Dysregulation of the Angiopoietin-2/Tie-2 Axis is Associated with Reduced Pulsatility and Increased Arteriovenous Malformation Related Gastrointestinal Bleeding Following Left Ventricular Assist Device Implantation

Abstract

Recent studies have suggested arteriovenous malformation related gastrointestinal bleeding (AVM-GIB) after left ventricular assist device (LVAD) implantation is associated with reduced arterial pulsatility and right heart failure. Angiopoietin-2 (Ang-2) is elevated among patients on LVAD support, and in concert with abnormal expression of vascular endothelial growth factor (VEGF), binding of Ang-2 to the Tie-2 receptor contributes to abnormal angiogenesis and post-LVAD GIB. The purpose of this study was to evaluate the association between Ang-2, Tie-2, and VEGF with AVM-GIB and its clinical associates. We evaluated 65 patients who underwent LVAD implantation at Loyola University Medical Center. Blood samples were obtained at a median follow up of 13 (interquartile range 1.7-31.5) months following LVAD implantation. A total of 19 (29%) patients developed AVM-GIB. Patients with AVM-GIB were older at the time of LVAD implantation (63±10 vs. 53±15 years; p=0.048), but the groups were otherwise balanced in baseline characteristics. Patients with AVM-GIB had increased levels of Ang-2 (8169±4.471 vs. 6560±397 pg/mL; p=0.02) and Tie-2 (20.0±3.3 vs. 17.3±4.0 ng/mL; p=0.07) without a difference in VEGF (200.5±183.3 vs. 216.6±220 pg/mL; p=0.7). Patients whose aortic valve opened less than 80% of cardiac cycles had significantly higher levels of Ang-2 (7948±4226 vs 5566±3691 pg/mL; p=0.02) and Tie-2 (19.6±4.5 vs. 16.3±3.2 ng/mL; p=0.001). There was no association between the evaluated biomarkers and other demographic or clinical characteristics including invasive and noninvasive hemodynamics. Our study suggests that dysregulation of the Ang-2/Tie-2 axis among LVAD patients is associated with AVM-GIB. Further, we find that reduced pulsatility is associated with elevations of Ang-2 and Tie-2, providing a possible mechanism for the link between reduced pulsatility and GIB. Whether hemodynamic optimization with ramp studies could reduce Ang-2 and AVM-GIB is a subject of our ongoing research.