Impaired exercise‐induced forearm blood flow in patients with systemic sclerosis (SSc) is restored after acute tetrahydrobiopterin (BH4) supplementation

SSc is a rare systemic auto‐immune disease characterized by fibrosis and vasculopathy. We have recently demonstrated that patients with SSc have impaired endothelial function and peripheral vasodilation to an ischemic challenge. We looked to extend these observations and determine if patients with SSc have a dysfunctional blood flow response to exercise. Furthermore, we sought to determine if acute supplementation of BH4, an essential cofactor for endothelial nitric oxide synthase, would ameliorate the putative dysfunctional blood flow response to exercise in SSc. We recruited 15 age‐ and sex‐matched healthy controls (10 women:5 men; age 56±5 yrs) and 10 patients with SSc (7 women:3 men; age 61±4 yrs). The patients with SSc then participated in a double‐blind, randomized, placebo‐controlled, crossover study to determine if acute oral BH4 (10mg/kg) supplementation would restore exercise‐induced blood flow and vascular conductance. Subjects reported to the laboratory fasted for 5 hours then performed intermittent static handgrip exercise (1 Hz, 3 min) at intensities corresponding to 15, 30, and 45% of maximal voluntary contraction (MVC). Forearm blood flow (duplex ultrasound Doppler), mean arterial blood pressure (MAP; brachial sphygmomanometry), and heart rate (HR) were determined at baseline and the final minute of each workload. Forearm vascular conductance was calculated as forearm blood flow / MAP. Controls and patients with SSc were similar in body stature, handgrip MVC, and MAP (P>0.05), however, resting forearm blood flow and vascular conductance were significantly higher in healthy controls compared to patients with SSc (blood flow: 57±7 vs. 33±6 ml/min; vascular conductance: 0.6±0.1 vs. 0.4±0.1 U, P<0.05). During handgrip exercise, HR and MAP increased in an intensity‐dependent manner with no differences between groups (P>0.05). Exercise‐induced forearm blood flow and vascular conductance was higher at all workloads in healthy controls compared to patients with SSc (blood flow: 15%: +67, 30%: +80, 45%: +85 ml/min, P<0.05; Figure 1). Resting forearm blood flow was unaffected by acute BH4 supplementation (P>0.05), but during exercise BH4 augmented forearm blood flow and vascular conductance at all workloads compared to placebo (blood flow at 15%: +30, 30%: +41, 45%: +59 ml/min, P<0.05; Figure 2), and was similar across workload loads to healthy controls (P>0.05). Furthermore, an increase in peak exercise‐induced forearm blood flow of at least 15% was observed in 9 of the 10 patients with SSc. In conclusion, patients with SSc have impaired exercise‐induced forearm blood flow and vascular conductance that is restored by acute BH4 supplementation. These improvements in vascular hemodynamics during exercise imply a BH4 facilitated improvement in endothelial vasodilator function during exercise in patients with SSc. Support or Funding Information Funded in part by grants from the National Institutes of Health (NIH R01 AG040297, NIH K02 AG045339, NIH P01 HL091830, NIH R01 HL118313) and the U.S. Department of Veterans Affairs (VA RR&D E6910R and E1697R).Exercise‐induced forearm blood flow was significantly higher at baseline and at each workload in age‐ and sex‐matched healthy controls compared to patients with systemic sclerosis (SSc). *P<0.05 vs. vs. SSc at same workload. Values are Mean±SEMExercise‐induced forearm blood flow was significantly higher at each workload following acute BH4 supplementation compared to placebo in patients with systemic sclerosis (SSc). *P<0.05 vs. vs. placebo at same workload. Values are Mean±SEM