S-09-5: HOMOARGININE AND CARDIOVASCULAR PROTECTION: POTENTIAL THERAPEUTIC TARGET?

Abstract

Increasing evidence suggests that homoarginine may offer cardiovascular protection via several mechanisms. We previously investigated prospective associations between homoarginine and i) incident hypertension; ii) carotid wall thickening; and iii) cardiovascular mortality over a five to ten year period in a South African cohort based in the North West Province of the international Prospective Urban and Rural Epidemiology (PURE) study. No significant associations were found between baseline homoarginine levels and incident hypertension (n = 166). However, in a group who remained normotensive over the course of ten years (n = 166), homoarginine levels correlated positively with brachial systolic blood pressure (β = 0.33; p = 0.001); brachial pulse pressure (β = 0.40; p = 0.001); and central pulse pressure (β = 0.30; p = 0.003). This may suggest that the protective effects of homoarginine is not infinite and may become overshowed by other factors once hypertension develops. When investigating prospective associations between homoarginine at baseline and cross-sectional wall area (CSWA) five years later, we indicated that the protective association between CSWA and homoarginine was limited to the female participants of this cohort (n = 396; β = - 0.11; p = 0.024). We also examined whether homoarginine could predict 10-year risk of all cause and cardiovascular mortality. Higher homoarginine levels were found in survivors when compared to nonsurvivors (n = 143; 1.25 μM vs. 0.89 μM P < 0.001) and in multivariable Cox regression analyses, higher homoarginine predicted a reduction in ten year cardiovascular (standardized hazard ratio, 0.61; 95% CI 0.50 to 0.75) and all cause (standardized hazard ratio, 0.59; 95% CI 0.41 to 0.84) mortality risk. Clearly, it would be beneficial to investigate the regulation of homoarginine levels as therapeutic target in the management of cardiovascular disease. Previous experimental findings indicated that homoarginine infusions have beneficial effects on left ventricular contractility and diastolic function, as well as blood pressure lowering effects to normotensive levels in hypertensive rats. The safety of oral homoarginine levels was established in healthy adults and provided the foundation for two clinical trials to provide data on the optimal dosing of homoarginine in humans (NCT02675660), and to evaluate the applicability of an oral formulation of homoarginine to normalize homoarginine blood levels in patients with acute ischemic stroke (NCT03692234).