The Impact of Acute Oral Tetrahydrobiopterin on Vascular Function in Heart Failure Patients with Reduced Ejection Fraction
Authors: Clifton Heather L. , Garten Ryan S. , Lee Joshua F. , Rossman Matthew J. , Clifford Jayson R. , Hydren Jay R. , Stehlik Josef , Richardson Russell S. , Wray D. Walter 
Published: November 2023

BackgroundPassive leg movement (PLM) has been developed as a non‐invasive model for assessing nitric oxide (NO)‐mediated vascular function, and has recently been utilized to demonstrate vascular dysfunction in heart failure with reduced ejection fraction (HFrEF) patients [1]. Tetrahydrobiopterin (BH4) is an essential cofactor of endothelial nitric oxide synthase (eNOS), and supplementation of BH4 should therefore promote increased NO bioavailability and improved vascular function in this cohort. The purpose of this study was to determine whether acute oral BH4 administration would improve vascular function, as assessed by PLM, in HFrEF patients.Materials and methodsSix NYHA Class II–III HFrEF patients participated in this study (5 M, 1 F; age 59 ± 11 yrs; ht 173 ± 6 cm; wt 81 ± 17 kg; BMI 27 ± 4 kg/m2). In a double‐blind, randomized, cross‐over design, the HFrEF patients ingested either BH4 (10mg/kg) or placebo 5 hours prior to arrival at the laboratory. Seated PLM was performed by a trained investigator moving the patient's knee joint from 180° to 90° and back continuously at a rate of 1 Hz for 2 minutes. Femoral artery diameter and blood velocity were measured with ultrasound Doppler (GE LogIQ 7), from which leg blood flow (LBF) was calculated. Arterial blood pressure was measured non‐invasively by finger photoplethysmography and used to estimate stroke volume (SV) and cardiac output (CO), as well as to calculate leg vascular conductance (LVC). Heart rate was determined by standard 3‐lead ECG. All measurements were made for 1 minute before and 2 minutes following the onset of PLM. Leg vascular function was quantified as the area‐under‐the‐curve (AUC) during the first 30 seconds of PLM for both LBF and LVC, and the peak change in LBF (ΔLBFpeak) and LVC (ΔLVCpeak).ResultsResting hemodynamic measurements did not differ between BH4 and placebo conditions. However, BH4 consumption improved LBF AUC (placebo: 13.8 ± 12.3 ml; BH4: 45.4 ± 13.5 ml, p<0.05) and ΔLBFpeak (placebo: 136 ± 25 ml/min; BH4: 255 ± 57 ml/min, p<0.05). Similarly, LVC AUC (placebo: 0.5 ± 0.3 ml/mmHg; BH4: 0.9 ± 0.3 ml/mmHg, p<0.05, Figure 1A) and ΔLVCpeak (placebo: 1.7 ± 0.4 ml/min/mmHg; BH4: 2.8 ± 0.6 ml/min/mmHg, p=0.05, Figure 1B) were also greater following BH4. Peak changes in HR, SV, CO and MAP during PLM were not different between conditions.ConclusionsThis study demonstrates the efficacy of acute, oral BH4 administration to significantly improve leg vascular function in Class II–III HFrEF patients, which may represent a new therapeutic strategy to combat peripheral vascular dysfunction in this patient population.Support or Funding InformationFunded in part by grants from the National Institutes of Health (NIH R01 HL118313, NIH PO1 HL091830) and the U.S. Department of Veterans Affairs (VA RR&D I01RX000182, VA RR&D I21 RX001433, VA RR&D I21 RX001418, VA RR&D I01RX001697)