Abstract
Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF.
Highlights
Heart failure (HF) is a leading cause of mortality
Our findings indicate that T cell-mediated responses are involved in the development of pathological cardiac hypertrophy and that interfering with these responses, using existing, clinically validated strategies, has the potential to become a therapeutic option for HF
In addition to the above, we examined samples from patients suffering from aortic stenosis, which leads to HF24 and represents the clinical condition that is mechanistically closest to the Transverse aortic constriction (TAC) mouse model
Summary
Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089 Milan, Italy. 3 Department of Cardiovascular Medicine, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089 Milan, Italy. 8 Cardiac Surgery, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089 Milan, Italy. Recent studies have uncovered that HF induced by hemodynamic overload involves a significant inflammatory component[3,4,5] This inflammation is characterized by the presence of innate immune cells (macrophages) in the myocardium and upregulation of pro-inflammatory cytokines, such as tumournecrosis factor-a, interleukin (IL)-6 and IL-1b, which impact negatively on disease outcome[3,6,7]. This assumption is supported by the implication of T cells in pressure overload-induced cardiac fibrosis[13]
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