Abstract
Background
Atrioventricular block (AVB) occurring exclusively at night has traditionally been considered a result of increased vagal tone and thought to have a favorable prognosis. While nocturnal AVB is generally not an indication for pacemaker implantation, supporting evidence remains limited. This study aimed to assess the natural history of nocturnal AVB.
Methods
Patients with 2:1, high-degree, or complete AVB (CAVB) detected exclusively during nighttime (21:00–07:00) on 24-hour electrocardiogram (ECG) monitoring were classified as having nocturnal AVB. The primary outcome was pacemaker implantation during the follow-up period.
Results
A total of 10,977 individuals underwent 24-hour ECG monitoring in Seoul St. Mary's Hospital between January 2000 and June 2020. Among them, 342 patients were diagnosed with CAVB, high-degree AVB, or 2:1 AVB, and 92 of these 342 patients had nocturnal AVB. Excluding 11 patients lost to follow-up, 81 patients were enrolled. Fourteen patients underwent immediate pacemaker implantation due to daytime bradycardia symptoms, while the remaining 67 patients underwent watchful waiting. During a median follow-up period of 2.4 years, 14 of these 67 patients received pacemaker implantation (n: CAVB 5/14, high-degree AVB 4/14, 2:1 AVB 5/14). The indications for pacemaker insertion included the development of bradycardia symptoms or signs (n = 13) and sick sinus syndrome (n = 1) during the daytime.
Conclusion
Despite being asymptomatic during the daytime, 21% (14/67) of patients with nocturnal AVB required pacemaker implantation during a median follow-up period of 2.4 years. These findings suggest that active surveillance is needed even in patients with nocturnal AVB.
Keywords: AV Block, Nocturnal AV Block, Artificial Pacemaker, Bradycardia, Electrocardiography
Graphical Abstract
INTRODUCTION
In the guidelines, a pacemaker insertion is strongly recommended for patients with symptomatic atrioventricular block (AVB) and for those with high-grade AVB, even in the absence of symptoms.1,2 In previous studies, high-grade AVB without appropriate treatments showed a low survival rate of 10–25% at 5 years.3,4 Particularly, complete AVB (CAVB) was generally considered an irreversible condition.5 Conversely, the permanence of AVB occurring exclusively at night remains uncertain. In cases of nocturnal AVB, guidelines have suggested that sleep-related bradyarrhythmia be considered.1,2 The clinical implications of AVB during sleep have been evaluated in several studies.6,7,8 Rapid eye movement (REM) sleep-related bradyarrhythmia syndrome was first described by Guilleminault et al.,7 who reported four cases of sinus arrest during REM sleep. They proposed that the mechanism of nocturnal AVB was likely associated with changes of autonomic tone due to the transition from non-REM to REM sleep.7 Serafini et al.8 examined the necessity of pacemaker implantation in patients with REM sleep-related bradyarrhythmia. Although untreated asymptomatic nocturnal bradyarrhythmia may have a benign course, they emphasized the importance of a cautious approach due to the potential risk of sudden unexpected death caused by nocturnal arrhythmia.8
To date, specific treatment guidelines for AVB occurring only at night remain lacking, largely due to the limited evidence based on case reports.6,7 In the present study, we evaluated the long-term outcomes of patients with nocturnal AVB and assessed the necessity for pacemaker implantation. Additionally, we analyzed risk factors associated with pacemaker insertion.
METHODS
Patients with nocturnal AVB
The present study included patients who underwent 24-hour electrocardiogram (ECG) monitoring at Seoul St. Mary’s Hospital, Seoul, Korea, from January 2000 to June 2020. Patients with AVB were classified into 2:1 AVB, high-degree AVB, and CAVB types. The rhythm recorded by 3-channel (leads V1, V3, and V5) 24-hour ECG monitoring was analyzed to determine whether AVB occurred exclusively at night. In addition, the presence of PR prolongation preceding AVB was assessed, as this typically suggests functional suppression of atrioventricular (AV) conduction. PR prolongation was defined as an increased PR interval in night time compared with baseline surface ECG. Two experienced electrophysiologists reviewed the 24-hour ECG monitoring reports. At the time of AVB diagnosis, the presence of reversible causes such as ischemic heart disease, thyroid disease, or use of medications including beta-blockers (BB), non-dihydropyridine calcium channel blockers (non-DHP CCBs), and antiarrhythmic drugs was evaluated.9,10,11 Nocturnal AVB was defined as AVB occurring exclusively between 21:00 and 07:00, as previously described.12,13 If two or more types of AVB were observed concurrently, the most severe type was assigned as the main diagnosis.
Nocturnal AVB and pacemaker insertion
The need for pacemaker insertion was assessed both at the time of AVB diagnosis and during the follow-up period. For patients under watchful waiting, indications for pacemaker implantation were evaluated throughout follow-up. The presence of bradyarrhythmia-related symptoms or signs during the daytime, as well as the occurrence of other bradyarrhythmias requiring pacemaker insertion, such as sick sinus syndrome (SSS), were also assessed. Patients were monitored through outpatient clinic visits and telephone follow-ups during the follow-up period.
Statistical analysis
Continuous variables are expressed as mean ± standard deviation and compared by Student’s t-test (P < 0.050). To evaluate the differences of continuous variables in baseline characteristics between patients with and without pacemaker insertion, χ2 test (P < 0.050) was used. Risk factors for pacemaker insertion were assessed using Cox regression analysis (P < 0.050). The temporal incidence of pacemaker insertion during the follow-up period in patients with nocturnal AVB was illustrated using a Kaplan-Meier curve. All statistical analyses were performed using SPSS version 28 (IBM Corp., Armonk, NY, USA).
Ethics statement
This study was approved by the Institutional Review Board (IRB) of Catholic Medical Center (KIRB-A20240223-082). The requirement for informed consent was waived by the IRB because anonymously encoded clinical and procedural data were used.
RESULTS
Baseline characteristics
A total of 10,977 individuals underwent 24-hour ECG monitoring at Seoul St. Mary's Hospital between January 2000 and June 2020. Among them, 342 patients were diagnosed with CAVB, high-degree AVB, or 2:1 AVB, and 92 of these 342 patients were classified as having nocturnal AVB. Eleven patients were excluded due to loss to follow-up, and 81 patients were finally enrolled in the study. The mean age was 68.3 ± 17.6 years and 27.2% were female. The proportions of CAVB, high-degree AVB, and 2:1 AVB were 29.6%, 19.8%, and 50.6%, respectively. Among the underlying diseases, hypertension (HT; 49.4%) was the most common, followed by arrhythmia (37.0%; atrial fibrillation [AF], premature ventricular complex [PVC], and paroxysmal supraventricular tachycardia [PSVT]). Additionally, 28.4% (n = 23) of patients were taking BBs and non-DHP CCBs at the time of diagnosis (Table 1). These medications were prescribed for arrhythmias (AF, n = 12, PVC, n = 4, PSVT, n = 2), CAD (variant angina, n = 3), and HT (n = 2). PR prolongation preceding the onset of AVB was observed in 76.5% of patients. The mean QRS width and RR interval (maximum) are 108 ± 25 and 2,249 ± 737 msec. When comparing patients with AVB detected exclusively at night (group 1) and those with AVB detected during both day and night (group 2), group 1 had a higher proportion of female patients and showed a tendency toward a higher prevalence of arrhythmias and CAD. The proportion of CAVB was higher and that of 2:1 AVB was lower in group 2 compared to group 1 (Table 1).
Table 1. Baseline characteristics (N = 331).
| Variables | Group 1 (n = 81) | Group 2 (n = 250) | P value | ||
|---|---|---|---|---|---|
| Type | 1 | 2 | |||
| CAVB | 24 (29.6) | 133 (53.2) | < 0.001 | ||
| High-degree AVB | 16 (19.8) | 53 (21.2) | 0.903 | ||
| 2:1 AVB | 41 (50.6) | 64 (25.6) | < 0.001 | ||
| Age, yr | 68.3 ± 17.6 | 69.54 ± 18.5 | 0.608 | ||
| Sex (female) | 22 (27.2) | 105 (42.0) | 0.024 | ||
| BMI, ≥ 23 kg/m2 | 48 (59.3) | 117 (46.8) | 0.054 | ||
| Comorbidities, yes | |||||
| OSA | 5 (6.2) | 0 (0.0) | 0.001 | ||
| Stroke | 3 (3.7) | 11 (14.4) | 1.000 | ||
| Arrhythmia | 30 (37.0) | 48 (19.2) | 0.002 | ||
| AF | 24 (29.6) | 37 (14.8) | |||
| PVC | 4 (4.9) | 6 (2.4) | |||
| PSVT | 2 (2.5) | 5 (2.0) | |||
| HT | 40 (49.4) | 117 (46.8) | 0.782 | ||
| DM | 13 (16.0) | 44 (17.6) | 0.760 | ||
| HF | 5 (6.2) | 4 (1.6) | 0.071 | ||
| Thyroid disease | 5 (6.2) | 5 (2.0) | 0.125 | ||
| CAD | 22 (27.2) | 18 (7.2) | < 0.001 | ||
| COPD | 1 (1.2) | 3 (1.2) | 1.000 | ||
| Drug, yes | 23 (28.4) | 29 (11.6) | < 0.001 | ||
| BB | 10 (12.3) | 13 (5.2) | |||
| Non-DHP CCB | 6 (7.4) | 2 (0.8) | |||
| Class Ic | 3 (3.7) | 3 (1.2) | |||
| Class Ic + BB/non-DHP CCB | 3 (3.7) | 2 (0.8) | |||
| Class III | 1 (1.2) | 6 (2.4) | |||
| Digoxin | 0 (0.0) | 3 (1.2) | |||
Values are presented as mean ± standard deviation or number (%).
Among the 331 patients diagnosed with CAVB, high-grade AVB, or 2:1 AVB on Holter monitoring, those in whom AVB was observed only during nighttime (group 1), and those in whom AVB was also observed during daytime (group 2).
CAVB = complete atrioventricular block, AVB = atrioventricular block, BMI = body mass index, OSA = obstructive sleep apnea, AF = atrial fibrillation, PVC = premature ventricular complex, PSVT = paroxysmal supraventricular tachycardia, HT = hypertension, DM = diabetes mellitus, HF = heart failure, CAD = coronary artery disease, COPD = chronic obstructive pulmonary disease, BB = beta blocker, Non-DHP CCB = non-dihydropyridine calcium channel blocker, Class Ic = Flecainide, Propafenone, Pilsicainide, Class III = Aamiodarone, Dronedarone, Sotalol.
Primary outcome
Among the 81 patients, 14 underwent pacemaker insertion at the time of diagnosis, primarily due to accompanying symptoms during the daytime. The remaining 67 did not report any symptoms or have other indications for pacemaker insertion. Therefore, they were carefully monitored during the follow-up period. The median follow-up duration was 2.4 years, with a maximum of 13.8 years (Fig. 1). During the follow-up, 14 of the 67 patients (21%) eventually required pacemaker insertion. The median time to pacemaker insertion was 1.5 years, with more than half of the procedures (8/14, 57%) occurring within the first 2 years (Fig. 2). The indications for pacemaker insertion during follow-up were symptoms or signs associated with daytime AVB (n = 13) and the development of SSS necessitating pacemaker insertion (n = 1). The symptoms or signs included syncope (n = 2), dizziness (n = 3), general weakness (n = 2), and asymptomatic daytime AVB documented on repeated holter monitoring (n = 6).
Fig. 1. The study population. Among 92 nocturnal AVB, 11 patients who were lost to follow-up were excluded and 14 patients who had immediate pacemaker implantation due to daytime bradycardia symptoms and other indications for the procedure (sick sinus syndrome, CRT-D indication). Sixty-seven patients underwent watchful waiting. Over a median follow-up period of 2.4 years, 14 out of these 67 patients eventually received pacemaker implantation.
AVB = atrioventricular block, CRT-D = cardiac resynchronization therapy-defibrillator, PM = pacemaker, CAVB = complete atrioventricular block.
Fig. 2. Pacemaker insertion during the follow-up period. The median follow-up period was 2.4 years and the maximum follow-up period was 13.8 years. Among 67 patients, pacemaker insertion was required for 14 patients. The median time to pacemaker insertion was 1.5 years, with more than half of patients undergoing the procedure in the first 2 years of follow-up.
PM = pacemaker.
Patients who underwent pacemaker insertion either at diagnosis or during follow-up were more likely to be aged ≥ 65 years and to be diagnosed with CAVB or high-degree AVB rather than 2:1 AVB. They also had higher rates of HT (39.6% vs. 67.9%, P = 0.016) and diabetes mellitus (DM) (7.5% vs. 32.1%, P = 0.004) at the time of the diagnosis. While the prevalence of arrhythmia was lower in the pacemaker insertion group (41.5% vs. 28.6%, P = 0.251), other comorbidities such as HF (3.8% vs. 10.7%, P = 0.217), thyroid disease (5.7% vs. 7.1%, P = 0.792), and chronic obstructive pulmonary disease (0 vs. 3.6%, P = 0.166) were more frequently observed in this group, although the differences were not statistically significant. Additionally, there were no significant differences between groups in other comorbidities, including obstructive sleep apnea (OSA) (7.5% vs. 3.7%, P = 0.502), stroke (3.8% vs. 3.6%, P = 0.963), body mass index (25.0 ± 3.7 vs. 24.0 ± 3.6, P = 0.893), and the proportion of female patients 32.1% vs. 17.9%, P = 0.171). Although patients who received pacemakers tended to have wider QRS durations, longer RR intervals, and a lower prevalence of PR prolongation prior to AVB onset, these differences were not statistically significant (Table 2). In univariate analysis, type of AVB, age ≥ 65 years, comorbidities (DM, HT), and absence of PR prolongation were identified as potential risk factors for pacemaker insertion. In multivariate Cox regression analysis, CAVB or high-degree AVB, absence of PR prolongation, and DM were statistically significant risk factors for pacemaker insertion (type of AVB: hazard ratio [HR], 2.76; P = 0.038; DM: HR, 3.99; P = 0.002; PR prolongation: HR, 3.10; P = 0.010; Table 3).
Table 2. The difference in baseline characteristics between the no pacemaker and pacemaker insertion group.
| Variables | No pacemakera (n = 53) | Pacemakerb (n = 28) | P value | ||
|---|---|---|---|---|---|
| Type, CAVB/high | 20 (37.7) | 20 (71.4) | 0.004 | ||
| Age, ≥ 65 yr | 29 (54.7) | 22 (78.6) | 0.034 | ||
| Sex, female | 17 (32.1) | 5 (17.9) | 0.171 | ||
| BMI, ≥ 23 kg/m2 | 25.0 ± 3.7 | 24.0 ± 3.6 | 0.893 | ||
| Comorbidities, yes | |||||
| OSA | 4 (7.5) | 1 (3.7) | 0.502 | ||
| Stroke | 2 (3.8) | 1 (3.6) | 0.963 | ||
| Arrhythmia | 22 (41.5) | 8 (28.6) | 0.251 | ||
| AF | 12 | 3 | |||
| PVC | 4 | ||||
| PSVT | 2 | ||||
| HT | 21 (39.6) | 19 (67.9) | 0.016 | ||
| DM | 4 (7.5) | 9 (32.1) | 0.004 | ||
| HF | 2 (3.8) | 3 (10.7) | 0.217 | ||
| Thyroid disease | 3 (5.7) | 2 (7.1) | 0.792 | ||
| CAD | 15 (28.3) | 7 (25) | 0.751 | ||
| COPD | 0 | 1 (3.6) | 0.166 | ||
| PR prolongation, noc | 9 (18.4) | 10 (37.0) | 0.072 | ||
| QRS width, msec | 107 ± 23 | 110 ± 28 | |||
| RR interval, msec, max | 2,203 ± 748 | 2,335 ± 707 | |||
Values are presented as number (%). P < 0.050 indicates statistically significant difference.
CAVB = complete atrioventricular block, BMI = body mass index, OSA = obstructive sleep apnea, AF = atrial fibrillation, PVC = premature ventricular complex, PSVT = paroxysmal supraventricular tachycardia, HT = hypertension, DM = diabetes mellitus, HF = heart failure, CAD = coronary artery disease, COPD = chronic obstructive pulmonary disease.
aCases not undergoing a pacemaker insertion.
bCases underwent a pacemaker insertion immediately after diagnosis or during watchful waiting period.
cAtrioventricular block without preceding PR prolongation.
Table 3. Risk factors of pacemaker insertion: univariate and multivariate Cox regression analysis.
| Variables | Total pacemaker insertion groupa | |||||
|---|---|---|---|---|---|---|
| Univariate | Multivariate | |||||
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Type, CAVB/high | 2.59 | 1.136–5.878 | 0.024 | 2.76 | 1.059–7.172 | 0.038 |
| Age, ≥ 65 yr | 2.20 | 0.889–5.425 | 0.088 | 1.44 | 0.529–3.911 | 0.476 |
| DM | 2.41 | 1.088–5.340 | 0.030 | 3.99 | 1.643–9.703 | 0.002 |
| HT | 2.24 | 1.005–5.000 | 0.049 | 1.47 | 0.602–3.570 | 0.500 |
| PR prolongation, nob | 2.17 | 0.991–4.762 | 0.053 | 3.10 | 1.315–7.308 | 0.010 |
P < 0.050 indicates statistically significant difference.
HR = hazard ratio, CI = confidence interval, CAVB = complete atrioventricular block, DM = diabetes mellitus, HT = hypertension.
aIncludes cases that underwent the procedure both immediately after diagnosis and during the watchful waiting period.
bAtrioventricular block without preceding PR prolongation.
Additional analysis was also performed solely for 67 patients undergoing watchful waiting, excluding the 14 patients who received immediate pacemaker insertion. In this subgroup the pacemaker insertion group during the follow-up period comprised 35.7% (5/14) with CAVB, 28.6% (4/14) with high-degree AVB, and 35.7% (5/14) with 2:1 AVB. The mean age of patients with watchful waiting was 66.5 ± 16.8 years and 7.1% were female.
DISCUSSION
An appropriate treatment guideline has not been established due to the lack of evidence regarding the natural history of the nocturnal AVB. This study is the first to evaluate the long-term prognosis and risk factors for pacemaker insertion in patients with nocturnal AVB. Our findings showed that 21% of patients required pacemaker implantation during follow-up, with the majority occurring within the first two years (Fig. 2). These results suggest that close observation is warranted for at least the first two years after diagnosis. In particular, patients with CAVB, absence of preceding PR prolongation, or comorbid DM may require more close monitoring.
The presence of daytime signs or symptoms and the development of SSS were the main indications for pacemaker insertion. Since only a few patients underwent repeated 24-hour ECG monitoring during follow-up, the emergence of daytime bradycardia symptoms was considered a marker of disease progression. Moreover, repeated 24-hour ECG monitoring does not consistently yield reproducible results. A previous study suggested that 24-hour ECG may inadequately reflect the day-to-day burden of arrhythmias, highlighting its limitations in reproducibility.14 Therefore, even if daytime AVB is not recorded on repeated 24-hour ECG monitoring, the presence of daytime bradycardia symptoms in patients previously diagnosed with nocturnal AVB may raise the possibility of progression to daytime AVB.
The proportion of female patients diagnosed with nocturnal AVB was lower than that of male patients (27.2%). Notably, only 7.1% of patients who received pacemaker implantation during the follow-up period were females. This may reflect sex differences in the epidemiology of conduction system disorders. Previous studies have reported that females were more likely to receive pacemaker implantation for SSS rather than AVB.15,16,17 Furthermore, a twofold lower rate of pacemaker implantation in females compared to males has been observed, possibly due to atypical symptom presentation and a higher tendency to decline invasive procedures.17 At the time of nocturnal AVB diagnosis, patients aged ≥ 65 years were more likely to require pacemaker implantation during follow-up than those under 65. In the elderly, the number of pacemaker cells and the velocity within the sinoatrial (SA) node decrease due to age-related fibrotic or fatty infiltration around the SA and AV nodes.18,19 These irreversible changes in cardiomyocytes associated with aging may contribute to disease progression and the development of other bradyarrhythmias, such as SSS. In this study, comorbidities such as DM and HT appeared to be associated with pacemaker implantation; however statistical significance was limited by the small sample size. Nevertheless, the observed association of older age, male sex, and comorbid DM and HT with conduction abnormalities aligns with findings from previous studies.20,21,22
The present study aimed to evaluate the clinical implication of PR interval prolongation at the onset of AVB compared to the baseline ECG. In this study, patients without PR prolongation preceding AVB recorded with 24-hour ECG monitoring showed a higher risk of pacemaker insertion. The PR interval reflects conduction through the atrium, AV node, and His-Purkinje system. While chronic PR prolongation is typically considered a risk factor for pacemaker implantation, both PR interval and heart rate can be influenced by circadian variations in parasympathetic tone.23,24,25 Moreover, AVB occurring without preceding PR prolongation may suggest structural abnormalities in the atria, including the AV node–His–Purkinje system, which are likely to be permanent and associated with worse outcomes during follow-up.26 In contrast, the presence of PR prolongation at the onset of nocturnal AVB may indicate a vagally mediated, functional AVB rather than structural conduction system disease.27,28
The baseline QRS width, interventricular conduction disease and the longest R-R interval in 24-hour ECG monitoring were also evaluated. Although both the QRS width and the longest R–R interval were greater in patients who underwent pacemaker implantation compared to those who did not, the differences were not statistically significant. The mean QRS width was in normal range and mean the longest RR interval was 2,249 ± 737 msec. A wide QRS complex, indicating infrahisian block, and interventricular conduction disease have been proposed as potential risk factors for pacemaker implantation in patients with AVB.29 However, in the present study, approximately 21% of patients required pacemaker implantation during follow-up despite the absence of these additional risk factors. This finding suggests that close monitoring is warranted even in patients without wide QRS complexes or interventricular conduction disease, and pacemaker implantation should be considered when clinically indicated. In the multivariate analysis including all patients (those with immediate and delayed pacemaker implantation), CAVB and high-degree AVB were associated with a higher risk of pacemaker implantation compared to 2:1 AVB. However, when the analysis was limited to patients under watchful waiting, no significant differences in pacemaker implantation rates were observed among AVB subtypes. This lack of statistical significance may be attributed to the small sample size and the limited number of patients in each AVB subtype group after excluding those who underwent immediate pacemaker implantation.
First, the study had limitations due to its retrospective design. OSA and REM sleep-associated bradyarrhythmia could not be assessed as polysomnography was not consistently performed at the time of diagnosis. A recent study suggesting that moderate-to-vigorous physical activity is associated with a lower risk of second- to third-degree AVB indicates that physical activity levels may also be a potential risk factor for AVB progression and pacemaker insertion.30 However, this factor was not evaluated as a risk factor in the present study. Second, due to the small sample size, statistical significance was not achieved in some analyses. Although certain risk factors such as age and HT did not reach statistical significance in the Cox regression analysis, their associations with increased risk of pacemaker implantation were consistent with findings from previous studies. Additionally, to confirm whether AVB is mediated by vagal tone, it is necessary to evaluate heart rate reduction accompanying PR prolongation. However, the study relied on 24-hour ECG monitoring, which selectively presents ECG strips for specific events, making it difficult to accurately assess heart rate changes preceding AVB. Moreover, repeated 24-hour ECG monitoring does not consistently yield reproducible results. Further prospective studies involving a larger number of patients are needed to validate these findings.
Footnotes
Disclosure: The authors have no potential conflicts of interest to disclose.
- Conceptualization: Kim SH.
- Data curation: Park S.
- Formal analysis: Kim SH, Kim H, Kim S,.
- Methodology: Kim SH, Park S.
- Software: Kim DY.
- Validation: Park S.
- Investigation: Oh YS.
- Writing - original draft: Park S, Kim SH.
- Writing - review & editing: Kim SH. Choi Y.
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