Project description:Catheter ablation is an effective treatment to prevent recurrence of Atrial fibrillation (AF) and can be used to maintain sinus rhythm and improve symptoms of AF, but to some extent it can cause a range of adverse effects associated with catheter ablation. Pulsed electric field is a newer treatment modality to replace catheter ablation for atrial fibrillation due to its fewer side effects. Different from radiofrequency ablation, which destroys diseased myocardial tissue by thermal energy, pulsed electric field ablation achieves the purpose of atrial fibrillation ablation by inducing damage to diseased myocardial cells through irreversible electroporation. However, some experimental parameters and mechanism of pulsed electric fields remain unclear.
Project description:Our study aims to elucidate the role of lncRNA-mRNA regulatory networks in AF recurrence after catheter ablation. We performed RNA sequencing to profile the transcriptomes of 5 samples from atrial fibrillation recurrence and 5 samples from sinus rhythm maintenance. 96 differentially expressed genes (DEGs) and 203 differentially expressed long non-coding RNAs (DE-lncRNAs) were identified between atrial fibrillation recurrence group and sinus rhythm maintenance group. Gene Ontology (GO) analysis showed that DEGs were enriched in “regulation of immune response”, and “regulation of immune system process” for biological processes (BP), enriched in “extracellular matrix”, “cell-cell junction” for cellular components (CC), and enriched in “signaling adaptor activity”, “protein-macromolecule adaptor activity” for molecular functions (MF). For KEGG analysis, DEGs are associated with “PI3K-Akt signaling pathway”, “MAPK signaling pathway”. 9 hub genes (MMP9, IGF2, FGFR1, HSPG2, GZMB, PEG10, GNLY, COL6A1, and KCNE3) were identified through the Protein-Protein Interaction network. LncRNA-TMEM51-AS1-201 was identified as a core regulator and may impact AF recurrence after catheter ablation by regulating “COL6A1, FGFR1, HSPG2, and IGF2.”
Project description:Background: Genomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess whether this association is relevant for recurrent AF in patients, we tested whether left atrial PITX2 affects recurrent AF after AF ablation. Methods: mRNA concentrations of PITX2 and its cardiac isoform, PITX2c, were quantified in left atrial appendages (LAA) from patients undergoing thoracoscopic AF ablation, either in whole LAA tissue (n=83) or in LAA cardiomyocytes (n=52), and combined with clinical parameters to predict AF recurrence. Literature suggests bone morphogenetic protein 10 (BMP10) as a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with eleven cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients. Results: Reduced cardiomyocyte PITX2 concentrations, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2-(ΔΔCt) increase in PITX2). RNA sequencing, qPCR and Western blotting confirmed BMP10 as one of most PITX2-repressed atrial genes. Left atrial size (hazard ratio per mm increase, HR [95%CI] 1.055 [1.028, 1.082], non-paroxysmal AF (HR 1.672 [1.206, 2.318]) and elevated BMP10 (HR 1.339 [CI 1.159, 1.546] per quartile increase) were predictive of recurrent AF. BMP10 outperformed eleven other cardiovascular biomarkers in predicting recurrent AF. Conclusions: Reduced left atrial cardiomyocyte PITX2 and elevated plasma concentrations of the PITX2-repressed, secreted, atrial protein BMP10 identify patients at risk of recurrent AF after ablation.
Project description:This study will report the incidence of atrial fibrillation after elective colorectal cancer resection in the over 65 age group. This will be used to validate a risk model for the development of post-operative atrial fibrillation.
Eligible patients will undergo electrocardiogram based screening for atrial fibrillation, as well as brain natriuretic peptide tests prior to surgery. They will undergo 24 hour holter monitor prior to surgery, and at 30 and 90 days following surgery.
The primary outcome will be occurrence of atrial fibrillation within 90 days of surgery. Secondary outcomes include quality of life change, use of hospital services for atrial fibrillation, and complications of atrial fibrillation. This will be used to validate the pre-existing model for prediction of atrial fibrillation.
Project description:Pitx2 is the homeobox gene located in proximity to the human 4q25 familial atrial fibrillation locus. Pitx2 haploinsufficient mice are prone to pacing induced atrial fibrillation indicating that reduced Pitx2 promotes an arrhythmogenic substrate within the atrium. Here, we inactivated Pitx2 in postnatal heart and discovered that unstressed adult Pitx2 mutant mice had sinus node dysfunction with impaired atrial conduction, an arrhythmia closely associated with atrial fibrillation. A genome-wide search for Pitx2 transcriptional targets using ChIP-sequencing and RNA expression profiling shows that Pitx2 represses target genes encoding cell junction proteins, ion channels, and critical transcriptional regulators many of which have been implicated in human atrial fibrillation by genome wide association studies. Our findings unveil a Pitx2 postnatal arrhythmogenic function, novel Pitx2 target genes relevant to atrial fibrillation, and reveal that Pitx2 stabilizes the intercalated disc in postnatal atrium. Genomic occupancy profiling of transcriptional factor Pitx2 in postnatal heart.
Project description:Spontaneous paroxysmal atrial fibrillation (PAF) is one of the very common heart rhythm disorders. The molecular mechanisms underlying PAF susceptibility and persistence are multiple and incompletely understood. To study the contribution of microRNAs (miRNAs) to the development and perpetuation of PAF, we used microarray/qPCR analyses to search for changes in miRNA expression in atrial myocardium upon pacing-induced PAF. The miRNA microarray analysis was performed at LC Sciences (Houston, TX, USA). Following screening-microarray, several miRNAs were selected for detailed real-time qPCR assay. Our results suggest that immediate-early miR remodeling of LAA underlies the development and persistence of PAF. A closed-chest model of PAF was established in postnatal pigs via a rapid atrial electrical stimulation with a controlled ventricular response rate. A pacing catheter (delivered into the right atrium via femoral vein access under fluoroscopic guidance) was connected with an external pulse generator for programmed pacing rates. The burst-pacing stimuli were repeated several times, and the induced PAF occurrence rates and durations were recorded. Burst pacing was not performed in sham-operated group. Animals were euthanized 24 hours after cessation of pacing. Given that the right atrium might have been damaged by catheter insertion, we studied miRNA expression changes associated with PAF in the left atrial appendage (LAA) from paced vs control pigs. Six piglet were randomized in two groups, the PAF group (3 replicates) and the sham-control group (3 replicates)
Project description:Atrial fibrillation (AF), which causes cardiogenic cerebral infarction, is the most common type of persistent arrhythmia, and its incidence increases with age. We performed a radial procedure using an RF ablation device to restore sinus rhythm (SR).
Project description:Pitx2 is the homeobox gene located in proximity to the human 4q25 familial atrial fibrillation locus. Pitx2 haploinsufficient mice are prone to pacing induced atrial fibrillation indicating that reduced Pitx2 promotes an arrhythmogenic substrate within the atrium. Here, we inactivated Pitx2 in postnatal heart and discovered that unstressed adult Pitx2 mutant mice had sinus node dysfunction with impaired atrial conduction, an arrhythmia closely associated with atrial fibrillation. A genome-wide search for Pitx2 transcriptional targets using ChIP-sequencing and RNA expression profiling shows that Pitx2 represses target genes encoding cell junction proteins, ion channels, and critical transcriptional regulators many of which have been implicated in human atrial fibrillation by genome wide association studies. Pitx2 control and mutant hearts were collected from 3-, 6- and 12-week-old mice. At each time point, three cotrols and three mutants were collected as biological replicates. cDNA microarray analysis was performed using Affymetrix GeneChip Mouse Genome 430 2.0 Array (Affymetrix, Santa Clara, CA).