Role of the IL-33/ST2 axis in cardiovascular disease: A systematic review and meta-analysis

Abstract

Interleukin (IL)-33 and its unique receptor, ST2, play a pivotal role in the immune response to infection and stress. However, there have been conflicting reports of the role of IL-33 in cardiovascular disease (CVD) and the potential of this axis in differentiating CVD patients and controls and with CVD disease severity, remains unclear. Aims 1) To quantify differences in circulating IL-33 and/or sST2 levels between CVD patients versus controls. 2) Determine association of these biomarkers with mortality in CVD and community cohorts. Methods and results Using Pubmed/MEDLINE, Web of Science, Prospero and Cochrane databases, systematic review of studies published on IL-33 and/or sST2 levels in patients with CVD (heart failure, acute coronary syndrome, atrial fibrillation, stroke, coronary artery disease and hypertension) vs controls, and in cohorts of each CVD subtype was performed. Pooled standardised mean difference (SMD) of biomarker levels between CVD-cases versus controls and hazard ratios (HRs) for risk of mortality during follow-up in CVD patients, were assessed by random effects meta-analyses. Heterogeneity was evaluated with random-effects meta-regressions. From 1071 studies screened, 77 were meta-analysed. IL-33 levels were lower in HF and CAD patients vs controls, however levels were higher in stroke patients compared controls [Meta-SMD 1.455, 95% CI 0.372–2.537; p = 0.008, I2 = 97.645]. Soluble ST2 had a stronger association with risk of all-cause mortality in ACS (Meta-multivariate HR 2.207, 95% CI 1.160–4.198; p = 0.016, I2 = 95.661) than risk of all-cause mortality in HF (Meta-multivariate HR 1.425, 95% CI 1.268–1.601; p<0.0001, I2 = 92.276). There were insufficient data to examine the association of IL-33 with clinical outcomes in CVD. Conclusions IL-33 and sST2 levels differ between CVD patients and controls. Higher levels of sST2 are associated with increased mortality in individuals with CVD. Further study of IL-33/ST2 in cardiovascular studies is essential to progress diagnostic and therapeutic advances related to IL-33/ST2 signalling.

Variations in serum low-density lipoprotein and sST2 among heart failure patients with different ejection fraction groups and their clinical significance

“…[11–15] A meta-analysis found that sST2 can assess the severity of HF and predict adverse outcomes and cardiovascular events in patients with chronic HF. [16] In the present study, across 3 HF groups, an increasing trend in sST2 was observed with decreasing LVEF, which is primarily used clinically to evaluate patient ejection fraction – a decrease in which indicates reduced myocardial contractile function and heightened HF severity [17] , thus underscoring the relevance of sST2 levels in assessing the severity of a patient’s HF condition.…”

Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis

“…The involvement of the IL-33/ST-2 axis has been reported in various cardiovascular diseases, like coronary artery disease, atrial fibrillation, heart failure, systemic hypertension, etc. [ 36 , 37 ]. In our present study, we found increased serum levels of IL-33 in the aAT group compared to the controls, along with detectable staining for IL-33R (ST-2) in the atherosclerotic plaques, suggesting the role of the IL-33/ST-2 axis in aAT patients.…”

Do Interleukin-1 and Interleukin-6 Antagonists Hold Any Place in the Treatment of Atherosclerotic Cardiovascular Disease and Related Co-Morbidities? An Overview of Available Clinical Evidence

“…Serum IL-1RA levels have been shown to correlate with increased risk positively and independently for incident CVD, after adjustment for possible confounders, including age, sex, anthropometric, metabolic, and lifestyle factors [ 12 ]. In addition, interleukin-33 (IL-33), a tissue-derived nuclear cytokine from the IL-1 family expressed in endothelial cells, epithelial cells, and fibroblast-like cells, and its unique receptor, ST2, have been shown to correlate with increased risk for all-cause death among individuals with established atherosclerotic CVD, especially in those who recently experienced an acute coronary syndrome [ 13 ]. IL-1 positive genotypes have been recently demonstrated to associate with increased risk for surrogate cardiovascular endpoints, including cardiovascular death, among individuals undergoing coronary angiography [ 14 ].…”