Endothelial Dysfunction May Link Interatrial Septal Abnormalities and MTHFR-Inherited Defects to Cryptogenic Stroke Predisposition

Sgarra, Luca; Bortone, Alessandro Santo; Potenza, Maria Assunta; Nacci, Carmela; Salvia, Maria Antonietta De; Acquaviva, Tommaso; Cillis, Emanuela De; Ciccone, Marco Matteo; Grimaldi, Massimo; Montagnani, Monica

doi:10.3390/biom10060861

Cited by 5 publications

(5 citation statements)

References 58 publications

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“…Dimethylarginines, including asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are endogenous methylated analogues of L-arg, the precursor of NO. By competing with L-arg, ADMA can inhibit eNOS and contribute to impaired endothelial-mediated activities, oxidative stress, and inflammation in cardiovascular diseases [ 68 , 69 , 70 ]. SDMA does not inhibit eNOS directly but could interfere with the cellular uptake of L-arg, resulting in similar NO-impaired production.…”

Section: Molecular and Cellular Mechanisms Linking Atrial Remodeling ...mentioning

confidence: 99%

microRNAs as Biomarkers of Endothelial Dysfunction and Therapeutic Target in the Pathogenesis of Atrial Fibrillation

Desantis

Potenza

Sgarra

et al. 2023

IJMS

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The pathophysiology of atrial fibrillation (AF) may involve atrial fibrosis/remodeling and dysfunctional endothelial activities. Despite the currently available treatment approaches, the progression of AF, its recurrence rate, and the high mortality risk of related complications underlay the need for more advanced prognostic and therapeutic strategies. There is increasing attention on the molecular mechanisms controlling AF onset and progression points to the complex cell to cell interplay that triggers fibroblasts, immune cells and myofibroblasts, enhancing atrial fibrosis. In this scenario, endothelial cell dysfunction (ED) might play an unexpected but significant role. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level. In the cardiovascular compartment, both free circulating and exosomal miRNAs entail the control of plaque formation, lipid metabolism, inflammation and angiogenesis, cardiomyocyte growth and contractility, and even the maintenance of cardiac rhythm. Abnormal miRNAs levels may indicate the activation state of circulating cells, and thus represent a specific read-out of cardiac tissue changes. Although several unresolved questions still limit their clinical use, the ease of accessibility in biofluids and their prognostic and diagnostic properties make them novel and attractive biomarker candidates in AF. This article summarizes the most recent features of AF associated with miRNAs and relates them to potentially underlying mechanisms.

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Section: Molecular and Cellular Mechanisms Linking Atrial Remodeling ...mentioning

confidence: 99%

microRNAs as Biomarkers of Endothelial Dysfunction and Therapeutic Target in the Pathogenesis of Atrial Fibrillation

Desantis

Potenza

Sgarra

et al. 2023

IJMS

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“…Nevertheless, recent studies have described additional factors that may contribute to the occurrence of PFO-associated cerebrovascular disease. Notably, patients with PFO have been found to exhibit endothelial dysfunction as evidenced by alterations in the L-arginine/ADMA ratio ( 18 ), reduced fibrinolytic activity ( 19 ), but also increased levels of total circulating homocysteine serum levels ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

PFO-spectrum disorder: two different cerebrovascular diseases in patients with PFO as detected by AI brain imaging software

Badea,

Mihăilă-Bâldea,

Ribigan

et al. 2024

Front. Neurol.

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BackgroundPatent foramen ovale (PFO) is a prevalent cardiac remnant of fetal anatomy that may pose a risk factor for stroke in some patients, while others can present with asymptomatic white matter (WM) lesions. The current study aimed to test the hypothesis that patients with a PFO who have a history of stroke or transient ischemic attack, compared to those without such a history, have a different burden and distribution of cerebral WM hyperintensities. Additionally, we tested the association between PFO morphological characteristics and severity of shunt, and their impact on the occurrence of ischemic cerebral vascular events and on the burden of cerebral WM lesions.Patients and methodsRetrospective, case–control study that included patients with PFO confirmed by transesophageal echocardiography. Right-to-left shunt size was assessed using transcranial Doppler ultrasound. Cerebral MRIs were analyzed for all participants using the semi-automated Quantib NDTM software for the objective quantification of WM lesions. WM lesions volume was compared between patients with and without a history of stroke. Additionally, the anatomical characteristics of PFOs were assessed to explore their relation to stroke occurrence and WM lesions volume.ResultsOf the initial 264 patients diagnosed with PFO, 67 met the inclusion criteria and were included in the analysis. Of them, 62% had a history of PFO-related stroke/TIA. Overall burden of WM lesions, including stroke volume, was not significantly different (p = 0.103). However, after excluding stroke volume, WM lesions volume was significantly higher in patients without stroke (0.27 cm3, IQR 0.03–0.60) compared to those with stroke/TIA (0.08 cm3, IQR 0.02–0.18), p = 0.019. Patients with a history of PFO-related stroke/TIA had a tendency to larger PFO sizes by comparison to those without, in terms of length and height, and exhibited greater right-to-left shunt volumes.DiscussionWe suggest that PFO may be associated with the development of two distinct cerebrovascular conditions (stroke and “silent” WM lesions), each characterized by unique imaging patterns. Further studies are needed to identify better the “at-risk” PFOs and gain deeper insights into their clinical implications.

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“…Sgarra et al evaluated the correlation, in terms of severity, between the degree of endothelial dysfunction assessed by the L-Arginine/asymmetric dimethylarginine ratio (L-Arg/ADMA ratio), the methylene tetrahydrofolate reductase (MTHFR) genotype, and the interatrial septum (IAS) phenotype in subject with a history of stroke [ 43 ]. L-arginine is the substrate for NO generation and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase.…”

Section: Patent Foramen Ovalementioning

confidence: 99%

“…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; R 2 = 0.14). The authors suggest that the L-Arg/ADMA ratio could be used as a reliable marker of stroke susceptibility in carriers of an interatrial septum abnormalities, hinting at its potential use both as a diagnostic tool and as a decision aid for therapy [ 43 ].…”

Section: Patent Foramen Ovalementioning

confidence: 99%

Update on Biomarkers Associated to Cardioembolic Stroke: A Narrative Review

Fonseca

Coelho

2021

Life

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Background: In the last years, several studies were conducted that evaluated biomarkers that could be helpful for cardioembolic stroke diagnosis, prognosis, and the determination of risk of stroke recurrence. Methods: We performed a narrative review of the main studies that evaluated biomarkers related to specific cardioembolic causes: atrial fibrillation, patent foramen ovale, atrial cardiomyopathy, and left ventricular wall motion abnormalities. Results: BNP and NT-proBNP are, among all biomarkers of cardioembolic stroke, the ones that have the highest amount of evidence for their use. NT-proBNP is currently used for the selection of patients that will be included in clinical trials that aim to evaluate the use of anticoagulation in patients suspected of having a cardioembolic stroke and for the selection of patients to undergo cardiac monitoring. NT-proBNP has also been incorporated in tools used to predict the risk of stroke recurrence (ABC-stroke score). Conclusions: NT-proBNP and BNP continue to be the biomarkers most widely studied in the context of cardioembolic stroke. The possibility of using other biomarkers in clinical practice is still distant, mainly because of the low methodological quality of the studies in which they were evaluated. Both internal and external validation studies are rarely performed for most biomarkers.

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Endothelial Dysfunction May Link Interatrial Septal Abnormalities and MTHFR-Inherited Defects to Cryptogenic Stroke Predisposition

Cited by 5 publications

References 58 publications

microRNAs as Biomarkers of Endothelial Dysfunction and Therapeutic Target in the Pathogenesis of Atrial Fibrillation

microRNAs as Biomarkers of Endothelial Dysfunction and Therapeutic Target in the Pathogenesis of Atrial Fibrillation

PFO-spectrum disorder: two different cerebrovascular diseases in patients with PFO as detected by AI brain imaging software

Update on Biomarkers Associated to Cardioembolic Stroke: A Narrative Review

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