Abstract 411: Decreased Circulating and Neutrophil Mediated Vegf Release in Stable Long-term Cardiac Transplant Recipients

Background: A chronic state of inflammation may contribute to the long-term cardiac and vascular complications following cardiac transplantation (CTx). However, the assessment of neutrophil pro- or anti-inflammatory response has not been investigated in long-term CTx recipients. Herein, we measured the circulating levels of pro-inflammatory (interleukin-8; IL-8), anti-inflammatory (interleukin 1 receptor antagonist; IL-1RA) and a pro-angiogenic and inflammatory cytokine (vascular endothelial growth factor; VEGF), concomitantly with their release from neutrophils of CTx recipients and as compared to healthy volunteers. Methods: Eighteen CTx recipients aged 49.6 ± 3.1 years being transplanted for 145 ± 20 months were aged-matched to 20 healthy control (HC) subjects. Seven (39%) patients exhibited coronary allograft vasculopathy (all CAV1). VEGF, IL-8 and IL-1ra plasmatic levels were measured in resting state. Circulating neutrophils were isolated, purified and stimulated by vehicle (PBS), N-Formyl-Met-Leu-Phe (fMLP, 10-7 M), bacterial lipopolysaccharide (LPS, 1 μg/ml), or tumor necrosis factor alpha (TNF-α, 10 ng/ml). Results: Compared with HC, CTx recipients exhibited a decrease (-80%) in circulating levels of VEGF (225 ± 42 (HC) versus 44 ± 10 pg/ml (CTx); (p < 0.001). There were no differences in the levels of IL-8 and IL-1ra. Under basal or stimulated conditions, neutrophils from CTx patients exhibited a significant decrease on their capacity to release VEGF, IL-8 and IL-1ra upon stimulation. Conclusions: Long-term CTx recipients exhibit a marked reduction in the circulating levels of VEGF, as well as neutrophil-mediated release of VEGF, IL-8 and IL-1ra. The mechanisms and physiological impacts of these findings in relationship with various severities of CAV deserve additional investigations.