FLRT3 and TGF-ß/SMAD4 signalling: Impacts on apoptosis, autophagy and ion channels in supraventricular tachycardia.

To explore the underlying molecular mechanisms of supraventricular tachycardia (SVT), this study aimed to analyse the complex relationship between FLRT3 and TGF-ß/SMAD4 signalling pathway, which affects Na+ and K+ channels in cardiomyocytes. Bioinformatics analysis was performed on 85 SVT samples and 15 healthy controls to screen overlapping genes from the key module and differentially expressed genes (DEGs). Expression profiling of overlapping genes, coupled with Receiver Operating Characteristic (ROC) curve analyses, identified FLRT3 as a hub gene. In vitro studies utilizing Ang II-stimulated H9C2 cardiomyocytes were undertaken to elucidate the consequences of FLRT3 silencing on cardiomyocyte apoptosis and autophagic processes. Utilizing a combination of techniques such as quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blotting (WB), flow cytometry, dual-luciferase reporter assays and chromatin immunoprecipitation polymerase chain reaction (ChIP-PCR) assays were conducted to decipher the intricate interactions between FLRT3, the TGF-ß/SMAD4 signalling cascade and ion channel gene expression. Six genes (AADAC, DSC3, FLRT3, SYT4, PRR9 and SERTM1) demonstrated reduced expression in SVT samples, each possessing significant clinical diagnostic potential. In H9C2 cardiomyocytes, FLRT3 silencing mitigated Ang II-induced apoptosis and modulated autophagy. With increasing TGF-ß concentration, there was a dose-responsive decline in FLRT3 and SCN5A expression, while both KCNIP2 and KCND2 expressions were augmented. Moreover, a direct interaction between FLRT3 and SMAD4 was observed, and inhibition of SMAD4 expression resulted in increased FLRT3 expression. Our results demonstrated that the TGF-ß/SMAD4 signalling pathway plays a critical role by regulating FLRT3 expression, with potential implications for ion channel function in SVT.

The Influence of Pulmonary Veins' Anatomic Features and Catheter Coaxiality on Cryoballoon Ablation Results for Paroxysmal Atrial Fibrillation.

A total of 172 consecutive patients with sympathetic paroxysmal atrial fibrillation who received cryoballoon (CB) ablation from 2020 to 2021 were retrospectively analyzed in this study. Catheter coaxiality and anatomic features of pulmonary veins (PVs) on computed tomography images were explored by several parameters and their influence on the cryoablation results was then analyzed. The rate of incomplete CB occlusion was significantly higher for inferior than superior PVs. A multivariate analysis revealed that a short distance (<6.3 mm) from PV ostium to first branch (D-PVB) and a small angle (<32.5°) of first branch were independent predict factors for an incomplete CB occlusion in right inferior PVs (RIPVs). A combination of D-PVB and angle of first branch could elevate the predictor value for an incomplete balloon occlusion with a sensitivity of 0.85 and specificity of 1.0 for RIPVs. For PVs with a perfect balloon occlusion, the best catheter coaxiality was observed in right superior PV while the worst catheter coaxiality was observed in RIPV. A more aggressive catheter manipulation with a "7" or "reverse-U" shape of long sheath could obtain a better catheter coaxiality compared with conventional manipulation strategy for RIPVs. In Conclusion, a short D-PVB and a small angle of first branch were independent predict factors for an incomplete CB occlusion in RIPVs. A more aggressive catheter manipulation strategy was recommended to achieve a complete balloon occlusion and a better catheter coaxiality for RIPVs.

Cryoballoon ablation for atrial fibrillation in patients with heart failure with mildly reduced and preserved ejection fraction.

AIMS: Limited data are available on the outcomes of cryoballoon ablation (CBA)-based pulmonary vein isolation (PVI) for atrial fibrillation (AF) in patients with heart failure (HF) with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF). The present study aimed to evaluate the safety and effectiveness of CBA in such patients. METHODS AND RESULTS: Consecutive patients with AF referred for CBA-based PVI from two highly experienced electrophysiology centres were included in this retrospective study. Of 651 patients undergoing CBA, 471 cases were divided into four groups: No HF (n = 255), HFpEF (n = 101), HFmrEF (n = 78), and HF with reduced ejection fraction (n = 37). Similar early recurrence of atrial arrhythmia was found among groups (16.2% vs. 15.4% vs. 14.9% vs. 12.2%, P = 0.798), and no significant difference of long-term sinus rhythm (SR) maintenance was identified among the HFmrEF, HFpEF, and No HF groups (71.8% vs. 75.2% vs. 79.6%, P = 0.334). CBA is safe for patients with HFmrEF and HFpEF with similar complications compared with the No HF group (3.8% vs. 4.0% vs. 3.1%, P = 0.814). The reassessment of cardiac function after CBA showed that patients with HF indicated beneficial outcomes. Left atrial diameter (LAD) and left ventricular ejection fraction were significantly improved in the HFmrEF group. There were 41.6% of patients in the HFpEF group who were completely relieved from HF. LAD and New York Heart Association (NYHA) were associated with recurrence in the HFpEF and HFmrEF groups, and the maintenance of SR was an independent predictor of NYHA improvement for all HF groups. CONCLUSIONS: Patients with HFmrEF and HFpEF could benefit from CBA with high SR maintenance and significant HF improvement.

A new insight into the different approaches for the ablation of para-Hisian accessory pathways: safety, effectiveness, and mechanism.

BACKGROUND: To compare the safety, effectiveness, electrophysiological characteristics, and mechanisms of different approaches for the ablation of para-Hisian accessory pathways (APs). METHOD: Eighteen consecutive patients with para-Hisian APs were enrolled in this study. Detailed mapping of retrograde conduction as well as antegrade conduction (if possible) in both the right sided His bundle region and non-coronary cusp (NCC) region was performed before ablation. Ten patients underwent initial ablation in the right septal (RS) region while the remaining 8 patients were ablated in NCC region. Repeat ablation was attempted in an alternative region if ablation at the first site failed. RESULTS: Among the patients whose procedures were successful, 7 cases were successfully ablated with a NCC approach while 10 were conventionally ablated in RS region. For successful procedures targeting the NCC region, the earliest atrial activation (EAA) in NCC region preceded that at RS region by 4-13 ms. The distance between NCC targets and near-field His potential (NFH) points was longer than that between RS targets and NFH points. Additionally, the risk of complication after ablation in NCC region was lower compared with that following RS-targeted procedure. CONCLUSION: NCC approach provided a high success rate and low risk of complication for the ablation of para-Hisian APs as long as EAA was observed in NCC region. Sites of successful para-Hisian AP ablation in NCC region had different retrograde mapping patterns in comparison with successful ablation sites in the RS region.

Moricizine prevents atrial fibrillation by late sodium current inhibition in atrial myocytes.

Background: Enhanced late sodium current (INaL) is reportedly related to an increased risk of atrial fibrillation (AF). Moricizine, as a widely used anti-arrhythmia drug for suppressing ventricular tachycardia, has also been shown to prevent paroxysmal AF. However, the mechanism of its therapeutic effect remains poorly understood. Methods: Angiotensin II (Ang II) was induced in C57Bl/6 mice (male wild-type) for 4 weeks to increase the susceptibility of AF, and acetylcholine-calcium chloride was used to induce AF. The whole-cell patch-clamp technique was used to detect INaL from isolated atrial myocytes. The expression of proteins in atrial of mice and HL-1 cells were examined by Western-blot. Results: The results showed that moricizine significantly inhibited Ang II-mediated atrial enlargement and reduced AF vulnerability. We found that the densities of INaL were enhanced in Ang II-treated left and right atrial cardiomyocytes. Simultaneously, the Ang II-induced increase in INaL currents density was alleviated by the administration of moricizine, and no alteration in Nav1.5 expression was observed. In normal isolated atrial myocytes, moricizine significantly reduced Sea anemone toxin II (ATX II)-enhanced INaL density with a reduction of peak sodium currents. In addition, moricizine reduced the Ang II-induced upregulation of phosphorylated calcium/calmodulin-dependent protein kinase-II (p-CaMKII) in both the left and right atria. In HL-1 cells, moricizine also reduced the upregulation of p-CaMKII with Ang II and ATX II intervention, respectively. Conclusions: Our results indicate that Ang II enhances the INaL via activation of CaMKII. Moricizine inhibits INaL and reduces CaMKII activation, which may be one of the mechanisms of moricizine suppression of AF.

Different approaches for ablation of RVOT-type arrhythmia: comparison between the choice of RVOT and pulmonary sinus cusp region for the first ablation attempt.

BACKGROUND: This study aimed (1) to explore the electrophysiological characteristics of the bipolar and unipolar electrograms of ablation targets for RVOT arrhythmias with different ablation methods and to access the clinical outcome with different ablation strategies. METHODS: A consecutive series of 106 patients with RVOT arrhythmias who underwent radiofrequency catheter ablation (RFCA) were studied. Conventional ablation method for RVOT targets and reverse U-curve technique for PSC targets were respectively used with different mapping outcomes. The electrophysiological characteristics of the bipolar and unipolar electrograms for ablation targets and clinical ablation outcome with different ablation strategies were evaluated. RESULTS: When there was an obvious difference (≥ 3 ms) of earliest targets (ETs) between the PSC and RVOT regions, conventional ablation technique in the RVOT region can achieve the same and high success rate compared with the reverse-U ablation technique in the PSC region as we choose the region with a better ET for first ablation attempt. When similar (< 3 ms) ETs were observed in the PSC and RVOT regions, ablation in the PSC region can achieve an apparently higher success rate compared with ablation in the RVOT region. ETs in the PSC region had a different pattern of bipolar potential compared with those in the RVOT region, as a discrete sharp near-field potential or a fractionated potential with low voltage was more frequently observed in the PSC region. CONCLUSIONS: Different mapping outcomes led to different success rate with two ablation strategies. When similar ETs were observed in the PSC and RVOT regions, ablation in the PSC region could achieve an apparently higher success rate. A discrete sharp or fractionated potential could help to identify the sites of PVCs' origination.

Exosomes and Exosomal Non-coding RNAs Are Novel Promises for the Mechanism-Based Diagnosis and Treatments of Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia worldwide and has a significant impact on human health and substantial costs. Currently, there is a lack of accurate biomarkers for the diagnosis and prognosis of AF. Moreover, the long-term efficacy of the catheter ablation in the AF is unsatisfactory. Therefore, it is necessary to explore new biomarkers and treatment strategies for the mechanism-based AF. Exosomes are nano-sized biovesicles released by nearly all types of cells. Since the AF would be linked to the changes of the atrial cells and their microenvironment, and the AF would strictly influence the exosomal non-coding RNAs (exo-ncRNAs) expression, which makes them as attractive diagnostic and prognostic biomarkers for the AF. Simultaneously, the exo-ncRNAs have been found to play an important role in the mechanisms of the AF and have potential therapeutic prospects. Although the role of the exo-ncRNAs in the AF is being actively investigated, the evidence is still limited. Furthermore, there is a lack of consensus regarding the most appropriate approach for exosome isolation and characterization. In this article, we reviewed the new methodologies available for exosomes biogenesis, isolation, and characterization, and then discussed the mechanism of the AF and various levels and types of exosomes relevant to the AF, with the special emphasis on the exo-ncRNAs in the diagnosis, prognosis, and treatment of the mechanism-based AF.

Six-Year Follow-Up Outcomes of Catheter Ablation of Para-Hisian Accessory Pathways.

Background: Ablation of para-hisian accessory pathways (APs) remains challenging due to anatomic characteristics, and a few studies have focused on the causes for recurrence of radiofrequency ablation of para-hisian APs. Objective: This retrospective single center study aimed to explore the risk factors for recurrence of para-hisian APs. Methods: One hundred thirteen patients who had para-hisian AP with an acute success were enrolled in the study. In the 6-year follow-up, 15 cases had a recurrent para-hisian AP. Therefore, 98 patients were classified into the success group, while 15 patients were classified into the recurrence group. Demographic and ablation characteristics were analyzed. Results: Gender difference was similar in two groups. The median age was 36.2 years old and was younger in the recurrence group. Maximum ablation power was significantly higher in the success group (29 ± 7.5 vs. 22.9 ± 7.8, p < 0.01). Ablation time of final target sites was found to be markedly higher in the success group (123.4 ± 53.1 vs. 86.7 ± 58.3, p < 0.05). Ablation time <60 s was detected in 12 (12.2%) cases in the success group and 7 (46.7%) cases in the recurrence group (p < 0.01). Occurrence of junctional rhythm was significantly higher in the recurrence group (25.5% vs. 53.3%, p < 0.05). No severe conduction block, no pacemaker implantation, and no stroke were reported. Junctional rhythm during ablation (OR = 3.833, 95% CI 1.083-13.572, p = 0.037) and ablation time <60 s (OR = 5.487, 95% CI 1.411-21.340, p = 0.014) were independent risk factors for the recurrence of para-hisian AP. Conclusions: With careful and accurate mapping, it is relatively safe to ablate para-hisian AP. If possible, proper extension of ablation time could reduce the recurrence rate of para-hisian APs.

Pulmonary artery pressure is associated with mid-term major adverse cardiovascular events and postprocedure pericardial effusion in atrial fibrillation patients undergoing left atrial appendage occlusion.

BACKGROUND: Patients with nonvalvular atrial fibrillation (NVAF) undergoing left atrial appendage occlusion (LAAO) are at high risk of stroke or bleeding. However, risk factors for their adverse cardiovascular events remain largely unknown. Pulmonary hypertension has been shown to be related to poor prognosis in many heart diseases. In this study, we determined whether elevated pulmonary artery systolic pressure (PASP) is associated with postprocedure adverse events and major adverse cardiovascular events (MACE) in these patients. METHODS: From June 2017 and December 2019, 530 consecutive patients with NAVF at high risk of stroke or bleeding who undergone LAAO were retrospectively enrolled in our study. The preprocecure PASP was obtained by transthoracic echocardiography using the simplified Bernoulli's equation. Patients were followed-up through clinic visits or over the phone at discharge at 1-3 months, 6 months, and annually thereafter. The median follow-up time was 12 months, and clinical data were analyzed. MACE was defined as myocardial infarction, definite heart failure, stroke, or all-cause death. The outcome of postprocedure pericardial effusion included in-hospital pericardial effusion and pericardial effusion detected after discharge. RESULTS: Univariate analyses indicated that patients who had MACE tended to have elevated PASP (P=0.005). After dividing the cohort according to the cut-off value of PASP, Kaplan-Meier curves indicated that patients with PASP ≥39.5 mmHg had a higher risk of MACE (P=0.007) and heart failure hospitalization (P=0.005) compared to patients whose PASP <39.5 mmHg. Cox regression analysis showed that PASP was a predominant risk factor of MACE (HR =2.337, 95% CI, 1.207-4.526, P=0.012) and heart failure hospitalization (HR =3.701, 95% CI, 1.118-12.251, P=0.032). Furthermore, the PASP cut-off added incremental discriminatory capacity to the MACE risk model of this cohort. In addition, logistic regression showed that PASP had as a significant association with postprocedure pericardial effusion (OR =1.061, P=0.032). CONCLUSIONS: Elevated PASP was associated with postprocedure pericardial effusion and mid-term MACEs in patients with atrial fibrillation (AF) undergoing LAAO.

The De Winter-like electrocardiogram pattern in inferior and lateral leads associated with left circumflex coronary artery occlusion.

The aim of this report was to investigate coronary artery occlusion related to De Winter-like electrocardiogram (ECG) pattern. A patient admitted to Zhongshan Hospital who was diagnosed with acute coronary syndrome with De Winter-like ECG pattern was reviewed in our case report. In this case, we found that a De Winter-like ECG change in the inferior and lateral leads was associated with left circumflex coronary artery occlusion. After a timely reperfusion therapy, the symptom was obviously alleviated with a normalization of upsloping ST-segment. Doctors should be aware that De Winter-like ECG changes can also predict acute occlusion in any coronary artery, not only in the left anterior descending artery and right coronary artery but also in the left circumflex coronary artery.

Cardiovascular manifestations in severe and critical patients with COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could cause virulent infection leading to Corona Virus Disease 2019 (COVID-19)-related pneumonia as well as multiple organ injuries. HYPOTHESIS: COVID-19 infection may result in cardiovascular manifestations leading to worse clinical outcome. METHODS: Fifty four severe and critical patients with confirmed COVID-19 were enrolled. Risk factors predicting the severity of COVID-19 were analyzed. RESULTS: Of the 54 patients (56.1 ± 13.5 years old, 66.7% male) with COVID-19, 39 were diagnosed as severe and 15 as critical cases. The occurrence of diabetes, the level of D-dimer, inflammatory and cardiac markers in critical cases were significantly higher. Troponin I (TnI) elevation occurred in 42.6% of all the severe and critical patients. Three patients experienced hypotension at admission and were all diagnosed as critical cases consequently. Hypotension was found in one severe case and seven critical cases during hospitalization. Sinus tachycardia is the most common type of arrythmia and was observed in 23 severe patients and all the critical patients. Atrioventricular block and ventricular tachycardia were observed in critical patients at end stage while bradycardia and atrial fibrillation were less common. Mild pericardial effusion was observed in one severe case and five critical cases. Three critical cases suffered new onset of heart failure. Hypotension during treatment, severe myocardial injury and pericardial effusion were independent risk factors predicting the critical status of COVID-19 infection. CONCLUSION: This study has systemically observed the impact of COVID-19 on cardiovascular system, including myocardial injury, blood pressure, arrythmia and cardiac function in severe and critical cases. Monitoring of vital signs and cardiac function of COVID-19 patients and applying potential interventions especially for those with hypotension during treatment, severe myocardial injury or pericardial effusion, is of vital importance.

A new quantitative mapping criterion to localize the ablation target of right ventricular outflow tract arrhythmias.

PURPOSE: (1) To explore the electrophysiological characteristics of the bipolar and unipolar electrogram (UEGM) of ablation targets for RVOT arrhythmias. (2) To optimize the diagnostic criteria of RVOT arrhythmia ablation targets. METHODS AND RESULTS: A consecutive series of 111 patients with RVOT arrhythmias who underwent radiofrequency catheter ablation (RFCA) were studied. The voltage of bipolar potential for ablation targets were evaluated by three-dimensional voltage mapping procedure. The max slope of the descending limb (MSDL)、local activation preceding time (LAPT), the interval of the descending limb (IDL) and the interval of MSDL (IMSDL) of the unipolar potential were then calculated and analyzed for successful targets(ST) and failed targets(FT)groups. Successful ablation was achieved in 102 patients and 9 patients failed. LAPT was higher in the ST group than that in FT group (30.0 ± 4.3 ms vs 22.8 ± 6.3 ms, P < 0.001). IMSDL was lower in the ST group than that in FT group (9.93 ± 6.32 ms vs 21.7 ± 16.1 ms, P < 0.001). IMSDL and LAPT have a predictive value for a ST (AUC 75% and 83.7%). The optimal cut off value for LAPT and IMSDL were 24.5 ms and 20 ms respectively. A better predictive value can be acquired when IMSDL and LAPT were used in combination (AUC 93.9%, Sensibility/Specificity 92.3%/84.2%). CONCLUSION: A combined use of LAPT and IMSDL may be helpful as an additional criterion for ST judgement.

Assessment of subtle cardiac dysfunction in patients with frequent premature ventricular complexes by real-time three-dimensional speckle tracking echocardiography.

BACKGROUND: To evaluate subtle and early premature ventricular complex (PVC)-induced ventricular impairment in patients with frequent PVCs and without structural heart disease by real-time 3-dimensional (3D) speckle tracking echocardiography (RT3D-STE). HYPOTHESIS: Patients with frequent premature ventricular complexes with normal left ventricular ejection fraction have subtle left ventricular dysfunction. METHODS: Forty patients (22 male) with a single source of frequent PVCs and 40 healthy controls (24 male) underwent assessment by conventional 2-dimensional (2D) echocardiography and RT3D-STE. Left ventricular ejection fraction (LVEF), and global longitudinal, circumferential, radial, and area strain (GLS, GCS, GRS, and GAS, respectively) and individual segment strain were calculated using off-line analysis software and compared between the 2 groups. RESULTS: There were no significant differences in baseline clinical or 2D echocardiographic variables including LVEF between groups. However, all RT3D-STE assessed variables, including GLS, GCS, GRS, GAS, and individual segment strain, were significantly lower (P < 0.05) in the PVC group than the control group, and showed strong correlations, most prominently GCS (r = -0.84, P = 0.020), with LV function as assessed by LVEF. 3D-STE measurements showed good intraobserver, interobserver, and test-retest agreement. CONCLUSIONS: In patients with frequent PVCs and normal LVEF, 3D -STE revealed lower global and regional strain values than in healthy controls. RT3D-STE is a novel, feasible and reproducible method to assess cardiac function and appears suitable to detect subtle left ventricular dysfunction.