Impact of Acute Antioxidant and Tetrahydrobiopterin (BH₄) Administration on Locomotor Muscle Microvascular Function...

Peripheral microvascular dysfunction is a hallmark feature of both heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) pathophysiology, due partly to impairments in nitric oxide signaling secondary to tetrahydrobiopterin (BH₄) deficiency and oxidative stress.

Using a randomized, double-blind, placebo-controlled crossover design, this study examined the impact of enteral BH₄ (10 mg/kg), an antioxidant cocktail (AOx), and coadministration of these 2 agents (BH₄+AOx) on microvascular function in patients with HFrEF (n=14, 64±10 years) and HFpEF (n=19, 74±9 years). Passive limb movement was utilized to assess locomotor muscle microvascular function, and biomarkers of inflammation and oxidative damage were measured.

Compared with placebo, the peak change in leg blood flow was not statistically different after AOx administration (HFrEF, P=0.60; HFpEF, P=0.61), but improved following BH₄ (P=0.033) and BH₄+AOx (P=0.019) in both HFrEF (placebo: 234±31; BH₄: 357±45; BH₄+AOx: 355±49 mL/min) and HFpEF (placebo: 269±33; BH₄: 367±47; BH₄+AOx: 394±65 mL/min). The total hyperemic response to passive limb movement (leg blood flow area under the curve) was not statistically different across treatments in patients with HFrEF (P=0.29), but increased following BH₄ (P=0.016) and BH₄+AOx (P=0.040) in the HFpEF group. CRP (C-reactive protein) was lower following BH₄ (P=0.007) and BH₄+AOx (P=0.007) in HFpEF (placebo: 4268±547; BH₄: 2721±391; BH₄+AOx: 2779±376 ng/mL), but was not statistically different in HFrEF (P=0.39).

Together, these results provide new evidence for the efficacy of acute BH₄ administration to improve some aspects of locomotor muscle microvascular function in patients with HFrEF and HFpEF, with no apparent benefit of AOx administration, alone or in combination with BH₄, in either group. These findings lend further conceptual support for the nitric oxide pathway as a modifiable target in the treatment of heart failure.