Homoarginine and cardiovascular outcome in the population-based Dallas Heart Study

Objective: The nonproteinogenic amino acid homoarginine has been postulated to have antiatherosclerotic effects as a weak substrate of nitric oxide synthase. This investigation in the population-based Dallas Heart Study (DHS) aimed to evaluate the association of homoarginine with clinical and subclinical cardiovascular outcomes.

Approach and results: Plasma homoarginine was measured in 3514 participants of the DHS using liquid chromatography-tandem mass spectrometry. Associations between homoarginine and major adverse cardiovascular events and all-cause mortality were analyzed using Cox proportional hazard models adjusting for cardiovascular risk factors. Linear regression was used to assess cross-sectional associations between homoarginine and subclinical cardiovascular disease, including coronary artery calcium measured by electron beam-computed tomography, and aortic plaque burden and aortic wall thickness by MRI. Median age was 43 (interquartile range, 36-52) years, with 56% women and 52% black participants. Median follow-up was 9.4 (9.0-9.8) years. Median plasma homoarginine was 2.80 (2.14-3.54) μmol/L. In multivariable models, higher homoarginine was associated with lower rate of major adverse cardiovascular events (hazard ratio, 0.86; 95% confidence interval, 0.75-0.98) and lower all-cause mortality (hazard ratio, 0.82; 0.73-0.92; per 1 log SD increase in homoarginine). Homoarginine was inversely and independently associated with aortic wall thickness (β-estimate, -0.04; P<0.01) but not with aortic plaque burden and coronary artery calcium.

Conclusions: Homoarginine is inversely associated with subclinical vascular disease and with risk for cardiovascular disease events. Additional studies are needed to evaluate whether the regulation of plasma homoarginine could emerge as a novel therapeutic option to improve outcomes in cardiovascular disease.