BACKGROUND:Atrial fibrillation (AF) ablation continues to offer mediocre outcomes, particularly for persistent AF. Obesity and epicardial adipose tissue (EAT) are associated with AF and ablation outcomes. Risk factor modification (RFM), including weight loss, improves AF treatment outcomes. Liraglutide, a glucagon-like peptide-1 receptor agonist, leads to weight loss and EAT reduction. OBJECTIVES:This study sought to test the effects of adjunctive therapy with liraglutide in patients with AF undergoing ablation. METHODS:In this randomized study of overweight/obese (body mass index ≥27 kg/m2) patients with AF (80% persistent AF) who opted for catheter ablation for treatment, 28 patients were assigned to RFM and 31 to risk factor modification (plus liraglutide (RFM+L) for 3 months preablation. EAT was evaluated with serial computed tomography scans at enrollment and preablation, and serial echocardiograms up to 1-year postablation. The primary endpoint was change in left atrial epicardial adipose tissue (LAEAT) volume. Total EAT and recurrent AF at 1 year were secondary endpoints. RESULTS:There were 28 patients (age 61.8 ± 10.3 years, 8 female) assigned to RFM and 31 patients (age 62.2 ± 8.6 years, 8 female) to RFM+L for 3 months preablation. Baseline characteristics were well-balanced between groups with median body mass index of 34.2-37.2 kg/m2. Forty-seven (80%) had persistent AF. One patient in the RFM group and 3 in the RFM+L group opted not to proceed with ablation, and "preablation" testing was performed at the time of this decision. Overall, there were reductions in LAEAT (median -1.0 [Q1-Q3: -4.5 to 1.4] mL; P = 0.02) and weight (-2.8 ± 4.0 kg; P < 0.001) but no difference between groups. One-year freedom from AF/atrial flutter was 81% (95% CI: 62%-91%) for RFM+L and 54% (95% CI: 34%-70%) for RFM (log-rank P = 0.007). Logistic regression models showed RFM+L was associated with lower risk of 12-month recurrence (LAEAT model: OR: 0.19; 95% CI: 0.05-0.73; P = 0.015; EAT model: OR: 0.08; 95% CI: 0.01-0.40; P = 0.002). Change in EAT density was associated with lower recurrence (OR: 0.55; 95% CI: 0.36-0.84; P = 0.006). CONCLUSIONS:Whereas adding liraglutide to RFM in obese patients with AF did not produce significant differences in early weight loss or LAEAT reduction, improved freedom from AF/atrial flutter was noted. Pleiotropic glucagon-like peptide-1 receptor agonist effects may provide novel pharmacologic targets for AF treatment that can substantially improve AF ablation outcomes. (Liraglutide Effect in Atrial Fibrillation [LEAF]; NCT03856632).

BACKGROUND:The electrocardiogram (ECG) in persistent atrial fibrillation (AF) is underused. Signal processing techniques can extract the f-waves from the QRS-T complex to generate the atrial ECG (A-ECG). OBJECTIVE:This study aimed to explore A-ECG technical and clinical issues. METHODS:Thirty patients (age, 62.6 ± 9.4 years; 80% male; CHA2DS2-VASc score, 2.2 ± 1.7; ejection fraction, 47.9% ± 10.4%) with persistent AF undergoing ablation were enrolled. ECGs were downloaded for offline analysis. A-ECG was derived by QRS-T subtraction and independent component analysis filtering. A-ECG short-term (DF10s, OI10s) and long-term (DF_Global, OI_Global) spectral features were derived. Optimal recording duration, temporal reproducibility, differences between leads, comparison to intracardiac dominant frequency (DF), acute ablation effect, and A-ECG differences based on ablation outcomes were evaluated. RESULTS:Time-frequency A-ECG analysis demonstrated dynamic spectral features. Repeated 10-second A-ECG recordings had higher coefficient of variation (7.5%-10.0%) compared with repeated 4- to 5-minute recordings (1.1%-3.4%). Short-term reproducibility of 2 recordings ∼30 minutes apart showed high correlation (r = 0.91-0.99; all P values < .0001). Regional lead analyses showed no significant differences except for the comparison of posterior leads V7-V9 vs V1-V3. A-ECG DF parameters correlated with right atrial DF (r = 0.64-0.72; P < .0001) and not left atrial DF. A-ECG DF declined after ablation (median-DF10s-1min, 5.94 ± 0.63 Hz vs 5.77 ± 0.63 Hz; P = .0003). Patients with successful ablation at 1 year had higher A-ECG DF vs those with recurrences (median-DF10s-5min, 6.04 ± 0.42 Hz vs 5.13 ± 0.93 Hz; P = .003). CONCLUSION:This study provides the practical basis for further use of the A-ECG as a novel tool for evaluating persistent AF and demonstrates its clinical relevance. Further phenotypic classification of AF based on the A-ECG and assessment of treatment response should be explored.

Background: The recent REDUCE-AMI trial showed no benefit to beta-blockers (BB) for patients post-myocardial infarction (MI) with preserved ejection fraction (EF≥50%). Target doses were metoprolol 100 mg and bisoprolol 5 mg daily (50% of the target doses used in the initial randomized clinical trials [RCTs] of BB post-MI). Research question: Do lower BB doses improve survival in post-MI patients with EF≥50%? Aims: To compare the effect of BB dose on all-cause mortality post-MI in patients with EF≥50%. Methods: This is a sub-study from the OBTAIN prospective multi-center registry. Of 7057 patients enrolled with acute MI, 3402 with EF≥50% were discharged alive (age:62.5±13.4 years, 67% male, 28% diabetics, length of stay 6.1±6.0 days). Discharge BB dose was indexed to the target daily BB dose used in RCTs, reported as %. Dosage groups were >0-12.5%, >12.5-25%, >25-50%, and >50% of the target dose. Follow-up vital status was obtained by chart review, Social Security Death Index, or direct contact up to 3 years post-MI. Kaplan-Meier (KM) method was used to calculate three-year survival. Cox proportional hazard regression model was used to identify significant predictors and conduct univariate and multivariate analysis. Results: The KM 3 year survival estimates were 89.0% and 84.3% for patients on and off BB, respectively (unadjusted hazard ratio (HR)=0.66, p=0.012; adjusted HR=0.52, p=0.18). The KM 3 year survival estimates(figure) were 89.8%, 91.0%, 87.9%, and 83.1% for patients on >0-12.5%, >12.5-25%, >25- 50%, and >50% of the BB target dose (unadjusted HR of 0.58, p=0.007; 0.58, p=0.003; 0.70; p=0.066; and 0.98, p=0.93), respectively, compared to no BB. After multivariate analysis, BB target dose showed similar trend, but not statistically significant (adjusted HR=0.65, p=0.46; 0.42, p=0.13; 0.53, p=0.31; 1.01, p=0.92). Conclusion: In OBTAIN, patients treated with low dose BB (≤25% of the target dose) had improved survival post-MI. As this dose was not studied in REDUCE-AMI, these findings are complementary and confirm only that high dose BB therapy provides no benefit post-MI in patients with preserved EF. RCTs to assess the benefit of low dose BB therapy post-MI with preserved EF are needed.

Success rates for catheter ablation of atrial fibrillation (AF), particularly persistent AF, remain suboptimal. Pulmonary vein isolation has been the cornerstone for catheter ablation of AF for over a decade. While successful for most patients, pulmonary vein isolation alone is still insufficient for a substantial minority. Frustratingly, multiple clinical trials testing a diverse array of additional ablation approaches have led to mixed results, with no current strategy that improves AF outcomes beyond pulmonary vein isolation in all patients. Nevertheless, this large collection of data could be used to extract important insights regarding AF mechanisms and the diversity of the AF syndrome. Mechanistically, the general model for arrhythmogenesis prompts the need for tools to individually assess triggers, drivers, and substrates in individual patients. A key goal is to identify those who will not respond to pulmonary vein isolation, with novel approaches to phenotyping that may include mapping to identify alternative drivers or critical substrates. This, in turn, can allow for the implementation of phenotype-based, targeted approaches that may categorize patients into groups who would or would not be likely to respond to catheter ablation, pharmacological therapy, and risk factor modification programs. One major goal is to predict individuals in whom additional empirical ablation, while feasible, may be futile or lead to atrial scarring or proarrhythmia. This work attempts to integrate key lessons from successful and failed trials of catheter ablation, as well as models of AF, to suggest future paradigms for AF treatment.

Background: Cardioversion (CV) for persistent atrial fibrillation (PeAF) restores sinus rhythm (SR) but its effects on left atrial (LA) and LA appendage (LAA) flow are not well established. Research question: Does restoring sinus rhythm improve LA/LAA hemodynamics in patients with PeAF? Aims: To compare changes in LA/LAA 4D flow MRI characteristics post-CV for PeAF versus repeated measurements in a control group without AF. Methods: We performed 4D flow MRI (3T Skyra) in 9 PeAF patients (8 males, age 68±8 yrs, 78% HTN, 44% DM, 22% CAD, CHA2DS2-VASc 2.7±1.5, LVEF 53±17%) prior to and 62±44 days after CV (in SR) (minimum 4 weeks after CV). We also performed repeat MRIs in 9 SR controls (6 males, age 51±11 yrs, 78% HTN, 22% DM, 11% CAD, CHA2DS2-VASc 1.6±0.9, LVEF 62±4%) 60±19 days apart, both in SR (minimum 4 weeks apart). Data analysis included 3D segmentation of LA and LAA for evaluation of atrial velocity data. Absolute atrial velocities were calculated for each voxel and time frame inside the LA and LAA, and used to derive blood stasis (quantified by determining number of cardiac time frames with velocities below a threshold of 20 cm/s, normalized by the total number of cardiac time frames: Stasis%= (Nstasis/ NTotal)*100 ) and median velocity. Results: In PeAF, restoring SR improved 4D flow characteristics by reducing stasis and increasing median velocity (p<0.003, figure). In the controls, there was no significant change in median velocity or stasis % between the two scans in either the LA or LAA. Bland-Altman analysis for the two control scans showed no significant differences in the controls. Pre-CV median velocities and stasis% in PeAF significantly differed from controls while post-CV, they did not. Conclusion: AF is associated with impaired LA and LAA flow characteristics that improve substantially with CV toward control values. Use of 4D MRI to quantify LA and LAA hemodynamic function is feasible; future studies are needed to correlate 4D MRI measurements to thromboembolic risk.

Background: The surface Atrial ECG (A-ECG) time and frequency domains features are not currently used clinically in patients with persistent atrial fibrillation (PeAF). Machine Learning (ML) can provide novel insight into various data sources. Research question: Can ML analysis of the A-ECG predict the outcome of catheter ablation (CA) of PeAF? Aim: To use ML Tools to assess A-ECG prediction of CA outcomes in PeAF patients at 1 and 2 years. Methods: Thirty-two patients (age 63±9 years; 71% males) with PeAF underwent two 5-minute epochs of surface ECG; 4 were excluded for significant artifacts and 2 more for unrelated clinical issues. The Pre-CA A-ECG was derived by QRST subtraction and independent component analysis filtering and divided into 50% overlap 10-second windows for spectral analysis. A-ECG mean dominant frequency DF, mean organization index and median amplitude M-AMP were computed for each lead. Freedom from atrial arrhythmia AA (Responders) was assessed at one and two years. The two 5-minute segments per patient were included in the data set. Classification Learner (Mathworks Inc., Natick, MA, USA) was used to train classifiers, looking for the minimum number of features able to explain the outcomes. Once the best (2-3) features were identified, a MATLAB program was used to visualize the decision regions and correlate with ablation outcomes. Results: ML identified A-ECG features DF and M-AMP of V 1 to well explain outcome. Specifically, an Artificial Neural Network (ANN) with 1 fully connected hidden layer of size 7 can explain the data with 90.4% accuracy. The figure shows the datasets for year 1 and year 2 CA outcomes, superimposed with ANN decision regions, for Responders and non-Responders. High DF and high M-AMP are predictors of responders and Low DF low M-AMP for non-Responders. Conclusion: ML analysis of the A-ECG is a promising tool to predict Responders to PVI CA for treatment of PeAF. This predictive algorithm needs to be tested on a prospective cohort.

Background: Electrogram (EGM) morphology recurrence (EMR) mapping of persistent atrial fibrillation (PeAF) quantifies consistency of activation at each site and is expected to be high and rapid near drivers of PeAF. Objective: To compare EMR in the left (LA) and right atrium (RA) in patients undergoing first- vs second-time PeAF catheter ablation (CA). Methods: Multisite bipolar EGM mapping of the LA (265±153 sites) and RA (224±148 sites) prior to CA for PeAF was performed in 40 patients (29 males, age 63±9 yrs, CHA2DS2-VASc 2.4±1.5, LVEF 48±12%) undergoing first (Group 1, n=31) or second-time (Group 2, n=9) CA. After cross-correlation of each automatically detected EGM with every other EGM in the recording, the most recurrent EGM morphology was identified and its frequency (Rec%) and cycle length of recurrence (CL R ) were computed (figure). The minimum CL R sites were identified. Results: In group 1, shortest CL R was in the LA in 26 patients (84%) and RA in 5 patients (16%). In the LA, there were 1 (n=23), 2 (n=2), or 3 (n=1) areas of shortest CL R , most commonly in the pulmonary veins (PV; n=19). In the RA, there was only 1 area of shortest CL R . Minimum CL R was 174.1±25.4 ms (LA-179.6±37.4 vs RA-207.9±34.5, p=0.0004), with Rec% 95±10%. In group 2, shortest CL R was in the LA in 5 patients and RA in 5 patients (56%)– one had both LA and RA. In the LA/RA, there were 1 (n=3/4) or 2 (n=2/1) areas of shortest CL R . The most common LA site was non-PV (6/7, 85.7%). The minimum CL R was 182.1±26.2ms (LA-190.8±36.2 vs RA-196.0±30.5, p=0.6), with Rec% 96±5%. Conclusion: In 61% of patients undergoing initial CA for PeAF, EMR identified LA drivers in the PVs which may explain why PV isolation has been reported to have 50-60% success rates in PeAF. In patients undergoing a 2 nd ablation for PeAF, EMR identified predominantly nonPV drivers with even distribution of shortest CL R between RA and LA and diminished CL R gradient between the LA and RA. EMR may be a useful mapping tool to characterize potential drivers of PeAF.

Background: There are no standard techniques to track effects of catheter ablation (CA) of persistent atrial fibrillation (PeAF). The Atrial ECG (A-ECG) derived from the standard ECG provides the atrial dominant frequency (DF), an estimation of atrial rate. Research Question: Does CA for PeAF diminish A-ECG DF? Aims: To evaluate change in A-ECG peak DF pre- and post-CA. Methods: We obtained 1-minute epochs of surface ECG pre- and post-CA in 32 patients (age 63±9 years; 71% males) undergoing CA for PeAF. A-ECG was derived by QRST subtraction and independent component analysis filtering, and divided into overlapping10-second windows, each subjected to Fast Fourier Transform. DF was calculated for each lead as the average DF for all 10-sec segments. Peak A-ECG DF was assessed by regional lead group and among all leads. 10 patients were excluded for significant artifact. Of the 22 analyzed patients, all had pulmonary vein isolation and 3 had posterior wall isolation. Two-year outcomes were available in 20 patients (13 were free from recurrent AF). Results: The figure shows the change in the time-frequency plot (left panel) of DF for one subject and the shift in the spectra (right panel) with CA. A-ECG peak DF was significantly lower post- versus pre-CA: 5.96±0.63 vs 6.16±0.64 Hz, p=0.0009. By lead group, peak DFs were all lower post CA - Anterior (V1-3): 5.94±0.62 vs 6.13±0.64 Hz, p=0.0015; Inferior (II, III, aVF): 5.82±0.63 vs 6.01±0.66 Hz, p=0.0040; Lateral (I, aVL, V5-6): 5.82±0.64 vs 5.99±0.63 Hz, p=0.0015. In this small cohort, there was no significant difference in change of peak DF in those free from AF versus with recurrent AF (-2.4±4.3% vs -4.6±3.7%, p=0.26). Conclusion: The A-ECG provides physiologic information of activation rate in PeAF, but despite current, advanced signal processing techniques is analyzable in only 69% of patients. CA results in a significant reduction in DF. Clinical implications of these CA induced changes require further study.

Weight loss is a class I indication for treatment of patients with atrial fibrillation (AF). We assessed the effect of a clinically implemented program for pre-procedure weight loss on AF ablation outcome.

Background: The surface Atrial ECG (A-ECG) is an underused tool in persistent atrial fibrillation (PeAF) that can provide dominant frequency (DF) of atrial activation. The association between A-ECG DF and left (LA) and right atrial (RA) DF has not been established. Research Question: Does surface A-ECG DF correlate with intracardiac DF? Aims: To investigate the correlation between A-ECG peak DF and peak DF of intracardiac RA and LA electrograms (EGM) in patients with PeAF. Methods: Thirty-two patients (age 63±9 years; 71% males) with PeAF underwent 5-minute epochs of surface ECG and comprehensive LA (261.5±185.1 sites/patient) and RA (211.5±174.6 sites/patient) intracardiac mapping with 15 second recordings. The A-ECG was derived by QRST subtraction and independent component analysis filtering, and divided into overlapping10-second windows which were subjected to Fast Fourier Transform (FFT). 4 were excluded for significant artifact. A-ECG DF was calculated for each lead from the power spectrum as the average of all 10-second segments. Peak A-ECG DF was determined by regional lead location and for all 12 leads. The intracardiac EGM DF was calculated from the FFT, and peak RA and LA DF was determined. Results: A-ECG peak DF was significantly lower than intracardiac peak DF 6.08±0.64 vs 9.72±1.19 Hz, p<0.0001(LA: 9.72±1.20 Hz, p<0.0001; RA: 8.40±0.80 Hz, p<0.0001). Figure shows that A-ECG peak DF correlated with peak RA DF, r=0.77 (p<0.0001), but not with peak LA DF (r=0.31, p=0.10). Regional A-ECG lead group DF correlated with RA DF (Inferior (II, III, aVF): r=0.79, p<0.0001; Lateral (I, aVL, V5-6): r=0.78, p<0.0001; Anterior (V1-3): r=0.75, p<0.0001) but not with peak LA DF. Conclusion: Surface A-ECG DF correlates with intracardiac RA DF and not LA DF. As in atrial flutter, the RA plays a prominent role in the surface ECG manifestation of the f waves. Further study is needed to determine whether A-ECG DF can be used to identify RA versus LA drivers that may require ablation.

INTRODUCTION Multiple analysis techniques evaluate electrograms during atrial fibrillation (AF), but none have been established to guide catheter ablation. This study compares electrogram properties recorded from multiple right (RA) and left atrial (LA) sites. METHODS Multisite LA/RA mapping (281 ± 176/239 ± 166 sites/patient) was performed in 42 patients (30 males, age 63 ± 9 years) undergoing first (n = 32) or redo-AF ablation (n = 10). All electrogram recordings were visually reviewed and artifactual signals were excluded leaving a total of 21 846 for analysis. Electrogram characteristics evaluated were cycle length (CL), amplitude, Shannon's entropy (ShEn), fractionation interval, dominant frequency, organizational index, and cycle length of most recurrent morphology (CLR ) from morphology recurrence plot analysis. RESULTS Electrogram characteristics were correlated to each other. All pairwise comparisons were significant (p < .001) except for dominant frequency and CLR (p = .59), and amplitude and dominant frequency (p = .38). Only ShEn and fractionation interval demonstrated a strong negative correlation (r = -.94). All other pairwise comparisons were poor to moderately correlated. The relationships are highly conserved among patients, in the RA versus LA, and in those undergoing initial versus redo ablations. Antiarrhythmic drug therapy did not have a significant effect on electrogram characteristics, except minimum ShEn. Electrogram characteristics associated with ablation outcome were shorter minimum CLR , lower minimum ShEn, and longer mimimum CL. There was minimal overlap between the top 10 sites identified by one electrogram characteristic and the top 10 sites identified by the other 10 characteristics. CONCLUSION Multiple techniques can be employed for electrogram analysis in AF. In this analysis of eight different electrogram characteristics, seven were poorly to moderately correlated and do not identify similar locations. Only some characteristics were predictive of ablation outcome. Further studies to consider electrogram properties, perhaps in combination, for categorizing and/or mapping AF are warranted.

Beta blockers are uniformly recommended for all patients after myocardial infarction (MI), including those with diabetes mellitus (DM). This study assesses the impact of fl-blocker type and dosing on survival in patients with DM after MI. A cohort of 6,682 patients in the Outcomes of Beta-blocker Therapy After Myocardial INfarction registry were discharged after MI. In this cohort, 2,137 patients had DM (32%). Beta-blocker dose was indexed to the target daily dose used in randomized clinical trials and reported as per-centage. Dosage groups were: no fl blocker, >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of the target dose. The overall mean discharge fl-blocker dose in patients with DM was 42.7 & PLUSMN; 34.1% versus 35.9 & PLUSMN; 27.4% in patients without DM (p <0.0001). Patients with DM were prescribed carvedilol at a higher rate than those without DM (27.8% vs 19.6%). The 3-year mortality estimates were 24.4% and 12.8% for patients with DM versus without DM (p <0.0001), respectively, with an unadjusted hazard ratio = 1.820 (confidence interval 1.587 to 2.086, p <0.0001). Patients with DM in the >12.5% to 25% dose category had the highest survival rates, whereas patients in the >50% dose had the lowest survival rate among patients discharged on fl blockers (p <0.0001). In the multivariable analysis among patients with DM after MI, all fl-blocker dose categories demonstrated lower mortality than no therapy; however, only the >12.5% to 25% dose had a statistically significant hazard ratio 0.450 (95% confidence interval 0.224 to 0.907, p = 0.025). In patients with DM, there was no statistically significant differ-ence in 3-year mortality among those treated with metoprolol versus carvedilol. In conclu-sion, our analysis in patients with DM after MI suggested a survival benefit from fl-blocker therapy, with no apparent advantage to high-versus low-dose fl-blocker ther-apy; although, physicians tended to prescribe higher doses in patients with DM. There was no survival benefit for carvedilol over metoprolol in patients with DM. & COPY; 2023 Elsevier Inc. All rights reserved. (Am J Cardiol 2023;198:124-132)