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Yu Hsia,1,2 Maharajan Sivasubramanian,1 Chia-Hui Chu,1 Yao-Chen Chuang,1,3 Yiu-Kay Lai,2 Leu-Wei Lo1 1Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan; 2Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; 3Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, TaiwanCorrespondence: Leu-Wei Lo, Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Zhunan, Taiwan, Tel +886-37-206-166 Ext 37115, Fax +886-37-586-440, Email lwlo@nhri.edu.tw Yiu-Kay Lai, Institute of Biotechnology, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, 300044, Taiwan, Tel +866-35-742-745, Email lslyk@life.nthu.edu.twBackground: Cancer multidrug resistance (MDR) is an important factor that severely affects the chemotherapeutic efficacy. Among various methods to bypass MDR, usage of cytokines, such as tumor necrosis factor alpha (TNFα) is attractive, which exerts antitumor effects of immunotherapeutic response and apoptotic/proinflammatory pathways. Nevertheless, the challenges remain how to implement targeted delivery of TNFα to reduce toxicity and manifest the involved signaling mechanism that subdues MDR.Methods: We synthesized a multifunctional nanosytem, in which TNFα covalently bound to doxorubicin (Dox)-loaded pH-responsive mesoporous silica nanoparticles (MSN) through bi-functional polyethylene glycol (TNFα-PEG-MSN-Hydrazone-Dox) as a robust design to overcome MDR.Results: The salient features of this nanoplatform are: 1) by judicious tailoring of TNFα concentration conjugated on MSN, we observed it could lead to a contrary effect of either proliferation or suppression of tumor growth; 2) the MSN-TNFα at higher concentration serves multiple functions, besides tumor targeting and inducer of apoptosis through extrinsic pathway, it inhibits the expression level of p-glycoprotein (P-gp), a cell membrane protein that functions as a drug efflux pump; 3) the enormous surface area of MSN provides for TNFα functionalization, and the nanochannels accommodate chemotherapeutics, Dox; 4) targeted intracellular release of Dox through the pH-dependent cleavage of hydrazone bonds induces apoptosis by the specific intrinsic pathway; and 5) TNFα-PEG-MSN-Hydrazone-Dox (MSN-Dox-TNFα) could infiltrate deep into the 3D spheroid tumor model through disintegration of tight junction proteins. When administered intratumorally in a Dox-resistant mouse tumor model, MSN-Dox-TNFα exhibited a synergistic therapeutic effect through the collective performances of TNFα and Dox.Conclusion: We hereby develop and demonstrate a multifunctional MSN-Dox-TNFα system with concentration-tailored TNFα that can abrogate the drug resistance mechanism, and significantly inhibit the tumor growth through both intrinsic and extrinsic apoptosis pathways, thus making it a highly potential nanomedicine translated in the treatment of MDR tumors.Graphical Abstract: Keywords: cytokine cancer therapy, tumor necrosis factor alpha, mesoporous silica nanoparticle, pH-responsive controlled release, intrinsic/extrinsic apoptosis pathways, cancer multidrug resistance

Chih-Kuang Chen,1 Ping-Kuan Huang,2 Wing-Cheung Law,3 Chia-Hui Chu,4 Nai-Tzu Chen,5 Leu-Wei Lo4 1Department of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; 2Department of Fiber and Composite Materials, Feng Chia University, Taichung 40724, Taiwan; 3Department of Industrial and Systems Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, People’s Republic of China; 4Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan; 5Institute of New Drug Development, China Medical University, Taichung 40402, TaiwanCorrespondence: Chih-Kuang ChenDepartment of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung 80424, TaiwanTel +886-7-5252000 ext. 4060Fax +886-7-5254099Email chihkuan@mail.nsysu.edu.twLeu-Wei LoInstitute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, TaiwanTel +886-37-246166 ext. 37115Email lwlo@nhri.org.twAbstract: Gene-based therapies have emerged as a new modality for combating a myriad of currently incurable diseases. However, the fragile nature of gene therapeutics has significantly hampered their biomedical applications. Correspondingly, the development of gene-delivery vectors is of critical importance for gene-based therapies. To date, a variety of gene-delivery vectors have been created and utilized for gene delivery. In general, they can be categorized into viral- and non-viral vectors. Due to safety issues associated with viral vectors, non-viral vectors have recently attracted much more research focus. Of these non-viral vectors, polymeric vectors, which have been preferred due to their low immunogenicity, ease of production, controlled chemical composition and high chemical versatility, have constituted an ideal alternative to viral vectors. In particular, biodegradable polymers, which possess advantageous biocompatibility and biosafety, have been considered to have great potential in clinical applications. In this context, the aim of this review is to introduce the recent development and progress of biodegradable polymers for gene delivery applications, especially for their chemical structure design, gene delivery capacity and additional biological functions. Accordingly, we first define and categorize biodegradable polymers, followed by describing their corresponding degradation mechanisms. Various types of biodegradable polymers resulting from natural and synthetic polymers will be introduced and their applications in gene delivery will be examined. Finally, a future perspective regarding the development of biodegradable polymer vectors will be given.Keywords: gene therapy, gene delivery, non-viral vectors, polymeric vectors, biodegradable polymers

Nai-Tzu Chen,1 Eugene D Barth,2,3 Tsung-Hsi Lee,4 Chin-Tu Chen,5 Boris Epel,2,3 Howard J Halpern,2,3 Leu-Wei Lo5,61Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan; 2Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; 3Center for EPR Imaging In Vivo Physiology, University of Chicago, Chicago, IL 60637, USA; 4Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan; 5Department of Radiology, University of Chicago, Chicago, IL 60637 USA; 6Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, TaiwanPurpose: Tumor oxygenation is a critical parameter influencing the efficacy of cancer therapy. Low levels of oxygen in solid tumor have been recognized as an indicator of malignant progression and metastasis, as well as poor response to chemo- and radiation therapy. Being able to measure oxygenation for an individual’s tumor would provide doctors with a valuable way of identifying optimal treatments for patients.Methods: Electron paramagnetic resonance imaging (EPRI) in combination with an oxygen-measuring paramagnetic probe was performed to measure tumor oxygenation in vivo. Triarylmethyl (trityl) radical exhibits high specificity, sensitivity, and resolution for quantitative measurement of O2 concentration. However, its in vivo applications in previous studies have been limited by the required high dosage, its short half-life, and poor intracellular permeability. To address these limitations, we developed high-capacity nanoformulated radicals that employed fluorescein isothiocyanate-labeled mesoporous silica nanoparticles (FMSNs) as trityl radical carriers. The high surface area nanostructure and easy surface modification of physiochemical properties of FMSNs enable efficient targeted delivery of highly concentrated, nonself-quenched trityl radicals, protected from environmental degradation and dilution.Results: We successfully designed and synthesized a tumor-targeted nanoplatform as a carrier for trityl. In addition, the nanoformulated trityl does not affect oxygen-sensing capacity by a self-relaxation or broadening effect. The FMSN-trityl exhibited high sensitivity/response to oxygen in the partial oxygen pressure range from 0 to 155 mmHg. Furthermore, MSN-trityl displayed outstanding intracellular oxygen mapping in both in vitro and in vivo animal studies.Conclusion: The highly sensitive nanoformulated trityl spin probe can profile intracellular oxygen distributions of tumor in a real-time and quantitative manner using in vivo EPRI.Keywords: tumor oxygenation, electron paramagnetic resonance imaging (EPRI), mesoporous silica nanoparticles (MSNs), triarylmethyl (trityl) spin probe

Background: Atrial fibrosis plays a role in the development of a vulnerable substrate for atrial fibrillation (AF). Transforming growth factor (TGF)-β(1) is related to the degree of atrial fibrosis and the recurrence of AF after surgical maze procedures. Whether TGF-β(1) is associated with the outcome after catheter ablation for AF remains unclear. Objective: The purpose of this study was to investigate whether plasma TGF-β(1) was an independent predictor of AF recurrence after catheter ablation. Methods: Two hundred consecutive AF patients (154 with paroxysmal AF and 46 with nonparoxysmal AF) underwent catheter ablation. Their TGF-β(1) levels and clinical and echocardiographic data were collected before ablation. Results: Thirty patients (65%) with nonparoxysmal AF and 57 (37%) with paroxysmal AF had AF recurrence after catheter ablation. Among patients with nonparoxysmal AF, those experiencing recurrence had higher TGF-β(1) levels than did those who did not experience recurrence (34.63 ± 11.98 ng/mL vs 27.33 ± 9.81 ng/mL; P = .026). In patients with paroxysmal AF, recurrence was not associated with different TGF-β(1) levels. In patients with nonparoxysmal AF, TGF-β(1) levels and left atrial diameter (LAD) were independent predictors of AF recurrence after catheter ablation. Moreover, TGF-β(1) levels had an incremental value over LAD in predicting AF recurrence after catheter ablation (global χ(2) of LAD alone: 6.3; LAD and TGF-β(1) levels: 11.9; increment in global χ(2) = 5.6; P = .013). Patients with small LAD and low TGF-β(1) levels had the lowest AF recurrence rate at 11%. Conclusion: TGF-β(1) level is an independent predictor of AF recurrence in patients with nonparoxysmal AF and might be useful for identifying those patients likely to have better outcomes after catheter ablation. [ABSTRACT FROM AUTHOR]

Background: Renal dysfunction is recognized as an important risk factor for thromboembolic (TE) events in patients with atrial fibrillation (AF) under medical treatment.Objective: To investigate whether renal dysfunction is a useful predictor of TE events among patients receiving AF ablation. We also aimed to determine whether the diagnostic accuracy of the CHA(2)DS(2)-VASc score in predicting TE events could be improved by adding renal dysfunction into the scoring system.Methods: We enrolled a total of 547 patients with AF who underwent catheter ablation. Renal dysfunction was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m(2). The clinical end point was the occurrence of TE events (ischemic stroke, transient ischemic attack, or other systemic embolisms) during follow-up after catheter ablation.Results: During a follow-up of 38.9 ± 22.5 months, 16 patients (2.9%) experienced TE events. Both the CHA(2)DS(2)-VASc score and renal dysfunction were independent predictors of TE events in the multivariate analysis. Among patients with a CHA(2)DS(2)-VASc score of 0 or 1, renal dysfunction can further stratify them into 2 groups with different event rates (4.3% vs 0.3%; P = .046). A new scoring system derived by assigning 1 more point representing renal dysfunction to the CHA(2)DS(2)-VASc score could improve its predictive accuracy; the area under the receiver operating characteristic curve increased from 0.84 to 0.88 (P = .043).Conclusions: Renal dysfunction was a significant risk factor for TE events after catheter ablation of AF and may improve the diagnostic accuracy of the CHA(2)DS(2)-VASc score. [ABSTRACT FROM AUTHOR]

Background: Catheter ablation of paroxysmal atrial fibrillation has been performed for more than 10 years. However, data about the long-term results were limited.Objectives: To evaluate the long-tem efficacy following paroxysmal atrial fibrillation ablation and to investigate whether there were different patterns of recurrences in patients with different CHADS(2) scores.Methods: A total of 238 patients with paroxysmal atrial fibrillation who received a catheter ablation from 2004 to 2007 were enrolled. Free of recurrence was defined as the absence of atrial arrhythmias without using any antiarrhythmic agents after ablation.Results: There were 121 patients (50.8%) suffering from recurrences after the first ablation procedure during a median follow-up period of 5 years. The CHADS(2) score and left atrial diameter were significant predictors of recurrences in the multivariate analysis. Different patterns of recurrence were observed in different groups of patients categorized on the base of CHADS(2) score. Among patients with a CHADS(2) score of ≥3 without recurrences at 2 years postablation, 63.6% experienced episodes of arrhythmias during the subsequent follow-up period. In contrast, in patients with a CHADS(2) score of 0 without recurrences at 2 years postablation, the future recurrence rate was only 2.7%.Conclusions: After a successful ablation, recurrences may continue to occur without reaching a plateau during the long-term follow-up, especially in patients with a high CHADS(2) score. The optimal follow-up strategy may differ and should be individualized for patients with different scores. [ABSTRACT FROM AUTHOR]

Background: The CHADS₂ score (congestive heart failure, hypertension, age >75 years, diabetes, and previous stroke/transient ischemic attack) is used for the risk stratification of strokes in patients with atrial fibrillation (AF).Objective: This study aimed to investigate the associations between the CHADS₂ score, atrial substrate, and outcome of catheter ablation in patients with paroxysmal AF.Methods: A total of 247 paroxysmal AF patients who received catheter ablation were enrolled. The patients were divided into 3 groups according to their CHADS₂ score (group 1: score 0, group 2: score 1 to 2, and group 3: score 3 to 6). The bi-atrial substrate properties and outcome of catheter ablation were analyzed.Results: The CHADS₂ scores in these 3 groups were 0 (group 1), 1.24 ± 0.48 (group 2), and 3.60 ± 0.83 (group 3), respectively. The left atrial voltage became lower (group 1 vs. 2 vs. 3 = 2.08 ± 0.73 mV vs. 1.80 ± 0.81 mV vs. 1.06 ± 0.69 mV) and the activation time longer (group 1 vs. 2 vs. 3 = 93.4 ± 17.7 ms vs. 101.9 ± 21.2 ms vs. 112.2 ± 21.7 ms), whereas the CHADS₂ score increased. During a follow-up of 17.3 ± 7.0 months, 23.1% of the study population suffered from recurrences. The recurrence rates of these 3 groups were 13.0% (group 1), 27.6% (group 2), and 45.9% (group 3), respectively. The groups of different CHADS₂ scores remained as the independent predictor of recurrence in the multivariate analysis.Conclusion: A high CHADS₂ score was associated with different left atrial substrate properties and a poor outcome after catheter ablation of paroxysmal AF. [ABSTRACT FROM AUTHOR]

Background: Inflammation, an important mechanism in the pathogenesis of atrial fibrillation (AF), can be regulated by CD36 in monocytes.Objective: The purpose of this study was to test the hypothesis that CD36 in monocytes contributes to the pathogenesis of AF.Methods: A prospective study that enrolled 87 patients with AF and 70 without AF was conducted.Results: Compared to patients without AF, patients with AF had monocytes with a lower level of CD36 protein, which correlated with left atrial diameter, left atrial emptying fraction, and left atrial mean voltage. In AF patients after catheter ablation, Kaplan-Meier analysis showed that the sinus rhythm maintenance rate was higher in patients with high CD36 levels. Low CD36 level was an independent predictor of recurrence. After successful ablation, the CD36 level increased by 57%, reaching that of control patients. CD36 level was not correlated with the level of high-sensitivity C-reactive protein. Analysis of mRNA levels from a buffy coat revealed that AF patients had lower CD36 and interleukin-10 levels and higher peroxisome proliferator-activated receptor-γ and tumor necrosis factor-α levels, with CD36 level positively correlated with interleukin-10 level but inversely correlated with peroxisome proliferator-activated receptor-γ and tumor necrosis factor-α levels.Conclusion: Low CD36 levels in circulating monocytes were associated with AF occurrence and predicted recurrence after catheter ablation. The link between CD36 and AF identified a novel AF-related inflammatory pathway. [ABSTRACT FROM AUTHOR]

Aims: A second procedure for recurrent atrial fibrillation (AF) may be associated with the need for a different positioning of the puncture site and may increase the difficulty and complications. This study investigated whether the transseptal puncture site changed and whether the difficult punctures increased in the patients who received a repeat ablation procedure for recurrent AF. Methods and Results: Twenty-nine AF patients (52 +/- 12 years old, 20 males) underwent catheter ablation for a recurrence of AF. Compared with the first procedure, the height between the transseptal puncture site and coronary sinus ostium was higher in the second procedure during both the atrial end-systolic phase (38.0 +/- 4.7 vs. 34.8 +/- 5.3 mm, P = 0.036), and end-diastolic phase (43.0 +/- 4.8 vs. 39.1 +/- 5.4 mm, P = 0.004) in the 30 degrees right anterior oblique view. No significant change in the vertical atrial diameter was noted between the first and second procedures. A higher incidence of a difficult puncture was noted during the second procedure than in the first procedure (28 vs. 7%, P = 0.014). All those difficult punctures were overcome by using a large-curved transseptal needle. No differences of age, gender, AF duration, interval between first and second procedures, procedure time of the first procedure, and left atrial anteroposterior diameter were noted between easy and difficult transseptal punctures during the second procedure. Conclusion: The incidence of a difficult puncture was higher in the second procedure compared with the first procedure. The transseptal puncture site moved higher in the second procedure. Chronic scarring over the previous transseptal site is a reasonable hypothesis to explain the observations. The difficult punctures experienced during the second procedure might be overcome by changing the needle curve from a small curve to a large curve design. [ABSTRACT FROM AUTHOR]

Background: Electrical isolation of pulmonary veins (PVs) is an effective therapy for atrial fibrillation (AF). Both segmental ostial PV ablation and circumferential ablation with PV-left atrial (LA) block have been implicated to eliminate AF. However, the mechanism of the recurrent AF after undergoing either strategy remains unclear. Methods and Results: Of the 73 consecutive patients with symptomatic AF that underwent PV isolation and had recurrences of AF, Group 1 consisted of 46 patients (age 56 +/- 13 years old, 35 males) who underwent PV isolation by segmental ostial PV ablation and Group 2 consisted of 27 patients (age 51 +/- 11 years old, 24 males) who underwent circumferential ablation with PV-LA block. In Group 1, the earliest ectopic beat or ostial PV potentials were targeted. In Group 2, circumferential ablation with PV-LA block was performed by encircling the extraostial regions around the left and right PVs. During the first procedure, all patients had PV-AF. There was no difference in the non-PV ectopy between Group 1 and Group 2. During the second procedure, the incidence of an LA posterior wall ectopy initiating AF was significantly lower (20% vs. 0%, P = 0.01) in Group 2. There was no difference in the PV ectopy initiating AF during the second procedure. Conclusion: Circumferential ablation of AF with PV-LA block may eliminate the LA posterior wall ectopy and decrease the incidence of LA posterior wall ectopy initiating AF during the second procedure. [ABSTRACT FROM AUTHOR]

BACKGROUND: Atrial substrate properties have been demonstrated to be related to atrial arrhythmias. This study investigated whether the atrial substrate exhibits progressive remodeling in patients with recurrence of atrial fibrillation (AF) after catheter ablation. METHODS AND RESULTS: Fifteen consecutive AF patients (52 +/- 12 years old, 12 males) underwent the same mapping technique (NavX, St. Jude Medical, Minnetonka, MN, USA) and same ablation technique for primary AF and recurrence of AF (170 +/- 66 days after the first procedure). The bipolar mean peak-to-peak voltage (PPV) of the global left atrium during sinus rhythm significantly decreased in the second procedure (2.25 +/- 0.62 vs. 1.79 +/- 0.60 mV, P = 0.008). Also, the percentage of the surface area of the low voltage zone (LVZ; less than 0.5 mV) in the left atrium increased from 6 +/- 4% to 13 +/- 6% (P = 0.001) in the second procedure. There was no significant change in the right atrial bipolar mean PPV or surface area of the LVZ in the second procedure. CONCLUSION: Atrial substrate remodeling with a progressive decrease in the left atrial voltage was demonstrated in patients with recurrent AF. [ABSTRACT FROM AUTHOR]

Catheter ablation for tachyarrhythmia via superior approach has been used in patients without possible inferior vena cava access such as in cases of venous occlusion or complex anomaly. Difficulty in catheter manipulation, instability, number of required vascular access, and radiation exposure of operator had been described in the procedure. Application of three-dimensional (3-D) mapping system in catheter ablation via superior approach could navigate the guiding catheter and provide more precise ablation. We reported four cases receiving catheter ablation due to atrioventricular nodal reentry tachycardia, atrial fibrillation, and right ventricular arrhythmia via superior approach facilitated by 3-D mapping system with fewer vascular access and catheters., (© 2024 The Author(s). Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

Here we demonstrate that cancer metastasis could be modulated by the judicious tuning of physical parameters such as photothermal temperature in nanoparticle-mediated photothermal therapy (PTT). This is supported by theranostic nanosystem design and characterization, in vitro and in vivo analyses, and transcriptome-based gene profiling. In this work, the highly efficient near-infrared II (NIR-II) photoacoustic image (PA)-guided PTT are selectively activated using our developed matrix metalloproteinase (MMP)-triggered in situ assembly of gold nanodandelions (GNDs@gelatin). Unlike other "always-on" NIR PTT agents lacking specific bioactivation and suffering from the intrinsic nonspecific pseudosignals and treatment-related side effects such as metastasis, our GNDs@gelatin possesses important advantages while deployed in cancer PTT that include the following: (1) The theranostic effects could be "turned on" only after specific MMP-2/-9 activity and with acidity in the tumor microenvironment. (2) The quantitative PA diagnosis allows for precise PTT planning for better cancer treatment. (3) GNDs@gelatin could noninvasively quantify MMP activity and efficiently harness NIR-I (808 nm) and NIR-II (1064 nm) energies for tumor ablation. (4) The multibranched nanostructures reabsorb scattered laser photons, thus enhancing the surface plasmons for the pronounced photothermal conversion of aggregated GNDs@gelatin in situ . (5) It is noteworthy that in situ tumor eradication at higher PTT temperature (>55 °C) mediated by GNDs@gelatin could induce subsequent metastasis, which could be otherwise abolished at lower PTT temperatures (50 °C > T > 43 °C). (6) Furthermore, the gene profiling using transcriptome-based microarray including GO and KEGG analyses revealed that 315 differentially expressed genes were identified in higher PTT temperature treated tumors compared with lower PTT temperature ones. These were enriched into some well-known cancer-related pathways, such as cell migration pathway, signal transductions, cell proliferation, wound healing, PPAR signaling, and metabolic pathways. These observations suggest a new perspective of "moderate-is-better" in nanoparticle-mediated PTT for maximizing its therapeutic/prognosis benefits and translational potential with metastasis inhibition.

Background: Prior studies have investigated cardiac anatomy and clinical parameters as predictors for pulmonary vein and non-pulmonary vein triggers., Objective: We aimed to assess the link between the descending aorta to left inferior pulmonary vein (Dao-LIPV) distance and the occurrence of triggers and drivers in atrial fibrillation (AF) ablation procedures., Methods: Drug-refractory AF patients who underwent first-time index catheter ablation from January 2010 to December 2019 were retrospectively assembled. The Dao-LIPV distance was measured from preablation pulmonary vein computed tomography. Patients were assigned to groups on the basis of the presence of LIPV triggers or drivers. Multivariate logistic regression was used to identify risk factors., Results: A total of 886 consecutive patients with drug-refractory AF were studied, and 63 (7.1%) patients were identified to have LIPV triggers or drivers. The Dao-LIPV distance had a better predictive performance (area under the curve, 0.70) compared with persistent AF (area under the curve, 0.57). Multivariate logistic regression analysis showed that Dao-LIPV distance ≤2.5 mm (odds ratio, 3.96; 95% CI, 2.15-7.29; P < .001) and persistent AF (odds ratio, 1.73; 95% CI, 1.02-2.94]; P = .044) were independent predictors for the presence of LIPV triggers or drivers. A risk score model was established to predict the probability of LIPV triggers or drivers with persistent AF (10.2%), Dao-LIPV distance ≤2.5 mm (11.4%), and both (15.0%)., Conclusion: The proximity of the Dao-LIPV was correlated to the presence of LIPV triggers or drivers. We developed a risk score model indicating that persistent AF and Dao-LIPV distances ≤2.5 mm significantly increase the risk of LIPV triggers or drivers, aiding electrophysiologists in preparing for and performing catheter ablation more effectively., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to build an auto-segmented artificial intelligence model of the atria and epicardial adipose tissue (EAT) on computed tomography (CT) images, and examine the prognostic significance of auto-quantified left atrium (LA) and EAT volumes for AF., Methods and results: This retrospective study included 334 patients with AF who were referred for catheter ablation (CA) between 2015 and 2017. Atria and EAT volumes were auto-quantified using a pre-trained 3-dimensional (3D) U-Net model from pre-ablation CT images. After adjusting for factors associated with AF, Cox regression analysis was used to examine predictors of AF recurrence. The mean (±SD) age of patients was 56±11 years; 251 (75%) were men, and 79 (24%) had non-paroxysmal AF. Over 2 years of follow-up, 139 (42%) patients experienced recurrence. Diabetes, non-paroxysmal AF, non-pulmonary vein triggers, mitral line ablation, and larger LA, right atrium, and EAT volume indices were linked to increased hazards of AF recurrence. After multivariate adjustment, non-paroxysmal AF (hazard ratio [HR] 0.6; 95% confidence interval [CI] 0.4-0.8; P=0.003) and larger LA-EAT volume index (HR 1.1; 95% CI 1.0-1.2; P=0.009) remained independent predictors of AF recurrence., Conclusions: LA-EAT volume measured using the auto-quantified 3D U-Net model is feasible for predicting AF recurrence after CA, regardless of AF type.

Competing Interests: Conflict of interest: The present work was supported by Abbott, Advanced applications department.

Background: Preoperative estimation of the volume of the left atrium (LA) and epicardial adipose tissue (EAT) on computed tomography (CT) images is associated with an increased risk of atrial fibrillation (AF) recurrence. We aimed to design a deep learning-based workflow to provide reliable automatic segmentation of the atria, pericardium, and EAT for future applications in the management of AF., Methods: This study enrolled 157 patients with AF who underwent first-time catheter ablation between January 2015 and December 2017 at Taipei Veterans General Hospital. Three-dimensional (3D) U-Net models of the LA, right atrium (RA), and pericardium were used to develop a pipeline for total, LA-EAT, and RA-EAT automatic segmentation. We defined fat within the pericardium as tissue with attenuation between -190 and -30 HU and quantified the total EAT. Regions between the dilated endocardial boundaries and endocardial walls of the LA or RA within the pericardium were used to detect voxels attributed to fat, thus estimating LA-EAT and RA-EAT., Results: The LA, RA, and pericardium segmentation models achieved Dice coefficients of 0.960 ± 0.010, 0.945 ± 0.013, and 0.967 ± 0.006, respectively. The 3D segmentation models correlated well with the ground truth for the LA, RA, and pericardium ( r = 0.99 and p < 0.001 for all). The Dice coefficients of our proposed method for EAT, LA-EAT, and RA-EAT were 0.870 ± 0.027, 0.846 ± 0.057, and 0.841 ± 0.071, respectively., Conclusion: Our proposed workflow for automatic LA, RA, and EAT segmentation using 3D U-Nets on CT images is reliable in patients with AF., Competing Interests: Conflicts of interest: Dr. Shih-Ann Chen, an editorial board member at Journal of the Chinese Medical Association , had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Background: Based solely on pre-ablation characteristics, previous risk scores have demonstrated variable predictive performance. This study aimed to predict the recurrence of AF after catheter ablation by using artificial intelligence (AI)-enabled pre-ablation computed tomography (PVCT) images and pre-ablation clinical data., Methods: A total of 638 drug-refractory paroxysmal atrial fibrillation (AF) patients undergone ablation were recruited. For model training, we used left atria (LA) acquired from pre-ablation PVCT slices (126,288 images). A total of 29 clinical variables were collected before ablation, including baseline characteristics, medical histories, laboratory results, transthoracic echocardiographic parameters, and 3D reconstructed LA volumes. The I-Score was applied to select variables for model training. For the prediction of one-year AF recurrence, PVCT deep-learning and clinical variable machine-learning models were developed. We then applied machine learning to ensemble the PVCT and clinical variable models., Results: The PVCT model achieved an AUC of 0.63 in the test set. Various combinations of clinical variables selected by I-Score can yield an AUC of 0.72, which is significantly better than all variables or features selected by nonparametric statistics (AUCs of 0.66 to 0.69). The ensemble model (PVCT images and clinical variables) significantly improved predictive performance up to an AUC of 0.76 (sensitivity of 86.7% and specificity of 51.0%)., Conclusions: Before ablation, AI-enabled PVCT combined with I-Score features was applicable in predicting recurrence in paroxysmal AF patients. Based on all possible predictors, the I-Score is capable of identifying the most influential combination., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Background: Modifying the autonomic system after catheter ablation may prevent the recurrence of atrial fibrillation (AF). Evaluation of skin sympathetic nerve activity (SKNA) is a noninvasive method for the assessment of sympathetic activity. However, there are few studies on the effects of different energy settings on SKNA., Objective: To investigate the changes in SKNA in different energy settings and their relationship to AF ablation outcomes., Methods: Seventy-two patients with paroxysmal and persistent AF were enrolled. Forty-three patients received AF ablation with the conventional (ConV) energy setting (low power for long duration), and 29 patients using a high-power, short-duration (HPSD) strategy. The SKNA was acquired from the right arm 1 day before and after the radiofrequency ablation. We analyzed the SKNA and ablation outcomes in the different energy settings., Results: Both groups had a similar baseline average SKNA (aSKNA). We found that the median aSKNA increased significantly from 446.82 μV to 805.93 μV (p = 0.003) in the ConV group but not in the HPSD group. In the ConV group, patients without AF recurrence had higher aSKNA values. However, the 1-year AF recurrence rate remained similar between both groups (35 % vs. 28 %, p = 0.52)., Conclusion: The post-ablation aSKNA levels increased significantly in the ConV group but did not change significantly in the HPSD group, which may reflect different neuromodulatory effects. However, the one-year AF recurrence rates were similar for both groups. These results demonstrate that the HPSD strategy has durable lesion creation but less lesion depth, which may reduce collateral damage., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Signal-averaged electrocardiography (SAECG) provides diagnostic and prognostic information regarding cardiac diseases. However, its value in other nonischemic cardiomyopathies (NICMs) remains unclear. This study aimed to investigate the role of SAECG in patients with NICM., Methods and Results: This retrospective study included consecutive patients with NICM who underwent SAECG, biventricular substrate mapping, and ablation for ventricular arrhythmia (VA). Patients with baseline ventricular conduction disturbances were excluded. Patients who fulfilled at least one SAECG criterion were categorized into Group 1, and the other patients were categorized into Group 2. Baseline and ventricular substrate characteristics were compared between the two groups. The study included 58 patients (39 men, mean age 50.4 ± 15.5 years), with 34 and 24 patients in Groups 1 and 2, respectively. Epicardial mapping was performed in eight (23.5%) and six patients (25.0%) in Groups 1 and 2 ( p  = 0.897), respectively. Patients in Group 1 had a more extensive right ventricular (RV) low-voltage zone (LVZ) and scar area than those in Group 2. Group 1 had a larger epicardial LVZ than Group 2. Epicardial late potentials were more frequent in Group 1 than in Group 2. There were more arrhythmogenic foci within the RV outflow tract in Group 1 than in Group 2. There was no significant difference in long-term VA recurrence., Conclusion: In our NICM population, a positive SAECG was associated with a larger RV endocardial scar, epicardial scar/late potentials, and a higher incidence of arrhythmogenic foci in the RV outflow tract., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Nguyen, Lin, Chung, Chang, Lo, Lin, Chang, Hu, Tuan, Chao, Liao, Kuo, Liu, Liu, Wu, Kuo, Li, Huang, Wu, Siow, Bautista, Cao and Chen.)

Introduction: The levels of low-density lipoprotein (LDL) cholesterol in plasma are important risk factors for coronary heart disease. Several reports suggest that elevated plasma cholesterol is associated with cardiac arrhythmias. In a subsequent study investigating LDL cholesterol levels and the frequency of LDL cholesterol measurements, a positive correlation was observed between the severity of sleep apnea and visit-to-visit LDL cholesterol variability. Our objective was to assess the effects of hypercholesterolemia on cardiac autonomic activity, disordered sleep patterns, and increased incidence of arrhythmias in freely moving rats., Methods: Wireless transmission of polysomnographic recordings was performed in control and high cholesterol male rats during normal daytime sleep. Spectral analyses were conducted on the electroencephalogram and electromyogram (EMG) recordings to distinguish active waking, quiet sleep, and paradoxical sleep. Heart rate variability power spectrum analysis was used to measure cardiac autonomic activity., Results: The high cholesterol group exhibited a higher low-frequency (LF)/high-frequency (HF) power ratio during all sleep stages compared to the control group. Additionally, the frequency of sleep interruptions was increased in the high cholesterol group compared to the control group., Conclusions: Our results show significant sleep fragmentation with sympathetic hyperactivity after exposure to high cholesterol. This indicates that high cholesterol may increase the risk of sleep apnea and poor sleep quality by disrupting autonomic homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Catheter ablation is an effective and safe strategy for treating atrial fibrillation patients. Nevertheless, studies on the long-term outcomes of catheter ablation in patients with dilated cardiomyopathy are limited. This study aimed to assess the electrophysiological characteristics of atrial fibrillation patients with dilated cardiomyopathy and compare the long-term clinical outcomes between patients undergoing catheter ablation and medical therapy., Method: Patient baseline characteristics and electrophysiological parameters were examined to identify the predictors of atrial fibrillation recurrence following catheter ablation. The clinical outcomes of catheter ablation and medical therapy were compared using the propensity score matched method., Results: A total of 343 patients were enrolled, with 46 in the catheter ablation group and 297 in the medical therapy group. Among the catheter ablation group, 58.7% ( n  = 27) had persistent atrial fibrillation. The recurrence rate of atrial arrhythmia was 30.4% ( n  = 14) after an average follow-up duration of 7.7 years following catheter ablation. The only predictive factor for atrial fibrillation recurrence after catheter ablation was the left atrial diameter. When compared to medical therapy, catheter ablation demonstrated significantly better outcomes in terms of overall survival, freedom from heart failure hospitalization, improvement in left ventricular ejection fraction, and a greater reduction in left ventricular diameter and left atrial diameter after propensity score matching., Conclusions: Therefore, catheter ablation proves to be effective in providing long-term control of atrial fibrillation in patients with dilated cardiomyopathy. In addition to standard heart failure care, catheter ablation significantly enhanced both morbidity and mortality outcomes and reversed structural remodeling when compared to heart failure medication alone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Siow, Lin, Chung, Lin, Chang, Lo, Hu, Liao, Chang, Tuan, Kuo, Wu, Liu, Liu, Li, Kuo, Wu, Bautista, Huang, Nguyen and Chen.)

Objectives: Obstructive sleep apnea (OSA) is known to increase the risk of cardiovascular disease and inflammation plays a significant role in this process. Renal denervation (RDN) is a novel approach aimed at reducing sympathetic nervous system activity. The role of RDN in the inflammatory response to chronic OSA (COSA) is currently unclear. The main objective was to study inflammatory mechanisms in the rabbit heart with COSA and the effects of RDN., Methods: Eighteen rabbits were randomized into three groups: sham control, COSA, and COSA-RDN. COSA and COSA-RDN groups received liquid silicone injections, while the sham control group received normal saline. We performed combined surgical and chemical RDN through bilateral retroperitoneal flank incisions in the COSA-RDN group after silicone injections. The inflammatory mechanisms were assessed through immunoblotting, real-time PCR, and ELISA after the experiment., Results: H&E staining showed immune cell infiltration in COSA, which decreased after RDN treatment. The level of α7nAChR was significantly reduced in COSA compared to the sham control but was restored to a similar level in the COSA-RDN group. Furthermore, the expressions of p-JAK2 and p-STAT3 were significantly reduced in COSA but showed an up-regulation following RDN treatment. Similarly, levels of the inflammatory markers IL-6, IL-1β and TNF-α were markedly increased in COSA but decreased after RDN therapy. We observed NF-κB activation in the COSA rabbit model, which decreased after RDN treatment, as evidenced by decreased NF-κB expression., Conclusions: Our study suggests that RDN treatment may prevent COSA-associated heart inflammation via the JAK2-STAT3 signaling pathway., Competing Interests: Declaration of competing interest The authors declare no competing interests regarding the publication of this research article. There are no financial, personal, or professional relationships that could potentially influence or bias the findings presented in this manuscript. The research was conducted with utmost transparency and objectivity, and no conflicts of interest exist that could undermine the integrity of the reported results., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Carina breakthrough (CB) at the right pulmonary vein (RPV) can occur after circumferential pulmonary vein isolation (PVI) due to epicardial bridging or transient tissue edema. High-power short-duration (HPSD) ablation may increase the incidence of RPV CB. Currently, the surrogate of ablation parameters to predict RPV CB is not well established. This study investigated predictors of RPV CB in patients undergoing ablation index (AI)-guided PVI with HPSD., Methods: The study included 62 patients with symptomatic atrial fibrillation (AF) who underwent AI-guided PVI using HPSD. Patients were categorized into two groups based on the presence or absence of RPV CB. Lesions adjacent to the RPV carina were assessed, and CB was confirmed through residual voltage, low voltage along the ablation lesions, and activation wavefront propagation., Results: Out of the 62 patients, 21 (33.87%) experienced RPV CB (Group 1), while 41 (66.13%) achieved first-pass RPV isolation (Group 2). Despite similar AI and HPSD, patients with RPV CB had lower contact force (CF) at lesions adjacent to the RPV carina. Receiver operating characteristic (ROC) curve analysis identified CF < 10.5 g as a predictor of RPV CB, with 75.7% sensitivity and 56.2% specificity (area under the curve: 0.714)., Conclusion: In patients undergoing AI-guided PVI with HPSD, lower CF adjacent to the carina was associated with a higher risk of RPV CB. These findings suggest that maintaining higher CF during ablation in this region may reduce the occurrence of RPV CB., (© 2023 Wiley Periodicals LLC.)

Introduction: Despite undergoing an index ablation, some patients progress from paroxysmal atrial fibrillation (PAF) to persistent AF (PersAF), and the mechanism behind this is unclear. The aim of this study was to investigate the predictors of progression to PersAF after catheter ablation in patients with PAF., Methods: This study included 400 PAF patients who underwent an index ablation between 2015 and 2019. The patients were classified into three groups based on their outcomes: Group 1 (PAF to sinus rhythm, n = 226), Group 2 (PAF to PAF, n = 146), and Group 3 (PAF to PersAF, n = 28). Baseline and procedural characteristics were collected, and predictors for AF recurrence and progression were evaluated., Results: The mean age of the patients was 58.4 ± 11.1 years, with 272 males. After 3 years of follow-up, 7% of the PAF cases recurred and progressed to PersAF despite undergoing an index catheter ablation. In the multivariable analysis, a larger left atrial (LA) diameter and the presence of non-pulmonary vein (PV) triggers during the index procedure independently predicted recurrence. Moreover, a larger LA diameter, the presence of non-PV triggers, and a history of thyroid disease independently predicted AF progression., Conclusion: The progression from PAF to PersAF after catheter ablation is associated with a larger LA diameter, history of thyroid disease, and the presence of non-PV triggers. Meticulous preprocedural evaluation, patient selection, and comprehensive provocation tests during catheter ablation are recommended., (© 2023 Wiley Periodicals LLC.)

Sonodynamic therapy (SDT) is a promising approach for cancer treatment that uses sonosensitizers (SNSs) to generate reactive oxygen species (ROS) in the presence of ultrasound (US). However, SDT is oxygen-dependent and requires an imaging tool to monitor the tumor microenvironment and guide treatment. Photoacoustic imaging (PAI) is a noninvasive and powerful imaging tool that offers high spatial resolution and deep tissue penetration. PAI can quantitatively assess tumor oxygen saturation (sO2) and guide SDT by monitoring time-dependent sO2 changes in the tumor microenvironment. Here, we discuss recent advances in PAI-guided SDT for cancer therapy. We discuss various exogenous contrast agents and nanomaterial-based SNSs developed for PAI-guided SDT. Additionally, combining SDT with other therapies, including photothermal (PTT) therapy, can enhance its therapeutic effect. However, the application of nanomaterial-based contrast agents in PAI-guided SDT for cancer therapy remains challenging due to the lack of simple designs, the need for extensive pharmacokinetic studies, and high production costs. Integrated efforts from researchers, clinicians, and industry consortia are necessary for the successful clinical translation of these agents and SDT for personalized cancer therapy. PAI-guided SDT shows the potential to revolutionize cancer therapy and improve patient outcomes, but further research is necessary to realize its full potential.

Background: Circumferential pulmonary vein isolation (CPVI) has supplanted segmental PVI (SPVI) as standard procedure for atrial fibrillation (AF). However, there is limited evidence examining the efficacy of these strategies in redo ablations. In this study, we investigated the difference in recurrence rates between SPVI and CPVI in redo ablations for PV reconnection., Methods and results: This study retrospectively enrolled 543 patients who had undergone AF ablation between 2015 and 2017. Among them, 167 patients (30.8%, including 128 male patients and 100 patients with paroxysmal AF) underwent redo ablation for recurrent AF. Excluding 26 patients without PV reconnection, 141 patients [90 patients of SPVI (Group 1) and 51 patients of CPVI (Group 2)] were included. The AF-free survival rates were 53.3% and 56.9% in Group 1 and Group 2, respectively (P=0.700). The atrial flutter (AFL)-free survival rates were 90% and 100% in Group 1 and Group 2, respectively (P=0.036). The ablation time was similar between groups, and there no major complications were observed., Conclusions: For redo AF ablation procedures, SPVI and CPVI showed similar outcomes, except for a higher AFL recurrence rate for SPVI after long-term follow-up (>2 years). This may be due to a higher probability of residual PV gaps causing reentrant AFL.

Importance: Catheter ablation for persistent atrial fibrillation (AF) has shown limited success., Objective: To determine whether AF drivers could be accurately identified by periodicity and similarity (PRISM) mapping ablation results for persistent AF when added to pulmonary vein isolation (PVI)., Design, Setting, and Participants: This prospective randomized clinical trial was performed between June 1, 2019, and December 31, 2020, and included patients with persistent AF enrolled in 3 centers across Asia. Data were analyzed on October 1, 2022., Intervention: Patients were assigned to the PRISM-guided approach (group 1) or the conventional approach (group 2) at a 1:1 ratio., Main Outcomes and Measures: The primary outcome was freedom from AF or other atrial arrhythmia for longer than 30 seconds at 6 and 12 months., Results: A total of 170 patients (mean [SD] age, 62.0 [12.3] years; 136 men [80.0%]) were enrolled (85 patients in group 1 and 85 patients in group 2). More group 1 patients achieved freedom from AF at 12 months compared with group 2 patients (60 [70.6%] vs 40 [47.1%]). Multivariate analysis indicated that the PRISM-guided approach was associated with freedom from the recurrence of atrial arrhythmia (hazard ratio, 0.53 [95% CI, 0.33-0.85])., Conclusions and Relevance: The waveform similarity and recurrence pattern derived from high-density mapping might provide an improved guiding approach for ablation of persistent AF. Compared with the conventional procedure, this novel specific substrate ablation strategy reduced the frequency of recurrent AF and increased the likelihood of maintenance of sinus rhythm., Trial Registration: ClinicalTrials.gov Identifier: NCT05333952.

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However, current DDSs require sophisticated design and construction based on xenogeneic nanomaterials, evoking feasibility and biocompatibility concerns. Herein, a simple but versatile biological DDS (bDDS) composed of human red blood cell (RBC)-derived vesicles (RDVs) with excellent biocompatibility was surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs that remarkably suppressed MDR in uterine sarcoma through a lysosomal-mitochondrial axis-dependent cell death mechanism. Dox-gluRDVs can efficiently deliver and accumulate Dox in lysosomes, bypassing drug efflux transporters and facilitating cellular uptake and retention of Dox in drug-resistant MES-SA/Dx5 cells. The transfer of lysosomal calcium to the mitochondria during mitochondria-lysosome contact due to lysosomal Dox accumulation may result in mitochondrial ROS overproduction, mitochondrial membrane potential loss, and activation of apoptotic signaling for the superior anti-MDR activity of Dox-gluRDVs in vitro and in vivo. This work highlights the great promise of RDVs to serve as a bDDS of Dox to overcome MDR cancers but also opens up a reliable strategy for lysosomal-mitochondrial axis-dependent cell death for fighting against other inoperable cancers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dong-Ming Huang has patent #Red blood cell-derived vesicles as a nanoparticle drug delivery system (US8,329,161 B2) issued to National Health Research Institutes., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Atrial fibrillation (AF) and mitral regurgitation (MR) have a complex interplay. Catheter ablation (CA) of AF may be a potential method to improve the severity of MR in AF patients., Methods: Patients with symptomatic AF and moderate to severe MR who underwent catheter ablation from 2011 to 2021 were retrospectively included in the study. Patients' baseline characteristics and electrophysiological features were examined. These patients were classified as group 1 with improved MR and group 2 with refractory MR after CA., Results: Fifty patients (age 60.2 ± 11.6 years, 29 males) were included in the study (32 in group 1 and 18 in group 2). Group 1 patients had a lower CHA 2 DS 2 -VASc score (1.7 ± 1.5 vs. 2.7 ± 1.5, P  = 0.005) and had a lower incidence of hypertension (28.1% vs. 66.7%, P  = 0.007) and diabetes mellitus (3.1% vs. 22.2%, P  = 0.031) as compared to group 2 patients. Electroanatomic three-dimensional (3D) mapping showed that group 1 patients demonstrated less scars on the posterior bottom of the left atrium compared to group 2 patients (12.5% vs. 66.7%, P  < 0.001). AF recurrence was not different between the two groups. After multivariate logistic regression analysis, a posterior bottom scar in the left atrium independently predicted refractory MR despite successful AF ablation., Conclusion: Most patients with AF and MR showed improvement of MR after AF ablation. A scar involving the posterior bottom of the left atrium is associated with poor recovery of MR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Bautista, Lin, Lu, Lo, Lin, Chang, Hu, Chung, Tuan, Chao, Liao, Chang, Kuo, Liu, Liu, Wu, Kuo, Li, Huang, Wu, Siow, Son, Tran and Chen.)

Background: Reentrant atrial tachycardias (ATs) utilize critical isthmus (CI) for the maintenance of the circuit. The electrophysiological characteristics and clinical implications of the targeted CI regions of reentrant ATs during sinus rhythm (SR) were not clear. Therefore, our research aims at studying the electrical properties of the CI sites for scar-related reentrant ATs and the functional substrate mapping identified during SR., Methods: Patients mapped with high-density catheters during SR and reentrant ATs were retrospectively analyzed. The CI regions of the reentrant ATs were confirmed by the combination of the activation map and the entrainment. The substrate mapping was analyzed for wavefront propagation, conduction velocity, and electrogram patterns., Results: Twenty patients with 22 reentrant ATs that underwent high-density maps were analyzed at 2 hospitals. Mapping performed during SR identified a scar region of 23.0 ± 13.6% of the left atrium. Regions of the CI in SR were characterized by low voltage (0.3 ± 0.2 mV), conduction slowing (0.4 ± 0.2 m/s), and fractionated electrogram (duration 62.5 ± 13.9 ms). Substrate mapping during SR showed that the regions of the CI located with the low-voltage zone in 16 out of 22 CI (72.7%), the deceleration zone in 15 out of 22 CI (68.2%), and late atrial activation in 12 out of 22 CI (54.5%). Targeting regions of CI achieve 94% of termination or change of the reentrant circuit. At 6.2 ± 7.1 months, there was 75% freedom from atrial arrhythmia., Conclusions: Novel high-density mapping can identify the functional substrates during SR and guide ablation. Low-voltage areas with conduction slowing are putative predictors of the CI for the maintenance of the reentrant ATs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Particulate matter < 2.5 μm (PM2.5) exposure is associated with increased arrhythmia events and cardiovascular mortality, but the detailed mechanism remained elusive. In the current study, we aimed to investigate the autonomic alterations in a rodent model after acute exposure to PM2.5. Twelve male WKY rats were randomized to control and PM2.5 groups. All were treated with 2 exposures of oropharyngeal aerosol inhalations (1 μg PM2.5 per gram of body weight in 100 μL normal saline for the PM2.5 group) separately by 7 days. Polysomnography and electrocardiography were surgically installed 7 days before oropharyngeal inhalation and monitored for 7 days after each inhalation. Physiologic monitors were used to define active waking (AW), quiet sleep (QS), and paradoxical sleep (PS). Autonomic regulations were measured by heart rate variability (HRV). The protein expression of ventricular tissue of the 2 groups was compared at the end of the experiment. In sleep pattern analysis, QS interruption of the PM2.5 group was significantly higher than the control group (0.52 ± 0.13 events/min, 0.35 ± 0.10 events/min, p = 0.002). In HRV analysis, the LF/HF was significantly higher for the PM2.5 group than the control group (1.15 ± 0.16, 0.64± 0.30, p = 0.003), largely driven by LF/HF increase during the QS phase. Ionic channel protein expression from Western blots showed that the PM2.5 group had significantly lower L-type calcium channel and higher SERCA2 and rectifier potassium channel expressions than the control group, respectively. Our results showed that acute PM2.5 exposure leads to interruption of QS, sympathetic activation, and recruitment of compensatory calcium handling proteins. The autonomic and calcium dysregulations developed after PM 2.5 exposure may explain the risk of sleep disturbance and sleep-related arrhythmia., (© 2023. Springer Nature Limited.)

Background: Pulmonary vein isolation (PVI) is a cornerstone therapy for paroxysmal atrial fibrillation (PAF). The variations in nonlinear heart rate variability (HRV) between patients with and without recurrences remain unclear. We aimed to characterize the nonlinear HRV before and after PVI in patients with and without recurrence., Methods: Twenty-five drug-refractory PAF patients (56.0 ± 9.1 years old, 20 males) who received PVI were enrolled. Holter electrocardiography were performed before, 1-3, and 6-12 months after PVI. After 8.2 ± 2.5 months of follow-ups after PVI, patients were divided into two groups: the recurrence (n = 8) and non-recurrence (n = 17) groups. Linear and nonlinear HRV variables were analyzed, including the Poincaré Plot analysis and the Detrended Fluctuation Analysis (DFA)., Results: The non-recurrence group, but not the recurrence group, had decreased high-frequency component (HF), the root mean square of successive RR interval differences (RMSSD), and the Poincaré Plot index SD1 1-3 months after PVI and increased DFA slope2 6-12 months after PVI. The non-recurrence group's LF/HF ratio and DFA slope1 decreased significantly 1-3 and 6-12 months after PVI, respectively, whereas there was no significant change in the recurrence group after PVI., Conclusions: Significantly reduced vagal tone 1-3 months after PVI, increased long-term fractal complexity 6-12 months after PVI, and decreased sympathetic tone as well as short-term fractal complexity 1-3 and 6-12 months after PVI led to a better AF-free survival after PVI. These findings suggest that neuromodulation and heart rate dynamics play crucial roles in AF recurrence following PVI., (© 2023 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Background: Treatment with oral anticoagulants (OACs) could prevent stroke in atrial fibrillation (AF), but side effects developed due to OACs may cause patients anxiety during decision making. This study aimed to investigate whether shared decision making (SDM) reduces anxiety and improves adherence to stroke prevention measures in patients with AF., Methods: A one-group pretest-posttest design using a questionnaire survey was applied at the outpatient cardiology clinic between July 2019 until September 2020. A Patient Decision Aid (PDA) tool was used for the completion of the questionnaire survey after health education and counseling. Ten questions were included for patients' recognition of SDM, and a 5-point scoring method was used, where "very much" was scored as 5 points, and "totally not" was scored as 1 point., Results: Fifty-two patients with AF were enrolled. In terms of patients' recognition of SDM, points of more than 4.17 out of 5 were noted, indicating recognition above the level of "very much." The patients' anxiety scores before SDM were 3.56 (1.2), with a decrease of 0.64 points (p < 0.001) to 2.92 (1.3) after SDM. After SDM, the number of patients who decided to take OAC increased from 76.9% to 88.5%, and the 15.4% answering "unclear" decreased to 1.9% (p = 0.006). The patients' anxiety levels after SDM were associated with gender (p = 0.025)., Conclusions: The approach using SDM enhanced our understanding of the pros and cons of OAC treatment and, in patients with AF, decreased anxiety about therapeutic decisions and increased willingness to accept treatment options., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: High-power short-duration (HPSD) and cryoballoon ablation (CBA) has been used for pulmonary vein isolation (PVI)., Objective: We aimed to compare the efficacy of PVI between CBA and HPSD ablation in patients with paroxysmal atrial fibrillation (PAF)., Methods: We retrospectively analyzed 251 consecutive PAF patients from January 2018 to July 2020. Of them, 124 patients (mean age 57.2 ± 10.1 year) received HPSD and 127 patients (mean age 59.6 ± 9.4 year) received CBA. In HPSD group, the radiofrequency energy was set as 50 W/10 s at anterior wall and 40 W/10 s at posterior wall. In CBA group, 28 mm s generation cryoballoon was used for PVI according the guidelines., Results: There was no significant difference in baseline characteristics between these 2 groups. The time to achieve PVI was significantly shorter in cryoballoon ablation group than in HPSD group (20.6 ± 1.7 min vs 51.8 ± 36.3, P = 0.001). The 6-month overall recurrence for atrial tachyarrhythmias was not significantly different between the two groups (HPSD:14.50% vs CBA:11.0%, P = 0.40). There were different types of recurrent atrial tachyarrhythmia between these 2 groups. Recurrence as atrial flutter was significantly more common in CBA group compared to HPSD group (57.1% vs 12.5%, P = 0.04)., Conclusion: In PAF patients, CBA and HPSD had a favourable and comparable outcome. The recurrence pattern was different between CBA and HPSD groups., Competing Interests: Declaration of competing interest The Authors declares that they have no conflict of interest., (Copyright © 2023 Indian Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.)

Optical clearing with high-refractive-index (high-n) reagents is essential for 3D tissue imaging. However, the current liquid-based clearing condition and dye environment suffer from solvent evaporation and photobleaching, causing difficulties in maintaining the tissue optical and fluorescent features. Here, using the Gladstone-Dale equation [(n-1)/density=constant] as a design concept, we develop a solid (solvent-free) high-n acrylamide-based copolymer to embed mouse and human tissues for clearing and imaging. In the solid state, the fluorescent dye-labeled tissue matrices are filled and packed with the high-n copolymer, minimizing scattering in in-depth imaging and dye fading. This transparent, liquid-free condition provides a friendly tissue and cellular environment to facilitate high/super-resolution 3D imaging, preservation, transfer, and sharing among laboratories to investigate the morphologies of interest in experimental and clinical conditions., (© 2023. The Author(s).)

Although radiotherapy is one of the most important curative treatments for cancer, its clinical application is associated with undesired therapeutic effects on normal or healthy tissues. The use of targeted agents that can simultaneously achieve therapeutic and imaging functions could constitute a potential solution. Herein, we developed 2-deoxy-d-glucose (2DG)-labeled poly(ethylene glycol) (PEG) gold nanodots (2DG-PEG-AuD) as a tumor-targeted computed tomography (CT) contrast agent and radiosensitizer. The key advantages of the design are its biocompatibility and targeted AuD with excellent sensitivity in tumor detection via avid glucose metabolism. As a consequence, CT imaging with enhanced sensitivity and remarkable radiotherapeutic efficacy could be attained. Our synthesized AuD displayed linear enhancement of CT contrast as a function of its concentration. In addition, 2DG-PEG-AuD successfully demonstrated significant augmentation of CT contrast in both in vitro cell studies and in vivo tumor-bearing mouse models. In tumor-bearing mice, 2DG-PEG-AuD showed excellent radiosensitizing functions after intravenous injection. Results from this work indicate that 2DG-PEG-AuD could greatly potentiate theranostic capabilities by providing high-resolution anatomical and functional images in a single CT scan and therapeutic capability.

Renal denervation (RDN) suppresses the activity of the renin-angiotensin-aldosterone system and inflammatory cytokines, leading to the prevention of cardiac remodeling. Limited studies have reported the effects of renal denervation on ventricular electrophysiology. We aimed to use optical mapping to evaluate the effect of RDN on ventricular structural and electrical remodeling in a tachycardia-induced cardiomyopathy rabbit model. Eighteen rabbits were randomized into 4 groups: sham control group (n = 5), renal denervation group receiving RDN (n = 5), heart failure group receiving rapid ventricular pacing for 1 month (n = 4), and RDN-heart failure group (n = 4). Rabbit hearts were harvested for optical mapping. Different cycle lengths were paced (400, 300, 250, 200, and 150 ms), and the results were analyzed. In optical mapping, the heart failure group had a significantly slower epicardial ventricular conduction velocity than the other three groups. The RDN-heart failure, sham control, and RDN groups had similar velocities. We then analyzed the 80% action potential duration at different pacing cycle lengths, which showed a shorter action potential duration as cycle length decreased (P for trend < 0.01), which was consistent across all groups. The heart failure group had a significantly longer action potential duration than the sham control and RDN groups. Action potential duration was shorter in the RDN-heart failure group than the heart failure group (P < 0.05). Reduction of conduction velocity and prolongation of action potential duration are significant hallmarks of heart failure, and RDN reverses these remodeling processes., (© 2023. The Author(s).)

Aims: This study investigated the epidemiological characteristics of new-onset dementia in patients with atrial fibrillation (AF) and the association of catheter ablation with different subtypes of dementia., Methods and Results: We conducted a population-based, retrospective cohort study using data from the Taiwan National Health Insurance Research Database. In total, 136 774 patients without a history of dementia were selected after 1:1 propensity score matching based on age (with AF vs. without AF). A competing risk model was used to investigate the three subtypes of dementia: Alzheimer's disease, vascular dementia, and other/mixed dementia. Inverse probability of treatment weighting (IPTW) was performed to minimize the impact on dementia risk due to the imbalanced baseline characteristics. After a median follow-up period of 6.6 years, 8704 events of new-onset dementia occurred. Among all AF patients developing dementia, 73% were classified as having Alzheimer's disease, 16% as having vascular dementia, and 11% as having other/mixed dementia. The cumulative incidence of dementia in AF patients was higher than those without AF (log-rank test: P < 0.001 for both before and after IPTW). In patients with AF undergoing catheter ablation, the total dementia risk decreased significantly [P = 0.015, hazard ratio (HR): 0.74, 95% confidence interval (CI): 0.58-0.94] after multivariable adjustment, but not for the subtype of vascular dementia (P = 0.59, HR: 0.86, 95% CI: 0.49-1.50)., Conclusion: Patients with AF have a higher incidence of all types of dementia, including Alzheimer's disease, vascular dementia, and a mixed type of dementia. Alzheimer's disease is less likely to occur in patients with AF undergoing catheter ablation., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Catheter ablation (CA) is a treatment strategy for atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM). We investigated the electrophysiological characteristics of recurrence in a tertiary referral center and compared long-term clinical outcomes after CA therapy with patients who did not undergo CA., Methods: Patients with HCM and AF who underwent CA (group 1, n  = 60) or pharmacological treatment (group 2, n  = 298) between 2006 and 2021 were enrolled in this study. The baseline characteristics and electrophysiological characteristics of group 1 patients were examined to elucidate the reason for the recurrence of AF after CA therapy. The clinical results of the patients in Group 1 and Group 2 were compared using a propensity score (PS)-matched method., Results: The most common cause of recurrence was pulmonary vein reconnection (86.5%), followed by non-pulmonary vein triggers (40.5%), cavotricuspid isthmus flutter (29.7%), and atypical flutter (24.3%). Thyroid disease (HR, 14.713; P  < 0.01), diabetes (HR, 3.074; P  = 0.03), and non-paroxysmal AF (HR, 4.012; P  = 0.01); these factors independently predicted recurrence. After the first recurrence, patients who underwent repeat CA showed a better arrhythmia-free state (74.1%) than those who underwent drug escalation therapy (29.4%, P  < 0.01). After matching, PS-group 1 patients showed significantly better outcomes in all-cause mortality, heart failure hospitalization, and left atrial reverse remodeling than PS-group 2 patients., Conclusions: Patients who underwent CA showed better clinical outcomes than those who underwent drug therapy. The main predictors of recurrence were thyroid disease, diabetes, and non-paroxysmal AF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Lin, Lin, Chung, Lin, Chang, Lo, Hu, Chao, Liao, Chang, Tuan, Kuo, Wu, Liu, Liu, Li, Kuo, Weng and Chen.)