High Initial Heart Rate Score is an Independent Predictor of New Atrial High-Rate Episodes in Pacemaker Patients with Sinus Node Dysfunction

word count: 245 21 Number of tables: 6; Number of figures: 3 22 23

Atrial fibrillation, Pacemaker, Outcomes, Rate responsive pacing 24 25 26 27 Address for Correspondence: 28 Katsuhide Hayashi MD 29 9500 Euclid Avenue Cleveland, Ohio 44195 30 Email: [email protected] 31 Phone: 216-808-1681 32 ORCID: 0000-0001-7269-9808 33 34 35 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 2

1

Heart Rate Score (HRSc), the percent of atrial beats in the largest paced/sensed 2 10-bpm histogram bin recorded in cardiac devices, is a metric of chronotropic incompetence. 3 It remains uncertain if HRSc independently predicts atrial high-rate episodes (AHREs) in 4 patients with sinus node dysfunction (SND) undergoing pacemaker (PM) implantation. 5

To determine the relationship between initial HRSc post-PM implant and 6 new-onset AHREs in patients with SND. 7

The cohort included patients with Boston Scientific PMs implanted for SND from 8 2012-2021 at Cleveland Clinic, University of Occupational and Environmental Health, Japan, 9 Kyushu Rosai Hospital, and JCHO Kyushu Hospital. Patients were excluded if they had atrial 10 fibrillation before PM implant or AHREs in the initial 3-months post-implant. Subsequent 11 AHREs post-implant (>1% of atrial beats>170 bpm) were evaluated. 12

Over 48.9 (IQR 25.8-50.4) months, 136 consecutive PM patients (age 75±10 years, 13 42% male) were followed. The median initial HRSc was 73(55-86)%. AHREs developed in 14 28/136 (21%). Although %RA pacing and HRSc correlated, rate-responsive pacing was 15 associated with a HRSc only in the patients with high %RA pacing. Patients with HRSc≥80% 16 had higher occurrence of AHREs than those with HRSc<80% (p=0.01, log-rank test). After 17 adjusting for age, race, comorbidities, left ventricular ejection fraction, left atrial 18 diameter, %RA/RV pacing, and rate-response programming, HRSc (HR:2.84, 95% 19 CI:1.17-6.92; P=0.02) and male sex (HR:2.55, 95% CI:1.15-6.19; P=0.04) were independent 20 predictors of AHREs. 21

HRSc≥80% independently predicted new-onset, device-determined AHREs for 22 patients undergoing PM implant for SND. HRSc may have prognostic and therapeutic 23 implications. 24 25 26 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 3

1 Heart Rate Score (HRSc) is a novel parameter of chronotropic incompetence using 2 long-term heart rate variation for patients with cardiac implantable electronic devices 3 (CIEDs).1 It is defined as the percent of atrial beats in the largest paced/sensed 4 10-beat/minutes histogram bin of a pacemaker (PM) or implantable cardioverter-defibrillator 5 (ICD) (Figure 1). HRSc ≥70% predicts mortality in patients without atrial fibrillation (AF) 6 who have ICDs2 or cardiac resynchronization therapy defibrillators (CRT-Ds).3,4 7 Atrial high-rate episodes (AHREs) have attracted much attention in anticoagulant 8 therapy decisions for the risk of stroke in CIED patients.5,6 Unfortunately, no established data 9 from electrocardiograms or device interrogation can yet predict development of AHREs. We 10 recently showed that HRSc, early post-implantation, can predict new-onset AHREs in PM 11 patients in a large database.7 In this prior study, the incidence of AHREs, defined as >1% of 12 atrial beats ≥170 bpm (primary endpoint), correlated with the incidence of mode switch 13 episodes ≥24 hours. However, that study could not collect clinical information, including PM 14 indication, as it used a retrospective, de-identified, database. Therefore, it remains uncertain 15 whether HRSc predicts AHREs in PM patients with sinus node dysfunction (SND) 16 independent of clinical parameters. 17 The goal of this study was to evaluate the baseline HRSc post-PM implant in lieu 18 of clinical characteristics and determine if an independent relationship exists between the 19 initial HRSc and subsequent development of AHREs in patients with SND who underwent 20 dual-chamber PM implant. We focused on the incidence of AHREs developing after implant 21 for those with no AHREs during an initial 3-month observation. 22

23 Study Cohort 24 The cohort included consecutive patients with Boston Scientific PMs implanted for 25 SND from 2012-2021 at 4 hospitals (Cleveland Clinic in the Unites States, University of 26 Occupational and Environmental Health, Japan, Kyushu Rosai Hospital, and JCHO Kyushu 27 Hospital in Japan). Patients were excluded if they had single chamber or biventricular PMs, 28 atrial fibrillation (AF) before PM implantation or detected device-determined AHREs 29 detection during the first 3 months after implantation. 30 Data were analyzed retrospectively. The study was approved by the Institutional 31 Review Board of the Cleveland Clinic, University of Occupational and Environmental Health, 32 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 4 Japan, Kyushu Rosai Hospital, and JCHO Kyushu Hospital. 1 Heart Rate Score (HRSc) and Baseline Period 2 HRSc was defined, as previously described, as the percent of all paced and sensed atrial 3 events in the most populated 10-bpm rate histogram bin of the CIED, shown in Figure 1.4 4 HRSc, used in all analyses, was determined from remote interrogation data from the 5 dual-chamber PM during the baseline period (the first 3 months after PM implantation). The 6 HRSc, calculated at the last transmission during the baseline period, was designated the 7 initial HRSc. 8 Outcome 9 The endpoint was device-determined AHREs after the baseline period. The endpoint for 10 AHREs was considered >1% of atrial beats ≥170 beats/min recorded by the PM. 11 Follow-up Data Analysis 12 The occurrence of AHREs was examined using stored remote monitoring data and 13 tracked during follow-up periods. The relationship between the initial HRSc and occurrence 14 of device-determined AHREs was assessed. 15 Statistical Analysis 16 Continuous variables were expressed as mean±standard deviation (SD), median 17 (interquartile range, IQR: 25th-75th), or range, depending on the distribution of data, whereas 18 categorical variables were expressed as counts and percentages. The optimal HRSc for 19 predicting device-determined AHREs was chosen to be 80% for AHREs based on J-statistics 20 (Figure 2). Kaplan-Meier analyses evaluated freedom from AHREs after the baseline period 21 for the two initial HRSc groups. Log-rank tests were performed to compare group classified 22 by initial HRSc. Variables with P values <0.05 after single variable analysis were entered 23 into a multiple variable regression analysis to assess if there is an independent predictor of 24 AHREs. P<0.05 was considered statistically significant. All statistical analysis were 25 performed using JMP version 15.2.0 (SAS Institute Inc., Cary, NC). 26

27 Subjects Demographics 28 A total of 310 consecutive patients were enrolled. Patients who had atrial 29 fibrillation before PM implantation or device-determined AHREs in the first three months 30 (n=174) were excluded. The remaining 136 were followed for a median of 48.9 (IQR, 31 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 5 25.8-50.4) months. 1 Patient characteristics are listed in Table 1. The mean patient age was 75±10 years; 2 57 (41.9%) were male. Almost 50% of patients were Asian and 40% were European 3 American. No patients were prescribed anti-arrhythmic drugs. The mean left ventricular 4 ejection fraction (LVEF) and left atrial diameter (LAD) by echocardiogram were 62±7 % and 5 41±7 mm, respectively. The atrial lead was placed in the right atrium appendage in almost all 6 patients. The ventricular lead was implanted in right ventricular septum in approximately 7 two-thirds. 8 Pacemaker Programming and Interrogation Data 9 Pacemaker programming at the time of implantation is shown in Table 2. 10 Rate-responsive pacing was programmed in 70% of patients. Atrial sensitivity was 11 programmed to a mean of 0.4±0.1 mV and the lower rate limit (LRL) was programmed to 60 12 bpm in 124/136 (91.2%) patients. The cumulative percent of RA and RV pacing (%RA 13 pacing and %RV pacing) during the baseline period were a mean of 57±32 %, and 13±27 %, 14 respectively. 15 Heart Rate Score 16 The initial HRSc was calculated at a median of 51 days (IQR, 7-84) after 17 pacemaker implantation. The median value of the HRSc was 73% (IQR, 55-86%). 18 Outcome 19 Over a median of 48.9 months (IQR, 25.8-50.4 months), 28/136 (21%) subjects 20 experienced the endpoint of >1% AHREs. Subjects with an initial HRSc ≥80% had a higher 21 incidence of AHREs (Kaplan-Meier rate of 40%) versus those with an initial HRSc <80% 22 (Kaplan-Meier rate of 24%) through the 90.0 months during post-baseline follow-up. 23 (log-rank P =0.01) (Figure 3). 24 Association of Heart Rate Score and Percent of Right Atrial Pacing 25 Figure 4 shows a positive correlation between %RA pacing during the baseline 26 period and initial HRSc (R2=0.725, P<0.0001) for all patients. Patients were analyzed 27 additionally by the %RA pacing and rate-response (ON or OFF). HRSc was plotted against 28 RA pacing (Figures 5 and 6). In all 7 patients with high %RA pacing (pacing ≥70%) and no 29 rate response (OFF), HRSc was high (≥80%). For those with rate response ON, with RA 30 pacing ≥70%, 14 /54 patients had HRSc <80% (Figure 5). In patients with mid and low %RA 31 pacing (<70%), the distribution of HRSc did not differ between those with rate response ON 32 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 6 and OFF (Figure 6). 1 Predictors for Incidence of Atrial High-Rate Episode 2 By multivariable analysis, the initial HRSc (HR: 2.84, 95% CI: 1.17-6.92; P=0.02) 3 and male sex (HR: 2.55, 95% CI: 1.15-6.19; P=0.04) were the only independent predictors of 4 AHREs incidence (Table 3). 5

6 We found that the initial HRSc ≥80 %, calculated within 3 months after 7 dual-chamber PM implantation for SND, independently predicted new-onset, device defined, 8 AHREs in subsequent follow-up. This report is the first to demonstrate a relationship 9 between HRSc and device-detected AHREs in this population. Subjects with an initial HRSc 10 ≥80% had an increased risk of AHREs. This analysis held true over the 48.9-month 11 follow-up, after adjustment for risk factors for AHREs including: age, race, histories of 12 hypertension, diabetes mellitus, coronary artery disease, cardiomyopathy, LVEF, 13 LAD, %RA/RV pacing, and rate-responsive pacing. Despite a positive correlation 14 between %RA pacing and HRSc for patients dependent on RA pacing, more than one-quarter 15 with rate-responsive pacing had HRSc <80%; those without rate-responsive pacing all had 16 HRSc ≥80%. 17 Our study indicates that a high initial HRSc (≥80%) predicts AHREs recorded after 18 PM implantation for SND independently. Currently no established indicator from 19 electrocardiograms or device interrogation has been shown to predict subsequent 20 development of AHREs. Although our prior report7 indicated that the HRSc predicts 21 subsequent AHREs in PM patients in a large de-identified database, clinical parameters 22 including PM indication could not be determined. Therefore, we investigated the relationship 23 between initial HRSc and subsequent AHREs focusing on PM patients implanted for SND in 24 the current study. 25 Our results demonstrate that HRSc predicts pacemaker detected AHREs. It is not 26 clear that this correlates directly to clinical AF. However, in our prior report7, the incidence 27 of AHREs defined by >1% of atrial beats ≥ 170 bpm correlated with the incidence of mode 28 switch episodes ≥24 hours which is likely to represent substantial paroxysmal or persistent 29 AF. 30 Age, gender, hypertension, diabetes mellitus, ischemic heart disease, 31 pharmacologic therapy, left atrial dilatation, and LVEF, are well known risk factors for 32 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 7 AF.8-11 In our study, HRSc predicted AHREs independent of other risk factors. 1 Interestingly, however, male gender also predicted AHREs. This result is consistent with 2 community-based ARIC (Atherosclerosis Risk In Communities) study that showed higher 3 incidence of AF in males than females.12 In pacemaker patients with SND, high %RV pacing 4 is found to be associated with an increased AF.13-15 In addition, the association between %RA 5 pacing and AF has been also identified.16,17 6 In the current study, the median HRSc of 73% in PM patients with SND was higher 7 than prior reports.2,7 This result indicates that our study patients have severe chronotropic 8 incompetence. Patients with little or no spontaneous heart rate change above the LRL have a 9 high HRSc1. In addition, the optimal HRSc cut-point to predict device-determined AHREs 10 was found to be ≥80%. Notably, this optimal cut-point is different from HRSc ≥70% for 11 predicting mortality in patients with ICDs or CRT-Ds.3,4 12 Rate-responsive pacing can decrease HRSc in patients with sinus node dysfunction 13 who pace predominantly at the LRL and have a high HRSc (Figure 5). On the other hand, for 14 patients with SND who have less chronotropic incompetence, rate-responsive RA pacing may 15 be less likely affect HRSc (Figure 6). Rate responsive pacing may be excessive or even 16 harmful for those who have chronotropic competence.3 Rate-responsive pacing may be best 17 reserved for those with high baseline HRSc. However, LRL programming affects %RA 18 pacing and HRSc. A high LRL can override the resting intrinsic rate resulting in an increase 19 in %RA pacing and subsequently increase in HRSc. Conversely, programming a lower LRL 20 may decrease %RA pacing and lower HRSc. Most subjects in this study were programmed to 21 an LRL of 60 but prior data showed that lower LRL programming improved survival in a 22 large database of CRT-D subjects.18 Further research is needed to assess the relationships of 23 LRL, AHREs, %RA pacing and HRSc. 24 Study Limitations 25 This was a retrospective analysis and therefore, may be affected by unknown 26 confounders. We were unable to assess the impact of rate responsive pacing on AHREs. The 27 present study also does not answer whether lowering HRSc with pacemaker programming 28 affects AHREs. The population was not large enough to determine relationships of HRSc to a 29 higher percentage of AHREs or episodes that could become persistent AF. 30

31 In patients undergoing PM implant for SND, HRSc≥80% independently predicted 32 device-determined AHREs in long-term follow-up. As initial HRSc predicts AHREs in this 33 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 8 population, this parameter may have prognostic and therapeutic implications. 1

2 Bruce L. Wilkoff, MD passed away before submitting this manuscript and authors express 3 our sincerest condolence to him and sincerely appreciate his incredible leadership, he gave to 4 see this project completed. And the authors sincerely appreciate Hiroyuki Takatsu, MD, of 5 Kyushu Rosai Hospital, and Kan Kikuchi, MD, of JCHO Kyushu Hospital for obtaining 6 patient’s demographic and HRSc data. 7 8 Sources of Funding: None 9 10 Disclosures: 11 KH and RK: have nothing to declare. 12 HA: Research Grant: Boston Scientific, Medtronic, Abbott 13 BO: Member of a DSMB sponsored by AstraZeneka 14 ADS: Consultant: VivaQuant, CardioSignal 15 PWJ, NW, and DP are salaried employees of Boston Scientific. 16 BLW: Consultant and Speaker: Boston Scientific, Medtronic, Abbott, Biotronik 17 GYHL: Consultant and speaker: BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. 18 He is a National Institute for Health and Care Research (NIHR) Senior Investigator and 19 co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has 20 received funding from the European Union’s Horizon 2020 research and innovation 21 programme under grant agreement No 899871. 22 23 Data Availability: The data underlying this article will be shared on reasonable request to the 24 corresponding authors. 25 26 27 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 9

1 1. Sharma A, Richards M, Olshansky B, Wold N, Jones P, Perschbacher D, Wilkoff BL. 2 Heart rate score, a measure related to chronotropic incompetence in pacemaker patients. 3 Heart Rhythm O2. 2021;2:124-131. 4 2. Gopinathannair R, Sharma A, Jones P, English C, Furmanek S, Olshansky B. Heart rate 5 score and outcomes in ICD patients: insights from the prospective randomized INTRINSIC 6 RV trial. J Interv Card Electrophysiol. 2022;64:87-93. 7 3. Olshansky B, Richards M, Sharma A, Wold N, Jones P, Perschbacher D, Wilkoff BL. 8 Survival after rate-responsive programming in patients with cardiac resynchronization 9 therapy-defibrillator implants is associate with a novel parameter: The Heart rate score. Circ 10 Arrhythm Electrophysiol. 2016;9:e003806. 11 4. Wilkoff BL, Richards M, Sharma A, Wold N, Jones P, Perschbacher D, Olshansky B. A 12 device histogram-based simple predictor of mortality risk in ICD and CRT-D patients: the 13 heart rate score. 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CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 10 fibrillation: An echocardiographic study. Stroke prevention in atrial fibrillation investigators. 1 Am Heart J. 1999;137:494-499. 2 11. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola VP, 3 Parissis J, Laroche C, Piepoli MF, Fonseca C, et al. Epidemiology and one-year outcomes in 4 patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an 5 analysis of the ESC Heart Failure long-term registry. Eur J Heart Fail. 2017;19:1574-1585. 6 12. 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Sharma AD, Wilkoff BL, Richards M, Wold N, Jones P, Perschbacher D, Olshansky B. 29 Lower rate limit for pacing by cardiac resynchronization defibrillators: Should lower rate 30 programming be reconsidered? Heart Rhythm. 2021;18:2087-2093. 31 32 33 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 11 Figure and Table Legends 1 Figure 1. Example of HRSc 2 3 The HRSc was defined as the percent of all paced and sensed atrial event in single most 4 populated 10-bpm rate histogram bin. This figure shows an example of HRSc of the patients 5 in DDD mode. Here, HRSc is calculated as 74%. 6 HRSc indicates heart rate score. 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 12 Figure 2. Optimal HRSc for predicting AHREs 1 2 3 J-statistic analysis shows 80% as the optimal HRSc for predicting device-determined AHREs. 4 AHREs, atrial high-rate episodes; HRSc, heart rate score. 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 13 Figure 3. Survival free from AHREs by HRSc 1 2 Survival free from AHREs by HRSc Grouping is shown in this Kaplan-Meyer analysis. 3 Kaplan-Meier analysis shows that subjects with an initial HRSc ≥80% had a higher incidence 4 of AHREs versus those with an initial HRSc <80%, the primary end point. 5 HRSc indicates heart rate score; AHREs, atrial high-rate episodes. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 14 Figure 4. Heart Rate Score and % RA pacing (Correlation by continuous measures) 1 2 The %RA pacing and initial HRSc were strongly correlated. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 15 Figure 5. Heart rate score and %RA pacing (%RA pacing ≥70%, N=61) 1 2 In the patients with %RA pacing ≥70%, when the rate response was OFF (red point, N=7), all 3 HRSc was ≥80%. On the other hand, when the rate response was ON (blue point, N=54), 14 4 /54 patients had HRSc <80% 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 16 Figure 6. Heart rate score and %RA pacing (%RA pacing <70%, N=75) 1 2 In the patients with RA pacing <70%, the distribution of HRSc did not differ between the 3 cases with rate response ON (blue point, N=40) and OFF (red point, N=35). 4 HRSc indicates heart rate score; RA, right atrium. 5 6 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 17 Table 1. Patient characteristics 1 Demographics Age (years) Gender: Male, n (%) Race, n (%) Asian European American African American Multi-racial Medical history, n (%) Hypertension Diabetes mellitus Ischemic heart disease Cardiomyopathy Medication regimen, n (%) Angiotensin converting enzyme inhibitor Angiotensin receptor blocker ꞵ-blocker Anti-arrhythmic drugs Anticoagulant Echocardiographic measurements Left ventricular ejection fraction, % Left atrial diameter, mm Pacing site, n (%) Right atrium Appendage Low septum Right ventricle Apex Septum 75 ± 10 57 (41.9) 73 (53.7) 56 (41.2) 6 (4.4) 1 (0.7) 76 (55.9) 24 (17.6) 14 (10.3) 10 (7.3) 6 (4.4) 26 (19.1) 19 (14.0) 0 (0) 6 (4.4) 62 ± 7 41 ± 7 131 (96.3) 5 (3.7) 47 (34.6) 89 (65.4) Continuous variables were expressed as mean ± standard deviation (SD); Categorical data are 2 presented as number (percentage). 3 4 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Heart Rate Score and Atrial High-Rate Episodes February 5, 2024 18 Table 2. Pacemaker programming and interrogation data 1 Pacing mode DDD DDDR DDIR Rate responsive pacing programming ON Dual sensors (Accelerometer and Minute ventilation) Single sensors Accelerometer Minute ventilation Atrial sensitivity Pacing rate, ppm Lower rate limit Max tracking rate limit Atrioventricular interval, ms Sensed Paced Cumulative% of Atrial paced Ventricular paced 42 (30.9) 93 (68.4) 1 (0.7) 94 (69.1) 63 31 11 20 0.4 ± 0.1 59 ± 4 124 ± 11 219 ± 74 238 ± 62 57 ± 32 13 ± 27 HR indicates heart rate; RV, right ventricle; DDD, non-rate responsive pacing; DDDR, DDIR, 2 rate responsive pacing. 3 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint Table 3. Predictors for AHREs 1 Univariate analysis Multivariable analysis OR (95% CI) P value OR (95% CI) P value Age, per year Gender, male Hypertension Diabetes mellitus Coronary artery disease Cardiomyopathy ꞵ-blocker Angiotensin receptor blocker European American (Race) vs. Japanese LV ejection fraction, per 1% Left atrium diameter, mm Rate response On Lower rate limit, ppm %RA pacing %RV pacing Initial heart rate score ≥ 80% 0.99 (0.96-1.04) 2.63 (1.12-6.17) 1.28 (0.55-3.00) 0.50 (0.14-1.80) 1.06 (0.27-4.08) 0.96 (0.19-4.80) 1.03 (0.31-3.34) 0.44 (0.12-1.60) 2.03 (0.85-4.86) 0.96 (0.90-1.02) 1.02 (0.95-1.10) 3.26 (1.05-10.08) 1.05 (0.93-1.19) 3.91 (0.94-16.27) 1.86 (0.45-7.68) 3.22 (1.37-7.61) 0.97 0.03 0.56 0.29 0.94 0.96 0.96 0.21 0.11 0.23 0.56 0.04 0.43 0.06 0.39 0.007 2.55 (1.05-6.19) 2.77 (0.86-8.91) 2.84 (1.17-6.92) 0.04 0.09 0.02 AHREs = Atrial high-rate episodes; RA = Right atrium; RV = Right ventricle; OR = Odds Ratio; CI = Confidence interval. 2 . CC-BY-NC 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 8, 2024. ; https://doi.org/10.1101/2024.02.07.24302470doi: medRxiv preprint