Chronic antioxidant administration restores macrovascular function in patients with heart failure with reduced ejection fraction

Abstract

Heart failure with reduced ejection fraction (HFrEF) is characterized by macrovascular dysfunction and elevated oxidative stress that may be mitigated by antioxidant (AOx) administration. In this prospective study, we assessed flow-mediated dilatation (FMD) and reactive hyperaemia responses in 14 healthy, older control participants and 14 patients with HFrEF, followed by 30 days of oral AOx administration (1 g vitamin C, 600 I.U. vitamin E and 0.6 g α-lipoic acid) in the patient group. Blood biomarkers of oxidative stress (malondialdehyde) and AOx capacity (ferric reducing ability of plasma) were also assessed. Patients with HFrEF had a lower %FMD (2.63 ± 1.57%) than control participants (5.62 ± 2.60%), and AOx administration improved %FMD in patients with HFrEF (30 days, 4.90 ± 2.38%), effectively restoring macrovascular function to that of control participants. In a subset of patients, we observed a progressive improvement in %FMD across the treatment period (2.62 ± 1.62, 4.23 ± 2.69, 4.33 ± 2.24 and 4.97 ± 2.56% at days 0, 10, 20 and 30, respectively, n = 12) that was abolished 7 days after treatment cessation (2.99 ± 1.78%, n = 9). No difference in reactive hyperaemia was evident between groups or as a consequence of the AOx treatment. Ferric reducing ability of plasma levels increased (from 6.08 ± 2.80 to 6.70 ± 1.59 mM, day 0 versus 30) and malondialdehyde levels decreased (from 6.81 ± 2.80 to 6.22 ± 2.84 μM, day 0 versus 30) after treatment. These findings demonstrate the efficacy of chronic AOx administration in attenuating oxidative stress, improving AOx capacity and restoring macrovascular function in patients with HFrEF.

Reactive Oxygen Species Induced Pathways in Heart Failure Pathogenesis and Potential Therapeutic Strategies

“…The second study of HFrEF patients was characterized by macrovascular endothelial dysfunction, which may be due, at least in part, to a change in redox balance, leading to increased oxidative stress and decreased endogenous AOx protection. The results of this small study showed that chronic AOx administration is a simple way to improve macrovascular function, reduce oxidative stress, and increase AOx capacity in patients with HFrEF [221] (Table 2). However, larger sample studies are needed to properly investigate the beneficial effects of this compound.…”

“…Vitamin-antioxidants, Mito-TENPO, enzyme-scavengers of ROS and elamipretide were investigated (Table 2). Some small studies evaluated vitamin-antioxidants combinations in HFpEF [216] and HFrEF [221] and discovered improvement in peripheral vascular function and decrease in oxidative stress (Table 2). In the first study, reactive hyperemia (RH), a measure of microvascular function, did not change after OC (combination of α-lipoic acid, vitamin C and vitamin E) administration.…”

The history and mystery of sacubitril/valsartan: From clinical trial to the real world

“…Sacubitril/valsartan downregulates the expression of proinflammatory cytokines IL-6, IL-1α, tumor necrosis factor (TNFβ), chemokine (MCP-1), and chemokine CXC motif ligand-1 (CXCL1) by inhibiting the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (Myd88) pathway, NF-κB p65 nuclear translocation, and improving lipopolysaccharide (LPS)-induced endothelial cell inflammation (20). It significantly reduces circulating TNF-α and IL-18 levels in patients with HF with reduced ejection fraction (HFrEF) after 4 weeks of treatment, accompanied by improved peripheral vascular function and increased exercise tolerance (21).…”

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…Antioxidant supplementation comprising vitamin C (1 g), vitamin E (600 I.U. ), and α-lipoic acid (0.6 g) for 30 days exerted beneficial effects on macrovascular function in patients with HFrEF ( Bunsawat et al, 2020 ). A recent meta-analysis also revealed that vitamin C administration augmented LVEF in heart failure patients ( Hemilä et al, 2022 ).…”