Persistent atrial fibrillation—seeking the sources of the cardiac electrical field

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Andrew Grace

Andrew Grace charts the evolution of non-contact mapping culminating in the current AcQMap systemthe technology has advanced understanding of persistent atrial fibrillation (AF), providing further support for the idea that AF is, in fact, a disorder of cardiac development.

Electromagnetic field theory was the single most important scientific advance of the 19th Century, and was founded on both physical and biological observation. Relevant to the emergence of cardiology, instruments were developed to examine bioelectric signals in experimental models. These measurement tools provided a route to recording surface electrocardiograms that, in turn, underpinned accurate diagnosis and the establishment of a distinct and effective clinical speciality. Non-contact recordings of unipolar electrograms from intracardiac locations (an electrocardiographic equivalent) were first achieved around 30 years ago, but although clinical application advanced the mechanistic understanding of several arrhythmias, the resolution achieved using voltage-based non-contact mapping was limited, and clinical practitioners’ enthusiasm accordingly muted.

The electrical fields that are responsible for all electrocardiograms arise from myocardial charge sources. Although these sources cannot be resolved on the basis of surface electrical recordings, they can now be calculated applying well-established mathematics from intracardiac voltage recordings when acquired using the AcQMap system. This step represents a major scientific and technical advance, with significant practical possibilities for immediately and accurately targeting therapy, and provides a versatile toolkit for advancing biology. The approach has already allowed the first “proof-of-principle” unperturbed, full-chamber recordings of atrial fibrillation (AF).

Multi-spline catheter

The most recognisable, differentiated component of the AcQMap system is a multi-spline catheter, harbouring 48 ultrasound crystals with corresponding unipolar electrodes. The catheter is placed in the chamber of interest, and anatomy is first defined through acquisition of >100,000 ultrasound points/minute localising the endocardial surface. This highly resolved accurate anatomical shell provides a platform that minimises motion errors, giving high quality input data for distance measurements to feed into charge density (CD) calculations. The activation wavefront that travels through the heart muscle comprises a continuous charge layer, and is more compact than the voltage field used in contact mapping that emerges from it. Calculation of CD using a Poisson formulation with substantial exclusion of unwanted far-field interference cannot be achieved with contact recordings.

The practical sequence in individual procedures leading to map generation involves acquisition of 150,000 unipolar electrograms/second, solution of charge densities across the endocardial surface at fixed times, and then the generation of real-time moving images that give a clear visual readout of the patterns of endocardial activation patterns, even in complex fibrillation rhythms.

Activation mechanisms

Conventional conceptual models of AF have posited a variety of activation mechanisms that include single foci, circus movement re-entry, and multiple wavelets. The evolving pattern classification for AcQMap-determined activation sequences refers to single foci, localised rotational activation (LRA) and localised irregular activation (LIA), and constructively accommodates most prior knowledge. Initial practical advantages are the full chamber views and the capacity to rapidly remap, so that the impact of the delivery of individual ablation lesions can be efficiently tracked.

The prospective, nonrandomised, multicentre UNCOVER-AF trial recruited 127 patients with persistent AF (PersAF) and was designed to examine both clinical safety and the efficacy of the system. The patients had no prior history of AF ablation and an approximately two-year history since their diagnosis of PersAF. No device-related major adverse events were reported and, at 12 months, single procedure efficacy assessed using continuous ECG-monitors was 73%, with a 93% second procedure freedom from AF.

Ablate non-pulmonary veins as well

Most strikingly, from both a mechanistic and target identification standpoint, sinus rhythm was much more likely when non-pulmonary vein (PV) targets were ablated. In the workflow, all patients underwent initial PV isolation, so this finding provides substantive support for the independent importance of alternative non-vein related drivers. Specifically, predictors of SR at 12 months included a 2.8-fold higher likelihood of success when at least two of three pattern types were ablated during the procedure, and a 9.4-fold higher likelihood when three to four focal, rotational or irregular patterns were ablated. We concluded that PV isolation plus ablation of individualised, patient specific non-PV targets provides is beneficial when compared to conventional PV isolation alone.

Results are consistent

The patterns observed and their locations are generally consistent with those seen using other approaches and technologies, and also seem to have some consistency and stability in terms of location and patterning over time, when assessed using AcQMap. Taken together, the results support the idea that AF often emerges against not only a well-described genetic diathesis but, more specifically, that the condition is in fact a “developmental” disorder. Such a proposition would imply foetal programming, with predisposition to the development of both PV and non-PV drivers. This idea is supported not just by what we are seeing with AcQMap, but also by a range of preclinical studies and by population-based findings from, for example, genome wide association studies (GWAS) that implicate transcription factors and other genes involved in aspects of cardiac development to AF susceptibility. The deep phenotyping capabilities of AcQMap in an accessible whole organ, such as the heart, now provide the community with the means to refine disease taxonomy, picking up subsets of AF that will then facilitate the interpretation of clinical genomic studies. Furthermore, through single cell analyses, including rescue experiments, we should be able to advance understanding of the fundamental basis of fibrillation syndromes, and so provide a platform for the design of a range of targeted therapeutic approaches.

In conclusion, the endocardial charge layer is the true source of the observed cardiac electrical field, and calculation of charge density based on standard mathematics has now made effective non-contact mapping a reality. The maps obtained are plausible and actionable, providing a rational means for personalising and targeting ablation procedures. However, the most profound impact may be through the provision of a discovery platform based on deep phenotyping in an accessible, highly quantifiable whole human organ in vivo.

Andrew Grace is a consultant cardiologist at the Royal Papworth Hospital, Cambridge, and research group head at the Department of Biochemistry, University of Cambridge, Cambridge, UK.


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