Gastrointestinal Bleeding is Associated with a Shift Towards a Pro-Angiogenic Phenotype after Continuous Flow Left Ventricular Assist Device Implantation

Abstract

Introduction Gastrointestinal bleeding (GIB) occurs in up to 20% of continuous-flow left ventricular assist device (CF-LVAD) recipients. A higher risk of GIB has been observed in CF-LVAD recipients with lower device pulsatility, yet a mechanism linking changes in hemodynamics to increased GIB is lacking. Hypothesis We hypothesized that 1) levels of Ang-1, a growth factor with vascular protective effects, would be lower while levels of vascular endothelial growth factor A (VEGF-A), an inducer of angiogenesis, and Ang-2, a promoter of vascular destabilization, would be higher in (a) CF-LVAD recipients compared to controls and (b) in CF-LVAD recipients with GIB as compared to those without; and that 2) CF-LVAD pulsatility and pulse pressure would be positively correlated with levels of Ang-1 and negatively correlated with VEGF-A and Ang-2. Methods Twenty-four participants from our institution, 12 with CF-LVADs (6 of whom had GIB after LVAD implantation) and 12 age-matched controls with no history of heart failure or GIB, contributed venous blood samples. We measured VEGF-A, Ang-2, and Ang-1 levels in serum fractions with immunoassays. Results Ang-2 levels were higher and Ang-1 levels lower in CF-LVAD recipients compared to controls with no difference in VEGF-A levels. Ang-1 levels were lower in CF-LVAD recipients with GIB compared to those without; Ang-2 and VEGF-A levels did not differ between the two groups. There was no correlation between pulsatility index and Ang-2, Ang-1, or VEGF-A levels. Pulse pressure was negatively correlated with Ang-2 levels (r = −0.578, P = 0.003), positively correlated with Ang-1 levels (r= 0.496, P = 0.014), and not correlated with VEGF-A levels. Conclusions CF-LVAD recipients demonstrate a shift toward a pro-angiogenic phenotype in the angiopoietin pathway, with increased levels of Ang-2 and lower levels of Ang-1 as compared to controls. Lower levels of Ang-1 were associated with GIB following CF-LVAD implantation. Lastly, lower pulse pressure was associated with higher Ang-2 levels and lower Ang-1 levels. These results suggest a contribution of altered angiogenesis to the observed increased risk of GIB in this population and a potential link to altered hemodynamics.