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Publications

Genomic risk scores, biomolecules, and clinical conditions to predict atrial fibrillation: time to integrate what we can measure
Kääb S, Holm H and Kirchhof P
Characterisation of patients referred to a tertiary-level inherited cardiac condition clinic with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC)
Aljehani A, Kew T, Baig S, Cox H, Sommerfeld LC, Ensam B, Kalla M, Steeds RP and Fabritz L
Arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy is a rare inherited disease with incomplete penetrance and an environmental component. Although a rare disease, ARVC is a common cause of sudden cardiac death in young adults. Data on the different stages of ARVC remains scarce. The purpose of this study is to describe the initial presentation and cardiac phenotype of definite and non-definite ARVC for patients seen at a tertiary service.
Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide
O'Reilly M, Sommerfeld LC, O'Shea C, Broadway-Stringer S, Andaleeb S, Reyat JS, Kabir SN, Stastny D, Malinova A, Delbue D, Fortmueller L, Gehmlich K, Pavlovic D, Skryabin BV, Holmes AP, Kirchhof P and Fabritz L
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients.
Role of microbiota and microbiota-derived short-chain fatty acids in PDAC
Temel HY, Kaymak Ö, Kaplan S, Bahcivanci B, Gkoutos GV and Acharjee A
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive lethal diseases among other cancer types. Gut microbiome and its metabolic regulation play a crucial role in PDAC. Metabolic regulation in the gut is a complex process that involves microbiome and microbiome-derived short-chain fatty acids (SCFAs). SCFAs regulate inflammation, as well as lipid and glucose metabolism, through different pathways. This review aims to summarize recent developments in PDAC in the context of gut and oral microbiota and their associations with short-chain fatty acid (SCFA). In addition to this, we discuss possible therapeutic applications using microbiota in PDAC.
Determinants and therapeutic potential of calcium handling abnormalities in atrial fibrillation: what can we learn from computer models?
Heijman J and Dobrev D
CACONET: a novel classification framework for microbial correlation networks
Xu Y, Nash K, Acharjee A and Gkoutos GV
Existing microbiome-based disease prediction relies on the ability of machine learning methods to differentiate disease from healthy subjects based on the observed taxa abundance across samples. Despite numerous microbes have been implicated as potential biomarkers, challenges remain due to not only the statistical nature of microbiome data but also the lack of understanding of microbial interactions which can be indicative of the disease.
Coagulation Factor Xa Induces Proinflammatory Responses in Cardiac Fibroblasts via Activation of Protease-Activated Receptor-1
D'Alessandro E, Scaf B, Munts C, van Hunnik A, Trevelyan CJ, Verheule S, Spronk HMH, Turner NA, Ten Cate H, Schotten U and van Nieuwenhoven FA
Coagulation factor (F) Xa induces proinflammatory responses through activation of protease-activated receptors (PARs). However, the effect of FXa on cardiac fibroblasts (CFs) and the contribution of PARs in FXa-induced cellular signalling in CF has not been fully characterised. To answer these questions, human and rat CFs were incubated with FXa (or TRAP-14, PAR-1 agonist). Gene expression of pro-fibrotic and proinflammatory markers was determined by qRT-PCR after 4 and 24 h. Gene silencing of (PAR-1) and (PAR-2) was achieved using siRNA. MCP-1 protein levels were measured by ELISA of FXa-conditioned media at 24 h. Cell proliferation was assessed after 24 h of incubation with FXa ± SCH79797 (PAR-1 antagonist). In rat CFs, FXa induced upregulation of (MCP-1; >30-fold at 4 h in atrial and ventricular CF) and (IL-6; ±7-fold at 4 h in ventricular CF). Increased MCP-1 protein levels were detected in FXa-conditioned media at 24 h. In human CF, FXa upregulated the gene expression of (>3-fold) and (>4-fold) at 4 h. Silencing of (PAR-1 gene), but not (PAR-2 gene), downregulated this effect. Selective activation of PAR-1 by TRAP-14 increased and gene expression; this was prevented by (PAR-1 gene) knockdown. Moreover, SCH79797 decreased FXa-induced proliferation after 24 h. In conclusion, our study shows that FXa induces overexpression of proinflammatory genes in human CFs via PAR-1, which was found to be the most abundant PARs isoform in this cell type.
Oxidative stress: a bystander or a causal contributor to atrial remodelling and fibrillation?
Dobrev D and Dudley SC
Remodeling of Ion Channel Trafficking and Cardiac Arrhythmias
Blandin CE, Gravez BJ, Hatem SN and Balse E
Both inherited and acquired cardiac arrhythmias are often associated with the abnormal functional expression of ion channels at the cellular level. The complex machinery that continuously traffics, anchors, organizes, and recycles ion channels at the plasma membrane of a cardiomyocyte appears to be a major source of channel dysfunction during cardiac arrhythmias. This has been well established with the discovery of mutations in the genes encoding several ion channels and ion channel partners during inherited cardiac arrhythmias. Fibrosis, altered myocyte contacts, and post-transcriptional protein changes are common factors that disorganize normal channel trafficking during acquired cardiac arrhythmias. Channel availability, described notably for hERG and K1.5 channels, could be another potent arrhythmogenic mechanism. From this molecular knowledge on cardiac arrhythmias will emerge novel antiarrhythmic strategies.
From translation to integration: how to approach the complexity of atrial fibrillation mechanisms
Schotten U