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Response by Handa et al to Letter Regarding Article, “Granger Causality–Based Analysis for Classification of Fibrillation Mechanisms and Localization of Rotational Drivers”
... In the studies that we included in our analysis, the adjunctive ablations were performed in all patients allocated to those treatment groups. With the increasing recognition of the existence of different phenotypes of AF, sustained by different AF mechanisms, 38,39 it is possible that these adjunctive ablation strategies can be effective if tailored and individualized to each patient's underlying AF mechanism. ...
Background:
Ablation for persistent atrial fibrillation (PsAF) has been performed for over 20 years, although success rates have remained modest. Several adjunctive lesion sets have been studied but none have become standard of practice. We sought to describe how the efficacy of ablation for PsAF has evolved in this time period with a focus on the effect of adjunctive ablation strategies.
Methods:
Databases were searched for prospective studies of PsAF ablation. We performed meta-regression and trial sequential analysis.
Results:
A total of 99 studies (15 424 patients) were included. Ablation for PsAF achieved the primary outcome (freedom of atrial fibrillation/atrial tachycardia rate at 12 months follow-up) in 48.2% (5% CI, 44.0-52.3). Meta-regression showed freedom from atrial arrhythmia at 12 months has improved over time, while procedure time and fluoroscopy time have significantly reduced. Through the use of cumulative meta-analyses and trial sequential analysis, we show that some ablation strategies may initially seem promising, but after several randomized controlled trials may be found to be ineffective. Trial sequential analysis showed that complex fractionated atrial electrogram ablation is ineffective and further study of this treatment would be futile, while posterior wall isolation currently does not have sufficient evidence for routine use in PsAF ablation.
Conclusions:
Overall success rates from PsAF ablation and procedure/fluoroscopy times have improved over time. However, no adjunctive lesion set, in addition to pulmonary vein isolation, has been conclusively demonstrated to be beneficial. Through the use of trial sequential analysis, we highlight the importance of adequately powered randomized controlled trials, to avoid reaching premature conclusions, before widespread adoption of novel therapies.
Aims:
Conflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganised multiple-wavelet activation to organised rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism.
Methods and results:
Optical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact (CF), diffuse (DiF) and patchy (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum.Enhanced GJ coupling with rotigaptide (n = 10) progressively organised fibrillation in a concentration-dependent manner; increasing FDI (0nM: 0.53±0.04, 80nM: 0.78±0.03, p < 0.001), increasing RA sustained VF time (0nM:44±6%, 80nM: 94±2%, p < 0.001) and stabilised RAs (maximum rotations for a RA; 0nM:5.4±0.5, 80nM: 48.2±12.3, p < 0.001). GJ uncoupling with carbenoxolone progressively disorganised VF; the FDI decreased (0µM: 0.60±0.05, 50µM: 0.17±0.03, p < 0.001) and RA-sustained VF time decreased (0µM: 61±9%, 50µM: 3±2%, p < 0.001).In CF, VF activity was disorganised and the RA-sustained VF time was the lowest (CF: 27±7% versus PF: 75±5%, p < 0.001). Global fibrillatory organisation measured by FDI was highest in PF (PF: 0.67±0.05 versus CF: 0.33±0.03, p < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411±266ms versus compact: 354±38ms, p < 0.001). DiF (n = 11) exhibited an intermediately organised VF pattern, sustained by a combination of multiple-wavelets and short-lived RAs.
Conclusion:
The degree of GJ coupling and pattern of fibrosis influences the mechanism sustaining VF. There is a continuous spectrum of organisation in VF, ranging between globally organised fibrillation sustained by stable RAs and disorganised, possibly multiple-wavelet driven fibrillation with no RAs.
Translational perspective:
Multiple competing mechanisms have been proposed for sustaining VF. We reframed conflicting mechanisms reported in sustaining fibrillation and defined them as part of a continuum of varying global organisation, with some sustained by stable rotationalactivities. The underlying cardiac electroarchitecture, namely gap junction coupling and fibrosis, were important determinants of the VF mechanism. Characterising the VF mechanism and its relationship to the cardiac electroarchitecture may facilitate a patient-tailored treatment approach towards VF prevention in VF survivors. Organised fibrillation sustained by stable rotational activities could be considered for targeted ablation. Disorganised fibrillation dynamics may be better suited for conventional pharmacotherapy.
Background - The mechanisms sustaining myocardial fibrillation remain disputed, partly due to a lack of mapping tools that can accurately identify the mechanism with low spatial resolution clinical recordings. Granger causality (GC) analysis, an econometric tool for quantifying causal relationships between complex time-series, was developed as a novel fibrillation mapping tool and adapted to low spatial resolution sequentially-acquired data.
Methods - VF optical mapping was performed in Langendorff-perfused Sprague-Dawley rat hearts (n=18), where novel algorithms were developed using GC-based analysis to: a) quantify causal dependence of neighbouring signals and plot GC-vectors, b) quantify global organisation with the causality pairing index (CPI), a measure of neighbouring causal signal pairs and c) localise rotational drivers (RDs) by quantifying the circular interdependence of neighbouring signals with the circular interdependence value (CIV). GC-based mapping tools were optimised for low spatial resolution from down-sampled optical mapping data, validated against high-resolution phase analysis and further tested in previous VF optical mapping recordings of coronary perfused donor heart LV wedge preparations (n=12), and adapted for sequentially-acquired intracardiac-electrograms during human persistent atrial fibrillation (PsAF) mapping (n=16).
Results - Global VF organisation quantified by CPI showed a negative correlation at progressively lower resolutions (50% resolution: p=0.006, R ² =0.38, 12.5% resolution, p=0.004, R ² =0.41) with a phase analysis derived measure of disorganisation, lps. In organised VF with high CPI values, GC-vector mapping characterised dominant propagating patterns and localised stable RDs, with the CIV showing a significant difference in driver versus non-driver regions (0.91±0.05 vs 0.35±0.06, p=0.0002). These findings were further confirmed in human VF. In PsAF, a positive correlation was found between the CPI and presence of stable RDs (p=0.0005,R ² =0.56). 50% of patients had RDs, with a low incidence of 0.9±0.3 RDs/patient.
Conclusions - GC-based fibrillation analysis can measure global fibrillation organisation, characterise dominant propagating patterns and map RDs using low spatial resolution sequentially-acquired data.
The analysis of complex mechanisms underlying ventricular fibrillation (VF) and atrial fibrillation (AF) requires sophisticated tools for studying spatio-temporal action potential (AP) propagation dynamics. However, fibrillation analysis tools are often custom-made or proprietary, and vary between research groups. With no optimal standardised framework for analysis, results from different studies have led to disparate findings. Given the technical gap, here we present a comprehensive framework and set of principles for quantifying properties of wavefront dynamics in phase-processed data recorded during myocardial fibrillation with potentiometric dyes. Phase transformation of the fibrillatory data is particularly useful for identifying self-perpetuating spiral waves or rotational drivers (RDs) rotating around a phase singularity (PS). RDs have been implicated in sustaining fibrillation, and thus accurate localisation and quantification of RDs is crucial for understanding specific fibrillatory mechanisms. In this work, we assess how variation of analysis parameters and thresholds in the tracking of PSs and quantification of RDs could result in different interpretations of the underlying fibrillation mechanism. These techniques have been described and applied to experimental AF and VF data, and AF simulations, and examples are provided from each of these data sets to demonstrate the range of fibrillatory behaviours and adaptability of these tools. The presented methodologies are available as an open source software and offer an off-the-shelf research toolkit for quantifying and analysing fibrillatory mechanisms.
BACKGROUND:
Recent studies have demonstrated conflicting mechanisms underlying atrial fibrillation (AF), with the spatial resolution of data often cited as a potential reason for the disagreement. The purpose of this study was to investigate whether the variation in spatial resolution of mapping may lead to misinterpretation of the underlying mechanism in persistent AF.
METHODS AND RESULTS:
Simulations of rotors and focal sources were performed to estimate the minimum number of recording points required to correctly identify the underlying AF mechanism. The effects of different data types (action potentials and unipolar or bipolar electrograms) and rotor stability on resolution requirements were investigated. We also determined the ability of clinically used endocardial catheters to identify AF mechanisms using clinically recorded and simulated data. The spatial resolution required for correct identification of rotors and focal sources is a linear function of spatial wavelength (the distance between wavefronts) of the arrhythmia. Rotor localization errors are larger for electrogram data than for action potential data. Stationary rotors are more reliably identified compared with meandering trajectories, for any given spatial resolution. All clinical high-resolution multipolar catheters are of sufficient resolution to accurately detect and track rotors when placed over the rotor core although the low-resolution basket catheter is prone to false detections and may incorrectly identify rotors that are not present.
CONCLUSIONS:
The spatial resolution of AF data can significantly affect the interpretation of the underlying AF mechanism. Therefore, the interpretation of human AF data must be taken in the context of the spatial resolution of the recordings.