ORIGINAL RESEARCH published: 25 February 2022 doi: 10.3389/fcvm.2022.838473 Sex-Related Differences in Patients With Unexplained Syncope and Bundle Branch Block: Lower Risk of AV Block and Lesser Need for Edited by: Cardiac Pacing in Women Jonathan Chrispin, Johns Hopkins Medicine, Jaume Francisco-Pascual 1,2,3*, Nuria Rivas-Gándara 1,2,3*, Montserrat Bach-Oller 4 , United States Clara Badia-Molins 4 , Manel Maymi-Ballesteros 4 , Begoña Benito 1,2,3 , Reviewed by: Jordi Pérez-Rodon 1,2,3 , Alba Santos-Ortega 1,2,3 , Antonia Sambola-Ayala 2,3,4 , Ronald Berger, Ivo Roca-Luque 1,3,5 , Javier Cantalapiedra-Romero 1,2,3 , Jesús Rodríguez-Silva 1 , Johns Hopkins University, Gabriel Pascual-González 1 , Àngel Moya-Mitjans 1,6 and Ignacio Ferreira-González 2,4,7 United States Andreas Barth, 1 Arrhythmia Unit, Cardiology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall Johns Hopkins Medicine, d’Hebron Barcelona Hospital Campus, Barcelona, Spain, 2 Department of Medicine, Universitat Autònoma de Barcelona, United States Bellaterra, Spain, 3 CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain, 4 Cardiology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron *Correspondence: Barcelona Hospital Campus, Barcelona, Spain, 5 Arrhythmia Section, Institut Clinic Cardiovascular, Hospital Clínic, Jaume Francisco-Pascual Barcelona, Spain, 6 Cardiology Department, Hospital Universitari Dexeus, Barcelona, Spain, 7 CIBER de Epidemiología y jafranci@vhebron.net Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain orcid.org/0000-0002-8841-2581 Nuria Rivas-Gándara nrivas@vhebron.net Objective: To analyze if there are sex-related differences in patients with unexplained syncope and bundle branch block (BBB). Specialty section: This article was submitted to Background: Despite increasing awareness that sex is a major determinant of the Sex and Gender in Cardiovascular incidence, etiology, and the outcomes of different arrhythmias, no studies have examined Medicine, a section of the journal differences in presentation and outcomes between men and women with syncope Frontiers in Cardiovascular Medicine and BBB. Received: 17 December 2021 Methods: Cohort study of consecutive patients with unexplained syncope and BBB Accepted: 21 January 2022 Published: 25 February 2022 was included from January 2010 to January 2021 with a median follow-up time of 3.4 Citation: years [interquartile range (IQR) 1.7–6.0 years]. They were evaluated by a stepwise workup Francisco-Pascual J, protocol based on electrophysiological study (EPS) and long-term follow-up with an Rivas-Gándara N, Bach-Oller M, Badia-Molins C, Maymi-Ballesteros M, implantable cardiac monitor (ICM). Benito B, Pérez-Rodon J, Results: Of the 443 patients included in the study, 165 (37.2%) were women. Compared Santos-Ortega A, Sambola-Ayala A, Roca-Luque I, with men, women had less diabetes (25.5 vs. 39.9%, p = 0.002) and less history of Cantalapiedra-Romero J, ischemic heart disease (IHD; 13.3 vs. 25.9%, p = 0.002). Left bundle branch block Rodríguez-Silva J, Pascual-González G, Moya-Mitjans À (LBBB) was more frequent in women (55.2 vs. 27.7%, p < 0.001) while right bundle and Ferreira-González I (2022) branch block (RBBB) was more frequent in men (41.5 vs. 67.7%, p < 0.001). His to Sex-Related Differences in Patients ventricle (HV) interval in the EPS was shorter in women (58 ms [IQR 52–71] vs. 60 ms With Unexplained Syncope and Bundle Branch Block: Lower Risk of [IQR 52–73], p = 0.035) and less women had an HV interval longer than 70 ms (28.5 AV Block and Lesser Need for Cardiac vs. 38.1%, p = 0.039), however, EPS and ICM offered a similar diagnostic yield in both Pacing in Women. Front. Cardiovasc. Med. 9:838473. sexes (40.6 vs. 48.9% and 48.4% vs. 51.1%, respectively). Women had a lower risk of doi: 10.3389/fcvm.2022.838473 developing atrioventricular block (AVB) (adjusted odds ratio [OR] 0.44–95% CI 0.26–0.74, Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope p = 0.002) and of requiring permanent pacemaker implantation (adjusted hazard ratio [HR] 0.72–95% CI: 0.52–0.99, p = 0.046). The mortality rate was lower in women (4.5 per 100 person-years [95% CI 3.1–6.4 per 100 person-years] vs. 7.3 per 100 person-years [95% CI 5.9–9.1 per 100 person-years]). Conclusions: Compared to men, women with unexplained syncope and BBB have a lower risk of AVB and of requiring cardiac pacing. A stepwise diagnostic approach has a similar diagnostic yield in both sexes, and it seems appropriate to guide the treatment and avoid unnecessary pacemaker implantation, especially in women. Keywords: syncope, pacemaker, electrophysiological study, loop recorder, cardiac monitor, gender differences, sex-related differences GRAPHICAL ABSTRACT | Risk of AVB and need for cardiac pacing. Left: Percentage of patients diagnosed with aAVB/sCD in both sexes. Right-top: Multivariate logistic regression analyses for risk of aAVB/sCD. Odds ratio and 95% CI are plotted. Right-bottom: Kaplan-Meier pacemaker-free survival estimates curves in both sexes. aAVB/sCD, advanced atrio-ventricular block or severe conduction disturbances; HR, hazard ratio; CI, confidence interval; y.o, years old; IHD, ischemic heart disease; LVEF, left ventricular ejection fraction; BBB, bundle branch block; LBBB, left bundle branch block; RBBB, right bundle branch block; LAFB, left anterior fascicular block. systematic diagnostic approach based on clinical evaluation, INTRODUCTION electrophysiological study (EPS), and the Implantable cardiac monitor (ICM) has shown to be safe and provide a high Although syncope in patients with bundle branch block (BBB) rate of etiological diagnosis (3, 5–7). However, due to the is often due to paroxysmal advanced atrioventricular block low predictive value of EPS, some investigators suggest that (aAVB), other mechanisms may also be involved (1–4). A a pacemaker should be implanted on an empirical basis (2, 8), therefore, the best way to manage these patients remains Abbreviations: aAVB, Advanced atrioventricular block; sCD, Severe conduction controversial. Increasing knowledge of the disease characteristics disturbances; BBB, Bundle branch block; EPS, electrophysiological study; ICM, can help clinicians to improve their management in specific Implantable cardiac monitor; SND, Sinus node dysfunction. subgroups of patients. Despite substantial efforts in recent years Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope to improve the understanding of the sex-related differences in the last 6 months is available). Those cases with no certain cardiovascular disease, there is still insufficient knowledge of or highly probable diagnosis were then considered unexplained physiology, epidemiology, and outcomes in women, leading to syncope, and these patients were admitted to the hospital with a lack of sex-specific recommendations. In this regard, there continuous ECG monitoring. Other complementary diagnostic is an increasing awareness that sex is a major determinant of tests, such as exercise stress test, myocardial perfusion gamma the incidence, etiology, and clinical presentation of arrhythmias scan, or MRI, were carried out at the treating clinician’s (9, 10). It is known that women have a major susceptibility to discretion in line with the suspected diagnosis and applicable reflex syncope (11–14) and probably to sinus node dysfunction recommendations. Step 2 involved the hospital admission with (SND) (9, 10, 15). However, no studies have examined differences continuous ECG monitoring and an invasive electrophysiology between men and women in the presentation and outcomes of study. Step 3 involved implanting an ICM with subsequent unexplained syncope and BBB. clinical monitoring (Figure 1). Given the susceptibility of women to syncope due to other mechanisms and the different comorbidities of the female sex, we hypothesize that women with unexplained syncope and Electrophysiology Study BBB would have a different risk of aAVB or severe conduction Two femoral venous accesses were gained and two tetrapolar disturbances (sCDs) and a different risk of needing cardiac pacing catheters (Supreme, Abbott, St. Jude Medical, St. Paul, MN, compared to men. The aim of this study was to analyze the sex- USA) were used for basic measurements, atrial stimulation, related differences in patients with syncope and BBB concerning and ventricular stimulation. Sinus node recovery time was the prevalence of aAVB/sCD, the diagnostic yield of tests, and obtained after 30 s of atrial pacing at 600 and 500 ms, and the clinical outcomes. highest value was corrected by basal heart rate. Programmed ventricular stimulation protocol utilized up to three extra stimuli delivered after eight paced ventricular cycle lengths at 600, METHODS 500, and 400 ms from de right ventricular apex and outflow Study Population tract in case no sustained ventricular tachycardia (VT) was We performed a prospective observational study on a consecutive induced before. patient cohort at a tertiary university hospital that is a reference In cases with basal conduction disturbances where the His to center for cardiology and arrhythmias [Hospital Universitari Vall ventricle (HV) interval was <70 ms, a class I drug (procainamide d’Hebron, Barcelona (Spain)]. From January 2010 to January 10 mg/kg or flecainide 2 mg/kg intravenously) was administered. 2021, we included those patients admitted for syncope with BBB, Continuous monitoring of the HV interval and atrial pacing was in whom no certain diagnosis was reached for the syncope in performed during the class I drug infusion and for 10 min after the initial assessment at the emergency department. We excluded the infusion. patients under the age of 18 years, those with pacemakers or Electrophysiological study was considered positive according implantable cardiac defibrillators (ICD) in situ, patients with to current ESC guidelines (1) in the following cases: (1) baseline left ventricular ejection fraction (LVEF) <35% or with another HV interval ≥70 ms or ≥100 ms after class I drug administration. ICD direct indication, and those who could not keep to the (2) Second- or third-degree infra- or intra-Hisian block (with study’s diagnostic protocol due to comorbidities or their own pacing cycle length above 400 ms) before or during incremental preference. In June 2021, we collected the final follow-up data of atrial pacing or after class I drug administration. (3) Induction of the patients. The patient’s clinical details, syncope characteristics, sustained VT. therapeutic management, and follow-up were recorded at the time of hospital admission. The study complies with the Helsinki declaration and was Monitoring With Implantable Cardiac approved by the local ethics committee. Monitor In Step 3, a Reveal XTTM (in patients included before 2014) Study Protocol or LinqTM (Medtronic, Inc. Minneapolis, MN, USA) device Patients were systematically assessed and managed according to was implanted. The implantation was performed under local the local clinical protocol which is based on recommendations anesthetic at the primary site recommended by the manufacturer from the European Society of Cardiology (ESC) syncope (fourth left intercostal space). The patients were instructed on guidelines (1). how to use it and were provided with a device for remote In summary, the diagnostic protocol for syncope in this monitoring (Medtronic CarelinkTM ). The ICM was programmed population was based on 3 phases or steps. Step 1, prior to the with the settings for syncope. patients’ inclusion in the study, consisted of the initial assessment Implantable cardiac monitor was considered diagnostic in the emergency department. In a systematic manner, clinical in the event of being able to correlate recurrence of syncope history and physical examination were performed, such as or presyncope with the ICM’s electrocardiographic trace, testing for orthostatic hypotension and carotid sinus massage or when the following rhythm disorders were documented (if not contraindicated), general bloodwork, chest x-ray, 12- in an asymptomatic patient: complete or advanced AV lead ECG, 12–24-h telemetry monitoring and a transthoracic block, asystole lasting >3 s while awake, or the presence of echocardiogram (in cases where no prior echocardiogram from sustained VT. Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope FIGURE 1 | Diagnostic protocol schema and flow chart of patient inclusion in the study. ED, emergency department; EPS, electrophysiological study; ICM, implantable cardiac monitor; pc, patients. Treatment and Clinical Follow-Up 70 ms or ≥100 ms after class I drug challenge, intra-Hisian, The syncope was treated appropriately following the clinical or infra-Hisian block (1, 16). The patient details were practice guidelines according to its etiology. In those patients analyzed by two cardiologists specialized in syncope to with syncope secondary to a conduction disorder, the establish the definitive diagnosis according to the definitions. implantation of a cardiac stimulation device was indicated. The etiology of syncopal recurrences was defined in the In patients with syncope secondary to ventricular tachycardia, same manner. defibrillator implantation was indicated. The device type Sudden death was defined as death occurring instantaneously (pacemaker, defibrillator, or resynchronizer) and treatments, or within 1 h of the onset of symptoms, non-sudden such as ablation, antiarrhythmic drugs, or angioplasty, were cardiac death was defined as a cardiac death occurring eventually discussed within the “heart team” and individualized 1 h after the onset of symptoms, and non-cardiac according to the patient’s functional status, the prior degree of death as deaths not directly related to a cardiac or heart failure, and patient preferences. In addition, all patients sudden condition. were educated on syncope and lifestyle changes to prevent and The primary endpoint of the study was a diagnosis treat reflex syncope. of the main syncope mechanism. The secondary After hospital discharge, patients were followed up in the endpoints were test diagnostic yields, need for cardiac outpatient cardiology clinic, and those who had received a pacing related to syncope, syncope recurrences, cardiac device were also followed up with the corresponding and mortality. remote function. Statistical Analysis Definitions and Endpoints The categorical variables are presented as absolute number The main etiological mechanism of the syncope was established (N) and percentages. The continuous quantitative variables as certain or highly probable according to the definitions in are presented as the median and interquartile range (IQR). the ESC guidelines on syncope (1) (Supplementary Table S1). The comparison of numerical variables was performed using aAVB/sCD was defined as the documentation of type II Student’s t-test or Wilcoxon’s rank-sum test, depending on second degree, third degree, or high-grade AVB or the the distribution of the variables. The Chi-squared test or following diagnostic findings in the EPS: HV interval ≥ Fisher’s exact test was used to compare qualitative variables as Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope TABLE 1 | Baseline characteristics of patients included in the study. Variable Total Men Women P (n = 443) (n = 278) (n = 165) Age (years)+ 77.9 [70.5–82.1] 77.0 [70.3–82.20] 78.7 [71.2–84.6] 0.122 Age >75 y.o, n (%) 273 (61.6) 167 (60.1) 106 (64.2) 0.383 Hypertension, n (%) 348 (78.6) 223 (80.2) 125 (75.8) 0.269 Diabetes, n (%) 153 (34.5) 111 (39.9) 42 (25.5) 0.002 Dyslipidemia, n (%) 266 (60.1) 168 (60.4) 98 (59.4) 0.829 No SHD, n (%) 346 (78.1) 212 (76.3) 134 (81.2) 0.223 Ischemic heart disease, n (%) 94 (21.2) 72 (25.9) 11 (13.3) 0.002 Old ST elevation infarction, n (%) 25 (5.6) 20 (7.2) 5 (3.0) 0.066 Non-ischemic dilated cardiomyopathy, n (%) 16 (3.6) 9 (3.2) 7 (4.2) 0.584 History of atrial fibrillation, n (%) 90 (20.3) 62 (22.3) 28 (17.0) 0.177 Previous syncope, n (%) 235 (53.1) 154 (55.4) 81 (49.1) 0.199 Use of negative chronotropic drugs, n (%) 149 (34.8) 95 (35.3) 54 (34.0) 0.776 Characteristics of the syncope Prodrome, n (%) 134 (30.5) 84 (30.3) 50 (30.8) 0.776 Severe trauma, n (%) 185 (42.1) 121 (43.6) 64 (39.5) 0.393 Echocardiogram EDD (mm) 47 [43–52] 48 [43–53] 46 [42–50] <0.001 ESD (mm) 31 [26–35] 32 [27–36] 30 [26–34] 0.016 Interventricular septum (mm) 13 [11–14] 13 [12–14] 12 [10–15] 0.021 LVEF (%) 58 [51–62] 57 [50–62] 58 [52–62] 0.746 LVEF <45%, n (%) 61 (14.7) 38 (14.8) 23 (14.7) 0.970 ECG on admission Heart rate (bpm) 70 [62–80] 70 [60–80] 70 [63–80] 0.996 Atrial fibrillation, n (%) 78 (17.8) 49 (17.9) 29 (17.6) 0.935 Long PR, n (%) 152 (40.2) 104 (43.7) 48 (34.3) 0.720 QRS duration (msec) 140 [130–153] 140 [130–153] 140 [130–152] 0.891 LBBB morphology, n (%) 167 (37.9) 77 (27.7) 90 (55.2) <0.001 Long PR and LBBB, n (%) 47 (10.6) 24 (8.6) 23 (13.9) 0.080 RBBB morphology, n (%) 259 (58.6) 191 (67.7) 68 (41.5) <0.001 Isolated RBBB 50 (11.7) 34 (12.6) 16 (10.2) 0.449 RBBB and LAFB 159 (35.9) 116 (41.7) 43 (26.1) 0.001 Long PR and RBBB 96 (21.7) 75 (27.) 21 12.7) <0.001 Long PR, RBBB and LAFB 71 (16.0) 52 (18.7) 19 (11.5) 0.046 + The quantitative variables are expressed as medians [interquartile range]. y.o, years old; mm, millimeters; bpm, beats per minute; msec, milliseconds; SHD, structural heart disease; LBBB, left bundle branch block; RBBB, right bundle branch block; LAFB, left anterior fascicular block. ESD, end-systolic diameter; EDD, end-diastolic diameter; LVEF, left ventricular ejection fraction. appropriate. Wald’s method was used to calculate the CI for the estimated, and simplified models were evaluated. A relevant population rates and proportions. The survival functions were confounding effect was judged when the hazard ratios (HRs) estimated using the Kaplan-Meier method and their comparison or odds ratios (ORs) with and without the adjustment for the was performed by the log-rank test. A multivariable logistic potential confounder differed more than 10%. The most precise regression model was used to assess the association between model with all relevant clinical covariates was finally selected. A sex and aAVB/sCD and to adjust for possible confounder p < 0.05 was considered statistically significant for all tests. All of variables. Moreover, a Cox proportional hazards multivariate the statistical analyses were performed using Stata, version 15.1.0 model was created to determine whether the sex was associated (StataCorp LLC College Station, TX, USA). with pacemaker implantation adjusted by possible confounding variables. When we estimated both the Cox proportional hazards model and the logistic regression model, we checked the different RESULTS possible interactions between pairs of explanatory variables and Baseline Characteristics found no statistically significant results. A saturated model, A total of 443 patients were included in the study, of whom such as all clinically relevant covariates (1, 4, 5, 7, 17–22), was 165 (37.2%) were women. The patients’ baseline characteristics Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope and the comparisons between men and women are shown in Table 1. The median age was 77.9 years [IQR 70.5–82.1] and aAVB/sCD, advanced atrio-ventricular block or severe conduction disturbances; VT, ventricular tachycardia; SND, sinus node dysfunction; SVT, supraventricular tachycardia; AF, atrial tachycardia; CSH, carotid sinushypersensitivity. 0.529 0.272 0.136 0.197 0.435 21.2% had ischemic heart disease (IHD). The median LVEF was P 58% [IQR 51–62%] and 14.7% of the patients had a depressed LVEF (<45%). The median QRS duration was 140 ms [IQR 130– 50 (61.0) 10 (12.2) 10 (12.2) (n = 82) Women 5 (6.1) 4 (4.9) 1 (1.2) 1 (1.2) 1 (1.2) 153 ms]. In the ECG on admission, 37.9% of patients had typical 0 (0) 0 (0) left bundle branch block (LBBB) morphology and 58.6% right bundle branch block (RBBB) morphology. Compared with men, women had less diabetes (25.5 vs. (n = 129) 73 (56.6) 23 (17.8) 16 (12.4) Step 3 3 (2.3) 1 (0.8) 4 (3.1) 39.9%, p = 0.002) and less history of IHD (13.3 vs. 25.9%, 9(7.0) Men 0 (0) 0 (0) 0 (0) p = 0.002). However, there were no differences regarding atrial fibrillation history and other comorbidities. The rate of conduction disturbances in the ECG on admission differed All patients 123 (58.3) (n = 211) between both sexes: LBBB was more frequent in women (55.2 vs. 33 (15.6) 21 (10.0) 19 (9.0) 7 (3.3) 1 (0.5) 2 (1.0) 5 (2.4) 0 (0) 0 (0) 27.7%, p < 0.001) while RBBB was more frequent in men (41.5 vs. 67.7%, p < 0.001). Etiology of the Syncope and Risk of >0.999 >0.999 0.502 0.045 0.337 P aAVB/sCD A certain or highly probable diagnosis of the main cause of syncope was reached in 320 patients (72.2%). In 232 (52.4%) (n = 165) 82 (49.7) 64 (38.8) Women 5 (3.3) 1 (0.6) 3 (1.8) 4 (2.4) 3 (1.8) 1 (0.6) 1 (0.6) 2 (1.2) patients, the diagnosis of syncope was reached in Step 2 (in 203 patients after a positive EPS and in another 29 due to presenting symptoms with diagnostic criteria during hospital stay). In Step 3, a definitive diagnosis was reached in an additional 88 (19.9%) 129 (46.4) (n = 278) 120(46.8) Step 2 5 (1.8) 2 (0.7) 5 (1.8) 1 (0.4) 2 (0.7) 2 (0.7) 1 (0.4) patients (77 due to the ICM findings and 11 due to clinical Men 0 (0) criteria; Figure 1). Table 2 summarizes the etiologies of syncope and the diagnoses reached in each step. Compared to men, women All patients 211 (47.6) 194 (43.8) had less frequent aAVB/sCD (44.9 vs. 55.0%, p = 0.038), (n = 443) 10 (2.3) 3 (0.7) 8 (1.8) 5 (1.4) 5 (1.1) 1 (0.2) 3 (0.7) 3 (0.7) which represents a risk ratio (RR) of 0.81 (95% CI 0.67– 0.99). Furthermore, in multivariate analyses, after adjusting for possible confounding variables (such as the type of BBB), women had a lower risk of developing aAVB/sCD than men [OR 0.358 0.038 0.551 0.204 0.443 0.44 (95% CI 0.26–0.74, p = 0.002); Graphical Abstract and P Supplementary Table S2]. (n = 165) 50 (30.3) 74 (44.9) Women 10 (6.1) 11 (6.7) 7 (4.2) 4 (1.2) 2 (1.2) 3 (1.8) 4(2.4) EPS and Implantable Cardiac Monitor 0 (0) Overall, EPS was positive in 203 (45.8%) patients, and it was due to aAVB/sCD in 193 (43.6%). Details of the EPS results are listed in Table 3. Baseline HV interval was shorter in women (58 ms (n = 278) 153(55.0) 73 (26.3) 21 (7.6) 11 (4.0) 8 (2.9) 1 (0.4) 2 (0.4) 1 (0.4) 3 (1.1) 5 (1.8) Total Men [IQR 52–71] vs. 60 ms [IQR 52–73], p = 0.035) than in men. Furthermore, fewer women had a baseline HV interval longer than 70 ms (28.5% vs. 38.1%, p = 0.039). Among those patients with negative EPS at baseline [241 All patients 123 (27.8) 227 (51.2) (n = 443) patients (55.1%)], class I drug challenge was positive in 25 31 (7.0) 22 (5.0) 15 (3.4) 5 (1.1) 6 (1.4) 3 (0.7) 3 (0.7) 8 (1.8) (10.3%). No significant differences between men and women were found in the increase of HV interval (Delta HV) or in the TABLE 2 | Etiological diagnosis. positivity of the test (Figure 2). Electrophysiological study had a similar diagnostic yield Low cardiac output, n % between women and men (40.6 vs. 48.9%, p = 0.089). In addition, EPS negative predictive value (NPV) was similar between both Fast SVT/AF, n % Orthostatic, n % aAVB/sCD, n % Unknown, n % sexes (76.6% [95% CI 67.1–84.0%] vs. 76.6 % [95% CI 69.0– Diagnostic Reflex, n % Other, n % 82.8%]). CSH, n % SND, n % VT, n % Among 154 patients who received an ICM, in 77 patients (50% of the implanted patients) a diagnosis was reached, with a similar Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope TABLE 3 | Electrophysiological study and implantable cardiac monitor. Variable Total Men Women P (n = 443) (n = 278) (n = 165) Electrophysiological study Baseline HV interval (msec) 59 [52–73] 60 [52–73] 58 [52–71] 0.035 HV≥70, n (%) 153 (34.5) 106 (38.1) 47 (28.5) 0.039 Intra or infra-Hisian AV block, n (%) 30 (6.9) 14 (5.1) 16 (9.9) 0.06 Basal EPS positive for aAVB/sCD, n (%) 168 (37.9) 112 (40.3) 56 (33.9) 0.183 Class I drug challenge, n % 241 (55.1) 146 (53.1) 95 (58.6) 0.349 Procainamide, n % 93 (21.3) 59 (21.2) 34 (21.0) Flecainide, n % 147 (33.6) 87 (31.6) 60 (37.0) HV interval after class I challenge (msec) 69 [61-78] 69 [61-78] 71 [61-78] 0.689 Delta HV interval (msec) 15 [10–22] 15 [10–22] 15 [11–21] 0.77 HV≥100 after class I challenge, n (%) 14 (3.2) 11 (3.4) 3 (1.8) 0.27 Intra or infra-Hisian AV block after IC challenge, n (%) 15 (6.0) 10 (6.4) 5 (5.4) 0.749 Positive class I challenge, n (%) 25 (10.3) 17 (11.6) 8(8.4) 0.433 cSNRT (msec) 210 [153–280] 206 [150–278] 220 [160–294] 0.492 VT induction, n (%) 6 (3.6) 2 (1.9) 4 (6.1) 0.211 EPS positive for aAVB/sCD, n (%) 193 (43.6) 129 (46.4) 64 (37.8) 0.118 EPS positive for all diagnoses, n (%) 203 (45.8) 136 (48.9) 67 (40.6) 0.089 Implantable cardiac monitor Patients implanted n = 154 n = 92 n = 62 ICM diagnostic, n (%) 77 (50) 47 (51.1) 30 (48.4) 0.742 Asymptomatic finding, n (%)* 23 (29.9) 14 (29.8) 9 (30.0) 0.984 Symptomatic finding, n (%)* 54 (70.1) 33 (70.2) 21 (70.0) *% refers to the total of patients diagnosed by ICM. HV, His to ventricle; aAVB/sCD, advanced atrio-ventricular block or severe conduction disturbances; VT, ventricular tachycardia; EPS, electrophysiological study; ICM, implantable cardiac monitor; cSNRT, corrected sinus node recovery time; msec, milliseconds. diagnostic yield between both sexes (48.4% in women and 51.1% implanted due to AVB 4 years before. The mortality rate in in men, p = 0.742; Table 3 and Figure 2). women was 4.5 per 100 person-years (95% CI 3.1–6.4 per 100 person-years) and 7.3 per 100 person-years (95% CI 5.9–9.1 per Pacemaker Implantation, Clinical 100 person-years) in men. Follow-Up, and Prognosis Patients were followed for a median of 3.4 years [IQR 1.7– DISCUSSION 6.0 years]. A total of 252 (58.2%) patients required pacing due to bradycardia related to the syncope at the end of follow- As far as we know, this is the first cohort study to specifically up (Table 4; Supplementary Table S3 shows the type of device evaluate sex-related differences in patients with unexplained implanted). Additionally, 2 ICD and 2 CRT-D were implanted syncope and BBB. In addition, it is one of the largest patient due to ventricular tachycardia, 3 pacemakers due to post- cohorts published evaluating the etiology of syncope and surgical AV block, and 3 additional pacemakers because of outcomes in this population. The main findings of this study chronotropic insufficiency. Two patients with VT were treated are that women with syncope of unknown origin and BBB are with antiarrhythmic drugs only due to their comorbidities. at lower risk of having aAVB/sCD and of requiring pacemaker In a Cox multivariate analysis, after adjusting for possible implantation than men. confounding variables, women had a lower risk of needing In the general population, syncope seems to be more frequent permanent pacemaker implantation compared to men [adjusted in women (1, 2, 14, 21, 23). In a recent national population-based HR 0.72 (95% CI: 0.52–0.99, p = 0.046); Table 5 and Figure 3]. cohort study that included more than 2.5 million participants, After the etiological diagnosis and appropriate treatment, Fedorowsky et al. (21) found that 62% of the patients with 30 patients (8.9%) experienced a syncopal recurrence (Table 4), syncope were women. However, this proportion is reversed when most of them due to a vagal or orthostatic mechanism a cohort of patients with structural heart disease (6, 24, 25) (Supplementary Table S4). or abnormal ECG (3, 5, 7, 26) is selected, probably because A total of 111 (25.1%) patients died during the follow-up, men have a higher prevalence of cardiovascular risk factors and 73% of them due to non-cardiovascular causes. Only 2 patients other comorbidities. In our study, which included consecutive experienced sudden death, one 80 years old female with syncope patients, 63% were men. Male patients had more diabetes of unknown origin and one 79 years old male with a pacemaker and IHD. Moreover, RBBB was more frequent in men while Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope FIGURE 2 | Electrophysiological study and implantable cardiac monitor. A comparison between sex of (A) baseline HV interval, (B) HV interval after class I challenge, and (C) absolute increase of HV interval (Delta HV) after class I challenge. (D) Percentage of patients with basal HV interval >70 ms in EPS. (E) ICM cumulative diagnostic yield according to time of follow-up. *p < 0.05. HV, His-ventricular; ICM, implantable cardiac monitor. LBBB morphology was more frequent in women. These findings observed in patients with syncope and BBB and it is not explained in baseline characteristics are consistent with data previously by differences in the comorbidities alone. published (3, 5, 7, 26–28), which suggests that patients included It is well-known that women have a major susceptibility in the present study are likely representative of the population to reflex syncope (11–14). Moreover, previous studies have with syncope and BBB. suggested that SND is also more prevalent in women (9, 10, 15). Paroxysmal aAVB is the most likely etiology of syncope in The higher prevalence of these etiologies in women observed in patients with BBB, but other causes also exist. In agreement with the general population is also applicable to patients with BBB and previous studies, we found that AVB is the mechanism of syncope it may partially explain the relative lower rate of aAVB in these in half of these patients, although significant differences were patients. In our study we only found small and not statistically found between the sexes. Women less frequently had aAVB/sCD. significant differences in the incidence of these mechanisms In only 44.9% of women, compared to 55.0% of men, aAVB/sCD between groups, probably because the study is underpowered. was found to be the cause of syncope, which represents a risk Moreover, it should be noted that some of these etiologies were ratio of 0.81. In other words, women have a 19% lower risk of usually diagnosed in Step 1 of the protocol that is not included in having aAVB/sCD. Even though there are some differences in the analysis. patients’ baseline characteristics, in multivariate analyses after Interestingly, we found that the HV interval in the EPS was adjusting for possible confounding variables, female sex was significantly longer in men. In particular, more men had an independently associated with a lower risk of advanced AVB (OR HV longer than 70 ms, suggesting that men have a more severe 0.44; 95% CI 0.26–0.74). Previous studies had shown that the conduction disease. Despite these differences, EPS in women risk of aAVB in the general population is higher in men (22, 29). still offers a considerable diagnostic yield as has been previously For example, in a recent population-based cohort study, Kerola reported (3, 8, 17), and even more importantly, NPV is similar et al. (22) reported that male sex was an independent risk factor between both sexes. In patients who were not diagnosed in Step for the development of aAVB [adjusted HR 2.04 (95% CI 1.19– 2, the use of an ICM offered a significant additional diagnostic 3.45)]. Thus, the present study reveals that these findings are also yield in both groups. Remarkably, only a third of the diagnoses Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope TABLE 4 | Outcomes during follow-up. Variable Total Men Women P (n = 443) (n = 278) (n = 165) Median follow-up time (years) 3.4 [1.7–6.0] 3.4 [1.5–5.8] 3.2 [1.8–6.2] 0.845 Pacing requirements Total patients requiring pacing due to the syncope, n (%) 252 (58.2) 167 (60.7) 85 (53.8) 0.159 Devices implanted during admission, n (%) 198 (44.7) 134 (48.2) 64 (38.8) 0.054 Devices implanted during follow up, n (%) 54 (22.5) 33 (23.24) 21 (21.4) 0.741 Syncope recurrence Total syncope recurrence, n (%) 95 (21.4) 63 (22.7) 32 (19.4) 0.418 Syncope recurrence after diagnosis, n (%) 30 (8.9) 19 (8.9) 11 (8.9) 0.998 Mortality Total deaths, n (%) 111 (25.1) 81 (29.1) 30 (18.2) 0.010 Mortality rate, (x100 person-years) 6.3 7.3 4.5 0.009 Cause of death Cardiovascular death 26 (23.4) 18 (22.2) 8 (26.7) 0.686 Non-cardiovascular death 81 (73.0) 60 (74.1) 21 (70.0) Unknown 4 (3.6) 3 (3.7) 1 (3.3) TABLE 5 | Cox proportional hazards multivariate model to assess the association between sex and pacing needs. Factor HR HR 95% CI p-value Unadjusted Women 0.82 0.63–1.06 0.131 Adjusted Women 0.72 0.52–0.99 0.046 Age>75 y.o 1.19 0.89–1.61 0.247 Hypertension 1.06 0.73–1.54 0.765 Diabetes 1.09 0.80–1.48 0.586 IHD 1.22 0.86–1.75 0.266 LVEF<45% 0.87 0.56–1.35 0.542 Atrial fibrillation 1.09 0.70–1.70 0.698 Recurrent syncope 1.20 0.89–1.61 0.236 LBBB 1.54 0.95–2.50 0.080 FIGURE 3 | Cardiac pacing. Kaplan-Meier pacemaker-free survival estimates Isolated RBBB 0.30 0.12–0.68 0.005 curves for women and men. RBBB and LAFH 1.05 0.65–1.69 0.846 Long PR interval 1.62 1.20–2.19 0.002 CI, confidence interval; HR, hazard ratio; y.o, years old; IHD, ischemic heart disease; LVEF, left ventricular ejection fraction; LBBB, left bundle branch block; RBBB, right bundle et al. investigated the predictors of pacemaker implantation branch block; LAFB, left anterior fascicular block. in patients with syncope receiving an ICM (19). They found that female sex was an independent predictive factor for bradycardia necessitating pacemaker implantation. However, reached in Step 3 was due to aAVB. This finding supports the several differences are evident compared to our study. Firstly, systematic use of an ICM in patients where EPS is not diagnostic. only a quarter of the patients included had a BBB and EPS was not Another key finding of the present study is that women have routinely performed. Second, less than of half of pacemakers were a lower risk of requiring a permanent pacemaker compared implanted due to AVB. SND was the most common indication to men [adjusted HR 0.72 (95% CI 0.52–0.99)]. From the for pacing and as has been commented previously, it seems to clinical point of view, this finding is especially relevant since be more prevalent in women. Indeed, in the general population, pacemakers are useful to treat not only syncope due to aAVB/sCD pacemaker implantation is more common in men (9, 15, 29, 30). but also due to other types of bradyarrhythmias and some In a German registry of more than 17,000 patients with primary cases of cardioinhibitory reflex syncope. Even though some pacemaker implantation, 53% were men (29). In this large-scale of these bradyarrhythmias, such as sinus node dysfunction, patient cohort, it was found that male patients had more AV seem to be more common in women, the overall risk of blocks when compared with women and less sick sinus syndrome needing pacing is lower in women compared to men. Ahmed and atrial fibrillation with bradycardia. Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope Although it was not the aim of the present study, it is CONCLUSIONS remarkable that our results confirm that a systematic stepwise approach to evaluate syncope in patients with BBB, which was In this cohort study evaluating sex-specific differences in patients initially evaluated in the B4 study (3) and detailed in the ESC with unexplained syncope and BBB, we found that compared guidelines (1), is safe and achieves a high rate of etiological to men, women are at lower risk of having aAVB/sCD and diagnosis allowing to select specific treatment and avoiding of requiring cardiac pacing. A stepwise diagnostic approach the implantation of unnecessary pacemakers. In the present based on EPS and long-term cardiac monitoring have similar study, once the diagnosis was reached and appropriately treated, diagnostic yield in both sexes and it seems appropriate to only a few patients (8.9%) experienced a syncopal recurrence, guide treatment and avoid unnecessary pacemaker implantation, most of them due to a vagal or orthostatic mechanism. This especially in women. finding suggests that the diagnoses were specific. We also found that, compared to men, women had nearly half the DATA AVAILABILITY STATEMENT mortality rate, probably in relation to a lower comorbidity burden (14). The raw data supporting the conclusions of this article will be The optimal management of patients with unexplained made available by the authors upon reasonable request. syncope and BBB is still controversial (1–4, 8, 18). In fact, the 2017 American College of Cardiology/the American Heart ETHICS STATEMENT Association (ACC/AHA) guidelines (2) suggest empirical direct pacemaker implantation after exclusion of other syncope The studies involving human participants were reviewed etiologies while ESC guidelines (1) recommend opting for and approved by Comitè d’Etica de Vall d’Hebron. Written a stepwise approach. In light of our results, gender may informed consent for participation was not required for this be an additional factor to be taken into account in the study in accordance with the national legislation and the workup of patients with syncope and BBB. A stepwise institutional requirements. approach seems reasonable to avoid unnecessary pacemaker implantation, especially in women, given that only half of AUTHOR CONTRIBUTIONS them will require pacing because of the syncope. Nonetheless, randomized controlled trials are warranted to better answer this JF-P prepared the concept, design the study, performed statistical important question. analysis, and draft and editing of the manuscript. NR-G participate in the study design, data review, and manuscript LIMITATIONS editing. IR-L prepared the clinical database and reviewed the study design. MB-O, CB-M, and MM-B recorded clinical data This study has certain limitations. It is an observational study and revised data in the database. All authors contributed to carried out at a single high-volume center with a dedicated design the manuscript, patients selection, manuscript review, and syncope clinic. To minimize potential biases inherent to the agreed with the content of its final version. study’s design, the patients were included consecutively, and possible confounding factors were analyzed. No genetic testing FUNDING was done systematically to identify certain inherit heart disease that present a higher prevalence of sCD, however, the prevalence This project was funded by ISCIII, CIBER, and Fundació Marató of these diseases is low. One aspect worth mentioning is that TV3 and co-funded by the European Regional Development in our series, the prevalence of reflex/orthostatic syncope was Fund (ERDF-FEDER). low. It should be noted that some of these episodes were usually diagnosed in Step 1 of the protocol, prior to the patients’ inclusion ACKNOWLEDGMENTS in the study. As such, this series refers not to the global etiology of syncope in this population, rather it focuses on those patients The authors would like to thank the staff of the Cardiology lacking an evident initial diagnosis. The study population was not Department and Arrhythmia Unit for their support in patient ethnically diverse. All patients included in the study were from management, monitoring, and follow-up. Caucasian or Latin, so the results observed may not be directly extrapolable to other ethnicities. Also, the tilt-test was not used in SUPPLEMENTARY MATERIAL the workup protocol due to its low specificity in this population (1). However, in selected patients, tilt-test could have revealed an The Supplementary Material for this article can be found indication for pacing (1). Moreover, the study was not designed online at: https://www.frontiersin.org/articles/10.3389/fcvm. to assess predictors of pacemaker implantation in both groups. 2022.838473/full#supplementary-material Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope REFERENCES 17. Roca-Luque I, Francisco-Pasqual J, Oristrell G, Rodríguez-García J, Santos- Ortega A, Martin-Sanchez G, et al. Flecainide versus procainamide in 1. 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Kusumoto FM, Schoenfeld MH, Barrett C, Edgerton JR, Ellenbogen KA, The remaining authors declare that the research was conducted in the absence of Gold MR, ACC/AHA/HRS Guideline on the Evaluation and Management any commercial or financial relationships that could be construed as a potential of Patients With Bradycardia and Cardiac Conduction Delay: a Report of conflict of interest. the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. Publisher’s Note: All claims expressed in this article are solely those of the authors (2019). 140:e382–482. doi: 10.1161/CIR.0000000000000627 and do not necessarily represent those of their affiliated organizations, or those of Frontiers in Cardiovascular Medicine | www.frontiersin.org 11 February 2022 | Volume 9 | Article 838473 Francisco-Pascual et al. Sex-Related Differences in Syncope the publisher, the editors and the reviewers. Any product that may be evaluated in and Ferreira-González. This is an open-access article distributed under the terms this article, or claim that may be made by its manufacturer, is not guaranteed or of the Creative Commons Attribution License (CC BY). The use, distribution endorsed by the publisher. or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in Copyright © 2022 Francisco-Pascual, Rivas-Gándara, Bach-Oller, Badia-Molins, this journal is cited, in accordance with accepted academic practice. No use, Maymi-Ballesteros, Benito, Pérez-Rodon, Santos-Ortega, Sambola-Ayala, Roca- distribution or reproduction is permitted which does not comply with these Luque, Cantalapiedra-Romero, Rodríguez-Silva, Pascual-González, Moya-Mitjans terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 12 February 2022 | Volume 9 | Article 838473