Background: Clinical data support that inflammation and the improper regulation of the immune response are intimately associated with Heart Failure (HF), however, the type of immune response involved and whether it regulates cardiac remodeling remains largely unexplored. We hypothesize that T cell mediated immune responses and their recruitment into the heart influence cardiac remodeling and contribute to the pathogenesis of pressure overload induced HF.
Methods and Results: Using quantitative flow cytometry we found that T cells infiltrated the heart as Wild-type mice (WT) developed systolic dysfunction and LV hypertrophy in response to transverse aortic constriction (TAC) (p<0.01 TAC vs Sham). Real time imaging demonstrated that T cells from TAC mice adhered to activated heart endothelial cells in higher numbers than T cells from Sham mice under physiological flow conditions in vitro (P<0.05) indicating a systemic T cell activation to pressure overload induced by TAC. Similarly, circulating T cells from patients with HF adhered more to activated human umbilical vein endothelial cells (HUVEC) than T cells from healthy volunteers. Based on these findings, we performed similar TAC studies in T cell deficient mice (TCRα-/-). In contrast with WT TAC mice, TCRα-/- had preserved LV systolic and diastolic function (p<0.01) determined by echocardiography and hemodynamic studies, reduced LV fibrosis (p<0.001) and TGFβ1, collagen Iα and αSMA gene expression (p<0.05), and reduced LV hypertrophy and gene expression of ANP and BNP (p<0.05), but unaltered expression of SerCA. Remarkably, TCRα-/- had improved survival after 4 weeks of TAC [100%(16/16) TCRα-/-vs 73.7%(14/19) WT, p=0.023]. Ongoing studies will determine the mechanisms regulating T cell recruitment into the heart, the type of T cell response involved and its contribution to pathological remodeling of the heart.
Conclusion: Our studies demonstrate that T cell immune responses and their recruitment into the LV contribute to the pathogenesis of pressure overload induced HF by mechanisms involving T cell regulation of cardiac hypertrophy and fibrosis, and open a window to develop novel therapeutic strategies to improve the structural, functional and molecular deficits of the failing heart.