to elucidate the effect of cholesterol crystals on clinical outcome.
In summary, cholesterol crystals within target vessels requiring percutaneous coronary intervention were observed in 39.6% of patients with stable coronary artery disease. Lesions containing cholesterol crystals exhibited FD-OCT–derived vulnerable plaque features. These findings suggest an important association between cholesterol crystals and plaque vulnerability in vivo.
The authors acknowledge the technical expertise of the Atherosclerosis Imaging Core Laboratory of the Cleveland Clinic.
Please note: Dr Nissen has received research support to perform clinical trials through the Cleveland Clinic Coordinating Center for Clinical Research from Pfizer, AstraZeneca, Novartis, Roche, Daiichi Sankyo, Takeda, Sanofi, Resverlogix, and Eli Lilly; and is a consultant/advisor for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. Dr Nicholls has received speaking honoraria from AstraZeneca, Pfizer, Merck/Schering-Plough, and Takeda; consulting fees from AstraZeneca, Abbott, AtheroNova, Esperion Therapeutics, Amgen, Eli Lilly, Sanofi Regeneron, Novartis, Omthera Pharmaceuticals, CSL Behring, Boehringer Ingelheim, Pfizer, Merck/Schering-Plough, Takeda, Roche, Novo Nordisk, LipoScience, and Anthera Pharmaceuticals; and research support from Anthera Pharmaceuticals, AstraZeneca, Cerenis Therapeutics, Eli Lilly, Infraredx, Roche, Resverlogix, Novartis, Amgen, and LipoScience. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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