Search

Background: Atrial fibrillation (AF) signifies the most prevalent supraventricular arrhythmia in humans and may lead to cerebral stroke, cardiac failure, and even premature demise. Aggregating strong evidence points to genetic components as a cornerstone in the etiopathogenesis of familial AF. However, the genetic determinants for AF in most patients remain elusive. Methods: A 4-generation pedigree with idiopathic AF and another cohort of 196 unrelated patients with idiopathic AF as well as 278 unrelated healthy volunteers were recruited from the Chinese population of Han ethnicity. A family-based whole-exome sequencing examination followed by a Sanger sequencing assay in all research subjects was implemented. The functional impacts of the identified SOX4 mutations were explored via a dual-reporter assay. Results: Two new heterozygous SOX4 mutations, NM_003107.3: c.211C>T; p.(Gln71*) and NM_003107.3: c.290G>A; p.(Trp97*), were observed in the family and 1 of 196 patients with idiopathic AF, respectively. The two mutations were absent in the 278 control individuals. The biochemical measurements revealed that both Gln71*- and Trp97*-mutant SOX4 failed to transactivate GJA1 (Cx43) . Moreover, the two mutations nullified the synergistic activation of SCN5A by SOX4 and TBX5. Conclusions: The findings first indicate SOX4 as a gene predisposing to AF, providing a novel target for antenatal genetic screening, individualized prophylaxis, and precision treatment of AF.

Minisci-type dehydrogenative coupling of C(sp 3 )-H and N-heteroaromatics was performed with N -hydroxysuccinimide as a hydrogen atom transfer catalyst in a photoelectrochemical cell composed of a mesoporous BiVO 4 photoanode and a Pt electrode. In the absence of metal catalysts and chemical oxidants, a range of N -heteroarenes (e.g., quinolines, isoquinolines, and quinoxaline) can undergo coupling with various C(sp 3 )-H partners to form the corresponding products in excellent yields.

Multisubstituted furans occupy a pivotal position within the realms of synthetic chemistry and pharmacological science due to their distinctive chemical configurations and inherent properties. We herein introduce a tandem difunctionalization protocol of alcohols for the efficient synthesis of multisubstituted 2,3-dihydrofurans and γ-butyrolactones through the combination of photocatalysis and iron catalysis under mild conditions. Photoredox alcohol α-C(sp 3 )-H activation and Pinner-type intramolecular cyclization are two key processes. This method features significant convenience, economic benefits, and environmental friendliness.

A successful synthesis of helical-shaped axially chiral bisoxime ethers is reported. This approach utilized symmetric L-shaped diketone scaffolds as carbonyl components for the enantioselective condensation with hydroxylamines, delivering dual axially chiral oxime ethers with up to 99% ee. Additionally, the axially chiral mono-oxime ethers of azabicyclic ketones with high ee's were also successfully produced. Various chiral bicyclic lactams can be readily synthesized via Beckmann rearrangement, demonstrating a potential application in organic synthetic chemistry.

Aims: MicroRNAs (miRs) are involved in endogenous neurogenesis, enhancing of which has been regarded as a potential therapeutic strategy for ischemic stroke treatment; however, whether miR-199a-5p mediates postischemic neurogenesis remains unclear. This study aims to investigate the proneurogenesis effects of miR-199a-5p and its possible mechanism after ischemic stroke., Methods: Neural stem cells (NSCs) were transfected using Lipofectamine 3000 reagent, and the differentiation of NSCs was evaluated by immunofluorescence and Western blotting. Dual-luciferase reporter assay was performed to verify the target gene of miR-199a-5p. MiR-199a-5p agomir/antagomir were injected intracerebroventricularly. The sensorimotor functions were evaluated by neurobehavioral tests, infarct volume was measured by toluidine blue staining, neurogenesis was detected by immunofluorescence assay, and the protein levels of neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), caveolin-1 (Cav-1), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) were measured by Western blotting., Results: MiR-199a-5p mimic enhanced neuronal differentiation and inhibited astrocyte differentiation of NSCs, while a miR-199a-5p inhibitor induced the opposite effects, which can be reversed by Cav-1 siRNA. Cav-1 was through the dual-luciferase reporter assay confirmed as a target gene of miR-199a-5p. miR-199a-5p agomir in rat stroke models manifested multiple benefits, such as improving neurological deficits, reducing infarct volume, promoting neurogenesis, inhibiting Cav-1, and increasing VEGF and BDNF, which was reversed by the miR-199a-5p antagomir., Conclusion: MiR-199a-5p may target and inhibit Cav-1 to enhance neurogenesis and thus promote functional recovery after cerebral ischemia. These findings indicate that miR-199a-5p is a promising target for the treatment of ischemic stroke., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Atrial fibrillation (AF), the most prevalent type of sustained cardiac dysrhythmia globally, confers strikingly enhanced risks for cognitive dysfunction, stroke, chronic cardiac failure, and sudden cardiovascular demise. Aggregating studies underscore the crucial roles of inherited determinants in the occurrence and perpetuation of AF. However, due to conspicuous genetic heterogeneity, the inherited defects accounting for AF remain largely indefinite. Here, via whole-genome genotyping with genetic markers and a linkage assay in a family suffering from AF, a new AF-causative locus was located at human chromosome 7p14.2-p14.3, a ~4.89 cM (~4.43-Mb) interval between the markers D7S526 and D7S2250. An exome-wide sequencing assay unveiled that, at the defined locus, the mutation in the TBX20 gene, NM_001077653.2: c.695A>G; p.(His232Arg), was solely co-segregated with AF in the family. Additionally, a Sanger sequencing assay of TBX20 in another family suffering from AF uncovered a novel mutation, NM_001077653.2: c.862G>C; p.(Asp288His). Neither of the two mutations were observed in 600 unrelated control individuals. Functional investigations demonstrated that the two mutations both significantly reduced the transactivation of the target gene KCNH2 (a well-established AF-causing gene) and the ability to bind the promoter of KCNH2 , while they had no effect on the nuclear distribution of TBX20. Conclusively, these findings reveal a new AF-causative locus at human chromosome 7p14.2-p14.3 and strongly indicate TBX20 as a novel AF-predisposing gene, shedding light on the mechanism underlying AF and suggesting clinical significance for the allele-specific treatment of AF patients.

Here we report facile and manipulable access to methylenebisamide derivatives via visible-light-driven radical cascade processes incorporating C(sp 3 )-H activation and C-N/N-O cleavage. Mechanistic studies reveal that a traditional Ir-catalyzed photoredox pathway and a novel copper-induced complex-photolysis pathway are both involved, contributing to activating the inert N -methoxyamides and rendering the valuable bisamides. This approach exhibits many advantages, including mild reaction conditions, broad scope and functional group tolerance, and competitive step economy. Given the mechanistic plenitude and operational simplicity, we believe this package deal paves a promising way for the synthesis of valuable nitrogen-containing molecules.

Treatment of atrial fibrillation (AF) remains challenging despite significant progress in understanding its underlying mechanisms. The first detailed, quantitative theory of functional re-entry, the 'leading circle' model, was developed more than 40 years ago. Subsequently, in decades of study, an alternative paradigm based on spiral waves has long been postulated to drive AF. The rotor as a 'spiral wave generator' is a curved 'vortex' formed by spin motion in the two-dimensional plane, identified using advanced mapping methods in experimental and clinical AF. However, it is challenging to achieve complementary results between experimental results and clinical studies due to the limitation in research methods and the complexity of the rotor mechanism. Here, we review knowledge garnered over decades on generation, electrophysiological properties, and three-dimensional (3D) structure diversity of the rotor mechanism and make a comparison among recent clinical approaches to identify rotors. Although initial studies of rotor ablation at many independent centres have achieved promising results, some inconclusive outcomes exist in others. We propose that the clinical rotor identification might be substantially influenced by (i) non-identical surface activation patterns, which resulted from a diverse 3D form of scroll wave, and (ii) inadequate resolution of mapping techniques. With rapidly advancing theoretical and technological developments, future work is required to resolve clinically relevant limitations in current basic and clinical research methodology, translate from one to the other, and resolve available mapping techniques., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The controllable design of multivariate heterojunction with sequential structures is of significant relevance for breaking the performance limit of binary composite photocatalysts. In this work, the novel dual S-scheme ternary-component AgI/Ag 6 Mo 7 O 24 /exfoliated g-C 3 N 4 (ECN) composite was prepared by a two-step in-situ synthetic strategy. The energy band bending at the heterointerface and the formation of dual built-in electric field could be observed due to distinct work functions of different components in the ternary composite. Benefiting from the sequential heterojunction structure, the AgI/Ag 6 Mo 7 O 24 /ECN composite achieved 98.7% removal efficiency of 2-nitrophenol (2-NP) within 70 min under visible light irradiation, and AgI/Ag 6 Mo 7 O 24 /ECN also showed higher degradation efficiency for a variety of organic pollutants such as methylene blue (MB), rhodamine B (RhB), methyl orange (MO), 4-nitrophenol (4-NP), 2-sec-butyl-4,6-dinitrophenol (DNBP) and tetracycline (TC). Notably, •OH and •O 2 - played dominant roles in the AgI/Ag 6 Mo 7 O 24 /ECN set up, which was consistent with the dual S-scheme charge transfer mechanism. In-depth insights for the photodegradation of 2-NP were presented based on a combined DFT study and GC-MS analysis. Additionally, the photoreduction of Ag + in AgI/Ag 6 Mo 7 O 24 /ECN was also evaded by the fast transfer of photogenerated electrons through the dual S-scheme pathway, achieving the effect of killing two birds with one stone., 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 © 2023. Published by Elsevier Ltd.)

Background: The changes in proarrhythmic substrates and malignant ventricular arrhythmia mechanisms caused by premature ventricular contraction-induced cardiomyopathy (PVCCM) remain unclear., Objectives: The goal of this study was to establish the electrophysiological mechanism of how high-load PVC causes malignant arrhythmia., Methods: Thirteen swine were exposed to 50% paced PVC from the right ventricular apex for 12 weeks (PVCCM, n = 6) and no pacing for 12 weeks (control, n = 7). Cardiac function was quantified biweekly with echocardiography. Computed tomography scans and electrophysiological examinations were performed monthly to dynamically evaluate the changes in the cardiac structure and the arrhythmogenic substrate., Results: The decreases in the cardiac function and ventricular enlargement in the PVCCM group were significant after 12 weeks of PVC stimulation compared with the control group (P < 0.001). Electrophysiological examination found that the ventricular effective refractory period dispersion (0.071 ± 0.008), area of the low-voltage zone (9.41 ± 1.55 cm 2 ), and malignant ventricular arrhythmia inducibility (33.3%) of the PVCCM group increased significantly at week 8 after pacing (P < 0.001 vs the control group); these changes slowed down after 8 weeks. Moreover, the distribution of the low-voltage zone presented obvious spatial heterogeneity, especially in the anterior wall of the right ventricle, accompanied by delayed activation in the sinus rhythm (67 ± 13 milliseconds). Consistently, the proportion of ventricular fibrosis- and expression-related proteins were significantly increased in the PVCCM group (P < 0.001), especially in the right ventricle. Moreover, proteomic analysis confirmed the spatial profile of these fibrotic changes in the PVCCM group., Conclusions: High-burden PVC can cause significant temporal and spatial heterogeneity changes in proarrhythmic substrates, which are potentially related to the upregulation of calcium signaling caused by asynchronous activation., Competing Interests: Funding Support and Author Disclosures This research was supported by the National Natural Science Foundation of China Grants (grant no. 81770324) and the National Natural Science Foundation of China Grants (grant no. 81800337).The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Objective: This study sought to study the feasibility, efficacy, and safety of using multiscale entropy (MSE) analysis to guide catheter ablation for persistent atrial fibrillation (PsAF) and predict ablation outcomes., Methods: We prospectively enrolled 108 patients undergoing initial ablation for PsAF. MSE was calculated based on bipolar intracardiac electrograms (iEGMs) to measure the dynamical complexity of biological signals. The iEGMs data were exported after pulmonary vein isolation (PVI), then calculated in a customed platform, and finally re-annotated into the CARTO system. After PVI, regions of the highest mean MSE (mMSE) values were ablated in descending order until AF termination, or three areas had been ablated., Results: Baseline characteristics were evenly distributed between the AF termination ( n = 38, 35.19%) and the non-termination group. The RA-to-LA mean MSE (mMSE) gradient demonstrated a positive gradient in the non-termination group and a negative gradient in the termination group (0.105 ± 0.180 vs. -0.235 ± 0.256, P < 0.001). During a 12-month follow-up, 29 patients (26.9%) had arrhythmia recurrence after single ablation, and 18 of them had AF (62.1%). The termination group had lower rates of arrhythmia recurrence (15.79 vs. 32.86%, Log-Rank P = 0.053) and AF recurrence (10.53 vs. 20%, Log-Rank P = 0.173) after single ablation and a lower rate of arrhythmia recurrence (7.89 vs. 27.14%, Log-Rank P = 0.018) after repeated ablation. Correspondingly, subjects with negative RA-to-LA mMSE gradient had lower incidences of arrhythmia (16.67 vs. 35%, Log-Rank P = 0.028) and AF (16.67 vs. 35%, Log-Rank P = 0.032) recurrence after single ablation and arrhythmia recurrence after repeated ablation (12.5 vs. 26.67%, Log-Rank P = 0.062). Marginal peri-procedural safety outcomes were observed., Conclusion: MSE analysis-guided driver ablation in addition to PVI for PsAF could be feasible, efficient, and safe. An RA < LA mMSE gradient before ablation could predict freedom from arrhythmia. The RA-LA MSE gradient could be useful for guiding ablation strategy selection., 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., (Copyright © 2022 Shi, Wu, Zou, Xu, Jiang, Zhang, Qin and Liu.)

Background: Blood urea nitrogen (BUN)/creatinine (Cr) ratio was an independent predictor of stroke-in-evolution (SIE) among patients who had suffered an acute ischemic stroke. We investigated the association of changes in BUN/Cr on stroke outcome during hospitalization after acute ischemic stroke (AIS)., Methods: AIS patients admitted within 3 days from stroke onset (2020-2021) were included in the study. Baseline data, including BUN and Cr levels, were collected. Univariate linear regression and a multivariate regression model were applied to assess the relationship between the change of BUN/Cr and short-term outcomes., Results: One hundred and eighty-one patients were included. The mean increase of BUN/Cr level was - 2.0 ± 1.78. Univariate linear regression suggested that baseline NIHSS, thrombolysis, change of BUN/Cr, and history of atrial fibrillation, statin use, and antiplatelet therapy was associated with the decrease in NIHSS during hospitalization (P < 0.05). After adjusting for potential confounders, multivariate regression analysis revealed the associations between the decrease in BUN/Cr and favorable outcome are significant (β = 0.21, 95% CI = 0.14,-0.28)., Conclusion: The decrease in BUN/Cr is positively correlated with a better early neurological improvement in AIS patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The construction of efficient and stable heterojunction photocatalysts with a controllable close contact interface and visible-light response is a challenging research topic in the field of photocatalysis. Herein, a series of BiOCl/rutile-TiO 2 (R-TiO 2 ) nanorod heterojunctions were constructed using R-TiO 2 nanorods as supporting frameworks followed by selective adsorption of Cl - on R-TiO 2 (110) facets and in situ growth of BiOCl on the surface of TiO 2 nanorods. The strong affinity of rhodamine B (RhB) as a photosensitizer for BiOCl allowed the prepared BiOCl/R-TiO 2 heterojunctions to work efficiently under visible-light irradiation. The dye-sensitized BiOCl/R-TiO 2 nanorod heterojunctions displayed promising photocatalytic performance for simultaneously treating RhB and the persistent organic pollutant 2- sec -butyl-4,6-dinitrophenol (DNBP). The highly enhanced photodegradation activity of the BiOCl/R-TiO 2 system was mainly attributed to the efficient RhB-photosensitization effect, the enhanced heterojunction effect, and the suitable conduction band match between BiOCl and R-TiO 2 , which facilitated electron transfer from the excited RhB to the catalyst surface and charge separation across the BiOCl/R-TiO 2 interface, thus promoting the formation of • O 2 - and h + as dominant active species in the reaction system for degradation of pollutants. The results demonstrate that the construction of a dye-sensitized BiOCl/R-TiO 2 heterojunction system is an effective strategy for improving the photocatalytic potential.

A new photocatalyst-free strategy for the cross-dehydrogenative C-C and C-P coupling reaction has been described. This protocol provides a concise method to synthesize various 1-substituted tetrahydroisoquinoline (THIQ) derivatives enabled by visible-light direct excitation of substrates without using any photocatalyst. Moreover, a wide substrate scope demonstrated good synthetic versatility and practicality.

As the most prevalent form of human birth defect, congenital heart disease (CHD) contributes to substantial morbidity, mortality and socioeconomic burden worldwide. Aggregating evidence has convincingly demonstrated that genetic defects exert a pivotal role in the pathogenesis of CHD, and causative mutations in multiple genes have been causally linked to CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic components underpinning CHD in the overwhelming majority of patients remain obscure. In this research, a four-generation consanguineous family suffering from CHD transmitted in an autosomal dominant mode was recruited. By whole-exome sequencing and bioinformatics analyses as well as Sanger sequencing analyses of the family members, a new heterozygous SOX17 variation, NM&#95;022454.4: c.553G > T; p.(Glu185*), was identified to co-segregate with CHD in the family, with complete penetrance. The nonsense variation was neither detected in 310 unrelated healthy volunteers used as controls nor retrieved in such population genetics databases as the Exome Aggregation Consortium database, Genome Aggregation Database, and the Single Nucleotide Polymorphism database. Functional assays by utilizing a dual-luciferase reporter assay system unveiled that the Glu185*-mutant SOX17 protein had no transcriptional activity on its two target genes NOTCH1 and GATA4, which have been reported to cause CHD. Furthermore, the mutation abrogated the synergistic transactivation between SOX17 and NKX2.5, another established CHD-causing transcription factor. These findings firstly indicate SOX17 loss-of-function mutation predisposes to familial CHD, which adds novel insight to the molecular mechanism of CHD, implying potential implications for genetic risk appraisal and individualized prophylaxis of the family members affected with CHD., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objectives: To evaluate the clinical safety and efficacy of radiofrequency catheter ablation for atrial fibrillation patients with a history of stroke. Methods and Results: A total of 116 symptomatic, drug-refractory AF patients with a history of stroke, and 1:2 matched patients without a history of stroke were enrolled. Of these, 28 cases occurred stroke within 3 months (Group 1), 88 cases with stroke history longer than 3 months (Group 2), and 232 cases without stroke (Group 3). PVI was performed in all patients, extended to ablation of linear lesions ablation. The periprocedural stroke rates and other procedure-related in-hospital complications did not differ significantly among the three groups. The maintenance rate of SR after the procedure showed no significant difference ( p = 0.333), 52.7, 66.4, and 70.7% in Group 1, 2, and 3, respectively. Furthermore, the comparison between a history of stroke and those without it were also shown no significant difference ( p = 0.351). Conclusions: Radiofrequency ablation for AF patients occurred stroke, even within 3 months is safe and effective, without higher periprocedural complication rate and recurrence rate., 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., (Copyright © 2021 Song, Wu, Zhang, Jiang, Qin and Liu.)

TBX5 has been linked to Holt-Oram syndrome, with congenital heart defect (CHD) and atrial fibrillation (AF) being two major cardiac phenotypes. However, the prevalence of a TBX5 variation in patients with CHD and AF remains obscure. In this research, by sequencing analysis of TBX5 in 178 index patients with both CHD and AF, a novel heterozygous variation, NM&#95;000192.3: c.577G>T; p.(Gly193*), was identified in one index patient with CHD and AF as well as bicuspid aortic valve (BAV), with an allele frequency of approximately 0.28%. Genetic analysis of the proband's pedigree showed that the variation co-segregated with the diseases. The pathogenic variation was not detected in 292 unrelated healthy subjects. Functional analysis by using a dual-luciferase reporter assay system showed that the Gly193*-mutant TBX5 protein failed to transcriptionally activate its target genes MYH6 and NPPA. Moreover, the mutation nullified the synergistic transactivation between TBX5 and GATA4 as well as NKX2-5. Additionally, whole-exome sequencing analysis showed no other genes contributing to the diseases. This investigation firstly links a pathogenic variant in the TBX5 gene to familial CHD and AF as well as BAV, suggesting that CHD and AF as well as BAV share a common developmental basis in a subset of patients.

Atrial fibrillation (AF) represents the most frequent form of sustained cardiac rhythm disturbance, affecting approximately 1% of the general population worldwide, and confers a substantially enhanced risk of cerebral stroke, heart failure, and death. Increasing epidemiological studies have clearly demonstrated a strong genetic basis for AF, and variants in a wide range of genes, including those coding for ion channels, gap junction channels, cardiac structural proteins and transcription factors, have been identified to underlie AF. Nevertheless, the genetic pathogenesis of AF is complex and still far from completely understood. Here, whole-exome sequencing and bioinformatics analyses of a three-generation family with AF were performed, and after filtering variants by multiple metrics, we identified a heterozygous variant in the ISL1 gene (encoding a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling), NM&#95;002202.2: c.481G > T; p.(Glu161*), which was validated by Sanger sequencing and segregated with autosome-dominant AF in the family with complete penetrance. The nonsense variant was absent from 284 unrelated healthy individuals used as controls. Functional assays with a dual-luciferase reporter assay system revealed that the truncating ISL1 protein lost transcriptional activation on the verified target genes MEF2C and NKX2-5. Additionally, the variant nullified the synergistic transactivation between ISL1 and TBX5 as well as GATA4, two other transcription factors that have been implicated in AF. The findings suggest ISL1 as a novel gene contributing to AF, which adds new insight to the genetic mechanisms underpinning AF, implying potential implications for genetic testing and risk stratification of the AF family members., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the role of driver mechanism and the effect of electrogram dispersion-guided driver mapping and ablation in atrial fibrillation (AF) at different stages of progression., Methods: A total of 256 consecutive patients with AF who had undergone pulmonary vein isolation (PVI) plus driver ablation or conventional ablation were divided into three groups: paroxysmal atrial fibrillation (PAF; group A, n = 51); persistent atrial fibrillation (PsAF; group B, n = 38); and long standing-persistent atrial fibrillation (LS-PsAF; group C, n = 39). PVI was performed with the guidance of the ablation index. The electrogram dispersion was analyzed for driver mapping., Results: The most prominent driver regions were at roof (28.0%), posterior wall (17.6%), and bottom (21.3%). From patients with PAF to those with PsAF and LS-PsAF: the complexity of extra-pulmonary vein (PV) drivers including distribution, mean number, and area of dispersion region increased (P < .001). Patients who underwent driver ablation vs conventional ablation had higher procedural AF termination rate (76.6% vs 28.1%; P < .001). With AF progression, the termination rate gradually decreased from group A to group C, and the role of PVI in AF termination was also gradually weakened from group A to group C (39.6%, 7.4%, and 4.3%; P < .001) in patients with driver ablation. At the end of the follow-up, the rate of sinus rhythm maintenance was higher in patients with driver ablation than those with conventional ablation (89.1% vs 70.3%; P < .001)., Conclusion: The formation of extra-PV drivers provides an important mechanism for AF maintenance with their complexity increasing with AF progression. Electrogram dispersion-guided driver ablation appears to be an efficient adjunctive approach to PVI for AF treatment., (© 2019 Wiley Periodicals, Inc.)

Aim: During cardiac resynchronization therapy (CRT), optimized programming of the atrioventricular (AV) delay and ventricular-to-ventricular (VV) interval can lead to improved hemodynamics, symptomatic response, and left ventricular systolic function. Currently, however, there is no recommendation for the best optimization method. This study aimed to compare the long-term clinical outcomes of 4 different CRT optimization methods., Methods: One hundred and twenty-four consecutive CRT patients with severe heart failure and left bundle-branch block configuration were randomly assigned into four groups to undergo AV/VV delay optimization through echocardiogram (ECHO; n = 30), electrocardiogram (ECG; n = 32), QuickOpt algorithm (n = 28), and nominal AV/VV (n = 36) groups. Patients were followed up and underwent examinations, including New York Heart Association (NYHA) cardiac functional classification, 6-min walking distance (6MWD), and echocardiography, at 6, 12, 24, 36, and 48 months, respectively. The patients' survival and clinical outcomes were compared among the four groups., Results: Kaplan-Meier survival analyses showed that the median survival was the same in the 4 groups: ECHO, 43 months; ECG, 44 months; QuickOpt, 44 months, and nominal, 41 months. At the 6-month follow-up, the reduction in left ventricular end diastolic diameter (LVEDD) was significantly less in the nominal group (-1.91 ± 2.58 mm) than that in the other three groups (ECHO: -3.70 ± 2.78 mm, p = 0.012; ECG: -3.53 ± 3.14 mm, p = 0.020; QuickOpt: -3.46 ± 2.65 mm, p = 0.032); 6MWD was significantly shorter in the nominal group (87.88 ± 34.76 m) than that in the other three groups (ECHO: 120.63 ± 56.93 m, p = 0.006; ECG: 114.97 ± 54.95 m, p = 0.020; QuickOpt: 114.57 ± 35.41 m, p = 0.027). Left ventricular ejection fraction (LVEF) significantly increased in ECHO (7.23 ± 2.76%, p = 0.010), ECG (8.50 ± 3.17%, p < 0.001), and QuickOpt (8.39 ± 2.90%, p < 0.001) compared with the nominal group (5.35 ± 2.59%). There were no significant differences among the groups in the aforementioned parameters at 24, 36, and 48 months, respectively., Conclusion: While LVEDD, LVEF, 6MWD, and NYHA were significantly improved in ECHO, ECG, and QuickOpt at 6 months, there were no significant improvements in any of the groups at 12, 24, and 48 months. These findings suggested that the long-term effect of the four CRT methods for heart failure was not significantly different., (© 2019 S. Karger AG, Basel.)

Background: Breast cancer is the second leading cause of cancer-related death among women worldwide. The aim of this study is to investigate the role of miR-142-3p in breast cancer cells and the related mechanism., Methods: Sixty paired breast cancer tissues were collected and 60 breast tissues from patients with mammary hyperplasia served as the control group. The expression of miR-142-3p was examined using RT-qPCR methods; moreover, we also performed receiver operating characteristic (ROC) curve analysis to determine whether miR142-3p can distinguish breast cancer patients from the controls. Next, HMGA1 and FZD7 have been predicted as target genes of miR-142-3p, and the expressions of HMGA1 and FZD7 in breast cancer tissue and the control group were examined using RT-qPCR and western blot methods., Results: miR-142-3p was significantly down-regulated in breast cancer tissue compared with the controls, and the levels of miR-142-3p was negatively correlated with the tumor size, degree of differentiation, and metastasis (p < 0.01). Moreover, results of ROC curve analysis indicated that the expression of miR-142-3p can distinguish between patients with breast cancer and the control group (AUC = 0.819, 95% CI, 0.756 - 0.881). Furthermore, the expressions of HMGA1 and FZD7 were significantly up-regulated in patients with breast cancer compared with the controls. The level of miR-142-3p was negatively correlated with expressions of HMGA1 (r = -0.3507, p = 0.006) and FZD7 (r = -0.3410, p = 0.0077) in patients with breast cancer., Conclusions: Our results proved that miR-142-3p may serve as a tumor suppressor in breast cancer by suppressing the expression of oncogene HMGA1 and FZD7, suggesting that miR-142-3p has the potential to become a diagnostic marker and therapeutic target for the early diagnosis and treatment of breast cancer.

Background: Leukaemia is a malignant leukocyte disorder with a high fatality rate, and current treatments for this disease are unsatisfactory. Therefore, new therapeutic strategies for leukaemia must be developed. Malaria parasite infection has been shown to be effective at combating certain neoplasms in animal experiments. This study is to demonstrate the anti-leukaemia activity of malaria parasite Plasmodium yoelii (P. yoelii) infection,., Methods: In this study, the proportion of CD3, CD19, CD11b and Mac-3 cells was analysed by flow cytometry; the levels of IFN-γ and TNF-α in individual serum samples were measured by enzyme-linked immunosorbent assay, and the phagocytic activity of macrophages and natural killer (NK) cell activity were measured by flow cytometry., Results: We found that P. yoelii infection significantly attenuated the growth of WEHI-3 cells in mice. In addition, tumor cell infiltration into the murine liver and spleen was markedly reduced. We also demonstrated that malaria parasite infection elicited anti-leukaemia activity by promoting immune responses, including increasing the surface markers of T cells (CD3) and B cells (CD19); decreasing the surface markers of monocytes (CD11b) and macrophages (Mac-3); inducing the secretion of IFN-γ and TNF-α; and increasing NK cell and macrophage activity., Conclusions: Malaria parasite infection significantly decreases the number of myeloblasts and inhibits neoplasm proliferation in mice. In addition, malaria parasite infection inhibits murine leukaemia by promoting immune responses.

Background: The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of the MEF2C gene results in dilated cardiomyopathy (DCM). However, in humans, the association of MEF2C variation with DCM remains to be investigated., Methods: The coding regions and splicing boundaries of the MEF2C gene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identified MEF2C mutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped for MEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system., Results: A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier's family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM., Conclusions: This study indicates MEF2C as a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.

Background: In longstanding persistent atrial fibrillation (LPeAF), the ideal endpoint of ablation remains to be determined. This study was to explore the value of pursuing AF termination or no with the same strategy during ablation on the long-term outcomes in patients with LPeAF., Methods: Utilized "CCL" strategy is a fixed ablation approach consisting of circumferential pulmonary vein antrum isolation, ablation of complex fractionated atrial electrogram, and linear ablation between two anatomical structures (the mitral isthmus, left atrial roof). Note that 400 patients were randomized to group A (technical endpoint) and group B (pursuing AF termination)., Results: A group with technical endpoint had lower rate of acute AF termination (AF→sinus rhythm, 3.5% vs 18.1%; AF→atrial tachycardia, 23.7% vs 44.7%; P < 0.01) and shorter duration of ablation (164.9 ± 20.8 vs 223.4 ± 24.9, P < 0.01), radiofrequency delivery time (69.8 ± 18.1 vs 102.2 ± 26.3, P < 0.01), and x-ray exposure time (18.2 ± 8.8 vs 27.9 ± 12.4, P < 0.01) than those in B group (pursuing AF termination). During follow-up, freedom from atrial arrhythmias did not differ between the two groups after a single ablation procedure (46.5% vs 54.3%, P=0.12) and the final ablation procedure (60.1% vs 65.8%, P  =  0.24)., Conclusion: In patients of LPeAF, pursuing AF termination during ablation was associated with similar long-term clinical outcome compared to that with technical endpoint. Ablation to termination is not the best strategy during ablation., (© 2017 Wiley Periodicals, Inc.)

Objectives: This study sought to determine if anatomic atrial ganglionated plexus (GP) ablation leads to long-term sinus rate (SR) increase and improves quality of life in patients with symptomatic sinus bradycardia (SB)., Background: Atrial GP ablation has been demonstrated to increase SR in our previous study. Atrial GP ablation may also be effective in treating patients with symptomatic SB., Methods: Sixty-two patients with symptomatic SB were recruited: Group A included patients <50 years of age (n = 40); Group B included patients ≥50 years of age (n = 22). All patients underwent anatomic ablation of the main atrial GP, and 24-h Holter monitoring and quality-of-life assessment were performed during 1 year of follow-up. Quality of life was accessed by the Medical Outcomes Study Short-Form 36 Health Survey., Results: Although SR markedly increased in all patients after GP ablation, the increase was significantly greater in patients <50 years of age than in patients ≥50 years of age (19.3 ± 9.9 beats/min vs. 10.8 ± 5.4 beats/min; p = 0.001). The right anterior GP and the GP at the junction of the aorta and superior vena cava made the greatest contributions to SR increase among all GP. The mean and minimal SR increased significantly after ablation and remained elevated for 12 months only in Group A patients. Although symptoms and quality of life improved in all patients, 5 of the 8 domains of the Medical Outcomes Study Short-Form 36 Health Survey did not show obvious improvements in patients of Group B at 12 months., Conclusions: Anatomic atrial GP ablation effectively increased SR and improved quality of life in patients <50 years of age with symptomatic SB., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The electrophysiological characteristics of patients without recurrence after ablation of persistent atrial fibrillation (AF) have not been systematically determined. This study compared the electrophysiological characteristics in patients with and without recurrence of AF after persistent AF ablation., Methods: Forty-five patients without recurrence of AF after persistent AF ablation were enrolled to assess electrophysiological characteristics including pulmonary vein (PV) reconnection, the mitral isthmus (MI) line and the roof line reconduction. Ninety-five patients with recurrence of AF after ablation were used as the control group., Results: Among patients without recurrence, recovery of PV conduction was observed in 37 of 45 (82.2%) patients: 3/45 (6.7%) reconnection in 4 veins, 7/45 (15.6%) in 3 veins, 11/45 (24.4%) in 2 veins, and 16/45 (35.6%) in 1 vein. No significant differences were seen in the proportion of patients with PV reconnection compared to patients with recurrence (p>0.05). Among patients without recurrence, the MI line reconduction was observed in 3/45 (6.7%) patients; the roof line conduction was observed in 5/45 (11.1%) patients. In comparison, patients with clinical recurrence of AF had recovery of the MI line conduction in 27/95 (28.4%) and recovery of the roof line conduction in 26/95 (27.4%). Significant differences were seen between these two groups (6.7% vs 28.4%, p=0.004; 11.1% vs 27.4%, p=0.031)., Conclusion: Although a high incidence of PV reconnection was similarly observed in patients with and without recurrence of AF, a lower incidence of lines reconduction was observed in patients without recurrence of AF., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The role of autonomic innervation around the pulmonary vein (PV) antrum in the genesis of atrial fibrillation (AF) has been demonstrated but the characteristics of radiofrequency induced vagal response (VR) in the PV antrum and its clinical impact on pulmonary vein isolation (PVI) for paroxysmal AF need to be further elucidated., Method: Of 995 consecutive patients with symptomatic paroxysmal AF undergoing PVI at a single center over a 2-year period, 516 met exclusion criteria and the remaining 479 patients, 156 positive VR (PVR) and 323 negative VR (NVR), underwent 12-month follow-up. The primary endpoint was freedom from AF or other sustained atrial tachycardia (AT), verified by monthly visits and electrocardiographic monitoring. The frequency-domain analysis was performed to evaluate the autonomic activity before and after the procedure., Results: VR was most commonly elicited during PVI at the LSPV roof (65.4%) and anterior RSPV (44.9%, with a >5s sinus pause in 37/70 [52.8%] cases). Compared with the NVR group, ablation was associated with reduced AF recurrence at 12 months in the PVR (hazard ratio: 0.53, 95% confidence interval: 0.22-0.89). Furthermore, the PVR group showed a significantly abbreviated AF cycle length at the left PV, and significantly lower HF and LF parameters with stable LF/HF ratio during follow-up., Conclusion: Complete elimination of vagal response, most commonly elicited by radiofrequency application around the roof of LSPV and anterior RSPV, appeared associated with reduced 12-month recurrence of AF and with marked heart rate variability changes consistent with autonomic nervous withdrawal., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: Atrial fibroblasts and macrophages have long been thought to participate in atrial fibrillation (AF). However, which specific mediator may regulate the interaction between them remains unclear., Methods and Results: We provided the evidence for the involvement of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), an important inflammation-related molecule, in the pathophysiology of AF. Patients with AF showed higher levels of angiotensin II (AngII) and TRIF expression and larger number of macrophages infiltration in left atria appendage than individuals with sinus rhythm (SR). In the cell study, AngII induced chemokines expressions in mouse atrial fibroblasts and AngII-stimulated atrial fibroblasts induced the chemotaxis of macrophages, which were reduced by losartan and TRIF siRNA. Meanwhile, AngII-stimulated atrial fibroblasts proliferation was enhanced by macrophages., Conclusions: Our data demonstrated that TRIF may be a crucial factor promoting the interaction between atrial fibroblasts and macrophages, leading to atrial fibrosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Dilated cardiomyopathy (DCM) represents the most prevalent form of primary cardiomyopathy, and is the most common reason for heart transplantation and a major cause of congestive heart failure. Aggregating evidence demonstrates that genetic defects are associated with DCM, and a great number of mutations in >50 genes have been linked to DCM. However, DCM is a genetically heterogeneous disorder and the genetic components underpinning DCM in a significant proportion of patients remain unknown. In the present study, the coding exons and flanking exon‑intron boundaries of the T-Box 5 (TBX5) gene, which encodes a T‑box transcription factor required for normal cardiac development, were sequenced in 146 unrelated patients with sporadic DCM. The functional characteristics of the mutant TBX5 were assayed in contrast to its wild‑type counterpart by using a dual‑luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.A143T, was identified in a patient with sporadic DCM. The missense mutation, which was absent in 400 control chromosomes, altered the amino acid that was completely conserved evolutionarily among species. Biological analyses revealed that the A143T mutation of TBX5 was associated with significantly decreased transcriptional activity on the promoter of the target gene atrial natriuretic factor (ANF), when compared to its wild‑type counterpart. Furthermore, the A143T mutation abolished the synergistic activation of the ANF promoter between TBX5 and GATA binding protein 4 (GATA4), another crucial transcriptional factor for heart development. To the best of our knowledge, this is the first report on the association of a TBX5 loss‑of‑function mutation with an enhanced susceptibility to sporadic DCM, providing novel insight into the molecular mechanisms of the pathogenesis of DCM and suggesting potential implications for the prenatal prophylaxis and personalized treatment of this commonest primary myocardial disease.

A miscible tetrahydrofuran-tris buffer mixture has been used to fabricate polydopamine hollow capsules with a size of 200 nm and with a shell thickness of 40 nm. An unusual non-emulsion soft template mechanism has been disclosed to explain the formation of capsules. The results indicate that the capsule structure is highly dependent on the volume fraction of tetrahydrofuran as well as the solvent, and the shell thickness of capsules can be controlled by adjusting the reaction time and dopamine concentration.

The exact mechanisms underlying inhibitory effects of pioglitazone (Pio) on Angiotensin II (AngII)-induced atrial fibrosis are complex and remain largely unknown. In the present study, we examined the effect of Pio on AngII-induced mice atrial fibrosis in vivo and atrial fibroblasts proliferation in vitro. In vivo study showed that AngII infusion induced atrial fibrosis and increased expressions of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and tumor necrosis factor receptor associated factor 6 (TRAF6) in mice models. However, those effects could be attenuated by Pio (P<0.01). As for in vitro experiment, Pio suppressed AngII-induced atrial fibroblasts proliferation via nuclear factor-κB/transforming growth factor-β1/TRIF/TRAF6 signaling pathway in primary cultured mice atrial fibroblasts (P<0.01). In conclusion, suppression of Pio on AngII-induced atrial fibrosis might be related to its inhibitory effects on above signaling pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Dilated cardiomyopathy (DCM), the most prevalent form of primary heart muscle disease, is the third most common cause of heart failure and the most frequent reason for cardiac transplantation. Mounting evidence has demonstrated that genetic risk factors are crucial in the pathogenesis of DCM. However, DCM is genetically heterogeneous, and the genetic basis of DCM in a large majority of cases remains unclear. In the current study, the coding exons and flanking introns of the GATA6 gene, which encodes a zinc‑finger transcription factor essential for cardiogenesis, was sequenced in 140 unrelated patients with DCM, and two novel heterozygous mutations, p.C447Y and p.H475R, were identified in two index patients with DCM, respectively. Analysis of the pedigrees showed that in each family the mutation co-segregated with DCM transmitted in an autosomal-dominant pattern, with complete penetrance. The missense mutations were absent in 400 control chromosomes and predicted to be disease-causing by MutationTaster or probably damaging by PolyPhen-2. The alignment of multiple GATA6 proteins across species revealed that the altered amino acids were completely conserved evolutionarily. The functional assays showed that the mutated GATA6 proteins were associated with significantly reduced transcriptional activation in comparison with their wild-type counterpart. To the best of our knowledge, this is the first study on the association of GATA6 loss-of-function mutations with enhanced susceptibility to familial DCM, which provides novel insight into the molecular mechanism of DCM and suggests potential implications for the antenatal prophylaxis and allele-specific treatment of DCM.

Aim: Although catheter ablation (CA) has replaced antiarrhythmic drugs (AAD) as first-line treatment in selected patients with atrial fibrillation (AF), optimal treatment of recurrent atrial tachycardia (AT) after AF ablation remains unclear. This parallel randomized controlled study compared CA vs. AAD for recurrent AT after persistent AF ablation., Methods and Results: Two-hundred and one patients (aged 59.1 ± 10.9 years, 68.7% male) with recurrent AT after persistent AF ablation were enrolled and randomized to either CA (n = 101) or AAD (n = 100) treatment. Primary endpoint was freedom from recurrent atrial tachyarrhythmia (ATa, including AT and AF) at 24-month follow-up. Composite secondary endpoints comprised procedural complications, long-term morbidity and improvement in quality of life (QoL). On an intention-to-treat basis, the CA group had a higher rate of freedom from recurrent ATa (56.4 vs. 34.0%; P = 0.001). Adjusted Cox regression analysis showed a significant treatment effect with a hazard ratio of 0.538 (95% CI: 0.355-0.816) in favour of CA. There was a higher proportion of periprocedural complications in the CA group (7.9 vs. 0; P = 0.012), and of long-term adverse events in the AAD group (10.9 vs. 24.0%; P = 0.014). Quality of life was significantly higher for CA., Conclusions: This study demonstrates superiority of CA over AAD for recurrent AT after persistent AF ablation with regard to SR maintenance, long-term safety and QoL improvement. However, CA use might be limited by a higher risk for periprocedural complications., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia in humans and is responsible for substantial morbidity and mortality worldwide. Emerging evidence indicates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2-5 gene, which encodes a homeodomain-containing transcription factor essential for cardiovascular genesis, were sequenced in 146 unrelated patients with lone AF as well as the available relatives of the mutation carriers. A total of 700 unrelated ethnically matched healthy individuals used as controls were genotyped. The disease-causing potential of the identified NKX2-5 variations was predicted by MutationTaster and PolyPhen-2. The functional characteristics of the mutant NKX2-5 proteins were analyzed using a dual-luciferase reporter assay system. As a result, two heterozygous NKX2-5 mutations, including a previously reported p.E21Q and a novel p.T180A mutation, were identified in two families with AF transmitted in an autosomal dominant pattern. The mutations co-segregated with AF in the families with complete penetrance. The detected substitutions, which altered the amino acids highly conserved evolutionarily across species, were absent in 700 control individuals and were both predicted to be causative. Functional analyses demonstrated that the NKX2-5 mutants were associated with significantly decreased transcriptional activity compared with their wild-type counterpart. The findings expand the spectrum of NKX2-5 mutations linked to AF and provide additional evidence that dysfunctional NKX2-5 may confer vulnerability to AF, suggesting the potential benefit for the early prophylaxis and personalized treatment of AF.

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disorder and is associated with substantial morbidity and mortality. Increasing evidence suggests that genetic risk factors play an important role in the pathogenesis of idiopathic DCM. However, DCM is a genetically heterogeneous disease, and the genetic defects responsible for DCM in an overwhelming majority of cases remain to be identified. In the present study, the entire coding region and the splice junction sites of the GATA4 gene, which encodes a cardiac transcription factor essential for cardiogenesis, were sequenced in 150 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional characteristics of the mutant GATA4 were delineated in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.V291L, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes, and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the GATA4 mutant was associated with significantly diminished transcriptional activity. The findings expand the mutational spectrum of GATA4 linked to DCM and provide novel insight into the molecular etiology involved in DCM, suggesting the potential implications in the early prophylaxis and allele-specific treatment for this common type of cardiomyopathy.

Interstitial cells of Cajal (ICC) are critical to gastrointestinal motility. The phenotypes of ICC progenitors have been observed in the mouse gut, but whether they exist in the human colon and what abnormal changes in their quantity and ultrastructure are present in Hirschsprung's disease (HSCR) colon remains uncertain. In this study, we collected the surgical resection of colons, both proximal and narrow segments, from HSCR patients and normal controls. First, we identified the progenitor of ICC in normal adult colon using immunofluorescent localization techniques with laser confocal microscopy. Next, the progenitors were sorted to observe their morphology. We further applied flow cytometry to examine the content of ICC progenitors in these fresh samples. The ultrastructural changes in the narrow and proximal parts of the HSCR colon were observed using transmission electron microscopy (TEM) and were compared with the normal adult colon. The presumed early progenitor (c-Kit(low)CD34(+)Igf1r(+)) and committed progenitor (c-Kit(+)CD34(+)Igf1r(+)) of ICC exist in adult normal colon as well as in the narrow and proximal parts of the HSCR colon. However, the proportions of mature, early and committed progenitors of ICC were dramatically reduced in the narrow segment of the HSCR colon. The proportions of mature and committed progenitors of ICC in the proximal segment of the HSCR colon were lower than in the adult normal colon. Ultrastructurally, ICC, enteric nerves, and smooth muscle in the narrow segment of the HSCR colon showed severe injury, including swollen vacuola or ted mitochondria, disappearance of mitochondrial cristae, dilated rough endoplasmic reticulum, vesiculation and degranulation, and disappearance of the caveolae on the ICC membrane surface. The contents of ICC and its progenitors in the narrow part of the HSCR colon were significantly decreased than those of adult colon, which may be associated with HSCR pathogenesis.

Background: The benefits and risks of additional complex fractionated atrial electrograms (CFAE) ablation in patients with atrial fibrillation (AF) remain unclear., Methods: Trials were identified in PubMed, Embase, Web of Science, and Cochrane Database, reviews, and reference lists of relevant papers. The primary end point was the recurrence of atrial arrhythmias after a single ablation., Results: We meta-analyzed 11 studies (total, n=983) using random-effects model to compare PVI (n=478) with PVI plus CFAE ablation (PVI+CFAE) (n=505). Additional CFAE ablation reduced recurrence of atrial tachyarrhythmia after a single procedure (pooled RR 0.73; 95% CI 0.61, 0.88; P=0.0007) at ≥ 3-month follow-up. There was no evidence of heterogeneity among studies (I(2)=33%). Subgroup analysis demonstrated that additional CFAE ablation reduced rates of recurrence in nonparoxysmal AF (RR 0.68; 95% CI 0.47, 0.99; P=0.05), whereas had no effect on patients with paroxysmal AF (RR 0.79; 95% CI 0.59, 1.06; P=0.12). Eight studies reported results of post-procedure ATs. The addition of CFAE ablation increased the rate of post-procedure ATs (RR 1.77; 95% CI 1.02, 3.07; P=0.04). Additional CFAE ablation significantly increased mean procedural times (245.4+75.7 vs. 189.5+62.3 min, P<0.001), mean fluoroscopy (72.1+25.6 vs. 59.5+19.3 min, P<0.001), and mean RF energy application times (75.3+38.6 vs. 53.2+27.5 min, P<0.001)., Conclusions: The adjunctive CFAE ablation could provide additional benefit in terms of reducing recurrence of atrial tachyarrhythmia for patients with nonparoxysmal AF but not for patients with paroxysmal AF after a single procedure with or without antiarrhythmic drugs (AADs). The main risk of adjunctive CFAE ablation is the increasing rate of untraceable postablation ATs., (© 2013.)

Background: In our previous prospective and randomized study, we have demonstrated that the concomitant surgical ablation using saline-irrigated cooled tip radiofrequency ablation (SICTRA) system is more effective than subsequent circumferential pulmonary vein isolation (CPVI) combined with substrate modification in treating patients with long-standing persistent atrial fibrillation (LS-AF) and rheumatic heart disease (RHD) undergoing cardiac surgery during middle-term follow-up. Whether this strategy also decreases longer-term arrhythmia recurrence is unknown. This study describes the 4-year efficacy of SICTRA for these patients. Furthermore, we seek to compare the electrophysiological characteristics for recurrent atrial tachyarrhythmia (ATa) at the session of catheter ablation between two groups., Methods: Long-term follow-up was performed in 95 patients who underwent the catheter ablation strategy (n=47, Group A) or SICTRA (n=48, Group B) combined with valvular surgery for symptomatic LS-AF patients with RHD., Results: After one procedure, Group B had a significantly higher freedom from ATa compared with Group A (29/48 vs 15/47, P=0.005) after a mean follow-up of 54 months (range 48 to 63 months). Catheter-based mapping and ablation of recurrent ATa showed larger amounts of macro-reentrant atrial tachycardias (ATs) in Group B and higher incidence of pulmonary vein (PV) recovery in Group A. After multiple catheter ablations for recurrent ATa, sinus rhythm (SR) could be maintained equally between two groups., Conclusions: Single procedure success seems to be higher with SICTRA but repeated catheter ablation potentially results in comparable outcomes in treating patients with LS-AF and RHD during long-term follow-up. More macro-reentrant ATs and more PV recoveries are identified to be responsible for ATa in SICTRA and catheter ablation group, respectively., (© 2013.)

The cardiac transcription factor GATA4 is essential for cardiac development, and mutations in this gene have been implicated in a wide variety of congenital heart diseases in both animal models and humans. However, whether mutated GATA4 predisposes to dilated cardiomyopathy (DCM) remains unknown. In this study, the whole coding region and splice junction sites of the GATA4 gene was sequenced in 110 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.C271S, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis demonstrated that the GATA4 mutant was associated with significantly decreased transcriptional activity and remarkably reduced synergistic activation between GATA4 and NKX2-5, another transcription factor crucial for cardiogenesis. The findings provide novel insight into the molecular mechanisms involved in the pathogenesis of DCM, suggesting the potential implications in the prenatal diagnosis and gene-specific treatment for this common form of myocardial disorder., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Catheter ablation (CA) has been the most effective treatment for both paroxysmal and persistent atrial fibrillation (AF). However, the impact of age on CA for persistent AF is not well defined., Methods: Between January 2010 and August 2011, 258 consecutive patients (85 females, 32.9%), with long-standing persistent AF who underwent CA were prospectively recruited. Age-related differences in clinical presentation, peri-procedural complications, and outcomes were compared., Results: The study population included 258 patients (85 females, 32.9%): 71 patients in Group I (≤ 55 years), 89 patients in Group II (56-65 years), and 98 patients in Group III (≥ 66 years). Younger patients were more likely to have lone AF (49.3% in Group I, 32.6% in Group II, and 30.6% in Group III; P = 0.029). There was a significant difference in the success rate with advancing age after a single CA (69.0% in Group I, 50.6% in Group II, 40.8% in Group III; P = 0.001). A Cox regression analysis demonstrated age (for each 10 years increase, HR 1.307, CI 1.081-1.580; P = 0.006), sex (HR 1.460, CI 1.017-2.097; P = 0.040) and total AF duration (per year, HR 1.033, CI 1.006-1.060; P = 0.015) as the independent predictors for recurrence after the first CA. However, there was no significant difference in the incidence of peri-procedural complications among the three groups., Conclusions: In this consecutive series of patients with long-standing persistent AF, female gender, total AF duration and advanced age were associated with the success of a single CA. The overall rate of complications was similar among all age groups., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: This randomized prospective study compared three ablation strategies in patients with long-standing persistent atrial fibrillation (LPeAF). It also explored the best procedural endpoint from among the following: circumferential pulmonary vein isolation (PVI) + left atrial (LA) linear lesions (roofline, mitral isthmus) + complex fractionated atrial electrogram (CFAE) ablation, PVI + LA linear lesions + cavotricuspid isthmus (CTI) ablation + CFAE ablation, and PVI + CFAE ablation., Methods and Results: A total of 210 patients with LPeAF referred for catheter ablation were enrolled and randomized into three ablation groups. The patients in group A (n = 70) underwent PVI followed by LA linear and CFAE ablation; in 93% of patients the primary endpoint was achieved (five patients with incomplete linear lesions). Of the 70 patients in group B who were subjected to PVI followed by LA linear, CFAE, and CTI ablations, in 94% of patients the primary endpoint was achieved (four patients with incomplete linear lesions). All patients in group C (n = 70) successfully underwent PVI and CFAE ablation. Direct current cardioversion was performed upon PVI, CFAE elimination, and completion of linear lesions. Patients were followed-up for atrial tachyarrhythmia recurrence for at least 24 months. After a single ablation procedure, group C (36%) exhibited the lowest success compared with group A (54%) and group B (51%) (P = 0.06). At the mean follow-up of 32 ± 9 months after the final ablation procedure, 53 patients (76%) in group A, 53 (76%) in group B, and 41 (59%) in group C were in sinus rhythm without antiarrhythmic drugs (P = 0.03)., Conclusions: In LPeAF, linear lesions in the LA help improve outcome of ablation, additional CTI ablation does not., (©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.)

Objectives: It is uncertain whether gender affects the outcomes of catheter ablation (CA) for atrial fibrillation (AF). The objective of the study is to evaluate the efficacy and safety of CA for long-standing persistent AF in women., Methods: Between January 2010 and May 2011, 220 consecutive patients (73 females, 33.2%), with long-standing persistent AF who underwent CA were prospectively recruited. Gender-related differences in clinical presentation, periprocedural complications, and outcomes were compared., Results: Women were less likely to have lone AF than men (27.4% vs 47.6%; P = 0.004). The incidence of rheumatic heart disease was higher in women (19.2% in women vs 1.4% in men; P < 0.001). Women had a lower initial ablation success rate than men (35.6% vs 57.1%; P = 0.003). Hematomas occurred more often in women (6.8% in women vs 0.7% in men; P = 0.027). A Cox regression analysis demonstrated total duration of AF (per month, hazard ratio [HR] 1.003, confidence interval [CI] 1.001-1.006; P = 0.006) and gender (HR 1.663, CI 1.114-2.485; P = 0.013) as the independent predictors for recurrence after the first CA., Conclusions: Women and long AF duration were closely related to the recurrence of AF after the first ablation in patients with long-standing persistent AF. Women also had a higher risk of vascular complications., (©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.)

Background: Circumferential pulmonary vein isolation (CPVI), as the basal ablation strategy for treating atrial fibrillation (AF), not only isolates the connection between the left atrium (LA) and the pulmonary veins (PVs), but also induces extensive atrial endocardia damage. This could have an effect on the sinus pulse conduction in the LA and subsequently result in changes of P-wave characteristics of surface electrocardiogram (ECG)., Methods: Fifty consecutive patients underwent CPVI for symptomatic drug-refractory paroxysmal AF. The 12-lead ECGs were recorded one day before CPVI and seven days after CPVI at sinus rhythm by a standard resting ECG device. Measured characteristics of the P-wave consisted of P-wave duration (PWD), P-wave amplitude (PWA), P-wave polarity (PWP), P-wave notch, P-wave dispersion and P-wave index., Results: After CPVI, a prevalent decrease of PWD, PWA, and P-wave dispersion was observed; a transition of P-wave polarity was observed in the leads of III, aVL and aVF. The rate of P-wave notch decreased significantly in all leads, especially in the leads of II, III, aVF and V3. Patients with sinus rhythm had a shorter P-wave dispersion and P-wave index and had a lower rate of P-wave notch compared with the patients with recurrent atrial tachyarrhythmia., Conclusion: Observations from using the surface ECG showed that CPVI has instant effects on the electrical conduction in the LA, and several changes of P-wave characteristics associated with development of AF are improved by CPVI.

Objective: To investigate the setting of ventilator volume tidal (VT) and airway pressure alarm threshold during cardiopulmonary resuscitation (CPR) by continuous extra-sternum heart compression., Methods: Forty cases with respiration and cardiac arrest in the department of critical care medicine were randomly divided into low VT ventilation group and conventional VT group. Both groups were given the volume control mode. In the low VT ventilation group, VT was set on 6 - 7 ml/kg, and high pressure alarm threshold was adjusted to 60 cm H2O by the conventional 40 cm H2O during CPR. In the conventional VT group, VT and high pressure alarm threshold were set at 8 - 12 ml/kg and 40 cm H2O, respectively. Real-time actual VT, peak inspiratory pressure (PIP), and arterial blood gas test, blood lactic acid at 10 minutes and 30 minutes after CPR were observed., Results: At 10 minutes after CPR, in the low VT ventilation group, arterial blood pH, arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), HCO3(-), arterial oxygen saturation (SaO2) and blood lactic acid were better as compared with those in the conventional VT ventilation group (pH: 7.21±0.09 vs. 7.13±0.07, PaO2: 45.35±5.92 mm Hg vs. 40.70±4.70 mm Hg, PaCO2: 57.10±7.59 mm Hg vs. 61.60±5.47 mm Hg, HCO3(-): 18.50±3.50 mmol/L vs. 14.75±2.65 mmol/L, SaO2: 0.796±0.069 vs. 0.699±0.066, blood lactic acid: 7.07±1.60 mmol/L vs. 8.13±1.56 mmol/L, all P<0.05). The success rate of resuscitation in the low VT ventilation group was higher than that of the conventional VT ventilation group (45% vs. 15%, P<0.05), and PIP (cm H2O) of low VT ventilation group was lower than that of the conventional VT group (37.25±7.99 cm H2O vs. 42.70±7.40 cm H2O, P<0.05). In all the patients in both groups barotrauma did not occur., Conclusion: The strategy of low ventilator VT (6 - 7 ml/kg) with appropriate elevation of airway pressure alarm threshold was better than that of conventional ventilation setting, with no increase in incidence of barotraumas during CPR.

Objective: The purpose of this study is to investigate the mechanism and the effectiveness of ablation of atrial tachycardia (AT) recurring after atrial fibrillation (AF) ablation in patients with rheumatic valvular disease (RVD) and mitral valve prosthesis., Methods: Twenty-eight consecutive patients with RVD and mitral valve prosthesis and a 1:2 matched control group (n = 56) without RVD underwent reablation for recurrent AT after catheter ablation of long-standing persistent AF., Results: Macro- or localized reentrant ATs were identified in 47 (87 %) of 54 ATs from RVD group and in 65 (78.3 %) of 83 ATs from control. There were more average ATs per patient in the RVD group than in the control (1.9 ± 0.6 vs.1.5 ± 0.6, P = 0.002). The proportion of patients having ≥2 ATs was significantly higher in the RVD group than in the control (78.6 vs.41.1 %, P = 0.001). In the RVD group, ATs were successfully ablated in 44 (81.5 %) of 54 ATs and terminated in 18 (64.3 %) of 28 patients. In the control, ATs were successfully ablated in 72 (86.7 %) of 83 ATs and terminated in 45 (80.4 %) of 56 patients, P = 0.54 and 0.10, respectively. After a mean follow-up of 13 months, 16 patients (57.1 %) from the RVD group and 45 patients (80.4 %) from the control were free of further recurrence, P = 0.02., Conclusions: Macro- or localized reentries were the predominant type of recurrent AT after long-standing persistent AF ablation in both the RVD and the control groups. Compared with patients without RVD, patients with RVD had more average number of ATs and had higher probability of further recurrence despite the similar acute effectiveness of reablation.

The renin-angiotensin-aldosterone system (RAAS) plays a key role in atrial structural and electrical remodeling. The aim of this study was to investigate the potential associations of angiotensin-converting enzyme (ACE) gene insertion/ deletion (I/D) and aldosterone synthase (CYP11B2) gene -344T/C polymorphisms with the risk and recurrence of lone atrial fibrillation (AF). One hundred and ninety-three patients who underwent successful catheter ablation for lone AF were recruited. Two hundred and ninety-seven sinus rhythm subjects without a history of arrhythmia served as controls. The subjects were genotyped for ACE gene I/D and CYP11B2 gene -344T/C polymorphisms. Results showed that the ACE gene DD genotype and D allele were associated with a greater prevalence of lone AF (both P<0.01). In addition, the ACE gene DD genotype had a significantly larger left atrial dimension (LAD; 41.6±5.7 mm vs. 39.6±5.2 mm; P=0.043) and higher risk of AF recurrence [44.7% vs. 23.2%; odds ratio (OR), 2.68; 95% confidence interval (CI), 1.28-5.61; P=0.008] compared with the II+ID genotype in lone AF patients. After adjustment for a variety of risk factors, the ACE gene DD genotype had a 1.97-fold increased risk for lone AF (OR, 1.97; 95% CI, 1.15-3.37; P= 0.013) and 2.35-fold increased risk for AF recurrence (RR, 2.35; 95% CI, 1.10-5.04; P=0.028) compared with the ACE gene II+ID genotype. However, no correlation between the CYP11B2 gene -344T/C polymorphism and lone AF or its recurrence was observed in this cohort. In conclusion, the ACE gene DD genotype was associated with an increased incidence of lone AF and its recurrence following ablation, which was partly mediated by LAD.

The activation of transforming growth factor-β1(TGF-β1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGFβ1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGFβ-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-β1/non-Smad signaling pathways. In the present study, we explored the role of TGF-β1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 μM) provoked the activation of P38 mitogen activated protein kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 μM) also promoted TGFβ1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGFβ1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGFβ1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Both fluorescence dynamics and time-dependent electron transitions are introduced within a previously developed molecule dynamics approach for treating conjugated polymers. This is able to provide a panoramic view of luminescence dynamics during singlet exciton decay, in which the fluorescence dynamics is largely determined by the electron population and the evolution of the dipole moment. The fluorescence intensity is weakened due to a reduced dipole moment and diminished decay rate of the electron, which validates a previous assumption based on experimental studies. The lifetime of the singlet exciton in a conjugated polymer is found to be 1.2 ns, and the calculated time profile of the fluorescence intensity is in agreement with recent experimental results., (© 2011 American Chemical Society)

Bone is the third most common site of cancer metastasis. Over 30 to 40% of lung cancers can develop skeletal metastasis and no effective curative therapy exists in clinic cases. Previously we screened the different expression of proteins between SBC-5 cells and SBC-3 cells by proteomic study methods (MALDI-TOF/TOF-MS) and found that calcineurin (hereafter referred as Cn) overexpresses in SBC-5 which has special priority in metastasis to bone in a multiple-organ metastasis mice model. However the roles of Cn in osteotropism of SCLC remain to be elucidated. At present study, we decrease CnAα expression in SBC-5 by lentiviral vector-mediated RNAi and found that down regulation of CnAα gene expression can decrease the proliferation and colony formation rate, impede the cell cycle progression, reduce the cell migration and invasion, and inhibit cells adhering to bone matrix, but not change the apoptosis rate of SBC-5 in vitro. In vivo down or up regulation of CnAα gene expression can only decrease or increase the bone metastasis rate, but not affect the metastasis rate to the visceral organs. Our research reveals that CnAα is closely related to the osteotropism metastasis of SCLC and a candidate tumor promotor gene for developing bone metastases.