Abstract
BackgroundPlasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are raised in patients with chronic vascular disease, causing increased cardiovascular risk and endothelial dysfunction, but the role of ADMA in acute inflammatory states is less well defined.Methods and ResultsIn a prospective longitudinal study in 67 patients with acute sepsis and 31 controls, digital microvascular reactivity was measured by peripheral arterial tonometry and blood was collected at baseline and 2–4 days later. Plasma ADMA and L-arginine concentrations were determined by high performance liquid chromatography. Baseline plasma L-arginine: ADMA ratio was significantly lower in sepsis patients (median [IQR] 63 [45–103]) than in hospital controls (143 [123–166], p<0.0001) and correlated with microvascular reactivity (r = 0.34, R2 = 0.12, p = 0.02). Baseline plasma ADMA was independently associated with 28-day mortality (Odds ratio [95% CI] for death in those in the highest quartile (≥0.66 µmol/L) = 20.8 [2.2–195.0], p = 0.008), and was independently correlated with severity of organ failure. Increase in ADMA over time correlated with increase in organ failure and decrease in microvascular reactivity.ConclusionsImpaired endothelial and microvascular function due to decreased endothelial NO bioavailability is a potential mechanism linking increased plasma ADMA with organ failure and death in sepsis.
Highlights
Asymmetric dimethylarginine (ADMA), an endogenous nonspecific nitric oxide synthase (NOS) inhibitor, is associated with chronic endothelial dysfunction [1] and increased cardiovascular risk [2], but its role in the setting of acute infections has been less well characterised.Severe sepsis is the leading cause of death in intensive care units in the USA [3], and is increasing in incidence globally [4]
We have previously shown that digital microvascular reactivity, a measure of endothelial NO bioavailability [22], is decreased in patients with sepsis [7]
The plasma L-arginine: ADMA ratio inversely correlated with severity of illness as measured by Acute Physiology and Chronic Health Evaluation (APACHE) II score (r = 20.4, R2 = 0.16, p = 0.003) and organ failure as measured by Sequential Organ Failure Assessment (SOFA) score (r = 20.5, R2 = 0.25, p = 0.0001)
Summary
Asymmetric dimethylarginine (ADMA), an endogenous nonspecific nitric oxide synthase (NOS) inhibitor, is associated with chronic endothelial dysfunction [1] and increased cardiovascular risk [2], but its role in the setting of acute infections has been less well characterised. Severe sepsis (acute infection resulting in organ dysfunction) is the leading cause of death in intensive care units in the USA [3], and is increasing in incidence globally [4]. Plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are raised in patients with chronic vascular disease, causing increased cardiovascular risk and endothelial dysfunction, but the role of ADMA in acute inflammatory states is less well defined
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