Abstract 17810: Alteration of the Global T-Lymphocyte Network in Chronic Heart Failure
A diminished circulating lymphocyte count carries prognostic import in chronic heart failure (HF), suggesting that T-cells are important intermediaries of disease progression. However, the global trafficking of T-cells and their roles during cardiac remodeling are poorly defined. We performed a detailed characterization of CD4+ T-cells during the progression of HF, induced by permanent coronary ligation in C57Bl/6 mice. Peripheral blood collected serially after ligation was analyzed by flow cytometry for T lymphocytes (CD3+CD4+) and CD4+ T-cell subsets: Th-1 (IFN-γ+), Th-2 (IL-4+), Th-17 (IL-17+), and regulatory T cells (Tregs, Foxp3+). Early after ligation (7 & 14 d) Th-1, Th-2, and Th-17 T-cells were significantly (p<0.05) increased as compared to sham-operated mice (195 ± 30%, 123 ± 9%, and 118 ± 14%, respectively). In contrast, Tregs exhibited a biphasic response, decreasing significantly at 7 d (76 ± 14%) and increasing at 14 d (125 ± 33%). Th-1/Th-2 and Th-1/Th-17 ratios were significantly higher vs sham at both time points (14 d: 0.24 ± 0.03 vs 0.15 ± 0.03; 0.32 ± 0.03 vs 0.20 ± 0.04, respectively) whereas Th-17/Th-2 ratios were unaltered, indicating an early Th-1 predominant pro-inflammatory response. During the later phases (28 d), all T-cell subsets were significantly increased in HF mice; Th-1/Th-2 ratios, however, were not significantly different from sham mice. In contrast, during more advanced remodeling (42 d), the Th-1/Th-2 ratio significantly decreased compared to sham, indicating a shift from Th-1 to Th-2 dominant responses. At 56 d, hearts were harvested and collagenase-digested, and cardiac mononuclear cells were isolated and analyzed using flow cytometry. Analogous to circulating levels, as compared to sham hearts, Th-2 and Th-17 cells were significantly increased (149 ± 31% and 144 ± 49%, respectively), the Th-1/Th-2 ratio significantly decreased (0.84 ± 0.13 vs 1.26 ± 0.3), and Treg infiltration enhanced ~2-fold in failing hearts. We conclude that the micro- and macro-environment in chronic HF is Th-2 predominant. Moreover, systemic kinetics of Th-2 and Tregs are similar to their infiltration patterns in the failing heart, and could potentially serve as cellular biomarkers of immune cell infiltration during disease progression.
- © 2013 by American Heart Association, Inc.