Transcriptome analysis reveals key pathways that vary in patients with paroxysmal and persistent atrial fibrillation.
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ABSTRACT:
SUBMITTER: Sun H
PROVIDER: S-EPMC8027719 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Atrial fibrillation (AF) is the most common cardiac arrhytmia, characterized by the chaotic motion of electrical wavefronts in the atria. In clinical practice, AF is classified under two primary categories: paroxysmal AF, short intermittent episodes separated by periods of normal electrical activity; and persistent AF, longer uninterrupted episodes of chaotic electrical activity. However, the precise reasons why AF in a given patient is paroxysmal or persistent is poorly understood. Recently, we have introduced the percolation-based Christensen-Manani-Peters (CMP) model of AF which naturally exhibits both paroxysmal and persistent AF, but precisely how these differences emerge in the model is unclear. In this paper, we dissect the CMP model to identify the cause of these different AF classifications. Starting from a mean-field model where we describe AF as a simple birth-death process, we add layers of complexity to the model and show that persistent AF arises from reentrant circuits which exhibit an asymmetry in their probability of activation relative to deactivation. As a result, different simulations generated at identical model parameters can exhibit fibrillatory episodes spanning several orders of magnitude from a few seconds to months. These findings demonstrate that diverse, complex fibrillatory dynamics can emerge from very simple dynamics in models of AF.
| S-EPMC7326608 | biostudies-literature
Project description:BackgroundRanolazine inhibits Na+ current (INa), but whether it can convert atrial fibrillation (AF) to sinus rhythm remains unclear. We investigated antiarrhythmic mechanisms of ranolazine in sheep models of paroxysmal (PxAF) and persistent AF (PsAF).MethodsPxAF was maintained during acute stretch (N=8), and PsAF was induced by long-term atrial tachypacing (N=9). Isolated, Langendorff-perfused sheep hearts were optically mapped.ResultsIn PxAF ranolazine (10 μmol/L) reduced dominant frequency from 8.3±0.4 to 6.2±0.5 Hz (P<0.01) before converting to sinus rhythm, decreased singularity point density from 0.070±0.007 to 0.039±0.005 cm-2 s-1 (P<0.001) in left atrial epicardium (LAepi), and prolonged AF cycle length (AFCL); rotor duration, tip trajectory, and variance of AFCL were unaltered. In PsAF, ranolazine reduced dominant frequency (8.3±0.5 to 6.5±0.4 Hz; P<0.01), prolonged AFCL, increased the variance of AFCL, had no effect on singularity point density (0.048±0.011 to 0.042±0.016 cm-2 s-1; P=ns) and failed to convert AF to sinus rhythm. Doubling the ranolazine concentration (20 μmol/L) or supplementing with dofetilide (1 μmol/L) failed to convert PsAF to sinus rhythm. In computer simulations of rotors, reducing INa decreased dominant frequency, increased tip meandering and produced vortex shedding on wave interaction with unexcitable regions.ConclusionsPxAF and PsAF respond differently to ranolazine. Cardioversion in the former can be attributed partly to decreased dominant frequency and singularity point density, and prolongation of AFCL. In the latter, increased dispersion of AFCL and likely vortex shedding contributes to rotor formation, compensating for any rotor loss, and may underlie the inefficacy of ranolazine to terminate PsAF.
| S-EPMC6788778 | biostudies-literature
Project description:BackgroundAblation reduces atrial fibrillation (AF) burden and improves health-related quality of life. The relationship between ablation, healthcare utilization, and AF type (paroxysmal AF [PAF] vs persistent AF [PsAF]) remains unclear.ObjectiveTo compare changes in AF-related healthcare utilization and costs from preablation to postablation among patients with PAF and PsAF.MethodsPatients (2794 PAF, 1909 PsAF) undergoing ablation (2016-2018) were identified using the Optum database. Outcomes included inpatient admissions, emergency department (ED) visits, office visits, cardioversion, and antiarrhythmic drug (AAD) use. Costs (2018 US$) and outcomes were compared for the year before/after ablation using the McNemar test and Wilcoxon signed rank test.ResultsCompared to PAF patients, PsAF patients were older (68.6 ± 9.0 years vs 67.4 ± 9.9 years, P < .0001), were less commonly female (36.3% vs 44.1%, P < .0001), and more commonly had a CHA2DS2-VASc ≥ 3(71.2% vs 62.7%, P < .0001). The 12-month postablation costs were lower for AF-specific inpatient admissions (PAF -28%, PsAF -33%), ED visits (PAF -76%, PsAF -70%), AAD prescription fills (PAF -25%, PsAF -7%), and cardioversions (PAF -59%, PsAF -55%) as compared to 12 months before ablation. Although these reductions were observed for both PAF and PsAF patients, absolute costs remained higher for PsAF. Total AF costs were higher during the 1 year after ablation vs before ablation (PAF: 11%, P < .0001; PsAF: 10%, P < .0001) owing to repeat ablation. However, in the 18-month follow-up analysis, postablation costs were overall reduced (PAF: 35%, P < .0001; PsAF: 34%, P < .0001), despite including costs from repeat ablation.ConclusionSignificant reductions in healthcare utilization and costs were observed among PAF and PsAF patients undergoing ablation. These data suggest a strategy of earlier ablation may reduce long-term healthcare utilization and costs.
| S-EPMC8183841 | biostudies-literature
Project description:ObjectiveThis study aimed to investigate the functions of mRNA, long non-coding RNA (lncRNA), and circular RNA (circRNA) in paroxysmal and persistent atrial fibrillation (AF) patients.MethodsA total of 9 left atrial appendage (LAA) tissues were collected from patients with AF (ParoAF patients = 3 and PersAF patients = 3) and donors (n=3). Genes and circRNAs were identified by per kilobase per million reads (RPKM) and number of circular reads/number of mapped reads/read length (SRPBM), respectively. Differentially expressed mRNAs (DE mRNAs), lncRNAs (DE lncRNAs), and circRNAs (DE circRNAs) were identified by | log2 (Fold Change) | ≥ 2 and p-value < 0.05. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Protein-protein, mRNA-lncRNA, and circRNA-miRNA interaction networks were constructed. In addition, logistic analysis was conducted among AF and circRNAs.ResultsA total of 285 (116 up-regulated and 169 down-regulated) and 275 (110 up-regulated and 165 down-regulated) DE mRNAs, 575 (276 up-regulated and 299 down-regulated) and 583 (330 up-regulated and 253 down-regulated) DE lncRNAs, and 83 (48 up-regulated and 35 down-regulated) and 99 (58 up-regulated and 41 down-regulated) circRNAs were detected in ParoAF and PersAF, respectively, as compared with control. MAPK signal pathway as well as voltage-dependent, L type, and alpha 1C subunit calcium channel (CACNA1C) might participate in AF occurrence by preventing atrial parasympathetic remodeling. Collagen type I alpha 1 (COL1A1) and COL1A2 mostly participated in the enriched GO and KEGG terms and connected with most of the DE mRNAs. The expression of chr10: 69902697|69948883 was a protective factor against PersAF after adjusting for age (p=0.022, 95% CI: 0.003-0.634).ConclusionWe found that some mRNAs, lncRNAs, circRNAs, and pathways play essential roles in AF pathogenesis and development. Moreover, one protective factor against PersAF was detected.
| S-EPMC8210924 | biostudies-literature
Project description:Understanding the interconnectedness of structural remodelling processes atrial fibrillation (AF) in patients could identify targets for future therapies. These data include transcriptome sequencing of atrial tissues of patients without AF, with paroxysmal AF and persistent AF (total n=64). In AF patients, epicardial cell gene expression decreased, contrasting with an upregulation of epithelial to mesenchymal transition (EMT) and mesenchymal cell gene expression. Immunohistochemistry demonstrated thickening of the epicardium and an increased proportion of (myo)fibroblast-like cells in the myocardium, supporting enhanced EMT in AF. We furthermore report an upregulation of endothelial cell proliferation, angiogenesis and endothelial signalling. EMT and endothelial cell proliferation concurred with increased interstitial (myo)fibroblast-like cells and extracellular matrix gene expression including enhanced tenascin-c, thrombospondins, biglycan and versican. Morphological analysis discovered increased and redistributed glycosaminoglycans and collagens in the atria of AF patients. Signalling pathways, including cell-matrix interactions, PI3K-AKT and Notch signalling, that could regulate mesenchymal cell activation, were upregulated. These dynamic processes may provide targets to prevent or reverse structural remodelling.
| EGAS00001005295 | EGA
Project description:MiRNAs regulate posttranscriptional gene expression and are widely implicated in the pathogenesis of complex diseases. We aim to elucidate miRNA regulation of the atrial mRNA signatures that associate with AF. This may provide novel mechanistical insights and candidate targets for therapies using miRNA mimics or antimiRs.
We present combined miRNAs-mRNAs sequencing in atrial tissues of patient without AF (n=22), with paroxysmal AF (n=22) and with persistent AF (n=20). MiRNA and mRNA signatures followed an ordinal scale from nonAF to paroxysmal to persistent AF patients. The previously reported mRNA sequencing identified 5228 differentially expressed genes involved in epithelial to mesenchymal transition, endothelial cell proliferation and extracellular matrix remodelling involving collagens, glycoproteins and proteoglycans. We discovered 103 differentially expressed miRNAs. Key downregulated miRNAs included miR-135b-5p, miR-138-5p, miR-200a-3p, miR-200b-3p and miR-31-5p and key upregulated miRNAs were miR-144-3p, miR-15b-3p, miR-182-5p miR-18b-5p, miR-4306 and miR-206. The expression levels of differentially expressed miRNAs were negatively correlated with the expression levels of their predicted target mRNAs. The downregulated miRNAs demonstrated a more profound transcriptome effect than the upregulated miRNAs. Upregulated biological processes enriched in miRNAs targets related to epithelial and endothelial cell migration and glycosaminoglycan biosynthesis, in line with the processes discovered by the mRNA sequencing analysis.
Combined analysis of miRNA and mRNA sequencing uncovered miRNAs with a broad transcriptional effect in human AF. Epithelial to mesenchymal transition and endothelial cell proliferation were processes controlled by downregulated miR-135b-5p, miR-138-5p, miR-200a-3p, miR-200b-3p and miR-31-5p, which in turn may contribute to (myo)fibroblast activation and structural remodeling.\
| EGAS00001005296 | EGA
Project description:AimsTo evaluate the effectiveness and safety of cryoballoon ablation (CBA) compared with radiofrequency ablation (RFA) for symptomatic paroxysmal or drug-refractory persistent atrial fibrillation (AF).Methods and resultsProspective cluster cohort study in experienced CBA and RFA centres. Primary endpoint was 'atrial arrhythmia recurrence', secondary endpoints were as follows: procedural results, safety, and clinical course. A total of 4189 patients were included: CBA 2329 (55.6%) and RFA 1860 (44.4%). Cryoballoon ablation population was younger, with fewer comorbidities. Procedure time was longer in the RFA group (P = 0.01). Radiation exposure was 2487 (CBA) and 1792 cGycm2 (RFA) (P < 0.001). Follow-up duration was 441 (CBA) and 511 days (RFA) (P < 0.0001). Primary endpoint occurred in 30.7% (CBA) and 39.4% patients (RFA) [adjusted hazard ratio (adjHR) 0.85, 95% confidence interval (CI) 0.70-1.04; P = 0.12). In paroxysmal AF, CBA resulted in a lower risk of recurrence (adjHR 0.80, 95% CI 0.64-0.99; P = 0.047). In persistent AF, the primary outcome was not different between groups. Major adverse cardiovascular and cerebrovascular event rates were 1.0% (CBA) and 2.8% (RFA) (adjHR 0.53, 95% CI 0.26-1.10; P = 0.088). Re-ablations (adjHR 0.46, 95% CI 0.34-0.61; P < 0.0001) and adverse events during follow-up (adjHR 0.64, 95% CI 0.48-0.88; P = 0.005) were less common after CBA. Higher rehospitalization rates with RFA were caused by re-ablations.ConclusionsThe primary endpoint did not differ between CBA and RFA. Cryoballoon ablation was completed rapidly; the radiation exposure was greater. Rehospitalization due to re-ablations and adverse events during follow-up were observed significantly less frequently after CBA than after RFA. Subgroup analysis suggested a lower risk of recurrence after CBA in paroxysmal AF.Trial registrationClinicalTrials.gov (NCT01360008), https://clinicaltrials.gov/ct2/show/NCT01360008.
| S-EPMC6735953 | biostudies-literature
Project description:Complex fractionated atrial electrograms (CFAEs) may represent a phenomenon associated with sources of atrial fibrillation (AF) and are being used increasingly as targets of catheter ablation. However, current methods have limited efficacy for characterizing CFAEs important to substrate arrhythmogenicity and do not measure electrogram morphology.The purpose of this study was to develop a methodology for quantifying the degree of morphologic heterogeneity in CFAE deflections, and to determine whether there are differences in this measurement between paroxysmal and persistent AF patients.Two successive bipolar CFAEs of length 8.4 seconds each were acquired during AF from two sites each at the ostia of the four pulmonary veins (PVs) and from the anterior and posterior left atrial free wall in patients with paroxysmal AF (N = 10) and long-standing persistent AF (N = 10). Extrinsic and intrinsic features of electrogram shape were used to characterize fractionation in CFAE sequences. The extrinsic parameters were the amplitude, upslope, downslope, and width of each deflection. The intrinsic parameter was the voltage profile as characterized by the sum of absolute values. These measurements were compared to the mean interval between CFAE deflections, a standard fractionation indicator.The variability of intrinsic/extrinsic morphologic parameters was higher in paroxysmal than persistent AF at the left superior PV (P < or =.003), the posterior left atrial free wall, anterior left atrial free wall, left inferior PV, and right superior PV (P <.05 for most parameters), and the right inferior PV (not significant). Mean CFAE deflection intervals were longer at all locations in paroxysmal AF but were significant only at the left superior PV and posterior left atrial free wall (P <.05). Quantitative morphologic parameters were not well correlated with dominant frequency (r(2) <0.32); thus, our new measures are robust to changes in activation rate.A novel method for quantifying CFAEs, independent of activation rate, has been developed. The method demonstrates greater significance in the difference between CFAE morphology in paroxysmal and long-standing AF compared with mean interval between CFAE deflections. The differences identified suggest that CFAE morphology may evolve as AF persists.
| S-EPMC4287370 | biostudies-literature
Project description:BackgroundIn patients with paroxysmal atrial fibrillation (PAF) or persistent atrial fibrillation (PeAF) symptom burden and fear of hospital readmission are major causes of reduced quality of life. We attempted to develop a prediction model for future atrial fibrillation hospitalization (AFH) risk in PAF and PeAF patients including all previously experienced AFHs in the analysis, as opposed to time to first event.MethodsRecurrent event survival analysis was used to model the impact of past AFHs on the risk of future AFHs. A recurrent event was defined as a hospitalization due to a new episode of AF. Death or progression to permanent AF were included as competing risks.ResultsWe enrolled 174 patients with PAF or PeAF, mean follow up duration was 1279 days, and 325 AFHs were observed. Median patient age was 63.0 (IQR 52.2-68.0), 29% had PAF, and 71% were male. Highly significant predictors of future AFH risk were PeAF (HR 3.20, CI 2.01-5.11) and number of past AFHs observed (HR for 1 event: 2.97, CI 2.04-4.32, HR for ≥2 events: 7.54, CI 5.47-10.40).ConclusionIn PAF and PeAF patients, AF type and observed AFH frequency are highly significant predictors of future AFH risk. The developed model enables risk prediction in individual patients based on AFH history and baseline characteristics, utilizing all events experienced by the patient. This is the first time recurrent event survival analysis has been used in AF patients.
| S-EPMC6555511 | biostudies-literature
Project description:Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent.Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (CaV1.2, NaV1.5, and KV4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up.In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.
| S-EPMC3981906 | biostudies-literature