Abstract
We explored the significance of the L-Arginine/asymmetric dimethylarginine (L-Arg/ADMA) ratio as a biomarker of endothelial dysfunction in stroke patients. To this aim, we evaluated the correlation, in terms of severity, between the degree of endothelial dysfunction (by L-Arg/ADMA ratio), the methylene tetrahydrofolate reductase (MTHFR) genotype, and the interatrial septum (IAS) phenotype in subject with a history of stroke. Methods and Results: L-Arg, ADMA, and MTHFR genotypes were evaluated; the IAS phenotype was assessed by transesophageal echocardiography. Patients were grouped according to the severity of IAS defects and the residual enzymatic activity of MTHFR-mutated variants, and values of L-Arg/ADMA ratio were measured in each subgroup. Of 57 patients, 10 had a septum integrum (SI), 38 a patent foramen ovale (PFO), and 9 an ostium secundum (OS). The L-Arg/ADMA ratio differed across septum phenotypes (p ≤ 0.01), and was higher in SI than in PFO or OS patients (p ≤ 0.05, p ≤ 0.01, respectively). In the PFO subgroup a negative correlation was found between the L-Arg/ADMA ratio and PFO tunnel length/height ratio (p ≤ 0.05; r = − 0.37; R2 = 0.14). Interestingly, the L-Arg/ADMA ratio varied across MTHFR genotypes (p ≤ 0.0001) and was lower in subgroups carrying the most impaired enzyme with respect to patients carrying the conservative MTHFR (p ≤ 0.0001, p ≤ 0.05, respectively). Consistently, OS patients carried the most dysfunctional MTHFR genotypes, whereas SI patients the least ones. Conclusions: A low L-Arg/ADMA ratio correlates with impaired activity of MTHFR and with the jeopardized IAS phenotype along a severity spectrum encompassing OS, PFO with long/tight tunnel, PFO with short/large tunnel, and SI. This infers that genetic MTHFR defects may underlie endothelial dysfunction-related IAS abnormalities, and predispose to a cryptogenic stroke. Our findings emphasize the role of the L-Arg/ADMA ratio as a reliable marker of stroke susceptibility in carriers of IAS abnormalities, and suggest its potential use both as a diagnostic tool and as a decision aid for therapy.
Highlights
The search for causes and mechanisms underlying strokes is important in young patients, where the absence of significant small- and large-vessel disease, and/or dissection accounts for the higher number of strokes diagnosed as cryptogenic [1]
We evaluated the potential correlation between the severity of methylene tetrahydrofolate reductase (MTHFR) mutation, the degree of endothelial dysfunction, and the interatrial septum (IAS) phenotype in patients diagnosed with Embolic Stroke of Undetemined Source (ESUS).If confirmed, this hypothesis might help to legitimize L-Arg/asymmetric dimethylarginine (ADMA) as a marker of endothelial dysfunction
Laboratory, and clinical characteristics of subjects are shown according to their IAS phenotype (Table 1) or MTHFR genotype (Table 2)
Summary
The search for causes and mechanisms underlying strokes is important in young patients, where the absence of significant small- and large-vessel disease, and/or dissection accounts for the higher number of strokes diagnosed as cryptogenic [1]. Echocardiographic assessment of PFO interatrial tunnel length has produced conflicting results as well, initially suggesting a greater risk to cryptogenic stroke in patients with larger defects [10], and recently re-evaluating such a statement on the basis of RoPE database analysis [11]. The correlative risk of embolism and stroke based on interatrial shunt extent has generated inconclusive, if not controversial, indications [12,13]. In this scenario of diagnostic and therapeutic uncertainty, additional evidence for risk stratification is highly pursued, and the search for potential biomarkers is strongly encouraged
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
