Beschreibung: Objective— Increased asymmetrical dimethylarginine (ADMA), a NO synthase inhibitor, and its congener symmetrical dimethylarginine (SDMA), predict cardiovascular and all-cause mortality in at-risk populations. Their prognostic value in the general population remains uncertain. We investigated the correlations of SDMA and ADMA with atherosclerosis and cardiovascular/all-cause mortality in the Dallas Heart Study, a multiethnic probability-based cohort aged 30 to 65 years. Approach and Results— SDMA and ADMA were measured by liquid chromatography-tandem mass-spectrometry (n=3523), coronary artery calcium by electron-beam computed tomography, and abdominal aortic wall thickness by MRI. In unadjusted analyses, categories of increasing SDMA and ADMA were associated with higher prevalence of cardiovascular risk factors, increased risk markers, and all-cause and cardiovascular mortality (median follow-up, 7.4 years). After adjustment for age, sex, and race, traditional cardiovascular risk factors, and renal function, SDMA and ADMA analyzed as continuous variables were associated with coronary artery calcium 〉10, but only SDMA was associated with abdominal aortic wall thickness. SDMA, but not ADMA, was associated with cardiovascular mortality (hazard ratio per log unit change, 3.36 [95% confidence interval, 1.49–7.59]; P =0.004). SDMA and ADMA were both associated with all-cause mortality, but after further adjustment for N-terminal pro–brain-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity cardiac troponin T, only SDMA was associated with all-cause mortality (hazard ratio per log unit change, 1.86 [95% confidence interval, 1.04–3.30]; P =0.01). Conclusions— SDMA, but not ADMA, was an independent predictor of all-cause and cardiovascular mortality in a large multiethnic population-based cohort.

Beschreibung: 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.

Beschreibung: Background— Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome. Methods and Results— Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64–0.96]; P =0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke ( P 〈0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the l -arginine:glycine amidinotransferase ( AGAT ) gene ( P 〈2.1 x 10 –8 ; n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT –/– ) and (2) a guanidinoacetate N -methyltransferase deletion (GAMT –/– ) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT –/– mice and increased in GAMT –/– mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT –/– mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT –/– mice was decreased compared with controls. Conclusions— Low homoarginine appears to be related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.

Beschreibung: Background The endogenous amino acid homoarginine predicts mortality in cerebro- and cardiovascular disease. The objective was to explore whether homoarginine is associated with atrial fibrillation (AF) and outcome in patients with acute chest pain. Methods and Results One thousand six hundred forty-nine patients with acute chest pain were consecutively enrolled in this study, of whom 589 were diagnosed acute coronary syndrome (ACS). On admission, plasma concentrations of homoarginine as well as brain natriuretic peptide (BNP), and high-sensitivity assayed troponin I (hsTnI) were determined along with electrocardiography (ECG) variables. During a median follow-up of 183 days, 60 major adverse cardiovascular events (MACEs; 3.8%), including all-cause death, myocardial infarction, or stroke, were registered in the overall study population and 43 MACEs (7.5%) in the ACS subgroup. Adjusted multivariable Cox regression analyses revealed that an increase of 1 SD of plasma log-transformed homoarginine (0.37) was associated with a hazard reduction of 26% (hazard ratio [HR], 0.74; 95% CI, 0.57–0.96) for incident MACE and likewise of 35% (HR, 0.65; 95% CI, 0.49–0.88) in ACS patients. In Kaplan–Meier survival curves, homoarginine was predictive for patients with high-sensitivity assayed troponin I (hsTnI) above 27 ng/L ( P 〈0.05). Last, homoarginine was inversely associated with QTc duration ( P 〈0.001) and prevalent AF (OR, 0.83; 95% CI, 0.71–0.95). Conclusion Low plasma homoarginine was identified as a risk marker for incident MACEs in patients with acute chest pain, in particular, in those with elevated hsTnI. Impaired homoarginine was associated with prevalent AF. Further studies are needed to investigate the link to AF and evaluate homoarginine as a therapeutic option for these patients.