Discovery of TBX20 as a Novel Gene Underlying Atrial Fibrillation.

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.

MiR-199a-5p enhances neuronal differentiation of neural stem cells and promotes neurogenesis by targeting Cav-1 after cerebral ischemia.

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.

Temporal and Spatial Changes of Proarrhythmic Substrate in Premature Ventricular Contraction-Induced Cardiomyopathy.

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 cm2), 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.

Rotor mechanism and its mapping in atrial fibrillation.

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.

A novel approach for quantitative electrogram analysis for driver identification: Implications for ablation in persistent atrial fibrillation.

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.

Prognostic impact of blood urea nitrogen/creatinine ratio changes in patients with acute ischemic stroke.

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 (ß = 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.

SOX17 loss-of-function variation underlying familial congenital heart disease.

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_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.

Clinical Safety and Efficacy of Ablation for Atrial Fibrillation Patients With a History of Stroke.

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.

A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve.

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_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.

ISL1 loss-of-function variation causes familial atrial fibrillation.

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_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.

Electrogram dispersion-guided driver ablation adjunctive to high-quality pulmonary vein isolation in atrial fibrillation of varying durations.

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.

Long-Term Effect of Different Optimizing Methods for Cardiac Resynchronization Therapy in Patients with Heart Failure: A Randomized and Controlled Pilot Study.

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.

Aberrant Expression of miR-142-3p and its Target Gene HMGA1 and FZD7 in Breast Cancer and its Clinical Significance.

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.

Optimal endpoint for catheter ablation of longstanding persistent atrial fibrillation: A randomized clinical trial.

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.

MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy.

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.

Atrial Ganglionated Plexus Modification: A Novel Approach to Treat Symptomatic Sinus Bradycardia.

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.

A clinical study on the electrophysiological characteristics of patients without recurrence after ablation of persistent atrial fibrillation.

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.

Vagal response during pulmonary vein isolation: Re-recognized its characteristics and implications in lone paroxysmal atrial fibrillation.

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.

TRIF promotes angiotensin II-induced cross-talk between fibroblasts and macrophages in atrial fibrosis.

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-ß (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.

A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy.

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 exon­intron boundaries of the T-Box 5 (TBX5) gene, which encodes a T­box 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 wild­type counterpart by using a dual­luciferase 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 wild­type 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 loss­of­function 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.