CCL21 is associated with fatal outcomes in chronic heart failure: Data from CORONA and GISSI-HF trials

Aims: Chronic heart failure (HF) is in part characterized by immune activation and inflammation, and factors that regulate lymphocyte trafficking and inflammation may contribute to the progression of this disorder. The homeostatic chemokine CCL21 is a potent regulator of T-cell migration into non-lymphoid tissue and may exert inflammatory properties and influence tissue remodelling. We therefore investigated CCL21 levels and association with fatal outcomes in patients with chronic HF. Methods and results: Plasma CCL21 was measured at randomization in 1456 patients enrolled in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) and in 1145 from the GISSI-HF trial. Association between CCL21 levels [given below as hazard ratio (HR) with 95% confidence interval (CI) for 1 SD increase] with all-cause (n = 741) or cardiovascular (CV) mortality (n = 576) was evaluated with multivariable Cox proportional hazard models, adjusting for clinical risk factors, C-reactive protein, and NT-proBNP. In multivariable Cox models, CCL21 was associated with higher risk of all-cause mortality (HR 1.16, 95% CI 1.02–1.32; P = 0.020) and CV mortality (HR 1.20, 95% CI 1.08–1.33; P < 0.001). When the two trials were analysed separately, CCL21 had a similar influence on risk prediction. Finally, CCL21 had a modest but significant impact on the discriminatory properties of the model (all-cause mortality, change in Harrell's C-statistic 0.004, P = 0.001; CV mortality, change in C-statistic 0.002, P = 0.002). Conclusion: Circulating CCL21 was associated with all-cause and CV mortality in two large populations of contemporary patients with chronic HF.