Cardiovascular disease (CVD) remains the leading cause of death within the European Union and new, more effective forms of treatment are urgently needed. Recent studies have shown that patients with low plasma homoarginine are at increased risk of stroke, myocardial infarction and heart failure (HF). This project aims to explore the underlying mechanisms of this association and to determine the therapeutic potential of homoarginine supplementation. We have already shown that mice with homoarginine-deficiency exhibit increased brain injury following an experimental stroke, and further, that elevating homoarginine levels is protective in normal mice. We hypothesize that homoarginine is more a mediator than a mere biomarker for positive outcome in CVD. Specifically, we propose that increased homoarginine in mice will also be beneficial in experimental models of acute ischaemia and chronic HF. Our objectives are, 1) to study whether low homoarginine levels are detrimental in the ischaemic and failing heart and demonstrate rescue by homoarginine treatment; 2) to determine whether homoarginine supplementation is beneficial; and 3) to elucidate the mechanism for how homoarginine exerts its cardiac effects. This interdisciplinary project brings together the applicant’s (Germany) specific expertise in pharmacology and detailed knowledge of the homoarginine research field, with the opportunity to receive extensive in vivo training in an array of cutting-edge murine cardiac phenotyping techniques developed by the scientist in charge (UK). For example, LV catheterization, in vivo MRI, echocardiography, 31P-NMR and surgical models of ischaemia and HF in mice. In conclusion, by extensive training of the Fellow, this project will 1) pave the road to develop scientific independence, 2) foster intra-European collaboration, 3) provide a basis for further funding, and 4) give novel insights into CVD pathophysiology to the scientific community and to the general public.