The predictive role of interleukin 6 trans-signalling in middle-aged men and women at low-intermediate risk of cardiovascular events

Abstract

Background Interleukin 6 trans-signalling is independently associated with the risk of cardiovascular events. The aim of this study was to investigate if interleukin 6 trans-signalling can identify individuals at risk for cardiovascular events (coronary artery disease and ischaemic stroke) among those at-low–intermediate risk. Methods In a cohort of 60-year-olds ( n = 4232, incident cardiovascular events n = 525), interleukin 6 trans-signalling was estimated by a ratio between the pro-inflammatory interleukin 6: soluble interleukin 6 receptor binary receptor complex and the inactivated interleukin 6: soluble interleukin 6 receptor: sgp130 ternary complex (B/T ratio). Risk associated with B/T ratio >median was investigated in individuals with low-density lipoprotein cholesterol ≤4.0 (mmol/l) and in those at low-intermediate risk according to the Framingham risk score (FRS) using Cox regression and expressed as hazard ratio and 95% confidence interval. Difference in time to event (years; 95% confidence interval) was analysed with quantile regression. The interaction between low-density lipoprotein cholesterol and B/T ratio was estimated on the additive scale. Incremental discriminatory value of the B/T ratio if low-density lipoprotein cholesterol ≤4.0 was compared to that of the FRS and interleukin 6. Results B/T ratio >median was associated with increased cardiovascular event risk when low-density lipoprotein cholesterol ≤4.0 (hazard ratio 1.59; 95% confidence interval 1.24–2.05) or FRS ≤ 10%, >10–≤20% (hazard ratio 1.27; 95% confidence interval 1.00–1.61 and hazard ratio 1.78; 95% confidence interval 1.36–2.34, respectively). B/T ratio >median and low-density lipoprotein cholesterol ≤4.0 were associated with early cardiovascular events, particularly ischaemic stroke. No interaction was observed between low-density lipoprotein cholesterol and the B/T ratio, both factors increasing cardiovascular event risk by 60%. In the presence of low-density lipoprotein cholesterol ≤4.0, the B/T ratio slightly improved discrimination measures. Conclusions Interleukin 6 trans-signalling increases cardiovascular event risk in middle-aged men and women otherwise classified at low-intermediate cardiovascular risk.

Bringing interleukin-6 complexity to preventive cardiology practice?

“…The current 15 and previous observations 9 of Ziegler et al add important information about the participation of IL-6 in ASCVD, and suggest that measurement of this cytokine pathway can give prognostic information. Despite the fact that CRP levels were not measured, the incorporation of B/T to a model including IL-6 levels, which modulates the classic signaling pathway, suggests that trans-signalling brings additional discriminatory information to the latter.…”

“…Finally, the possible elevated costs of the B/T complex determination should be considered as a barrier for its implementation in preventive cardiology practice. At any rate the studies of Ziegler et al 9,15 add important confirmatory information for the participation of IL-6 on atherogenesis. Whether specific inhibitors of IL-6 trans-signalling 18 may reduce ASCVD events and could add to benefits shown by upstream interleukin-1b inhibition as shown in CANTOS 8 remains to be determined.…”

“…5,6,9,11 Indeed, there is very recent evidence showing that the evaluation of the IL-6 trans-signalling pathway may help discriminate and reclassify ASCVD risk in middle-aged primary prevention individuals as has been shown by Ziegler et al 9 In this issue of the journal the same authors expand and test their previous findings according to LDL-cholesterol values and the estimated Framingham risk score (FRS) in 4232 middle-aged Swedish individuals (60YO cohort) without previous manifestations of ASCVD. 15 The intensity of IL-6 trans-signalling was estimated by the B/T complex ratio as previously described. 9 After a median 16.5year follow-up, 15% of studied subjects presented one cardiovascular event (n ¼ 525).…”

“…9 In this issue of the journal the same authors expand and test their previous findings according to LDL-cholesterol values and the estimated Framingham risk score (FRS) in 4232 middle-aged Swedish individuals (60YO cohort) without previous manifestations of ASCVD. 15 The intensity of IL-6 trans-signalling was estimated by the B/T complex ratio as previously described. 9 After a median 16.5-year follow-up, 15% of studied subjects presented one cardiovascular event ( n = 525).…”

Cross-Talk between Lipoproteins and Inflammation: The Role of Microvesicles

“…The involvement of inflammation besides LDL in atherosclerosis has been recently proven in the proof-of-concept CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial, showing that interleukin 1β inhibition resulted in a 15% reduction in cardiovascular events [12]. Supporting these findings, it has been recently observed that interleukin 6 trans-signaling increases the risk of cardiovascular events [13]. Interleukin 1β/ interleukin 6 signaling is activated by the nucleotide-binding leucine-rich repeat-containing pyrine receptor 3 (NLRP3) inflammasome platform [14].…”