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. 2022 Jul 8;131(2):e22-e33.
doi: 10.1161/CIRCRESAHA.122.320877. Epub 2022 Jun 17.

Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability, and Progression

Joseph Kamtchum-Tatuene  1 , Luca Saba  2 , Mirjam R Heldner  3 , Michiel H F Poorthuis  4 , Gert J de Borst  5 , Tatjana Rundek  6 , Stavros K Kakkos  7 , Seemant Chaturvedi  8 , Raffi Topakian  9 , Joseph F Polak  10 , Glen C Jickling  11 ; Carotid Atherosclerosis and Stroke Collaboration (CASCO)
Affiliations

Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability, and Progression

Joseph Kamtchum-Tatuene et al. Circ Res. .

Abstract

Background: IL-6 (interleukin-6) has important roles in atherosclerosis pathophysiology. To determine if anti-IL-6 therapy warrants evaluation as an adjuvant stroke prevention strategy in patients with carotid atherosclerosis, we tested whether circulating IL-6 levels predict carotid plaque severity, vulnerability, and progression in the prospective population-based CHS (Cardiovascular Health Study).

Methods: Duplex carotid ultrasound was performed at baseline and 5 years. Baseline plaque severity was scored 0 to 5 based on North American Symptomatic Carotid Endarterectomy Trial grade of stenosis. Plaque vulnerability at baseline was the presence of markedly irregular, ulcerated, or echolucent plaques. Plaque progression at 5 years was a ≥1 point increase in stenosis severity. The relationship of baseline plasma IL-6 levels with plaque characteristics was modeled using multivariable linear (severity) or logistic (vulnerability and progression) regression. Risk factors of atherosclerosis were included as independent variables. Stepwise backward elimination was used with P>0.05 for variable removal. To assess model stability, we computed the E-value or minimum strength of association (odds ratio scale) that unmeasured confounders must have with log IL-6 and the outcome to suppress the association. We performed internal validation with 100 bootstrap samples.

Results: There were 4334 participants with complete data (58.9% women, mean age: 72.7±5.1 years), including 1267 (29.2%) with vulnerable plaque and 1474 (34.0%) with plaque progression. Log IL-6 predicted plaque severity (β=0.09, P=1.3×10-3), vulnerability (OR, 1.21 [95% CI, 1.05-1.40]; P=7.4×10-3, E-value=1.71), and progression (OR, 1.44 [95% CI, 1.23-1.69], P=9.1×10-6, E-value 2.24). In participants with >50% predicted probability of progression, mean log IL-6 was 0.54 corresponding to 2.0 pg/mL. Dichotomizing IL-6 levels did not affect the performance of prediction models.

Conclusions: Circulating IL-6 predicts carotid plaque severity, vulnerability, and progression. The 2.0 pg/mL cutoff could facilitate the selection of individuals that would benefit from anti-IL-6 drugs for stroke prevention.

Trial registration: ClinicalTrials.gov NCT02089217.

Keywords: atherosclerosis; carotid stenosis; inflammation; interleukin-6; stroke.

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Conflict of interest statement

Disclosures

Joseph Kamtchum-Tatuene was funded by the Faculty of Graduate Studies and Research Doctoral Recruitment Scholarship, the Bank of Montreal Graduate Scholarship, the Alberta Graduate Excellence Scholarship, the Faculty of Medicine and Dentistry Motyl Graduate Studentship in Cardiac Sciences, the Alberta Innovates Graduate Scholarship, the Department of Medicine Ballermann Translational Research Fellowship, the Izaak Walton Killam Memorial Scholarship, and the Andrew Stewart Memorial Graduate Prize. All awards, prizes, and scholarships managed by the University of Alberta.

Luca Saba reports no conflicts of interest.

Mirjam R. Heldner reports grants from the Swiss Heart Foundation and the Bangerter Foundation, and Advisory Board participation for Amgen.

Michiel H. F. Poorthuis reports no conflicts of interest.

Gert J. de Borst reports no conflicts of interest.

Tatjana Rundek is funded by grants from the National Institutes of Health (R01 NS040807, R01 NS029993, R01 MD012467, RF1AG074306, U24 NS107267, P30 AG066506, HHSN268200625234C, U19 AG056169), the National Center for Advancing Translational Sciences (UL1 TR002736, KL2 TR002737), and the Florida Department of Health.

Stavros K. Kakkos reports no conflicts of interest.

Seemant Chaturvedi serves on the Executive Committee of the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2, NCT02089217).

Raffi Topakian has received fees for serving as Advisory Board Member (Alexion, Roche, Sanofi-Aventis) and conference support from the industry (Daiichi-Sankyo, Pfizer, Roche), all within the last three years.

Joseph F. Polak reports no conflicts of interest.

Glen C. Jickling receives research grant support from Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation, Alberta University Hospital Foundation, Canada Foundation for Innovation (CFI), and National Institutes of Health (NIH).

Figures

Figure 1:
Figure 1:. Relationship of IL-6 with cardiovascular risk factors
Panels illustrate the comparison of mean log IL-6 across categories of sex (A), hyperuricemia (B), atrial fibrillation (C), hypertension (D), diabetes mellitus (E), dyslipidemia (F), smoking status (G), coronary artery disease (H), and peripheral artery disease (I). The prevalence of each cardiovascular risk factor is available in Supplementary Table S1. Counts are provided when they cannot be derived from the table. All p-values are derived from unadjusted two-sample Student t tests. Violin plots are available in Supplementary Figure S6.
Figure 2:
Figure 2:. Relationship of IL-6 with the grade of carotid stenosis
A: Univariable linear regression of log IL-6 over the baseline carotid stenosis score (β = 0.08, p-value of the t test for significance of the coefficient p=1.6 × 10−14). B: Distribution of log IL-6 across categories of stenosis severity. All p-values are derived from unadjusted two-sample Student t tests. C: Comparison of mean log IL-6 in patients with versus without markedly irregular or ulcerated carotid plaques. The p-value is derived from an unadjusted two-sample Student t test. D: Comparison of mean log IL-6 in patients with versus without echolucent carotid plaques. The p-value is derived from an unadjusted two-sample Student t test. Panels B-D are also presented as violin plots in Supplementary Figure S7.
Figure 3:
Figure 3:. Linear relationship of IL-6 with the probability of carotid plaque vulnerability and progression
The curves are derived from the optimism-adjusted multivariable logistic regression models reported in Tables 2 and 3.
Figure 4:
Figure 4:. Calibration plots for the logistic regression models to predict plaque vulnerability and plaque progression
E:O = ratio of expected and observed probabilities CITL = Calibration-in-the-large indicates whether predictions are systematically too low (CITL>0) or systematically too high (CITL<0). AUC = Area under the receiver operating characteristic curve The 45° reference line represents the line of perfect agreement between the model and the data (equality of observed and predicted probabilities). The groups are created using deciles of risk as cut points (10 risks groups). The Locally Weighted Scatterplot Smoothing (lowess) is the smoothed calibration line across individuals displayed on the bar graph at the bottom of each plot. Optimism-adjusted performance parameters are obtained after applying a bootstrap shrinkage factor derived from an internal validation process with 100 bootstrap samples. A: Calibration plot for the logistic regression model to predict plaque vulnerability B: Calibration plot for the logistic regression model to predict plaque progression
See this image and copyright information in PMC

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