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.

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.

The Proportion of Circulating CD45RO+CD8+ T Cells is Associated with the Coronary Slow Flow.

Background: Circulating memory CD8+ T cells have been shown to be a crucial mediator of chronic inflammation. This study investigated whether the baseline proportion of circulating CD45RO+CD8+ T cells was associated with the coronary slow flow (CSF) phenomenon. Methods: A total of 160 consecutive patients [mean (standard deviation (SD)) age, 67.86 (9.55) years; 51.25% male] who were admitted to our hospital between August 2020 and October 2020 for chest pain and underwent coronary angiography with the absence of coronary stenosis were enrolled in this cross-sectional analysis. The patients' admission CD45RO+ CD8+ T cell plasma levels were measured using flow cytometry. Angiographic CSF was defined as thrombolysis in myocardial infarction (TIMI) flow of ≤ 2 without coronary stenosis, and non-CSF was defined as coronary arteries (< 50% stenosis) with TIMI 3 flow. Results: The incidence of angiographic CSF was 22.5%. Patients with angiographic CSF had higher levels of CD45RO+CD8+ T cells than those without CSF [56.18 (13.93) vs. 45.26 (16.45); p < 0.001]. After multivariable adjustment, the risk of incident CSF was 2.41 [95% confidence interval (CI) 1.46-3.97] per SD change in CD45RO+ CD8+ T cells. Further, coronary microvascular resistance was significantly higher in patients with CSF than in those without CSF. A positive linear relationship between CD45RO+CD8+ T cells and coronary microvascular resistance was observed. Conclusions: The proportion of circulating CD45RO+CD8+ T cells is an independent indicator of CSF. This observation may provide insights into the pathophysiological mechanism of CSF.

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.

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.

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).

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.

Blockade of NaV1.8 Increases the Susceptibility to Ventricular Arrhythmias During Acute Myocardial Infarction.

SCN10A/NaV1.8 may be associated with a lower risk of ventricular fibrillation in the setting of acute myocardial infarction (AMI), but if and by which mechanism NaV1.8 impacts on ventricular electrophysiology is still a matter of debate. The purpose of this study was to elucidate the contribution of NaV1.8 in ganglionated plexi (GP) to ventricular arrhythmias in the AMI model. Twenty beagles were randomized to either the A-803467 group (n = 10) or the control group (n = 10). NaV1.8 blocker (A-803467, 1 µmol/0.5 mL per GP) or DMSO (0.5 mL per GP) was injected into four major GPs. Ventricular effective refractory period, APD90, ventricular fibrillation threshold, and the incidence of ventricular arrhythmias were measured 1 h after left anterior descending coronary artery occlusion. A-803467 significantly shortened ventricular effective refractory period, APD90, and ventricular fibrillation threshold compared to control. In the A-803467 group, the incidence of ventricular arrhythmias was significantly higher compared to control. A-803467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP, suggesting that A-803467 could inhibit GP activity. SCN10A/NaV1.8 was readily detected in GPs, but was not validated in ventricles by quantitative RT-PCR, western blot and immunohistochemistry. While SCN10A/NaV1.8 is detectible in canine GPs but not in ventricles, blockade of NaV1.8 in GP increases the incidence of ventricular arrhythmias in AMI hearts. Our study shows for the first time an influence of SCN10A/NaV1.8 on the regulation of ventricular arrhythmogenesis via modulating GP activity in the AMI model.

Association between delayed transthoracic echocardiography and in-hospital mortality in type A acute aortic dissection-associated ST-segment elevated myocardial infarction.

BACKGROUND: This study evaluates the association between transthoracic echocardiography (TTE) timing and in-hospital mortality among individuals presenting with ST-segment elevated myocardial infarction (STEMI) complicating type A acute aortic dissection (TAAAD). METHODS: This cohort study obtained the data of previously published case reports from searches of PubMed (1990-2020), and adults with STEMI secondary to TAAAD were finally included. Delayed TTE (dTTE) exposure was defined as when the TTE test was made available after antithrombotic management for STEMI due to an initially missed diagnosis of TAAAD. The primary outcome of interest was in-hospital mortality, comparing individuals with dTTE and those with emergency TTE (eTTE). The odds ratio (OR) with 95% confidence interval (CI) were calculated to provide an estimate of association. RESULTS: A total of 109 individuals with a mean age of 56.7 [standard deviation (SD) 12.9] years, and of whom 75 were men (68.8%) presenting with STEMI complicating TAAAD were included. Of all patients, 68 (62.4%) had a dTTE test, which tended to be associated with increased in-hospital mortality after adjustment (OR, 2.320; 95% CI, 0.743-7.248). The association between dTTE and in-hospital death was significant only among patients presenting with a high-risk examination (HRE) (OR, 11.196; 95% CI, 1.322-94.803) and with surgical therapy (OR, 5.375; 95% CI, 1.080-26.700), and not among those presenting with negative HRE (OR, 0.150; 95% CI, 0.016-1.397) and no surgical therapy (OR, 0.177; 95% CI, 0.008-4.018). CONCLUSIONS: This study found an association between dTTE and increased in-hospital mortality in TAAAD-associated STEMI patients with surgical management. This association warrants further investigation.

[Effects of activated CD4+ T cell-derived exosomes on cardiac remodeling after myocardial infarction].

OBJECTIVE: To explore the role of activated CD4+ T cells in cardiac remodeling after myocardial infarction (MI). METHODS: (1) Experiment in vitro: naive CD4+ T cells were isolated in mouse spleen, and then stimulated with plate-bound anti-CD3 and anti-CD28 for 48 hours. Exosomes isolated from the supernatant of activated CD4+ T cells were incubated with cardiac fibroblasts (CFs) for 48 hours, and then the ability of CFs proliferation, migration and differentiation were detected by cell counting kit-8 (CCK-8) assay, Transwell assay, and immunofluorescence assay. (2) Experiment in vivo: 40 male C57 mice were divided into 4 groups according to random number table method, including control group (Ctrl group), sham operation group (Sham group), MI group, and exosome treatment group (MI+Exo group), with 10 in each group. The mice model of MI was established by ligating the left anterior descending coronary artery. In MI+Exo group, 40 µg/d exosomes were injected intravenously into the tail after modeling. Cardiac function and cardiac fibrosis post-MI were assessed by echocardiography and quantitative polymerase chain reaction (qPCR) at 4th week. RESULTS: (1) In vitro: exosomes derived from activated CD4+ T cells significantly promote CFs proliferation, migration and differentiation [proliferation ability (A value): 0.31±0.01 vs. 0.21±0.01, migration capability (cells/MP): 79.20±3.34 vs. 48.80±2.13, differentiation ability (α-smooth muscle actin, α-SMA; fluorescence intensity): 1.56±0.03 vs. 1.00±0.02, all P < 0.05]. (2) In vivo: echocardiographic analysis showed that exosomes derived from activated CD4+ T cells aggravated the deterioration of cardiac dysfunction post-MI than MI group, as indicated by left ventricular ejection fraction (LVEF) and fractional shortening (FS) decreased significantly [LVEF: 0.185±0.008 vs. 0.257±0.022, FS: (9.72±1.72)% vs. (14.08±1.08)%, both P < 0.05], left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) increased significantly [LVEDD (mm): 5.43±0.29 vs. 4.62±0.35, LVESD (mm): 4.94±0.12 vs. 3.69±0.29, both P < 0.05]. Additionally, qPCR showed that exosomes derived from activated CD4+ T cells remarkably promoted myocardial fibrosis post-MI than MI group, as indicated by the mRNA expression of α-SMA, collagens (Col1a1, Col3a1) in MI+Exo group was significantly higher than that in MI group [α-SMA (2-ΔΔCT): 4.72±0.89 vs. 3.58±0.78, Col1a1 (2-ΔΔCT): 6.59±0.56 vs. 4.23±0.42, Col3a1 (2-ΔΔCT): 13.40±1.03 vs.4.96±0.36, all P < 0.05]. CONCLUSIONS: Activated CD4+ T cells promote cardiac remodeling following MI through transferring exosomes to CFs.

Anatomical insights into posterior wall isolation in patients with atrial fibrillation: A hypothesis to protect the esophagus.

INTRODUCTION: Left atrial posterior wall (LAPW) isolation may be performed as an additional atrial fibrillation (AF) ablation strategy based on pulmonary vein isolation. A modified posterior-inferior line (MPL) was proposed for reducing esophageal injury. The aim of this study was to evaluate the anatomical characteristics of the MPL, compared with the conventional posterior line (CPL). METHODS AND RESULTS: Multidetector computed tomography was performed in 102 consecutive AF patients (male/female = 60/42) preoperative, and the parameters were evaluated as follows: the distance from MPL and CPL to the esophagus, fat pad presence and thickness in the course of MPL and CPL, and the esophageal route below CPL. The average distance from the MPL to the esophagus was longer than from CPL to the esophagus (3.7 ± 1.5 vs. 1.7 ± 0.4 mm, p < .001). Proportion of fat pad was higher in the course of MPL than CPL. The myocardium tissue and fat pad under MPL was thicker than under CPL (2.9 ± 1.1 vs. 1.6 ± 0.3 mm, p < .001; 1.4 ± 0.6 vs. 0.9 ± 0.2 mm, p < .001), respectively. In patients whose esophagus was unconfined in a triangular space at the left inferior pulmonary vein level, the average distance from MPL to esophagus was longer than the confined patients (4.0 ± 1.7 vs. 3.2 ± 1.0 mm, p = .001). CONCLUSION: The MPL was far away from the esophagus with thicker myocardium tissue and more fat pad than the CPL; thus, MPL could serve as a favorable alternative in linear ablation for LAPW isolation.

Acute conduction recurrence of mitral isthmus: Incidence, clinical characteristics, and implications.

BACKGROUND: Data on the incidence, clinical characteristics, and implications of acute conduction recurrence during mitral isthmus (MI) ablation are scarce. METHODS: MI ablation was performed in patients with atrial fibrillation. After confirming bidirectional conduction block, the acute conduction recurrence of MI was systematically evaluated. Clinical and electrophysiological characteristics were analyzed. RESULTS: A total of 66 consecutive patients in whom bidirectional conduction block of MI was achieved were prospectively enrolled in a single center. Acute conduction recurrence of MI developed in 12 (18.2%) patients within 14.2 ± 11.5 minutes after the confirmation of bidirectional conduction block. There were two recurrent conduction breakthrough sites of MI along the course of the great cardiac vein (4.5 ± 3.5 min) in two patients and 11 along the course of the ligament of Marshall (LOM) (16.0 ± 11.6 min, P = .035) in 11 patients. LOM accounted for most (84.6%, 11/13) acute MI conduction recurrence. MI length, total ablation time, and procedure time for MI were greater in patients with acute conduction recurrence than in those without acute conduction recurrence. During follow-up, arrhythmia recurrences were less observed in patients with acute conduction when compared to patients without acute conduction recurrence (0% vs 26.4%, P = .055). CONCLUSION: Acute conduction recurrence, predominantly due to recurrent LOM conduction, was a common phenomenon during MI ablation, and its evaluation should therefore be the focus to improve MI ablation efficacy and durability.

QRS complex axis deviation changing in catheter ablation of left fascicular ventricular tachycardia.

AIMS: The mechanisms of the QRS complex axis deviation changing of idiopathic left fascicular ventricular tachycardia (FVT) during or after radiofrequency catheter ablation were investigated in this study, which were still not well defined. METHODS AND RESULTS: In the index procedure, FVTs characterized by right bundle branch block configuration and left-axis deviation (LAD-FVT) were ablated at the VT exit site guided by the earliest ventricular activation with fused presystolic Purkinje potential (PP) in 234 consecutive patients. A new type of FVT characterized by right-axis deviation (RAD-FVT) was identified after successful elimination of the LAD-FVT in 12 patients, including 9 patients during the index procedure and 3 patients during follow-up. The QRS duration of RAD-FVT was shorter than that of LAD-FVT (115.3 ± 15.2 vs. 125.3 ± 16.4 ms, P = 0.006). The RAD-FVTs showed an earliest ventricle activation site localized at anterior fascicle area in 11 patients and anterior-median fascicle area in 1. However, the earliest PP during the RAD-FVT was still identified within the posterior fascicular network. Elimination of the RAD-FVTs was successfully achieved by applying radiofrequency current at a more proximal site within the left posterior fascicular network guided by the earliest PP. After a mean of 1.6 ± 0.8 ablation procedures and median follow-up of 132 (range 19-216) months since the last procedure, no recurrence was observed in any patients. CONCLUSION: The axis deviation changing of QRS complex in FVT may be attributed to the different exit sites of the reentry.

Clinical efficacy and safety of radiofrequency catheter ablation for atrial fibrillation in patients aged ≥80 years.

AIM: To evaluate the clinical safety and efficacy of radiofrequency catheter ablation for atrial fibrillation (AF) in patients aged ≥80 years. METHODS: A total of 333 AF patients aged ≥60 years were enrolled, who underwent contact force-guided radiofrequency catheter ablation with uninterrupted anticoagulation. All patients were followed-up for at least 12 months. Success was defined by the absence of episodes of AF/atrial tachycardia lasting more than 30 seconds after a 3-month blanking period, without antiarrhythmic drugs. RESULTS: Compared to patients aged 60-79 years (Group 2, n = 244), patients aged ≥80 years (Group 1, n = 89) were presented with higher rate of diabetes (36.0% vs 22.1%, P = .011), lower body mass index (23.4 ± 3.1 vs 24.9 ± 3.4 kg/m2 , P = .001), lower creatinine clearance (56.9 ± 16.5 vs 83.3 ± 24.5 mL/min, P < .001), higher CHA2 DS2 -VASc score (4.3 ± 1.3 vs 3.3 ± 1.4, P < .001), and HAS-BLED score (2.2 ± 0.8 vs 1.8 ± 0.8, P < .001). Wide antral pulmonary vein isolation was achieved in all patients, and there was no significant difference in procedure time, ablation time, fluoroscopy time, and complications rate between two age groups (P > .05). After a mean follow-up of 24.4 ± 9.6 months, the overall success rate was 78.2% in Group 1 and 78.9% in Group 2 (P = .622). CONCLUSIONS: Radiofrequency ablation with contact force sensing catheters for AF is safe and effective in selected patients aged ≥80 years.

Activated CD4+ T cells-derived exosomal miR-142-3p boosts post-ischemic ventricular remodeling by activating myofibroblast.

Cardiac fibrosis is a primary phenotype of cardiac remodeling that contributes to cardiac dysfunction and heart failure. The expansion and activation of CD4+ T cells in the heart has been identified to facilitate pathological cardiac remodeling and dysfunction; however, the underlying mechanisms remained not well clarified. Herein, we found that exosomes derived from activated CD4+ T cells (CD4-activated Exos) evoked pro-fibrotic effects of cardiac fibroblasts, and their delivery into the heart aggravated cardiac fibrosis and dysfunction post-infarction. Mechanistically, miR-142-3p that was enriched in CD4-activated Exos recapitulated the pro-fibrotic effects of CD4-activated Exos in cardiac fibroblasts, and vice versa. Furthermore, miR-142-3p directly targeted and inhibited the expression of Adenomatous Polyposis Coli (APC), a negative WNT signaling pathway regulator, contributing to the activation of WNT signaling pathway and cardiac fibroblast activation. Thus, CD4-activated Exos promote post-ischemic cardiac fibrosis through exosomal miR-142-3p-WNT signaling cascade-mediated activation of myofibroblasts. Targeting miR-142-3p in CD4-activated Exos may hold promise for treating cardiac remodeling post-MI.

Ablation at Right Coronary Cusp as an Alternative and Favorable Approach to Eliminate Premature Ventricular Complexes Originating From the Proximal Left Anterior Fascicle.

BACKGROUND: Premature ventricular complex (PVC) with narrow QRS duration originating from proximal left anterior fascicle (LAF) is challenging for ablation. This study was performed to evaluate the safety and feasibility of ablation from right coronary cusp (RCC) for proximal LAF-PVC and to investigate this PVC's characteristics. METHODS: Mapping at RCC and left ventricle and ECG analysis were performed in 20 patients with LAF-PVC. RESULTS: The earliest activation site (EAS), with Purkinje potential during both PVC and sinus rhythm, was localized at proximal LAF in 8 patients (proximal group) and at nonproximal LAF in 12 patients (nonproximal group). The Purkinje potential preceding PVC-QRS at the EAS in proximal group (32.6±2.5 ms) was significantly earlier than that in nonproximal group (28.3±4.5 ms, P=0.025). Similar difference in the Purkinje potentials preceding sinus rhythm QRS at the EAS was also observed between proximal and nonproximal groups (35.1±4.7 versus 25.2±5.0 ms, P<0.001). In proximal group, the distance between the EAS to left His bundle and to RCC was shorter than that of nonproximal group (12.3±2.8 versus 19.7±5.0 mm, P=0.002, and 3.9±0.8 versus 15.7±7.8 mm, P<0.001, respectively). No difference in the distance from RCC to proximal LAF was identified between the 2 groups. PVCs were successfully eliminated from RCC for all proximal groups but at left ventricular EAS for nonproximal groups. The radiofrequency application times, ablation time, and procedure time of nonproximal group were longer than that of proximal group. Electrocardiographic analysis showed that, when compared with nonproximal group, the PVCs of proximal group had narrower QRS duration; smaller S wave in leads I, V5, and V6; lower R wave in leads I, aVR, aVL, V1, V2, and V4; and smaller q wave in leads III and aVF. The QRS duration difference (PVC-QRS and sinus rhythm QRS) <15 ms predicted the proximal LAF origin with high sensitivity and specificity. CONCLUSIONS: PVCs originating from proximal LAF, with unique electrocardiographic characteristics, could be eliminated safely from RCC.

Circular RNA Ttc3 regulates cardiac function after myocardial infarction by sponging miR-15b.

The apoptotic death of cardiomyocytes critically contributes to cardiac remodeling after myocardial infarction (MI). Circular RNAs (circRNAs) are important regulators for a variety of biological functions. Circ-Ttc3 represents one of the top highest expressed circRNAs in the heart; however, its role in MI remains unknown. Herein, we found that circ-Ttc3 was markedly upregulated in the ischemic myocardium and the cardiomyocytes subjected to hypoxic insult. Forced expression of circ-Ttc3 in cardiomyocytes counteracted hypoxia-induced ATP depletion and apoptotic death, in sharp contrast to circ-Ttc3 knockdown. Accordingly, experiments with AAV9-cTnt-mediated knockdown of cardiac circ-Ttc3 in a rat model of MI recapitulated the in vitro findings, and showed the deterioration of cardiac dysfunction after MI. Furthermore, we identified that circ-Ttc3 sponged an endogenous miR-15b-5p to sequester and inhibit its activity, leading to the increased Arl2 expression. Conversely, knockdown of Arl2 partially abolished the beneficial effects of circ-Ttc3 overexpression on ATP production and apoptosis of cardiomyocytes. Thus, our findings revealed the cardioprotective role of circ-Ttc3 in MI. The miR-15b-Arl2 regulatory cascade underlies the protection against MI-induced cardiomyocyte apoptosis by circ-Ttc3.

The importance of identifying conduction breakthrough sites across the mitral isthmus by elaborate mapping for mitral isthmus linear ablation.

AIMS: Mitral isthmus (MI) ablation is challenging. We hoped to close those conduction breakthrough sites (CBS) across the MI by elaborate mapping. METHODS AND RESULTS: After the initial linear ablation, elaborately mapping large areas above and below the MI line and inside the coronary sinus (CS) was sequentially performed to identify the CBS. The shortest distance from the CBS to the MI line was measured. The distant CBS (D-CBS) was identified as those CBS >5.0 mm away from the MI line. We prospectively enrolled 177 consecutive patients. Bidirectional conduction blockage across MI was obtained in 50 (28.2%) patients after the initial linear ablation and was achieved in additional 115 (65.0%) patients following elaborate mapping and reinforcement ablation. After initial linear ablation, 272 CBS (2.14 ± 0.99 CBS/person) were identified, and 226 (83.1%) of them were characterized as D-CBS, including 98 sites (36.0%) >10.0 mm and 39 sites (14.3%) >15.0 mm away. Endocardial and epicardial (CS) reinforcement ablation eliminated 119/272 (43.8%) and 58/272 (21.3%) CBS, respectively. Among the 177 eliminated CBS, 138 D-CBS (78.0%, 11.2 ± 5.6 mm) were confirmed in 95 (74.8%) patients. Moreover, CBS along the course of ligament of Marshall was closed by endocardial ablation more frequently than that along the course of great cardiac vein (52.6%% vs. 35.1%, P = 0.004). Eventually, CS ablation was required only in 64 (38.8%) patients. CONCLUSION: Distant CBS, accounted for the majorities of the residual conduction across the MI after initial ablation, could be effectively identified and accurately eliminated by elaborate mapping and ablation around the MI ablation line.

MicroRNA-30c suppresses the pro-fibrogenic effects of cardiac fibroblasts induced by TGF-ß1 and prevents atrial fibrosis by targeting TGFßRII.

Atrial fibrosis serves as an important contributor to atrial fibrillation (AF). Recent data have suggested that microRNA-30c (miR-30c) is involved in fibrotic remodelling and cancer development, but the specific role of miR-30c in atrial fibrosis remains unclear. The purpose of this study was to investigate the role of miR-30c in atrial fibrosis and its underlying mechanisms through in vivo and in vitro experiments. Our results indicate that miR-30c is significantly down-regulated in the rat abdominal aortic constriction (AAC) model and in the cellular model of fibrosis induced by transforming growth factor-ß1 (TGF-ß1). Overexpression of miR-30c in cardiac fibroblasts (CFs) markedly inhibits CF proliferation, differentiation, migration and collagen production, whereas decrease in miR-30c leads to the opposite results. Moreover, we identified TGFßRII as a target of miR-30c. Finally, transferring adeno-associated virus 9 (AAV9)-miR-30c into the inferior vena cava of rats attenuated fibrosis in the left atrium following AAC. These data indicate that miR-30c attenuates atrial fibrosis via inhibition of CF proliferation, differentiation, migration and collagen production by targeting TGFßRII, suggesting that miR-30c might be a novel potential therapeutic target for preventing atrial fibrosis.