Integration of “Omics” Strategies for Biomarkers Discovery and for the Elucidation of Molecular Mechanisms Underlying Brugada Syndrome

Scumaci, Domenica; Oliva, Antonio; Concolino, Antonio; Curcio, Antonio; Fiumara, Claudia Vincenza; Tammè, Laura; Campuzano, Òscar; Pascali, Vincenzo Lorenzo; Coll, Mónica; Iglesias, Anna; Berne, Paola; Casu, Gavino; Olivo, Erika; Ausania, Francesco; Ricci, Pietrantonio; Indolfi, Ciro; Brugada, Josép; Brugada, Ramón; Cuda, Giovanni

doi:10.1002/prca.201800065

Cited by 7 publications

(8 citation statements)

References 77 publications

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“…Scumaci et al . 33 studied 179 miRNAs in 13 Brugada patients and 10 control individuals but did not find a molecular signature that was associated with adverse cardiac events. The sample size and number of screened miRNA molecules in their study may account for these differences.…”

Section: Discussionmentioning

confidence: 99%

Leucocyte-derived micro-RNAs as candidate biomarkers in Brugada syndrome

et al. 2023

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Aims Risk stratification for sudden cardiac death in patients with Brugada syndrome remains a major challenge. Contemporary risk prediction models have only modest predictive value. The aim of this study was to assess the role of micro-RNAs from peripheral blood as candidate biomarkers in Brugada syndrome. Methods and results In this prospective study, Brugada patients and unaffected control individuals were enrolled for analysis of leucocyte-derived microRNAs (miRNAs) levels. Expression levels of 798 different circulating miRNAs were analysed on the NanoString® nCounter platform. All results were cross-validated by using a quantitative polymerase chain reaction. Micro-RNA expression levels of Brugada patients were compared with clinical data. A total of 21 definite Brugada patients (38% with a history of ventricular arrhythmia or cardiac arrest) and 30 unaffected control individuals were included in the study. Micro-RNA analysis showed a distinct expression profile in Brugada patients with 42 differentially expressed markers (38 up-regulated, 4 down-regulated miRNAs). The symptom status of Brugada patients was associated with a distinct miRNA signature. Micro-RNAs 145-5p and 585-3p were significantly up-regulated in symptomatic Brugada patients (P = 0.04). Incorporating miRNAs 145-5p and 585-3p into a multivariable model demonstrated significantly increased symptom prediction (area under the curve = 0.96; 95% confidence interval: 0.88–1.00). Conclusion Brugada patients display a distinct miRNA expression profile compared with unaffected control individuals. There is also evidence that certain miRNAs (miR-145-5p and miR-585-3p) are associated with the symptom status of Brugada patients. The results suggest the principal utility of leucocyte-derived miRNAs as prognostic biomarkers for Brugada syndrome.

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Section: Discussionmentioning

confidence: 99%

Leucocyte-derived micro-RNAs as candidate biomarkers in Brugada syndrome

et al. 2023

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“…Indeed, genes associated with BrS, such as SCN5A , have been shown to be expressed throughout the body and could contribute to the occurrence of overlapping pathologies, although solid evidence of a multi-organ or systemic disease is still lacking [ 26 ]. Moreover, observations of altered plasma proteins in BrS patients were not conclusive [ 24 , 25 ], as they could simply reflect cardiac dysfunction [ 27 ]. In this study, we provide decisive evidence that BrS also affects extracardiac tissues, as we found significant alterations in gene expression and protein sialylation in PBMCs of affected patients.…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, the involvement of sialylation in BrS remains unknown. Although alterations in plasma proteins have been reported in BrS patients [ 24 , 25 ], changes in the protein sialylation machinery or other PTMs have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Alterations of the Sialylation Machinery in Brugada Syndrome

Ghiroldi

Ciconte

Creo

et al. 2022

IJMS

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Brugada Syndrome (BrS) is an inherited arrhythmogenic disorder with an increased risk of sudden cardiac death. Recent evidence suggests that BrS should be considered as an oligogenic or polygenic condition. Mutations in genes associated with BrS are found in about one-third of patients and they mainly disrupt the cardiac sodium channel NaV1.5, which is considered the main cause of the disease. However, voltage-gated channel’s activity could be impacted by post-translational modifications such as sialylation, but their role in BrS remains unknown. Thus, we analyzed high risk BrS patients (n = 42) and healthy controls (n = 42) to assess an involvement of sialylation in BrS. Significant alterations in gene expression and protein sialylation were detected in Peripheral Blood Mononuclear Cells (PBMCs) from BrS patients. These changes were significantly associated with the phenotypic expression of the disease, as the size of the arrhythmogenic substrate and the duration of epicardial electrical abnormalities. Moreover, protein desialylation caused a reduction in the sodium current in an in vitro NaV1.5-overexpressing model. Dysregulation of the sialylation machinery provides definitive evidence that BrS affects extracardiac tissues, suggesting an underlying cause of the disease. Moreover, detection of these changes at the systemic level and their correlation with the clinical phenotype hint at the existence of a biomarker signature for BrS.

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“…The importance of non-coding RNAs in the context of Brugada syndrome has been recently explored using an integrative omics approach [388]. These authors identified several microRNAs that are distinctly upregulated in BrS, such as miR-92a-3p and miR-320b, or down-regulated such as miR-425-5p and established their plausible links as molecular determinants of Brugada syndrome, yet functional evidence is missing.…”

Section: Brugada Syndromementioning

confidence: 99%

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

Daimi

Lozano-Velasco

Aránega

et al. 2022

IJMS

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Nav1.5 is the predominant cardiac sodium channel subtype, encoded by the SCN5A gene, which is involved in the initiation and conduction of action potentials throughout the heart. Along its biosynthesis process, Nav1.5 undergoes strict genomic and non-genomic regulatory and quality control steps that allow only newly synthesized channels to reach their final membrane destination and carry out their electrophysiological role. These regulatory pathways are ensured by distinct interacting proteins that accompany the nascent Nav1.5 protein along with different subcellular organelles. Defects on a large number of these pathways have a tremendous impact on Nav1.5 functionality and are thus intimately linked to cardiac arrhythmias. In the present review, we provide current state-of-the-art information on the molecular events that regulate SCN5A/Nav1.5 and the cardiac channelopathies associated with defects in these pathways.

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Integration of “Omics” Strategies for Biomarkers Discovery and for the Elucidation of Molecular Mechanisms Underlying Brugada Syndrome

Abstract: This study provides the basis to shed light on the specific molecular fingerprints underlying BrS development and to gain further insights on the pathogenesis of this life-threatening cardiac disease.

Cited by 7 publications

References 77 publications

Leucocyte-derived micro-RNAs as candidate biomarkers in Brugada syndrome

Leucocyte-derived micro-RNAs as candidate biomarkers in Brugada syndrome

Alterations of the Sialylation Machinery in Brugada Syndrome

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

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