Wei-Feng Jiang

Beneficial effect of pioglitazone on the outcome of catheter ablation in patients with paroxysmal atrial fibrillation and type 2 diabetes mellitus

AIMS Pioglitazone, one of the peroxisome proliferator-activated receptor-gamma activators, possesses anti-inflammatory and antioxidant properties. In the present study, we sought to identify the impact of pioglitazone on the outcome of catheter ablation for paroxysmal atrial fibrillation (PAF). METHODS AND RESULTS We conducted a prospective observational cohort study of 150 consecutive patients undergoing catheter ablation of drug-refractory PAF. All patients had a history of type 2 diabetes mellitus (T2DM) and were divided based on whether they received pioglitazone before ablation or not. After grouping, 51 patients treated with pioglitazone and 99 control subjects were followed up at least 15 months after ablation. After a single ablation, sinus rhythm was maintained in 44 patients (86.3%) of the pioglitazone group vs. 70 patients (70.7%) of the control group (P = 0.034) without antiarrhythmic drug during a mean follow-up of 22.9 ± 5.1 months. The second ablation was performed in 5 patients (9.8%) from the pioglitazone group and in 24 patients (24.2%) from the control group (P = 0.034). Multivariate logistic analysis showed left atrium diameter was associated with a high risk of atrial tachyarrhythmias recurrence, and treatment with renin-angiotensin system inhibitor as well as pioglitazone was associated with a reduced atrial tachyarrhythmias recurrence rate. CONCLUSION Pioglitazone improved the preservation of sinus rhythm and reduced the reablation rate in patients with PAF and T2DM after catheter ablation.

Pioglitazone inhibits angiotensin II-induced atrial fibroblasts proliferation via NF-κB/TGF-β1/TRIF/TRAF6 pathway.

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.

Novel connexin40 missense mutations in patients with familial atrial fibrillation.

AIMS This research was aimed at screening connexin40, a cardiac gap junction protein alpha 5, for genetic defects in patients with familial atrial fibrillation (AF). METHODS The subjects included 218 unrelated families with lone AF and 200 ethnically matched unrelated healthy individuals as controls. The entire coding region of the connexin40 gene was sequenced initially in 218 unrelated probands with familial AF. The relatives of mutation carriers and 200 controls were subsequently genotyped for the presence of mutations identified in probands. RESULTS Three novel connexin40 mutations, p.V85I, p.L221I, and p.L229M, were identified in 3 of 218 unrelated AF families, respectively. These heterozygous missense mutations co-segregated with AF in the families and were absent in the 200 unrelated control subjects. A cross-species alignment of connexin40 protein sequences revealed that the altered amino acids were completely conserved evolutionarily. CONCLUSION The findings expand the spectrum of mutations in connexin40 linked to AF and provide new insight into the molecular aetiology involved in the pathogenesis of AF.

Angiotensin II increases CTGF expression via MAPKs/TGF-β1/TRAF6 pathway in atrial fibroblasts.

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.

GATA4 loss-of-function mutations in familial atrial fibrillation

BACKGROUND Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major source of the substantially increased morbidity and mortality. Growing studies demonstrate that genetic defects play pivotal roles in a subgroup of AF. However, AF is a genetically heterogeneous disorder and the molecular basis of AF in a majority of cases remains unknown. METHODS The whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was analyzed in 130 unrelated probands with AF in contrast to 200 unrelated ethnically matched healthy individuals used as controls. The available family members of the probands harboring the identified mutations were genotyped. The functional effect of the mutant GATA4 was characterized using a luciferase reporter assay system. RESULTS Two novel heterozygous GATA4 mutations, p.S70T and p.S160T, were identified in 2 unrelated families with AF inherited as an autosomal dominant trait, respectively, which co-segregated with AF in each family with complete penetrance. Functional analysis showed that the mutations of GATA4 were associated with a significantly decreased transcriptional activity. CONCLUSION The findings provide new insight into the molecular mechanism involved in the pathogenesis of AF, suggesting the potential implications in the genetic diagnosis and gene-specific therapy of this common arrhythmia.

Benefits and risks of additional ablation of complex fractionated atrial electrograms for patients with atrial fibrillation: A systematic review and meta-analysis

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.

GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy

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.

Efficacy, safety and outcome of catheter ablation for atrial fibrillation in octogenarians

BACKGROUND AND OBJECTIVES Catheter ablation is effective in treating patients with atrial fibrillation (AF). The aim of the study was to evaluate the safety, efficacy and outcome of catheter ablation for AF in octogenarians. METHODS AND RESULTS 377 consecutive patients were divided into three groups based on age: ≥80 years (group 1; n=49), 70-79 years (group 2; n=151), 60-69 years (group 3; n=177). The efficacy and safety for those three groups were determined. The success rate after one procedure was similar in three groups (70% in group 1, 72% in group2 and 74% in group 3, P=NS) during a mean follow-up of 18 months. Major complication rates were comparable between the three groups. However, the octogenarians were less likely to undergo a repeated procedure than other groups (8% in group 1, 15% in group 2 and 18% in group 3, P<0.05), and were more likely to remain on antiarrhythmic drugs. CONCLUSION Catheter ablation for AF attempted in octogenarians appears to be effective and with low risk. Ablation results are comparable with those noted in younger patients.

Efficacy and Safety of Catheter Ablation for Long‐Standing Persistent Atrial Fibrillation in Women

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.

A novel GATA4 loss-of-function mutation responsible for familial dilated cardiomyopathy

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.