The present study shows that serum IL-6 is predictive of long-term cardiovascular events in symptomatic patients with stable coronary disease who have a high cardiovascular risk. Serum IL-6 measurements above 0.44 pg/mL increased the risk of cardiovascular events by 2.8 times. Although there was an increased proportion of T2DM, hypertension, and obesity in the group with increased levels of IL-6, it was unlikely that it would have influenced the results, as the sub-group analysis showed no interaction among these sub-groups and there was no statistical difference in between groups with the increasing levels of A1c hemoglobin, BMI and blood pressure values considering the outcomes.
A previous study based on the analysis of two population-based cohorts  suggested that circulating serum IL-6 levels could be associated with increased coronary risk (defined as nonfatal MI or fatal coronary heart disease [CHD]). In that study, stored blood samples of patients who later developed non-fatal MI or died of CHD were used for baseline measurements. Patients who developed CHD had greater levels of IL-6 compared with controls with no history of CHD. The odds ratio for CHD, adjusted for several established risk factors, was 1.46 (95% CI = 1.29–1.65) per 2 SDs of increase in baseline IL-6 values.
IL-6 has been associated with increased cardiovascular risk in some populations. In a meta-analysis of 29 population-based prospective studies , the adjusted relative risk for non-fatal MI or CHD death was 1.25 for every point of higher baseline SD in IL-6. However, in this meta-analysis, there was considerable heterogeneity (I2 = 53.6%, p = 0.001), and not all studies included indicated a clear risk prediction for IL-6. One possible reason is that many co-variables may have impacted the results in some studies.
In the present study, we observed that the predictive cut-off value of IL-6 was relatively lower (0.44 pg/mL) compared to that in other studies. In the sub-analysis of the STABILITY trial , the risk of cardiovascular death and major adverse cardiovascular events in 3–4 years started to increase progressively when IL-6 levels were above 1.5 ng/L. In the FRISC II trial , the highest predictive value was obtained when IL-6 levels were above > 5 pg/mL. We attribute our findings to the fact that we were able to exclude patients with chronic inflammatory diseases and severe obesity, which are major confounders when studying sub-clinical vascular inflammation as there is a strong relationship (rho = 0.85; p < 0.00001) between IL-6 levels and BMI . We believe that the strict selection criteria improved the accuracy of IL-6, also increasing the negative predictive value.
There is a clear plausibility for IL-6 levels to be associated with a higher risk of cardiovascular events. Experimental studies indicate that vascular endothelial and smooth muscle cells from normal and aneurysmal arteries can produce IL-6 [13, 14]. Moreover, IL-6 gene transcripts are expressed in atherosclerotic lesions , confirming local production. IL-6 has procoagulant effects , and elevated levels have been reported among patients with acute coronary syndromes . Considering that atherosclerosis is a chronic inflammatory disorder, IL-6 levels are expected to be increased among individuals with sub-clinical atherosclerosis who are at greater risk for future MI. However, a cause-and-effect relationship between IL-6 and cardiovascular events cannot be clearly defined so far, as few randomized trials are targeting IL-6 treatment.
In the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), a randomized, double-blind, placebo-controlled trial involving stable patients with previous myocardial infarction, the human monoclonal antibody, canakinumab, that targets the interleukin-1β innate immunity pathway, led to a significant decrease of recurrent cardiovascular events compared to placebo, independently of lipid-level lowering . In this trial, patients had a clinical atherosclerotic disease and a high mean baseline IL-6 (2,54 pg/mL), consistent with an inflammatory state. After 48 months, canakinumab 150 mg reduced significantly the relative event rate by 15%. In a sub-analysis of the CANTOS trial (19) patients who achieved IL-6 levels lower than 1.65pg/mL experienced a 32% reduction in cardiovascular events, a 52% reduction in cardiovascular mortality, and a 48% reduction in all-cause mortality. These results suggest the existence of a clear association between lower levels of IL-6 and reduced incidence of cardiovascular events.
Despite the substantial IL-6 fall seen in the CANTOS study, the mean IL-6 levels at 3 months seen in that study, continued high even in the group with the lowest IL-6 (1.93 (1.45–2.63 pg/mL). The mean IL-6 achieved in the present study, however, was much lower than in CANTOS. In our study, the mean IL-6 in the group with low levels was 0.09 pg/mL (95% CI 0.04–0.14) and was associated with a low incidence of cardiovascular events.
In the present study, because we selected patients excluding most common inflammatory confounders that could raise IL-6, we were able to include patients with even normal levels of IL-6, despite the established coronary disease. This allowed us to evaluate the negative predictive value of IL-6. We observed that levels of IL-6 below 0.44pg/mL were predictive of a better prognosis in 82%, an indication of a lower inflammatory status seen in that group. This may be a useful tool to evaluate the cardiovascular risk of candidates to coronary angiography.
The main limitations of this study were that being an observational study, we could not confirm a cause-effect relationship between IL-6 levels and the incidence of cardiovascular events. It is also possible that IL-6 may be a marker of cardiovascular disease rather than a risk factor per se. We also were not able to make adjustments to covariates due to the relatively low incidence of cardiovascular events.
The most important strengths in this study were the long follow-up period we obtained and the virtual absence of covariates such as chronic non-cardiovascular inflammatory disease, obesity. This is very difficult to obtain in a group of patients at high cardiovascular risk that frequently has many comorbidities.