The Impact of Short‐Term Tetrahydrobiopterin (BH4) Supplementation on Peripheral Vascular Function in Heart Failure with Preserved Ejection Fraction (HFpEF)

Abstract

BackgroundPatients with heart failure with preserved ejection fraction (HFpEF) exhibit macro‐ and microvascular dysfunction in both the upper and lower limbs that may be mediated by a decline in nitric oxide (NO) bioavailability. Tetrahydrobiopterin (BH4) is a vital cofactor for NO synthase (NOS) activity, the principal enzyme for NO production. BH4 insufficiency contributes to NOS uncoupling, which promotes cellular oxidative stress and limits NO production. While evidence supports the efficacy of BH4 supplementation to reverse NOS uncoupling in other patient populations, the utility of this intervention to restore vascular health has not been examined in HFpEF. We tested the hypothesis that short‐term BH4 supplementation would improve peripheral vascular function in patients with HFpEF.MethodsFive patients with HFpEF (3F/2M; 72±8 years; 31.7±6.1 kg/m2) participated in a randomized, double‐blind crossover study, having consumed either BH4 (Sapropterin, 10 mg/kg) or placebo for 10 days, separated by a 14‐day washout period. Peripheral vascular function was assessed via flow‐mediated dilation (FMD; an index of macrovascular function) and reactive hyperemia (RH, an index of microvascular function) in both the arm (brachial artery, BA) and leg (popliteal artery, PA) at the beginning (pre) and end (post) of each treatment period.ResultsThere were no baseline hemodynamic differences between trials (p>0.05). BA FMD was unchanged following either trial (pre vs. post; BH4: 3.2±2.5% vs. 4.0±1.9%, Δ 0.8±1.4%; Placebo: 2.9±1.9% vs. 2.2±2.2%, Δ ‐0.7±1.1%; p>0.05). Likewise, BA RH was unchanged following either trial (pre vs. post; BH4: 399±206 ml vs. 387±161 ml; Placebo: 242±126 ml vs. 174±149 ml; p>0.05). In contrast, PA FMD improved following the BH4 trial, but was unchanged in the placebo trial (pre vs. post; BH4: 1.5±1.2% vs. 2.5±0.8%; Placebo: 1.6±1.1% vs. 1.3±1.3%; p=0.03). Changes in %FMD for the PA were greater in BH4 compared to placebo (∆ values: 1.0±1.0% vs. ‐0.4±0.4%; p=0.03). No improvements were observed for PA RH (pre vs. post; BH4: 533±257 ml vs. 561±191 ml; Placebo: 682±284 ml vs. 656±107 ml; p>0.05).ConclusionThese findings identify a potential for short‐term BH4 supplementation to improve lower limb macrovascular function in patients with HFpEF. This apparent vascular plasticity suggests that drugs targeting discreet points in the NO pathway may be efficacious in mitigating the disease‐related decline in vascular health in this patient group.