Improved vascular function and functional capacity following l-citrulline administration in patients with heart failure with preserved ejection fraction: a single-arm, open-label, prospective pilot study

There is accumulating evidence for both peripheral vascular dysfunction and impaired functional capacity in patients with heart failure with a preserved ejection fraction (HFpEF). Although derangements in the l-arginine-nitric oxide (l-Arg-NO) pathway are likely to contribute to these aspects of HFpEF pathophysiology, the impact of increased NO substrate on vascular health and physical capacity has not been evaluated in this patient population. Thus, using a single-arm study design, we evaluated the impact of enteral l-citrulline (l-Cit, 6 g/day for 7 days), a precursor for l-Arg biosynthesis, on vascular function [flow-mediated dilation (FMD), reactive hyperemia (RH), and passive limb movement (PLM)], functional capacity [6-min walk test (6MWT)], and biomarkers of l-Arg-NO signaling in 14 patients with HFpEF ( = 14, 4 M/10 F, 70 ± 10 yr, EF: 66 ± 7%). Compared with baseline (0d), 7 days of l-Cit administration improved FMD (0d: 2.5 ± 1.6%, 7d: 4.5 ± 2.9%), RH (0d: 468 ± 167 mL, 7d: 577 ± 199 mL), PLM blood flow area-under-the-curve (0d: 139 ± 130 mL, 7d: 198 ± 115 mL), and 6MWT distance (0d: 377 ± 27 m, 7d: 397 ± 27 m) ( < 0.05). An increase in plasma l-Cit (0d: 42 ± 11 µM/L, 7d: 369 ± 201 µM/L), l-Arg (0d: 65 ± 8 µM/L, 7d: 257 ± 25 µM/L), and the ratio of l-Arg to asymmetric dimethylarginine (ADMA) (0d: 136 ± 13 AU, 7d: 481 ± 49 AU) ( < 0.05) was also observed. Though preliminary in nature, these functional and biomarker assessments demonstrate a potential benefit of l-Cit administration in patients with HFpEF, findings that provide new insight into the mechanisms that govern vascular and physical dysfunction in this patient group. The current investigation has demonstrated that l-Cit administration may improve brachial artery endothelium-dependent vasodilation, upper and lower limb microvascular function, and physical capacity in patients with HFpEF, highlighting the potential therapeutic potential of interventions targeting the l-Arg-NO signaling cascade to improve outcomes in this patient group.