FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation.

Abnormal cardiac fibrosis is the main pathological change of post-myocardial infarction (MI) heart failure. Although the E3 ubiquitin ligase FBXL8 is a key regulator in the cell cycle, cell proliferation, and inflammation, its role in post-MI ventricular fibrosis and heart failure remains unknown. FBXL8 was primarily expressed in cardiac fibroblasts (CFs) and remarkably decreased in CFs treated by TGFß and heart subjected to MI. The echocardiography and histology data suggested that adeno-associated viruses (AAV9)-mediated FBXL8 overexpression had improved cardiac function and ameliorated post-MI cardiac fibrosis. In vitro, FBXL8 overexpression prevented TGFß-induced proliferation, migration, contraction, and collagen secretion in CFs, while knockdown of FBXL8 demonstrated opposite effects. Mechanistically, FBXL8 interacted with Snail1 to promote Snail1 degradation through the ubiquitin-proteasome system and decreased the activation of RhoA. Moreover, the FBXL8ΔC3 binding domain was indispensable for Snail1 interaction and degradation. Ectopic Snail1 expression partly abolished the effects mediated by FBXL8 overexpression in CFs treated by TGFß. These results characterized the role of FBXL8 in regulating the ubiquitin-mediated degradation of Snail1 and revealed the underlying molecular mechanism of how MI up-regulated the myofibroblasts differentiation-inducer Snail1 and suggested that FBXL8 may be a potential curative target for improving post-MI cardiac function.

Long Non-coding RNA Involved in the Pathophysiology of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a prevalent and chronic cardiovascular disorder associated with various pathophysiological alterations, including atrial electrical and structural remodeling, disrupted calcium handling, autonomic nervous system dysfunction, aberrant energy metabolism, and immune dysregulation. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a significant role in the pathogenesis of AF. OBJECTIVE: This discussion aims to elucidate the involvement of AF-related lncRNAs, with a specific focus on their role as miRNA sponges that modulate crucial signaling pathways, contributing to the progression of AF. We also address current limitations in AF-related lncRNA research and explore potential future directions in this field. Additionally, we summarize feasible strategies and promising delivery systems for targeting lncRNAs in AF therapy. CONCLUSION: In conclusion, targeting AF-related lncRNAs holds substantial promise for future investigations and represents a potential therapeutic avenue for managing AF.

Selective blockade of interleukin 6 trans-signaling depresses atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) has been accepted as an inflammatory atrial myopathy. Interleukin 6 (IL-6)-dependent inflammatory signaling pathways take context-dependent effects on cardiovascular diseases. IL-6 trans-signaling is predominantly pro-inflammatory. However, its effect on AF is unclear. OBJECTIVE: The purpose of this study was to investigate the role of IL-6 trans-signaling in AF. METHODS: Circulating levels of IL-6, soluble IL-6 receptor, and soluble glycoprotein 130 (sgp130) in patients with AF and controls were measured to estimate the activation of IL-6 trans-signaling. A mouse model of AF was established by transverse aortic constriction surgery. Sgp130Fc administration was used for the selective blockade of IL-6 trans-signaling. Studies were conducted to evaluate the effects and underlying mechanisms of sgp130Fc on AF inducibility and atrial conduction abnormalities and structural remodeling. RESULTS: In patients, the elevation of IL-6 trans-signaling level was positively associated with AF occurrence. IL-6 trans-signaling activation was recapitulated in the mouse model of AF. In transverse aortic constriction-challenged mice, the selective blockade of IL-6 trans-signaling with sgp130Fc attenuated AF inducibility, which was attributable to the amelioration of slow conduction and conduction heterogeneity induced by atrial dilation, fibrosis, and reduction in connexin 40 and redistribution of connexin 43. Sgp130Fc administration also reduced immune cell infiltration and oxidative stress in the mouse atrium and abrogated IL-6 trans-signaling activation-mediated connexin dysregulation and reactive oxygen species production in atrial myocytes. CONCLUSION: IL-6 trans-signaling activation contributes to AF development, and its selective blockade may promise a novel therapeutic strategy.

Chinese expert consensus on the construction of the fluoroless cardiac electrophysiology laboratory and related techniques.

Transcatheter radiofrequency ablation has been widely introduced for the treatment of tachyarrhythmias. The demand for catheter ablation continues to grow rapidly as the level of recommendation for catheter ablation. Traditional catheter ablation is performed under the guidance of X-rays. X-rays can help display the heart contour and catheter position, but the radiobiological effects caused by ionizing radiation and the occupational injuries worn caused by medical staff wearing heavy protective equipment cannot be ignored. Three-dimensional mapping system and intracardiac echocardiography can provide detailed anatomical and electrical information during cardiac electrophysiological study and ablation procedure, and can also greatly reduce or avoid the use of X-rays. In recent years, fluoroless catheter ablation technique has been well demonstrated for most arrhythmic diseases. Several centers have reported performing procedures in a purposefully designed fluoroless electrophysiology catheterization laboratory (EP Lab) without fixed digital subtraction angiography equipment. In view of the lack of relevant standardized configurations and operating procedures, this expert task force has written this consensus statement in combination with relevant research and experience from China and abroad, with the aim of providing guidance for hospitals (institutions) and physicians intending to build a fluoroless cardiac EP Lab, implement relevant technologies, promote the standardized construction of the fluoroless cardiac EP Lab.

Integrin beta-like 1 mediates fibroblast-cardiomyocyte crosstalk to promote cardiac fibrosis and hypertrophy.

AIMS: Crosstalk between fibroblasts and cardiomyocytes (CMs) plays a critical role in cardiac remodelling during heart failure (HF); however, the underlying molecular mechanisms remain obscure. Recently, a secretory protein, Integrin beta-like 1 (ITGBL1) was revealed to have detrimental effects on several diseases, such as tumours, pulmonary fibrosis, and hepatic fibrosis; whereas the effect of ITGBL1 on HF is unclear. The purpose of this study was to evaluate its contribution to volume overload-induced remodelling. METHODS AND RESULTS: In this study, we identified ITGBL1 was highly expressed in varied heart diseases and validated in our TAC mice model, especially in fibroblasts. To investigate the role of ITGBL1 in in vitro cell experiments, neonatal rat fibroblasts (NRCFs) and cardiomyocytes (NRCMs) were performed for further study. We found that in comparison to NRCMs, NRCFs expressed high levels of ITGBL1. Meanwhile, ITGBL1 was upregulated in NRCFs, but not in NRCMs following angiotensin-II (AngII) or phenylephrine stimulation. Furthermore, ITGBL1 overexpression promoted NRCFs activation, whereas knockdown of ITGBL1 alleviated NRCFs activation under AngII treatment. Moreover, NRCFs-secreted ITGBL1 could induce NRCMs hypertrophy. Mechanically, ITGBL1-NME/NM23 nucleoside diphosphate kinase 1 (NME1)-TGF-ß-Smad2/3 and Wnt signalling pathways were identified to mediate NRCFs activation and NRCMs hypertrophy, respectively. Finally, the knockdown of ITGBL1 in mice subjected to transverse aortic constriction (TAC) surgery recapitulated the in vitro findings, demonstrating blunted cardiac fibrosis, hypertrophy, and improved cardiac function. CONCLUSIONS: ITGBL1 is an important functional mediator between fibroblast-cardiomyocyte crosstalk and could be an effective target for cardiac remodelling in HF patients.

Latest incidence and electrocardiographic predictors of atrial fibrillation: a prospective study from China.

BACKGROUND: China bears the biggest atrial fibrillation (AF) burden in the world. However, little is known about the incidence and predictors of AF. This study aimed to investigate the current incidence of AF and its electrocardiographic (ECG) predictors in general community individuals aged over 60 years in China. METHODS: This was a prospective cohort study, recruiting subjects who were aged over 60 years and underwent annual health checkups from April to July 2015 in four community health centers in Songjiang District, Shanghai, China. The subjects were then followed up from 2015 to 2019 annually. Data on sociodemographic characteristics, medical history, and the resting 12-lead ECG were collected. Kaplan-Meier curve was used for showing the trends in AF incidence and calculating the predictors of AF. Associations of ECG abnormalities and AF incidence were examined using Cox proportional hazard models. RESULTS: This study recruited 18,738 subjects, and 351 (1.87%) developed AF. The overall incidence rate of AF was 5.2/1000 person-years during an observation period of 67,704 person-years. Multivariable Cox regression analysis indicated age (hazard ratio [HR], 1.07; 95% confidence interval [CI]: 1.06-1.09; P < 0.001), male (HR, 1.30; 95% CI: 1.05-1.62; P = 0.018), a history of hypertension (HR, 1.55; 95% CI: 1.23-1.95; P < 0.001), a history of cardiac diseases (HR, 3.23; 95% CI: 2.34-4.45; P < 0.001), atrial premature complex (APC) (HR, 2.82; 95% CI: 2.17-3.68; P < 0.001), atrial flutter (HR, 18.68; 95% CI: 7.37-47.31; P < 0.001), junctional premature complex (JPC) (HR, 3.57; 95% CI: 1.59-8.02; P = 0.002), junctional rhythm (HR, 18.24; 95% CI: 5.83-57.07; P < 0.001), ventricular premature complex (VPC) (HR, 1.76; 95% CI: 1.13-2.75, P = 0.012), short PR interval (HR, 5.49; 95% CI: 1.36-22.19; P = 0.017), right atrial enlargement (HR, 6.22; 95% CI: 1.54-25.14; P = 0.010), and pacing rhythm (HR, 3.99; 95% CI: 1.57-10.14; P = 0.004) were independently associated with the incidence of AF. CONCLUSIONS: The present incidence of AF was 5.2/1000 person-years in the studied population aged over 60 years in China. Among various ECG abnormalities, only APC, atrial flutter, JPC, junctional rhythm, short PR interval, VPC, right atrial enlargement, and pacing rhythm were independently associated with AF incidence.

Puerarin Protects against Myocardial Ischemia/Reperfusion Injury by Inhibiting Ferroptosis.

This study investigated whether pretreatment with puerarin could alleviate myocardial ischemia/reperfusion (I/R) injury in a cardiomyocyte oxygen-glucose deprivation and reoxygenation (OGD/R) model and in a mouse I/R injury model. For in vitro experiments, H9C2 cells were divided into control, erastin, OGD/R, OGD/R + puerarin, and OGD/R + ferrostatin (Fer)-1 groups. Parameters related to ferroptosis included levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), ATP, reactive oxygen species (ROS), glutathione (GSH), prostaglandin endoperoxide synthase (Ptgs) 2 mRNA, glutathione peroxidase (GPX) 4 protein and iron. In H9C2 cells, puerarin or Fer-1 pretreatment reduced ferroptosis, as indicated by decreased ROS and increased GSH, ATP levels. In vivo, wild-type mice were randomly divided into sham, I/R + vehicle, I/R + puerarin, and IR + Fer-1 groups. The I/R model was established by 30 min of left anterior descending artery occlusion followed by 24 h of reperfusion. Pretreatment with puerarin or Fer-1 significantly reduced infarct size in I/R mice, and decreased the activities of Myeloperoxidase (MPO) and cardiac enzymes such as creatine kinase MB isoenzyme (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) compared to those in the vehicle-treated group. Puerarin also reduced the production of MDA and 4-HNE, reduced the mRNA expression of Ptgs2 mRNA, and increased GPX4 protein expression. These results showed that puerarin exerted protective effects against myocardial I/R injury by inhibiting ferroptosis and inflammation, and therefore may have therapeutic potential for treatment of acute myocardial infarction.

Triglyceride-glucose index and the risk of heart failure: Evidence from two large cohorts and a mendelian randomization analysis.

BACKGROUND: The relationship between triglyceride-glucose (TyG) index, an emerging marker of insulin resistance, and the risk of incident heart failure (HF) was unclear. This study thus aimed to investigate this relationship. METHODS: Subjects without prevalent cardiovascular diseases from the prospective Kailuan cohort (recruited during 2006-2007) and a retrospective cohort of family medicine patients from Hong Kong (recruited during 2000-2003) were followed up until December 31st, 2019 for the outcome of incident HF. Separate adjusted hazard ratios (aHRs) summarizing the relationship between TyG index and HF risk in the two cohorts were combined using a random-effect meta-analysis. Additionally, a two-sample Mendelian randomization (MR) of published genome-wide association study data was performed to assess the causality of observed associations. RESULTS: In total, 95,996 and 19,345 subjects from the Kailuan and Hong Kong cohorts were analyzed, respectively, with 2,726 cases of incident HF in the former and 1,709 in the latter. Subjects in the highest quartile of TyG index had the highest risk of incident HF in both cohorts (Kailuan: aHR 1.23 (95% confidence interval: 1.09-1.39), PTrend <0.001; Hong Kong: aHR 1.21 (1.04-1.40), PTrend =0.007; both compared with the lowest quartile). Meta-analysis showed similar results (highest versus lowest quartile: HR 1.22 (1.11-1.34), P < 0.001). Findings from MR analysis, which included 47,309 cases and 930,014 controls, supported a causal relationship between higher TyG index and increased risk of HF (odds ratio 1.27 (1.15-1.40), P < 0.001). CONCLUSION: A higher TyG index is an independent and causal risk factor for incident HF in the general population. CLINICAL TRIAL REGISTRATION: URL: https://www.chictr.org.cn ; Unique identifier: ChiCTR-TNRC-11,001,489.

Comparisons of electrophysiological characteristics, pacing parameters and mid- to long-term effects in right ventricular septal pacing, right ventricular apical pacing and left bundle branch area pacing.

BACKGROUND: As a near-physiological pacing innovation, left bundle branch area pacing (LBBAP) has drawn much attention recently. This study was aimed to investigate the electrophysiological characteristics, unipolar/bipolar pacing parameters and mid- to long-term effects and safety of three different pacing methods and identify possible predictors of adverse left ventricular remodeling. METHODS: Ninety-two patients were divided into the LBBAP group, right ventricular septal pacing (RVSP) group and right ventricular apical pacing (RVAP) group. Baseline information, electrophysiological, pacing and echocardiographic parameters were collected. RESULTS: The three pacing methods were performed with a similar high success rate. The paced QRSd was significantly different among the LBBAP, RVSP and RVAP groups (105.93 ± 15.85 ms vs. 143.63 ± 14.71 ms vs. 155.39 ± 14.17 ms, p < 0.01). The stimulus to left ventricular activation time (Sti-LVAT) was the shortest in the LBBAP group, followed by the RVSP and RVAP groups (72.80 ± 12.07 ms vs. 86.29 ± 8.71 ms vs. 94.14 ± 10.14 ms, p < 0.001). LBBAP had a significantly lower tip impedance during the procedure and 3-month follow up as compared to RVSP and RVAP (p < 0.001). Higher bipolar captured thresholds were observed in LBBAP during the procedure (p < 0.001). Compared to the baseline values, there was a greater reduction in left ventricular end-diastolic dimension (LVEDD) in the LBBAP group (p = 0.046) and a significant enlargement in LVEDD in the RVAP group (p = 0.008). Multiple regression analysis revealed that the Sti-LVAT was a significant predictor of LVEDD at 12 months post-procedure. At the 24-h post-procedure, significant elevations were observed in the cTnI levels in LBBAP (p < 0.001) and RVSP (p < 0.05). More transient RBB injury was observed in LBBAP. But no significant difference was found in cardiac composite endpoints among three groups (p > 0.05). CONCLUSIONS: LBBAP demonstrated a stable captured threshold, a low tip impedance and a high R-wave amplitude during the 12-month follow-up. Left ventricular remodeling was improved at 12 months post-procedure through LBBAP. The Sti-LVAT was a significant predictor of left ventricular remodeling. LBBAP demonstrated its feasibility, effectiveness, safety and some beneficial electrophysiological characteristics during this mid- to long-term follow-up, which should be confirmed by further studies.

Complete Atrioventricular Block Caused by Retrograde Transaortic Approach.

A 61-year-old female was referred for catheter ablation of symptomatic and frequent premature ventricular complexes presented with right bundle branch block and a prominent inferior frontal plane QRS axis. A retrograde transaortic approach was routinely performed. A sustained complete atrioventricular block was repeatedly encountered while the ablation catheter was attempting to cross the aortic valve with different curves and manipulations. The procedure was abandoned. The mechanical atrioventricular block could only have been caused by the retrograde transaortic approach. We should be cautious when performing a retrograde transaortic catheter manipulation in some patients.

Contemporary survival and anticoagulation of patients with atrial fibrillation: A community based cohort study in China.

Backgrounds: The understanding of death in patients with atrial fibrillation (AF) in China is limited. This study aimed to assess the contemporary survival of AF patients in China and to explore risk factors for deaths. Methods: This was a prospective community-based cohort study including 559 AF patients, who were followed-up from July 2015 to December 2020. Results: During 66-month follow-up, there were 200 deaths (56.5% cardiovascular, 40.0% non-cardiovascular, and 3.5% unknown causes) among 559 AF patients with the median age of 76 years. The top three causes of death were heart failure (33.0%), ischemic stroke (17.0%) and cancer (16.5%). Multivariate Cox regression analysis indicated baseline variables positively associated with all-cause death were age (HR: 1.10, 95% CI: 1.08-1.13), AF subtype (HR: 1.37, 95% CI: 1.08-1.73), prior myocardial infarction (HR: 3.40, 95% CI: 1.48-7.78), previous tumor (HR: 2.61, 95% CI: 1.37-4.98), hypoglycemic therapy at baseline (HR: 1.81, 95% CI: 1.13-2.91), but body weight (HR: 0.98, 95% CI: 0.97-1.00) and use of calcium channel blocker (CCB) (HR: 0.62, 95% CI: 0.41-0.95) played a protective role to all-cause death. Of patients who were alive at the end of follow-up, 24.0% were on oral anticoagulants (OAC) alone, 4.5% on dual antithrombotic therapy, 33.1% on antiplatelet agents alone and 38.4% weren't on any antithrombotic medication. Conclusion: Ischemic stroke still remains one of the leading causes of death and OAC is seriously underused in AF patients in China. Independent risk factors for death are age, AF subtype, previous tumor, prior myocardial infarction, hypoglycemic therapy, low body weight and no CCB use. Clinical Trial Registration: http://www.chictr.org.cn/ (ChiCTR-ICR-15007036).

Inferior Vena Cava as a Trigger for Paroxysmal Atrial Fibrillation: Incidence, Characteristics, and Implications.

BACKGROUND: Identifying nonpulmonary vein triggers during atrial fibrillation (AF) ablation is of great importance. Currently, there are limited data on AF triggered by the inferior vena cava (IVC). OBJECTIVES: This study was performed to investigate the incidence, characteristics, and implications of IVC triggers for AF. METHODS: A total of 661 patients who underwent initial paroxysmal AF ablation were included. After pulmonary vein isolation, ectopic beats that triggered AF were further studied. Activation mapping and angiography were performed to confirm the location of ectopic origin. Electrocardiographic analysis of the ectopic P-wave (P'-wave) was performed. RESULTS: Six patients (0.91%) with AF triggered by the IVC were confirmed. The mean distance from the earliest activation site to the IVC ostium was 6.8 ± 2.5 mm (5.2 to 11.2 mm). Furthermore, the arrhythmogenic foci within the IVC were all located at the apical hemisphere of the IVC (3 at the septal side and 3 at the anterior side). A total of 2.3 ± 0.5 applications of radiofrequency energy were delivered to eliminate IVC triggers. The mean duration of the P' wave was 91.2 ± 11.2 milliseconds (81 to 108 milliseconds), which was narrower than that of the sinus P-wave (115.2 ± 19.3 milliseconds [87 to 139 milliseconds]; P = 0.002). Moreover, the configuration of all P' waves in the inferior leads was negative. During a mean follow-up period of 25.5 ± 7.3 months, all 6 patients remained arrhythmia free without antiarrhythmic drugs. CONCLUSIONS: IVC trigger, a rare but latent source of paroxysmal AF, could be identified and safely eliminated by focal radiofrequency ablation. Ectopic beats originating from the IVC presented with narrow P'-wave duration and negative P' waves in all inferior leads.

Emergency catheter ablation: A feasible option for acute treatments of patients with unstable pre-excited atrial fibrillation.

BACKGROUND: Pre-excited atrial fibrillation (AF) is associated with increased risk of life-threatening events. However, at times, patients with pre-excited AF still repetitively suffer from hemodynamic disturbance, with resistance to acute treatments of antiarrhythmic therapy and cardioversion. METHODS: To evaluate the feasibility in correcting hemodynamic disturbance, patients with pre-excited AF who underwent catheter ablation of accessory pathway as an emergency procedure, were retrospectively collected from two centers of China. The medical records of patients were analyzed and summarized in this case series. RESULTS: Five patients with pre-excited AF who received emergency catheter ablation of accessory pathway, were collected from two contributor centers and reported in this case series. All collected patients still repetitively suffered from hemodynamic disturbance induced by rapid anterograde conduction of AF via pathway, even guideline recommended acute interventions of intravenous antiarrhythmic therapy and cardioversion had been performed. Finally, as an emergency procedure, catheter ablation of accessory pathway was performed in collected patients. Correspondingly, the hemodynamic unstable status was greatly relieved. Meanwhile, all collected patients with high risk of pre-excited AF were combined with left-sided accessory pathway, with shortest RR interval of widened pre-excited QRS complex less than 250 ms. Thus, combination with left-sided pathway is proposed as an indicator for the increased risk of life-threatening events in patients with high risk of pre-excited AF. CONCLUSIONS: Emergency catheter ablation of accessory pathway is an effective option for the acute managements of patients with high risk of pre-excited AF in unstable hemodynamics, which is resistant to antiarrhythmic therapy and cardioversion.

C-reactive protein and atrial fibrillation: Insights from epidemiological and Mendelian randomization studies.

BACKGROUND AND AIMS: This study aimed to investigate the role of C-reactive protein (CRP) in atrial fibrillation (AF) from epidemiological and genetic perspectives. METHODS AND RESULTS: Individual-level data from the Kailuan cohort recruited between 2006 and 2017 were included. Serum CRP levels were measured at baseline and at biennial follow-up visits, and incident AF was ascertained from biennial 12-lead ECG assessment and medical records. Cox proportional hazards models were used to assess the association between baseline CRP levels or cumulative exposure to CRP and incident AF. A meta-analysis including nine prospective cohort studies and our current study was also conducted. Mendelian randomization (MR) analysis was performed to evaluate the aetiological role of CRP in AF. In our observational study (n = 86,424), high baseline CRP levels (>3 mg/L), compared with low CRP (<1 mg/L), were not significantly associated with AF risk (HR: 1.18; 95% CI: 0.99-1.40). High cumulative exposure to CRP (HR: 1.49; 95%CI: 1.01-2.21) was significantly associated with an increased risk of AF. Our meta-analysis suggested a positive association between elevated CRP levels and incident AF (relative risk: 1.27; 95% CI: 1.14-1.42). However, no significant association between genetically determined CRP and AF risk was observed in the MR analysis. CONCLUSION: Evidence from observational studies suggested that elevated serum CRP levels were positively associated with incident AF, while the causal effects of CRP on AF were not supported by the MR analysis. CLINICAL TRIAL REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR-TNRC-11001489.

Sub-pocket small-hole drainage for pocket hematoma after cardiac device implantation.

AIMS: Pocket hematoma is a common complication associated with cardiac device implantation, but there are limited strategies to deal with this problem. We aimed to evaluate the effectiveness of sub-pocket small-hole drainage (SSD) as a new way to manage severe pocket hematoma. METHODS: A total of 11 patients with severe pocket hematoma were selected for this case series study. The SSD procedure was performed and wound healing was monitored. RESULTS: The SSD procedure was successfully performed on all 11 patients. The time window for SSD was 10-14 days (mean 12.0 ± 1.3 days) after cardiac device implantation. On average, 18.3 ± 2.3 ml of hematoma was drained , with a mean procedural time of 21.3 ± 2.6 min. The patients were followed up for 4-12 months and all pockets healed well, without any complications such as pocket infection, bleeding, device exposure, and electrode fracture. CONCLUSION: Sub-pocket small-hole drainage is an alternative approach for dealing with severe pocket hematoma after cardiac device implantation.