Interleukin-6 – a Better Predictor of Cardiovascular Events
In a study published in the journal Cytokine, Hidenori Nishida and colleagues from the National Cerebral and Cardiovascular Center, Suita, Japan, demonstrate that an increased level of serum interleukin-6 (IL-6) is a signiﬁcant predictor of future cardiovascular (CV) events in high-risk Japanese patients, independently of a variety of inﬂuencing factors.
One of the paradigm shifts in our understanding about atherosclerosis in the last 10-15 years is the development of the concept that it is potentially caused by a chronic inﬂammation.
In fact, it is now well recognized that low-grade inﬂammation is an important factor contributing to the initiation and progression of CV lesions.
It is important to distinguish between local inﬂammation within the plaque microenvironment and systemic inﬂammation, as evident by acute-phase protein production and circulating proinﬂammatory mediators. Systemic mediators and markers of inﬂammation include C-reactive protein (CRP), interleukin (IL)-6 and IL-8.
Large epidemiological studies have suggested that CRP measurement predicts the risk of future CV events, but others have failed to identify CRP as a signiﬁcant independent risk factor. Thus, the value of CRP as an independent risk marker for CV events remains controversial at present.
IL-6 is a central mediator of the acute-phase response, and serum or plasma levels of IL-6 are elevated in various cardiovascular (CV) disorders. The degree of increase in IL-6 levels is in proportion to the clinical severity of these diseases, whereas elevated levels of IL-6 are associated with increased risk of the progression of atherosclerotic lesions and future CV events.
Notably, increased IL-6 is also associated with elevated ﬁbrinogen levels, which leads to an increased tendency to thrombosis, independent of the effects of IL-6.
In the Cytokine study the authors compared the predictive value of IL-6 with that of high-sensitivity (hs)-CRP, and found that hs-CRP was not a signiﬁcant predictor of future CV events, in contrast to the powerful prognostic value of IL-6. The authors discuss why serum IL-6, but not CRP may be a signiﬁcant predictor of CV events.
According to the authors IL-6 is produced not only by leukocytes but also by vascular endothelial cells and smooth muscle cells, and IL-6 protein and gene expression has been demonstrated in human atherosclerotic lesions. Thus, IL-6 may directly reﬂect vascular inﬂammation and endothelial injury during the initiation and development of atherosclerosis.
Furthermore, since ischemic and hypoxic conditions stimulate IL-6 production, it is possible that the increase in baseline IL-6 might be induced by silent cerebral, myocardial, or peripheral arterial ischemia before the event. Thus, serum IL-6 might represent a sensitive marker for progression of vascular lesions and future CV events.
A 2013 study in Chinese hospitalised patients with coronary artery disease (CAD) indicates that serum IL-6 concentrations are associated with all-cause and cardiovascular mortality independent of potential confounders. Patients in the highest serum IL-6 tertile versus the lowest tertile were at higher risk of all-cause and cardiovascular mortality.
Another 2017 study indicates that in intermediate risk patients referred for coronary angiography, a serum IL-6 level above 1 pg/mL is highly predictive for CAD. The authors of this study discussed that a high IL-6 serum level in non-diabetic overweight patients, at intermediate ASCVD risk can be useful to indicate a higher risk condition and the need for a more invasive approach.
A third 2017 study concluded: Although both IL-6 and CRP were significantly associated with all-cause mortality, only IL-6 provided a substantial improvement in discrimination. Similarly, IL-6 demonstrated a notable prognostic value for predicting cardiovascular mortality, but not CRP.
Importantly, the authors noted that levels of IL-6 and CRP are physiologically linked because of the function of IL-6 on hepatic synthesis and excretion of CRP. Markers of systemic inflammation, pro-inflammatory cytokines, and anti-inflammatory cytokines may reflect different features of atherosclerotic processes.
A 2020 studyindicates that in patients experiencing acute coronary syndrome (ACS), IL-6 assessed in the acute setting emerged as an improved predictor for long-term cardiovascular mortality as compared to hsCRP. Combining both IL-6 and hsCRP did not provide any additional predictive value. Furthermore, patients with low IL-6 values (<3.3 pg/mL) had a 99% probability (negative predictive value) to survive the period of 6 years.
A 2022 studydemonstrates that serum IL-6 is predictive of long-term cardiovascular events in symptomatic patients with stable coronary disease who have a high cardiovascular risk. An interleukin-6 level higher than 0.44 pg/mL, obtained just before elective coronary angiography, was associated with a poorer prognosis after a mean of 5,7-years. The IL-6 levels above 0.44 pg/mL increased the risk of cardiovascular events by 2.8 times.
What’s more, another 2022 study included patients with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 h following intensive care unit admission. The primary objective was to determine the association between baseline IL-6 or CRP concentration and survival until day 90.
The major conclusion was that IL-6, rather than CRP, associates with organ dysfunction, need for organ support, and worse 90-day survival. Thus, as per the authors of this study, IL-6 should be preferred over CRP to evaluate critically ill patients’ prognoses and possibly to guide potential therapeutic interventions aimed at taming inflammation.
Also, and interestingly, along these lines, a 2009 study indicated that periodontitis results in higher systemic levels of CRP and IL-6. The authors of this work discussed that these elevated inflammatory factors may increase inflammatory activity in atherosclerotic lesions and potentially increasing the risk for cardiovascular events.
To conclude, let’s mention a recent review article by Yongqi Feng et al. published in Front. Cardiovasc. Med., 23 March 2022. The authors of this work summarize and discuss recent experimental and clinical evidence indicating the involvement of the IL-6 family members in the pathogenesis of cardiovascular diseases such as atherosclerosis, hypertension, aortic dissection, cardiac fibrosis, and cardiomyopathy. They illustrated the relationship between IL-6 and atherosclerosis, MI, and vascular calcification in the Figure shown below:
Figure 1. The relationship between IL-6 and atherosclerosis, MI, and vascular calcification. The IL-6 trans-signaling activates the JAK/STAT pathway that leads to chronic inflammation. It increases the adhesion molecules in the vasculature, endothelial dysfunction, the recruitment of monocytes/macrophages, and SMC migration. Monocytes uptake LDL and transform into foam cells that accelerate the progression of atherosclerosis. These pathological processes cause lipid deposition, plaque development, and plaque destabilization. With increasing severity of atherosclerosis, the plaque ruptures, and thrombosis result in myocardial infarction. IL-6 upregulates RUNX2 and RANKL/RANK, which induces the differentiation of VSMC to osteoblast and then induces the calcium-phosphate complexes deposition. JAK, Janus Kinase; STAT, Signal transducers and activators of transcription; LDL, Low-density lipoprotein; RUNX2, Runt-related transcription factor 2; RANKL, Receptor activator of NF-κB ligand; SMC, Smooth muscle cell; VSMC, Vascular smooth muscle cell. From ‘The Role of Interleukin-6 Family Members in Cardiovascular Diseases’ by Yongqi Feng et al. Front. Cardiovasc. Med., 23 March 2022, Public Domain.