Abstract Background Endothelial dysfunction, a common feature in heart failure with reduced ejection fraction (HFrEF), is a negative prognostic marker but the mechanism is unknown. It has recently been demonstrated that the red blood cell (RBC), a largely overlooked cell type in cardiovascular disease, serve as a mediator of endothelial dysfunction in diseases related to, and often co-existing with, HFrEF, like diabetes mellitus type 2 and familial hypercholesterolaemia. In these patient groups, arginase activity in RBCs is increased, resulting in an increase in reactive oxygen species (ROS) and impaired endothelial function. We hypothesize that this mechanism is relevant for HFrEF as well. Purpose To investigate the role of RBCs as mediators of endothelial dysfunction in drug naive HFrEF patients, and the impact of guideline directed medical therapy (GDMT). Methods We included 17 patients with newly diagnosed HFrEF and naive to GDMT. A healthy control group donated RBCs at one timepoint (n=14). Endothelial function was assessed using pulse amplitude tonometry following reactive hyperaemia and expressed as reactive hyperaemia index (RHI). RBCs were isolated from peripheral blood and arginase activity evaluated with a colorimetric enzymatic assay at baseline and after three months of GDMT (n=14). From a subgroup of patients the effect of RBCs on endothelium-dependent relaxation (EDR), induced by acetylcholine, was assessed in aortic segments from healthy rats (following co-incubation for 18h) at baseline and after three months of GDMT. These experiments were performed in the absence and presence of an arginase inhibitor (2(S)-amino-6-boronohexanoic acid; ABH, 10mM) and the antioxidant N-acetyl-cystein (NAC, 10mM) respectively. Results Twelve out of 17 HFrEF patients had endothelial dysfunction at baseline defined as RHI 1.67. RHI did not improve during the study period. EDR was reduced in rat aortas incubated with RBCs from HFrEF patients (n=7) compared to RBCs from healthy controls (p0.05, Fig. 1A). After three months with GDMT the RBC induced EDR improved (p0.05, Fig. 1B, n=3). Co-incubation with ABH had no significant effect on EDR (Fig. 1C), while NAC showed a trend towards improved EDR (p=0.10, Fig. 1D). RBC arginase activity did not differ nor between HFrEF patients at baseline and healthy controls (Fig. 2A), or after three months with GDMT (Fig. 2B). Conclusion Our preliminary findings on a limited sample size suggest that endothelial dysfunction in HFrEF is mediated by RBC dysfunction likely through increased oxidative stress, but not arginase activity, and is reversed by GDMT. This indicates an RBC involvement in endothelial dysfunction in HFrEF but the mechanism differs from that observed in patients with diabetes mellitus type 2.
Reistam et al. (Sat,) studied this question.