Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool to conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due to high target burden. However, the requirements for optimal binding kinetic framework and extent of pH dependence for these antibodies to maximize target clearance from circulation are not well understood. We have identified a series of naturally-occurring high affinity antibodies with pH-dependent target binding properties. By in vivo studies in cynomolgus monkeys, we show that pH-dependent binding to the target alone is not sufficient for effective target removal from circulation, but requires Fc mutations that increase antibody binding to FcRn. Affinity-enhanced pH-dependent FcRn binding that is double-digit nM at pH 7.4 and single-digit nM at pH 6 achieved maximal target reduction when combined with similar target binding affinities in reverse pH directions. Sustained target clearance below the baseline level was achieved 3 weeks after single-dose administration at 1.5 mg/kg. Using the experimentally derived mechanistic model, we demonstrate the essential kinetic interplay between target turnover and antibody pH-dependent binding during the FcRn recycling, and identify the key components for achieving maximal target clearance. These results bridge the demand for improved patient dosing convenience with the “know-how” of therapeutic modality by design.

Since the STAR-AF II trial, there has been a trend toward pulmonary vein isolation (PVI)-only ablation strategies for persistent atrial fibrillation (PeAF). Electrographic Flow (EGF) mapping can identify active sources of AF and estimate the electrographic flow consistency (EGFC) of wavefront propagation through substrate, revealing functional AF mechanisms. Examine the success of a PVI-only ablation strategy for a redo PeAF/long-standing PeAF population. FLOW-AF (NCT04473963) prospectively enrolled non-paroxysmal AF patients undergoing redo ablation at 4 centers. One-minute EGF recordings using 64-pole basket catheters were obtained both pre-PVI and post-PVI following a 20-minute wait and confirmation of electrical isolation of veins. Patients with EGF-identified sources were randomized 1:1 to EGF-guided source ablation v. PVI-only. Patients with no sources were not randomized and mostly received PVI-only. Study of 85 patients enrolled: 24 with EGF-identified sources randomized to PVI-only and 23 with no sources receiving PVI-only. Of these 47 patients, those with sources (Group 2) had different clinical characteristics including older age and higher CHA₂DS₂-VASc compared with those with sources (Group 1). After PVI-only, Group 1 had 70% (16/23) freedom from recurrent AF (FFAF) within one year v. Group 2 with 35% (8/23), p=0.018. Additionally, patients with high electrographic flow consistency (EGFC) indicative of healthy or normal substrate had 67% (10/15) FFAF v. 45% (14/31) in those with low EGFC suggestive of abnormal substrate, p=0.011. Success rate in no sources patients receiving PVI-only is better than in those with sources randomized to PVI-only. For the clinically heterogenous population of PeAF patients, the presence of EGF-identified sources matters clinically, and PVI-only will not be enough for all patients.

Background: Electrographic flow (EGF) mapping allows for the visualization of global atrial wavefront propagations. One mechanism of initiation and maintenance of atrial fibrillation (AF) is stimulation from EGF‐identified focal sources that serve as driver sites of fibrillatory conduction. Electrographic flow consistency (EGFC) further quantifies the concordance of observed wavefront patterns, indicating that a healthier substrate shows more organized wavefront propagation and higher EGFC. Freedom from AF (FFAF) recurrence has accordingly been shown to be higher in patients with ablated vs. unablated sources and with high vs. low EGFC.Objectives: (1) Measure FFAF across EGF‐derived phenotypes in patients enrolled in the AF‐FLOW Global Registry; (2) determine if a relationship exists between EGFC and percentage of healthy voltage as measured from bipolar voltage maps.Methods: The AF‐FLOW Global Registry is a multicenter, prospective study of 25 all‐comer AF patients who underwent concomitant high‐density bipolar voltage mapping with a 16‐electrode grid mapping catheter and EGF mapping with a 64‐pole basket catheter. The EGF algorithm detects extra‐pulmonary vein sources as origins of excitation from a singularity of divergent flow vectors and was used to localize RF ablation targets. Overall, EGFC per atrium was also computed as the average of the modulus of individual EGF vectors, where the vector length represents the consistency of flow patterns. Patients were then assigned phenotypes on the basis of source presence or absence and EGFC, and rates of FFAF at 1‐year were compared across the four resulting phenotypes. Atrial EGFC was also compared to the percentage of healthy tissue determined by bipolar voltage mapping.Results: Patients with paroxysmal AF had higher FFAF than persistent AF (PeAF) and long‐standing PeAF patients; patients receiving de novo ablation had higher FFAF than those receiving redo ablation. Patient phenotyping revealed that those with high EGFC had higher FFAF than those with low EGFC (p = 0.015). Atrial EGFC was also correlated to the percent of high voltage tissue across all patients (r = 0.651, p < 0.0001).Conclusions: EGF mapping provides insights into the mechanistic nature of AF and the atrial health of the underlying substrate. Therefore, further studies are needed to develop phenotype‐specific treatments for the disease.Trial Registration: ClinicalTrials.gov identifier: NCT05481359.

Purpose of review: A low ceiling of efficacy exists for the treatment of persistent atrial fibrillation via pulmonary vein isolation without adjunctive ablations, which is likely because they do not target an individual patient's specific underlying disease mechanisms. Electrographic flow (EGF) mapping is the first system that reliably displays wavefront propagation through the atria. It is a promising tool for localizing sources of atrial fibrillation, guiding targeted ablation, and visualizing conduction through the atrial substrate. Recent findings: We describe EGF mapping with emphasis on contemporary studies examining map reproducibility and use cases in the preclinical and clinical environment. Animal experiments demonstrated that maps were interpretable across increasingly complex rhythms with pacing during spontaneously persistent atrial fibrillation reliably simulating EGF sources. The FLOW-AF randomized controlled trial showed that source ablation improved outcomes and that EGF map properties may be used to phenotype patients based on their atrial fibrillation mechanisms and recurrence likelihoods. Summary: Targeted ablation strategies balance the risks of insufficiently ablating atrial fibrillation triggers with exacerbating disease through additional scar formation. EGF mapping leverages spatiotemporal relationships in voltage to localize sources and quantify substrate health. Further research is needed to optimize phenotyping and treatment efforts.

Background Electrographic flow (EGF) mapping reconstructs atrial electrical wavefront propagation, potentially revealing sources of atrial fibrillation (AF). Electrographic flow consistency (EGFC) measures the concurrence of wavefront patterns and may provide insights into atrial substrate health. This study aimed to compare EGF patterns during atrial fibrillation (AF) with sinus rhythm (SR) and explore the correlation between EGFC and regional bipolar voltage. Methods In this single-center, prospective study, AF patients underwent mapping of the atria using bipolar voltage and EGF mapping. Mapping was performed during both AF and SR using a 16-electrode grid catheter (bipolar mapping) and a 64-pole basket catheter (EGF mapping). EGFC was computed as the average modulus of individual EGF vectors, reflecting flow pattern consistency. Results Ten patients were enrolled. EGF identified 11 sources with a mean source activity of 32 ± 9% during AF. Eight out of eleven sources in AF converted to passive “sinks” when mapped in SR. EGFC was significantly lower during AF compared to SR (0.74 ± 0.14 vs 1.0 ± 0.11 AUs, P < 0.01), consistent with EGFC quantifying the more chaotic wavefront propagation during arrhythmia. No spatial correlation between areas of high EGFC during AF and SR was observed. EGFC correlated with bipolar voltage across rhythms and atria (r = 0.647, P < 0.0001). Conclusion EGF patterns varied by rhythm with AF showing lower EGFC values. EGFC correlated with bipolar voltage across rhythms and atria, suggesting its potential as an atrial myopathy marker akin to high-density voltage mapping and offering insights into atrial substrate health. Trial registration ClinicalTrials.gov Identifier: NCT06260670. Graphical Abstract

Background/Objectives: Electrographic flow (EGF) mapping allows for the visualization and quantification of atrial fibrillation (AF) wavefront propagation patterns. EGF-identified sources were shown in the randomized controlled FLOW-AF trial to significantly increase the likelihood of AF recurrence within 1 year if left unablated. Electrographic flow consistency (EGFC) additionally measures the stability of observed wavefront patterns, such that patients with more organization have a healthier substrate and lower recurrence. Source presence and EGFC can be used collectively to assign mechanistic phenotypes to AF patients. Methods: The patient phenotypes, treatment modalities, and outcomes in FLOW-AF were compared with those of patients in the ensuing AF-FLOW Global Registry, which was conducted by separate physicians at discrete clinical centers. Results: Patients with low EGFC (≤0.62) had a 12-month freedom from AF (FFAF) of 46%, while those with a high mean EGFC (>0.62) had a FFAF of 81%. Right atrial EGFC was correlated with left atrial EGFC, and the highest recurrence occurred in those with biatrial low EGFC. Source presence also affected the recurrence rates in both trials, such that the presence of EGF-identified sources in PVI-only patients lowered the FFAF from 65% to 36%, but the elimination of sources produced a 30% absolute increase in FFAF from 36% to 66%. Conclusions: Patient outcomes by EGF-based AF phenotype were consistent across two cohorts of patients from separate clinical trials at distinct centers. Patients with a high EGFC and no sources post-procedure had the best outcomes. EGF mapping provides insights into underlying disease pathophysiology and may be employed prospectively to predict recurrence.