Europace (2020) 22, 704–715 CLINICAL RESEARCH doi:10.1093/europace/euz331 Atrial fibrillation Personalized monitoring of electrical remodelling during atrial fibrillation progression via remote transmissions from implantable devices Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 José Marı́a Lillo-Castellano1,2, Juan José González-Ferrer3,4†, Manuel Marina-Breysse1,5†, José Bautista Martı́nez-Ferrer6, Luisa Pérez-Álvarez7, Javier Alzueta8, Juan Gabriel Martı́nez9, Anı́bal Rodrı́guez10, Juan Carlos Rodrı́guez-Pérez11, Ignasi Anguera12, Xavier Vi~ nolas13, Arcadio Garcı́a-Alberola14, Jorge G. Quintanilla1,3,4, José Manuel Alfonso-Almazán1, Javier Garcı́a15, Luis Borrego3, Victoria Can ~ adas-Godoy3,4, Nicasio Pérez-Castellano3,4, Julián Pérez-Villacastı́n2,3,4, Javier Jiménez-Dı́az16, José Jalife4,17, and David Filgueiras-Rama 1,3,4* 1 Advanced Development in Arrhythmia Mechanisms and Therapy Laboratory, Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; 2Fundación Interhospitalaria para la Investigación Cardiovascular (FIC), Madrid, Spain; 3Instituto de Investigación Sanitaria del Hospital Clı́nico San Carlos (IdISSC). Cardiovascular Institute, Madrid, Spain; 4Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; 5Agencia Espa~ nola de Protección de la Salud en el Deporte (AEPSAD), Madrid. Spain; 6Department of Cardiology, Hospital Universitario de Áraba, Vitoria, Spain; 7Department of Cardiology, Hospital 8 9 Hospital Universitario de A Coru~ na, La Coru~ na, Spain; Department of Cardiology, Hospital Universitario Virgen de la Victoria, Málaga, Spain; Department of Cardiology, Hospital General Universitario de Alicante, ISABIAL-FISABIO, Alicante, Spain; 10Department of Cardiology, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain; 11 Department of Cardiology, Hospital Insular de Gran Canaria, Las Palmas, Spain; 12Department of Cardiology, Hospital Universitario de Bellvitge, Barcelona, Spain; 13 Department of Cardiology, Hospital Santa Creu i san Pau, Barcelona, Spain; 14Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, IMIB, Murcia, Spain; 15 Department of Cardiology, Hospital Universitario de Getafe, Madrid, Spain; 16Department of Cardiology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain; and 17Cardiac Arrhythmia Laboratory, Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain Received 5 March 2019; editorial decision 10 November 2019; accepted 12 November 2019; online publish-ahead-of-print 16 December 2019 Aims Atrial electrical remodelling (AER) is a transitional period associated with the progression and long-term mainte- nance of atrial fibrillation (AF). We aimed to study the progression of AER in individual patients with implantable devices and AF episodes. ................................................................................................................................................................................................... Methods Observational multicentre study (51 centres) including 4618 patients with implantable cardioverter-defibrillator and results þ/resynchronization therapy (ICD/CRT-D) and 352 patients (2 centres) with pacemakers (median follow-up: 3.4 years). Atrial activation rate (AAR) was quantified as the frequency of the dominant peak in the signal spectrum of AF episodes with atrial bipolar electrograms. Patients with complete progression of AER, from paroxysmal AF episodes to electrically remodelled persistent AF, were used to depict patient-specific AER slopes. A total of 34 712 AF tracings from 830 patients (87 with pacemakers) were suitable for the study. Complete progression of AER was documented in 216 patients (16 with pacemakers). Patients with persistent AF after completion of AER showed 30% faster AAR than patients with paroxysmal AF. The slope of AAR changes during AF progression revealed patient-specific patterns that correlated with the time-to-completion of AER (R2 = 0.85). Pacemaker * Corresponding author. Tel: þ34 914531200 (Ext. 1510); fax: þ34 914531265. E-mail address: david.filgueiras@cnic.es † Both authors contributed equally. C The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Monitoring of electrical remodelling during AF progression 705 patients were older than patients with ICD/CRT-Ds (78.3 vs. 67.2 year olds, respectively, P < 0.001) and had a shorter median time-to-completion of AER (24.9 vs. 93.5 days, respectively, P = 0.016). Remote transmissions in patients with ICD/CRT-D devices enabled the estimation of the time-to-completion of AER using the predicted slope of AAR changes from initiation to completion of electrical remodelling (R2 = 0.45). ................................................................................................................................................................................................... Conclusion The AF progression shows patient-specific patterns of AER, which can be estimated using available remote- monitoring technology. 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 Keywords Atrial fibrillation • Atrial fibrillation progression • Electrical remodeling • Implantable cardioverter-defibrillator • eHealth • Telemedicine • Mobile health Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 diagnostic and therapeutic implications in the clinic, it has not been What’s new? demonstrated that AER also follows patient-specific patterns. • Current remote-monitoring technology in implantable devices We tested the hypothesis that AAR changes during AF progres- enables the identification of patient-specific slopes of atrial sion show patient-specific patterns that can be estimated using electrical remodelling (AER) during atrial fibrillation (AF) clinical variables and remote-monitoring tracings from implantable progression. devices. We aimed to study AARs and the time-course of AER • Time-to-completion of AER can be estimated using the com- progression using bipolar AF recordings obtained from two popula- puted patient-specific slope of atrial activation rate changes tions of patients with implantable cardioverter-defibrillatorþ/re and the underlying cardiac condition. synchronization therapy (ICD/CRT-D) and pacemaker devices. We • The results represent a step forward in monitoring the pro- also aimed to study the effect of the underlying clinical conditions on gression of AER, which may further assist physicians in the the AER process of AF. stratification and personalized care of patients with AF. Introduction Methods Atrial fibrillation (AF) is currently considered a growing and inevitable Study design worldwide epidemic with important economic and social burden.1,2 The ICD/CRT-D data were obtained from an observational multi- Atrial fibrillation diagnosis is simple when using non-invasive surface centre registry from 51 Spanish centres included in the UMBRELLA electrocardiographic (ECG) recordings,3 although can also be study (NCT01561144 at clinicaltrials.gov). This database is supported obtained from intracardiac atrial recordings in patients with implant- by the scientific co-operation platform, which is a cloud-based big- able devices and atrial leads.4 Characteristically, both surface and in- data tool that enables automatic and non-invasive data transmission tracardiac AF tracings will show fast atrial activation rate (AAR) and with digitally structured storage. The database consisted of 4618 irregular activity.3,4 patients undergoing a Medtronic (Tolochenaz, Switzerland) ICD/ Atrial fibrillation is often a progressive cardiac arrhythmia from CRT-D implantation from August 2011 to November 2017. A total of short-lasting episodes to long-standing persistent episodes,3 which 2074 patients with dual-chamber ICD/CRT-D devices and remote- monitoring transmissions were considered for the study. Pacemaker increases the risk of hospitalization and adverse cardiovascular data were obtained from a retrospective observational study in two events.5 Atrial fibrillation itself induces progressive functional and Spanish centres. All patients undergoing a dual-chamber Microport structural changes in the atrial myocardium that facilitate long-term (Clamart, France) pacemaker implantation from December 2009 to perpetuation of the arrhythmia.6 Concomitant genetic and cardiovas- December 2018 were considered for the study. Atrial leads were rou- cular conditions also establish an underlying substrate favouring AF tinely implanted in the right atrial appendage. Figure 1 shows the study initiation and perpetuation,2 although they do not provide informa- flow chart. tion about individualized progression of AF remodelling as the ar- We obtained ethics committee approval for both ICD/CRT-D and rhythmia persists. pacemaker series in accordance with the Helsinki Declaration. All Initially, AF provokes ion channel changes leading to shortening of patients signed an informed consent. In patients with ICD/CRT-D devi- the action potential duration and progressively faster AAR until ces, clinical baseline and demographic data were retrospectively collected reaching a complete electrically remodelled state.6,7 As AF evolves at the time of device implantation using the official data collection sheet from the Spanish Society of Cardiology (see also Supplementary material other mechanical and structural changes also progressively develop,6 online). In cases with device replacement during follow-up, the baseline which further decrease the probability of achieving a successful data were selected using the data collection that was closest to the initia- rhythm control strategy.8 Interestingly, in translational animal models tion of AF history. In pacemaker patients, clinical data and pharmacologi- of persistent AF, the time-course of atrial electrical remodelling cal history were obtained from electronic medical records during the (AER) has been shown to present distinct progression from animal follow-up period. In these patients, left atrial (LA) diameter was also mea- to animal,6 whose remodelling slopes are sensitive to the effect of sured using transthoracic echocardiography and a parasternal long-axis pharmacological treatment.7 Although monitoring AER may have view. 706 J.M. Lillo-Castellano et al. PACEMAKER ICD/CRT-D (No remote transmissions) 51 hospitals 2 hospitals 4618 patients 352 patients 185 401 ICD/CRT-D tracings EXCLUDED EXCLUDED - Lack of remote monitoring (n = 322) - Lack of atrial arrhythmia - Single chamber ICD (n = 2027) (n = 192) - CRT-D without atrial lead (n = 195) Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 2074 patients 160 patients Dual chamber ICD (n = 972) Dual chamber device (n = 160) CRT-D with atrial lead (1297) CRT-P device (n = 0) EXCLUDED - Lack of AF episodes (n = 707) EXCLUDED - Lack of AF episodes (n = 65) - Tracing artefacts (n = 8) 1367 patients 51672 ICD/CRT-D tracings 87 patients EXCLUDED 794 pacemaker tracings - Lack of atrial bipolar (tip-ring) tracings (n = 624) 743 patients 33918 ICD/CRT-D bipolar atrial tracings PAROXYSMAL AF PERSISTENT AF ICD/CRT-D PACEMAKER ICD/CRT-D PACEMAKER 427 patients 61 patients 116 patients 10 patients 15318 atrial tracings 492 atrial tracings 5683 atrial tracings 38 atrial tracings ELECTRICAL REMODELLING PROGRESSION 200 patients 16 patients 12 737 atrial tracings 264 atrial tracings EARLY ELECTRICAL COMPLETE ELECTRICAL REMODELLING STAGES REMODELLING Figure 1 Study flow chart. AF, atrial fibrillation; CRT-D/P, cardiac resynchronization therapy plus defibrillator/pacemaker; ICD, implantable cardi- overter-defibrillator. Data selection and rhythm classification remote-monitoring transmissions. Stored pacemaker tracings obtained at The UMBRELLA scientific committee initially reviewed and classified the time of regular device interrogations were reviewed using the same 27461 ICD/CRT-D stored episodes registered in a digital two-channel software tool. Poor signal quality tracings were excluded from the study electrogram format. Three independent investigators used a custom- during the review process. Then, all AF tracings with a bipolar lead config- made Java-based software tool (Standard Edition 8, Oracle, Redwood, uration (tip-ring; Figure 2A), overt irregular and fast activation rates >3 Hz, CA, USA) to further review and classify 31 672 tracings obtained from and >_3-s long recordings were included in the study. Manual selection of Monitoring of electrical remodelling during AF progression 707 Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 Figure 2 Sample signal processing and representation of the time-course of AER. (A) Schematic representation of a dual-chamber implantable car- dioverter-defibrillator to obtain atrial bipolar electrograms during AF episodes. (B) Sample time-course of AAR during AF progression from early stages of AER (light green background colour) with paroxysmal AF episodes to completion of AER in persistent AF (red light background colour). (C) Sample tracings from downward arrows in B that represent different stages of AER. (D) Power spectra and DF values associated with the sample trac- ings in C. AAR, atrial activation rate; AER, atrial electrical remodelling; AF, atrial fibrillation; DF, dominant frequency. AF segments was performed in tracings with documented AF termination 10 Hz was normalized to the amplitude of the highest spectral peak at the end of the tracing. Signal artefacts were manually excluded if within this band. The dominant frequency (DF) was defined as the fre- necessary. quency with the highest power within this band. The DF value for each Selected AF tracings were further classified as paroxysmal or persis- AF tracing was reviewed to detect potential harmonic peaks, and if tent AF based on the recorded episode duration. In pacemaker patients, needed, it was manually corrected to the estimated average local AAR us- further confirmation of AF classification was obtained from clinical ing a custom-made Java tool. Thus, the DF peak provided a robust and records. Atrial fibrillation episodes lasting <7 days were classified as par- rapid calculation of the reciprocal average local activation intervals [esti- oxysmal AF and episodes lasting >_7 days as persistent AF.3 In ICD/CRT- mated average cycle length (ms) = [(1/DF)  1000]; Figure 2B–D]. D patients, AF tracings without episode duration were classified using subsequent recordings in a way that two or more consecutive remote transmissions documenting AF, at least 7 days apart, were considered as Time-course analysis of atrial electrical persistent AF. remodelling The DF-derived AARs were ordered by date to depict any changes Computation of atrial activation rates during the follow-up period (Figure 2B). Then, patients with progres- Atrial signals from stored episodes (ICD/CRT-Ds and pacemakers) were sion of AER from paroxysmal AF episodes (AER remodelling not pre- obtained at 128 Hz and data from remote transmissions (ICD/CRT-Ds sent or incomplete) to persistent AF episodes with complete only) were obtained at 256 Hz. Signals were high-pass filtered with cut- electrical remodelling were used to plot remodelling slopes. Pre- and off frequency of 0.5 Hz. The median duration of AF tracings per patient post-electrical remodelling segments were manually selected using a was 9.6 [5.03, 10.00] s in ICD/CRT-D devices and 14.6 [10.6, 19.7] s in custom-made Java tool. Because atrial activations during AF are irregu- pacemakers. Local right AAR was computed using spectral analysis and lar and DF values may slightly vary during consecutive tracings, we the fast Fourier transform to convert the tracing into the frequency do- used median DF values during the pre- and post-remodelling phases main as reported elsewhere.6 Specifically, we used the non-parametric to compute the difference between the two stages. Then, the slope Welch method for power spectrum estimation with a median spectral of AER was computed automatically by fitting the DF values to a lin- resolution per patient of 0.10 [0.06, 0.24] Hz and 0.07 [0.05, 0.09] Hz in ear regression function dependent on both the median DF values and ICD/CRT-Ds and pacemakers, respectively. Spectral information below the documented date of initiation and completion of AER (Figure 2B). 708 J.M. Lillo-Castellano et al. Statistical analysis intermediate period between them. This increase in AAR was pre- All data are presented as median and inter-quartile range [25th, 75th per- sent in both pacemaker and ICD/CRT-D populations, although pace- centiles], except where noted. Normal distribution of variables was maker patients showed slower AAR during paroxysmal AF episodes assessed with the Shapiro–Wilk test. Statistical significance was assessed compared with ICD/CRT-D patients (4.12 [3.64, 4.53] Hz vs. 4.63 by the T-test or the Mann–Whitney–Wilcoxon test, as appropriate. The [4.07, 5.34] Hz, respectively, P < 0.001). These differences were not ANOVA or the Kruskal–Wallis test was used for three- to four-group documented after completion of AER in persistent AF (Figure 3C). comparisons according to data distribution. Categorical variables were Moreover, in the pacemaker population, echocardiography data compared using the v2 test. The log() function was used to transform showed a progression in structural remodelling reflected by a signifi- the exponential nature of the time-to-completion of AER distribution to cantly larger LA diameter after completion of AER compared with a normally distributed variable. Pearson’s correlation coefficient (R2) was early electrical remodelling stages (50 [40, 56] mm vs. 38 [41, 45] used for correlation analysis between continuous variables and DF values during persistent AF. A P-value of <0.05 was considered statistically mm, P = 0.006; Figure 3D). significant. More specific analysis of AARs in patients with an ICD or CRT-D Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 The large series of patients with ICD/CRT-D devices was used to device and complete monitoring of AER (n = 200) showed that AARs study the predictive value of clinical variables to establish the time-to- during paroxysmal AF episodes were significantly slower in CRT-D completion of AER, by means of univariate analysis and a multivariate patients compared with ICD patients (4.15 [3.48, 4.80] Hz vs. 4.45 stepwise linear regression model. Then, we developed a computational [3.81, 5.25] Hz, respectively, P = 0.005). However, these differences method using remote-monitoring tracings to estimate patient-specific were not statistically significant after completion of AER in persistent times-to-completion of AER. First, all variables statistically associated AF (Supplementary material online, Figure S1). Biventricular capture with DF values during persistent AF were included in a multivariate step- in CRT-D patients was 95.4 [89.3, 99.0] %. In the pacemaker popula- wise linear regression model to predict AAR during persistent AF after tion, we also documented a trend to slower AARs under Class I/III completion of AER. Then, for each patient, the time-to-completion of antiarrhythmic drugs (Supplementary material online, Figure S2). AER was estimated using the predicted values of AAR after completion of the AER process and the computed slope at 25% of the expected change in AAR from paroxysmal AF to complete electrical remodelling in Prediction of atrial activation rates after persistent AF. The analyses were carried out using SPSS v21 (IBM Corp, completion of atrial electrical New York, NY, USA) and custom Matlab (MathWorks Inc., Natick, MA, remodelling USA) scripts for mathematical assistance. In ICD/CRT-D patients with complete monitoring of AER, there was a statistically significant correlation between AARs during paroxysmal AF and at the completion of AER in persistent AF (R2 = 0.424, Results P < 0.001; Figure 4A). Thus, the slower the AAR during paroxysmal A total of 34 712 AF tracings from 830 patients (87 with pacemakers) AF, the slower the expected AAR after completion of AER. were suitable for the study. Patients with pacemakers showed a simi- Moreover, AARs after completion of AER were significantly lower in lar follow-up period to ICD/CRT-D patients (3.4 [1.7, 5.3] and 3.4 patients with ICM compared with patients with DCM or other struc- [1.9, 4.3] years, respectively), although the former were significantly tural cardiomyopathies (6.30 [5.60, 6.70] Hz vs. 6.48 [5.96, 7.20] Hz, older (78.3 [73.1, 85.3] vs. 67.2 [59.3, 73.7] year old, P < 0.001, re- and vs. 6.93 [5.61, 7.45] Hz, respectively, P = 0.015 and P = 0.036, re- spectively) and had a predominant left ventricular ejection fraction spectively; Figure 4B). Left ventricular ejection fraction <_35% was also (LVEF) >35%. Table 1 shows baseline clinical characteristics and com- associated with lower AARs compared with LVEF >35% (6.30 [5.61, parisons between pacemaker and ICD/CRT-D populations. 6.79] Hz vs. 6.84 [5.72, 7.38] Hz, respectively, P = 0.013). Table 3 Complete progression of AER from pre-remodelling to complete shows the univariate analysis of baseline clinical characteristics and remodelling in persistent AF was documented in 216 patients (16 any statistically significant association with AAR values during persis- with pacemakers). Other 543 patients in the ICD/CRT-D population tent AF after completion of AER. Importantly, a predictive model us- and 71 patients in the pacemaker population were classified as parox- ing the underlying cardiac condition and the AAR during early stages ysmal (no progression to persistent AF during the follow-up) or per- of AER in paroxysmal AF significantly correlated with AAR values af- sistent AF (repeated transmissions in AF during the follow-up; ter completion of AER in persistent AF (Table 4; R2 = 0.460). Figure 1). The ICD/CRT-D indication was for primary prevention in the majority of patients (71.7%) and the underlying myocardial sub- Atrial fibrillation progression shows strates were mainly ischaemic cardiomyopathy (ICM, 50.6%) and patient-specific patterns of electrical non-ischaemic dilated cardiomyopathy (DCM, 33.2%), with a LVEF remodelling <_35% in 73.4% of patients (Table 2). The log(slope) of AARs during AF progression showed patient- specific patterns that strongly correlated with the log(time-to- Atrial fibrillation stage determines atrial completion of AER), both in the ICD/CRT-D and pacemaker popula- activation rates and structural changes tions (R2 = 0.852 and R2 = 0.853, respectively; P < 0.001; Figure 4C Patients with paroxysmal AF showed slower AAR than patients with and Supplementary material online, Figure S3). Using the large popula- persistent AF. Two representative cases are shown in Figure 3A, B. tion of patients with ICD/CRT-D devices, univariate analysis of base- Overall, AAR was 30% higher after completion of AER compared line clinical variables showed that only the presence of left bundle with pre-remodelling stages in paroxysmal AF (Figure 3C). The data branch block (P = 0.036) was associated with the time-to-completion reflect the presence of two electrical remodelling stages with an of AER (Supplementary material online, Table S1). However, Monitoring of electrical remodelling during AF progression 709 Table 1 Baseline clinical and demographic characteristics of implantable cardioverter-defibrillator 1/2resynchronization therapy and pacemaker populations Clinical characteristics ICD/CRT-D (n 5 743) Pacemaker (n 5 87) P-value .................................................................................................................................................................................................................... Age (years), n (median [IQR]) 67.2 [59.3, 73.7] 78.3 [73.1, 85.3] <0.001 Male, n (%) 609 (82.0) 51 (58.6) <0.001 Cardiomyopathy, n (%) <0.001 ICM 376 (50.6) 19 (21.8) DCM 247 (33.2) 1 (1.1) Other SCM: HCM, ARVC, VHD, or CHD 97 (13.1) 3 (3.4) Non-structural arrhythmogenic disease 23 (3.1) 0 (0.0) Non-cardiomyopathy 0 (0) 64 (73.6) Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 LBBB, n (%) 334 (45.6) 12 (13.8) <0.001 LVEF (<_35%), n (%) 544 (73.4) 4 (4.6) <0.001 Functional class, n (%) <0.001 NYHA I 119 (18.2) 34 (39.5) NYHA II 288 (44.0) 41 (47.7) NYHA III 235 (35.9) 10 (11.6) NYHA IV 12 (1.8) 1 (1.2) Clinical history, n (%) Hypertension 434 (59.9) 77 (88.5) <0.001 Diabetes mellitus 227 (31.2) 25 (28.7) 0.641 Hyperlipidaemia 388 (54.6) 50 (57.5) 0.608 Current smoking 206 (30.2) 5 (5.7) <0.001 Chronic renal failure 143 (20.0) 12 (13.8) 0.168 Previous stroke or TIA 50 (7.5) 6 (6.9) 0.852 Medications during the AF period, n (%) b-blocker – 40 (46.0) ACE-inhibitor/ARB – 61 (70.1) Verapamil/diltiazem – 6 (6.9) Mineralocorticoid receptor antagonist – 9 (10.3) Statins – 52 (59.8) Class I antiarrhythmic drug – 8 (9.2) Class III antiarrhythmic drug – 9 (10.3) Anticoagulant – 58 (66.7) Bold values highlight statistical significance. ACE, angiotensin-converting-enzyme; AF, atrial fibrillation; ARB, angiotensin-receptor blocker; ARVC, arrhythmogenic right ventricu- lar cardiomyopathy; CHD, congenital heart disease; DCM, non-ischaemic dilated cardiomyopathy; ICD/CRT-D, implantable cardioverter-defibrillatorþ/resynchronization therapy; ICM, ischaemic cardiomyopathy; HCM, hypertrophic cardiomyopathy; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; SCM, structural cardio- myopathy; TIA, transient ischaemic attack; VHD, valvular heart disease. multivariate analysis did not identify any statistically significant associa- pacemakers (24.9 [14.3, 108.2] d vs. 93.5 [36.6, 190.5] d, respectively; tion of clinical variables with the time-to-completion of AER. P = 0.016; Figure 4F). Despite limitations to identify the underlying Importantly, patient-specific time-to-completion of AER could be causes of such differences, older ages in the pacemaker population estimated in a subset of the ICD/CRT-D population (n = 51) with may be involved (Table 1). remote-monitored AF tracings. Thus, the predicted value of AARs at the completion of the AER process and the computed slope at 25% of the expected change in AARs, from paroxysmal AF to complete Discussion electrical remodelling in persistent AF, correlated with the time-to- completion of AER (R2 = 0.458; Figure 4D, E and Supplementary ma- We studied the time-course of AER in two populations of patients terial online, Figure S4). Error quantification of the estimated with implantable devices during AF progression. Patients with parox- log(time-to-completion of AER) showed a median value of 33.56% ysmal and persistent AF showed significantly different AARs, with [12.72, 57.06]. faster activation rates during persistent AF after completion of AER. Further comparisons between the pacemaker population and We have identified that AAR after completion of AER could be pre- patients with ICD/CRT-D devices showed that the time-to- dicted using the underlying cardiac condition and the AAR during completion of AER was significantly shorter in patients with paroxysmal AF. Moreover, we have documented patient-specific 710 J.M. Lillo-Castellano et al. Table 2 Baseline clinical and demographic characteristics of patients with implantable cardioverter-defibrillator 1/2resynchronization therapy devices in different atrial fibrillation groups Clinical characteristics Paroxysmal AF Complete AER Persistent AF P-value (n 5 427) progression (n 5 200) (n 5 116) .................................................................................................................................................................................................................... Age (years), median [IQR] 66.2 [58.1, 72.9] 67.9 [58.1, 74.5] 69.3 [62.7, 75.3] 0.005 Male, n (%) 334 (78.2) 178 (89.0) 97 (83.6) 0.004 Cardiomyopathy, n (%) 0.575 ICM 214 (50.1) 101 (50.5) 61 (52.6) DCM 141 (33.0) 68 (34.0) 38 (32.8) Other SCM: HCM, ARVC, VHD, or CHD 55 (12.9) 29 (14.5) 13 (11.2) Non-structural arrhythmogenic disease 17 (4.0) 2 (1.0) 4 (3.4) Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 LBBB, n (%) 195 (46.5) 84 (42.0) 55 (48.7) 0.444 LVEF (<_35%), n (%) 303 (71.1) 147 (73.5) 94 (81.7) 0.073 Functional class, n (%) 0.073 NYHA I 79 (21.6) 30 (16.8) 10 (9.1) NYHA II 156 (42.7) 80 (44.7) 52 (47.3) NYHA III 124 (34.0) 67 (37.4) 44 (40.0) NYHA IV 6 (1.6) 2 (1.1) 4 (3.6) Clinical history, n (%) Hypertension 244 (59.2) 120 (61.2) 70 (60.3) 0.891 Diabetes mellitus 134 (32.5) 57 (28.5) 36 (31.0) 0.601 Hyperlipidaemia 220 (55.1) 110 (55.0) 58 (51.8) 0.812 Current smoking 127 (32.5) 53 (28.8) 26 (24.5) 0.253 Chronic renal failure 73 (18.0) 44 (22.6) 26 (22.6) 0.312 Previous stroke or TIA 24 (6.3) 16 (8.7) 10 (9.1) 0.464 Clinical presentation, n (%) Asymptomatic 184 (44.0) 92 (46.5) 44 (39.3) 0.473 Syncope 68 (16.3) 32 (16.2) 18 (16.1) 0.999 Sudden cardiac death 40 (9.6) 15 (7.6) 7 (6.3) 0.459 Primary prevention, n (%) 305 (71.4) 143 (71.5) 85 (73.3) 0.923 Device type (ICD), n (%) 229 (53.6) 91 (45.5) 41 (35.3) <0.001 ACE, angiotensin-converting-enzyme; AF, atrial fibrillation; ARB, angiotensin-receptor blocker; ARVC, arrhythmogenic right ventricular cardiomyopathy; CHD, congenital heart disease; DCM, non-ischaemic dilated cardiomyopathy; ICD/CRT-D, implantable cardioverter-defibrillatorþ/resynchronization therapy; ICM, ischaemic cardiomyopathy; HCM, hypertrophic cardiomyopathy; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; SCM, structural cardiomyopathy; TIA, transient ischaemic attack; VHD, valvular heart disease. patterns of time-to-completion AER, which were significantly faster also associated with atrial diastolic dysfunction and increased LA in the older population of patients with pacemakers compared with pressures.10 Therefore, atrial stretch may represent the cause of the ICD/CRT-D population. Individual patterns of AER progression faster AARs in patients with other structural cardiomyopathies com- could be estimated using the predicted values of AAR at the comple- pared with patients with ICM. Although patients with ICM can also tion of the AER process and the computed slope at 25% of the have increased intracavitary pressures,11 infarct-related scar tissue expected change in AAR from the initiation to complete electrical may affect atrial activation and potentially decrease AAR. The latter remodelling in persistent AF. would be consistent with the study by Swartz et al.12 showing an in- The influence of the underlying cardiac condition and therapies verse correlation between LA fibrosis and LA activation frequencies. (e.g. CRT-D) on AARs may represent different predominant mecha- This is also consistent with our data from patients with pacemakers; a nisms affecting atrial electrophysiology. Yoshida et al.9 have reported more advanced age in this population justifies higher levels of under- a direct relationship between LA pressure and the DF of AF at the lying atrial fibrosis and significantly slower AAR during paroxysmal AF LA appendage. Thus, atrial stretch in the presence of increased intra- compared with the ICD/CRT-D population. At the cellular level, the cavitary pressures may lead to faster AARs as we have documented myofibroblast/myocyte ratio in two-dimensional cardiac monolayers in patients with DCM. Slower AARs during paroxysmal AF episodes has also shown an inverse relationship with activation frequencies of in patients with CRT-D compared with ICD patients may also reflect re-entrant activity.13 an improvement in cardiac haemodynamic status upon resynchroni- The data demonstrate the potential of personalized monitoring of zation therapy. Interestingly, the majority of patients with other struc- AARs as a marker of electrical remodelling during AF progression. tural cardiomyopathies had hypertrophic cardiomyopathy, which is Moreover, regardless of the current classification of paroxysmal vs. Monitoring of electrical remodelling during AF progression 711 Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 Figure 3 Atrial activation rates during paroxysmal and persistent AF and associated structural changes. (A, B) Left panels show the time-course of AAR during paroxysmal and persistent AF. Right panels show sample AF tracings at downward arrows. Light green and red background colours indi- cate early and complete AER stages, respectively. (C) Box plots and comparisons of AAR during paroxysmal (pre-AER) and persistent AF (complete AER) between patients with ICD/CRT-D and pacemaker devices. (D) Box plots and comparison of left atrial diameters between pre-AER and com- plete AER stages. Box plot data show median and inter-quartile ranges. Central dots inside the box plots show the mean. AAR, atrial activation rate; AER, atrial electrical remodelling; AF, atrial fibrillation; ICD/CRT-D, implantable cardioverter-defibrillatorþ/resynchronization therapy. persistent AF, which does not provide accurate information about recurrences, which suggests that within the same time period slower the underlying remodelling stage, our approach to assess the pro- progression of AER will lead to slower AARs and higher probability gression and stage of AER may have important therapeutic and prog- of sinus rhythm maintenance. Bollman et al.15 have also shown that nostic implications. Lankveld et al.14 have documented that slower single ECG-derived atrial fibrillatory frequencies of 5.9 Hz in patients AARs on single surface ECG recordings of patients with persistent with persistent AF were associated with successful pharmacological AF undergoing electrical cardioversion were associated with sinus cardioversion. Conversely, mean atrial fibrillatory frequencies of rhythm maintenance after 1 year of follow-up. Interestingly, the mean 6.4 Hz did associate with unsuccessful pharmacological cardioversion, episode duration was 3 months in patients with and without AF while mean episode duration (4 to 6 months) was not significantly 712 J.M. Lillo-Castellano et al. Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 Figure 4 Monitoring and prediction of time-to-completion of AER. (A) Scatter-plot of AAR during paroxysmal (pre-AER stage) AF and after com- pletion of AER in persistent AF. Each black dot represents an individual patient. The diagonal dashed line represents the line of equality. (B) Box plots and comparisons of AAR during persistent AF among patients with ICM, DCM, and other SCM. (C) Log(slope) correlation with log(time-to-comple- tion AER). (D) Correlation of predicted and actual log(time-to-completion of AER). (E) Sample case with the predicted and actual times-to-comple- tion of AER. (F) Box plots and comparison of time-to-completion of AER between the ICD/CRT-D and pacemaker populations. All panels, but F shows data from the ICD/CRT-D population. P25th, P50th, P75th, P100th in panels C, D indicate percentiles. AAR, atrial activation rate; AER, atrial electrical remodelling; AF, atrial fibrillation; DCM, non-ischaemic dilated cardiomyopathy; ICD/CRT-D, implantable cardioverter-defibrillatorþ/ resynchronization therapy; ICM, ischaemic cardiomyopathy; SCM, structural cardiomyopathies. different between the two groups. Data from ablation procedures DF values were mainly present in AF episodes with duration have also documented the role of ECG-based parameters to predict <12 months. The latter is consistent with our data in which the ma- AF termination during the procedure and long-term freedom from jority of patients in the ICD/CRT-D population (n = 150, 75th per- AF. Using a retrospective cohort of patients undergoing persistent centile) showed complete electrical remodelling after 191 days of AF ablation, Lankveld et al.16 could document that DF values <6.0 Hz remodelling initiation. were frequently associated with AF termination during the ablation Remote monitoring of different cardiac conditions has already procedure, along with long-term freedom from the arrhythmia. Such demonstrated an impact on clinical outcomes, health care utilization Monitoring of electrical remodelling during AF progression 713 Table 3 Univariate analysis of variables potentially associated with atrial activation rates during persistent atrial fibril- lation after completion of atrial electrical redemolling Clinical characteristics No Yes P-value/R2 .................................................................................................................................................................................................................... Age 0.002/0.047 Male, n (Hz) 22 (6.29) 178 (6.40) 0.925/ Cardiomyopathy, n (Hz) 0.008/ ICM 101 (6.30) DCM 68 (6.48) Other SCM: HCM, ARVC, VHD, or CHD 29 (6.93) Non-structural arrhythmogenic disease 2 (7.76) LBBB, n (Hz) 116 (6.40) 84 (6.28) 0.536/– Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 LVEF (<_35%), n (Hz) 53 (6.84) 147 (6.30) 0.013/– Functional class, n (Hz) 0.194/– NYHA I 30 (6.60) NYHA II 80 (6.39) NYHA III 67 (6.30) NYHA IV 2 (5.26) Clinical history, n (Hz) Hypertension 76 (6.31) 120 (6.39) 0.930/– Diabetes mellitus 143 (6.40) 57 (6.30) 0.314/– Hyperlipidaemia 90 (6.47) 110 (6.28) 0.136/– Current smoking 131 (6.28) 53 (6.50) 0.169/– Chronic renal failure 151 (6.30) 44 (6.43) 0.671/– Previous stroke or TIA 167 (6.30) 16 (6.86) 0.242/– Clinical presentation, n (Hz) Asymptomatic 106 (6.27) 92 (6.42) 0.263/– Syncope 166 (6.40) 32 (6.30) 0.900/– Sudden cardiac death 183 (6.36) 15 (6.50) 0.787/– Primary prevention, n (Hz) 57 (6.32) 143 (6.40) 0.926/– Device type (ICD), n (Hz) 109 (6.30) 91 (6.44) 0.118/– AAR during paroxysmal AF <0.001/0.424 Data are shown as the number of patients (n) and the median AAR during persistent AF after completion of AER (in Hz). AAR, atrial activation rate; ACE, angiotensin-converting-enzyme; AER, atrial electrical remodelling; AF, atrial fibrillation; ARB, angiotensin-receptor blocker; ARVC, arrhythmo- genic right ventricular cardiomyopathy; CHD, congenital heart disease; DCM, non-ischaemic dilated cardiomyopathy; ICD/CRT-D, implantable cardioverter-defibrillator þ/resynchronization therapy; ICM, ischaemic cardiomyopathy; HCM, hypertrophic cardiomyopathy; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; SCM, structural cardiomyopathy; TIA, transient ischaemic attack; VHD, valvular heart disease. Table 4 Predictive model of atrial activation rates during persistent atrial fibrillation after completion of atrial electri- cal remodelling Estimate Standard error t-statistic P-value .................................................................................................................................................................................................................... Intercept 2.947 0.270 10.923 <0.0001 Cardiomyopathy 0.258 0.071 3.6311 <0.0001 AAR during paroxysmal AF 0.675 0.056 12.150 <0.0001 R2 0.460 AAR, atrial activation rate; AF, atrial fibrillation. and expenditures.17 Continuous ECG monitoring with implantable therapeutic interventions are warranted. Our data represent one cardiac monitors has also demonstrated that AF detection can be step forward in AF monitoring to detect both the electrical remodel- substantially improved in patients at high risk of both AF and stroke.18 ling stage during AF episodes and the progression rate of AER as AF However, despite the potential impact of early AF detection on clini- evolves. These two aspects may potentially assist physicians in per- cal outcomes as rhythm control or stroke, data from trials with early sonalized care of patients with AF and implantable devices; e.g. 714 J.M. Lillo-Castellano et al. adjusting medical therapy and further monitoring its effects or pro- implementation in implantable devices or remote-monitoring plat- posing an early interventional ablation procedure before completion forms to validate the impact in prospective series. of AER. We have obtained AARs from intracardiac bipolar tracings, which provided local activation rates from the right atrium. However, remodelling progression could also be monitored using single-lead Conclusion ECG tracings after QRS-T subtraction as it has been performed in an- Atrial fibrillation progression shows patient-specific patterns of AER, imal models of long-standing persistent AF.6 The latter opens new di- which can be estimated using the computed individual slope of AAR agnostic options for monitoring AF progression using non-invasive changes and the underlying cardiac condition. long-term recording devices such as smart watches or wearable Holter ECG, which would require implementing appropriate algo- rithms for QRS-T subtraction and optimization of remote transmis- Supplementary material Downloaded from https://academic.oup.com/europace/article/22/5/704/5678518 by guest on 27 October 2023 sions once AF is detected. Importantly, AF is an irregular rhythm with variations in local AAR within specific time windows.4 Therefore, a Supplementary material is available at Europace online. single ECG tracing or DF value may not represent an accurate mea- surement of AAR compared with repeating measurements for the same day. In patients with complete monitoring of AER in the ICD/ Acknowledegments CRT-D population, we have used a median of 64 [34, 122] AF trac- We thank the UMBRELLA study (NCT01561144 at clinicaltrials.gov) ings per patient, which minimized this potential limitation. Moreover, and the scientific co-operation platform for providing a valuable estimated slope calculations were performed using median DF values source of data to independent investigators in Spain. We thank for repeating tracings from the same day. The latter could be further Stuart Pocock for his statistical advice. improved using algorithms that can store reliable DF values or aver- Conflict of interest: none declared. age atrial activation cycle lengths using repeating samples from the same day. The DF values will have the advantage of providing a rapid Funding measurement with no need for detecting individual activations, which The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is sup- may be challenging in the presence of fragmented electrograms or ported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de low amplitude signals.19,20 In fact, low fibrillatory wave amplitudes are Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC commonly present in long-standing AF episodes.16 Conversely, DF Foundation and is a Severo Ochoa Center of Excellence (SEV-2015– values may be affected by harmonic peaks, which may require im- 0505). This study was supported by grants from the Fondo Europeo de proved algorithms or additional revision by the physician using repre- Desarrollo Regional (CB16/11/00458) and the Spanish MCNU (SAF2016- sentative tracings that could be transmitted to a cloud-based data 80324-R). The study was also partially supported by the Fundación tool and avoid compromising devices’ battery longevity. Interhospitalaria para la Investigación Cardiovascular (FIC, Madrid, Spain) and the Heart Rhythm Association of the Spanish Society of Cardiology Limitations (D.F.-R., J.J.G.-F.). J.J. is supported by R01 Grant HL122352 from the National Heart Lung and Blood Institute, USA National Institutes of The design of the study did not enable us to obtain remote-monitor- Health. ing transmissions using specific criteria, which could have improved the estimation of AER slopes. This limitation was more relevant in pacemaker devices, in which remote transmissions were not available References 1. 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Upper loop re-entry atrial flutter with its critical isthmus identified in the vicinity of his bundle Tomoki Watanabe, Nobuhiro Takasugi *, Genki Naruse, and Hiroyuki Okura Division of Cardiovascular Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan * Corresponding author. Tel: 181 58 230 6523; fax: 181 58 230 6524. E-mail address: sunanezumi417@yahoo.co.jp A 62-year-old man with a history of mitral valve repair and cavotricuspid isthmus ablation underwent catheter ablation for persistent atrial flutter. The right atrial activation and voltage maps during the flutter demonstrated its re-entry circuit rotating around the superior vena cava (SVC) and a linear scar in the anteroseptal wall (Upper Panel). The scar contained a small area of preserved voltage near the tricuspid valve annulus (dashed arrows). The low- voltage fractionated potentials lasting 100 ms, sug- gesting an area of slow conduction, and His poten- tials were simultaneously recorded in the grid mapping catheter (Lower Panel). Concealed entrain- ment was demonstrated by pacing from multiple sites around the SVC, leading to a diagnosis of upper loop re-entry (ULR). A single radiofrequency appli- cation at the slow conduction area, 15 mm supero- lateral to the site recording the His potential (white tags), successfully terminated the flutter. Upper loop re-entry is a rare form of atypical atrial flutter and an area of slow conduction exists in the crista terminalis. Our case suggests that an area of slow conduction in the ULR does not always exist in the crista terminalis and that a detailed voltage map may be helpful to determine the site at which ablation should be performed. The full-length version of this report can be viewed at: https://www.escardio.org/Education/E-Learning/Clinical-cases/Electrophysiology. Published on behalf of the European Society of Cardiology. All rights reserved. V C The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.