Nitric Oxide Dysregulation in Patients With Heart Failure: The Association of Depressive Symptoms With L-Arginine, Asymmetric Dimethylarginine, Symmetric Dimethylarginine, and Isoprostane

Objective Nitric oxide (NO) regulation plays a critical role in cardiovascular diseases including heart failure (HF). Markers of NO dysregulation have been found in individuals with depression without cardiovascular disease. Because depression is associated with poor HF outcomes, the present study tested the hypothesis that depression is associated with a dysregulated NO pathway in patients with HF. Methods Serum levels of NO regulation (l-arginine, asymmetric dimethylarginine [ADMA], and symmetric dimethylarginine [SDMA]) and oxidative stress (isoprostane 8-epi prostaglandin F-2) were measured in 104 patients with HF (mean [standard deviation] age = 65.7 [8.4] years, 28% women) at baseline and 12 months. Depressive symptoms were measured using the Beck Depression Inventory. The associations between depressive symptoms with markers of NO regulation were examined with mixed-model analysis, adjusted for age, sex, time of assessment, left ventricular ejection fraction, creatinine, and hypertension. Results Depressive symptoms were correlated with a lower l-arginine/ADMA ratio (r = -0.22, p = .003) and higher SDMA levels (r = 0.28, p <.001). Associations were similar for somatic depressive symptoms and cognitive-affective symptoms (l-arginine/ADMA ratio: r = -0.20 [p = .009] versus r = -0.19 [p = .013]; ADMA: r = 0.16 [p = .043] versus r = 0.10 [p = .20]; SDMA: r = 0.27 [p <.001] versus r = 0.22 [p = .005], respectively). No associations were found between depressive symptoms and isoprostane. The association between depression and the l-arginine/ADMA ratio remained significant in multivariate adjusted models. Conclusions Depressive symptoms were associated with markers of NO dysregulation, particularly the l-arginine/ADMA ratio and SDMA, in patients with HF. The lower l-arginine/ADMA ratio indicates less available NO, suggesting that NO-related endothelial dysfunction may play a role in the adverse risk of HF progression associated with depression.