Association between Interleukin-6 and Multiple Acute Infarctions in Symptomatic Intracranial Atherosclerotic Disease
  • * (Excluding Mailing and Handling)

Abstract

Background: Interleukin-6 (IL-6) plays an important role in the pathophysiology of atherosclerosis. This study aimed to determine whether IL-6 is a crucial biomarker associated with Multiple Acute Infarctions (MAIs), which indicate an important stroke mechanism of artery-- to-artery embolism with a high risk of stroke recurrence in symptomatic Intracranial Atherosclerotic Disease (sICAD). We tested the association between circulating IL-6 levels and the presence of MAIs in a prospective population-based registry.

Methods: We included 1,919 patients with sICAD and baseline IL-6 levels from the Third China National Stroke Registry for the current analysis, The baseline IL-6 was centrally measured at Beijing Tiantan Hospital, Images of the brain parenchyma and vascular structures were digitized and then blindly and independently read by two groups of trained readers, The recruited patients were divided into 3 groups according to IL-6 tertiles, The relationship between baseline IL-6 tertile levels and the presence of MAIs was modeled using multivariate logistic regression.

Results: Compared to patients in the first IL-6 tertile those in the second and third tertiles demonstrated a significantly higher proportion of MAIs. The odds ratios were 1.81 [95% Confidence Interval (CI), 1.42-2.30] for the second versus first tertile and 2.15 (95% CI 1.66-2.79) for the third versus first tertile, The proportion of patients with MAIs increased with rising IL-6 tertiles observed at 59.3%, 71.6% and 76.4% for the first, second and third tertiles, respectively (P for trend < 0.001). The association between higher IL-6 tertiles and increased proportion of MAIs was also present in subgroups defined by age < 65 years, age ≥ 65 years, male, and high-sensitivity C-reactive Protein (hs-CRP) ≥ 2 mg/L. Furthermore, a significant interaction was detected for the hs- CRP subgroup (P = 0.038). In sensitivity analyses, the positive correlation between IL-6 levels and the proportion of MAIs remained consistent.

Conclusion: In patients with sICAD, higher IL-6 levels were associated with an increased proportion of MAIs. IL-6 could be used as a biomarker and a potential therapeutic target for future atherosclerosis treatment and prevention in patients with sICAD.

[1]
Gutierrez J, Turan TN, Hoh BL, Chimowitz MI. Intracranial atherosclerotic stenosis: risk factors, diagnosis, and treatment. Lancet Neurol 2022; 21(4): 355-68.
[http://dx.doi.org/10.1016/S1474-4422(21)00376-8] [PMID: 35143758]
[2]
Chen Z, Qin H, Liu J, et al. Characteristics of wall shear stress and pressure of intracranial atherosclerosis analyzed by a computational fluid dynamics model: A pilot study. Front Neurol 2020; 10(0): 1372.
[http://dx.doi.org/10.3389/fneur.2019.01372] [PMID: 32010041]
[3]
Puig N, Solé A, Aguilera-Simon A, et al. Novel therapeutic approaches to prevent atherothrombotic ischemic stroke in patients with carotid atherosclerosis. Int J Mol Sci 2023; 24(18): 14325.
[http://dx.doi.org/10.3390/ijms241814325] [PMID: 37762627]
[4]
Gao S, Wang YJ, Xu AD, Li YS, Wang DZ. Chinese ischemic stroke subclassification. Front Neurol 2011; 2: 6.
[http://dx.doi.org/10.3389/fneur.2011.00006] [PMID: 21427797]
[5]
Khan M, Naqvi I, Bansari A, Kamal AK. Intracranial atherosclerotic disease. Stroke Res Treat 2011; 2011(0): 282845.
[PMID: 21772967]
[6]
Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014; 114(12): 1852-66.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.302721] [PMID: 24902970]
[7]
William J. Correction to: Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the american heart association/american stroke association. Stroke 2019; 50(12): e440-1.
[PMID: 31765293]
[8]
Prapiadou S, Živković L, Thorand B, et al. Proteogenomic data integration reveals CXCL10 as a potentially downstream causal mediator for IL-6 signaling on atherosclerosis. Circulation 2024; 149(9): 669-83.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.123.064974] [PMID: 38152968]
[9]
Huber SA, Sakkinen P, Conze D, Hardin N, Tracy R. Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1999; 19(10): 2364-7.
[http://dx.doi.org/10.1161/01.ATV.19.10.2364] [PMID: 10521365]
[10]
Biscetti F, Tinelli G, Rando MM, et al. Association between carotid plaque vulnerability and high mobility group box-1 serum levels in a diabetic population. Cardiovasc Diabetol 2021; 20(1): 114.
[http://dx.doi.org/10.1186/s12933-021-01304-8] [PMID: 34044825]
[11]
Kamtchum-Tatuene J, Saba L, Heldner MR, et al. Interleukin-6 predicts carotid plaque severity, vulnerability, and progression. Circ Res 2022; 131(2): e22-33.
[http://dx.doi.org/10.1161/CIRCRESAHA.122.320877] [PMID: 35713008]
[12]
Bambrough P, Peverelli M, Brown AJ, et al. Trans-myocardial blood interleukin-6 levels relate to intracoronary imaging-defined features of plaque vulnerability and predict procedure-induced myocardial infarction. Cardiovasc Revasc Med 2022; 39(0): 6-11.
[http://dx.doi.org/10.1016/j.carrev.2021.10.006] [PMID: 34670726]
[13]
Wang Y, Jing J, Meng X, et al. The Third China National Stroke Registry (CNSR-III) for patients with acute ischaemic stroke or transient ischaemic attack: design, rationale and baseline patient characteristics. Stroke Vasc Neurol 2019; 4(3): 158-64.
[http://dx.doi.org/10.1136/svn-2019-000242] [PMID: 31709123]
[14]
Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352(13): 1305-16.
[http://dx.doi.org/10.1056/NEJMoa043033] [PMID: 15800226]
[15]
Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365(11): 993-1003.
[http://dx.doi.org/10.1056/NEJMoa1105335] [PMID: 21899409]
[16]
Jing J, Meng X, Zhao X, et al. Dual antiplatelet therapy in transient ischemic attack and minor stroke with different infarction patterns. JAMA Neurol 2018; 75(6): 711-9.
[http://dx.doi.org/10.1001/jamaneurol.2018.0247] [PMID: 29582084]
[17]
McCabe JJ, Walsh C, Gorey S, et al. C-reactive protein, interleukin-6, and vascular recurrence according to stroke subtype. Neurology 2024; 102(2): e208016.
[http://dx.doi.org/10.1212/WNL.0000000000208016] [PMID: 38165328]
[18]
Chaturvedi S, De Marchis GM. Inflammatory biomarkers and stroke subtype. Neurology 2024; 102(2): e208098.
[http://dx.doi.org/10.1212/WNL.0000000000208098] [PMID: 38165352]
[19]
Zietz A, Gorey S, Kelly PJ, Katan M, McCabe JJ. Targeting inflammation to reduce recurrent stroke. Int J Stroke 2024; 19(4): 379-87.
[http://dx.doi.org/10.1177/17474930231207777] [PMID: 37800305]
[20]
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377(12): 1119-31.
[http://dx.doi.org/10.1056/NEJMoa1707914] [PMID: 28845751]
[21]
Kaptoge S, Seshasai SRK, Gao P, et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014; 35(9): 578-89.
[http://dx.doi.org/10.1093/eurheartj/eht367] [PMID: 24026779]
[22]
Patterson CC, Smith AE, Yarnell JWG, Rumley A, Ben-Shlomo Y, Lowe GDO. The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: The Caerphilly Study. Atherosclerosis 2010; 209(2): 551-7.
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.09.030] [PMID: 19836021]
[23]
Sarwar N, Butterworth AS, Freitag DF, et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012; 379(9822): 1205-13.
[http://dx.doi.org/10.1016/S0140-6736(11)61931-4] [PMID: 22421339]
[24]
Okazaki S, Sakaguchi M, Miwa K, et al. Association of interleukin-6 with the progression of carotid atherosclerosis: a 9-year follow-up study. Stroke 2014; 45(10): 2924-9.
[http://dx.doi.org/10.1161/STROKEAHA.114.005991] [PMID: 25139874]
[25]
Kelly PJ, Lemmens R, Tsivgoulis G. Inflammation and stroke risk: A new target for prevention. Stroke 2021; 52(8): 2697-706.
[http://dx.doi.org/10.1161/STROKEAHA.121.034388] [PMID: 34162215]
[26]
Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 2000; 148(2): 209-14.
[http://dx.doi.org/10.1016/S0021-9150(99)00463-3] [PMID: 10657556]
[27]
Schieffer B, Selle T, Hilfiker A, et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation 2004; 110(22): 3493-500.
[http://dx.doi.org/10.1161/01.CIR.0000148135.08582.97] [PMID: 15557373]
[28]
Guo F, Dong M, Ren F, et al. Association between local interleukin-6 levels and slow flow/microvascular dysfunction. J Thromb Thrombolysis 2014; 37(4): 475-82.
[http://dx.doi.org/10.1007/s11239-013-0974-0] [PMID: 24242026]
[29]
Feng Y, Ye D, Wang Z, et al. The role of interleukin-6 family members in cardiovascular diseases. Front Cardiovasc Med 2022; 9(0): 818890.
[http://dx.doi.org/10.3389/fcvm.2022.818890] [PMID: 35402550]
[30]
McCabe JJ, O’Reilly E, Coveney S, et al. Interleukin-6, C-reactive protein, fibrinogen, and risk of recurrence after ischaemic stroke: Systematic review and meta-analysis. Eur Stroke J 2021; 6(1): 62-71.
[http://dx.doi.org/10.1177/2396987320984003] [PMID: 33817336]