
==== Front
Ann Noninvasive Electrocardiol
Ann Noninvasive Electrocardiol
10.1111/(ISSN)1542-474X
ANEC
Annals of Noninvasive Electrocardiology
1082-720X
1542-474X
John Wiley and Sons Inc. Hoboken

10.1111/anec.70011
ANEC70011
ANEC-23-4924.R1
Original Article
Original Article
Incidentally Induced Atrial Fibrillation During Programmed Electrical Stimulation in Patients With Depressed Left Ventricular Systolic Function After an Acute Myocardial Infarction
Sakthivel Tharsika https://orcid.org/0000-0001-5744-7311
1 tharsika.sakthivel@regionh.dk

Risum Niels 1
Bundgaard Henning 1
Joergensen Rikke Moerch 2
Jacobsen Uffe G. 3
Huikuri Heikki V. 4
Thomsen Poul Erik Bloch 5
Jons Christian 1
Thomsen Anna F. 1
1 Department of Cardiology Rigshospitalet University Hospital Copenhagen Denmark
2 Department of Cardiology North Zealand University Hospital Hillerød Denmark
3 Department of Cardiology Zealand University Hospital Roskilde Denmark
4 Department of Cardiology Oulu University Hospital Oulu Finland
5 Department of Cardiology Aalborg University Hospital Aalborg Denmark
* Correspondence:
Tharsika Sakthivel (tharsika.sakthivel@regionh.dk)

03 9 2024
9 2024
29 5 10.1111/anec.v29.5 e7001131 7 2024
02 1 2024
17 8 2024
© 2024 The Author(s). Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

ABSTRACT

Background

The aim of this study was to investigate the clinical implication of incidentally induced atrial fibrillation (AF) during programmed electrical stimulation (PES) in patients with left ventricular systolic dysfunction (≤40%) after an acute myocardial infarction (MI).

Methods

In this study, we included 231 patients from the Cardiac Arrhythmias and RIsk Stratification after Myocardial InfArction (CARISMA) study with left ventricular ejection fraction ≤40% and no prior history of AF. These patients underwent PES 6 weeks post‐MI as part of the study protocol. Patients all received an implantable cardiac monitor (ICM) 3–21 days post‐MI and were continuously monitored for cardiac arrhythmias for 2 years. Induction of AF was unwanted but reported if this incidentally occurred.

Results

A total of 61 patients (26%) developed AF within 2 years of follow‐up, in which n = 10 (29%) had incidental AF during PES at baseline. The overall risk of AF was not significantly increased in patients with incidental AF (n = 34) during PES compared to patients without incidental AF (n = 197) (HR 1.6 [0.9–3.0], p = 0.14). The risk of bradyarrhythmia (HR = 0.2 [0.0–1.2], p = 0.07), ventricular arrhythmias (HR = 0.7 [0.1–5.8], p = 0.77), and major cardiovascular events (MACE) (HR 0.5 [0.2–1.7], p = 0.28) was not significantly different in patients with versus without incidental AF.

Conclusions

Incidentally induced AF during PES in post‐MI patients with reduced LVEF was not significantly associated with a higher risk of long‐term atrial fibrillation, other cardiac arrhythmias, or major cardiac events.

Trial Registration

NCT00145119

Two hundred and thirty‐one patients post‐acute myocardial infarction (AMI) underwent programmed electrical stimulation (PES) and 34 patients had incidental induced atrial fibrillation (AF). An implantable cardiac monitor (ICM) was implanted in all patients. Through 2 years of follow‐up, 61 patients in total (26%) and 10 patients with incidental AF during PES (29%) developed AF.

acute myocardial infarction
atrial fibrillation
CARISMA
implantable loop recorder
programmed electrical stimulation
source-schema-version-number2.0
cover-dateSeptember 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:03.09.2024
Funding: The authors received no specific funding for this work.
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pmc1 Introduction

Programmed electrical stimulation (PES) has primarily been used to evaluate the inducibility of sustained ventricular tachycardias, which, depending on the cardiac function and coronary status, correlates to the risk of malignant arrythmias and sudden cardiac death (Zaman et al. 2016; Dhingra 1991; Bourke et al. 1991; Denniss et al. 1986; Schmitt et al. 2001; Buxton et al. 1999). Atrial fibrillation (AF) during PES is often incidental, but whether AF during PES is correlated with a future risk of developing AF is yet to be investigated.

In‐hospital AF is a common complication to myocardial infarction (MI), particularly in patients with reduced left ventricular ejection fraction (LVEF) and is associated with increased in‐hospital short‐ and long‐term mortality (Schmiegelow et al. 2011; Eldar et al. 1998; Schmitt et al. 2009; Behar et al. 1992). A previous study has found an association between new‐onset AF post‐MI and an increased risk of developing both bradyarrhythmia and ventricular tachycardia (VT) (Ruwald et al. 2013). Yet the related risk of long‐term malignant arrhythmias and major cardiovascular events in patients with incidental AF during PES is undescribed.

In the Cardiac Arrhythmias and RIsk Stratification after Acute Myocardial Infarction (CARISMA) study, patients with MI and LVEF ≤40% were implanted with an implantable cardiac monitor (ICM) and followed for 2 years (Huikuri, Mahaux, and Bloch‐Thomsen 2003). The primary aims were to describe the incidence of malignant arrhythmias after MI and to predict fatal or near‐fatal cardiac arrhythmic events using invasive and noninvasive electrophysiologic examinations 6 weeks post‐MI including PES. AF during PES was reported if incidentally induced. The aim of this substudy was to investigate the possible predictive value of incidentally induced AF during PES in patients with depressed left ventricular systolic dysfunction after an MI.

2 Methods

The study was conducted in agreement with recommendations for cohort studies by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative (Cuschieri 2019).

2.1 Population

The CARISMA study was a multicenter observational study that included 312 patients with acute MI and LVEF ≤40% between 2001 and 2006. A total of 297 patients received an implantable cardiac monitor (ICM) 5–21 days post‐MI and 273 of these patients underwent PES 6 weeks post‐MI. Twenty‐five patients had known AF at enrollment (chronic: n = 8, paroxysmal: n = 17), and 17 developed AF before week 6. These patients were excluded due to bias. This led to a total of 231 patients were included in this study. Further information on the population has been described in detail previously (Huikuri et al. 2009). Clinical follow‐up visits were scheduled at 3‐month intervals for up to 2 years after the MI. During the study, a pacemaker was implanted in 14 patients and an ICD in 43 patients of the 231 patients included. The choice of medical treatment was made by the treating electrophysiologist independently of the trial.

2.2 Implantation and Programming of the Loop Recorder

The ICM (Medtronic Reveal Plus) was implanted subcutaneously under local anesthesia in the left parasternal area 5–21 days post‐MI. The device was programmed to document and store any tachyarrhythmias ≥125 beats per minute (bpm) with a duration of at least 16 consecutive beats, any bradyarrhythmias ≤30 bpm lasting at least four consecutive beats, and asystolic events lasting at least 4.5 s. Arrhythmias occurring outside this diagnostic window were not stored as events. The memory of the loop recorder was interrogated, and the sensitivity of arrhythmia detection was adjusted individually according to the number of false events at each clinical visit during follow‐up. All arrhythmias were diagnosed using the ICM, pacemaker, or ICD, and any new device was programmed with parameters analogous to the ICM. Each stored episode was primarily interpreted locally by the investigator. After study closure, all arrhythmias confirmed by the investigator were adjudicated centrally by members of the steering committee blinded to the outcome. The ICM was found to document 70% of all supraventricular arrhythmias in a pilot study on the CARISMA population (Huikuri, Mahaux, and Bloch‐Thomsen 2003).

2.3 Electrophysiological Study

A PES study was performed 6 weeks post‐MI following a standard protocol pacing from the right atrium or coronary sinus, right ventricular apex, and outflow tract with up to three extra stimuli with the shortest coupling interval of 200 ms (basic drive cycle lengths 600 ms and 400 ms + S2 + S3 + S4). The procedure was performed before and during the infusion of isoprenaline. The protocol included measurement of the following atrial parameters: sinus node recovery time (SNRT), atrial effective refractory period (AERP600), the AV Wenckebach point (AVWP), AV nodal effective refractory period (AVERP600), and ventricular parameters: right ventricular effective refractory period (RVERP600) and right ventricular outflow tract refractory period (RVOERP600). Induction of AF or atrial flutter was not intended but reported if incidentally induced. The PES was performed 6 weeks post‐MI.

2.4 Diagnosis of Arrhythmias

Arrhythmias were defined as: Atrial fibrillation: Irregular rhythm with no visible p‐waves and the presence of a fibrillatory line lasting ≥16 beats with a heart rate of ≥125 bpm identified by an implanted device (ICM, pacemaker or ICD) (Bloch Thomsen et al. 2010) or documented by electrocardiogram (ECG) between clinical visits.

Ventricular tachycardia: Nonsustained VT (NSVT) >125 bpm lasting more than 16 consecutive beats, sustained VT (SVT) lasting more than 30 s and ventricular fibrillation (VF). Bradyarrhythmia: 2nd degree type II or 3rd degree AV block (AVB), sinus bradycardia (SB) ≤30 bpm lasting more than 8 s, and sinus arrest (SA) lasting >4.5 s.

If the initiation of an AF event was not captured by the device at the time of AF diagnosis during the study period, the onset date was considered the date of the visit where new‐onset AF was diagnosed. Only AF events occurring after PES were included in this study.

2.5 End Points

The endpoints used in this study were new‐onset atrial fibrillation, bradyarrhythmia or ventricular tachycardia and a combined endpoint of reinfarction, stroke, hospitalization for heart failure, and cardiac death defined as major cardiovascular events (MACE). Hospitalizations for reinfarctions, stroke, and heart failure were determined by the investigator locally, whereas the mode of death was adjudicated by the endpoint committee.

2.6 Statistics

Demographic and clinical baseline characteristics were tested for normality using the Shapiro–Wilk's test and Student's t‐test, χ 2 test, and Wilcoxon test were used where appropriate. Time to first arrhythmic or major cardiovascular event was estimated using the cumulative incidence function (CIF), and graphic presentation of the cumulative probability was done using the CIF curve. All ICM‐documented arrhythmias and major cardiovascular events were treated as time‐dependent covariates with the index MI as the time of origin. We used the Kaplan–Meier method and the log‐rank test to generate the landmark estimate (188 days post‐MI) for the risk of AF within 2 years of follow‐up. Univariate and multivariate hazard ratios were obtained from Cox proportional hazard regression using patients without incidental AF as reference group. Significant univariate risk factors were added to the multivariate Cox model along with significant baseline and clinically relevant variables: age, QRS >120 ms, CHF, NYHA II–III, hypertension, previous stroke, no revascularization, Q‐wave infarction, and septal located infarction. If the multivariate Cox models could not accommodate all significant covariates, we did the best subset selection using the branch‐and‐bound algorithm of Furnival and Wilson (Cristian Gatu 2002). This in order to reduce the risk of overfitting. We limited the maximum number of descriptive variables to 1 per 5 endpoint events to secure model stability.

All analyses were performed with SAS Enterprise Guide (SAS Institute Inc., Cary, NC, USA). Two‐sided p‐values <0.05 were considered significant.

3 Results

Of the 231 patients included in this study, a total of 34 patients developed AF during the PES. A total of 61 patients developed AF during the 2 years of follow‐up (patients with incidental AF = 10, without incidental AF = 51; Figure 1). Baseline characteristics are summarized in Table 1. The mean age of patients at enrolment was 62 years (±11) and 78% were male. Patients with incidental AF during PES were slightly younger (p = 0.03), had a higher proportion of q‐wave infarction, fewer heart failure symptoms corresponding to New York Heart Association (NYHA) class II–III and were more often revascularized compared to those without incidental AF. The medical treatment, echocardiographic findings, and the distribution of multivessel disease, previous stroke, MI, and CABG were balanced in the two groups (Table 1, Table S1). Also, atrial, and ventricular electrophysiological data including AERP600, AVERP600, AVWP, SNRT, RVERP600, and RVOERP600 were equal in both groups, and they had similar frequencies of incidentally induced atrial flutter, sustained ventricular tachycardia (monomorphic and polymorphic) and ventricular fibrillation during PES (Table S2).

FIGURE 1 Patient flow. AF = atrial fibrillation; MI = myocardial infarction.

TABLE 1 Baseline characteristics at enrollment.

Demography	Patients without incidental atrial fibrillation, n = 197 (%)	Patients with incidental atrial fibrillation, n = 34 (%)	p	
Age at enrollment	63 ± 11	59 ± 12	0.03	
Male	155 (79)	25 (74)	0.50	
Hypertension	87 (44)	14 (41)	0.75	
Diabetes	43 (22)	4 (12)	0.18	
COPDa	7 (4)	2 (6)	0.52	
Renal insufficiency	10 (5)	1 (3)	0.59	
Hypercholesterolemia	76 (43)	10 (29)	0.12	
Smokers (current/former)	56 (28)/69 (35)	13 (38)/11 (32)	0.79	
Thyroid disease	10 (5)	1 (3)	0.59	
NYHA II–IIIa	154 (79)	19 (58)	0.01	
Congestive heart failure	13 (7)	4 (12)	0.29	
Previous stroke	13 (7)	2 (6)	0.88	
Previous TCIa	3 (2)	0	0.47	
Previous MIa	74 (38)	11 (32)	0.56	
Previous CABGa	37 (19)	2 (6)	0.06	
AF events (ICMa)	5 ± 6	10 ± 15	0.56	
AF days (ICM)	3 ± 4	4 ± 3	0.72	
Medical treatment	
Beta‐blocker	191 (97)	33 (97)	0.97	
Statins	167 (85)	26 (76)	0.23	
ACE‐Ia/ATIIa	179 (91)	33 (97)	0.22	
Anti‐platelet	191 (97)	34 (100)	0.30	
Digoxin	14 (7)	2 (6)	0.80	
Calcium antagonist	21 (11)	1 (3)	0.16	
Amiodaron	2 (1)	0	0.56	
LVEFa at enrollment	32 ± 6	33 ± 6	0.31	
Any PCIa	95 (48)	27 (79)	0.001	
aAbbreviations: ACE‐I = ACE inhibitors; AF = atrial fibrillation; ATII = angiotensin II receptor antagonist; CABG = coronary artery bypass graft; COPD = chronic obstructive pulmonary disease; ICM = implantable cardiac monitor; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; TCI = transient cerebral ischemia; VF = ventricular fibrillation.

3.1 Risk of New‐Onset Arrhythmias

The CIF curves in Figure 2 show the absolute risk for AF (Figure 2a), bradyarrhythmia (Figure 2b), and VT (Figure 2c) in patients with incidental and without incidental AF. Patients with incidental AF had a 6‐month and a 2‐year cumulative risk of AF of 26% and 29% respectively compared to 13% and 26% in patients without incidental AF. These results correspond to a significantly increased risk of short‐term AF in patients with incidental AF (HR 3.0 [1.3–6.7], p = 0.01). However, the risk of long‐term AF (HR 0.3 [0.1–1.9], p = 0.19) and overall AF (HR 1.6 [0.9–3.0], p = 0.14) were not increased. The mean duration of AF during PES was 571 ± 11,874 s, and the average number of AF events measured by the ICM was highest in patients with incidental AF, whereas the mean duration in days was balanced in the two groups. The multivariate HR for time to first arrhythmic event and time to first MACE with patients without incidental AF as reference group are displayed in Table 2. The overall risk of AF was not significantly increased in patients with versus without incidental AF during PES as shown in Figure 2. We found incidentally induced AF to be associated with a significantly increased risk of short‐term AF. Short‐term AF was defined as ≤188 days based on our log‐rank test landmark estimate. The risk of bradyarrhythmias or ventricular arrhythmias was not significantly different in patients with versus without incidental AF (Table 2).

FIGURE 2 Cumulative incidence function curves depicting the probability of an arrhythmic event over time divided into patients with and without incidental atrial fibrillation. (a) The probability of atrial fibrillation before and after 188 days post myocardial infarction, (b) the probability of bradyarrhythmia, (c) the probability of ventricular tachycardia including sustained ventricular tachycardia and ventricular fibrillation.

TABLE 2 Results from Cox proportional hazards regression.

Risk of an arrhythmic or major cardiovascular event in patients with incidental atrial fibrillation	
	HR a	95% CI	p	
Atrial fibrillation, overall b	1.6	0.9–3.0	0.14	
Atrial fibrillation, short‐term b	3.0	1.3–6.7	0.01	
Atrial fibrillation, long‐term b	0.3	0.1–1.9	0.19	
Bradyarrhythmia	0.2	0.0–1.2	0.07	
Ventricular tachycardia	0.7	0.1–5.8	0.77	
Major cardiovascular event	0.5	0.2–1.7	0.28	
Note: Multivariate hazard ratios (HR) for time to first arrhythmic event and time to first major cardiovascular event including re‐AMI, stroke, hospitalization for heart failure or cardiovascular death, with patients without incidental atrial fibrillation as reference group.

a Adjusted for significant univariate, baseline, and clinically relevant variables: age, QRS >120 ms, CHF, NYHAII–III, hypertension, previous stroke, no revascularization, Q‐wave infarction, and septal located infarction.

b Overall including short‐term: ≤188 days post‐MI and long‐term: >188 days post‐MI.

3.2 Risk of Major Cardiovascular Events

The adjusted multivariate HRs with 95% confidence limits for time to first re‐AMI, stroke, hospitalization for heart failure, or cardiovascular death after new‐onset AF are shown in Table 2. A CIF curve in Figure 3 depicts the probability of MACE in patients with versus without incidental AF. Patients with incidental AF had a 2‐year cumulative risk of MACE of 13% compared to 15% in patients without incidental AF. The risk of MACE was not significantly different in patients with versus without incidental AF (Table 2). None of the patients with incidental AF experienced a stroke after 2 years of follow‐up, whereas five patients with nonincidental AF did. However, the number of events was very low, and conclusions must be taken with caution.

FIGURE 3 Cumulative incidence function curve depicting the probability of a major cardiovascular event over time in patients with and without incidental atrial fibrillation.

4 Discussion

In evaluation of the inducibility of sustained ventricular tachycardias, high‐rate atrial burst pacing can incidentally induce AF, also in patients without known history of the disease. This substudy to the CARISMA trial is the first to describe the potentially risk‐stratifying value of incidentally induced AF during PES in high‐risk post‐MI patients, a frequent patient population with an increased risk of thromboembolic events. We found no statistically significant association between incidental AF during PES and the risk of long‐term AF. A significant association between incidental AF and the development of AF short‐term (within 188 days post‐AMI) was identified however AF development was equalized in patients with and without incidentally induced AF throughout the full 2 years of follow‐up. Furthermore, the observed increase in short‐term development of AF may not hold any clinical significance as there was no estimated difference in the development of MACE between the two groups in this study.

Finally, we found no significant differences between incidentally induced AF and the long‐term risk of bradyarrhythmia, ventricular arrhythmias, or MACE including stroke, when comparing patients with versus without incidental AF. Still, the study population was small, and conclusions must be drawn with caution.

Programmed electrical stimulation as a tool for risk stratification has primarily demonstrated its validity as to identify the risk of ventricular arrhythmia. A CARISMA substudy showed that PES‐induced monomorphic VT was a predictor of ECG‐documented fatal or near‐fatal cardiac arrhythmia (Huikuri et al. 2009). Similarly, another study showed a significant reduction in sudden cardiac death within the study population when ventricular tachyarrhythmia was not inducible (Buxton et al. 2000). Only limited data have described the prognostic value of incidentally induced AF during PES. However as AF diagnosis post‐MI has been found to be prognostic for both short‐term and long‐term mortality, there is considerable importance in identifying patients who may be at risk of developing AF (Pedersen et al. 1999, 2006).

Marquardt et al. (2018) demonstrated the inducibility of AF via burst pacing during PES in 62 patients without a prior history of AF, and they found that incidental AF was associated with a subsequent higher risk of out‐of‐hospital new‐onset AF. The prognostic value was short‐termed (up to 5 months) when compared to our study. Yet the study was retrospective, and only half of the patients in both groups (incidental and nonincidental AF) received Holter Electrocardiograms (ECGS) or interrogations of implantable defibrillators (ICD's), pacemakers, or event recorders. Also Baek et al. (2017) showed that incidental AF during PES in 915 patients with paroxysmal supraventricular tachycardia predicted new‐onset AF during a mean follow‐up of 14 months by undescribed methods. Still, no one has to our knowledge, monitored patients with incidental AF during PES in such detail as our study regarding long‐term arrhythmias and MACE.

Whether there is a clinical advantage in discovering AF that would otherwise not have been detected is highly debatable. In the Loop study, the implantation of an ICD led to a trifold increase in the detection of AF lasting more than 6 min. However, initiation of anticoagulation therapy did not significantly reduce the risk of stroke or systemic arterial embolism compared with standard care (Svendsen et al. 2021). Contrary, the STROKESTOP results show that screening individuals with twice‐daily ECGs for 2 weeks, then treating those with detected AF, led to a small but significant reduction in ischemic/hemorrhagic stroke, systemic embolism, bleeding resulting in hospitalization, and all‐cause death (Svennberg et al. 2021). In addition to this, other substudies to the CARISMA trial found a fourfold higher incidence of new‐onset AF than earlier reported and these were associated with a more than two times increased risk of developing malignant arrhythmias (Ruwald et al. 2013; Jons et al. 2011). Similarly, AF diagnosis has in previous studies proven to be an independent predictor of ventricular arrhythmias (Grönefeld et al. 2000) and in a recent study been correlated to the development of bradyarrhythmia (Frausing et al. 2023).

Though the CARISMA trial can not to be directly compared with the LOOP or STROKESTOP trials, our results do not suggest incidental AF during PES as a prognostic marker for long‐term AF, other arrhythmias, or MACE.

To understand the conflicting outcomes from these trials we might need to rethink that not all AF is created equal and whether a classification system regarding the prognostic value of AF could be of interest. The patients with incidental AF in our study were relatively young and well, revascularized, which may imply a healthier myocardium, which, in the acute phase of an MI, might be more irritable and prone to electrical stimuli, but on the long‐term less scarred and electrical unstable, thus less prone to developing arrhythmias. These are only hypotheses, and the true relationship between patient characteristics, AF inducibility, and the long‐term risk of arrhythmias and MACE is uncertain. Our study does not suggest incidentally induced AF during PES in post‐MI patients to be a prognostic tool for long‐term AF, brady‐ or tachyarrhythmias, or MACE. However, our study population is limited. Larger studies and more data are needed in the evaluation of incidentally induced AF during PES and the potential clinical impact to further conclude on the matter.

4.1 Limitations

This study had some limitations, but many of these were mitigated by the study design. The sample size was limited. Still, the patients were monitored in much more detail than any other study population. Second, arrhythmias occurring outside the diagnostic window (30 bpm ≤ heart rate ≤ 125 bpm) were not systematically detected. However, by scheduling regular clinical visits (every 3 months for up to 2 years after the MI) there was a relatively good chance of diagnosing AF close to the real onset date. Third, the memory of the ICM contains 13 slots for automatic recording, hereafter the oldest recording is deleted when a new event is stored. Lastly, there is a risk of overfitting when including covariates in the multivariate Cox models. However, we limited the number of covariates by using the branch‐and‐bound algorithm of Furnival and Wilson if the models could not accommodate all significant covariates.

5 Conclusion

Incidentally induced atrial fibrillation during programmed electrical stimulation in patients surviving an acute myocardial infarction was associated with a slight increase in short‐term risk for AF. However, no associations were found in this study in the long‐term risk of developing atrial fibrillation other arrhythmias or major cardiovascular events. Further studies should be conducted to fully investigate the prognostic significance of incidental AF during PES and to assess the need for initiating anticoagulation therapy in these patients.

Author Contributions

TS wrote the manuscript and contributed to the review and editing of the manuscript. NR contributed with supervision and review and editing of the manuscript. HB contributed with supervision and review and editing of the manuscript. RMJ contributed to conceptualization, investigation, data validation, and the review and editing of the manuscript. RGJ contributed to conceptualization, investigation, data validation, and the review and editing of the manuscript. HVH contributed to conceptualization, investigation, project administration, and the review and editing of the manuscript. PEBT contributed to conceptualization, investigation, project administration, funding acquisition, and the review and editing of the manuscript. CJ contributed with supervision, investigation, data validation and review and editing of the manuscript. AT contributed to the data analysis, supervision and review and editing of the manuscript. All authors had final responsibility for the decision to submit for publication.

Ethics Statement

The main CARISMA study was approved by the local ethics committee, the Danish National Board of Health, and the Danish Data Protection Agency and conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from each patient.

Conflicts of Interest

Dr. Bloch Thomsen and Dr. Heikki V. Huikuri received research grants and speakers' fees from Medtronic Inc., St. Jude Medical, and Boston Scientific. None of the other authors have any financial conflicts of interest to declare. Heikki V. Huikuri is an Editorial Board member of Annals of Noninvasive Electrocardiology and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication.

Supporting information

Tables S1–S2

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to information that could compromise the privacy of research participants.
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