Simultaneous Whole-Chamber Non-contact Mapping of Highest Dominant Frequency Sites During Persistent Atrial Fibrillation: A Prospective Ablation Study

Purpose Sites of highest dominant frequency (HDF) are implicated by many proposed mechanisms underlying persistent atrial fibrillation (persAF). We hypothesized that prospectively identifying and ablating dynamic left atrial HDF sites would favorably impact the electrophysiological substrate of persAF. We aim to assess the feasibility of prospectively identifying HDF sites by global simultaneous left atrial mapping.Methods: PersAF patients with no prior ablation history underwent global simultaneous left atrial non-contact mapping. 30 s of electrograms recorded during AF were exported into a bespoke MATLAB interface to identify HDF regions, which were then targeted for ablation, prior to pulmonary vein isolation. Following ablation of each region, change in AF cycle length (AFCL) was documented (≥ 10 ms considered significant). Baseline isopotential maps of ablated regions were retrospectively analyzed looking for rotors and focal activation or extinction events.ResultsA total of 51 HDF regions were identified and ablated in 10 patients (median DF 5.8Hz, range 4.4–7.1Hz). An increase in AFCL of was seen in 20 of the 51 regions (39%), including AF termination in 4 patients. 5 out of 10 patients (including the 4 patients where AF termination occurred with HDF-guided ablation) were free from AF recurrence at 1 year. The proportion of HDF occurrences in an ablated region was not associated with change in AFCL (τ = 0.11, p = 0.24). Regions where AFCL decreased by 10 ms or more (i.e., AF disorganization) after ablation also showed lowest baseline spectral organization (p < 0.033 for any comparison). Considering all ablated regions, the average proportion of HDF events which were also HRI events was 8.0 ± 13%. Focal activations predominated (537/1253 events) in the ablated regions on isopotential maps, were modestly associated with the proportion of HDF occurrences represented by the ablated region (Kendall’s τ = 0.40, p < 0.0001), and very strongly associated with focal extinction events (τ = 0.79, p < 0.0001). Rotors were rare (4/1253 events).ConclusionTargeting dynamic HDF sites is feasible and can be efficacious, but lacks specificity in identifying relevant human persAF substrate. Spectral organization may have an adjunctive role in preventing unnecessary substrate ablation. Dynamic HDF sites are not associated with observable rotational activity on isopotential mapping, but epi-endocardial breakthroughs could be contributory.</p

I_to reduction in cardiomyocytes isolated from the left atrial poisterior wall (LAPW).

<p>(a) Example voltage-sensitive, Ca²⁺ independent, macroscopic K⁺ currents evoked in cardiomyocytes isolated from the left atrial appendage (LAA, left) and LAPW (right). Voltage protocol is shown inset. (b-d) LAA and LAPW I/V relationships for the peak outward K⁺ current, I_to and steady state K⁺ current. Data presented as mean ± SEM. * denotes P<0.05 LAA (N = 16 cells) v LAPW (N = 12 cells), two way repeated measures Analysis of Variance (ANOVA) with Bonferroni post hoc analysis.</p

Action potential (AP) prolongation and heterogeneity in the left atrial posterior wall (LAPW).

<p>(a) Examples of left atrial (LA) isochronal action potential duration (APD) distribution maps at 30 and 70% repolarisation. (b) A raw fluorescence image of an LA loaded with Di-4-ANEPPS, along with the 9 region grid used for quantitative regional analysis. (c) Example optical action potentials (OAPs) recorded from the 9 different LA regions during 10Hz pacing. The green dotted line indicates APD70. (d) Box and whisker plot of APD70 values measured in each LA region. * denotes P<0.05 vs regions 7,8,9 inclusive, + P<0.05 vs region 7 only, one way repeated measures Analysis of Variance (ANOVA) with Bonferroni post hoc analysis, N = 18 LA. Inset: Heat map depicting mean APD70 values of the 9 LA regions of the LA. (e) Example isochronal APD70 distribution maps of the same LA at 10 and 1Hz (same scale). (f) Mean APD70 at 10 and 1Hz for the left atrial appendage (LAA) and left atrial posterior wall (LAPW). * denotes P<0.05 LAA v LAPW, one way repeated measures Analysis of Variance (ANOVA) with Bonferroni post hoc analysis, N = 5 LA. (g) LA gradients at 10 and 1Hz. * denotes P<0.05 LAA v LAPW, paired t-test, N = 5 LA.</p

I_KACh is depleted in left atrial posterior wall (LAPW) cardiomyocytes.

<p>(a) Current traces demonstrating isolation of BaCl₂ sensitive (I_K1) and CCh induced (I_KACh) currents in a single left atrial cardiomyocyte. Voltage protocol is shown inset. (b & c) Comparison of LAA and LAPW I/V relationships for I_K1 and I_KACh. The dashed lines indicate mean best fit I_K1 and I_KACh I/V curves with liquid junction potential correction, for both LAA and LAPW. Data presented as mean ± SEM. * denotes P<0.05 LAA (N = 25 cells) v LAPW (N = 17 cells), two way repeated measures Analysis of Variance (ANOVA) with Bonferroni post hoc analysis.</p

Ion channel expression differences between the left atrial posterior wall (LAPW) and left atrial appendage (LAA).

<p>(a-c) Comparisons of K⁺, Na⁺ and background/leak channel gene expression, between the LAPW and LAA, measured using Taqman Low Density Array (TDLA). Control sample was the LAA. ** and *** denote P<0.01 and P<0.001 respectively, LAA v LAPW, paired t-test, N = 9 LA.</p

Action potential differences between cardiomyocytes in the left atrial posterior wall (LAPW) and left atrial appendage (LAA).

<p>(a) Example intracellular recording trace demonstrating the stimulation protocol used to achieve sufficient action potential rate adaptation. (b) Example transmembrane action potentials (TAPs) taken from the LAA and LAPW of the same left atrium. TAPs are aligned at the resting membrane potential (RMP). The green vertical line indicates action potential duration at 90% repolarisation (APD90). (c-f) Box and whisker plots and individual values comparing the RMP, APD50-90, action potential amplitude (APA) and dV/dt (Vmax), of the LAA and LAPW, at 10Hz pacing frequency. **, *** denotes P<0.01 and P<0.001, LAA v LAPW, one way repeated measures Analysis of Variance (ANOVA) with Bonferroni post hoc analysis, or paired t-test; N = 20 LA.</p