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Abstract Background Despite improvement in treatment strategies for atrial fibrillation (AF), a significant proportion of patients still experience recurrence after ablation. This study aims to propose a novel algorithm based on Transformer using surface electrocardiogram (ECG) signals and clinical features can predict AF recurrence. Methods Between October 2018 to December 2021, patients who underwent index radiofrequency ablation for AF with at least one standard 10-second surface ECG during sinus rhythm were enrolled. An end-to-end deep learning framework based on Transformer and a fusion module was used to predict AF recurrence using ECG and clinical features. Model performance was evaluated using areas under the receiver operating characteristic curve (AUROC), sensitivity, specificity, accuracy and F1-score. Results A total of 920 patients (median age 61 [IQR 14] years, 66.3% male) were included. After a median follow-up of 24 months, 253 patients (27.5%) experienced AF recurrence. A single deep learning enabled ECG signals identified AF recurrence with an AUROC of 0.769, sensitivity of 75.5%, specificity of 61.1%, F1 score of 55.6% and overall accuracy of 65.2%. Combining ECG signals and clinical features increased the AUROC to 0.899, sensitivity to 81.1%, specificity to 81.7%, F1 score to 71.7%, and overall accuracy to 81.5%. Conclusions The Transformer algorithm demonstrated excellent performance in predicting AF recurrence. Integrating ECG and clinical features enhanced the models’ performance and may help identify patients at low risk for AF recurrence after index ablation.

Abstract Background Ventricular tachycardia (VT) is the primary cause of sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). However, the strategy for VT treatment in HCM patients remains unclear. This study is aimed to compare the effectiveness of catheter ablation versus antiarrhythmic drug (AAD) therapy for sustained VT in patients with HCM. Methods A total of 28 HCM patients with sustained VT at 4 different centers between December 2012 and December 2021 were enrolled. Twelve underwent catheter ablation (ablation group) and sixteen received AAD therapy (AAD group). The primary outcome was VT recurrence during follow-up. Results Baseline characteristics were comparable between two groups. After a mean follow-up of 31.4 ± 17.5 months, the primary outcome occurred in 35.7% of the ablation group and 90.6% of the AAD group (hazard ratio [HR], 0.29 [95%CI, 0.10–0.89]; P = 0.021). No differences in hospital admission due to cardiovascular cause (25.0% vs. 71.0%; P = 0.138) and cardiovascular cause-related mortality/heart transplantation (9.1% vs. 50.6%; P = 0.551) were observed. However, there was a significant reduction in the composite endpoint of VT recurrence, hospital admission due to cardiovascular cause, cardiovascular cause-related mortality, or heart transplantation in ablation group as compared to that of AAD group (42.9% vs. 93.7%; HR, 0.34 [95% CI, 0.12–0.95]; P = 0.029). Conclusions In HCM patients with sustained VT, catheter ablation reduced the VT recurrence, and the composite endpoint of VT recurrence, hospital admission due to cardiovascular cause, cardiovascular cause-related mortality, or heart transplantation as compared to AAD.

Summary: Background: Previous trials of renal denervation (RDN) have been designed to investigate reduction of blood pressure (BP) as the primary efficacy endpoint using non-selective RDN without intraoperatively verified RDN success. It is an unmet clinical need to map renal nerves, selectively denervate renal sympathetic nerves, provide readouts for the interventionalists and avoid futile RDN. We aimed to examine the safety and efficacy of renal nerve mapping/selective renal denervation (msRDN) in patients with uncontrolled hypertension (HTN) and determine whether antihypertensive drug burden is reduced while office systolic BP (OSBP) is controlled to target level (＜140 mmHg). Methods: We conducted a randomized, prospective, multicenter, single-blinded, sham-controlled trial. The study combined two efficacy endpoints at 6 months as primary outcomes: The control rate of patients with OSBP ＜140 mmHg (non-inferior outcome) and change in the composite index of antihypertensive drugs (Drug Index) in the treatment versus Sham group (superior outcome). This design avoids confounding from excess drug-taking in the Sham group. Antihypertensive drug burden was assessed by a composite index constructed as: Class N (number of classes of antihypertensive drugs) × (sum of doses). 15 hospitals in China participated in the study and 220 patients were enrolled in a 1:1 ratio (msRDN vs Sham). The key inclusion criteria included: age (18–65 years old), history of essential HTN (at least 6 months), heart rate (≥70 bpm), OSBP (≥150 mmHg and ≤180 mmHg), ambulatory BP monitoring (ABPM, 24-h SBP ≥130 mmHg or daytime SBP ≥135 mmHg or nighttime SBP ≥120 mmHg), renal artery stenosis (＜50%) and renal function (eGFR ＞45 mL/min/1.73 m2). The catheter with both stimulation and ablation functions was inserted in the distal renal main artery. The RDN site (hot spot) was selected if SBP increased (≥5 mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was performed at the same site. At sites where there was decreased SBP (≥5 mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was performed. The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested then either treated or avoided. After msRDN, patients had to follow a predefined, vigorous drug titration regimen in order to achieve target OSBP (＜140 mmHg). Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine. This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing. Findings: Between July 8, 2016 and February 23, 2022, 611 patients were consented, 220 patients were enrolled in the study who received standardized antihypertensive drug treatments (at least two drugs) for at least 28 days, presented OSBP ≥150 mmHg and ≤180 mmHg and met all inclusion and exclusion criteria. In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively. Hot, cold and neutral spots was 48.0%, 27.5% and 24.4% of total mapped sites, respectively. At 6 M, the Control Rate of OSBP was comparable between msRDN and Sham group (95.4% vs 92.8%, p = 0.429), achieved non-inferiority margin −10% (2.69%; 95% CI −4.11%, 9.83%, p ＜ 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to Sham group (4.37 (6.65) vs 7.61 (10.31), p = 0.010) and superior to Sham group (−3.25; 95% CI −5.56, −0.94, p = 0.003), indicating msRDN patients need significantly fewer drugs to control OSBP ＜140 mmHg. 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and Sham groups, respectively (p 0.05 between groups). Safety profiles were comparable between msRDN and Sham groups, demonstrating the safety and efficacy of renal mapping/selective RDN to treat uncontrolled HTN. Interpretation: The msRDN therapy achieved the goals of reducing the drug burden of HTN patients and controlling OSBP

Abstract On May 27, 2022, the Asia Pacific Heart Rhythm Society and the Heart Rhythm Society convened a meeting of leaders from different professional societies of healthcare providers committed to arrhythmia care from the Asia Pacific region. The overriding goals of the meeting were to discuss clinical and health policy issues that face each country for providing care for patients with electrophysiologic issues, share experiences and best practices, and discuss potential future solutions. Participants were asked to address a series of questions in preparation for the meeting. The format of the meeting was a series of individual country reports presented by the leaders from each of the professional societies followed by open discussion. The recorded presentations from the Asia Summit can be accessed at https://www.heartrhythm365.org/URL/asiasummit‐22. Three major themes arose from the discussion. First, the major clinical problems faced by different countries vary. Although atrial fibrillation is common throughout the region, the most important issues also include more general issues such as hypertension, rheumatic heart disease, tobacco abuse, and management of potentially life‐threatening problems such as sudden cardiac arrest or profound bradycardia. Second, there is significant variability in the access to advanced arrhythmia care throughout the region because of differences in workforce availability, resources, drug availability, and national health policies. Third, collaboration in the area already occurs between individual countries, but no systematic regional method for working together is present.

Abstract Background Pulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation. General anesthesia (GA) resolves the problem of pain intolerability and provides regular respiratory mode which might improve the catheter maneuverability of AF ablation. This study aims to compare the procedural performance of PVI under GA versus conscious sedation (CS) from multiple perspectives. Methods A total of 36 consecutive patients undergoing first AF ablation under GA were enrolled in GA group. Another 109 patients receiving AF ablation under CS in the same period were selected as the control group. After propensity score matching, 29 matched pairs with similar baseline characteristics were available for further analysis. The AIFV (using AI to analyze the raw data from CARTO3 system) system was used to evaluate six procedural parameters in each PVI procedure. Results Compared with CS, PVI under GA had a significantly shorter total PVI time (51.4 min vs. 67.8 min; p = .003) and higher radiofrequency ratio (62.6% vs. 55.8%; p = .032). The number of gaps (1.0 vs. 3.0; p

Abstract Background Catheter ablation is recommended in patients with frequent and symptomatic ventricular arrhythmias (VAs) in an otherwise normal heart. Right or left outflow tract (OT) are the most common origins, and catheter ablation is highly effective with low complication rates. However, outcome of catheter ablation of VAs other than the OT (non-OTVAs) is limited. The aim of this single-center study was to assess the safety and mid-term outcome of catheter ablation for non-OTVAs. Method and Results From 2013 to 2018, 251 patients who underwent catheter ablation for idiopathic non-OTVAs were enrolled and grouped according to the origins including His-Purkinje system (HPS, n = 108), papillary muscle / moderator band (PM/MB, n = 47), tricuspid annulus (TA, n = 70), and mitral annulus (MA, n = 26), 244 (97.2%) had acute elimination of VAs. The time of VAs recurrence of the single procedure was 1.69 (0.12,9.72) months, with 66% occurring within the first 3 months. The recurrence rate was significantly higher in the PM/MB group than in the TA (p = 0.025) and MA groups (p = 0.023). The single procedure success rate in all patients was 70.1%, in which 66.7%, 59.6%, 80%, and 76.9% were achieved in the HPS, PM/MB, TA, and MA groups, respectively (p = 0.284). After multiple procedures, the total success rate was 76.5% at the follow-up of 4.38 ± 2.42 years. The rate was significantly lower in the PM/MB group than in the TA group (p = 0.035). In subgroup analysis, no significant difference was observed in the recurrence rate of single procedure in patients with different VA origins within the PM/MB (log-rank test, p = 0.546). Conclusion Despite a certain percentage of recurrences observed in the mid-term follow-up, catheter ablation remained feasible and effective for idiopathic non-OTVAs.

Background This study aimed to investigate the predictive value of parameters of every precordial lead and their combinations in differentiating between idiopathic ventricular arrhythmias (IVAs) from the right ventricular outflow tract and aortic sinus of Valsalva (ASV). Methods and Results Between March 1, 2018, and December 1, 2021, consecutive patients receiving successful ablation of right ventricular outflow tract or ASV IVAs were enrolled. The amplitude and duration of the R wave and S wave were measured in every precordial lead during IVAs. These parameters were either summed, subtracted, multiplied, or divided to create different indexes. The index with the highest area under the curve to predict ASV IVAs was developed, compared with established indexes, and validated in an independent prospective multicenter cohort. A total of 150 patients (60 men; mean age, 45.3±16.4 years) were included in the derivation cohort. The RV1+RV3 index (summed R‐wave amplitude in leads V1 and V3) had the highest area under the curve (0.942) among the established indexes. An RV1+RV3 index >1.3 mV could predict ASV IVAs with a sensitivity of 95% and a specificity of 83%. Its predictive performance was maintained in the validation cohort (N=109). In patients with V3 R/S transition, an RV1+RV3 index >1.3 mV could predict ASV IVAs, with an area under the curve of 0.892, 93% sensitivity, and 75% specificity. Conclusions The RV1+RV3 index is a simple and novel criterion that accurately differentiates between right ventricular outflow tract and ASV IVAs. Its performance outperformed established indexes, making it a valuable tool in clinical practice.

Abstract Background The autonomic nervous system can be responsible for the initiation and maintenance of arrhythmias. Low-level tragus stimulation (LLTS), a noninvasive form of autonomic neuromodulation, has been shown to be effective in treating atrial fibrillation. We intended to treat frequent premature ventricular complexes (PVCs) with LLTS. Methods and design The present study will be a prospective multicenter, double-blind, randomized, controlled trial to assess the antiarrhythmic effects of LLTS on frequent PVCs in patients without structured heart disease (SHD). A total of 100 patients with PVC burden > 10% will be randomly assigned to the active or sham LLTS in 1:1 fashion and receive the proposed intervention for 6 months. The primary outcome is PVC burden at 6 months as assessed by 10 days of continuous ambulatory electrocardiographic monitoring. Secondary outcomes include heart rate variability (HRV), quality of life, skin sympathetic nerve activity, and inflammatory markers. Adverse events will also be recorded. Discussion The present trial will be the first to evaluate the effect of LLTS on frequent PVCs on patients without SHD. LLTS may serve as a low-cost, minimal-risk, and non-invasive alternative to conventional antiarrhythmic therapy. Trial registration ClinicalTrial.gov NCT04909528. Registered on 17 June 2021. World health organization trial registration data set was shown in Supplementary Table 1.

Background: Previous studies have reported the direct or indirect relationship between the renin-angiotensin-aldosterone system (RAAS) and atrial fibrillation (AF). However, in patients with “apparently” idiopathic AF without possible external influence, whether RAAS is dysregulated at an early stage of AF and its relationship with the recurrence of AF after ablation have not been studied. Methods: This single-center, prospective, case-control study included apparently healthy individuals with AF (the case group) or paroxysmal supraventricular tachycardia (PSVT, the control group) referred for catheter ablation at the same period. The primary outcome was RAAS activation in these two groups. The secondary outcome was the 1-year recurrence of AF after ablation. Results: This study included 51 “apparently” idiopathic AF and 91 patients with PSVT. A greater proportion of patients in the case group had plasma renin activity (PRA) levels

Abstract Objective A rapid and accurate forecast for the early prognosis of ICH patients is challenging. This study investigated whether heart rate variability (HRV) and skin sympathetic nerve activity (SKNA) could prognosticate poor neurological outcomes in ICH patients. Methods Between November 2020 and November 2021, we studied 92 spontaneous ICH patients in the First Affiliated Hospital of Nanjing Medical University. Glasgow Outcome Scale (GOS) score at 2 weeks after the ICH was used to categorize patients into good and poor outcome groups. The modified Rankin Scale (mRS) assessed patients' ability to live independently for 1 year. We utilized a portable high‐frequency electrocardiogram (ECG) recording system to record the HRV and SKNA information in ICH patients and control participants. Results 77 patients were eligible for the prediction of neurological outcome and were allocated into the good (n = 22) or poor (n = 55) outcome groups based on the GOS grade. In univariate logistic regression analysis, significant variables that could differentiate the outcomes were age, hypertension, tracheal intubation, Glasgow Coma Scale (GCS) score, existing intraventricular hemorrhage, white blood cells, neutrophil, lnVLF, lnTP, and aSKNA. Variables in the best fit multivariable logistic regression model were age, hypertension, GCS score, neutrophils, and aSKNA. The GCS score was the only independent risk factor for poor outcomes. At 30 days and 1 year of follow‐up, patients with lower aSKNA had poor outcomes. Interpretation ICH patients had reduced aSKNA, which could be a prognostic indicator. A lower aSKNA suggested a worse prognosis. The present data indicate that ECG signals could be helpful for prognosticating ICH patients.

Abstract Background The study aimed to assess the correlation between the monitoring frequency of PT-INR and the long-term prognosis in patients with mechanical heart valve (MHV) replacement after discharge. Methods This single-center, observational study enrolled patients who underwent MHV replacement and discharged from June 2015 to May 2018. Patients or their corresponding family members were followed with a telephone questionnaire survey in July-October 2020. Based on monitoring intervals, patients were divided into frequent monitoring (FM) group (≤ 1 month) and less frequent monitoring (LFM) group (> 1 month). The primary endpoint was the composite of thromboembolic event, major bleeding or all-cause death. The secondary endpoints were thromboembolic event, major bleeding or all-cause death, respectively. Results A total of 188 patients were included in the final analysis. The median follow-up duration was 3.6 years (Interquartile range: 2.6 to 4.4 years). 104 (55.3%) patients and 84 (44.7%) patients were classified into the FM group and the LFM group, respectively. The FM group had a significantly lower incidence of the primary endpoint than the LFM group (3.74 vs. 1.16 per 100 patient-years, adjusted HR: 3.31 [95% CI 1.05–10.42, P = 0.041]). Secondary analysis revealed that the risk of thromboembolic events and all-cause death were also reduced in the FM group. Conclusions The management of warfarin treatment in patients after MHV replacement remains challenging. Patients with less frequent monitoring of PT-INR might have worse clinical prognosis than those with frequent PT-INR monitoring.

Background: Ibrutinib could increase the risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL) patients. However, the precise mechanism underlying ibrutinib-induced AF remains incompletely elucidated. Methods: We investigated the proportion of ibrutinib-treated CLL patients with new-onset AF. Optical mapping was conducted to reveal the proarrhythmic effect of ibrutinib on HL-1 cells. Fluorescence staining and western blot were used to compare connexins 43 and 40 expression in ibrutinib-treated and control groups. To identify autophagy phenotypes, we used western blot to detect autophagy-related proteins, transmission electron microscopy to picture autophagosomes, and transfected mCherry-GFP-LC3 virus to label autophagosomes and lysosomes. Hydroxychloroquine as an autophagy inhibitor was administered to rescue ibrutinib-induced Cx43 and Cx40 degradation. Results: About 2.67% of patients developed atrial arrhythmias after ibrutinib administration. HL-1 cells treated with ibrutinib exhibited diminished conduction velocity and a higher incidence of reentry-like arrhythmias compared to controls. Cx43 and Cx40 expression reduced along with autophagy markers increased in HL-1 cells treated with ibrutinib. Inhibiting autophagy upregulated Cx43 and Cx40. Conclusions: The off-target effect of ibrutinib on the PI3K-AKT-mTOR signaling pathway caused connexin degradation and atrial arrhythmia via promoting autophagy. Clinical Trial Registration: ChiCTR2100046062, https://clin.larvol.com/trial-detail/ChiCTR2100046062.

Heart-on-chip emerged as a potential tool for cardiac tissue engineering, recapitulating key physiological cues in cardiac pathophysiology. Controlled electrical stimulation and the ability to provide directly analyzed functional readouts are essential to evaluate the physiology of cardiac tissues in the heart-on-chip platforms. In this scenario, a novel heart-on-chip platform integrating two soft conductive hydrogel pillar electrodes was presented here. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts were seeded into the apparatus to create 3D human cardiac tissues. The application of electrical stimulation improved functional performance by altering the dynamics of tissue structure and contractile development. The contractile forces that cardiac tissues contract was accurately measured through optical tracking of hydrogel pillar displacement. Furthermore, the conductive properties of hydrogel pillars allowed direct and non-invasive electrophysiology studies, enabling continuous monitoring of signal changes in real-time while dynamically administering drugs to the cardiac tissues, as shown by a chronotropic reaction to isoprenaline and verapamil. Overall, the platform for acquiring contractile force and electrophysiological signals in situ allowed monitoring the tissue development trend without interrupting the culture process and could have diverse applications in preclinical drug testing, disease modeling, and therapeutic discovery.

To assess the prevalence and management of atrial thrombus in patients with nonvalvular atrial fibrillation (NVAF) and identify the risk factors of the nonresolution of atrial thrombus. This single-center retrospective observational study consecutively enrolled patients with NVAF and atrial thrombus detected using transesophageal echocardiography (TEE) or cardiac computed tomography angiography (CTA) from January 2012 to December 2020. Patients with prior left atrial appendage (LAA) intervention were excluded. The primary endpoint was the presence of atrial thrombus, while the secondary endpoint was the complete resolution of atrial thrombus. The prevalence of atrial thrombus in patients with NVAF was 1.4%. Ninety patients with atrial thrombus (mean age 62.8 ± 11.9 years and 61.1% men) were finally analyzed. Atrial thrombus was in the LAA in 82 (91.1%) patients. During follow up, 60% of the patients showed complete resolution of atrial thrombus. Congestive heart failure (odds ratio [OR]: 8.94; 95% confidence interval [CI]: 1.67-47.80) and a history of ischemic stroke (OR: 8.28; 95% CI: 1.48-46.42) were independently associated with the risk of the nonresolution of atrial thrombus. The presence of atrial thrombus in patients with NVAF who received anticoagulation therapy is non-negligible. Even in anticoagulated patients, TEE or cardiac CTA might still be needed. Congestive heart failure and a history of ischemic stroke are risk factors of the nonresolution of atrial thrombus.

Abstract Background To assess the clinical outcomes after endovascular thrombectomy (EVT) in elderly large vessel occlusion (LVO)-related acute ischemic stroke (AIS) patients with atrial fibrillation (AF). Methods Between January 2019 and December 2020, consecutive AF patients who received EVT due to anterior-circulation stroke were enrolled. The primary outcome was modified Rankin scale (mRS) score at 90 days. Secondary outcomes included all-cause mortality, the recanalization status after EVT (assessed using modified thrombolysis in cerebral infarction scale, mTICI) and any intracranial hemorrhage (ICH). A multivariate logistic regression model was performed to identify predictors of the functional outcome. Results A total of 148 eligible patients were finally enrolled. Among them, 42 were ≥ 80 years old. Compared to their younger counterparts, patients aged ≥80 years had lower likelihood of good functional outcome (mRS score 0–2) at 90 days (26.2% vs. 48.1%, P = 0.015), less satisfied recanalization (mTICI, 2b-3) (78.6% vs. 94.3%, P = 0.004) and higher all-cause mortality rate (35.7% vs. 14.2%, P = 0.003). A multivariable logistic regression analysis showed that age ≥ 80 years at baseline were the significant predictors for a poor functional outcome (OR: 3.72, 95% CI: 1.17–11.89, p = 0.027). Intravenous thrombolysis (IVT) prior to EVT and longer time intervals from onset of symptoms to EVT tended to be associated with poor functional outcome in patients ≥80 years old. Conclusions Age ≥ 80 years was a significant predictor of unfavorable outcomes after EVT for AIS patients with AF. An increased risk of adverse events must be balanced against the benefit from EVT in elderly patients with AF.

Objectives The initial medical contact of patients with atrial fibrillation (AF) and ischaemic stroke is often performed by neurologists. However, when stand care with oral anticoagulants (OACs) adherence and persistence was emphasised by cardiologists, data regarding the gap between current neurology care and standard care from Chinese tertiary hospitals is scarce and the long-term outcome is unknown. This study was to investigate the AF detection rate, the use of anticoagulation therapy and posthospital clinical outcomes associated with neurology care in patients with AF and ischaemic stroke in China.Design A retrospective cohort study.Setting Clinical data of all patients who had an ischaemic stroke discharged from the neurologic department of a high-volume academic hospital from 1 January 2013 to 31 December 2017 were analysed and patients were followed.Participants Patients diagnosed with ischaemic stroke and AF were included.Main outcome measures The usage of anticoagulation at discharge, the posthospital restroke rate and all-cause mortality.Results Among 5797 patients who had an ischaemic stroke, 373 (6.43%) patients were diagnosed with AF during hospitalisation. Among them, only 198 (53.66%) patients were on anticoagulation therapy at discharge. A total of 325 (88.08%) patients were accessible and received follow-up. After a median 3-year follow-up, 103 (31.69%) patients died due to all causes. Among them, 53 (16.31%) patients died from recurrent stroke. And 86 (26.46%) patients restroked. In multivariable analysis, patients without anticoagulation therapy, muscle strength

BackgroundPulmonary vein isolation (PVI) is the standard ablation strategy for treating atrial fibrillation (AF). However, the optimal strategy of a repeat procedure for PVI non-responders remains unclear.ObjectiveThis study aims to investigate the incidence of PVI non-responders in patients undergoing a repeat procedure, as well as the predictors for the recurrence of repeat ablation.MethodsA total of 276 consecutive patients who underwent repeat ablation from August 2016 to July 2019 in two centers were screened. A total of 64 (22%) patients with durable PVI were enrolled. Techniques such as low voltage zone modification, linear ablation, non-PV trigger ablation, and empirical superior vena cava (SVC) isolation were conducted.ResultsAfter the 20.0 ± 9.9 month follow-up, 42 (65.6%) patients were free from atrial arrhythmias. A significant difference was reported between the recurrent and non-recurrent groups in non-paroxysmal AF (50 vs. 23.8%, p = 0.038), diabetes mellitus (27.3 vs. 4.8%, p = 0.02), and empirical superior vena cava (SVC) isolation (28.6 vs. 60.5%, p = 0.019). Multivariate regression analysis demonstrated that empirical SVC isolation was an independent predictor of freedom from recurrence (95% CI: 1.64–32.8, p = 0.009). Kaplan-Meier curve demonstrates significant difference in recurrence between empirical and non-empirical SVC isolation groups (HR: 0.338; 95% CI: 0.131–0.873; p = 0.025).ConclusionAbout 22% of patients in repeat procedures were PVI non-responders. Non-paroxysmal AF and diabetes mellitus were associated with recurrence post-re-ablation. Empirical SVC isolation could potentially improve the outcome of repeat procedures in PVI non-responders.

Abstract Background Accelerated idioventricular rhythm (AIVR) is often transient, considered benign and requires no treatment. This observational study aims to investigate the clinical manifestations, treatment, and prognosis of frequent AIVR. Methods Twenty-seven patients (20 male; mean age 32.2 ± 17.0 years) diagnosed with frequent AIVR were enrolled in our study. Inclusion criteria were as follows: (1) at least three recordings of AIVR on 24-h Holter monitoring with an interval of over one month between each recording; and (2) resting ectopic ventricular rate between 50 to 110 bpm on ECG. Electrophysiological study (EPS) and catheter ablation were performed in patients with distinct indications. Results All 27 patients experienced palpitation or chest discomfort, and two had syncope or presyncope on exertion. Impaired left ventricular ejection fraction (LVEF) was identified in 5 patients, and LVEF was negatively correlated with AIVR burden (P

BackgroundThere is a paucity of data about VAs clustered at the vicinity of the basal septum of the ventricle. We aimed to report and characterize the clinical and electrophysiological features of basal septum VAs and explore the systematic ablation approach.MethodsA consecutive series of 51 patients who had their VAs successfully ablated at the basal septum of the ventricle was enrolled in this study. The basal septum was defined as the area 2 cm away from the septal annulus, the upper boundary was the site of the left or right His-Purkinje system, and the lower boundary was the borderline that separated away from the septum. RFCA was performed based on detailed activation mapping or pace mapping. Patients who underwent VA ablation from other areas of the tricuspid annulus (TA) and mitral annulus (MA) during the same period were enrolled as the control group.ResultsThe patients with basal septum VAs were significantly older (p < 0.01) and had more comorbidities (hypertension and coronary artery disease) (p < 0.01). Meanwhile, the precordial R wave transition was significantly different in right side, left side and intramural foci group (p < 0.001). Acute procedural success was achieved in 44 patients (86.3%) in the study group and in 63 patients (95.5%) in the control group. After a median of 12 (6–36) months of follow-up, compared with VA recurrence in the control group (2 cases), 11 patients with basal septum VAs had recurrences (p = 0.002), while a delayed cure was observed in 3 in intramural foci group.ConclusionBased on the unique anatomical and electrophysiological characteristics, a systematic approach for VAs originating from the basal septal area is warranted. Moreover, the follow-up data seemed to show a relative high recurrence rate for basal septal VAs during a period of time.

The iPSC line was generated from the peripheral blood mononuclear cells (PBMCs) from a 53-year-old female patient carrying the LMNA gene mutation (c.1304_1307dup) diagnosed with atrial fibrillation and paroxysmal ventricular tachycardia. Through comprehensive detection, it was verified that the cell line had the LMNA gene mutation, normal karyotype, and the potential to differentiate into the three germ layers. This cell line may reveal potential therapeutic targets for atrial and ventricular arrhythmias caused by LMNA mutations.

BackgroundThree-dimensional activation mapping during sinus rhythm can demonstrate the earliest atrial activation (EAA) site, which could be the sinoatrial node (SAN). We aimed to compare the electroanatomical characteristics of superior vena cava (SVC), myocardial sleeve, and SAN between patients with atrial fibrillation (AF) and non-AF.Materials and methodsIn this study, 136 patients with AF were assigned to the study group, and 20 patients with premature ventricular contractions (PVCs) who had no history of AF were assigned to the control group. The right atrium (RA) and SVC anatomical activation models were constructed, and the EAA of SAN was delineated using the CARTO3 mapping system. The length of the SVC myocardial sleeve (LSVC) was measured.ResultsOf the 136 patients, 93 patients had paroxysmal AF (PAF), and 43 patients had persistent AF (PsAF). The LSVC was not significantly different among AF and non-AF, PAF, and PsAF. The LSVC in men was longer than in women (42.1 ± 9.4 mm vs. 35.4 ± 8.1 mm, p < 0.001). The LSVC was longer in patients with EAA of SAN above the RA-SVC junction than in those with below the RA-SVC junction (p < 0.001). The EAA of SAN was below the RA-SVC junction in 64/136 (47.1%) and was above the junction in 72/136 (52.9%) patients with AF. The spatial distribution of the EAA of SAN between PAF and PsAF was not different. There was a trend of statistical difference in the distribution of the EAA of SAN between PsAF and non-AF.ConclusionThe EAA of SAN was located in the SVC in most of the patients, especially in patients with PsAF.

Abstract Background Deep terminal negativity of the P‐wave in V1 (DTNPV1) was considered if the absolute value of the depth of the negative phase was >100 μV in the presence of a biphasic P‐wave in V1. In this study, we aimed to determine the association between DTNPV1, a simpler P‐wave index, and the risk of stroke. Methods We compared P‐wave indices between participants with and without a self‐reported history of stroke in the United States Third National Health and Nutrition Examination Survey (NHANES III). The association between DTNPV1 and stroke was quantified with logistic regression models. Results In total, 7732 participants were included (307 with a history of stroke). Patients with stroke had deeper terminal negativity of the P‐wave in V1 (52.3 ± 33.9 μV vs. 41.4 ± 27.0 μV, p 0 μV but ≤100 μV and > 100 μV) in V1 (2.8%, 3.3%, and 10.3%, respectively, p = .005). Conclusion In NHANES III, DTNPV1 was associated with a higher prevalence of stroke, suggesting that DTNPV1 might be a convenient marker to distinguish the risk of stroke.

We generated an iPSCs line from the peripheral blood mononuclear cells (PBMCs) collected from a patient with long QT syndrome type 1 (LQT1) via a non-integrating system. We identified and verified a missense mutation in the KCNQ1 gene (c.773A > T) by whole-exome sequencing and Sanger sequencing. The established iPSC line was tested for pluripotency, differentiation potential, and karyotype. This cell-based model can help study the molecular mechanism and develop personalized drug therapies for LQT1.

BackgroundNon-valvular atrial fibrillation (NVAF) in patients at low risk of thromboembolism (TE) does not mean “no risk.” We sought to assess the risk factors associated with TE in clinically low-risk AF patients with a non-gender CHA2DS2-VASc score (CHA2DS2-VA score) of 0 or 1.MethodsIn this single-center cross-sectional study, NVAF patients with a CHA2D-VA score of 0 or 1 who underwent index high-density bipolar voltage mapping of the left atrium (LA) and AF ablation were consecutively enrolled from 2017 to 2020. The population was divided into patients with and without TE history before voltage mapping. AF patients with CHA2DS2-VA score of 0 to 1 before TE (TE group) were analyzed and compared with clinically low-risk AF patients without TE history (non-TE group). The association among LA low voltage area (LVA), other clinical factors and TE history was analyzed with logistic regression.ResultsIn the TE group, LVA was more prevalent [15/25 (60%) vs. 105/359 (29.2%), p = 0.003] and more preferentially located at the anterior wall [8/15 (53%) vs. 24/105 (23%), p = 0.025]. Among patients with LVA, the activation time from the sinus node to the left atrial appendage was significantly longer in the TE group (77.09 ± 21.09 vs. 57.59 ± 15.19 ms, p < 0.001). Multivariate analysis demonstrated that LVA at the anterior wall of the LA [OR: 4.17 (95% CI: 1.51 to 11.51); p = 0.006] and being female [OR: 3.40 (95% CI: 1.36 to 8.51); p = 0.009] were associated with TE history.ConclusionsLVA at the anterior wall of the LA is associated with TE history in NVAF patients with a low CHA2DS2-VA score.

Background: Autonomic nervous regulation plays a critical role in end-stage kidney disease (ESKD) patients with cardiovascular complications. However, studies on autonomic regulation in ESKD patients are limited to heart rate variability (HRV) analysis. Skin sympathetic nerve activity (SKNA), which noninvasively reflects the sympathetic nerve activity, has not been used in ESKD patients.Methods: Seventy-six patients on maintenance hemodialysis (MHD) treatment (a 4-h HD session, three times a week) were enrolled. Utilizing a noninvasive, single-lead, high-frequency recording system, we analyzed the dynamic change in HRV parameters and SKNA during HD. The different characteristics between the subgroups divided based on interdialytic weight gain (IDWG,

Hypoglycemic agents have been shown to reduce the incidence of atrial fibrillation (AF) in patients with diabetes mellitus. Azoramide is a novel anti-diabetic agent which protects cells against endoplasmic reticulum (ER) stress; however, the cardioprotective effect of azoramide against AF is not clear. In this study, we aimed to investigate the protective effect of azoramide in human iPS-derived atrial myocytes (a-iCMs) against injury induced by high-frequency electrical stimulation. Human-induced pluripotent stem cells were differentiated into a-iCMs by treatment of retinoic acid. The tachypacing group was subjected to 7 Hz tachypacing for 48 h. Azoramide was preconditioned 2-hours before tachypacing. a-iCMs expressed atria-specific genes and the characteristics of the action potential were analogous to those of human atrial myocytes. Tachypacing induced disorder of intracellular calcium homeostasis, apoptosis, depressed ATP level, and severer myofilament dissolution. MetaboAnalysis revealed that tachypacing induced remarkable changes in metabolites involved in energy, amino acid, and glucose metabolism, whereas there was no significant effect on lipid metabolism. Azoramide pretreatment partly alleviated tachypacing-induced calcium dyshomeostasis, ATP consumption, and accelerated apoptosis, which was likely achieved by regulating the PERK/CHOP/CaMKII pathway. Azoramide protected atrial myocytes against injury induced by high-frequency electrical stimulation by regulating ER stress, which may inhibit cell apoptosis and calcium dyshomeostasis via the PERK/CHOP/CaMKII pathway.

PRKAG2 cardiomyopathy is a rare progressive disease characterized by increased ventricular wall thickness and preexcitation. Dysfunction of the protein 5′-AMP-activated protein kinase (AMPK) plays a decisive role in the progression of ventricular lesions. Although patients with the PRKAG2-R302Q mutation have a high incidence of atrial fibrillation (AF), the molecular mechanism contributing to the disease remains unclear. We carried out whole-genome sequencing with linkage analysis in three affected members of a family. Atrial samples were obtained from the proband via surgical intervention. Control atrium biopsies were obtained from patients with persistent AF. Pathological changes were analyzed using the hematoxylin and eosin (H&E), Masson, and periodic acid–Schiff (PAS) staining. The AMPK signaling pathway was investigated by western blot. A murine atrial cardiomyocyte cell line (HL-1) and human induced pluripotent stem derived atrial cardiomyocytes (hiPSC-ACMs) were transfected with an adenovirus carrying the same mutation. We used enzyme linked immunosorbent assay (ELISA) to determine the AMPK activity in HL-1 cells and hiPSC-ACMs overexpressing PRKAG2-R302Q. Pathological results showed a large quantity of glycogen accumulation and vacuolization in cardiomyocytes from the proband atrial tissue. Western blot analysis revealed that the AMPK activity was significantly downregulated compared with that of the controls. Furthermore, remarkable glycogen deposition and impairment of AMPK activity were reproduced in HL-1 cells overexpressing PRKAG2-R302Q. Taken together, PRKAG2-R302Q mutation directly impair atrial cardiomyocytes. PRKAG2-R302Q mutation lead to glycogen deposition and promote the growth of atrial lesions by disrupting the AMPK pathway.

BackgroundLeft anterior fascicle (LAF) premature ventricular contractions (PVC) are rarely reported. We described the electrocardiographic and electrophysiological characteristics of PVCs originating from LAF and evaluated the results of catheter ablation.MethodsThe baseline AH and HV intervals were recorded during normal sinus rhythm (NSR), and the HV interval of LAF-PVC was measured during the procedure. During the index procedure, the conduction interval from the earliest Purkinje potential (PP) site to the His was labeled as time A, the conduction interval from the earliest site to the onset of the QRS as time B, then the HV interval during NSR (HVNSR) is A + B, and the HV interval during PVC (HVPVC) is B-A; a predicted PP time was calculated using HVNSR and HVPVC. The calculated formula is as follows: Predicted target PP = (HVNSR + HVPVC)/2. During the repeat procedure, the mapping strategy only focuses on the earliest retrograde PP due to the injury or block of LAF sustained at the index procedure.ResultsNotably, 24 patients with LAF-PVC were included. The ECG characteristics of PVC exhibited right bundle branch block (RBBB) morphology with right-axis deviation (RAD) in 18 patients and only RAD in 6 patients. The QRS durations of NSR and PVC were 78.8 ± 7.9 and 106.8 ± 12.3 ms, respectively. There was no significant difference between the predicted and mapped PP site (31.5 ± 8.1 vs. 30.6 ± 7.8 ms; P = 0.17). There was a significant difference between the mean axis deviation before and after ablation (46.3 ± 25.4° vs. 18.3 ± 44.1°; P = 0.001); however, only 10 patients had a complete LAF block. Eight patients had a recurrence, the QRS morphology of LAF-PVC became narrower (95.9 ± 17.2 vs. 105.3 ± 16.9 ms, P = 0.003), and 4 patients’s PVC QRS morphology was similar to NSR. During the repeat procedure, the earliest retrograde PP interval was longer than the index procedure in four patients (12.0 ± 1.9 vs. 37.8 ± 1.1 ms; P < 0.001).ConclusionThe target PP site for ablation of the LAF region can be calculated using the HV interval during NSR and PVC at the index procedure. The mapping strategy at repeat procedures focused on the earliest retrograde PP interval.

The Coronavirus Disease 2019 (COVID-19) pandemic has caused numerous unexpected changes for families and societies, which have likely contributed to higher amounts of stress for most parents. This study aimed to examine the relationship between burnout and mental health among parents during the COVID-19. Pandemic exposure and household factors (e.g., family structure, family function) were examined as moderators. An online cross-sectional survey recruiting 1,209 adults was conducted from April 21st to April 28th, 2020 during the COVID-19 lockdown in China. The multivariable linear regression analysis was employed to test the association between burnout, household factors, and mental health among parents. Findings suggested that for parents with a young child, poorer mental health was related to a higher level of burnout (β = 0.220, P < 0.001) and greater exposure to the pandemic. Mothers of a single and/or young child had considerably poorer mental health. Moreover, the relationship between mental health and burnout among parents was significantly moderated by epidemic exposure (β = 2.561, P < 0.001), family structure (number of children: β = −1.257, P < 0.001; first child age: β=-1.116, P < 0.001) and family function (β = −0.574, P < 0.05). This study indicated that burnout symptoms were significantly associated with worse mental health among parents in China. Besides, exposure to the pandemic, family structure, and family function was found to moderate the association between burnout and mental health among parents. Therefore, the present study stressed enhanced access to mental health resources and emotional supports for parents during a public crisis to reduce the deleterious effects of burnout.

ObjectivesCardiac magnetic resonance imaging (CMR) can be used for a one-step evaluation of myocardial function and pathological features after acute ST-elevation myocardial infarction (STEMI). We aimed to evaluate the value of fast microvascular occlusion (MVO) identification from contrast-enhanced steady-state free precession (CE-SSFP) combined with myocardial strain in predicting major cardiovascular adverse events (MACEs) in primary percutaneous coronary intervention (pPCI) patients with STEMI.MethodsIn total, 237 patients with STEMI who received pPCI and completed CMR scans within the following week were enrolled, MVO identification and the myocardial strain analysis were performed in CE-SSFP images without an additional method. The primary endpoint was the presence of MACE, which is defined as a composite of death, reinfarction, and congestive heart failure (HF).ResultsAfter 13 months of follow-up [interquartile range (IQR): 11–24], 30 patients (14%) developed MACE; the MVO (hazard ratio (HR) was 3.10; 95% CI: 1.14–8.99, p = 0.028), and the infarct size (IS) (HR: 1.03; 95% CI: 1.0–1.06, p = 0.042) and global longitudinal strain (GLS) (HR: 1.08; 95% CI: 1.01–1.17, p = 0.029) were finally associated with MACE. Receiver operating characteristic (ROC) analyses show that the area under the curve (AUC) of GLS was large (0.73 [95% CI, 0.63–0.82], p = 0.001), and the best cut-off was −11.8%, with 76.7% sensitivity and 58.9% specificity, which are greater than those of IS (0.70, 95% CI, 0.60–0.81, p < 0.001) and MVO (0.68, 95% CI, 0.58–0.78, p < 0.001). However, combining MVO and GLS resulted in a much greater finding (AUC = 0.775, 95% CI: 0.727–0.824, p < 0.001) and better sensitivity and specificity (83.3%, 66.5%).ConclusionMicrovascular occlusion identification from contrast-enhanced cine combined with myocardial strain could be a quick and reliable option for patients with STEMI who underwent pPCI; it correlates well with the prognosis of patients with STEMI in terms of MACE.

Diabetes is well recognized to increase the risk of heart failure, which is associated with higher mortality and morbidity. It is important for the development of novel therapeutic methods targeting heart failure in diabetic patients. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the progression of diabetes-induced heart failure (DIHF). This study was designed to investigate the contribution of Nr2f2 to the activation of ferroptosis and mitochondrial dysfunction in DIHF. We established a diabetic model by a high-fat feeding diet combined with an intraperitoneal injection of streptozotocin. After 16 weeks, Nr2f2 expression was increased in heart tissue of DIHF mice. In vivo, DIHF mice overexpressing Nr2f2 (AAV9-cTNT-Nr2f2) exhibited severe heart failure and enhanced cardiac ferroptosis compared with DIHF control mice (AAV9-cTNT-ctrl), accompanied by mitochondrial dysfunction and aggravated oxidative stress reaction. In vitro, Nr2f2 knockdown ameliorated ferroptosis and mitochondrial dysfunction by negatively regulating PGC-1α, a crucial metabolic regulator. PGC-1α knockdown counteracted the protective effect of Nr2f2 knockdown. These data suggest that Nr2f2 promotes heart failure and ferroptosis in DIHF by modulating the PGC-1α signaling. Our study provides a new idea for the treatment of diabetes-induced heart failure.

Abstract Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta‐analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow‐up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias.

Mesoporous silica with uniform 2-D hexagonal pores has been newly employed as facile reservoir to impove the dissolution rate of water insoluble drugs. However, rapid drug release from mesoporous silica is usually accompanied by the generation of supersaturated solution, which leads to the drug precipitation and compromised absorption. To address this issue, a supersaturated ternary hybrid system was constructed in this study by utilizing inorganic mesoporous silica and organic precipitation inhibitor. Vinylprrolidone-vinylacetate copolymer (PVP VA64) with similar solubility parameter to model drug fenofibrate (FNB) was expected to well inhibit the precipitation. Mesoporous silica Santa Barbara amorphous-15 (SBA-15) was synthesized in acidic media and hybrid matrix was produced by hot melt extrusion technique. The results of in vitro supersaturation dissolution test obviously revealed that the presence of PVP VA64 could effectively sustain a higher apparent concentration. PVP VA64 was suggested to simultaneously reduce the rate of nucleation and crystal growth and subsequently maintain a metastable supersaturated state. The absorption of FNB delivered by the organic-inorganic hybrid matrix was remarkably enhanced in beagle dogs, and its AUC value was 1.92-fold higher than that of FNB loaded mesoporous silica without PVP VA 64. In conclusion, the supersaturated organic-inorganic hybrid matrix can serve as a modular strategy to enhance the oral availability of water insoluble drugs.

Background: New-onset atrial fibrillation (AF) after ablation of typical atrial flutter (AFL) is not rare. This study aimed to investigate the predictive value of electrocardiographic parameters on new-onset AF post-typical AFL ablation.Methods: A total of 158 consecutive patients (79.1% males, mean age 57.8 ± 14.3 years) with typical AFL were enrolled between January 2012 and August 2017 in this single-center study. Patients with a history of AF before ablation were excluded. ECGs during sinus rhythm (SR) and AFL were collected. The duration of the negative component of flutter wave in lead II (DFNII), proportion of the DFNII of the total circle length of AFL (DFNII%), amplitude of the negative component of flutter wave in lead II (AFNII), duration (DPNV1), and amplitude (APNV1) of negative component of the P wave in lead V1, and P wave duration in lead II (DPII) during sinus rhythm were measured.Results: During a median follow-up of 26.9 ± 11.8 months, 22 cases (13.9%) developed new-onset AF. DFNII was significantly longer in patients with new-onset AF compared to patients without AF (114.7 ± 29.6 ms vs. 82.7 ± 12.8 ms, p < 0.0001). AFNII was significantly lower (0.118 ± 0.034 mV vs. 0.168 ± 0.051 mV, p < 0.0001), DPII (144.21 ± 23.77 ms vs. 111.46 ± 14.19 ms, p < 0.0001), and DPNV1 was significantly longer (81.07 ± 16.87 ms vs. 59.86 ± 14.42 ms, p < 0.0001) in patients with new-onset AF. In the multivariate analysis, DFNII [odds ratio (OR), 1.428; 95% CI, 1.039–1.962; p = 0.028] and DPII (OR, 1.429; 95% CI, 1.046–1.953; p = 0.025) were found to be independently associated with new-onset AF after typical AFL ablation.Conclusion: Parameters representing left atrial activation time under both the SR and AFL were independently associated with new-onset AF post-typical AFL ablation and may be useful in risk prediction, which needs to be confirmed by further prospective studies.

Background: Pulmonary vein isolation (PVI) is an effective strategy in the treatment of paroxysmal atrial fibrillation (PAF). Yet, there are limited data on additional ablation beyond PVI. In this study, we sought to assess the prevalence, predictors, and outcomes of additional ablation in PAF patients.Methods: A total of 537 consecutive patients with PAF were retrospectively evaluated for the index procedure. PVI was successfully conducted in all patients, after which electrophysiological study and drug provocation were performed, and additional ablations were delivered for concomitant arrhythmias, non-PV triggers, and low voltage zone (LVZ). The prevalence, predictors, and outcomes of additional ablation were analyzed.Results: Among 537 consecutive patients, 372 addition ablations were performed in 241 (44.88%) patients, including 252 (67.74%) concomitant arrhythmias in 198 (36.87%) patients, 56 (15.05%) non-PV triggers in 52 (9.68%) patients and 64 (17.20%) LVZ modification in 47 (8.75%) patients. Lower LVEF (OR = 0.937, p = 0.015), AF episode before procedure (OR = 2.990, p = 0.001), AF episode during procedure (OR = 1.998, p = 0.002) and AF episode induced after PVI (OR = 15.958, p < 0.001) were independent predictors of additional ablation. Single-procedure free from atrial arrhythmias at 58.36 ± 7.12 months post-ablation was 70.48%.Conclusions: Additional ablations were common in patients with PAF for index procedure. Lower LVEF and AF episodes before, during the procedure, and induced after PVI predicts additional ablation.

Peripheral blood mononuclear cells (PBMCs) were harvested and reprogramed to induced pluripotent stem cells (iPSCs) from a 46-year-old male patient with familial dilated cardiomyopathy and atrial fibrillation via a non-integrating system. A missense mutation in the LMNA gene (c.1003C > T) was identified by whole-exome sequencing and verified by Sanger sequencing. The pluripotency, differentiation potential, and karyotype of this cell line were also tested. This model is helpful to study the phenotype, mechanism, and therapy for laminopathy.

Abstract Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta‐analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow‐up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias.

Background/Aims: Heart failure induced by tachycardia, the most common arrhythmia, is frequently observed in clinical practice. This study was designed to investigate the underlying mechanisms. Methods: Rapid electrical stimulation (RES) at a frequency of 3 Hz was applied on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for 7 days, with 8 h/day and 24 h/day set to represent short-term and long-term tachycardia, respectively. Age-matched hiPSC-CMs without electrical stimulation or with slow electrical stimulation (1 Hz) were set as no electrical stimulation (NES) control or low-frequency electrical stimulation (LES) control. Following stimulation, JC-1 staining flow cytometry analysis was performed to examine mitochondrial conditions. Apoptosis in hiPSC-CMs was evaluated using Hoechst staining and Annexin V/propidium iodide (AV/PI) staining flow cytometry analysis. Calcium transients and L-type calcium currents were recorded to evaluate calcium homeostasis. Western blotting and qPCR were performed to evaluate the protein and mRNA expression levels of apoptosis-related genes and calcium homeostasis-regulated genes. Results: Compared to the controls, hiPSC-CMs following RES presented mitochondrial dysfunction and an increased apoptotic percentage. Amplitudes of calcium transients and L-type calcium currents were significantly decreased in hiPSC-CMs with RES. Molecular analysis demonstrated upregulated expression of Caspase3 and increased Bax/Bcl-2 ratio. Genes related to calcium re-sequence were downregulated, while phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) was significantly upregulated following RES. There was no significant difference between the NES control and LES control groups in these aspects. Inhibition of CaMKII with 1 µM KN93 partly reversed these adverse effects of RES. Conclusion: RES on hiPSC-CMs disturbed calcium homeostasis, which led to mitochondrial stress, promoted cell apoptosis and caused electrophysiological remodeling in a time-dependent manner. CaMKII played a central role in the damages induced by RES, pharmacological inhibition of CaMKII activity partly reversed the adverse effects of RES on both structural and electrophysiological properties of cells.

Background: Atrial tissue fibrosis can cause electrical or structural remodeling in patients with atrial fibrillation. Transforming growth factor beta 1(TGF-β1) signaling acts as a central role in fibroblast activation. In this report, we aimed to investigate the relationship between serum level of TGF-β1 and mean left atrial voltage in patients with chronic atrial fibrillation (CAF). Methods: A total of 16 consecutive adult patients with CAF who underwent catheter ablation were enrolled. Blood samples for measurement of TGF-β1 were collected from periphery veins and coronary sinus before pulmonary vein isolation. The measurement was performed with a commercially available ELISA kit. Cardiac indices were measured using echocardiography. The left atrial electroanatomic mapping was performed after pulmonary vein isolation. Results: Serum level of TGF-β1 in peripheral blood was higher than that in coronary sinus (p

Abstract Background Long-term ventricular pacing has deleterious effects and becomes more significant when cumulative percent ventricular pacing (Cum%VP) exceeds 40% of time. However, cellular disturbances and pathways by which pacing leads to myocardial disorders are not well understood. Attempts to resolve these questions have been hampered by difficulties in obtaining human cardiac tissue and the inability to build a longer-lasting (lasting longer than weeks) pacing model in vitro. Methods Human induced pluripotent stem cell-derived ventricular cardiomyocytes (VCMs) were cultured in the presence of electrical stimulation for 2 weeks. Quantitative structural and electrophysiological analyses were used to define the functional disturbances of pacing. Results Compared to controls, paced VCMs exhibited a remarkable reduction in the contractile protein expression, an increased apoptosis ratio and electrophysiological remodelling in a Cum%VP-dependent manner. Investigation of the protein expression levels revealed that long-term pacing universally activated both ER stress and downstream calpain. Moreover, the inhibition of calpain attenuated the adverse effects on the structural remodelling and increased the ICa, L in paced VCMs. Conclusions The results demonstrated that pacing VCMs for 2 weeks in vitro led to a series of structural and electrophysiological dysfunctions. The increased ER stress and downstream calpain could be a central mechanism underlying the disease pathogenesis. This finding could represent a new therapeutic target in the management of long-term pacing patients.

Many studies have focused on identifying therapeutic targets of myocardial hypertrophy for the treatment of correlative cardiac events. Wogonin is a natural flavonoid compound that displays a potent anti-hypertrophic effect. Knowledge of its pharmacological mechanisms might reveal an effective way to search for therapeutic targets. Myocardial hypertrophy was replicated by the subcutaneous implantation of an isoprenaline mini-pump in mice or isoprenaline treatment of H9C2 cells. Pathologic changes in cardiac structure were assessed by echocardiographic and histological examinations. The signaling transduction in hypertrophy-promoting pathways and the genes involved were detected by western blot and RT-qPCR. Wogonin significantly attenuated isoprenaline-induced myocardial hypertrophy in vivo and in vitro by suppressing phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) hypertrophy-promoting pathway. Wogonin promoted the ubiquitination and degradation of PI3K catalytic subunit alpha (Pik3ca), the catalytic subunit of PI3K, which was upregulated by isoprenaline treatment. Wogonin also increased the expression of neural precursor cells expressing developmentally down-regulated gene 4-like (Nedd4l), the ubiquitin E3 ligase of Pik3ca. Therefore, wogonin targets Nedd4l to induce the degradation of Pik3ca, which reverses the over-activation of the PI3K/Akt pathway and consequently relieves the isoprenaline-induced myocardial hypertrophy.

PurposeThis study aimed to explore the diagnostic performance of single photon emission computed tomography / computerized tomography (SPECT/CT) using a new radiotracer 99mTc-RGD-BBN for breast malignant tumor compared with 99mTc-3P4-RGD2.Methods6 female patients with breast malignant tumors diagnosed by fine needle aspiration cytology biopsy (FNAB) who were scheduled to undergo surgery were included in the study. 99mTc-3P4-RGD2 and 99mTc-RGD-BBN were performed with single photon emission computed tomography (SPECT) at 1 hour after intravenous injection of 299 ± 30 MBq and 293 ± 32 MBq of radiotracers respectively at separate day. The results were evaluated by the Tumor to non-Tumor ratios (T/NT). 99mTc-RGD-BBN and 99mTc-3P4-RGD2 SPECT/CT images were interpreted independently by 3 experienced nuclear medicine physicians using a 3-point scale system. All of the samples were analyzed immunohistochemically to evaluate the integrin αvβ3 and gastrin-releasing peptide receptor (GRPR) expression. The safety, biodistribution and radiation dosimetry of 99mTc-RGD-BBN were also evaluated in the healthy volunteers.ResultsNo serious adverse events were reported in any of the patients during the study. The effective radiation dose entirely conformed to the relevant standards. A total of 6 palpable malignant lesions were detected using 99mTc-RGD-BBN SPECT/CT with clear uptake. All malignant lesions were also detected using 99mTc-3P4-RGD2 SPECT/CT. The results showed that five malignant lesions were with clear uptake and the other one with barely an uptake. 4 malignant cases were found with both αvβ3 and GRPR expression, 1 case with only GRPR positive expression (integrin αvβ3 negative) and 1 case with only integrin αvβ3 positive expression (GRPR negative).Conclusion99mTc-RGD-BBN is a safe agent for detecting breast cancer. 99mTc-RGD-BBN may have the potential to make up for the deficiency of 99mTc-3P4-RGD2 in the detection of breast cancer with only GRPR positive expression (integrin αvβ3 negative). The preliminary application of 99mTc-RGD-BBN has demonstrated its powerful potential in breast cancer diagnosis and therapy.

BACKGROUND AND OBJECT:Cell apoptosis is a contributing factor in the initiation, progression and relapse of atrial fibrillation (AF), a life-threatening illness accompanied with stroke and heart failure. However, the regulatory cascade of apoptosis is intricate and remains unidentified, especially in the setting of AF. The aim of this study was to explore the roles of endoplasmic reticulum (ER) stress, mitochondrial apoptotic pathway (MAP), mitogen-activated protein kinases (MAPKs), and their cross-talking in tachypacing-induced apoptosis. METHODS AND RESULTS:HL-1 cells were cultured in the presence of tachypacing for 24 h to simulate atrial tachycardia remodeling. Results showed that tachypacing reduced cell viability measured by the cell counting kit-8, dissipated mitochondrial membrane potential detected by JC-1 staining and resulted in approximately 50% apoptosis examined by Hoechst staining and annexin V/propidium iodide staining. In addition, the proteins involved in ER stress, MAP and MAPKs were universally up-regulated or activated via phosphorylation, as confirmed by western blotting; and reversely silencing of ER stress, caspase-3 (the ultimate executor of MAP) and MAPKs with specific inhibitors prior to pacing partially alleviated apoptosis. An inhibitor of ER stress was applied to further investigate the responses of mitochondria and MAPKs to ER stress, and results indicated that suppression of ER stress comprehensively but incompletely attenuated the activation of MAP and MAPKs aroused by tachypacing, with the exception of ERK1/2, one branch of MAPKs. CONCLUSIONS:Our study suggested tachypacing-induced apoptosis is regulated by ER stress-mediated MAP and MAPKs. Thus, the above three components are all promising anti-apoptotic targets in AF patients and ER stress appears to play a dominant role due to its comprehensive effects.

Atrial hypertrophy and fibrosis are essential pathological features of atrial fibrillation. Recently, adiponectin has become a protein of interest due to its beneficial effects on cardiovascular diseases. However, the molecular mechanism of atrial structural remodeling and signaling pathways evoked by adiponectin remain unclear. In the present study, we investigated the cardioprotective effect of globular adiponectin (gAcrp) on angiotensin II-induced atrial hypertrophy and fibrosis in neonatal Sprague-Dawley rat. To further investigate the molecular mechanisms underlying the preventive effect of gAcrp, transfection of cells with siRNA was used to suppress the mRNA expression of adiponectin receptor 1 (AdipoR1) and its downstream adaptor protein APPL1. Non-silencing-Cy-3 labelled siRNA was used to determine transfection efficiency using fluorescence microscopy. The expression of atrial natriuretic peptide and procollagen type1 α-1, hypertrophy marker and fibrosis one, respectively, was detected by real-time PCR. Furthermore, the expression of adenosine monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K) and Akt was detected by western blotting. In addition, nuclear p65 translocation activity was analyzed by EMSA supershift assay. Our results showed that AdipoR1 and the adaptor protein APPL1 mediated the protective effects of gAcrp. In addition, the function of adiponectin and phosphorylation of AMPK were prominently diminished by inhibition of PI3K. Furthermore, nuclear factor-κB (NF-κB) transcription was diminished by the specific inhibition of AMPK. Taken together, AMPK pivotally interacts with NF-κB and PI3K, mediating the cardioprotective effect of adiponectin, and may serve as a therapeutic target for preventing atrial hypertrophy and fibrosis. Our present study suggests that gAcrp could ameliorate AngII-induced cardiac hypertrophy and fibrosis in rat atrial cells, which is mediated by the activation of AMPK signaling pathways. APPL1 and AdipoR1 are the key factors involved in the downstream of gAcrp approach.