Asymmetric and symmetric dimethylarginine and risk of secondary cardiovascular disease events and mortality in patients with stable coronary heart disease: the KAROLA follow-up study.

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor, which has been associated with total and cardiovascular mortality in various clinical settings. Studies on its structural isomer, symmetric dimethylarginine (SDMA), are scarce. This study aimed to determine the associations of both ADMA and SDMA levels with secondary cardiovascular disease events and all-cause mortality in patients with stable coronary heart disease (CHD). In the observational prospective cohort study KAROLA, 1,148 CHD patients were followed for a median of 8.1 years. ADMA and SDMA were determined by liquid chromatography-tandem mass spectrometry. Baseline ADMA and SDMA levels were categorized in quartiles or standardized by their respective standard deviation, and appropriate hazard ratios and 95 % confidence intervals (HR [95 % CI]) were estimated in Cox proportional hazards models. 150 patients experienced secondary cardiovascular disease events (CVD) and 121 patients died. After adjustment for confounders, ADMA was not associated with the risk of secondary CVD events (HR per standard deviation increase: 1.02 [95 %CI: 0.86-1.21]), whereas an association was suggested for SDMA (HR 1.17 [1.00-1.37]). Higher hazard ratios were observed in all-cause mortality models (ADMA: HR 1.15 [0.95-1.37]; SDMA: HR 1.29 [1.09-1.52]). Our results suggest that especially SDMA might possibly have potential as a risk marker for all-cause mortality and to a lesser extent for secondary cardiovascular events. Future studies are needed to quantify these associations more precisely and should, in particular, further address the possibility of residual confounding by impaired kidney function.