Digoxin Treatment Reverses Angiogenic Switch during HeartMate 3 Support and is Associated with Decrease Risk for Gastrointestinal Bleeding

Abstract

Gastrointestinal bleeding (GIB) in LVAD patients is most commonly caused by gastrointestinal angiodysplasia (GIAD). Non-pulsatile blood flow in LVAD patients can cause splanchnic submucosal hypoperfusion and hypoxia leading to activation of a HIF1-α /Angiopoietins (Ang) signaling cascade, that can trigger pathological angiogenesis. We have recently shown that the use of digoxin, a potent inhibitor of HIF1-α, is associated with a significant reduction in GIAD related GIB in HeartMate (HM) II and HeartWare HVAD patients. However, HM3 support is associated with less GIB then previous generation pumps. We now hypothesize that dysregulation of Ang-1 and Ang-2 levels in patients with HM3 can be restored by digoxin treatment and may contribute to decreased incidence of GIB. We have collected blood samples from 7 patients supported with HM3 before and after two weeks of digoxin therapy (0.125 mg daily). Ang-1 and Ang-2 levels were measured in patients' serum by ELISA. In single-center retrospective study, charts of all patients implanted with HM3 between June 2015 and October 2019 were reviewed with emphasis on the occurrence of GIB and digoxin therapy. Pearson's chi-squared test was used to assess the frequency of overall GIB and their association with digoxin therapy. Digoxin treatment in HM3 patients increased Ang-1 (11.5 to 30.7 ng/ml, p=0.02), and decreased Ang-2 levels (14.9 to 9.4 ng/ml, p=0.04), reversing angiogenic switch. Seven of 72 patients (10%) supported by HM3 during median observation time (236, IQR76-620) days experienced a GIB. We identified 38 patients treated and 34 not treated with digoxin (age 52.38 vs. 52.65, p=0.97). The frequency of GIB was significantly lower in the patients receiving compared to the ones not receiving digoxin (3% vs. 17% p=0.03; Fig.1), respectively. Digoxin, an inhibitor of HIF1-α signaling cascade, may contribute to a lower risk of GIB in HM3 patients by restoring angiogenic equilibrium.