{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:39:06Z","timestamp":1792157946976,"version":"4.4.0"},"reference-count":58,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T00:00:00Z","timestamp":1591228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005362","name":"Universita degli Studi di Bari Aldo Moro","doi-asserted-by":"publisher","award":["CUP H96J15001610005 to M.M."],"award-info":[{"award-number":["CUP H96J15001610005 to M.M."]}],"id":[{"id":"10.13039\/501100005362","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005362","name":"Universita degli Studi di Bari Aldo Moro","doi-asserted-by":"publisher","award":["UPB:DIMO 102200201 to C.N."],"award-info":[{"award-number":["UPB:DIMO 102200201 to C.N."]}],"id":[{"id":"10.13039\/501100005362","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>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 \u2264 0.01), and was higher in SI than in PFO or OS patients (p \u2264 0.05, p \u2264 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 \u2264 0.05; r = \u2212 0.37; R2 = 0.14). Interestingly, the L-Arg\/ADMA ratio varied across MTHFR genotypes (p \u2264 0.0001) and was lower in subgroups carrying the most impaired enzyme with respect to patients carrying the conservative MTHFR (p \u2264 0.0001, p \u2264 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.<\/jats:p>","DOI":"10.3390\/biom10060861","type":"journal-article","created":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T03:32:21Z","timestamp":1591327941000},"page":"861","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Endothelial Dysfunction May Link Interatrial Septal Abnormalities and MTHFR-Inherited Defects to Cryptogenic Stroke Predisposition"],"prefix":"10.3390","volume":"10","author":[{"given":"Luca","family":"Sgarra","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology\u2014Section of Pharmacology, Medical School, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro Santo","family":"Bortone","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation\u2014Section of Cardiovascular Diseases, Medical School, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Assunta","family":"Potenza","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology\u2014Section of Pharmacology, Medical School, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Nacci","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology\u2014Section of Pharmacology, Medical School, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Antonietta","family":"De Salvia","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology\u2014Section of Pharmacology, Medical School, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Acquaviva","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation\u2014Section of Cardiovascular Diseases, Medical School, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"De Cillis","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation\u2014Section of Cardiovascular Diseases, Medical School, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco Matteo","family":"Ciccone","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation\u2014Section of Cardiovascular Diseases, Medical School, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Grimaldi","sequence":"additional","affiliation":[{"name":"General Hospital \u201cF. Miulli\u201d Acquaviva delle Fonti, 70021 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Montagnani","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology\u2014Section of Pharmacology, Medical School, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1161\/01.STR.0000079818.08343.8C","article-title":"Differences in Vascular Risk Factors between Etiological Subtypes of Ischemic Stroke","volume":"34","author":"Schulz","year":"2003","journal-title":"Stroke"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1161\/CIRCULATIONAHA.106.627224","article-title":"Congenital heart disease in the general population: Changing prevalence and age distribution","volume":"115","author":"Marelli","year":"2007","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1161\/CIRCULATIONAHA.104.524371","article-title":"Patent foramen ovale and stroke","volume":"112","author":"Homma","year":"2005","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1056\/NEJMoa1009639","article-title":"Closure or Medical Therapy for Cryptogenic Stroke with Patent Foramen Ovale","volume":"366","author":"Furlan","year":"2012","journal-title":"N. 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