Homoarginine Supplementation Improves Cardiac Function in a Murine Model of Ischaemic Heart Failure

Introduction: Homoarginine (HA) is an emerging biomarker with low levels associated with increased risk of stroke, myocardial infarction and heart failure (HF) in epidemiological studies. Recently, we identified HA as an independent predictor of mortality in patients with HF. We therefore hypothesized that HA supplementation might be beneficial in a murine model of chronic heart failure. Methods: C57BL/6J mice were treated with 14 mg/L HA in drinking water for 4 weeks prior to coronary artery occlusion to induce infarction. Infarct size and HF severity were assessed 6 weeks later by cine-MRI and LV haemodynamics under isoflurane anaesthesia. HA and biopterins were measured using LC-MS/MS and HPLC. Protein S-nitrosylation (SNO) was quantified using biotin switch assay. Results: We first established that HA supplementation significantly increased both plasma and myocardial HA levels in normal C57BL/6J mice (mean±SEM 0.29±0.03 vs. 0.89±0.07 μmol/L and 8.8±1.4 vs. 24.4±3.4 nmol/g protein; n=5-10; P Conclusions: HA supplementation improves LV haemodynamic function and contractile reserve in mice with chronic HF, potentially via altered redox regulation or SNO status. Our data suggest HA is more than a simple biomarker, since higher levels directly influence HF pathophysiology. Further studies aimed at clinical translation are merited.