The atrial fibrillation burden during the blanking period is predictive of time to recurrence after catheter ablation

IJC Hea & Vascula u e 43 (2022) 101138 A ailable online 14 Oc obe 2022 2352-9067/© 2022 The Au ho s. Published by Else ie B.V. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by- nc-nd/4.0/). The a ial ib illa ion bu den du ing he blanking pe iod is p edic i e o ime o ecu ence a e ca he e abla ion Ped o Sil a Cunha a , b , * , 1 , Guilhe me Po ugal a , b , 1 , S´ e gio La anjo a , c , d , 1 , Ma a Al es c , e , 1 , Ana Luísa Papoila c , e , 1 , B uno Valen e a , 1 , Ana So ia Delgado a , 1 , Ana Lousinha a , 1 , Ma ga ida Paulo a , 1 , Manuel B ´ as a , 1 , C´ a ia Gue a a , 1 , Rui C uz Fe ei a a , 1 , M´ a io Ma ins Oli ei a a , b , 1 a A hy hmology, Pacing and Elec ophysiology Uni , Ca diology Se ice, San a Ma a Hospi al, Cen o Hospi ala Uni e si ´ a io de Lisboa Cen al, Lisbon, Po ugal b LisbonSchool o Medicine, Uni e sidade de Lisboa, Lisbon, Po ugal c NOVAMedical School/Faculdade de Ciˆ encias M´ edicas, Uni e sidade No a de Lisboa and CEAUL (Cen e o S a is ics and I s Applica ions), Lisbon, Po ugal d Comp ehensi eHeal h Resea ch Cen e , Uni e sidade NOVA de Lisboa, Lisbon, Po ugal e Epidemiology and S a is ics Uni , Resea ch Cen e, Cen o Hospi ala de Lisboa Cen al, Lisbon, Po ugal ARTICLE INFO Keywo ds: A ial ib illa ion Pulmona y ein isola ion A hy hmia ecu ence A hy hmia bu den Blanking pe iod Ca he e abla ion ABSTRACT Objec i e: This s udy aimed o assess whe he a ial ib illa ion (AF) occu ence o i s co esponding daily mean bu den (in minu es/day) du ing he mid o la e blanking pe iod a e pulmona y ein isola ion (PVI), p edic s AF ecu ence. Me hods: Analysis o consecu i e i s PVI abla ion pa ien s unde going p olonged elec oca diog am (ECG) moni o ing du ing he second and hi d mon hs a e PVI. The clinical a iables, o al AF bu den, and hei ela ionship wi h ime o ecu ence we e s udied. Resul s: 477 pa ien s wi h a mean age o 56.9 (SD =12.3) yea s (63.7 % male; 71.7 % pa oxysmal AF), om which 317 (66.5 %) had an ex e nal e en eco de be ween 30 and 90 days a e abla ion. Median ollow-up o 16.0 (P 25:12.0: P 75:33.0) mon hs, 177 (37 %) pa ien s had an AF ecu ence, wi h 106 (22.2 %) ha ing he i s episode a e 12 mon hs o ollow-up. In he g oup o pa ien s wi h an e en eco de , 80 (25.2 %) had AF documen ed du ing he blanking pe iod. Mul i a iable analysis showed ha AF du ing he blanking pe iod was associa ed wi h a 4- old highe isk o ecu ence (HR: 3.98; 95 %CI: 2.95–5.37), and, compa ed o pa ien s in sinus hy hm, hose wi h an AF bu den ≥23 min/day had an app oxima ely 7- old highe isk o ecu ence (HR es ima e: 6.79; 95 %CI: 4.56–10.10). Conclusions: The p obabili y o expe iencing AF ecu ence can be p edic ed by a ial achya hy hmia episodes du ing he second and hi d mon hs a e PVI. A ial a hy hmias bu den >23 min/day has a high p edic i e abili y o ecu ence. 1. Backg ound A ial ib illa ion (AF) is he mos common sus ained a hy hmia and is associa ed wi h a subs an ial economic bu den and signi ican mo bidi y and mo ali y [1,2]. In he pas wo decades, he knowledge o AF pa hophysiology has led o signi ican de elopmen s in he ea men op ions, pa icula ly ega ding ca he e abla ion [3,4,5]. Abla ion, based on pulmona y ein isola ion (PVI), ep esen s an essen ial hy hm-con ol s a egy o he managemen o pa oxysmal, d ug- e ac o y AF, being one o he mos common ca diac abla ion p oced- u es pe o med wo ldwide. A undamen al aspec a e PVI is he assessmen o a hy hmic ecu ence. AF can occu in he i s weeks o mon hs a e PVI o e en a e a long- e m pe iod ee o AF [6]. The i s h ee mon hs a e PVI is known as he blanking pe iod, and a ial achya hy hmias (AT/AF) du ing i is conside ed a ansi o y phenomenon wi hou clinical * Co esponding au ho a : San a Ma a Hospi al, Ca diology Se ice, A hy hmology, Pacing, and Elec ophysiology Uni , R. de San a Ma a 50, 1169-024 Lisboa, Po ugal. E-mail add ess: [email p o ec ed] (P. Sil a Cunha). 1 This au ho akes esponsibili y o all aspec s o he eliabili y and eedom om bias o he da a p esen ed and hei discussed in e p e a ion. Con en s lis s a ailable a ScienceDi ec IJC Hea & Vascula u e jou nal homepage: www.sciencedi ec .com/jou nal/ijc-hea -and- ascula u e h ps://doi.o g/10.1016/j.ijcha.2022.101138 Recei ed 31 July 2022; Recei ed in e ised o m 22 Sep embe 2022; Accep ed 11 Oc obe 2022 IJC Hea & Vascula u e 43 (2022) 101138 2 signi icance in p edic ing la e AF ecu ence. Howe e , in ecen yea s, he clinical implica ion o he occu ence o AT/AF in his pe iod has come o be alued. The incidence o AT/AF is highes in he immedia e pos -abla ion pe iod and p og essi ely dec eases a e ha [7,8]. Since he obse a- ion by O al e al. in 2002 [9], di e en s udies ha e consis en ly ound ha ea ly ecu ence o AT/AF occu s mainly du ing he i s wo weeks a e PVI [10,11]. This means ha AT/AF as a p edic o o la e e- cu ences p obably became mo e signi ican a e he i s mon h [12]. The e o e, we conduc ed his s udy o in es iga e he incidence o AT/ AF du ing he ea ly pe iod a e PVI by using an ex e nal e en loop eco de and i s ela ionship wi h ecu ence a e and ime o AF occu ence du ing ollow-up. 2. Me hods 2.1. S udy popula ion We s udied 477 consecu i e pa ien s wi h symp oma ic d ug- e ac o y pa oxysmal (PAF) o pe sis en (PsAF) AF who ecei ed an index AF ca he e abla ion be ween 05/2005 and 02/2020 in he Cen o Hospi ala de Lisboa Cen al. Subjec da a we e excluded om he cu en analysis i pa ien s we e diagnosed wi h long-s anding pe sis en AF (con inuous AF >12 mon hs), had incomple e baseline da a e- po ed, o we e edo p ocedu es. AF was classi ied as PAF i a hy hmia episodes e mina ed spon aneously, o wi h in e en ion wi hin se en days o onse , o as PsAF i he episodes we e sus ained, las ed longe han se en days, bu <12 mon hs [1]. The hospi al e hics commi ee app o ed he s udy p o ocol (E hics Commi ee app o al numbe 974/2020). All pa icipan s p o ided w i en in o med consen o da a collec ion, and he s udy was con- duc ed acco ding o he Decla a ion o Helsinki guidelines. 2.2. Abla ion p ocedu e E e y pa ien unde wen a ou ine p ep ocedu al ans ho acic echoca diog am o e alua e le en icula ejec ion ac ion le a ial dimensions, sc een o s uc u al hea disease, and compu ed omog- aphy o magne ic esonance imaging (wi h he segmen a ion o he le a ium) o assess le a ial ana omy and o exclude he p esence o in aca diac h ombi. Addi ionally, i he men ioned imaging s udy was pe o med >48 h be o e abla ion, ansesophageal echoca diog aphy was done on he day o he p ocedu e ( o exclusion o h ombi). Pa- ien s unde wen abla ion a e con inued o al an icoagula ion ( o a leas ou weeks be o e abla ion) using wa a in wi h a he apeu ic INR (2.0–3.0) o di ec o al an icoagulan s (DOAC), wi h one dosage omi ed in he e ening be o e he abla ion. Con inuous moni o ing o oxygen sa u a ion and ECG we e main ained h oughou he abla ion. All p o- cedu es we e ca ied ou unde conscious seda ion o gene al anes hesia. In b ie , he p o ocol s eps o adio equency ca he e abla ion (RFCA) in he esea che s’ ins i u ion consis ed in: 1. posi ioning a decapola ca he e h ough he igh emo al ein o guide he ans- sep al punc u e and o pace he le a ium, 2. A anssep al punc u e by luo oscopic guidance 3. h ee-dimensional mapping o he le a ium pe o med wi h ei he he EnSi e Na X/Veloci y (Abbo Labo a o ies, Abbo Pa k, IL) o CARTO (Biosense Webs e , I ine, Cali o nia) sys- em. Radio equency applica ions we e pe o med using an open- i iga ed- ip ca he e (FlexAbili y™, Abbo o The moCool Sma - Touch® Su oundFlow, Biosense Webs e ) wi h poin -by-poin -lesions. When using he c yoene gy, he abla ion balloon sys em used was he A c ic F on ™ (Med onic, Inc., Minneapolis, MN, USA) wi h he 28-mm balloon. Di e en c yoballoon posi ions we e assessed (by injec ing con as in o he ein dis al o he balloon) o ensu e op imal occlusion. Rega ding ene gy applica ions, a e success ul PVI (240 s, aiming o a minimum empe a u e o less han −40 ◦C), an addi ional eeze-cycle o he same du a ion was applied a he ope a o ’s disc e ion. The ph enic ne e unc ion was checked du ing ene gy applica ion in he igh pulmona y eins [13]. 2.3. Pos abla ion e alua ion AF ecu ence- ee su i al was he p ima y endpoin , conside ing an AF ecu ence as any pos –90-day blanking a ial achya hy hmias las ing 30 s o longe , sus ained symp oma ic episodes o apid palpi- a ions, p esc ip ion o an ia hy hmic d ugs (class I o III), o epea abla ion. A e he abla ion p ocedu e, pa ien s we e discha ged on an ia - hy hmic d ugs (AAD) a he ope a o ’s disc e ion, oge he wi h o al an icoagula ion. Pa ien s we e obse ed o ou ine ollow-up in he ou pa ien clinic 1–3 mon hs a e he p ocedu e and e e y six mon hs (o ea lie , i symp oms) du ing he i s wo yea s pos -abla ion. A each isi , a s anda d 12-lead ECG was ob ained. Pa ien s we e moni o ed wi h an ex e nal loop eco de (Spide lash™ and E en scope™ 3 analysis so wa e, Mic oPo CRM, Clama , F ance) be ween 30 and 90 days a e AF abla ion. A e he blanking pe iod, pa ien s we e ollowed-up wi h a 24-hou -Hol e a each ou pa ien isi . AAD was con inued o six mon hs a e he abla ion p ocedu e and was wi hd awn - excep o be a-blocke s - i he pa ien s we e ee om a hy hmia- ela ed symp oms. O al an icoagula ion was e-e alua ed in he hi d mon h, and he decision o con inue was based on he CHA2DS2-VASc sco e. Clinical e en s occu ing du ing he ollow-up we e e alua ed. 2.4. S a is ical analysis Resul s a e exp essed as mean (±s anda d de ia ion, SD), median (P25; P75), o as equencies and pe cen ages, as app op ia e. AT/AF bu den du ing he blanking pe iod, co esponding o he mean du a ion ime o AT/AF pe day ( e e ed o as AF bu den), was ob ained by di iding he numbe o minu es wi h a hy hmia by he numbe o days o de ice use. A ime-dependen a ea unde he ROC (Recei e Ope - a ing Cha ac e is ic) cu e was used o s udy i s disc imina i e abili y ega ding u u e ecu ence along he ollow-up ime. The in e se p obabili y o censo ing weigh ing (IPCW) me hod was applied o es i- ma e hese ime-dependen a eas unde he ROC cu e. A cu -o poin o his AF bu den ha bes p edic ed AF ecu ence was ob ained wi h only hose pa ien s wi h an AF bu den di e en om ze o, and a new bina y a iable was cons uc ed. Ma ingale esiduals, p ope o assess he unc ional o m o co a ia es in he Cox p opo ional haza ds model, we e used o iden i y his poin [14]. Time-dependen sensi i i y, speci ici y, and posi i e and nega i e p edic i e alues we e es ima ed o his bina y AF bu den a iable. Two su i al analyses o s udy ime un il ecu ence we e pe o med conside ing he p ima y exposu es: ha ing had (o no ) AF episodes du ing he blanking pe iod, and co esponding AF bu den. Fi s ly, Kaplan-Meie es ima o was used o ob ain ecu ence- ee su i al es- ima es. Log- ank es was u he applied o compa e AF su i al unc ions be ween g oups. Secondly, uni a iable and mul i a iable Cox eg ession models we e i ed o he da a, conside ing he occu ence o AF episodes o AF bu den, du ing he blanking pe iod, as independen a iables in wo sepa a e mul i a iable analyses. The associa ion o hese wo isk ac o s wi h ecu ence- ee su i al was adjus ed by se e al co a ia es, such as age, sex, como bidi ies, episodes o a hy hmia pa e n, and body mass index, among o he s. The p opo - ional haza ds assump ion was checked using o mal s a is ical es s and g aphical diagnos ics based on he scaled Schoen eld esiduals. Because his assump ion was iola ed o he bina y a iable co esponding o he numbe o como bidi ies (ze o o one s. ≥2), a model wi h ime- a ying coe icien s was i ed o he da a [15]. A le el o signi icance α =0.05 was conside ed. All da a we e analyzed using STATA (S a aCo p. 2017. S a a S a is ical So wa e: P. Sil a Cunha e al. IJC Hea & Vascula u e 43 (2022) 101138 3 Release 15. College S a ion, TX: S a aCo p LLC.) and R so wa e (R Co e Team (2021). R: A language and en i onmen o s a is ical compu ing. R Founda ion o S a is ical Compu ing, Vienna, Aus ia. URL h ps:// www.R-p ojec .o g/.). 3. Resul s 3.1. Baseline clinical cha ac e is ics This e ospec i e coho s udy conside ed ou hund ed and se en y-se en consecu i e pa ien s wi h a median ollow-up ime o 16.0 (P 25 :12.0; P 75 :33.0) mon hs. Coho ’s mean age was 56.9 (SD =12.3), and 36.3 % we e women (Table 1). The baseline pa e n o AF was pa oxysmal in 71.7 % and pe sis en in 28.3 %. All pa ien s unde wen ci cum e en ial PVI. RFCA using con ac - o ce echnology was used in 295 pa ien s, and abla ion using he second-gene a ion c yoballoon in 182 pa ien s. Ca o- icuspid is hmus abla ion was pe o med in 29 pa- ien s wi h p e ious documen a ion o ypical a ial lu e . De ailed baseline clinical and demog aphic cha ac e is ics o he s udy popula ion a e epo ed in Table 1. 3.2. A ial ib illa ion ecu ence One hund ed and se en y-se en (37.1 %) pa ien s had an AF ecu - ence, om which 106 (59.9 %) occu ed a e 12 mon hs o ollow-up. Recu ence- ee su i al es ima e is depic ed in Fig. 1. Conside ing he ca diac hy hm eco ded du ing he blanking pe iod (sinus hy hm s. AF): om pa ien s wi h sinus hy hm (n =370), 99 (26.8 %) had an AF ecu ence, whe eas, in pa ien s wi h documen ed AF (n =107, 22,4 %), 78 (72.9 %) had an AF ecu ence. Fig. 2 shows a signi ican di e ence in ecu ence- ee su i al be ween hese wo g oups o pa ien s (p <0.001). 3.3. E en eco de da a analysis The ex e nal e en eco de was used by 317 pa ien s du ing he “la e” blanking pe iod a e he abla ion p ocedu e o a median ime o 21 (min =5, max =34) days. Rega ding AT/AF bu den, 237 pa ien s had no AT/AF (ze o minu es), and 80 (25.2 %) wi h AT/AF episode(s) had a median o 29.5 (P 25 =6.9, P 75 =96.2) minu es o a hy hmia bu den. The ime-dependen disc imina i e abili y o AF bu den du ing he blanking pe iod o dis inguish be ween pa ien s who elapsed om hose who did no was cha ac e ized by he ollowing ime-dependen a ea unde he cu e o he ecei e -ope a o cha ac e is ic o ( ime in mon hs) 6 =85.4 %, =9, 78.3 %, =12, 71.2 %, =24, 68.9 % (see Table 2). A dec easing end in he a ea unde he ROC cu e may be obse ed. Using he da a co esponding o he 80 pa ien s wi h an AT/AF bu den di e en om ze o, in whom 67.5 % (n =54) had a ecu ence, a cu -o poin o his bu den (AF mean du a ion ime pe day) was de e mined (Fig. 3). In his igu e, he smoo h unc ion should be linea o sa is y he s anda d Cox p opo ional haza ds model linea i y assump ion [14]. Howe e , his g aphical check shows a nonlinea i y and, acco dingly, al hough his co a ia e could be modeled wi h a nonlinea unc ion, we p oceeded o i s disc e iza ion o clinical p ac ice use. We conside ed he cu -o poin whe e he smoo h unc ion c osses he e e ence line (23 min o AF pe day), below which he isk o ecu ence is lowe . A 24 mon hs o ollow-up, his a iable (AF bu den <23 min s. AF bu den ≥23 min) showed a sensi i i y o 33.4 %, a speci ici y o 91.1 %, and posi i e and nega i e p edic i e alues o 60.0 % and 77.5 %, espec i ely (Table 3). A ca ego ical a iable wi h h ee ca ego ies (no AF bu den, wi h bu den <23 min pe day, ≥23 min pe day) eme ged om he o me analysis. No AF bu den ca ego y includes pa ien s wi h ze o minu es o a hy hmia (n =237) and hose ha did no use he ex e nal e en eco de bu had no clinical AF episodes (n =133). The compa ison o ecu ence- ee su i al o hese h ee g oups o pa ien s is shown in Fig. 4. 3.3.1. Uni a iable analysis Resul s o he uni a iable analysis o AF ecu ence a e shown in Table 4. Va iables ha a ained a p- alue <0.25 we e selec ed o he mul i a iable s udy. 3.3.2. Mul i a iable analysis Rega ding he occu ence o AF episode(s) du ing he blanking pe iod, no mul i a iable model was achie ed, and only his a iable emained in he inal model. Acco dingly, he esul s a e he same as hose o he uni a iable analysis (Table 3) and pa ien s ha had AF episodes du ing he blanking pe iod had app oxima ely a 4- old highe isk o ecu ence (HR: 3.98; 95 %CI: 2.95–5.37); p <0.001). Rega ding AF bu den du ing he blanking pe iod, esul s o he mul i a iable analysis a e p esen ed in Table 4. A iola ion o he p o- po ional haza ds assump ion was obse ed o he numbe o como - bidi ies du ing he mul i a iable modeling p ocess o he da a using he Cox eg ession model (supplemen a y ma e ial Fig. 1). Mul i a iable analysis esul s showed ha , compa ed o pa ien s wi h sinus hy hm, hose wi h an AF bu den ≥23 min/day had an app oxima ely 7- old highe isk o ecu ence (HR es ima e: 6.79; 95 % CI: 4.56–10.10), while o pa ien s wi h an AF bu den <23 min/day his isk inc ease was lowe (HR es ima e: 2.60; 95 %CI: 1.54–4.47). Changing he e e ence ca ego y o an AF bu den ≥23 min/day enabled he compa ison o he isk ecu ence o pa ien s wi h an AF bu den <23 min/day wi h hose wi h a highe bu den. Acco dingly, pa ien s wi h a lowe AF bu den had a 61 % dec ease in he isk o ecu ence when compa ed wi h hose wi h an AF bu den ≥23 min/day (HR es ima e: 0.39; 95 %CI: 0.21–0.70). Rega ding he numbe o como bidi ies, ha ing mo e han one como bidi y inc eases he isk o ecu ence, al hough his inc ease was only s a is ically signi ican beyond ≈30 mon hs o ollow-up a e ca he e abla ion (HR es ima e: 3.25; 95 %CI: 1.70–6.23). 4. Discussion 4.1. Main indings The main indings o he p esen s udy a e 1) pa ien s wi h AT/AF episodes las ing >30 s du ing he “la e” blanking pe iod (be ween 31 Table 1 Popula ion cha ac e is ics. Va iables Numbe o pa ien s (n ¼477) Pa oxysmal AF, n (%) 342 (71.7) Male sex, n (%) 304 (63.7) Mean age (SD), yea s 56.9 (12.3) Mean LA diame e (SD), mm 43.9 (6.9) Mean le a ial indexed olume (SD), ml/m 2 38.3 (12.1) Median CHA 2 DS 2 -VASc (P 25 ; P 75 ) 1.0 (1.0; 2.0) Mean Body Mass Index (SD), Kg/m 2 28.15 (4.88) Hype ension, n (%) 281 (58.9) Hype choles e olemia, n (%) 135 (28.3) Diabe es melli us, n (%) 35 (7.3) Co ona y a e y disease, n (%) 25 (5.2) OSAS, n (%) 52 (10.9) Hea ailu e, n (%) 44 (9.2) Ch onic kidney disease, n (%) 5 (1.0) P e ious S oke/TIA, n (%) 17 (3.6) P e ious pulmona y/pe iphe al Embolism, n (%) 7 (1.5) Median ollow-up (P 25 ; P 75 ), mon hs 16.0 (12.0; 33.0) Legend: AF =a ial ib illa ion, LA =le a ium, OSAS =obs uc i e sleep apnea synd ome, TIA = ansien ischemic acciden , SD =s anda d de ia ion, P 25 =25 h pe cen ile, P 75 =75 h pe cen ile. P. Sil a Cunha e al. IJC Hea & Vascula u e 43 (2022) 101138 4 and 90 days pos -PVI) had a signi ican ly highe isk o long- e m AF ecu ence han hose wi h sinus hy hm du ing all blanking pe iod, 2) a o al bu den o AT/AF abo e 23 min du ing he blanking pe iod was co ela ed wi h an app oxima ely 7- old isk o AF ecu ence. Also, ha ing mo e han one como bidi y signi ican ly inc eases he isk o ecu ence beyond 30 mon hs a e ca he e abla ion. In he ea ly pe iod a e AF abla ion, he occu ence o AT/AF is a common inding bu may no necessa ily imply long- e m abla ion ailu e. The i s h ee mon hs a e abla ion a e usually no conside ed ega ding ein e en ion and p ocedu al success epo s [16,17]. Fu he mo e, i has been accep ed ha he incidence o ea ly AT/AF episodes is equen soon a e he abla ion, dec easing in he ollowing days [18]. Indeed, he numbe o a ial a hy hmias dec eases du ing he 3-mon h blinding pe iod [19,20]. Fig. 1. Kaplan-Meie es ima e o ecu ence- ee su i al (es ima ed median =47 mon hs; 95 % CI: 38.71–55.29). Fig. 2. Kaplan-Meie es ima es ecu ence- ee su i al acco ding o ca diac hy hm du ing he blanking pe iod: sinus hy hm (g een line) and a ial ib illa ion ( ed line). (Fo in e p e a ion o he e e ences o colou in his igu e legend, he eade is e e ed o he web e sion o his a icle.) P. Sil a Cunha e al. IJC Hea & Vascula u e 43 (2022) 101138 5 Al hough he p e alence o AT/AF is signi ican du ing he blanking pe iod, wi h a ious s udies iden i ying>50 % o he pa ien s ha ing an ea ly ecu ence, depending on he ype o hy hm moni o ing used, a good p opo ion o pa ien s will s ill be ee o AF a p olonged ollow-up [6,16,17]. Howe e , i has been shown ha la e ecu ence is mo e equen in pa ien s who expe ience AT/AF du ing he blanking pe iod [20]. The e o e, pa ien s wi hou a ial a hy hmias du ing he con en ional 3-mon h blanking pe iod a e mo e likely o be AF- ee a long- e m ollow-up. P e ious s udies ha e u ilized a wide ange o du a ions o he blanking pe iod pos -abla ion, making i di icul o de ine he op imal du a ion o his pa icula e alua ion pe iod. Also, he deg ee o a hy hmia bu den ha be e p edic s longe - e m success has no been quan i ied. In ou s udy, we decided o analyze he p edic i e alue o AT/AF occu ence du ing he “la e” blanking pe iod a e he abla ion p o- cedu e (be ween he 31s and he 90 h day) and o assess he bes cu -o poin o he AT/AF bu den ega ding he p edic ion o la e AF ecu - ence. The o e all p e alence o AF ecu ence was 37,1 % du ing a long- e m ollow-up, wi h a good pe o mance o bina y AF bu den du ing he blanking pe iod as a diagnos ic es o AF ecu ence. An a hy hmia bu den >23 min/day had a nega i e p edic i e alue o 91,3 % and a posi i e p edic i e alue o 40,6 % in he p edic ion o la e AF ecu ence. I is impo an o highligh ha close moni o ing o ecu ence du ing he blanking pe iod is uncommon [21], which may make ou s udy pa icula ly in e es ing since we ca ied ou p ospec i ely and sys ema ically an ex e nal loop eco ding in a signi ican pe cen age o ou pa ien popula ion. 4.2. Mechanisms o ea ly a ial a hy hmias du ing he blanking pe iod The unde lying pa hophysiological p ocesses esponsible o ea ly AT/AF ecu ence a e no en i ely known. Se e al explana ions [22] ha e been sugges ed o cause a hy hmias in he ea ly phase a e AF abla ion. T ansien ac o s [23,24,25], like in lamma ion, au onomic imbalance, lesions o ma ion, o mo e ex ensi e abla ions, may con ibu e o he equen occu ence o AT/AF in he ea ly pe iod pos - AF abla ion. A hy hmogenesis du ing he blanking pe iod seems o be a dynamic p ocess. To a oid he acu e e ec s o ene gy deli e y o he a ial issue, we included pa ien s s udied wi h he long-du a ion ex e nal moni o ing a e he i s 30 days ollowing he abla ion p ocedu e. 4.3. P edic i e alue o ea ly a ial a hy hmias ecu ence The e en ex e nal loop eco de is an easily accessible complimen- a y exam sui able o pe o ming du ing he blanking pe iod. Ou s udy showed a 25,2 % incidence o AT/AF while moni o ing ca diac hy hm du ing he la e blanking pe iod. O e all, hese pa ien s had app oxi- ma ely a 4- old highe isk o la e ecu ence. The o iginali y o ou wo k is ha he cu -o in e al o 23 min pe day signi ican ly inc eased he incidence o AF ecu ence, wi h pa ien s showing almos a 7- old chance compa ed o hose wi hou ea ly AT/AF de ec ion. In ou analysis, no only eedom om ea ly ecu ence is a guide o an icipa ing ou comes, bu also he o al bu den o a ial a hy hmias is an impo an pa ame e o be acknowledged. The e o e, he egula use o long-du a ion moni o ing wi h an ex e nal loop eco de can be bene icial, as i allows he assessmen o a simple pa ame e o e alua ing he isk o AF ecu ence. The ea ly occu ence o AF abo e he e e ed cu -o bu den can be seen as a ed lag ha can e en ually jus i y a mo e in ensi e ollow-up, main enance o AAD, and decide ch onic an icoagula ion (combined wi h he CHADs- VASc sco e) o ul ima ely conside unde going a e-abla ion p ocedu e. 5. Limi a ions This s udy had se e al limi a ions. Fi s , his s udy was designed as a single-cen e p ospec i e s udy; hus, i is necessa y o alida e he e- sul s om a p ospec i e s udy wi h la ge sample size. Secondly, we used s anda d nonin asi e ollow-up me hods, no in asi e me hods (e.g., an Table 2 Pe o mance o bina y AF bu den du ing he blanking pe iod as a diagnos ic es o AF ecu ence. Time (mon hs) Sensi i i y (%) Speci ici y (%) PPV (%) NPV (%) =6 68.8 88.4 24.3 98.1 =9 58.5 89.6 37.0 95.4 =12 47.1 88.9 40.6 91.3 =24 33.4 91.1 60.0 77.5 Legend: AF-a ial ib illa ion; PPV: Posi i e P edic i e alue; NPV: Nega i e P edic i e alue. Fig. 3. The plo o ma ingale esiduals e sus AF mean du a ion ime pe day o assess he unc ional o m o his co a ia e in he Cox p opo ional haza ds model. The supe imposed smoo h unc ion in his plo is ep esen ed by he solid black line (wi h a co esponding 95 % con idence in e al – dashed lines). Table 3 Uni a iable analysis esul s. Va iables HR es ima e 95 % CI p- alue Female sex 1.26 0.93–1.70 0.145 Age 1.02 1.01–1.03 0.001 Body Mass Index 1.03 1.01–1.06 0.018 Pa oxysmal AF 0.65 0.47–0.89 0.008 Como bidi ies (≥2) 1.40 1.04–1.87 0.027 Ana omical a ian (yes) 1.33 0.97–1.84 0.082 A e age Pla ele Volume 1.07 0.94–1.22 0.339 PDW 0.96 0.89–1.04 0.275 Monocy es/HDL a io* 1.03 1.00–1.06 0.025 Neu ophil/lymphocy e a io 0.93 0.83–1.05 0.233 Monocy e/lymphocy e a io ** 0.49 0.11–2.13 0.342 CT scan LA 1.04 1.00–1.09 0.047 AF du ing blanking pe iod 3.98 2.95–5.37 <0.001 AF bu den <23 min/day AF bu den ≥23 min/day 2.37 6.54 1.39–4.03 4.40–9.71 0.001 <0.001 AF bu den min/day *** 1.07 1.05–1.09 <0.001 Legend: AF =a ial ib illa ion, PDW =Pla ele Dis ibu ion Wid h, HDL = High-densi y lipop o ein, CT Compu ed Tomog aphy, LA =le a ium, HR – Haza d Ra io, CI – Con idence In e al; * Fo each 0.001 uni inc ease; ** Fo each 10 uni s inc ease; *** o each 30 min/day inc ease. P. Sil a Cunha e al. IJC Hea & Vascula u e 43 (2022) 101138 6 inse able ca diac moni o ). The e o e, de ec ing AF ecu ences a e ca he e abla ion, ou side he eco ding pe iod, pa icula ly in cases wi h asymp oma ic AF, is di icul , and he s udy migh unde es ima e he ecu ence a e. Thi dly, an i-a hy hmic d ugs we e con inued du ing he blanking pe iod, which is an impo an con ounde . A ou h limi a ion conce ns he low numbe o pa ien s used o ob ain he cu -o poin o AF bu den du ing he blanking pe iod. 6. Conclusions The p obabili y o expe iencing la e ecu ence a e PVI can be p edic ed by a ial a hy hmias du ing he blanking pe iod, wi h a highe likelihood i he bu den is >23 min. The blanking pe iod AF bu den a e PVI should be in es iga ed in u u e s udies. 7. G an suppo This wo k did no ecei e any g an s o unding. 8. E hical disclosu es P o ec ion o human and animal subjec s. The au ho s decla e ha he e we e no expe imen s pe o med on humans o animals o his s udy. Regis a ion numbe and Hospi al E hics Commi ee app o al: numbe 974/2020. 9. Con iden iali y o da a The au ho s decla e ha hey ollowed hei hospi al cen e ’s p o- ocols on he pa ien da a publica ion. 10. Righ o p i acy and in o med consen The au ho s decla e ha no pa ien da a appea in his a icle. Decla a ion o Compe ing In e es The au ho s decla e ha hey ha e no known compe ing inancial in e es s o pe sonal ela ionships ha could ha e appea ed o in luence he wo k epo ed in his pape . Appendix A. Supplemen a y ma e ial Supplemen a y da a o his a icle can be ound online a h ps://doi. o g/10.1016/j.ijcha.2022.101138. Fig. 4. Kaplan-Meie es ima es o ecu ence- ee su i al acco ding o AF bu den eco ded du ing he blanking pe iod: sinus hy hm (g een line), AF wi h a mean du a ion ime <23 min pe day (blue line), and AF wi h a mean du a ion ime ≥23 min pe day ( ed line). Twen y-se en pa ien s wi h AF had missing alues in AF bu den. (Fo in e p e a ion o he e e ences o colou in his igu e legend, he eade is e e ed o he web e sion o his a icle.) Table 4 Mul i a iable analysis esul s. Va iables HR es ima e 95 % CI p- alue AF bu den* AF bu den <23 min/day AF bu den ≥23 min/day AF bu den ** No AF bu den (sinus hy hm) AF bu den <23 min/day 2.60 6.79 0.15 0.39 1.54–4.47 4.56–10.10 0.10–0.22 0.21–0.70 <0.001 <0.001 <0.001 0.002 Como bidi ies *** ≥2 o ollow-up ime <≈30 mon hs ≥2 o ollow-up ime ≥ ≈30 mon hs 1.31 3.25 0.91–1.90 1.70–6.23 0.147 <0.001 Legend: AF- a ial ib illa ion; HR – Haza d Ra io, CI – Con idence In e al; * Re e ence ca ego y: no AF bu den (sinus hy hm); ** Re e ence ca ego y: AF bu den ≥23 min/day; *** Re e ence ca ego y: Ze o o one como bidi ies. P. Sil a Cunha e al. IJC Hea & Vascula u e 43 (2022) 101138 7 Re e ences [1] G. Hind icks, T. Po pa a, N. Dag es, e al., 2020 ESC Guidelines o diagnosing and managing a ial ib illa ion, Eu . Hea J. 42(5) (2021) 373–498. [2] C.A. Mo illo, A. Bane jee, P. 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