Abstract 406: Interaction of T Cells From Non-ischemic Heart Failure Patients With the Activated Vascular Endothelium is Dependent on Intercellular Adhesion Molecule-1

Abstract

Background: Increasing evidence supports a role for inflammation in the pathogenesis of chronic heart failure (HF). Our previous studies demonstrate that T cell recruitment to the heart contributes to the progression of non-ischemic pressure overload induced HF. However, clinical data describing T cell dependent mechanisms contributing to the etiology of this disorder remains unknown. We hypothesized that non-ischemic HF activates human T cells resulting in increased adhesion to the vascular endothelium and recruitment to the heart through mechanisms involving specific endothelial adhesion molecules. Methods and Results: We used T cells from non-ischemic HF patients and non-HF controls as well as left ventricular (LV) tissue from end stage HF after LV assisted device (LVAD) support. Using FACS analysis we found that systemic T cells are significantly elevated in HF patients compared to controls (p<0.05), including Th1, Th17, and Treg cells. Immunohistochemistry analysis revealed that CD3+ and CD4+ T cells infiltrate the LV of HF subjects which were not observed in control. To evaluate the mechanisms through which T cells interact with the vasculature and potentially infiltrate the heart, we used in vitro real time video microscopy under shear flow conditions and found that T cells from HF patients firmly adhered to TNF[[Unsupported Character - Symbol Font ]] activated HUVECS. Further analysis indicated that HF T cells adhered to ICAM-1, but not to VCAM-1 in higher numbers than control T cells. The surface expression levels of the integrin ligands for VCAM-1 and ICAM-1 (VLA-4 and LFA-1 respectively) were similar between both groups, however, HF T cells exhibited a highly polarized phenotype on ICAM-1 (p<0.005 vs control), suggesting LFA-1 is in its high affinity conformation in HF T cells. Conclusions: Our findings suggest that T cells are activated in non-ischemic HF and have high affinity for the activated endothelium through mechanisms involving ICAM-1- LFA-1 adhesion. Future studies will evaluate the mechanisms regulating LFA-1 activation in HF T cells and their contribution to cardiac remodeling.