To quantify any risk of atrial fibrillation (AF) associated with ivabradine treatment by meta-analysis of clinical trial data.
Medline, Embase, Web of Knowledge and the Cochrane central register of ...controlled trials were searched for double-blinded randomised controlled trials of ivabradine with a minimum follow-up period of 4 weeks. For studies where AF data were unpublished, safety data were obtained from the European Medicines Agency (EMeA) website and personal communications. Studies were appraised for risk of bias using components recommended by the Cochrane Collaboration. Meta-analyses were performed of relative risk of AF and absolute risk difference of AF per year of treatment. The main outcome measure was incident AF during the follow-up period.
AF data were available from 11 studies: one from the published report, six from the EMeA and four from personal communications. Ivabradine treatment was associated with a relative risk of AF of 1.15 (95% CI 1.07 to 1.24, p=0.0027) among 21 571 patients in the meta-analysis. From this we estimated that the number needed to harm for ivabradine would be 208 (95% CI 122 to 667) per year of treatment.
AF is a substantially more common side effect of ivabradine treatment than one patient in 10 000, the risk presently reported in the product literature. The incidence of AF has not routinely been reported in clinical trials of ivabradine.
Abstract Genome-wide association studies (GWAS) have identified genetic variants in a number of chromosomal regions that are associated with atrial fibrillation (AF). The mechanisms underlying these ...associations are unknown, but are likely to involve effects of the risk haplotypes on expression of neighbouring genes. To investigate the association between genetic variants at AF-associated loci and expression of nearby candidate genes in human atrial tissue and peripheral blood. Right atrial appendage (RAA) samples were collected from 122 patients undergoing cardiac surgery, of these, 12 patients also had left atrial appendage samples taken. 22 patients had a history of AF. Peripheral blood samples were collected from 405 patients undergoing diagnostic cardiac catheterisation. In order to tag genetic variation at each of nine loci, a total of 367 single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom platform. Total expression of 16 candidate genes in the nine AF-associated regions was measured by quantitative PCR. The relative expression of each allele of the candidate genes was measured on the Sequenom platform using one or more transcribed SNPs to distinguish between alleles in heterozygotes. We tested association between the SNPs of interest and gene expression using total gene expression (integrating cis and trans acting sources of variation), and allelic expression ratios (specific for cis acting influences), in atrial tissue and peripheral blood. We adjusted for multiple comparisons using a Bonferroni approach. In subsidiary analyses, we compared the expression of candidate genes between patients with and without a history of AF. Total expression of 15 transcripts of 14 genes and allelic expression ratio of 14 transcripts of 14 genes in genomic regions associated with AF were measured in right atrial appendage tissue. 8 of these transcripts were also expressed in peripheral blood. Risk alleles at AF-associated SNPs were associated in cis with an increased expression of PITX2a (2.01-fold, p = 6.5 × 10 − 4 ); and with decreased expression of MYOZ1 (0.39 fold; p = 5.5 × 10 − 15 ), CAV1 (0.89 fold; p = 5.9 × 10 − 8 ), C9orf3 (0.91 fold; 1.5 × 10 − 5 ), and FANCC (0.94-fold; p = 8.9 × 10 − 8 ) in right atrial appendage. Of these five genes, only CAV1 was expressed in peripheral blood; association between the same AF risk alleles and lower expression of CAV1 was confirmed (0.91 fold decrease; p = 4.2 × 10 − 5 ). A history of AF was also associated with a decrease in expression of CAV1 in both right and left atria (0.84 and 0.85 fold, respectively; p = 0.03), congruent with the magnitude of the effect of the risk SNP on expression, and independent of genotype. The analyses in peripheral blood showed association between AF risk SNPs and decreased expression of KCNN3 (0.85-fold; p = 2.1 × 10 − 4 ); and increased expression of SYNE2 (1.12-fold; p = 7.5 × 10 − 24 ); however, these associations were not detectable in atrial tissue. We identified novel cis- acting associations in atrial tissue between AF risk SNPs and increased expression of PITX2a/b; and decreased expression of CAV1 (an association also seen in peripheral blood), C9orf3 and FANCC . We also confirmed a previously described association between AF risk variants and MYOZ1 expression. Analyses of peripheral blood illustrated tissue-specificity of cardiac eQTLs and highlight the need for larger-scale genome-wide eQTL studies in cardiac tissue. Our results suggest novel aetiological roles for genes in four AF-associated genomic regions.
Atrial tachycardias (ATs) are often seen in the context of atrial fibrillation (AF) ablation.
To evaluate the role of the Marshall bundle (MB) network in left atrial (LA) ATs using high-density ...3-dimensional mapping.
A total of 199 ATs were mapped in 140 patients (112 male, mean age: 61.8 years); 133 (66.8%) were macroreentrant and 66 (33.2%) were scar-related reentry circuits. MB-dependent ATs were suggested by activation mapping analysis and confirmed with entrainment along the circuit.
The MB network participated in 60 (30.2%) reentrant ATs: 31 perimitral ATs (PMATs) and 29 localized reentry circuits. Of 60 MB-related ATs, 49 (81.6%) terminated with radiofrequency (RF) ablation: 44 (73.3%) at the MB-LA junction and 5 (8.3%) at the MB-coronary sinus (CS) junction, while 9 (15%) terminated after 2.5-5 cc of ethanol infusion inside the vein of Marshall (VOM). Of the 31 PMATs, 17 (54.8%) terminated at the MB-LA junction, 5 (16.1%) at the MB-CS junction, and 7 (22.6%) with ethanol infusion. Of the 29 localized reentry circuits using the MB, 27 (93.1%) terminated at the MB-LA junction, none at the MB-CS junction, and 2 (6.9%) after ethanol infusion. Recurrences were mostly observed after RF ablation (18 of 37 patients, 49%) compared to ethanol infusion (1 of 9 patients, 11%) (P = .06).
MB reentrant ATs accounted for up to 30.2% of the left ATs after AF ablation. Ablation of the MB-LA or CS-MB connections or ethanol infusion inside the VOM is required to treat these arrhythmias.
Introduction
We aimed to evaluate the extent of atrial fibrosis in paroxysmal atrial fibrillation (AF) and the correlation with ablation outcomes after pulmonary vein antral isolation (PVΑI) using a ...mapping system with high‐resolution and high‐spatial sampling.
Methods and results
We prospectively enrolled 80 consecutive patients (45 males, median age 60.26 years) with symptomatic paroxysmal AF who were scheduled for PVAI. Prior to PVAI, high‐density bipolar voltage mapping (median number of 2,485 points) was carried out during sinus rhythm in all patients. Criteria for an adequate left atrium (LA) shell were > 2,000 points. Each acquired point was classified according to the peak‐to‐peak bipolar voltage electrogram based on two criteria (criterion A: healthy > 0.8 mV, border zone: 0.4–0.8 mV and scarred: < 0.4 mV, criterion Β: healthy: > 0.5 mV, border zone: 0.25–0.5 mV and scarred: < 0.25 mV). The extent of low‐voltage area < 0.4 mV significantly predicted atrial tachyarrhythmia recurrence after the blanking period (P = 0.002). In univariate analysis, the presence of LA voltage areas < 0.4 mV more than 10% of the total surface area was the only significant predictor of arrhythmia recurrence. The analysis based on window B cutoff values failed to demonstrate any predictors of arrhythmia recurrence.
Conclusion
These data demonstrate that the existence of LA voltage areas < 0.4 mV more than 10% of the total LA surface area predicts arrhythmia recurrence following PVAI for paroxysmal AF.
Anatomic macroreentrant atrial tachycardias (MATs) are conventionally reported to depend on the cavotricuspid isthmus, the mitral isthmus, or the left atrial roof, and are commonly seen following ...catheter ablation for atrial fibrillation.
To define the precise circuits of anatomic MAT with ultrahigh-resolution mapping.
In 57 patients (mean age, 62 years; 10 female) who developed ≥1 anatomic MAT, we analyzed 88 MAT circuits including 16 peritricuspid, 42 perimitral, and 30 roof-dependent circuits, using high-density mapping and entrainment.
Of 16 peritricuspid atrial tachycardias (ATs), 8 (50.0%) showed a circuit not limited to the tricuspid annulus. However, cavotricuspid isthmus ablation terminated the tachycardia in all patients. Similarly, 26 of 42 perimitral ATs (61.9%) showed a circuit not limited to the mitral annulus, and a low-voltage zone <0.1 mV around the mitral annulus was associated with nontypical perimitral ATs (P < .0001). The practical isthmus was not in the mitral isthmus in 13 of these 26 perimitral ATs (50%). Finally, 22 of 30 roof-dependent ATs (73.3%) had a circuit not rotating around both pairs of pulmonary veins. Brief assessment of the activation direction on the posterior wall in relation to that on the septal, anterior, and lateral wall helped deduce the circuit of roof-dependent AT in 27 of 30 (90.0%). Practical isthmus was not in the roof in 8 of 22 (36.4%). Practical isthmuses mapped with the system were significantly shorter than the usual anatomic isthmuses (16.1 ± 8.2 mm vs 33.7 ± 10.4 mm) (P < .0001).
High-density mapping successfully identified the precise circuits and the practical isthmus of anatomic MATs in patients with prior atrial fibrillation ablation.
Introduction
Successful catheter ablation is limited by both poor spatial resolution of abnormal local signals and inability to deliver an effective lesion due to poor tissue contact. We report first ...worldwide use of the Intellanav MiFi OI catheter (Boston Scientific), providing ultra‐high density mapping and incorporating a “DirectSense” algorithm to measure local tissue impedance (LI).
Methods and results
31 patients (65±6 years, 20 male) underwent ablation. LI from the catheter, generator impedance (GI) and maximum electrogram amplitude were recorded in the blood pool, and in regions from healthy to dense scar before, during and after ablation. The catheter demonstrated clear nearfield signal where standard bipolar recordings included farfield signal. LI was lower in dense scar than either healthy tissue or blood pool, and demonstrated an exponential relationship with maximum electrogram amplitude.
Maximum LI drop on ablation linearly correlated with initial LI. The median LI drop for successful lesions, resulting in lack of local tissue capture, was 16.0Ω (12.1–19.8 Ω) for LV and 14.6 Ω (10.0–18.3 Ω) for LA, which was larger than for unsuccessful lesions (LV: 9.4 Ω 5.4–15.6 Ω P = 0.001; LA: 6.8 Ω 4.7–13.0 Ω, P = 0.049). LI percentage drop was also significantly larger for successful than unsuccessful lesions (LV: 17.1 Ω 14.0–19.6 Ω vs. 10.6 Ω (7.1–16.5 Ω) P = 0.002; LA: 14.2 Ω 10.8‐19.5 Ω vs. 7.5Ω 5.1–11.0 Ω, P = 0.005).
Conclusion
This novel catheter gives reproducible recordings of local impedance, which are dependent on scar level. Absolute LI drop, and also percentage drop, on ablation may give an indication of tissue contact and subsequent effective lesion formation.
A novel "LUMIPOINT" software in the Rhythmia system (Boston Scientific) displays a histogram of activated area over the entire atrial tachycardia (AT) cycle length (CL) with a normalized score.
The ...purpose of this study was to examine whether the pattern of this global activation histogram (GAH) identified reentrant vs focal AT and whether a decrease in atrial activation area, shown as valleys in the GAH, identifies isthmuses.
One hundred eight activation maps of ATs (17 focal, 57 macroreentrant, 21 localized, 13 multiple loop) in 67 patients were reviewed retrospectively with the LUMIPOINT software. The ACTIVATION SEARCH feature highlighted the activated area in a given time period irrespective of the activation map. A 30-ms unit time interval was set, and the GAH patterns and electrophysiological properties of highlighted areas were examined.
Focal ATs systematically displayed a plateau with GAH-Score <0.1 for at least 30% of the CL. Most reentrant ATs (90/91 98.9%) lacked this plateau and displayed activity covering the entire CL, with 2 1-2 GAH-Valleys per tachycardia. Each GAH-Valley highlighted 1 1-2 areas in the map. Among 264 highlighted areas, 198 (75.0%) represented slow conduction, 19 (7.2%) lines of block, 27 (10.2%) wavefront collision, 3 (1.1%) unknown, and 17 (6.4%) absence of activation in focal ATs. Practical ablation sites all matched one of the highlighted areas based on GAH-Valleys, and they corresponded better with areas highlighted by GAH-Score ≤0.2 (P <.0001).
GAH shows focal vs reentrant mechanisms at first glance. Decrease in activated areas (displayed by GAH-Valleys) is mostly due to slow conduction and highlights areas of special interest, with 100% sensitivity for isthmus identification.
Sudden cardiac death because of ventricular fibrillation (VF) is commonly unexplained in younger victims. Detailed electrophysiological mapping in such patients has not been reported.
We evaluated 24 ...patients (29±13 years) who survived idiopathic VF. First, we used multielectrode body surface recordings to identify the drivers maintaining VF. Then, we analyzed electrograms in the driver regions using endocardial and epicardial catheter mapping during sinus rhythm. Established electrogram criteria were used to identify the presence of structural alterations.
VF occurred spontaneously in 3 patients and was induced in 16, whereas VF was noninducible in 5. VF mapping demonstrated reentrant and focal activities (87% versus 13%, respectively) in all. The activities were dominant in one ventricle in 9 patients, whereas they had biventricular distribution in others. During sinus rhythm areas of abnormal electrograms were identified in 15/24 patients (62.5%) revealing localized structural alterations: in the right ventricle in 11, the left ventricle in 1, and both in 3. They covered a limited surface (13±6 cm
) representing 5±3% of the total surface and were recorded predominantly on the epicardium. Seventy-six percent of these areas were colocated with VF drivers (
<0.001). In the 9 patients without structural alteration, we observed a high incidence of Purkinje triggers (7/9 versus 4/15,
=0.033). Catheter ablation resulted in arrhythmia-free outcome in 15/18 patients at 17±11 months follow-up.
This study shows that localized structural alterations underlie a significant subset of previously unexplained sudden cardiac death. In the other subset, Purkinje electrical pathology seems as a dominant mechanism.
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