Impact of Acute Antioxidant and Tetrahydrobiopterin (BH 4 ) Administration on Locomotor Muscle Microvascular Function in Patients With Heart Failure

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Abstract
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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