Improved Vascular Function Following 7 days of L‐Citrulline Administration in Heart Failure with Preserved Ejection Fraction

Abstract

BackgroundThere is increasing evidence to support the presence of peripheral vascular dysfunction in patients with heart failure with preserved ejection fraction (HFpEF), which may be due, at least in part, to disease‐related changes in nitric oxide (NO) signaling. L‐Arginine (L‐Arg) is the sole substrate for NO synthesis, but is susceptible to intestinal and hepatic degradation via arginase when administered orally. L‐Citrulline (L‐Cit) is catabolized to L‐Arg at the tissue level and is not a substrate for arginase, and therefore enteral L‐Cit administration has emerged as an effective approach for increasing NO substrate bioavailability.PurposeThe present investigation sought to determine whether oral L‐Cit administration (6g/day for 7 days) would improve vascular function in patients with HFpEF.MethodsIn 13 patients NYHA Class II (n=9) and III (n=4) with HFpEF (2M/11F, 69±10y, EF: 66±7%), flow mediated dilation (FMD) and reactive hyperemia (RH) were evaluated to assess conduit artery and microvascular function, respectively. FMD was expressed as % change in brachial artery diameter (%FMD) and % change corrected for shear rate (%FMD/shear), and RH was calculated as area‐under‐the‐curve for brachial artery blood flow. Plasma L‐Cit and L‐Arg concentrations were assessed to confirm absorption and evaluate circulating NO substrate, and the ratio of L‐Arg to plasma asymmetric dimethylarginine (ADMA) was calculated as a biomarker of NO bioavailability.ResultsCompared to baseline, L‐Cit administration improved FMD (0d: 2.5 ± 0.5%, 7d: 4.7 ± 0.9%), FMD/shear (0d: 0.07 ± 0.02, 7d: 0.12 ± 0.01AU) and RH (0d: 450 ± 46ml, 7d: 574 ± 62ml). L‐Cit (0d: 42 ± 3μM/L, 7d: 370 ± 60 μM/L), L‐Arg (0d: 65 ± 8μM/L, 7d: 257 ± 25μM/L), and L‐Arg:ADMA (0d: 136 ± 14AU, 7d: 481 ± 50AU) all increased following L‐Cit administration.ConclusionsThis study has identified the efficacy of a 7d administration of L‐Cit to improve NO substrate bioavailability, the L‐Arg/ADMA ratio, and both conduit artery and microvascular function in patients with HFpEF. These results provide new insight into the mechanisms that govern peripheral vascular dysfunction in this patient group, and demonstrate a promising plasticity in the peripheral vasculature among patients with this chronic disease.Support or Funding InformationSupport or Funding Information: This project is funded in part by the National Institutes of Health (HL118313; D.W.W., R56AG057584; R.S.R., T32HL139451 R.S.R) and the U.S. Department of Veterans Affairs (I01RX001311; D.W.W., I01RX001697; R.S.R., I01RX002323; R.S.R., I21RX001433; R.S.R., I01RX000182; R.S.R.) and the American Heart Association (18POST33960192; K.B.).