Targeting myocardial inflammation: investigating the therapeutic potential of atrial natriuretic peptide in atrial fibrosis.

BACKGROUND: Atrial Fibrillation (AF), a prevalent arrhythmic condition, is intricately associated with atrial fibrosis, a major pathological contributor. Central to the development of atrial fibrosis is myocardial inflammation. This study focuses on Atrial Natriuretic Peptide (ANP) and its role in mitigating atrial fibrosis, aiming to elucidate the specific mechanisms by which ANP exerts its effects, with an emphasis on fibroblast dynamics. METHODS AND RESULTS: The study involved forty Sprague-Dawley rats, divided into four groups: control, Angiotensin II (Ang II), Ang II + ANP, and ANP only. The administration of 1 µg/kg/min Ang II was given to Ang II and Ang II + ANP groups, while both Ang II + ANP and ANP groups received 0.1 µg/kg/min ANP intravenously for a duration of 14 days. Cardiac fibroblasts were used for in vitro validation of the proposed mechanisms. The study observed that rats in the Ang II and Ang II + ANP groups showed an increase in blood pressure and a decrease in body weight, more pronounced in the Ang II group. Diastolic dysfunction, a characteristic of the Ang II group, was alleviated by ANP. Additionally, ANP significantly reduced Ang II-induced atrial fibrosis, myofibroblast proliferation, collagen overexpression, macrophage infiltration, and the elevated expression of Interleukin 6 (IL-6) and Tenascin-C (TN-C). Transcriptomic sequencing indicated enhanced PI3K/Akt signaling in the Ang II group. Furthermore, in vitro studies showed that ANP, along with the PI3K inhibitor LY294002, effectively reduced PI3K/Akt pathway activation and the expression of TN-C, collagen-I, and collagen-III, which were induced by Ang II. CONCLUSIONS: The study demonstrates ANP's potential in inhibiting myocardial inflammation and reducing atrial fibrosis. Notably, ANP's effect in countering atrial fibrosis seems to be mediated through the suppression of the Ang II-induced PI3K/Akt-Tenascin-C signaling pathway. These insights enhance our understanding of AF pathogenesis and position ANP as a potential therapeutic agent for treating atrial fibrosis.

MicroRNA-499-5p inhibits transforming growth factor-ß1-induced Smad2 signaling pathway and suppresses fibroblast proliferation and collagen synthesis in rat by targeting TGFß-R1.

BACKGROUND: Artial fibrosis has been recognized as a typical pathological change in atrial fibrillation. Although present evidence suggests that microRNA-499-5p (miR-499-5p) plays an important role in the development of atrial fibrosis, the specific mechanism is not fully understood. Therefore, this study attempted to assess the influence of miR-499-5p on atrial fibroblasts and explore the potential molecular mechanism. METHODS: Atrial fibroblasts from sprague dawley rat were respectively transfected with miR-499-5p mimic, miR-499-5p negative control and miR-499-5p inhibitor, atrial fibroblasts without any treatment were also established. Cell counting kit-8 assay and transwell assay were used to detect the proliferation and migration of atrial fibroblasts in each group. Expressions of miR-499-5p, TGF-ß1, smad2, α-SMA, collagen-I and TGFß-R1 in mRNA and protein level were subsequently detected via quantitative real-time polymerase chain reaction and western blot. Furthermore, the prediction of the binding sites of miR-499-5p and TGFß-R1 was performed via the bioinformatics online software TargetScan and verified by dual luciferase reporter. RESULTS: By utilizing miR-499-5p-transfected atrial fibroblasts model, expression of miR-499-5p in the miR-499-5p mimic group was upregulated, while it was downregulated in the miR-499-5p inhibitors group. Upregulated miR-499-5p expression led to to a significant decrease in the proliferative and migratory ability of cultured atrial fibroblasts, while downregulated miR-499-5p expression led to a significant increase in the proliferative and migratory ability of cultured atrial fibroblasts. Additionally, upregulated miR-499-5p expression made a significant rise in TGF-ß1-induced mRNA and protein expression of TGF-ß1, TGFß-R1, smad2, α-SMA and collagen-I in atrial fibroblasts. Furthermore, results from the dual luciferase reporter conformed that miR-499-5p may repress TGFß-R1 by binding the 3'UTR of TGFß-R1 directly. CONCLUSIONS: miR-499-5p is able to inhibit the activation of transforming growth factor ß-induced Smad2 signaling and eventually suppressed the proliferation, migration and invasion of atrial fibroblasts and collagen synthesis by targeting TGFß-R1.

Amplitude reduction of autonomic nerve function is correlated with ablation lesion quality in patients with paroxysmal atrial fibrillation.

OBJECTIVE: Circumferential pulmonary vein isolation (CPVI) is a common procedure that is performed on patients with atrial fibrillation (AF). However, AF may recur in some patients after treatment. This study assesses the association between autonomic modulation and late recurrence after CPVI and between autonomic modulation and ablation lesion quality. METHODS: We prospectively enrolled 72 patients with paroxysmal AF who underwent CPVI from January 2017 to January 2018. Pre- and post-ablation 24 h electrocardiograms were performed to document heart rate variability (HRV), which represents cardiac autonomic function. The intraablation force-time integral (FTI) was used to indicate the extent of ablation injury. Patients were followed up for 12 months after the procedure and cases of AF recurrence were recorded. RESULTS: Changes in HRV decreased after the procedure, which was correlated with FTI (ΔSDNN: r = -0.26, P = 0.03; ΔrMMSD: r = -0.28, P = 0.02; ΔlnHF: r = -0.22, P = 0.04; ΔLnLF: r = -0.29, P = 0.01). Patients without AF recurrence had more pronounced ΔLF (-21.84 ± 33.21% vs. -8.68 ± 34.59%, P = 0.01) and ΔHF (-17.26 ± 16.61% vs. -1.28 ± 9.81%, P = 0.01) than patients with recurrence. Multivariate regression analysis showed that both ΔLF (HR: 1.07, P = 0.04) and ΔHF (HR: 1.11, P = 0.01) were associated with AF recurrence. After adjusting for FTI, ΔLF was no longer associated with AF recurrence (HR: 1.05, P = 0.10). ΔHF remained associated with AF recurrence (HR: 1.08, P = 0.03), but the correlation coefficient was decreased (HR: 1.08, P = 0.03). CONCLUSION: Decreased autonomic nerve function is a valid predictor of AF recurrence and is indicated by the extent of ablation injury, which is independently associated with AF recurrence after CPVI.

Surface electrocardiography characteristics and radiofrequency catheter ablation of idiopathic ventricular arrhythmias originating from the left infero-septal papillary muscles: differences from those originating from the left posterior fascicle.

Aims: Distinguishing between ventricular arrhythmias originating from the left ventricular infero-septal papillary muscles (PM) and those from the left posterior fascicle (LPF) by surface electrocardiography (ECG) is very difficult. This study aimed to report the ECG characteristics and radiofrequency catheter ablation of PM and LPF ventricular arrhythmias. Methods and results: A total of 127 patients underwent catheter ablation of idiopathic ventricular arrhythmias originating from the LPF (n = 106; 85 males; 10-70 years) or PM (n = 21; 14 males; 4-68 years) were studied. A three-dimensional electroanatomic system (3D-EAS) was used to aid ablation. PM ventricular arrhythmias had a longer QRS duration (154.4 ± 18.0 vs. 119.7 ± 12.6 ms, P < 0.001) than LPF ventricular arrhythmias. All 7 ventricular arrhythmias with QRS duration >160 ms originated from the PM, whereas all 87 ventricular arrhythmias with QRS duration <130 ms arose from the LPF. In 33 ventricular arrhythmias with QRS 130-160 ms, all 13 with Vi/Vt ≤ 0.85 originated from the PM, and 19 of 20 with Vi/Vt > 0.85 arose from the LPF. Of the 8 PM ventricular arrhythmias patients whose initial ablation was undertaken using a non-irrigated 4 mm-tip catheter, 1 failed and 6 recurred. However, of the remaining 13 ones using an irrigated catheter and the 3D-EAS, all succeeded and 2 recurred. No complications were noted in any patient. Conclusion: PM ventricular arrhythmias could be identified from LPF ventricular arrhythmias by calculation of QRS duration combined with Vi/Vt using ECG.

Increased CD160 expression on circulating natural killer cells in atherogenesis.

BACKGROUND: Atherosclerosis (AS) presents characteristic of a chronic inflammatory disease in which both adaptive and innate immune cells play roles. Accumulating evidence has showed the impairment of natural killer (NK) cells in atherosclerosis, however, the mechanisms of this impairment remain unclear. In this study, we investigated the expression of CD160 on NK cells and assessed its pathological roles in NK loss during atherogenesis. METHODS: CD160 expression on NK cells was measured in 49 AS patients and 41 healthy controls (HC) by flow cytometry, their inflammatory cytokine levels in sera were determined by ELSIA, and the effect of CD160 engagement on NK cells was evaluated by in vitro culture experiments. RESULTS: Compared to HC, AS patients had a significantly increased CD160 expression on peripheral NK cells and concomitantly decreased peripheral NK cell number, and increased CD160 expression was positively related to the levels of serum lipids and IFN-γ, TNF-α and IL-6 inflammation cytokines, which all are risk factors for atherogenesis, and inversely correlated with peripheral NK cell number. Furthermore, engagement of CD160 receptor on NK cells from AS patients triggers a significantly increased production of inflammation cytokines and subsequent NK cell apoptosis, and blockade of TNF-α prevented the increased apoptosis of NK cells from AS patients after CD160 engagement, indicating a critical role of TNF-α in mediating NK cell loss by CD160 engagement. RESULTS: Our results provide evidence that elevated CD160 expression on NK cells plays an important role in NK cell loss in atherosclerosis. The increased CD160 expression on NK cells might be used as an indicator for disease progression.

[Predict value of time to peak of systolic velocity derived from velocity vector imaging on cardiac resynchronization therapy response in refractory heart failure patients].

OBJECTIVE: To investigate the impact of cardiac resynchronization therapy (CRT) on left ventricular systolic function evaluated by velocity vector imaging (VVI) in refractory heart failure patients and the predictive value of VVI on CRT responses. METHODS: This study included 38 patients with medically refractory heart failure (HF) patients underwent CRT in our department from May 2007 to April 2011. Left ventricular long axis dyssynchrony indexes including time to peak of systolic velocity (Ts max-min), standard deviation of the time to peak of systolic velocity (Ts-SD) before and at 3-6 months post CRT. CRT response was defined as 15% decrease in left ventricular end-systolic volume. ROC curve and the area under the curve (AUC) were calculated. RESULTS: Twenty-four patients were defined as responder. No significant difference was observed between responders and non-responders in medical therapy. When using Ts max-min to predict response, the AUC of ROC curves was 0.76 ± 0.07. The sensitivity and specifity was 70.8% and 77.8% respectively with Ts max-min ≥ 124.0 ms. When using Ts-SD to predict response, the AUC of ROC curves was 0.82 ± 0.07. The sensitivity and specifity was 79.2% and 71.2% respectively with Ts-SD ≥ 40.5. CONCLUSION: Ts-SD is a useful index to predict CRT response in refractory HF patients.

Protective effects of apocynin on atrial electrical remodeling and oxidative stress in a rabbit rapid atrial pacing model.

It has been proposed that apocynin might be used in the prevention and management of atrial fibrillation (AF). The purpose of this study was to investigate the effects of apocynin on atrial electrical remodeling and oxidative stress promoted by rapid atrial pacing (RAP) in rabbits. New Zealand white rabbits were subjected to RAP with or without apocynin treatment. Serial electrophysiological studies (EPS) were performed at baseline and every half hour after RAP onset. Superoxide dismutase (SOD) and lactate dehydrogenase (LDH) activities and Ca²âº content in tissue homogenates of both atria were assayed after EPS. In the RAP group but not in the sham-operated and RAP with apocynin groups, atrial effective refractory periods (AERPs) at cycle length of 200 and 150 ms shortened most clearly by 20.8 ± 10.2 ms at 3 h (P < 0.001) and by 12.8 ± 11.1 ms at 2 h (P < 0.05) respectively, and AERP rate adaptation decreased to minus values. Higher AF inducibility (66.7%) and longer AF duration (an average of 37.8 min) were presented in the RAP group. Compared with the other groups, SOD activity was lower, and LDH activity and Ca²âº content were higher in the RAP group. Similar differences were not found between the sham-operated and the RAP with apocynin treatment groups. These data show that apocynin attenuates the development of atrial electrical remodeling in a short period of 3-hour RAP, and reduces RAP-mediated inducibility and duration of AF in this model.

mtDNA extramitochondrial replication mediates mitochondrial defect effects.

A high ratio of severe mitochondrial defects causes multiple human mitochondrial diseases. However, until now, the in vivo rescue signal of such mitochondrial defect effects has not been clear. Here, we built fly mitochondrial defect models by knocking down the essential mitochondrial genes dMterf4 and dMrps23. Following genome-wide RNAi screens, we found that knockdown of Med8/Tfb4/mtSSB/PolG2/mtDNA-helicase rescued dMterf4/dMrps23 RNAi-mediated mitochondrial defect effects. Extremely surprisingly, they drove mtDNA replication outside mitochondria through the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis to amplify cytosolic mtDNA, leading to activation of the cGAS-Sting-like IMD pathway to partially mediate dMterf4/dMrps23 RNAi-triggered effects. Moreover, we found that the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis also mediated other fly mitochondrial gene defect-triggered dysfunctions and Drosophila aging. Overall, our study demarcates the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis as a candidate mechanism to mediate mitochondrial defect effects through driving mtDNA extramitochondrial replication; dysfunction of this axis might be used for potential treatments for many mitochondrial and age-related diseases.

Transcriptomic analysis of epicardial adipose tissue reveals the potential crosstalk genes and immune relationship between type 2 diabetes mellitus and atrial fibrillation.

BACKGROUND: The complex relationship between atrial fibrillation (AF) and type 2 diabetes mellitus (T2DM) suggests a potential role for epicardial adipose tissue (EAT) that requires further investigation. This study employs bioinformatics and experimental approaches to clarify EAT's role in linking T2DM and AF, aiming to unravel the biological mechanisms involved. METHOD: Bioinformatics analysis initially identified common differentially expressed genes (DEGs) in EAT from T2DM and AF datasets. Pathway enrichment and network analyses were then performed to determine the biological significance and network connections of these DEGs. Hub genes were identified through six CytoHubba algorithms and subsequently validated biologically, with further in-depth analyses confirming their roles and interactions. Experimentally, db/db mice were utilized to establish a T2DM model. AF induction was executed via programmed transesophageal electrical stimulation and burst pacing, focusing on comparing the incidence and duration of AF. Frozen sections and Hematoxylin and Eosin (H&E) staining illuminated the structures of the heart and EAT. Moreover, quantitative PCR (qPCR) measured the expression of hub genes. RESULTS: The study identified 106 DEGs in EAT from T2DM and AF datasets, underscoring significant pathways in energy metabolism and immune regulation. Three hub genes, CEBPZ, PAK1IP1, and BCCIP, emerged as pivotal in this context. In db/db mice, a marked predisposition towards AF induction and extended duration was observed, with HE staining verifying the presence of EAT. Additionally, qPCR validated significant changes in hub genes expression in db/db mice EAT. In-depth analysis identified 299 miRNAs and 33 TFs as potential regulators, notably GRHL1 and MYC. GeneMANIA analysis highlighted the hub genes' critical roles in stress responses and leukocyte differentiation, while immune profile correlations highlighted their impact on mast cells and neutrophils, emphasizing the genes' significant influence on immune regulation within the context of T2DM and AF. CONCLUSION: This investigation reveals the molecular links between T2DM and AF with a focus on EAT. Targeting these pathways, especially EAT-related ones, may enable personalized treatments and improved outcomes.

Predictive value of pre-procedural N-terminal pro-B-type natriuretic peptide level for atrial fibrillation recurrence after radiofrequency catheter ablation.

Introduction: N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been demonstrated as a valuable risk marker for mortality and morbidity of cardiovascular disease. Recurrence after atrial fibrillation (AF) radiofrequency catheter ablation remains common. Aim: We investigated the predictive value of the pre-procedural level of NT-proBNP to differentiate high-risk patients for post-ablation AF recurrence. Material and methods: 326 individuals with nonvalvular AF and preserved systolic function after enduring an initial radiofrequency catheter ablation (RFCA) between March 2018 and December 2019 were categorized into a recurrent group and a non-AF recurrent group. The serum NT-proBNP levels were examined before the ablation procedure. The researchers used multivariate logistic regression to find the determinants of AF recurrence. Results: During a 14-month (interquartile range (IQR): 12-16) median follow-up, AF recurred in 84 (25.8%) patients. Patients in the recurrence group had considerably greater pre-ablation NT-proBNP levels (389.4 vs. 141.7 pg/ml, p < 0.001 in non-paroxysmal AF and 348.0 vs. 99.4 pg/ml, p < 0.001 in paroxysmal AF) as well as a greater left atrium (40 vs. 36 mm, p = 0.01 in non-paroxysmal AF and 38 vs. 36 mm, p = 0.01 in paroxysmal AF) than the non-AF recurrence group. A cut-off value of NT-proBNP ≥ 168.05 pg/ml identified AF recurrence with a sensitivity of 78.6% and specificity of 53.7% (area under ROC curve 0.68, 95% confidence interval (CI) 0.62-0.74, p < 0.001). Kaplan-Meier examination revealed that the elevated NT-proBNP (≥ 168.05 pg/ml) group presented a considerably shorter period without an occurrence compared to the low-NT-proBNP group (18.4 vs. 22.2 months, log-rank p = 0.001). Multivariate cox regression investigation showed that a level of NT-proBNP ≥ 168.05 pg/ml (hazard ratio (HR): 2.89, 95% CI: 1.71-4.903, p < 0.001) was a reliable predictor of AF recurrence after RFCA. Conclusions: A high pre-ablation NT-proBNP level was associated with AF recurrence, and it was also discovered to be a prognostic factor of recurrence of AF following RFCA.

HIB/SPOP inhibits Ci/Gli-mediated tumorigenesis by modulating the RNA Polymerase II components stabilities.

Hedgehog (Hh) signaling mediated by transcription factor Ci/Gli plays a vital role in embryonic development and adult tissue homeostasis in invertebrates and vertebrates, whose dysregulation leads to many human disorders, including cancer. However, till now, cofactors of Ci/Gli which can affect tumorigenesis are not well known. Here, through genetic screen, we find overexpression of active Ci alone is not sufficient to generate tumor-like eye phenotype in Drosophila, however, its overexpression combined with knockdown of hib causes a striking tumor-like big eye phenotype. Mechanistically, HIB/SPOP inhibits Ci/Gli-mediated tumorigenesis by modulating the RNA polymerase II (RNAPII) components Rpb3/Rpb7 stabilities in E3 ligase dependent manner. In addition, Ci/Gli can promote HIB/SPOP-mediated Rpb7/Rpb3 degradation. Taken together, our results indicate Ci/Gli needs to hook up with suitable RNAPII together to achieve the tumor-like eye phenotype and HIB/SPOP plays dual roles through controlling Ci/Gli and Rpb3/Rpb7 protein stabilities to temper Ci/Gli/RNAPII-mediated tumorigenesis.

Influence of acute stress on cardiac electrophysiological stability in male goats.

OBJECTIVE: Stress plays an important role in the pathogenesis of ventricular arrhythmias. This study was designed to examine the effect of acute stress and metoprolol, a beta adrenergic receptor blocker, on cardiac electrophysiological stability of male goats. METHODS: Fifteen male goats were randomly divided into three groups: (i) control animals (n=5), (ii) a compound stimuli group including noise and red flash (n=5), (iii) and a compound stimuli group with metoprolol treatment (n=5). Plasma catecholamines were determined by using high performance chromatography with electrochemical detection. Heart rate turbulence (HRT) and heart rate variability (HRV) were analysed with the MGY-H12L analysis system. Also, the ventricular fibrillation threshold (VFT) and the ventricular vulnerable period (VVP) were determined by programmed S1S2 stimulus with bipolar electrodes at the apex of the goat hearts. RESULTS: Compound stimuli increased plasma catecholamine levels progressively and decreased the negative value of turbulence onset (TO), turbulence slope (TS), SDNN, PNN50. Moreover, compound stimuli broadened VVP and decreased VFT significantly. Although metoprolol treatment failed to affect plasma catecholamine levels, TS and PNN50 value of the compound stimuli group, it significantly increased the negative value of TO, SDNN, VFT and narrowed VVP. CONCLUSION: Our data demonstrates that compound stimuli can induce acute stressful reactions, and decrease the cardiac electrophysiological stability of male goats, which can be counteracted by metoprolol treatment.

The transformation of atrial fibroblasts into myofibroblasts is promoted by trimethylamine N-oxide via the Wnt3a/ß-catenin signaling pathway.

Background: Atrial fibrosis is an important pathophysiological mechanism in the development and maintenance of atrial fibrillation. Trimethylamine N-oxide (TMAO) is one of the most widely studied microbial metabolites involved in the promotion of cardiac fibrosis. TMAO promotes phenotypic transformation, proliferation, and migration and increases collagen secretion in cardiac fibroblasts. The Wnt/ß-catenin pathway also plays a key role in the promotion of cardiac fibroblasts into myofibroblasts. Methods: The expression of Alpha-smooth muscle actin (α-SMA) was determined to identify the formation of myofibroblasts. The effects of TMAO on the proliferation and migration of atrial fibroblasts were detected by cell counting kit 8, and transwell assays, respectively. Western blot and immunofluorescence were used to detect the activation of the ß-catenin pathway by TMAO and the phenotypic transformation and collagen secretion of the atrial fibroblasts. Western blot and immunofluorescence assays were performed to detect the effects of exogenous Wnt3a and TMAO on the activation of ß-catenin pathway and the phenotypic transformation of atrial fibroblasts. Results: TMAO promoted the proliferation and migration of atrial fibroblasts. TMAO also promoted the phenotypic transformation, migration, and collagen secretion of the atrial fibroblasts by activating the ß-catenin pathway. Exogenous Wnt3a and TMAO synergistically promoted the activation and phenotypic transformation of the ß-catenin pathway in atrial fibroblasts. Conclusions: TMAO promotes the transformation of atrial fibroblasts into myofibroblasts by activating Wnt3a/ß-catenin signaling pathway.

The prognostic significance of left atrial appendage peak flow velocity in the recurrence of persistent atrial fibrillation following first radiofrequency catheter ablation.

BACKGROUND: Atrial fibrillation (AF) relapse following radiofrequency catheter ablation (RFCA) for persistent atrial fibrillation (PeAF) continues to be a concern. This study establishes a connection between left atrial appendage peak flow velocity (LAAV) and recurrence of AF in individuals having PeAF following first RFCA. METHODS: We retrospectively studied 164 successive PeAF patients who had first RFCA between January 2018 and December 2019. Before the ablation, the LAAV was recorded using transesophageal echocardiography (TEE). The demographic and clinical data of the individuals were gathered. Participants were monitored at regular intervals to monitor for recurrence of AF. We employed Cox proportional hazards regression to determine if LAAV, as well as other clinical indicators, were predictive of AF recurrence in follow-up. RESULTS: In this study, AF relapse was seen in 43 patients (26.2%) following a median follow-up of 15 [interquartile range (IQR): 12-18] months. It was shown that the LAAV was decreased in individuals who had recurrences of AF (0.36±0.05 vs. 0.45±0.17 m/s, P=0.004). Using Kaplan-Meier analysis, it was discovered that the low LAAV (0.37 m/s) group had a poorer event-free survival rate compared to the high LAAV (>0.37 m/s) group (17.6 vs. 21.2 months, log-rank P=0.002) group. Based on the results of the multivariate Cox regression analysis, a LAAV of fewer than 0.37 m/s [hazard ratio (HR): 2.32; 95% confidence interval (CI): 1.177-4.227; P=0.014] was shown to be an independent predictor of AF recurrence following RFCA. CONCLUSIONS: A low LAAV is associated with AF relapse, and it is a predictor of AF relapse following the first RFCA for PeAF. This discovery may be useful in the optimization of treatment strategies and the care of patients with PeAF.

Role of progressive widening of the temporal excitable gap for perpetuation of atrial fibrillation in the goat.

BACKGROUND: Previous studies suggest that a short temporal excitable gap exists between the fibrillation waves during atrial fibrillation (AF). The aim of this study was to investigate the role of that gap in the development of sustained AF in goats. METHODS AND RESULTS: Eight female goats were instrumented with left atrium (LA) electrodes, and sustained AF (>24 h) was induced by intermittent rapid atrial pacing for 9.3+/-4.6 days. In the process of sustained AF development, the atrial effective refractory period (AERP), refractory period during AF (RP(AF)), mean AF cycle length (AFCL), temporal excitable gap during AF (EG(AF) = AFCL - RP(AF)) and degree of fractionation of fibrillation electrograms at LA were studied. When the induced AF lasted for 3-10 min, AFCL, RP(AF) and EG(AF) were 98.3+/-11.0 ms, 90.5+/-13.2 ms and 7.8+/-2.4 ms, respectively. During sustained AF, the values were 84.9+/-5.2 ms, 63.0+/-4.8 ms and 21.9+/-3.5 ms, respectively (P<0.05). Percentage of single potentials was 94.2+/-3.9% and 75.6+/-5.5%, respectively (P<0.05). CONCLUSIONS: In this model progressive shortening of atrial refractoriness and widening of the temporal excitable gap induced by electrical remodeling created an electrophysiologic substrate for the perpetuation of AF.

E3 ligase Herc4 regulates Hedgehog signalling through promoting Smoothened degradation.

Hedgehog (Hh) signalling plays conserved roles in controlling embryonic development; its dysregulation causes many diseases including cancers. The G protein-coupled receptor Smoothened (Smo) is the key signal transducer of the Hh pathway, whose posttranslational regulation has been shown to be critical for its accumulation and activation. Ubiquitination has been reported an essential posttranslational regulation of Smo. Here, we identify a novel E3 ligase of Smo, Herc4, which binds to Smo, and regulates Hh signalling by controlling Smo ubiquitination and degradation. Interestingly, our data suggest that Herc4-mediated Smo degradation is regulated by Hh in PKA-primed phosphorylation-dependent and independent manners.

Effects of febuxostat on atrial remodeling in a rabbit model of atrial fibrillation induced by rapid atrial pacing.

BACKGROUND: Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase (XO), may be used in the prevention and management of atrial fibrillation (AF). The purpose of this study was to evaluate the effects of febuxostat on atrial remodeling in a rabbit model of AF induced by rapid atrial pacing (RAP) and the mechanisms by which it acts. METHODS: Twenty-four rabbits were randomly divided into four groups: sham-operated group (Group S), RAP group (Group P), RAP with 5 mg/kg per day febuxostat group (Group LFP), and RAP with 10 mg/kg per day febuxostat group (Group HFP). All rabbits except those in Group S were subjected to RAP at 600 beats/min for four weeks. The effects of febuxostat on atrial electrical and structural remodeling, markers of inflammation and oxidative stress, and signaling pathways involved in the left atrium were examined. RESULTS: Shortened atrial effective refractory period (AERP), increased AF inducibility, decreased mRNA levels of Cav1.2 and Kv4.3, and left atrial enlargement and dysfunction were observed in Group P, and these changes were suppressed in the groups treated with febuxostat. Prominent atrial fibrosis was observed in Group P, as were increased levels of TGF-ß1, Collagen I, and α-SMA and decreased levels of Smad7 and eNOS. Treatment with febuxostat attenuated these differences. Changes in inflammatory and oxidative stress markers induced by RAP were consistent with the protective effects of febuxostat. CONCLUSIONS: This study is the first to find that febuxostat can inhibit atrial electrical and structural remodeling of AF by suppressing XO and inhibiting the TGF-ß1/Smad signaling pathway.

Diagnostic Performance of a Smart Device With Photoplethysmography Technology for Atrial Fibrillation Detection: Pilot Study (Pre-mAFA II Registry).

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The asymptomatic nature and paroxysmal frequency of AF lead to suboptimal early detection. A novel technology, photoplethysmography (PPG), has been developed for AF screening. However, there has been limited validation of mobile phone and smart band apps with PPG compared to 12-lead electrocardiograms (ECG). OBJECTIVE: We investigated the feasibility and accuracy of a mobile phone and smart band for AF detection using pulse data measured by PPG. METHODS: A total of 112 consecutive inpatients were recruited from the Chinese PLA General Hospital from March 15 to April 1, 2018. Participants were simultaneously tested with mobile phones (HUAWEI Mate 9, HUAWEI Honor 7X), smart bands (HUAWEI Band 2), and 12-lead ECG for 3 minutes. RESULTS: In all, 108 patients (56 with normal sinus rhythm, 52 with persistent AF) were enrolled in the final analysis after excluding four patients with unclear cardiac rhythms. The corresponding sensitivity and specificity of the smart band PPG were 95.36% (95% CI 92.00%-97.40%) and 99.70% (95% CI 98.08%-99.98%), respectively. The positive predictive value of the smart band PPG was 99.63% (95% CI 97.61%-99.98%), the negative predictive value was 96.24% (95% CI 93.50%-97.90%), and the accuracy was 97.72% (95% CI 96.11%-98.70%). Moreover, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of mobile phones with PPG for AF detection were over 94%. There was no significant difference after further statistical analysis of the results from the different smart devices compared with the gold-standard ECG (P>.99). CONCLUSIONS: The algorithm based on mobile phones and smart bands with PPG demonstrated good performance in detecting AF and may represent a convenient tool for AF detection in at-risk individuals, allowing widespread screening of AF in the population. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-OOC-17014138; http://www.chictr.org.cn/showproj.aspx?proj=24191 (Archived by WebCite at http://www.webcitation/76WXknvE6).

The deubiquitinase UCHL5/UCH37 positively regulates Hedgehog signaling by deubiquitinating Smoothened.

The Hedgehog (Hh) signaling pathway plays important roles in developmental processes including pattern formation and tissue homeostasis. The seven-pass transmembrane receptor Smoothened (Smo) is the pivotal transducer in the pathway; it, and thus the pathway overall, is regulated by ubiquitin-mediated degradation, which occurs in the absence of Hh. In the presence of Hh, the ubiquitination levels of Smo are decreased, but the molecular basis for this outcome is not well understood. Here, we identify the deubiquitinase UCHL5 as a positive regulator of the Hh pathway. We provide both genetic and biochemical evidence that UCHL5 interacts with and deubiquitinates Smo, increasing stability and promoting accumulation at the cell membrane. Strikingly, we find that Hh enhances the interaction between UCHL5 and Smo, thereby stabilizing Smo. We also find that proteasome subunit RPN13, an activator of UCHL5, could enhance the effect of UCHL5 on Smo protein level. More importantly, we find that the mammalian counterpart of UCHL5, UCH37, plays the same role in the regulation of Hh signaling by modulating hSmo ubiquitination and stability. Our findings thus identify UCHL5/UCH37 as a critical regulator of Hh signaling and potential therapeutic target for cancers.