Author + information
- aDivision of Imaging Sciences and Biomedical Engineering, King’s College London, London, United Kingdom
- bDepartment of Cardiology, St Thomas’ Hospital, London, United Kingdom
- ↵∗Reprint requests and correspondence:
Prof. Mark D. O’Neill, Division of Imaging Sciences and Biomedical Engineering and Cardiovascular Medicine, 4th Floor, North Wing, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom.
Catheter ablation is an effective treatment for appropriately selected patients with atrial fibrillation (AF). What constitutes appropriate selection, however, remains poorly understood and vigorously debated. In the emerging era of “mechanism-directed therapy,” one perspective might be that any patient with AF is a potential candidate for ablation when an electrophysiological target can be identified and therefore eliminated. An alternative perspective considers catheter ablation as a precious resource, to be offered only when there is a high likelihood of a clinically successful and relevant outcome for the patient. An understanding of the complex interplay of mechanisms in their structural context represents a major goal of patient-tailored AF therapy.
There has been a welcome investment of effort in noninvasive atrial characterization over the past decade or so, in particular using cardiac magnetic resonance imaging. The evidence continues to mount that assessment of baseline atrial fibrosis is here to stay as a marker of atrial pathology beyond what can be gleaned from simple clinical and echocardiographic measures. Although simple in concept, that areas of enhancement in the atrial wall should represent regions of fibrosis, the image acquisition and processing are not understood by the vast majority of electrophysiologists, who are therefore understandably reluctant to trust in recommendations based thereon. As Khurram et al. (1) rightly point out in this issue of iJACC, the disparity of methods among groups continues to make the comparison of studies particularly difficult (2–5). If magnetic resonance assessment of pre-ablation fibrosis—atrial baseline late gadolinium enhancement (bLGE)—is to take the leap from research to global clinical tool, a reproducible, time-efficient method that can be implemented in the busy clinical environment is required.
Consensus is required regarding the steps necessary to extract a meaningful bLGE metric to describe the atrium of an individual patient, and at each phase of the pipeline, the potential for confounders arises. For the acquisition of magnetic resonance images, groups have universally used a 3-dimensional late gadolinium enhancement acquisition technique, using respiratory and electrocardiographic navigation to acquire the atrium in standstill. Parameters differ slightly between groups, but generally, in-plane resolution, slice thickness, and pulse sequences remain broadly similar. However, they are not identical, and the effect of subtle differences has never been quantified; for example, even within a formalized study such as DECAAF (Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation), the dosage of gadolinium varied widely (2). Subanalyses have unsurprisingly reported higher image quality at those centers that perform most scans, and the 96.5% rate of adequate-quality scans reported in the present study is a testament to the high level of expertise at the investigators’ center.
Image processing plays an even more important role in the derivation of the atrial scar index. The concept seems simple: to derive the signal from the imaging voxels that make up the atrial wall and to dichotomize into those that represent atrial scar versus normal myocardium. The reality is that of manual segmentation, partial voluming, low signal-to-noise ratio, and different indexing methods for an atrial wall signal that is expressed in arbitrary units. Interobserver variability is probably unacceptably high on objective review (6), and the call for conformity is to be welcomed.
The impact of differing image acquisition and processing techniques has resulted in profoundly different bLGE values reported by Khurram et al. (1) in comparison with previous studies such as DECAAF. The investigators of both these studies went to great lengths to adjust for baseline covariates, yet the crossover point for hazard ratio (from below- to above-average cohort risk) was about 35% bLGE fibrosis burden for Khurram et al. (1) and 18% for DECAAF. Although some of this can be explained by differing baseline patient characteristics, the discrepancy remains and limits the utility of the technique to single, expert centers and their patients.
The need for further validation of bLGE measurements is also apparent. Studies performing histological validation are limited (7), and substantial difficulties in precise registration of left atrial locations and the recognition of different pathological patterns and distributions of fibrosis mean that further work is warranted. Correlation of bLGE with intracardiac voltage measurements (3) or complex fractionated electrograms (4) has also been detailed, but again, imperfections in point-by-point registration and voltage mapping techniques mean that it is difficult to derive a gold standard. Furthermore, there is a profound scarcity of data to quantify reproducibility of the technique, repeating the measurements on the same patient on separate days: this requires addressing.
Despite these reservations regarding validation, there is a growing wealth of data to suggest that bLGE is predictive of outcome, and perhaps the end justifies the means? Clinical application of a technique has often preceded detailed understanding of its mechanism. However, in this case validation, and hence a gold standard, would be a driving force in the achievement of consensus in imaging acquisition and processing.
The final hurdle to the use of atrial bLGE as a routine clinical tool is that of viability. Khurram et al. (1) report a processing time of 30 min per case, for a team with a great deal of experience in the processing of these images. Those who perform the measurements less frequently, and without the substantial imaging science support, could not hope to achieve such a swift assessment. A substantial portion of the image processing time at most centers is required for manual segmentation of the left atrial endocardial and epicardial borders (2,3); a remedy to this is still required, and automated techniques have been used with limited success in smaller cohorts (5).
So let us suppose that a routine, robust atrial bLGE assessment tool is achieved. In what way will this marker help us guide patient selection? Much of the incremental value of this study rests in the stratification of patients within the persistent and paroxysmal AF groups. The impact of fibrosis burden is profound: 15% of patients with persistent AF and severe fibrosis (>35%) experienced a recurrence by only 126 days, compared with 294 days for those with persistent AF and mild fibrosis (156 vs. 252 days for paroxysmal AF). Data are lacking on the temporal aspect of AF pathogenesis and the duration of AF, but otherwise, the patient baseline characterization is comprehensive and detailed. It is clear that bLGE is an independent and strong predictor of poor outcome. So should patients with fibrosis above a predefined limit be denied ablation therapy?
There is a caveat that should be considered carefully in the interpretation of these figures, and this relates to ablation strategy. Pulmonary vein isolation alone has been demonstrated to be insufficient in the prevention of arrhythmia recurrence in some patient groups, either because of failure to address the primary arrhythmia mechanism or failure to achieve permanent pulmonary vein isolation. The bLGE may be a marker of distinct clinical entities, far more specific than the crude traditional dichotomization of AF into paroxysmal and persistent. Khurram et al. (1) performed uniform wide-area circumferential pulmonary vein isolation, albeit without the use of contact force catheters, with excellent acute clinical assessment of procedural adequacy, but non—pulmonary vein drivers of AF have not been identified or ablated. Notwithstanding the results of STAR-AF (Substrate and Trigger Ablation for Reduction of Atrial Fibrillation) (8), the possibility remains that the high recurrence rate in severe fibrosis is a reflection of the unsuitability of the ablation technique for that group, rather than an irreversible baseline risk factor for recurrence. The proposed DECAAF 2 study may go some way to answering this question, aiming to ablate atrial enhanced regions in addition to pulmonary vein isolation.
Assessment of baseline atrial fibrosis by late gadolinium enhancement magnetic resonance imaging remains an intriguing tool, but further work is required before it can be rolled out for every patient prior to ablation. The technique of image assessment used by the Johns Hopkins group is attractive. It requires fewer subjective steps than the approaches of other groups and is easier to replicate, but a consensus on technique remains absent. However, the key question is how to interpret the values derived: is the bLGE index a means of patient stratification to decline ablation, or to tailor it?
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Dr. O’Neill has received research support, honoraria, and travel expenses from Biosense Webster and St. Jude Medical. Dr. Chubb has reported that he has no relationships relevant to the contents of this paper to disclose.
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