Cardioneuroablation: the known and the unknown.

Cardioneuroablation (CNA) is a novel interventional procedure for the treatment of recurrent vasovagal syncope (VVS) and advanced atrioventricular block secondary to hyperactivation of vagal tone in young patients. By damaging the cardiac parasympathetic ganglia, CNA seems to be able to mitigate and/or abolish the excessive vagal activity and improve patients' outcome. This review is intended to give a detailed and comprehensive overview of the current evidences regarding (1) the clinical applications of CNA (2) the identification of ablation targets and procedural endpoints (3) the medium-long term effect of the procedure and its future perspectives. However, clinical data are still limited, and expert consensus or recommendations in the guidelines regarding this technique are still lacking.

The triggers of situational syncope do not influence the head-up tilt test response and prognosis.

AIMS: The study evaluated the positivity rate, haemodynamic responses, and prognosis in terms of syncopal recurrence among patients with situational syncope (SS) stratified according to the underlying situational triggers. METHODS AND RESULTS: We retrospectively evaluated all consecutive patients with SS who underwent nitroglycerine (NTG)-potentiated head-up tilt test (HUTT) at Syncope Unit of the University of Campania 'Luigi Vanvitelli'-Monaldi Hospital from 1 March 2017 to 1 May 2023. All patients were followed for at least one year. The study population was divided according to the underlying triggers (micturition, swallow, defaecation, cough/sneeze, post-exercise). Two hundred thirty-six SS patients (mean age 50 ± 19.3 years; male 63.1%) were enrolled; among them, the situational trigger was micturition in 109 patients (46.2%); swallow in 32 (13.6%) patients; defaecation in 35 (14.8%) patients; post-exercise in 41 (17.4%) patients; and cough/sneeze in 17 (7.2%) patients. There were no significant differences in baseline clinical characteristics and HUTT responses between different situational triggers. The Kaplan-Meier analysis did not show a statistically different rate of syncope recurrence across patients stratified by baseline situational triggers (log-rank P = 0.21). CONCLUSION: Situational syncope appears to be a homogenous syndrome, and different triggers do not impact the HUTT response or syncope recurrence at 1 year.

Cardioneuroablation for Drug Refractory Vasovagal Syncope After COVID-19 Infection.

Cardioneuroablation is a novel approach to treat patients with recurrent vasovagal syncope (VVS), targeting the ganglionated plexi around the atria and thus reducing the vagal input to the heart. This study reports a case of drug-refractory VVS after COVID-19 infection, successfully managed with cardioneuroablation.

Syncope or seizure: that is the question-case report of a young patient with convulsive cardioinhibitory syncope treated with cardioneuroablation.

Background: Differentiation of syncope from seizure is challenging and has therapeutic implications. Cardioinhibitory reflex syncope typically affects young patients where permanent pacing should be avoided whenever possible. Cardioneuroablation may obviate the need for a pacemaker in well-selected patients. Case summary: A previously healthy 24-year-old woman was referred to the emergency department after recurrent episodes of transient loss of consciousness (TLOC). The electrocardiogram (ECG) and the echocardiogram were normal. An electroencephalogram (EEG) showed intermittent, generalized pathological activity. During EEG under photostimulation, the patient developed a short-term TLOC followed by brachial myocloni, while the concurrent ECG registered a progressive bradycardia, which turned into a complete atrioventricular block and sinus arrest with asystole for 14 s. Immediately after, the patient regained consciousness without sequelae. The episode was interpreted as cardioinhibitory convulsive syncope. However, due to the pathological EEG findings, an underlying epilepsy with ictal asystole could not be fully excluded. Therefore, an antiseizure therapy was also started. After discussing the consequences of pacemaker implantation, the patient agreed to undergo a cardioneuroablation and after 72 h without complications, she was discharged home. At 10 months, the patient autonomously discontinued the antiepileptics. The follow-up EEG displayed unspecific activities without clinical correlations. An implantable loop recorder didn't show any relevant bradyarrhythmia. At 1-year follow-up, the patient remained asymptomatic and without syncopal episodes. Discussion: Reflex syncope must be considered in the differential diagnosis of seizures. The cardioneuroablation obviated the need for a pacemaker and allowed for the withdrawal of anticonvulsants, originally started on the premise of seizure.

Cardioneuroablation for severe neurocardiogenic syncope.

INTRODUCTION AND OBJECTIVES: Cardioneuroablation (CNA), a technique based on radiofrequency ablation of cardiac vagal ganglia, was developed to treat recurrent vasovagal syncope (VVS) with a predominant cardioinhibitory component, as an alternative to pacemaker implantation. The aim of our study was to evaluate the safety and success rate of CNA guided by extracardiac vagal stimulation in patients with highly symptomatic cardioinhibitory VVS. METHODS: Prospective study of patients who underwent anatomically guided CNA at two cardiology centers. All patients had a history of recurrent syncope with a predominant cardioinhibitory component and refractory to conventional measures. Acute success was determined by the absence or significant reduction of cardiac parasympathetic response to extracardiac vagal stimulation. The primary endpoint was the recurrence of syncope during follow-up. RESULTS: In total, 19 patients (13 males; mean age 37.8±12.9 years) were included. Ablation was acutely successful in all patients. One patient had a convulsive episode after the procedure, which was deemed unrelated to the ablation, requiring admission to intensive care but without sequelae. No other complications occurred. At a mean follow-up of 21.0±13.2 months (range 3-42 months), 17 patients remained free of syncope. The remaining two patients had recurrence of syncope and, despite undergoing a new ablation procedure, required pacemaker implantation during follow-up. CONCLUSION: Cardioneuroablation, confirmed by extracardiac vagal stimulation, appears to be an effective and safe treatment option for highly symptomatic patients with refractory VVS with a predominant cardioinhibitory component, providing a new potential approach as an alternative to pacemaker implantation.

Ganglionated plexi ablation in the right atrium for the treatment of cardioinhibitory syncope.

Neurocardiogenic syncope, also called vasovagal syncope, represents one of the clinical manifestations of neurally mediated syncopal syndrome. Generally, the prognosis of the cardioinhibitory form of neurocardiogenic syncope is good, but quality of life is seriously compromised in patients who experience severe forms. Drug therapy has not achieved good clinical results and very heterogeneous data come from studies regarding permanent cardiac pacing. In this scenario, the ganglionated plexi ablation has been proposed as an effective and safe method in patients with cardioinhibitory neurocardiogenic syncope, especially in young patients in order to avoid or prolong, as much as possible, the timing of definitive cardiac pacing. Certainly, making this procedure less extensive and limiting the ablation in the right atrium (avoiding the potential complications of a left atrial approach) and at level of anatomical regions of the most important ganglionated plexy, considered 'gateway' of the sino-atrial and atrio-ventricular node function (through the recognition of specific endocardial potentials), could be very advantageous in this clinical scenario. Finally, randomized, multicentre, clinical trials on a large population are needed to better understand which is the best ablation treatment (right-only or bi-atrial) and provide evidence for syncope guidelines.

A Case Report of a Young Patient Presenting With Syncope Secondary to Arrhythmogenic Ventricular Cardiomyopathy.

Arrhythmogenic ventricular cardiomyopathy is an inherited condition mainly affecting adults. A 35-year-old Asian male patient presented with syncope while walking home. He experienced a number of episodes of light-headedness and dizziness over the past few weeks. A clinical examination found visible injuries to his face and hands. An electrocardiogram showed right axis deviation and right bundle branch block. Echocardiography showed normal biventricular function and the left ventricular ejection fraction was > 55%. A computerized tomography scan of the head and face showed a small fracture to the superior maxillary wall and a computerized tomography pulmonary angiogram demonstrated an inflammatory nodule with right upper and middle lobes changes as well as right hilar lymphadenopathy, suggestive of possible tuberculosis. Blood tests were unremarkable, and troponin was negative. Cardiovascular magnetic resonance imaging showed preserved biventricular function, mild bi-atrial dilatation, and extensive, crescentic-shaped, subepicardial late gadolinium enhancement from basal to apical inferior, basal to apical lateral, and mid to apical anterior segments of the left ventricle suggestive of arrhythmogenic ventricular cardiomyopathy. The patient was commenced on bisoprolol and had an implantable cardioverter defibrillator fitted. He was discharged home with outpatient cardiology follow-up.

Paxlovid-Induced Symptomatic Bradycardia and Syncope.

Paxlovid (nirmatrelvir/ritonavir) is a game changer in the fight against COVID-19 due to its ease of administration and significant benefits of reducing progression to severe COVID-19, hospitalization, and death. Cardiac adverse events such as bradycardia and syncope are not known with this medication. We report a case of a 71-year-old patient who developed symptomatic bradycardia, syncopal episodes, and sinus pause after taking Paxlovid. Discontinuing medication and intravenous atropine helped to reverse the bradycardia and symptoms promptly. She did not require a pacemaker. We would like to report this possible association between Paxlovid and bradycardia. Until further information or studies are available, it is advised to promptly discontinue Paxlovid after any evidence of bradycardia and closely monitor for at least 40 hours in a hospital setting. The reported half-life (t 1/2) of the medication is 6.05 ± 1.79 hours and using 8 hours as a reference for the upper limit of t 1/2, around 97 % of the medication should be cleared off in about 40 hours (five half-lives).

The clinical presentation of syncope influences the head-up tilt test responses.

INTRODUCTION: Little is still known about the positivity rate of nitroglycerin (NTG) potentiated head-up tilt test (HUTT) according to the history-based clinical features of syncope. The study aimed to compare the HUTT positivity rate and type of responses in patients with classical and non-classical vasovagal syncope (VVS). MATERIALS AND METHODS: We retrospectively evaluated all consecutive patients who underwent NTG-potentiated HUTT for VVS. The study population was dichotomized into classical and non-classical VVS. RESULTS: A total of 1285 VVS patients (45± 19.1 years; 49.6% male) were enrolled: 627 (48.8%) had a history of classical VVS and 658 (51.2%) of non-classical VVS. HUTT was positive in 866 (67.4%) patients. The positivity rate was significantly higher in patients with classical compared to those with non-classical VVS (81.5% vs 54%; P< 0.0001). Cardioinhibitory response showed similar total positivity rate (27.6% vs 31%; P= 0.17), but higher relative prevalence among positive tests (57.7% vs 33.9%, P< 0.0001) in patients with non-classical VVS. At multivariable analysis, classical reflex syncope, male sex, history of traumatic syncope and use of diuretics were independent predictors of HUTT positivity. CONCLUSION: The clinical presentation of syncope influences the overall HUTT positivity rate and the type of responses. Cardioinhibitory response and traumatic syncope are more likely in patients with non-classical VVS.

Reflex cardioinhibitory syncope potentially related to SARS-CoV-2 infection: a case report / Síncope cardioinibitória reflexa potencialmente relacionada à infecção por SARS-CoV-2: um relato de caso

Autonomic dysfunction related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is increasingly described in the literature. We report the case of a 30-year-old male with a background of asthma and migraine who experienced a second episode of SARS-CoV-2 infection characterized by mild respiratory symptoms. Twenty-four days after the symptom onset, he developed acute syncope. A tilt test revealed a neuromediated cardioinhibitory response with asystole (Vasovagal Syncope International Study ­ VASIS type 2B). The temporal association between SARS-CoV-2 infection and syncope seems to indicate a probable causal relationship, which requires corroboration by future studies.

Disfunção autonômica relacionada à infecção por coronavírus-2 da síndrome respiratória aguda grave (SARS-CoV-2) vem sendo cada vez mais descrita na literatura. Relatamos o caso de um homem de 30 anos de idade, com histórico de asma e enxaqueca, que apresentou um segundo episódio de infecção por SARS-CoV-2 caracterizado por sintomas respiratórios leves. Vinte e quatro dias após o início dos sintomas, desenvolveu um quadro agudo de síncope. Um teste de inclinação revelou uma resposta cardioinibitória neuromediada com assistolia (Vasovagal Syncope International Study ­ VASIS tipo 2B). A associação temporal entre infecção por SARS-CoV-2 e síncope parece indicar uma provável relação causal, a qual requer corroboração por estudos futuros.

A case report of severe cardioinhibitory reflex syncope associated with coronavirus disease 2019.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been recognized as a disease with a broad spectrum of clinical manifestations. In this report, we illustrate an extraordinary case of severe cardioinhibitory reflex syncope with prolonged asystole associated with COVID-19. CASE SUMMARY: A 35-year-old male patient presented to the emergency department with a 10-day history of postural syncope and fever. Electrocardiogram monitoring during positional change revealed reflex syncope with cardioinhibitory response, exhibiting sinus bradycardia, subsequent asystole, and syncope. The patient tested positive for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and was admitted to the intensive care unit where temporary transvenous pacing was necessary because of prolonged episodes of asystole. Work-up included extensive cardiac and neurological diagnostic testing, but did not yield any structural abnormalities. Although temporary pacing was able to abort syncope, a decision was made to hold off on permanent pacing as the most likely aetiology was felt to be temporary cardioinhibitory reflex syncope associated with COVID-19. The patient was discharged with mild symptoms of orthostatic intolerance and responded well to education and lifestyle modification. Outpatient follow-up with repeat tilt testing after 3 and 6 months initially showed residual inducible syncope but was eventually normal and the patient remained asymptomatic. DISCUSSION: We believe that autonomic imbalance with a strong vagal activation due to acute SARS-CoV-2 infection played a pivotal role in the occurrence of transient syncope in this patient's condition. Although pacemaker implantation would have been a reasonable alternative, a watch-and-wait approach should be considered in similar instances.

Reflex Anoxic Seizures Induced by Needle Stick and Successfully Treated With Intranasal Midazolam.

Reflex anoxic seizures are a type of convulsive syncope seen more commonly in children. In rare cases, they may develop into true epileptic seizures. There is no current consensus on treatment. In this case report, we present an adult patient with reflex anoxic seizures, along with EEG monitoring from an event. Our patient had a successful trial with intranasal midazolam preventing the episode, suggesting that anxiety played a significant role in her case. Reflex anoxic seizures in adults are rare and need to be properly identified, as treatment can lead to significant improvements in patient quality of life.

Electrocardiographic Patterns in Patients with Neurally Mediated Syncope.

The baseline electrocardiogram (ECG) is less informative in neurally mediated syncope (NMS) than in arrhythmic syncope. However, some of the ECG patterns present in NMS can have diagnostic and prognostic value in such patients. Electrocardiographic documentation of a syncopal spell and thus identification of the ECG changes can be performed during tilt table test (TTT) or during prolonged ECG monitoring. This work reviews the specific ECG patterns in NMS, which are primarily related to the cardioinhibitory reflex. In addition, there are other ECG findings present in patients with NMS that are being analyzed, such as increased heart rate variability as well as specific QRS voltage patterns. In addition to the diagnostic and prognostic value, these ECG patterns in NMS may help improving the selection of patients for pacemaker implant.

Fractionation Mapping of the Ganglionated Plexi for Cardioneuroablation.

Cardioneuroablation (CNA) is an emerging technique used to treat patients with vasovagal syncope (VVS). We herein describe a case of CNA targeting the atrial ganglionated plexi (GPs) based upon anatomical landmarks and fractionated electrogram (EGM) localization in a 20-year-old healthy female who presented to our center with malignant VVS and symptomatic sinus pauses, the longest of which measured 10 seconds. She underwent acutely successful CNA with a demonstration of vagal response noted following ablation of the left-sided GPs, and tachycardia was noted with right-sided GP ablation. All GP sites were defined by anatomical landmarks and EGM analysis. By using the fractionation mapping software of the EnSite Precision™ cardiac mapping system (Abbott, Chicago, IL, USA) with high-density mapping, fragmented EGMs were successfully detected in each GP site. One month after vagal denervation, no recurrent syncopal episodes or sinus pauses had been recorded. Longer-term follow-up with an implantable loop recorder is planned. Broadly, we performed CNA in a patient with VVS by combining high-density mapping and fractionation mapping software in a novel approach, which allowed us to detect fractionation in all GP sites and demonstrate an acute vagal response. This workflow may facilitate the introduction of a standardized technique suitable for widespread use.

Long-Term Effects of Ivabradine on Cardiac Vagal Parasympathetic Function in Normal Rats.

Background: The complex interactions that exist between the pacemaker current, I f, and the parasympathetic nervous system could significantly influence the course of patients undergoing chronic therapy with the I f blocker ivabradine. We thus aimed to assess the effects of chronic ivabradine therapy on autonomic modulation and on the cardiovascular response to in situ and in vitro parasympathetic stimulation. The right atrial expression of HCN genes, encoding proteins for I f, was also evaluated. Methods: Sympathetic and parasympathetic heart rate variability parameters and right atrial HCN(1-4) RNA levels were analyzed in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day). The heart rate (HR) and systolic blood pressure (SBP) responses to in situ electrical stimulation of the vagus nerve (2-20 Hz) were assessed in 6 additional Control and 10 IVA rats. The spontaneous sinus node discharge rate (SNDR) response to in vitro cholinergic receptors stimulation using carbamylcholine (10-9-10-6 mol/L) was also assessed in these later rats. Results: Ivabradine significantly increased vagal modulation and shifted the sympatho-vagal balance toward vagal dominance. In Control, in situ vagus nerve stimulation induced progressive decrease in both the SBP (p = 0.0001) and the HR (p< 0.0001). Meanwhile, in IVA, vagal stimulation had no effect on the HR (p = 0.16) and induced a significantly lower drop in SBP (p< 0.05). IVA also displayed a significantly lower SNDR drop in response to carbamylcholine (p< 0.01) and significantly higher right atrial HCN4 expression (p = 0.02). Conclusion: Chronic ivabradine administration enhanced vagal modulation in healthy rats. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to in situ vagal stimulation. These data bring new insights into the mechanisms of ivabradine-related atrial proarrhythmia and suggest that long-term I f blockade may protect against excessive bradycardia induced by acute vagal activation.

Cardioneuroablation for cardioinhibitory vasovagal syncope.

BACKGROUND: Cardioneuroablation (CNA) is an emerging technique being used to treat patients with cardioinhibitory vasovagal syncope (VVS). We describe a case of CNA in targeting atrial ganglionated plexi (GP) based upon anatomical landmarks and fractionated electrogram (EGM) localization in a patient with cardioinhibitory syncope. CASE PRESENTATION: A 20-year-old healthy female presented with malignant VVS and symptomatic sinus pauses, with the longest detected at 10 s. She underwent acutely successful CNA with demonstration of vagal response (VR) noted after ablation of left sided GP, and tachycardia noted with right sided GP ablation. All GP sites were defined by anatomical landmarks and EGM analysis. By using the fractionation mapping software of Ensite Precision mapping system with high density mapping, fragmented EGMs were successfully detected in each GP site. One month after vagal denervation, there were no recurrent syncopal episodes or sinus pauses. Longer term follow-up with implantable loop recorder is planned. CONCLUSION: We performed CNA in a patient with VVS by utilizing a novel approach of combined use of high density mapping and fractionation mapping software. With this approach, we were able to detect fractionation in all GP sites and demonstrate acute VR. This workflow may allow for a new, standardized technique suitable for widespread use.

Cardiac Pacing in Cardioinhibitory Reflex Syncope: Clinical Use of Closed-loop Stimulation.

Cardiac pacing has been studied extensively in patients with reflex syncope over the past two decades. The heterogeneity of the forms and clinical manifestations of reflex syncope explain the controversial results of older randomised clinical trials. New evidence from recent trials has changed medical practice, now leading to clear indications for pacing in patients with asystolic syncope documented during carotid sinus massage, implantable cardiac monitoring or tilt testing. Given that recent trials in reflex syncope have been performed using the closed-loop stimulation algorithm, the authors will briefly discuss this pacing mode, review hypotheses about the mechanisms underlying its activation during syncope and provide practical instructions for programming and troubleshooting.

Catheter ablation of right atrial ganglionated plexi to treat cardioinhibitory neurocardiogenic syncope: a long-term follow-up prospective study.

PURPOSE: Several reports have focused on biatrial ganglionated plexi (GP) transcatheter ablation to treat cardioinhibitory neurocardiogenic syncope (CNS). Considering that anatomical studies showed a significant number of GP in the right atrium (RA), we hypothesized that RA "cardioneuroablation" could be an effective treatment for CNS. METHODS: Eighteen consecutive patients (mean age: 36.9 ± 11.2 years) with severe CNS were submitted to transcatheter ablation of GPs in the RA alone using an anatomical approach. Head up tilt test evaluation was performed during the follow-up period at 6, 12, and 24 months and in case of significant symptoms, while heart rate variability parameters were evaluated at patients discharge at 1, 3, 6, 12, 24, and 36 months after ablation. RESULTS: At a mean follow-up of 34.1 ± 6.1 months, 3 (16.6%) patients experienced syncopal episodes and 5 patients (27.7%) only prodromal episodes. Syncopal and prodromal recurrences were significantly decreased both in overall population (P = 0.001) and in symptomatic patients after ablation (P = 0.003). Heart rate variability analysis showed the loss of autonomic balance secondary to a reincrease of sympathetic tone after the acute phase faster than vagal tone more evident at 12 months (LF/HF vs preablation, P < 0.001) and persistent until 24 months. Finally, a good correlation was observed between symptomatic events and the extension of RF lesions in supero-, middle-, and infero-posterior RA areas (r = 0.73, P = 0.03; r = 0.85, P = 0.02; r = 0.87, P = 0.004, respectively). CONCLUSIONS: Cardioneuroablation in the RA can be considered safe and an effective technique to treat CNS episodes.

Cardioinhibitory syncope: from pathophysiology to treatment-should we think on cardioneuroablation?

Vasovagal syncope (VVS) is the most common type of syncope; the lone cardioinhibitory syncope represents only a small group of patients; however, the "cardioinhibitory component" is highly prevalent in reflex syncope and can be severe enough to produce asystole, lasting for a few seconds followed by a recovery to sinus beats. The environment in which syncope occurs can compromise life, and in-depth knowledge of the disease can prevent deaths and guide the appropriate management. The therapeutic cornerstone is general measures (increase water and salt) followed by pharmacologic therapy; for cardioinhibitory syncope, both treatments fail most of the time, and the next therapeutic option is pacemaker implantation. However, although the pacemaker causes a reduction in syncope, recurrence is high, and a one-time, effective, and safe intervention would be ideal. Cardioneuroablation (CNA) therapy has been proposed as a pacemaker alternative with these characteristics. CNA has shown a high reduction or even complete syncope elimination during 3 years of follow-up in some studies. Patients also reported prolonged prodromal periods, which allowed them enough time to abort the syncope. Invasive therapies like CNA require further extensive cohort studies, randomized clinical trials, and more substantial follow-up to evaluate adverse side effects. This review highlights syncope pathophysiology, dividing it into a central theory and a peripheral theory, the diagnosis explaining the head-up tilt test protocols, and treatments like CAN, representing it with figures for a simplified understanding.