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Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER
Daniel Sedding1, Tim M Schmidt2, Heike Bähre3
1Klinik für Kardiologie, Universitätsklinikum Halle, Halle, Germany; Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Insights
L-citrulline supplementation significantly improved walking distance in peripheral artery disease (PAD) patients. Adding tetrahydrobiopterin (H4Bip) further enhanced benefits, particularly in those with high ADMA levels.
Area of Science:
- Cardiovascular Research
- Nutritional Science
- Vascular Biology
Background:
- Peripheral artery disease (PAD) presents a significant public health challenge with limited effective pharmacological treatments.
- Current interventions for PAD have varying efficacy, with high numbers needed-to-treat for some medications.
Purpose of the Study:
- To evaluate the impact of L-citrulline and tetrahydrobiopterin (H4Bip) on walking distance in PAD patients.
- To stratify treatment effects based on plasma levels of asymmetric dimethyl L-arginine (ADMA), an inhibitor of nitric oxide synthase.
Main Methods:
- A randomized, placebo-controlled, double-blinded crossover trial involving 51 PAD patients.
- Assessed changes in absolute claudication distance (dACD) after 12 weeks of L-citrulline (3g BID) and an additional 2 weeks of H4Bip (0.45g QD).
- Measured preinterventional ADMA levels to stratify patient groups.
Main Results:
- L-citrulline supplementation increased plasma L-citrulline and L-arginine levels significantly compared to placebo.
- L-citrulline improved dACD by 20.11% versus 5.73% with placebo (P=0.011).
- Addition of H4Bip further increased dACD by 28.15% in patients with pathological ADMA levels (P=0.021).
Conclusions:
- L-citrulline serves as an effective nutritional intervention for improving walking capacity in PAD patients.
- Tetrahydrobiopterin (H4Bip) offers additional benefits in PAD patients with elevated ADMA levels.
- Further trials are warranted to confirm these findings for PAD management.
Background:
Peripheral artery disease (PAD) is a major public health concern due to its high prevalence, severe impact on individuals' health and quality of life, and substantial economic burden. Pharmacological interventions are still limited with numbers needed-to-treat ranging from 6 (cilostazol) to 50 (aspirin, statins, and vorapaxar).
Objectives:
This randomized, placebo-controlled, double-blinded crossover interventional trial aims to measure the effect of L-citrulline and tetrahydrobiopterin (H4Bip) on walking distance in patients with PAD, stratified by plasma levels of asymmetric dimethyl L-arginine (ADMA), the endogenous inhibitor of endothelial nitric oxide (NO) synthase.
Methods:
We measured preinterventional ADMA levels in 51 patients with PAD in Australia and Germany with mean changes in absolute claudication distance (dACD) as the primary outcome upon orally supplementing the L-arginine precursor, L-citrulline (3 g) twice daily for 12 weeks, and, in one arm, additionally H4Bip (0.45 g) once per day for a further 2 weeks.
Results:
Preinterventional ADMA levels were pathological (>0.4 μM) in 34 patients. Supplementation with L-citrulline significantly increased the mean plasma levels of both L-citrulline and L-arginine, from 41.8 ± 2.7 μmol/l to 246.3 ± 67.3 μmol/l (P = 0.004) and from 75.2 ± 4.2 μmol/l to 119.2 ± 6.9 μmol/l (P < 0.0001) respectively, when compared with placebo. dACD in % of control was significantly improved by L-citrulline vs placebo (20.11% ± 4.50% vs 5.73% ± 2.74%, respectively; P = 0.011). Further addition of H4Bip increased the mean percentage dACD to 28.15% ± 6.84% (P = 0.021), but only in patients with preinterventional pathological ADMA levels.
Conclusions:
L-citrulline and, when ADMA levels are pathological, H4Bip are effective nutritional interventions in patients with PAD warranting further confirmatory trials.
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