Permanent pacemaker implantation in unexplained syncope patients with borderline sinus bradycardia and electrophysiology study‐proven sinus node disease

Abstract Background Significant sinus bradycardia (SB) in the context of sinus node dysfunction (SND) has been associated with neurological symptoms. The objective was to evaluate the effect of permanent pacing on the incidence of syncope in patients with rather mild degrees of SB, unexplained syncope, and “positive” invasive electrophysiologic testing. Methods This was an observational study based on a prospective registry of 122 consecutive mild SB patients (61.90 ± 18.28 years, 61.5% male, 57.88 ± 7.73 bpm) presenting with recurrent unexplained pre and syncope attacks admitted to our hospital for invasive electrophysiology study (EPS). Τhe implantation of a permanent antibradycardia pacemaker (ABP) was offered to all patients according to the results of the EPS. Eighty patients received the ABP, while 42 denied. Results The mean of reported syncope episodes was 2.23 ± 1.29 (or presyncope 2.36 ± 1.20) in the last 12 months before they were referred for a combined EP guided diagnostic and therapeutic approach. Over a mean follow‐up of approximately 4 years (50.39 ± 32.40 months), the primary outcome event (syncope) occurred in 18 of 122 patients (14.8%), 6 of 80 (7.5%) in the ABP group as compared to 12 of 42 (28.6%) in the no pacemaker group (P = .002). Conclusions Among patients with mild degree of SB and a history of unexplained syncope, a set of positivity criteria for the presence of EPS defined SND after differentiating reflex syncope, identifies a subset of patients who will benefit from permanent pacing.


| INTRODUC TI ON
Significant sinus bradycardia (SB) in the context of sinus node dysfunction (SND) has been associated with neurological symptoms such as dizziness, vertigo, or near syncope and syncope attacks. [1][2][3] Syncope, defined as a transient loss of consciousness caused by transient global cerebral hypoperfusion, is a relatively common cause for seeking medical help, with visits progressively increasing with age. 4 It has been suggested that a persistent fall in the heart rate of ≤50 Bpm or/and the presence of sinus pause of ≥3 seconds on a 12lead ECG and 24h Holter monitor recording respectively, during the workup of unexplained syncope, should be treated with permanent antibradycardia pacing (ABP). 4 An ABP is also recommended when the electrophysiological study (EPS) reveals marked prolongation of the corrected sinus node recovery time. 4 It is of note that official guideline recommendations for permanent pacing are not based on clinical studies. Other means of EPS derived evidence of SND such as sinoatrial conduction time (SACT) and the chronotropic response to atropine have not been included in the European and American guidelines for the management of unexplained syncope patient. [4][5][6] Furthermore, we still lack clear answers to seemingly simple questions including the appropriate use of EPS and the exact criteria for pacing based on the results. In relation to the above, we have previously shown that a strong correlation exists between a variety of EPS derived SND parameters and even mild degrees of SB among such unexplained syncope patients. 7 Whether these symptomatic patients with mild degrees of SB and EPS evidence of SND would benefit from ABP while avoiding the need for an implantable loop recorder to further establish the diagnosis, is a highly debatable issue.
The objective of the present "real-world" study was to evaluate the effect of permanent pacing on the incidence of syncope in patients with mild degrees of SB, unexplained syncope and "positive" invasive electrophysiologic testing.

| ME THODS
This was an observational study based on a prospective registry of 665 screened patients (195 patients with heart rate ≤60 bpm in the 12-lead ECG obtained at the time of admission, mean heart rate: 55.44), presenting with recurrent unexplained pre and syncope attacks admitted to our hospital for invasive EPS from 1995 until 2017 ( Figure 1).

| 12-lead electrocardiography and 24-hour ambulatory monitor and EPS findings
The methodology of obtaining the noninvasive ECG features and the invasive EPS results has been previously published and has been consistently performed since the beginning of the study. 7 The 12lead ECG resting heart rate was the one observed in the EP laboratory before the introduction of the EP catheters. The mean 24-Hour ambulatory monitor derived heart rate was calculated after careful elimination of artifacts and any ventricular ectopic beats on appropriate template recognition patterns. Any sinus pauses <3 seconds were identified and noticed. SND was considered to be present when any of the following was detected:

| Patient follow-up and outcome measures
Patients with ABP where followed up by at least 12-month visits in the pacemaker clinic where telemetric interrogation of the device was performed regularly. In case of symptom recurrence and based on the degree of clinical suspicion, apart from the device interrogation to exclude malfunction, alternative causes of syncope recurrence were sought, occasionally repeating noninvasive testing such as tilt table testing or even EPS if complex ventricular arrhythmia in the device memory were detected. Any atrial high rate episodes detected by the device were noticed and recorded. Patients not receiving ABP were also followed up at least yearly with either clinic visits or/and telephone contacts. The study primary outcome measure was the time to the event of syncope (syncope-free survival). Secondary outcome was time-to-death from any cause.

| Statistical analysis
Continuous variables were summarized with mean and standard deviation (SD) and compared using independent samples t test or Mann-Whitney U test as appropriate. Categorical variables were described with frequencies and percentage and compared using chisquared test. Kaplan-Meier curves were used to visualize survival free from primary endpoint occurrence and the log rank test was applied to assess the presence of statistically significant differences.
Multivariate Cox regression was used in order to assess and compare impact of parameters on survival free from primary endpoint occurrence. Significance level was set to P < .05 and two tailed. Data analysis was performed using the IBM/Statistical Package for Social Sciences (SPSS version 24; IBM, Chicago, IL, USA) program.

| RE SULTS
The clinical laboratory patients' characteristics are presented in Table 1. Most of the patients were elderly male without an underlying organic heart disease and with well-maintained LVEF.
The mean of reported syncope episodes was 2.23 ± 1.29 (or presyncope 2.36 ± 1.20) in the last 12 months before they were referred for a combined EP guided diagnostic and therapeutic approach.
There were no statistical differences in the number of reported pre or/and syncope episodes in those who were later implanted with a pacemaker vs in those who did not receive a pacemaker. The 12-lead ECG heart rate was 57.88 ± 7.73, and approximately 50% of patients had mean 24-hour heart rate ≤60 bpm. A significant proportion of patients had associated conduction defects on the 12-lead ECG in the form of 1st degree atrioventricular block (1st AVB), right or left bundle branch block (LBBB), bifascicular or trifascicular block. A 1st AVB, LBBB and bifascicular block were more frequently observed among pacemaker patients.
The EPS results are presented in Table 2. In the multivariable analysis, permanent pacing remained associated with syncope-free survival in the predefined Cox regression model including age, ejection fraction, and organic heart disease: multivariable odds ratio 0.17 (95% confidence interval 0.06-0.50).
Pacemaker status was the only independent predictor of the primary event, associated with 83% decrease in the risk of recurrent syncope (Table 3). Adding 1st AVB, LBBB and Bifascicular block before EPS to the variables of the model did not change the result in any significant way.

| D ISCUSS I ON
In this analysis of "real-world" data in patients with mild degrees of SB, with a history of unexplained syncope, a set of positivity criteria for EPS evidence of SND identifies a subset of patients who will definitely benefit from permanent pacing, in terms of both preventing new syncopal episodes and reducing total mortality. A rather significant proportion of these SB/SND patients had an associated AVNCD based on the presence of both noninvasive and invasive abnormal electrophysiological parameters.
None of our syncope patients had severe SB or long enough pauses on the noninvasive electrocardiographic screening, to justify direct permanent antibradycardia pacing. Furthermore, the documentation of SND on EPS was supported by additional to those referred in the guidelines criteria of positivity. 4,7 Thus, even mild degrees of SB may be associated with EPS evidence of SND among recurrent syncope patients in whom atrioventricular pacing may suppress neurological symptoms during follow-up. After a noninvasive ECG examination, a thorough EPS should follow in a combined EP guided risk stratification approach in such symptomatic SB patients. Within the advantages of such an approach are apart from the obvious clinical benefits, the avoidance of the need to resort to an implantable loop recorder policy which is associated with increased costs and the recurrent risk of injury secondary to syncope. [8][9][10] In our study protocol we used quite "strict" criteria of abnormal electrophysiology test findings. 5,[11][12][13][14][15] On the contrary, in the guidelines the sinus node function assessment was limited to the sinus node recovery time, ignoring other parameters such as the SACT and the chronotropic response to atropine. 4 In agreement to our study results, the detection of SND on EPS is significantly improved when