Inflammatory signatures are associated with increased mortality after transfemoral transcatheter aortic valve implantation

Abstract

Aims: Systemic inflammatory response, identified by increased total leucocyte counts, was shown to be a strong predictor of mortality after transcatheter aortic valve implantation (TAVI). Yet the mechanisms of inflammation-associated poor outcome after TAVI are unclear. Therefore, the present study aimed at investigating individual inflammatory signatures and functional heterogeneity of circulating myeloid and T-lymphocyte subsets and their impact on 1 year survival in a single-centre cohort of patients with severe aortic stenosis undergoing TAVI.

Methods and results: One hundred twenty-nine consecutive patients with severe symptomatic aortic stenosis admitted for transfemoral TAVI were included. Blood samples were obtained at baseline, immediately after, and 24 h and 3 days after TAVI, and these were analysed for inflammatory and cardiac biomarkers. Myeloid and T-lymphocyte subsets were measured using flow cytometry. The inflammatory parameters were first analysed as continuous variables; and in case of association with outcome and area under receiver operating characteristic (ROC) curve (AUC) ≥ 0.6, the values were dichotomized using optimal cut-off points. Several baseline inflammatory parameters, including high-sensitivity C-reactive protein (hsCRP; HR = 1.37, 95% CI: 1.15-1.63; P < 0.0001) and IL-6 (HR = 1.02, 95% CI: 1.01-1.03; P = 0.003), lower counts of Th2 (HR = 0.95, 95% CI: 0.91-0.99; P = 0.009), and increased percentages of Th17 cells (HR = 1.19, 95% CI: 1.02-1.38; P = 0.024) were associated with 12 month all-cause mortality. Among postprocedural parameters, only increased post-TAVI counts of non-classical monocytes immediately after TAVI were predictive of outcome (HR = 1.03, 95% CI: 1.01-1.05; P = 0.003). The occurrence of SIRS criteria within 48 h post-TAVI showed no significant association with 12 month mortality (HR = 0.57, 95% CI: 0.13-2.43, P = 0.45). In multivariate analysis of discrete or dichotomized clinical and inflammatory variables, the presence of diabetes mellitus (HR = 3.50; 95% CI: 1.42-8.62; P = 0.006), low left ventricular (LV) ejection fraction (HR = 3.16; 95% CI: 1.35-7.39; P = 0.008), increased baseline hsCRP (HR = 5.22; 95% CI: 2.09-13.01; P < 0.0001), and low baseline Th2 cell counts (HR = 8.83; 95% CI: 3.02-25.80) were significant predictors of death. The prognostic value of the linear prediction score calculated of these parameters was superior to the Society of Thoracic Surgeons score (AUC: 0.88; 95% CI: 0.78-0.99 vs. 0.75; 95% CI: 0.64-0.86, respectively; P = 0.036). Finally, when analysing LV remodelling outcomes, ROC curve analysis revealed that low numbers of Tregs (P = 0.017; AUC: 0.69) and increased Th17/Treg ratio (P = 0.012; AUC: 0.70) were predictive of adverse remodelling after TAVI.

Conclusions: Our findings demonstrate an association of specific pre-existing inflammatory phenotypes with increased mortality and adverse LV remodelling after TAVI. Distinct monocyte and T-cell signatures might provide additive biomarkers to improve pre-procedural risk stratification in patients referred to TAVI for severe aortic stenosis.

Keywords: Aortic stenosis; Inflammation; Monocytes; T cells; TAVI.

Figure 1

Intraindividual time courses in circulating leucocyte subset counts. (A–C) Major leucocyte subsets of (A) neutrophils, (B) eosinophils, and (C) lymphocytes. (D–F) Kinetics of T‐cell counts including (D) total T cells, (E) CD4⁺ T cells, and (F) CD8⁺ T cells. Subset counts are shown as percentage change (median) during the prespecified time points after transcatheter aortic valve implantation (TAVI), with the baseline value (pre‐TAVI) set to 0% (Friedman test, with Dunn's multiple‐comparisons test).

Figure 2

Intraindividual time courses in circulating monocyte subset counts. (A) Representative flow cytometry plots showing changes in monocyte subset distribution after transcatheter aortic valve implantation (TAVI). (B) Kinetics of monocyte counts including total monocytes, classical, intermediate, and non‐classical monocytes. Subset counts are shown as percentage change (median) during the prespecified time points after TAVI, with the baseline value (pre‐TAVI) set to 0% (Friedman test, with Dunn's multiple‐comparisons test).

Figure 3

Intraindividual time courses in circulating CD4⁺ T‐cell subset counts. (A) CD4⁺ effector T‐cell subset flow gating strategy and immunophenotyped legend (box). (B) Kinetics of CD4⁺ effector T‐cell counts including Th1, Th2, Th9, TH17, Th17/Th1, and Th22 cells. (C) Gating strategy and representative flow plots showing changes in CD4⁺ T regulatory cells after transcatheter aortic valve implantation (TAVI). (D) Kinetics of Treg counts following TAVI. Subset counts are shown as percentage change (median) during the prespecified time points after TAVI, with the baseline value (pre‐TAVI) set to 0% (Friedman test, with Dunn's multiple‐comparisons test).

Figure 4

Inflammatory predictors of 12 month mortality after transcatheter aortic valve implantation (TAVI). (A) Circos plots showing significant predictors of 12 month mortality (univariate analysis of dichotomized parameters). (B) The composite (linear predictor score) of diabetes, low left ventricular ejection fraction (LVEF), increased C‐reactive protein (calculated optimal cut‐off 0.052 mg/dL), and decreased circulating Th2 cells (calculated cut‐off: 24.3 cells/μL) provided significantly higher area under receiver operating characteristic (ROC) curve (AUC) when compared with traditional Society of Thoracic Surgeons (STS) score. (C) Survival rate in patients with diabetes mellitus (DM) and preserved Th2 cell counts (higher than or equal to the calculated optimal cut‐off of 24.3 cells/μL) was comparable with that of patients without DM, whereas diabetic patients with reduced Th2 cells (<24.3 cells/μL) showed significantly higher mortality within 12 months after TAVI. (D) Serum levels of high‐sensitivity C‐reactive protein (hsCRP) did not show any significant impact on the prognosis of patients with DM.

Figure 5

Pro‐inflammatory T‐cell polarization predicts adverse (LV) remodelling after transcatheter aortic valve implantation (TAVI). Low numbers of T regulatory cells (Tregs) (A) and increased TH17/Treg ratio (B) were associated with adverse (Group 4) remodelling. The Kruskal–Wallis H test was used for multi‐group analysis (framed P‐values shown in the upper left‐hand corner of the graph) and post‐hoc Mann–Whitney U test for two‐group comparison was also performed.