Key result
Acute BH4 improves peak leg blood flow vs placebo in both HFrEF and HFpEF.
Why the study?
Peripheral microvascular dysfunction is common in HFrEF and HFpEF, partly due to impaired nitric oxide signaling secondary to tetrahydrobiopterin deficiency and oxidative stress.
Does acute enteral BH4 and/or antioxidant cocktail administration improve locomotor muscle microvascular function in patients with HFrEF and HFpEF?
RCT (n=33)
Double-blind
Crossover
Does acute enteral BH4 and/or antioxidant cocktail administration improve locomotor muscle microvascular function in patients with HFrEF and HFpEF?
p-value: p=0.033
Acute BH4 administration improves locomotor muscle microvascular function in patients with HFrEF and HFpEF, highlighting the nitric oxide pathway as a potential therapeutic target.
Supports nitric oxide pathway targeting in HF; extends acute BH4 benefit to microvascular function in HFrEF/HFpEF.
BACKGROUND: 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 (BH 4 ) deficiency and oxidative stress. METHODS: Using a randomized, double-blind, placebo-controlled crossover design, this study examined the impact of enteral BH 4 (10 mg/kg), an antioxidant cocktail (AOx), and coadministration of these 2 agents (BH 4 +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. RESULTS: 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 BH 4 ( P =0.033) and BH 4 +AOx ( P =0.019) in both HFrEF (placebo: 234±31; BH 4 : 357±45; BH 4 +AOx: 355±49 mL/min) and HFpEF (placebo: 269±33; BH 4 : 367±47; BH 4 +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 BH 4 ( P =0.016) and BH 4 +AOx ( P =0.040) in the HFpEF group. CRP (C-reactive protein) was lower following BH 4 ( P =0.007) and BH 4 +AOx ( P =0.007) in HFpEF (placebo: 4268±547; BH 4 : 2721±391; BH 4 +AOx: 2779±376 ng/mL), but was not statistically different in HFrEF ( P =0.39). CONCLUSIONS: Together, these results provide new evidence for the efficacy of acute BH 4 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 BH 4 , in either group. These findings lend further conceptual support for the nitric oxide pathway as a modifiable target in the treatment of heart failure.
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Ratchford et al. (2025) conducted an RCT in Heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) (n=33). Tetrahydrobiopterin (BH4) and/or antioxidant cocktail (AOx) vs. Placebo was evaluated on Peak change in leg blood flow during passive limb movement (p=0.033). Acute administration of BH4 improved peak change in leg blood flow compared with placebo in patients with HFrEF (357 vs 234 mL/min) and HFpEF (367 vs 269 mL/min) (P=0.033).
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