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.
SOURCE: Cytokine 2011, 53:342. Epub 2010 Dec 28.
Read more: Cytokine 2011
Updates
A 2013 study in Chinese hospitalised patients with coronary artery disease (CAD) indicated 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.
In a 2017 long‐term prospective study on patients with stable CHD with optimal medical treatment, the inflammatory biomarker IL‐6, but not CRP, was independently associated with the risk of cardiovascular death, major adverse cardiac events (MACE), MI, hospitalization for heart failure, and all‐cause mortality.
Another 2017 study indicated 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.
Interestingly, along these lines, we also discussed a study in Brain, Behavior and Immunity suggesting that adversity during childhood and trauma during adulthood are associated with elevated high sensitivity C-reactive protein (hsCRP).
A 2020 study indicated 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 2021 review by Jian-Hui Su et al. discussed the link of the increased expression of interleukin-6 (IL-6) to atherosclerosis, myocardial infarction, heart failure and ischemic stroke. And, moreover, IL-6 as a key risk factor for these diseases by triggering inflammation, and its complications in Cardio-Cerebrovascular Diseases (CCVDs). Importantly, the authors reviewed many studies that made it clear that the level of IL-6 increases in varying degrees in CCVDs including atherosclerosis (AS), myocardial infarction (MI), heart failure (HF) and ischemic stroke (IS) (Figure 1).
Figure 1. Schematic representation of risk factor inducing IL-6 in Cardio-Cerebrovascular Disease. In response to stimulation by ischemia and hypoxia, oxidative stress, inflammation and vascular occlusion, IL-6 levels are elevated, which partly leads to the production of the acute phase protein CRP in the liver, thereby stimulating leukocyte recruitment and thrombosis, ultimately causing multiple cardio-cerebrovascular diseases. From: Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases, Jian-Hui Su et al., Front Pharmacol. 2021 Aug 24:12:745061. doi: 10.3389/fphar.2021.745061.
The authors discussed that
- once the inflammation is out of control or exists for a long time, a large number of inflammatory cells would gather in the vascular lesion sites, release potential toxic substances, directly damage the heart and brain tissue;
- macrophages can penetrate damaged vascular endothelium to promote plaque formation and vascular wall fibrosis in the case of immune disorder and excess inflammation, then resulting in vascular lumen occlusion and aggravating ischemia/reperfusion injury;
- cytokines release during inflammation also has the ability to alter the normal anticoagulant and pro-fibrinolytic properties of endothelium, especially IL-6, which accelerates fibrinogen production through signal transduction, accordingly promoting thrombosis and reducing myocardial contractility.
A 2022 study demonstrated 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.
Let’s also mention a recent review article by Yongqi Feng et al. published in Front. Cardiovasc. Med., 23 March 2022. The authors of this work summarized and discussed 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 2. 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.
A 2024 study examined the association between circulating IL-6 levels and cardiovascular disease (CVD) events without baseline CVD across racial and ethnic groups. This included 6,622 individuals: non-Hispanic White (39%), African American (27%), Hispanic (22%), and Chinese American (12%).
The authors reported that compared to tercile 1, participants with IL-6 tercile 3 had a higher adjusted risk of and all-cause mortality, CV mortality, non-CV mortality, and heart failure. When tested as a continuous variable, higher levels of IL-6 were associated with an increased risk of all individual outcomes.
Of note, as per the authors’ evaluation, patients with higher IL-6 levels were more likely to be older, female, current smokers; had hypertension, diabetes, and a family history of CHD; had a higher median systolic blood pressure, heart rate, and waist circumference; and included a larger proportion of African American and Hispanic individuals compared to those with lower IL-6 levels.
The investigators also found a significant association between high circulating IL-6 levels and all-cause mortality in a healthy, relatively young cohort (median age ∼62 years). According to the authors, this indicates that a pro-inflammatory state even in younger adults with average CVD risk leads to worse outcomes.
The authors concluded that high levels of circulating IL-6 were found to be associated with worse CVD outcomes and all-cause mortality in this ethnically diverse cohort. This association was consistent for most outcomes across all races and ethnicities.
A 2025 review concluded that IL-6 is a prime driver of cardiovascular inflammation, linking systemic inflammation to vascular dysfunction, atherosclerosis, myocardial fibrosis, and adverse cardiac remodeling.
As per the authors IL-6 plays a dual role-protective versus pathogenic and acute versus chronic. Chronic IL-6 links inflammation and metabolic dysregulation to structural cardiovascular damage.
IL-6 signaling exerts context-dependent effects: transient, classic signaling via the membrane-bound IL-6 receptor promotes tissue repair, metabolic adaptation, and cardioprotection in acute injury or infection, whereas persistent or excessive activation (particularly through trans-signaling) triggers endothelial activation, immune cell recruitment, and chronic inflammatory damage.
Thus, the net impact of IL-6 depends on timing, receptor engagement, signaling pathway, and cellular context, highlighting its double-edged role in cardiovascular pathophysiology and other organ systems such as the kidney. Overall, according to authors, the epidemiological, genetic, and mechanistic evidence supports a causal role of IL-6 in CV health and disease.
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