ABSTRACT
INTRODUCTION: Substrate-based ablation for scar-related ventricular tachycardia (VT) has gained prominence: however, there is limited data comparing it to ablation guided predominantly by activation and entrainment mapping of inducible and hemodynamically tolerated VTs. We compared the acute procedural efficacy and outcomes of predominantly substrate-based ablation versus ablation guided predominantly by activation and entrainment mapping. METHODS AND RESULTS: Database searches through April 2016 identified 6 eligible studies (enrolling 403 patients, with 1 randomized study) comparing the 2 strategies. The relative risk of VT recurrence at follow-up was assessed as the primary outcome using a random-effects meta-analysis. Secondary endpoints of acute success (based on noninducibility of VT), procedural complications, and mortality were assessed using weighted mean difference with the random effects model. At a median follow-up of 18 months, the relative risk (RR) of VT recurrence was not significantly different with substrate-based versus activation/entrainment guided VT ablation (0.72, 95% confidence interval [CI] 0.44-1.18), P = 0.2). Acute success (RR 1.02, 95% CI 0.95-1.1, P = 0.6), procedural complications (RR 0.8, 95% CI 0.35-1.82, P = 0.5) cardiovascular mortality and total mortality did not differ significantly (RR 0.83, 95% CI 0.38-1.79, P = 0.6 and RR 0.76, 95% CI 0.36-1.59, P = 0.5, respectively). CONCLUSIONS: This meta-analysis demonstrates similar acute procedural efficacy, and complications, VT recurrence and mortality rates when comparing a predominantly substrate-based ablation strategy to a strategy guided predominantly by activation and entrainment mapping of inducible and hemodynamically tolerated VTs.
Subject(s)
Catheter Ablation/methods , Heart Ventricles/surgery , Tachycardia, Ventricular/surgery , Action Potentials , Catheter Ablation/adverse effects , Catheter Ablation/mortality , Chi-Square Distribution , Electrophysiologic Techniques, Cardiac , Female , Heart Rate , Heart Ventricles/physiopathology , Humans , Male , Middle Aged , Odds Ratio , Predictive Value of Tests , Recurrence , Risk Factors , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/mortality , Tachycardia, Ventricular/physiopathology , Treatment OutcomeABSTRACT
AIMS: Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated. METHODS AND RESULTS: We screened six candidate genes (CAV1, KCNJ2, KCNQ1, NKX2.5, PITX2, and TBX5) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1, KCNJ2, KCNQ1, NKX2.5, and PITX2. These mutations increased the expression of atrial natriuretic peptide (ANP) and connexin-40 (CX40) in the primarily cultured rat atrial myocytes but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-α (MHC-α) and myosin light chain-2α (MLC-2α). Overexpression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. To replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (ΔAsp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects. CONCLUSION: Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40.
Subject(s)
Atrial Fibrillation/genetics , Genetic Predisposition to Disease , Mutation/genetics , T-Box Domain Proteins/genetics , Adult , Age of Onset , Aged , Asian People , Atrial Fibrillation/metabolism , Connexins/genetics , Female , Homeodomain Proteins/genetics , Humans , Middle Aged , Mutation, Missense/genetics , Pregnancy , T-Box Domain Proteins/metabolism , Transcription Factors/metabolism , White People , Gap Junction alpha-5 ProteinABSTRACT
BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia, and a recent genome-wide association study identified the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) as a novel AF susceptibility locus. HCN4 encodes for the cardiac pacemaker channel, and HCN4 mutations are associated with familial sinus bradycardia and AF. OBJECTIVE: The purpose of this study was to determine whether novel variants in the coding region of HCN4 contribute to the susceptibility for AF. METHODS: We sequenced the coding region of HCN4 for novel variants from 527 cases with early-onset AF from the Massachusetts General Hospital AF Study and 443 referents from the Framingham Heart Study. We used site-directed mutagenesis, cellular electrophysiology, immunocytochemistry, and confocal microscopy to functionally characterize novel variants. RESULTS: We found the frequency of novel coding HCN4 variants was 2-fold greater for individuals with AF (7 variants) compared to the referents (3 variants). We determined that of the 7 novel HCN4 variants in our AF cases, 1 (p.Pro257Ser, located in the amino-terminus adjacent to the first transmembrane spanning domain) did not traffic to cell membrane, whereas the remaining 6 were not functionally different from wild type. In addition, the 3 novel variants in our referents did not alter function compared to wild-type. Coexpression studies showed that the p.Pro257Ser mutant channel failed to colocalize with the wild-type HCN4 channel on the cell membrane. CONCLUSION: Our findings are consistent with HCN4 haploinsufficiency as the likely mechanism for early-onset AF in the p.Pro257Ser carrier.
