Prognosis of programmed ventricular stimulation in adult patients with syncope of unexplained origin: A historical cohort

Abstract Background Programmed ventricular stimulation (PVS) during electrophysiological study (EPS), is a globally accepted tool for risk stratification of sudden cardiac death (SCD) in some specific clinical situations. The aim of this study was to evaluate the prognosis of ventricular arrhythmia induction in a cohort of patients with syncope of undetermined origin (SUO). Methods This is a historical cohort study in a population of patients with SUO referred for EPS between the years 2008–2021. In this interval, 575 patients underwent the procedure. Results Patients with induced ventricular arrhythmias had a higher occurrence of structural heart disease (36.7% vs. 76.5%), ischemic heart disease (28.2 vs. 57.1%), heart failure (15.5% vs. 34.4%), and lower left ventricular ejection fraction (59.16% vs. 47.51%), when compared to the outcome with a negative study. PVS triggered ventricular arrhythmias in 98 patients, 62 monomorphic and 36 polymorphic. During a median follow‐up of 37.6 months, 100 deaths occurred. Only the induction of sustained ventricular arrhythmias showed a significant association with the primary outcome (all‐cause mortality) with a p value <.001. After the performance of EPS, 142 patients underwent cardioverter‐defibrillator (ICD) implantation. At study follow‐up, 30 patients had therapies by the device. Only the induction of sustained monomorphic ventricular arrhythmia showed statistically significant association with appropriate therapies by the device (p = .012). Conclusion In patients with SUO, the induction of sustained monomorphic ventricular arrhythmia after programmed ventricular pacing is related to a worse prognosis, with a higher incidence of mortality and appropriate therapies by the ICD.


| INTRODUC TI ON
Syncope, defined as a transitory loss of consciousness and postural tone followed by spontaneous recovery, is a common symptom that corresponds to approximately 3% of the complaints in emergency care and up to 6% of hospital admissions. 1,2Even with the use of complementary exams, up to 40% of the cases do not present a clear elucidation for the syncope diagnosis, being this picture classified as syncope of undetermined origin (SUO). 3e presence of syncope is associated with increased mortality regardless of its cause, and that it often occurs in patients with underlying heart disease. 4ogrammed ventricular stimulation (PVS), as part of the electrophysiological study (EPS), is a globally accepted tool for risk stratification of sudden cardiac death (SCD) in patients with structural heart disease and presenting with SUO, 5 and is even useful in identifying patients at low risk for syncope of arrhythmic origin, when its result is negative in inducing sustained ventricular arrhythmias.
However, there is still great uncertainty about the real prognostic value of inducing ventricular arrhythmias in other scenarios, such as patients with preserved ejection fraction, non-ischemic heart failure, and in the absence of structural heart disease.7][8] The aim of this study was to evaluate the prognosis of ventricular arrhythmia induction in a cohort of patients with SUO.

| ME THODS
This is a historical cohort study, which included patients with SUO and who underwent EPS at the Instituto de Cardiologia do Rio Grande do Sul -Fundação Universitária de Cardiologia (IC/FUC).The study was approved by the ethics and research committee of the institution and is in accordance with the guidelines of the Declaration of Helsinki.

| Inclusion criteria
All adult patients with a diagnosis of SUO, who underwent EPS in the period from January/2008 to December/2021, were included in the study.Patients' clinical data and test results (laboratory and electrocardiogram), as well as controls after EPS, were recorded in physical and electronic medical records.The EPS data were obtained from the electrophysiology records.

| Exclusion criteria
Patients with a diagnosis of syncope suggestive of neurocardiogenic etiology or a clinical condition with a previous ICD indication, and those who could not be contacted to confirm their current clinical status were excluded.We also excluded patients with clinical conditions in which the programmed ventricular stimulation for stratification of sudden death risk is already well defined by the current literature, such as patients with Brugada syndrome, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and hypertrophic cardiomyopathy (condition in which its performance is not recommended).

| Primary outcome
-All-cause mortality rate.

| Secondary outcomes
-Incidence of mortality from cardiovascular causes.

| Clinical data
Age, sex, diseases such as hypertension, type II diabetes mellitus, coronary artery disease (CAD), congestive heart failure (CHF), and the presence of structural heart disease were collected from the medical history.Left ventricular ejection fraction (LVEF) was obtained from echocardiogram data.

| Electrophysiologic study
The procedures were performed in the Electrophysiology Laboratory

| Definition of variables
Mortality: defined as death from any cause.It was obtained from the Central Civil Registry of the State of Rio Grande do Sul and confirmed through calls to the numbers registered in the hospital database.
Coronary artery disease: obstruction of the coronary arteries diagnosed by any currently recommended imaging method or have a history of acute coronary syndrome with demonstration of coronary lesions, previous myocardial infarction, or history of coronary angioplasty.
Congestive heart failure: defined according to the diagnostic criteria for heart failure, in addition to having had at least one episode of water retention or pulmonary congestion requiring medical treatment.
Structural heart disease: any alteration in heart structure and function, demonstrated by echocardiography, CT scan or cardiac magnetic resonance imaging, in the latter including the presence of cardiac fibrosis.

| Clinical follow-up
All information was obtained from the physical or electronic medical

| Statistical analysis
The database was generated using SPSS Mac OS version 25.0 software (IBM SPSS Statistics, Chicago, Illinois).Continuous variables were described as mean ± standard deviation (SD) or median with 95% confidence interval for that value.Categorical variables were represented as absolute numbers and percentages.A descriptive analysis of clinical, ECG, and EPS-related variables was performed.All-cause death-free survival was assessed by the Kaplan-Meier method.The significance level was set as p < .05.Univariate analysis was performed by the χ 2 test, Fisher's exact test, analysis of variance, or the t-test, as necessary.Those variables with p < .05were included for multivariate analysis.Independent predictors of all-cause death were analyzed by multivariable logistic regression.

| RE SULTS
Between the years 2008-2021, 610 patients were referred to perform an EPS due to syncope of undetermined origin in the institution.
Of these, 35 were excluded because they did not meet the inclusion criteria of the study (15 patients without a clinical picture suggestive of syncope, 9 patients with Brugada Syndrome, 6 patients with suspected arrhythmogenic right ventricular dysplasia, 5 patients with hypertrophic cardiomyopathy).Thus, 575 patients were included in the final analysis of the study (Figure 1).Of the patients evaluated, 56.1% had only 1 episode of syncope and 25.4% were hospitalized for investigation of the condition.The median follow-up of patients in this time interval was 37.6 months.
Table 1 shows the characteristics of the study population.The mean age of the patients was 64.5 ± 16.2 years among the patients who did not induce arrhythmias and 66.Clinical follow-up of the patients showed that 142 patients underwent ICD, and 30 of these had device therapies.Regarding the induction of ventricular arrhythmias in the EPS, only the occurrence of sustained VT was associated with appropriate ICD therapies.
Among the 18 appropriate therapies that occurred in the follow-up, 10 occurred in patients with monomorphic VT induction (27%p = .012).Among patients who underwent ICD implantation even in the absence of induction of ventricular arrhythmias in the EPS (74 patients), only 3 patients had appropriate therapies at clinical follow-up (Table 3).The presence of structural heart disease was a risk factor for the occurrence of ventricular arrhythmias, and 30.4% of them presented triggering of arrhythmias in EPS (p < .001).The stratification according to the ventricular ejection fraction showed that the cutoff point below 40% correlated positively with the occurrence of ventricular arrhythmias (p < .001).

Characteristics
Regarding the number of ventricular extra stimuli, only the performance of 3 extra stimuli showed a statistically significant relationship with the occurrence of ventricular arrhythmias (p < .001).
The Kaplan curve of survival over time showed that only the induction of monomorphic ventricular arrhythmias was significantly associated with the main outcome (p = .004-log-rank test) (Figure 2).Stratification with respect to ventricular arrhythmia episodes showed that only the induction of sustained episodes of monomorphic ventricular arrhythmias was significantly associated with mortality (p < .001).
Logistic regression was performed using a model in which variables were included using the backward method based on probability.The criteria for entry into the regression analysis were a p-value of .05 and a removal value of 0.20.The variables selected to enter the model were those that showed statistical significance in the univariate analysis and were deemed relevant by the investigators.The logistic regression analysis showed that the independent variables related to mortality were age, heart failure, atrial fibrillation, and induction of monomorphic ventricular arrhythmia (Table 4).

| DISCUSS ION
The performance of EPS with PVS is often performed to unmask the cause of syncope in patients who present without a defined etiology for it.The results of the study corroborate some current data in the literature, showing that patients with induction of sustained monomorphic ventricular arrhythmias in EPS of patients with SUO have a higher risk of adverse outcomes than other patients.The induction of sustained ventricular arrhythmias, in addition to being associated with mortality, also showed a positive association with the occurrence of appropriate ICD therapies, identifying patients at high risk for future arrhythmic events.Similarly, Andrews NP et al. 10 published a retrospective case-control study with patients with syncope of undetermined origin, structural heart disease, and spontaneous or induced ventricular arrhythmias on electrophysiological study.
In this study, they were able to identify that the incidence of ventricular tachycardia at follow-up was identical between patients in the control group (patients with VT induced on electrophysiological study) and patients with previously documented spontaneous VT.
They also demonstrated the positive correlation between induction of ventricular arrhythmias with the PVS and the occurrence of ICD therapies.
Similarly,  In the study described above, induction of ventricular fibrillation is suggested to be a less specific finding for future ICD therapies (35% of patients with monomorphic VT had ICD therapies versus 18% with VF induction).
The 1997 AVID study 13 (Antiarrhythmics Versus Implantable  15 demonstrated in their study that the induction of VT in patients with ischemic heart disease was significantly associated with the occurrence of sudden death (p < .01),with respect to patients in whom it was not possible to induce ventricular arrhythmias.
The study shows that the positive predictive value of inducing ventricular arrhythmias is low (18%) for predicting sudden death, but with high negative predictive value (97%) for the same outcome.
To verify the effect of programmed ventricular pacing in patients with SUO and idiopathic ventricular dysfunction, Brilaskis ES and colleagues 16 performed a systematic review of the literature.Through the review, the authors conclude that PVS was able to induce sustained ventricular arrhythmias in 53% of the cases and is associated with a higher rate of appropriate ICD therapies.However, they also demonstrated that in a 28-month follow-up, 24% of the patients with negative results in ventricular pacing presented appropriate shocks by ICD.These data suggest that ventricular pacing with a negative result may not have as favorable a prognosis in patients with dilated cardiomyopathy as in those with ischemic heart disease.
The morphology of the induced ventricular arrhythmia in the electrophysiological study seems to be related to the prognosis of new future arrhythmic events, ICD therapies, and mortality.Similar findings were demonstrated by Mittel S et al. 17 who presented that in patients with ischemic heart disease and syncope of undetermined origin, the induction of VF with programmed pacing showed no difference in patient survival during follow-up, demonstrating a low specificity of the induction of this ventricular arrhythmia morphology, especially when using more aggressive pacing protocols, with three extrastimuli. 18conducted a retrospective study analyzing the induction of ventricular arrhythmias in patients with structural heart disease.They showed that the induction of ventricular arrhythmias was associated with the occurrence of ischemic heart disease and left ventricular dysfunction.Similarly, to the present study, they identified that the occurrence of sustained monomorphic ventricular tachycardia was associated with ICD shocks (p < .001)and VT recurrence (p < .001) in the follow-up, but with no association with mortality (p = .139).

Gurbhej Singh and colleagues
The PVS has an important role in risk stratification in patients with syncope of undetermined origin.The present study, despite its retrospective design, presents a long follow-up of patients with syncope without defined etiology who underwent EPS as an auxiliary diagnostic method, showing that patients with monomorphic ventricular arrhythmias have a higher rate of mortality and appropriate therapies by ICD, without stratification by the presence or absence of baseline structural heart disease.
The most current guidelines on syncope and sudden death prevention support the use of electrophysiologic study with programmed ventricular pacing for risk stratification of patients with syncope.The guideline of the American Heart Association classifies as recommendation class IIa, level of evidence B, the performance of EPS with ventricular pacing for patients with syncope and ischemic heart disease, nonischemic dilated heart disease or adults with congenital heart disease who do not meet criteria for ICD as primary prevention. 18The European Society of Cardiology guideline describes as a strong prognostic factor the induction of sustained monomorphic ventricular arrhythmias in patients with previous myocardial infarction, whereas the induction of ventricular fibrillation is considered a nonspecific finding.
They classify as recommendation class I, level of evidence B, the performance of EPS in patients with syncope and previous infarction, with inconclusive non-invasive investigation, and recommendation class IIb, level of evidence C, for patients with syncope preceded by palpitations.
They further describe that induction of polymorphic VT and VF in patients with nonischemic dilated cardiomyopathy and ischemic heart disease should not be interpreted as causes of syncope. 19,20

| Limitations
This work presents limitations, starting with its retrospective design, which to a certain extent limits the extrapolation of its results.The ventricular pacing protocol performed was the responsibility of the electrophysiologist responsible for the procedure, with no predetermined standard for each specific clinical situation, which can limit its evaluation, but at the same time reflects a situation of real clinical practice, considering that, as has been reviewed in the current guidelines, there is no description of specific protocols to be followed in this clinical situation.We also highlight as a limiting factor the small number of patients in each subgroup of patients with induction of ventricular arrhythmias, after stratification by morphology and duration.TA B L E 4 Logistic regression model.

| CON CLUS ION
The present study is a large cohort of patients with syncope of undetermined origin undergoing electrophysiological study, showing that the induction of sustained monomorphic ventricular arrhythmia, after programmed ventricular pacing, is related to a worse prognosis, with a higher incidence of mortality and appropriate ICD therapies, regardless of stratification by the presence of structural heart disease.

CO N FLI C T O F I NTER E S T S TATEM ENT
There are no conflicts of interest or financial disclosures to declare regarding this study.

E TH I C S A PPROVA L S TATEM ENT
This study was approved by the research ethics committee under number 5256/16.

PATI ENT CO N S ENT S TATEM ENT
Written informed consent for the ablation and participation in this study was obtained from all patients.

CLI N I C A L TR I A L R EG I S TR ATI O N
N/A.

R E FE R E N C E S
of our institution with a fluoroscopy device.The data related to the results of the electrophysiological study were evaluated by analyzing the study in the electrophysiology polygraph (WorkMate™ system-St Jude Medical/Abbot).All patients underwent intravenous sedation with propofol (100-150 mcg/kg/min), midazolan (0.02-0.04 mg/kg) and fentanyl (0.5-2 mcg/kg).The right femoral veins were punctured using two introducer sheaths.Fluoroscopy with traditional technology was used as a reference for the introduction and placement of two quadripolar catheters in their specific locations, initially in right atrium and His bundle, and later the right atrium catheter was moved to the right ventricle for the ventricular pacing protocol.The ventricular pacing protocol consists of performing at least two basal cycles of ventricular pacing (600 and 400 ms) with 8 stimuli plus extra stimuli (one, two, or three extra stimuli) at the tip of the right ventricle.All protocols were performed without isoproterenol infusion.The prematurity of the extra stimulus was limited to a minimum coupling of 200 ms.Those patients who induced nonsustained and sustained VT or nonsustained and sustained VT/VF were considered positive.The criteria for defining sustained ventricular arrhythmia were duration longer than 30 s or association with hemodynamic instability.
records regarding clinical history, physical examination, laboratory tests (including ECG and echocardiogram), procedures, outpatient care, emergency care, and in-hospital death record.Clinical followup was performed until December 31, 2021.All patients were contacted by telephone in July 2022 to obtain information about the occurrence of death outside the hospital.Patients were excluded from the study if it was not possible to establish any form of contact to determine the patient's status at the end of the follow-up period.The present study was conducted following the guidelines of the Strengthening the Reporting of Observational Studies (Strobe statement).9 2 ± 16.3 years among those who induced some type of ventricular arrhythmia.The patients who induced ventricular arrhythmias were mostly male (269-56.8% vs. 80-80.6%-p < .001),72.4% were hypertensive and 27.6% were diagnosed with diabetes mellitus.The diagnosis of heart failure (HF) was present in 33 patients with induction of ventricular arrhythmias (p < .001),with 19 (19.8%) presenting heart failure with reduced ejection fraction (HFrEF) of ischemic etiology, 14 (14.6%)nonischemic HFrEF and 6 (18.1%) of valvular etiology.Regarding the previous diagnosis of arrhythmia, 77% of patients had no previous diagnosis, 11.4% had atrial fibrillation, 5.1% had other supraventricular tachyarrhythmias, and around 2% had ventricular ectopy.The measurement of ejection fraction showed a significant difference between patients who did not induce and those who induced ventricular arrhythmias in the EPS (59.16% vs. 47.51%,p < .001).Performing EVP caused ventricular arrhythmias in 98 patients, Table 2 describes these results.Of these 98 patients, 62 F I G U R E 1 Study flowchart.VF, ventricular fibrillation; VT, ventricular tachycardia.were monomorphic ventricular arrhythmias (17 nonsustained and 45 sustained) and 36 were polymorphic (8 nonsustained and 28 sustained).Regarding mortality, the main outcome of the study, 100 (17.6%) patients died during clinical follow-up.Among the patients who induced VT, 22 (36%) evolved to death, presenting a statistically significant association in relation to the patients who did not induce arrhythmias [n = 22 (35.4%) vs. n = 72 (15%); p < .001].The induction of polymorphic ventricular tachycardia showed no significant correlation with the occurrence of death.
igin and with induced and ventricular arrhythmias in the EPS (VT or VF) versus 568 patients with syncope and documented ventricular arrhythmias.After a mean follow-up of 11 ± 10 months, they found that patients with induction of ventricular arrhythmias in the EPS had a similar incidence of death, syncope recurrence, and ICD therapy as patients with documented ventricular arrhythmias.
Defibrillators) was one of the major studies to demonstrate the benefit of ICDs for secondary prevention of sudden death.In 2001 Steinberg, J and colleagues 14 published a sub-study from the AVID data, including 80 patients with syncope of undetermined origin and with induction of ventricular arrhythmias on EPS: 21 patients (26%) with polymorphic VT/VF, 11 (14%) monomorphic VT with frequency <200 bpm and 48 (60%) monomorphic VT with frequency >200 bpm.In this study it was concluded that induction of ventricular arrhythmias is associated with a higher mortality rate comparable to patients in the AVID study (with spontaneous VT/VF) and future ventricular arrhythmic events.The type of ventricular arrhythmia induced did not show a significant difference in the outcomes studied.The data demonstrated in the present study, showed that the induction of sustained monomorphic ventricular arrhythmias showed an association with mortality regardless of the presence or absence of associated structural heart disease, although the presence of structural F I G U R E 2 Survival curve.VT, ventricular tachycardia.heart disease and reduced EF were independent factors for the occurrence of VT.Seeking to evaluate risk stratification in patients with syncope and ischemic heart disease or left ventricular dysfunction, Bembrila-Perrot, B et al., Study population characteristics.Patients undergoing ICD implantation with appropriate therapies.
a Patients with a clinical diagnosis of heart failure; HFrEF-Heart failure with reduced ejection fraction (<40%); NS-statistically non-significant "p" value.TA B L E 1 TA B L E 2 Mortality results.TA B L E 3Abbreviations: ICD, implantable cardioverter-defibrillator; *NS, statistically non-significant "p" value; VT, ventricular tachycardia; VF, ventricular fibrillation.