Homoarginine, Cardiovascular Risk, and Mortality

Abstract

Background-Homoarginine is an amino acid derivative that may increase nitric oxide availability and enhance endothelial function. The effect of the level of homoarginine on cardiovascular outcome and mortality is unknown. Methods and Results-We assessed cardiovascular and all-cause mortality according to homoarginine levels in a cohort of 3305 subjects referred for coronary angiography from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study. After investigating the relation of homoarginine with kidney function and markers of endothelial dysfunction, we explored its effects on adverse outcomes in a second high-risk cohort of 1244 patients with type 2 diabetes mellitus receiving maintenance hemodialysis (4D study [Die Deutsche Diabetes Dialyse Studie]). In the LURIC study, mean serum homoarginine levels were 2.6Ϯ1.1 mol/L. During a median follow-up of 7.7 years, 766 patients died. After adjustments for age and sex, patients in the lowest quartile (Ͻ1.85 mol/L) had a Ͼ4-fold higher rate of dying of cardiovascular disease (hazard ratio 4.1, 95% confidence interval 3.0 to 5.7) than patients in the highest quartile (Ͼ3.1 mol/L). Lower homoarginine levels were associated with lower estimated glomerular filtration rate and higher levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Hemodialysed patients had lower mean homoarginine levels of 1.2Ϯ0.5 mol/L and experienced a 5-fold increased mortality rate compared with LURIC patients (608 deaths during a median follow-up of 4 years). Homoarginine consistently affected mortality, which was 2-fold higher in 4D study patients in the lowest quartile (Ͻ0.87 mol/L) than in patients in the highest quartile (Ͼ1.4 mol/L). Conclusions-Homoarginine levels are independently associated with cardiovascular and all-cause mortality in patients referred for coronary angiography and in patients undergoing hemodialysis. Future studies are needed to elucidate the underlying pathomechanisms. (Circulation. 2010;122:967-975.)

Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

“…Elevated plasma a-aminoadipic acid and homoarginine, two metabolites of L-Lys, in group Lys indicated that the rats in group Lys had increased intestinal absorption of L-Lys. [23][24][25] However, the elevation of plasma Lys in group Lys was not statistically significant. As far as we examined, plasma Ala, Pro, Arg, Gln, Asn, homoarginine, and a-aminoadipic acid in group Lys seemed to play some roles in the suppression of vascular calcification.…”

“…23,44 The causal relationship between low homoarginine and an increased incidence of cardiovascular events has been mainly attributed to suppressed nitric oxide (NO), because homoarginine induces NO by two pathways: (1) homoarginine itself serves as a substrate for NO synthase; and (2) homoarginine inhibits arginase and thereby increases arginine, a major substrate for NO synthase. 23 In addition to the property of homoarginine as an inducer of NO, our current study revealed that homoarginine works as an inhibitor of mineral precipitations ( Figure 8A). The property of homoarginine as an inhibitor of arginase seems to explain the reason, at least in part, why plasma Arg, another precipitate-inhibitory amino acid, was elevated in group Lys ( Figure 8A, Table 4).…”

“…The property of homoarginine as an inhibitor of arginase seems to explain the reason, at least in part, why plasma Arg, another precipitate-inhibitory amino acid, was elevated in group Lys ( Figure 8A, Table 4). 23 Therefore, homoarginine is likely to have both direct and indirect precipitate-inhibitory effects in vivo. Because vascular calcification has been revealed to be associated with an increased incidence of cardiovascular events, 1-4 the property of homoarginine as a precipitate-inhibitor seems to play important roles.…”

Assessment of asymmetrical dimethylarginine metabolism in patients with critical illness

“…A potentially more important role that has received some attention is in the inhibition of the enzyme arginase with consequent preservation of arginine for NOS [24]. Indeed, low homoarginine concentrations have been recently shown to be associated with mortality and cardiovascular events [25]. Furthermore, increased homoarginine concentrations during normal pregnancy are associated with increases in brachial artery diameter and flow-mediated dilatation [26].…”

Asymmetric dimethylarginine, arginine and homoarginine at 11–13 weeks’ gestation and preeclampsia: a case–control study

“…26 Such a role of L-homoarginine in endothelial function is supported by the findings of a study in patients undergoing coronary angiography or maintenance hemodialysis, where a low serum level of L-homoarginine was a strong predictor of subsequent mortality. 53 Homoarginine may also inhibit platelet aggregation and stimulate insulin secretion, 54 --56 actions, which affect cardiovascular health and may have a role in PE.…”