Somatic GATA4 mutation contributes to tetralogy of Fallot.

Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart pathology and causes infant morbidity and mortality worldwide. GATA-binding protein 4 (GATA4) serves as a pivotal transcriptional factor for embryonic cardiogenesis and germline GATA4 mutations are causally linked to TOF. However, the effects of somatic GATA4 mutations on the pathogenesis of TOF remain to be ascertained. In the present study, sequencing assay of GATA4 was performed utilizing genomic DNA derived from resected heart tissue specimens as well as matched peripheral blood specimens of 62 patients with non-familial TOF who underwent surgical treatment for TOF. Sequencing of GATA4 was also performed using the heart tissue specimens as well as matched peripheral venous blood samples of 68 sporadic cases who underwent heart valve displacement because of rheumatic heart disorder and the peripheral venous whole blood samples of 216 healthy subjects. The function of the mutant was explored by dual-luciferase activity analysis. Consequently, a new GATA4 mutation, NM_002052.5:c.708T>G;p.(Tyr236*), was found in the heart tissue of one patient with TOF. No mutation was detected in the heart tissue of the 68 cases suffering from rheumatic heart disorder or in the venous blood samples of all 346 individuals. GATA4 mutant failed to transactivate its target gene, myosin heavy chain 6. Additionally, this mutation nullified the synergistic transactivation between GATA4 and T-box transcription factor 5 or NK2 homeobox 5, two genes causative for TOF. Somatic GATA4 mutation predisposes TOF, highlighting the significant contribution of somatic variations to the molecular pathogenesis underpinning TOF.

Identification of BMP10 as a Novel Gene Contributing to Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM), characterized by left ventricular or biventricular enlargement with systolic dysfunction, is the most common type of cardiac muscle disease. It is a major cause of congestive heart failure and the most frequent indication for heart transplantation. Aggregating evidence has convincingly demonstrated that DCM has an underlying genetic basis, though the genetic defects responsible for DCM in a larger proportion of cases remain elusive, motivating the ongoing research for new DCM-causative genes. In the current investigation, a multigenerational family affected with autosomal-dominant DCM was recruited from the Chinese Han population. By whole-exome sequencing and Sanger sequencing analyses of the DNAs from the family members, a new BMP10 variation, NM_014482.3:c.166C > T;p.(Gln56*), was discovered and verified to be in co-segregation with the DCM phenotype in the entire family. The heterozygous BMP10 variant was not detected in 268 healthy volunteers enrolled as control subjects. The functional measurement via dual-luciferase reporter assay revealed that Gln56*-mutant BMP10 lost the ability to transactivate its target genes NKX2.5 and TBX20, two genes that had been causally linked to DCM. The findings strongly indicate BMP10 as a new gene contributing to DCM in humans and support BMP10 haploinsufficiency as an alternative pathogenic mechanism underpinning DCM, implying potential implications for the early genetic diagnosis and precision prophylaxis of DCM.

VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.

Dilated cardiomyopathy (DCM), characteristic of left ventricular or biventricular dilation with systolic dysfunction, is the most common form of cardiomyopathy, and a leading cause of heart failure and sudden cardiac death. Aggregating evidence highlights the underlying genetic basis of DCM, and mutations in over 100 genes have been causally linked to DCM. Nevertheless, due to pronounced genetic heterogeneity, the genetic defects underpinning DCM in most cases remain obscure. Hence, this study was sought to identify novel genetic determinants of DCM. In this investigation, whole-exome sequencing and bioinformatics analyses were conducted in a family suffering from DCM, and a novel heterozygous mutation in the VEZF1 gene (coding for a zinc finger-containing transcription factor critical for cardiovascular development and structural remodeling), NM_007146.3: c.490A > T; p.(Lys164*), was identified. The nonsense mutation was validated by Sanger sequencing and segregated with autosome-dominant DCM in the family with complete penetrance. The mutation was neither detected in another cohort of 200 unrelated DCM patients nor observed in 400 unrelated healthy individuals nor retrieved in the Single Nucleotide Polymorphism database, the Human Gene Mutation Database and the Genome Aggregation Database. Biological analyses by utilizing a dual-luciferase reporter assay system revealed that the mutant VEZF1 protein failed to transactivate the promoters of MYH7 and ET1, two genes that have been associated with DCM. The findings indicate VEZF1 as a new gene responsible for DCM, which provides novel insight into the molecular pathogenesis of DCM, implying potential implications for personalized precisive medical management of the patients affected with DCM.

SOX7 loss-of-function variation as a cause of familial congenital heart disease.

INTRODUCTION: As the most frequent type of birth defect in humans, congenital heart disease (CHD) leads to a large amount of morbidity and mortality as well as a tremendous socioeconomic burden. Accumulating studies have convincingly substantiated the pivotal roles of genetic defects in the occurrence of familial CHD, and deleterious variations in a great number of genes have been reported to cause various types of CHD. However, owing to pronounced genetic heterogeneity, the hereditary components underpinning CHD remain obscure in most cases. This investigation aimed to identify novel genetic determinants underlying CHD. METHODS AND RESULTS: A four-generation pedigree with high incidence of autosomal-dominant CHD was enrolled from the Chinese Han race population. Using whole-exome sequencing and Sanger sequencing assays of the family members available, a novel SOX7 variation in heterozygous status, NM_031439.4: c.310C>T; p.(Gln104*), was discovered to be in co-segregation with the CHD phenotype in the whole family. The truncating variant was absent in 500 unrelated healthy subjects utilized as control individuals. Functional measurements by dual-luciferase reporter analysis revealed that Gln104*-mutant SOX7 failed to transactivate its two important target genes, GATA4 and BMP2, which are both responsible for CHD. In addition, the nonsense variation invalidated the cooperative transactivation between SOX7 and NKX2.5, which is another recognized CHD-causative gene. CONCLUSION: The present study demonstrates for the first time that genetically defective SOX7 predisposes to CHD, which sheds light on the novel molecular mechanism underpinning CHD, and implies significance for precise prevention and personalized treatment in a subset of CHD patients.

Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy.

OBJECTIVES: Dilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive. METHODS: Whole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system. RESULTS: A heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM. CONCLUSIONS: The findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM 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.

A New TBX5 Loss-of-Function Mutation Contributes to Congenital Heart Defect and Atrioventricular Block.

Congenital heart defect (CHD) represents the most common birth deformity, afflicting 1% of all births worldwide, and accounts for substantial morbidity and mortality. Increasing evidence highlights the pivotal roles of genetic etiologies in the pathogenesis of CHD, and pathogenic mutations in multiple genes, including TBX5 encoding a cardiac core transcription factor key to cardiovascular morphogenesis, have been involved in CHD. However, due to pronounced genetic heterogeneity of CHD, the genetic determinants underlying CHD in most cases remain obscure. In this investigation, by sequencing analysis of the coding exons and flanking introns of the TBX5 gene in 198 unrelated patients affected with CHD, a novel heterozygous mutation, NM_000192.3: c.692C>T; p. (Pro231Leu), was identified in an index patient with familial double outlet right ventricle (DORV), ventricular septal defect (VSD), and atrioventricular block (AVB). Genetic analysis of the proband's pedigree showed that the mutation co-segregated with the diseases. The missense mutation, which altered the amino acid conserved evolutionarily, was absent from 266 unrelated healthy subjects. Functional analyses with a dual-luciferase reporter assay system unveiled that the Pro231Leu-mutant TBX5 was associated with significantly reduced transcriptional activity on its target genes MYH6 and NPPA. Furthermore, the mutation disrupted the synergistic transactivation between TBX5 and NKX2-5 as well as GATA4, two other transcription factors causally linked to CHD. This study firstly links TBX5 loss-of-function mutation to familial DORV, VSD, and AVB, which provides novel insight into the mechanism underpinning CHD and AVB, suggesting potential implications for genetic evaluation and individualized treatment of patients affected by CHD and AVB.

Identification and functional characterization of KLF5 as a novel disease gene responsible for familial dilated cardiomyopathy.

As a prevalent primary myocardial disease, dilated cardiomyopathy (DCM) represents the most common cause of heart failure in the young and the most frequent indication for cardiac transplantation. Aggregating evidence highlights the genetic basis of DCM. However, due to substantial genetic heterogeneity, the genetic defects of DCM in most cases remain elusive. In the current investigation, the entire coding exons and splicing junctions of the KLF5 gene, which encodes a key transcription factor required for cardiac structural and functional remodeling, were sequenced in 234 probands affected with DCM, and a heterozygous KLF5 mutation, NM_001730.5: c.1100T > A; p.(Leu367*), was identified in a proband. Genetic analysis of the proband's family members revealed that the identified KLF5 mutation co-segregated with DCM in the family with complete penetrance. The nonsense mutation was neither detected in 506 control individuals nor reported in such population-genetics databases as ExAC, dbSNP and gnomAD. Biological assays with a dual-luciferase reporter assay system demonstrated that the mutant KLF5 protein had no transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation abrogated the synergistic transactivation between KLF5 and NFKB1, another pivotal transcription factor that has been causally linked to DCM. The whole-exome sequencing analysis of the proband's family members revealed no other causative genes. The findings indicate KLF5 as a new gene contributing to DCM in humans, implying potential implications for the precision medicine of DCM.

Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is the most prevalent cause of non-ischemic cardiac failure and the commonest indication for cardiac transplantation. Compelling evidence highlights the pivotal roles of genetic defects in the occurrence of DCM. Nevertheless, the genetic determinants underpinning DCM remain largely obscure. In this study, the coding regions of ISL1, which encodes a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling, were sequenced in 216 unrelated patients with DCM, and a novel heterozygous ISL1 mutation, NM_002202.2: c.631A>T; p.(Lys211*), was identified in a proband. The mutation, which co-segregated with DCM in the family, was absent in 238 unrelated controls, as well as in the Genome Aggregation and the Exome Aggregation Consortium population databases. Functional analyses unveiled that the mutant ISL1 protein lost transcriptional activity alone or in synergy with TBX20 or GATA4, two other transcription factors associated with DCM. These findings indicate ISL1 as a new gene of DCM.

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.

Comparison of catheter ablation and surgical ablation in patients with long-standing persistent atrial fibrillation and rheumatic heart disease: a four-year follow-up study.

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.

Efficacy and safety of catheter ablation for long-standing persistent atrial fibrillation in women.

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.

The impact of age on the efficacy and safety of catheter ablation for long-standing persistent atrial fibrillation.

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.

Left atrial wall thickness: anatomic aspects relevant to catheter ablation of atrial fibrillation.

BACKGROUND: The success and complication rates of atrial fibrillation (AF) ablation may be related to regional differences in left atrial (LA) wall thickness. The purpose of this study was to investigate the transmural LA wall thickness in various regions. METHODS: We measured LA wall thickness in 36 human heart specimens using calipers at three planes including left pulmonary veins (PVs) vestibule plane, right PVs vestibule plane and the middle plane between the two. In each plane, eight points were selected, including superior, middle and inferior levels at anterior and posterior wall, roof and bottom. RESULTS: The anterior and posterior wall thickness displayed gradient from superior to inferior level (anterior wall: (2.73 ± 1.01) mm, (2.08 ± 0.91) mm and (1.54 ± 0.69) mm; posterior wall: (1.74 ± 0.68) mm, (1.48 ± 0.39) mm and (1.27 ± 0.42) mm). At the roof, LA wall thickness was thickest in middle plane ((2.01 ± 1.02) mm) and was thinnest in left PVs vestibule plane ((1.29 ± 0.41) mm). The posterior wall thickness in left PVs vestibule plane was thinner than in the other two planes (P < 0.05 - 0.001), and was thinner in right PVs vestibule plane than in middle plane (P < 0.01 - 0.001). Whereas in anterior wall, the wall thickness in left PVs vestibule plane was thicker than in middle and right PVs vestibule plane. CONCLUSIONS: Significant variations exist for mean LA wall thickness at different regions which are often targeted during circumferential pulmonary venous ablation (CPVA). Appreciating these differences may have significant implications in catheter ablation of AF.

Congestive heart failure after extensive catheter ablation for atrial fibrillation: prevalence, characterization, and outcome.

INTRODUCTION: This study sought to describe a new complication of catheter ablation for atrial fibrillation (AF): new onset congestive heart failure (CHF) after extensive ablation for AF. METHODS AND RESULTS: Data from 12 patients developing CHF after ablation were prospectively collected. All patients underwent extensive ablation for AF including circumferential pulmonary venous ablation and complex fractionated atrial electrograms guided ablation. CHF was diagnosed using the following criteria: symptoms or signs of heart failure, elevated BNP, and echocardiographic evidence of left ventricular diastolic dysfunction. Twelve patients (5 persistent and 7 permanent AF) had CHF after extensive ablation out of 484 consecutive AF patients who underwent catheter ablation (prevalence 2.5%). None of these 12 patients had CHF prior to the procedure. The mean onset of the symptoms was 39 ± 14 hours after the index procedure. Dyspnea and pulmonary rales were the most observed symptoms or signs. White blood cell count, serum CRP, BNP, and echocardiographic parameters of left ventricular diastolic dysfunction (E/A, E/E') were significantly increased after the onset of symptoms. All patients had complete recovery with supportive therapy within 3 days of the onset of symptoms. CONCLUSIONS: In this single-center experience, CHF after extensive ablation for AF was a well-recognized complication with a relatively high incidence of 2.5%. Measurement of BNP, CRP, and E/A, E/E' is useful in managing these patients.

Efficacy of catheter ablation and surgical CryoMaze procedure in patients with long-lasting persistent atrial fibrillation and rheumatic heart disease: a randomized trial.

AIMS: Catheter ablation and surgical Maze procedure are effective in treating atrial fibrillation (AF) patients. However, there is no study that compares the effect of circumferential pulmonary vein isolation (CPVI) combined with substrate ablation after valvular surgery and the concomitant Maze procedure for the treatment of AF in patients with rheumatic heart disease (RHD). The aim of this study was to compare the effectiveness of CPVI combined with substrate modification and surgical Maze procedure using Saline-Irrigated Cooled-tip Radiofrequency Ablation (SICTRA) system for the treatment of long-lasting persistent AF in patients with RHD. METHODS AND RESULTS: Between January 2006 and June 2008, 99 patients with long-lasting persistent AF and RHD were randomly assigned to undergo valvular operation and CPVI combined with substrate modification 6 months after the surgery (Group A, 49 patients) or valvualr operation and concomitant Maze procedure (Group B, 50 patients). The mean follow-up periods were 15 ± 5 and 20 ± 8 months in Groups A and B, respectively. After one procedure, Group B had a significantly higher freedom from artial arrhythmias compared with Group A (82% in Group B vs. 55.2% in Group A, P < 0.001). Fifteen patients in Group A underwent a redo procedure. Six patients in Group B underwent catheter ablation and four were treated successfully. The cumulative rates of sinus rhythm were 71% in Group A and 88% in Group B (P < 0.001). CONCLUSION: The concomitant Cox Maze procedure using SICTRA is more effective than subsequent CPVI combined with substrate modification in treating patients with long-lasting persistent AF and RHD.

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.

Decreased connexin 43 and increased fibrosis in atrial regions susceptible to complex fractionated atrial electrograms.

BACKGROUND AND OBJECTIVES: Complex fractionated atrial electrograms (CFAE) is distributed at preferential sites of atrium, and the mechanism underlying CFAE is not fully understood. We hypothesized that preexisting atrial abnormalities may be involved in the formation of CFAE. METHODS: Twelve pigs were subjected to acetylcholine infusion and right atrial pacing to induce sustained atrial fibrillation. The shortest complex interval map was used to visualize CFAE on three-dimensional anatomic structure of left atrium, and the CFAE sites were labeled by ablation. The expression of connexin 43 (Cx43) and myocardial fibrosis were examined. RESULTS: The expression of Cx43 at CFAE sites was significantly decreased when compared with non-CFAE sites, while myocardial fibrosis was enhanced in CFAE sites compared with non-CFAE sites. CONCLUSIONS: These results suggested that the decreased expression of Cx43 and enhanced myocardial fibrosis at CFAE sites of the left atrium may be the structure abnormalities underlying CFAE.

Pulmonary vein isolation combined with superior vena cava isolation for atrial fibrillation ablation: a prospective randomized study.

AIMS: Circumferential pulmonary vein isolation (CPVI) is an established strategy for atrial fibrillation (AF) ablation. Superior vena cava (SVC), by harbouring the majority of non-pulmonary vein (PV) foci, is the most common non-PV origin for AF. However, it is unknown whether CPVI combined with SVC isolation (SVCI) could improve clinical results and whether SVCI is technically safe and feasible. METHODS AND RESULTS: A total of 106 cases (58 males, average age 66.0 +/- 8.8 years) with paroxysmal AF were included for ablation. They were allocated randomly to two groups: CPVI group (n = 54) and CPVI + SVCI group (n = 52). All cases underwent the procedure successfully. Pulmonary vein isolation was achieved in all cases. The procedural time and fluoroscopic time were comparable between the two groups. The mean ablation time for SVC was 7.8 +/- 2.7 min. Superior vena cava isolation was obtained in 50/52 cases. In the remaining two cases, SVCI was not achieved because of obviating diaphragmatic nerve injury. During a mean follow-up of 4 +/- 2 months, 12 (22.2%) cases in the CPVI group and 10 (19.2%) cases in the CPVI + SVCI group had atrial tachyarrhythmias (ATa) recurrence (P = 0.70). Nine of 12 cases in the CPVI group and 8/10 cases in the CPVI + SVCI group underwent reablation (P = 0.86), and PV reconnection occurred in 7/9 cases in the CPVI group and in 8/8 cases in the CPVI + SVCI group. All PV reconnection was reisolated by gaps ablation. There was no SVC reconnection in the CPVI + SVCI group. In two cases without PV reconnection from the CPVI group, SVC-originated short run of atrial tachycardia was identified and eliminated by the SVCI. At the end of 12 months of follow-up, 50 cases (92.6%) in the CPVI group and 49 (94.2%) in the CPVI + SVC group were free of ATa recurrence (P = 0.73). CONCLUSION: In our series of paroxysmal AF patients, empirically adding SVCI to CPVI did not significantly reduce the AF recurrence after ablation. Superior vena cava isolation may be useful, however, in selected patients in whom the SVC is identified as a trigger for AF. However, because of the preliminary property of the study and its relatively small sample size, the impact of SVCI on clinical results should be evaluated in a large series of patients.

Circumferential pulmonary vein isolation: the role of key target sites.

AIMS: Circumferential pulmonary vein isolation (CPVI) had been proved effective for treating atrial fibrillation (AF). However, the achievement of pulmonary vein (PV) isolation was sometimes challenging. PVs could not be isolated until some key target sites (KTSs) were ablated thoroughly. The aim of our study was to explore the distribution of KTSs. METHODS AND RESULTS: Four hundred and fifty-two cases (271 males, mean age 62.5 +/- 12.6 years) with drug-refractory AF were enrolled for catheter ablation. CARTO-guided CPVI was performed in all cases with one circular catheter for verification of PVs isolation. Target sites where PV potentials delayed, conduction sequence changed, slowed down, or isolated were defined as KTSs. From 452 CPVI procedures, 1520 KTSs were identified; 813 of which were located at left PV antrums and 707 were at right PV antrums. KTSs at left PV antrums were most commonly situated at anterior wall (63%), while KTSs at right PV antrums were most commonly situated at posterior wall (66.2%). Additional gaps ablation was performed for left PVs in 344 cases and for right PVs in 248 cases owing to incomplete PVs isolation by a single attempt of CPVI. One thousand one hundred and fifty-eight KTSs were identified, 662 of which were located at left PV antrums and 496 were at right PV antrums. At the anterior wall, 66.1% of left PV KTSs were located, and 67.9% of right PV KTSs were located at the posterior wall. Out of 1158, 961 (82.99%) KTSs were predicted correctly by circular mapping. PV isolation could not be achieved until some KTSs were ablated by higher power, longer duration, and higher irrigation rate than usual. CONCLUSION: KTSs during CPVI were most commonly situated at the anterior wall of left PVs and at the posterior wall of right PVs. Circular mapping within ipsilateral PVs' ostia could accurately predict the location of KTSs. Some KTSs must be ablated thoroughly by applying higher power, longer duration, and higher irrigation rate than usual to achieve PV isolation.