ADMA as a possible marker of endothelial damage. A study in young asymptomatic patients with cerebral small vessel disease

Abstract

Sporadic small vessel disease (SVD) has high prevalence in aging population and stroke patients, but also in younger asymptomatic subjects. In this last group it can represents a prelude to stroke and cognitive impairment. Still nowadays, its pathogenesis is unclear. 35 consecutive patients with SVD at brain MRI and 35 age- and sex-matched controls, between January 2016 and February 2018, underwent an extended screening for thrombophilia, autoimmunity and evaluated levels of blood markers of inflammation and endothelial activation. Asymmetric DiMethyl Arginine (ADMA) levels proved higher in patients (70.44 ± 36.25 ng/ml vs. 46.58 ± 30.67 ng/ml; p = 0.004), also after controlling for confounding factors. ADMA levels showed positive correlation with Fazekas score (r = 0.304; p = 0.01). ROC curve analysis showed a moderate accuracy in discriminating patients and controls (AUC = 0.70; CI 0.57–0.82; p = 0.004): a cut-off of 46 ng/ml is associated with 80% sensitivity, but limited (54%) specificity. Higher ADMA levels characterize selected subjects with sporadic SVD, asymptomatic for vascular diseases and without latent inflammatory conditions or coagulopathy. This reinforces the hypothesis of the key role of endothelial dysfunction in SVD. Further studies should explore the cause-effect relationship between ADMA pathway and SVD.

Arginine and Endothelial Function

“…One of the mechanisms that may help explain the arginine paradox comes from the discovery of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS [ 152 , 153 , 154 , 155 ]. Given its own structure similar to arginine, ADMA is a direct competitor for NOS binding.…”

Arginine Derivatives in Cerebrovascular Diseases: Mechanisms and Clinical Implications

“…Moreover, ADMA correlated with the extent of cerebral leukoaraiosis. This finding was recently confirmed in a study investigating persons with asymptomatic white matter hyperintensities in whom inflammatory or coagulation disorders have been excluded [151]. Besides the association of ADMA to imaging measures of small vessel disease, a relation of ADMA levels with progression of cognitive impairment has been reported [152].…”

High expression of a vascular stricture‐related marker is predictive of an early response to tolvaptan, and a low fractional excretion of sodium is predictive of a poor long‐term survival after tolvaptan administration for liver cirrhosis

“…ADMA is an endogenous inhibitor of endothelial NOS and inhibits acetylcholine-induced vasodilator in endothelial cells; 26 it was shown to be correlated with several vascular diseases, such as cerebral endothelial damage and cardiovascular diseases. 27,28 The ADMA levels depend on the renal function and dimethylaminohydrolase (DDAH) activity. 28 DDAH hydrolyzes ADMA to citrulline and dimethylamines, resulting in its inactivation.…”

“…In addition, the vascular tonus‐related marker ADMA was shown to be a significant marker. ADMA is an endogenous inhibitor of endothelial NOS and inhibits acetylcholine‐induced vasodilator in endothelial cells; 26 it was shown to be correlated with several vascular diseases, such as cerebral endothelial damage and cardiovascular diseases 27,28 . The ADMA levels depend on the renal function and dimethylaminohydrolase (DDAH) activity 28 .…”