Syncope associated with supraventricular tachycardia: Diagnostic role of implantable loop recorders

Abstract Syncope represents a relatively uncommon symptom of supraventricular tachycardia (SVT). It is likely that an impaired autonomic vasomotor response to the hemodynamic stress of tachycardia is the determinant of hemodynamic changes leading to cerebral hypoperfusion and syncope. In this regard, tilt‐table test may detect abnormalities in the autonomic nervous function and predict the occurrence of syncope during SVT. Electrophysiology studies may reproduce the SVT, distinguish it from other life‐threatening ventricular tachyarrhythmias, and exclude other causes of syncope. Not infrequently mixed syncope mechanisms are revealed during the above diagnostic workup raising doubts about the operating mechanism in the clinical setting. In such cases of uncertainty, an implantable loop recorder, providing long‐term cardiac monitoring, may play a pivotal role in the establishment of the diagnosis, confirming the association of an arrhythmic event with the symptom. Herein, we present four such cases with recurrent unexplained syncope finally attributed to paroxysmal SVT guiding them to a potentially radical treatment through radiofrequency catheter ablation.

without structural heart disease, are listed among the most common causes of syncope and present varying prognosis (Soteriades et al., 2002). The identification of the precise mechanism of syncope is crucial to assess prognosis and proceed to the optimal treatment option in order to minimize the risk of recurrence. However, not uncommonly, several different syncope mechanisms may operate in the same patient as suggested by different aspects of the diagnostic approach, namely the electrophysiology study (EPS), the tilt-tabletesting(TTT),andtheimplantablelooprecorder(ILR)monitoring(Dilaverisetal.,2020; Gatzoulis,Georgopoulos,etal.,2018;Vouliotis et al., 2013) Although the pathogenetic background is not totally clarified, supraventricular arrhythmias are rather infrequently recognized as the only underlying condition responsible for syncope. Typical symptoms of supraventricular tachycardia, such as sensation of palpitations, dizziness, or shortness of breath, preceding a syncopal episode, raise the suspicion for a causal link between arrhythmia and loss of consciousness, especially when no signs indicating lifethreatening ventricular tachyarrhythmias have been identified in the diagnostic workup.
Herein, we present a series of four such patients with recurrent syncope episodes with several potential syncope mechanisms revealed on baseline diagnostic approach, thus requiring the documentationofacause-and-effectrelationshipthroughanILR.The recording of supraventricular tachycardia during a recurrent event suggested the optimal treatment approach.

| C A S E 1
A 41-year-old female patient with no past medical history was referred to our outpatient clinic after experiencing recurrent unexplained syncope episodes associated with chest pain and troponin elevation.Hergrandfatherdiedsuddenlyatageof70years,whileher cousin suffered an acute myocardial infarction at the age of 45 years.
Shehadanormal12-leadECG,whilenoepisodesoftachyarrhythmia, bradycardia,orcardiacpausesweredetectedina24-hrECGHolter monitoring with the exception of 374 isolated premature ventricular contractions. There were no late potentials in signal-averaged electrocardiography(SAECG)neitherstenoticlesionsfoundoncoronary angiography, while on magnetic resonance imaging (MRI) of the heart, limited fibrosis of probable ischemic pattern with slight left ventricular (LV) dilatation and normal LV contractility was noticed.
An electrophysiology study (EPS) revealed the substrate presence for both atrioventricular node reentry tachycardia (AVNRT) and a hemodynamically unstable atrial tachycardia (cycle length 270 ms) that was induced with programmed atrial stimulation, after the intravenous administration of isoproterenol (IVISO). Despite a rather aggressiveprogrammedventricularstimulation(PVS)protocolfrom two right ventricular (RV) sites introducing up to three extrastimuli before and after IVISO, no ventricular tachyarrhythmias were induced. A TTT was positive for the induction of neurocardiogenic syncope(NCS).Inthepresenceofmultiplesyncopemechanismsand in order to resort to the most appropriate and effective treatment modality,adecisiontoproceedwithanILRwasmade.Threemonths after the implantation, the patient presented again with a new presyncopeepisodeassociatedwithpalpitations.TheanalysisofILR data revealed an episode of supraventricular tachycardia (SVT) at a rateof207bpmself-terminatingafter9s(Figure1).Anablationprocedure was suggested, but the patient declined the offer.

| C A S E 2
A 67-year-old female patient was referred to our institution for investigation of recurrent unexplained syncope episodes, once resulting in a head injury and other times preceded by prodromal symptoms,mainlydizziness.Shehadahistoryofarterialhypertension and dyslipidemia. No abnormalities were detected during a neurological and otolaryngologic examination. She had sinus rhythm on ECG and mild LV hypertrophy with a normal LV ejection fraction in echocardiography with no evidence of organic heart disease. vagotonic reaction associated with atypical chest pain was observed on TTT. In light of these findings, a treatment with verapamil targeting at the suppression of AVNRT episodes was initiated. In the following 2 years, the patient reported several presyncope episodes, sometimes accompanied by chest discomfort, leading to coronary angiography showing no critical stenosis, before presenting with a new syncope episode resulting in a head injury.
Once again, facing a patient with multiple potential syncope mechanisms and in order to establish a firm causal relationship, thus establishing the most appropriate treatment plan, namely ablation, pacing, or/and drugs, we decided to proceed with an ILR. Indeed, 6monthslater,asymptomaticSVTepisodewasrecorded (Figure2) andasuccessfulanduncomplicatedslowAVNpathwayablationfollowed. During the 30-month follow-up, no recurrent syncope occurred neither any significant tachyarrhythmic nor bradyarrhythmic episodes were recorded.

| C A S E 3
A 71-year-old man with a 12-year history of recurrent unexplained syncope episodes in the absence of organic heart disease, occurring once during driving resulting in a car accident and at different times associated with either palpitations or abdominal discomfort, To further investigate the syncope mechanism, an ILR was offered.Amonthlater,anewsyncopeepisodewasassociatedwithan The patient remains asymptomatic οver the last 12 months.

| C A S E 4
A27-year-oldmalepatientwithahistoryofoperatedTetralogyof F I G U R E 1 Implantable loop recorder data demonstrating an episode of supraventricular tachycardia at an average rate of 207 bpm, selfterminating after 9 s, clinically presenting with presyncope

| D ISCUSS I ON
In this case series of four patients presented with rather mixed syncope mechanisms, the ILR was crucial in defining the most appropriate and cost-effective treatment plan. During the baseline pre-implantation diagnostic workup of these four patients, more than two potential syncope mechanisms were revealed, namely the presence of at least one SVT substrate with or without evidence  Accordingtoformerstudiesinvestigatingthespectrumofsymptoms in patients with SVT, syncope represents a rather uncommon event following tachycardia, more frequently occurring in patients over 65 years of age (Dhala et al., 1995;Kalusche et al., 1998;Wood etal.,1997).However,amongolderpatients,syncopeornear-syncope symptoms are not related to the tachycardia rate, occurring at slower rates than those observed in younger patients (Kalusche et al., 1998).
It is still unclear whether an association between hemodynamic instability, responsible for syncope or presyncope symptoms, and tachycardia rate exists (Yusoff et al., 1988). A heart rate over 170 beats/min was the major factor that was associated with syncope among 167 patients with SVT (Wood et al., 1997). In line with this study and in agreement with the tachycardia rates observed in ourpatientsonILR,tworeportsunderlinethatanextremelyrapid heart rate during tachycardia is a sufficient condition for the in- An impairedresponse of theautonomic vasomotor function to the tachycardia has been proposed as an alternative mechanism for SVT-associated syncope. Indeed, 3 out of our 4 SVT patients exhibited an abnormal vagotonic reaction on the TTT. Sharing common pathogenetic features with vasovagal syncope, it is assumed that the activation of cardiac mechanoreceptors during tachycardia may lead to a reflex withdrawal of sympathetic tone and an inappropriate stimulation of parasympathetic tone, resulting in vasodepressor mediated syncope (Waxman & Cameron, 1990).
High rate SVT leads to an impaired left ventricular filling due to shortening of diastolic time, resulting in a decrease in cardiac output (Inchaustegui et al., 2020). This causes an initial fall in systemic blood pressure followed by a reflex increase in sympathetic tone (Márquezetal.,2016).Sympatheticactivationisresponsibleforfurther tachycardia acceleration and vigorous ventricular contraction, which, in combination with diminished left ventricular volume, leads to a paradoxical stimulation of left ventricular mechanoreceptors (Iwase et al., 2014). These mechanoreceptors trigger an exaggerated parasympathetic response with further drop of systemic blood F I G U R E 4 Implantable loop recorder data from a grown-up congenital heart disease patient showing a regular fast tachycardia run with a median ventricular rate of 222 bpm, self-terminating after 26 s, associated with syncope pressure,finallyresultinginsyncope (Gatzoulis&Toutouzas,2001).
Upright position may itself amplify such an inadequate response of the autonomous nervous system due to a greater reduction in left ventricular volume and further enhancement of sympathetic tone (Stewart, 2012). Providing support to the aforementioned hypothesis,Leitchetal.reportednoassociationbetweensyncopeduring SVT induced on EPS occurring in upright position and the rate of tachycardia (Leitchetal.,1992).Ofnote,theseinvestigatorsfound a tendency toward a longer cycle length during tachycardia-induced syncope in the presence of significant hypotension also suggesting parasympathetic stimulation, with both cardioinhibitory and vasodepressor effects, at the time of the event. To further support this hypothesis, a significant association between tachycardia-induced syncope and a positive TTT for the induction of neurocardiogenic syncope was demonstrated.
In addition to the above mechanisms, several other factors may influence and accelerate the occurrence of SVT-associated syncope.
Among these, patient's behavior at the time of tachycardia seems to play an important role. Immediate cessation of activity after the onset of tachycardia or sensation of prodromal symptoms of syncope and assumption of the supine position may prevent syncope.
Furthermore, hypovolemia due to dehydration or blood loss, body position, hypersensitivity of left ventricular wall mechanoreceptors, antiarrhythmic drugs, and any kind of emotional stress may also create the suitable substrate for an SVT-related syncopal episode (Fentonetal.,2000).
Despite the evolution of novel diagnostic technologies, the identification of the etiology of syncope continues to pose major diagnostic and therapeutic challenges. Initial assessment includes a detailed history, physical examination, a 12-lead electrocardiogram (ECG), and an echocardiography study to exclude structural heart disease.AmbulatoryECGHoltermonitoringisalmostroutinelyused in the investigation of syncope with a rather less diagnostic yield in termsofcorrelatingsymptomswithpotentialarrhythmias (Gibson& Heitzman,1984;Kühneetal.,2007;Sarasinetal.,2005).ASAECG may reveal late potentials, pointing to the presence of a ventricular reentrymechanism (Gatzoulis,Arsenos,etal.,2018).AnEPSinthe presenceofabnormal12-lead,signal-averagedandambulatoryECG findings may identify cardiac production and conduction abnormalities or supraventricular and/or ventricular arrhythmias as potential syncope mechanisms (Gatzoulis et al., 2009). In particular, if tachyarrhythmiaeventsarehighlysuspected,EPSmaydistinguishalifethreatening ventricular arrhythmia from an SVT as the underlying syncopecause(Muresanetal.,2019).
For infrequently occurring unexplained recurrent syncope episodes, long-term monitoring with an ILR is highly recommended, establishing a definite diagnosis in a significant proportion of cases (Edvardsson et al., 2011). In fact, an ILR implantation at an early phase of the diagnostic evaluation of unexplained syncope is preferable and highly recommended by current guidelines, especially in patients with structurally normal hearts, who are considered low risk for malignant ventricular arrhythmias after the initial noninvasive evaluation. In such cases, an EPS could be preserved for further investigation of syncope that remains unexplained or as the final step in the therapeutic management of SVT-associated syncope combined with the performance of a curative ablation procedure (Brignole et al., 2018). On the contrary, we decided to perform an There is an ongoing debate about the diagnostic value of the TTT. Exposing the patient to an orthostatic challenge in the upright tilt, the test may unmask autonomic system malfunction responsible for inappropriate vasodepressive and/or cardioinhibitory response (Teodorovich & Swissa, 2016). In addition to this, TTT is recommended as a useful method to predict impaired vasomotor function accompanied by syncope during SVT episodes (Doi et al., 2000).
Our case series demonstrate clearly that mixed syncope mechanismsmaycoexistinsomepatients(Dilaverisetal.,2020; Gatzoulis, Georgopoulos,etal.,2018;Vouliotisetal.,2013).Thismightexplain the occasional syncope recurrence in a small proportion of appropriatelytreatedwithpermanentpacingbradycardiapatients (Gatzoulis et al., 1999). It is also well known that vasovagal syncope patients may develop alternative syncope mechanisms during long-term follow-up In conclusion, a definite cause of syncope was established by onlyresortingtoanILRpolicyinthesepatientswithseveralsyncope mechanisms uncovered during a full-blown conventional diagnostic strategy, including noninvasive ECG-related indices and TTT along withacomprehensiveEPS.Suchastrategynotonlyconfirmedthe SVT-induced syncope mechanism but also led to a curative ablative procedure justifying any associated procedural risks.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflicts of interest.

AUTH O R CO NTR I B UTI O N S
The authors confirm contribution to the paper as follows: study conception and design: K.A. Gatzoulis; data collection: S.

E TH I C S
Informed consent for publication of data was obtained from each patient.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.