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