Catheter-based neuromodulation of intrinsic cardiac autonomic nervous system is increasingly being used to improve outcomes in patients with vasovagal syncope and bradyarrhythmias caused by vagal overactivity. However, there is still no consensus for patient selection, technical steps, and procedural end points. This review takes the reader on a practical exploration of neuromodulation for bradyarrhythmias, concentrating on the critical aspects of proper patient selection, evidence-based insights, and anatomic intricacies within the intrinsic cardiac autonomic nervous system. Also discussed are different mapping techniques and outcome measures. Future directions to optimize the utilization of this technique in clinical practice are highlighted.

The mechanism of vasovagal syncope (VVS) is multifaceted and involves a delicate balance within the autonomic nervous system (ANS). This review delves into the complex interplay between the ANS and VVS, elucidating the pivotal role that autonomic imbalance plays in the pathophysiology of this condition. Through a comprehensive exploration of the sympathetic and parasympathetic branches of the ANS, this review provides insights into the mechanisms that underlie VVS. In addition, this article discusses established and emerging research on the management of VVS.

Cardioneuroablation has emerged as a potential alternative to cardiac pacing in selected cases with vasovagal reflex syncope, extrinsic vagally induced sinus bradycardia-arrest or atrioventricular block. The technique was first introduced decades ago, and its use has risen over the past decade. However, as with any intervention, proper patient selection and technique are a prerequisite for a safe and effective use of cardioneuroablation therapy. This document aims to review and interpret available scientific evidence and provide a summary position on the topic.

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OBJECTIVE: The goal of this manuscript was to review the biological and clinical evidence that serotonin neurotransmission might play an important role in the  physiology and treatment of vasovagal syncope.
METHODS: The authors reviewed PubMed and handsearches of secondary sources for papers related to the Bezold-Jarisch reflex and serotonin, the plausible involvement of the Bezold-Jarisch reflex in vasovagal syncope, and three lines of clinical evidence involving serotonin and the syncope.
RESULTS: The Bezold-Jarisch reflex was first described following the infusion of veratrum alkaloids into animals in the 19th century. The reflex is triggered by serotonin stimulation chemoreceptors and mechanoreceptors in the the left ventricle. The afferent component of the reflex is carried by unmyelinated type C vagal nerve fibers, which results in parasympathetic efferent stimulation that causes bradycardia. The similarity of the combination of hypotension and bradycardia in the Bezold-Jarisch reflex and in vasovagal syncope led to the suggestion that the reflex was the cause of the syndrome.  Three lines of evidence implicate the serotonin 5HT3 receptors in the heart in the reflex. There is genetic and physiologic evidence for the serotonin 5HT1A and 5HT3 receptors and the serotonin reuptake transporter (SERT). Acute blockade of SERT induces vasovagal syncope in humans undergoing head-up tilt table testing, and SERT inhibition reduces hypotension and bradycardia during spinal anaesthesia. Finally, three randomized clinical trials of SERT inhibitors uniformly reported that they significantly reduce the likelihood of vasovagal syncope recurrences.
CONCLUSIONS: Multiple lines of evidence implicate serotonin neurotransmission in the cause of vasovagal syncope.

OBJECTIVE: Syncope is a transient loss of consciousness resulting from cerebral hypoperfusion. Vasovagal syncope (VVS) is a form of orthostatic intolerance (OI). Its clinical signs such as dizziness and hypotension may mimic symptoms of adrenal insufficiency. The objective of this study was to evaluate the adrenal gland function in patients with vasovagal syncope after stimulation with synthetic adrenocorticotropic hormone (ACTH).
METHODS: Case-control study on patients with VVS and healthy controls.
METHODS: The study involved 42 participants, including 27 patients diagnosed with VVS using the head-up tilt test and 15 healthy individuals with no history of syncope or any orthostatic symptoms. Serum cortisol and aldosterone concentrations were measured under basal conditions and at 30 and 60 min after intramuscular ACTH stimulation.
RESULTS: Patients with VVS had significantly higher cortisol levels at baseline (441 ± 143 vs. 331 ± 84.7 nmol/L, p = 0.01), at 30 min (802 ± 143 vs. 686 ± 105 nmol/L, p = 0.01) and at 60 min (931 ± 141 nmol/L vs. 793 ± 147 nmol/L, p = 0.001) after ACTH administration (Synacthen 250 μg). Plasma aldosterone increased after ACTH stimulation, but did not show significant differences among groups. Furthermore, there was also no significant correlation between cortisol levels and blood pressure or heart rate.
CONCLUSIONS: Patients diagnosed with VVS have higher cortisol levels both at baseline and after ACTH stimulation. This finding indicates that individuals with VVS have higher adrenocortical activity potentially as a response to the orthostatic stress induced by syncope, which acts as a stressful stimulus on the autonomic nervous system.

BACKGROUND: There is no universally followed protocol for managing Reflex Vasovagal syncope (VVS).
METHODS: VVS patients were treated with a 2 step protocol. Step I - counseling, hydration, physiotherapy, and Tadasana Yoga maneuver. Patients with ≥2 VVS recurrences were given step II care - intensification of step I, elastic stockings,and pharmacotherapy. Follow-up included assessment by periodic functional status questionnaires.
RESULTS: 157 patients (103 males & 54 females,mean age - 53 ± 20 years & mean LVEF - 62 ± 5%.) experienced 867 total events - 382 syncopal, and 485 near syncopal episodes over 14 ± 9 months. After step I protocol, the mean total, syncopal and near syncopal events declined from 5 ± 7 to 0.3 ± 1.2 (P < 0.0001), 3 ± 2 to 0.1 ± 0.4 (P < 0.0001) and 3 ± 6 to 0.2 ± 1.1 (P < 0.0001) respectively. Twenty (12.7%) patients had 53 event recurrences, 15- syncopal episodes in 7 and 38 near syncope events in 13. After step II, 5 patients had 14 events. At 33 ± 15 months, in 152 patients (96.8%) there were no recurrences and syncope was prevented in all (100%). The median total, syncopal and near syncopal events declined from 3 to 0,(p < 0.001) 2 to 0 (p < 0.001) and 1 to 0 (p < 0.001) respectively. There was an improvement in all the 3 quality of life parameters.
CONCLUSIONS: We demonstrate a simple and effective protocol that can be universally adopted to prevent VVS recurrences,with improvement in quality of life.

OBJECTIVE: The compensatory mechanisms supporting cerebral perfusion throughout head-up tilt (HUT) in patients with vasovagal syncope (VVS) remain unclear. We tested the hypothesis that increased cerebrovascular compliance (Ci) and decreased cerebrovascular resistance (CVR) support cerebral blood velocity (CBV) during pre-syncope in VVS.
METHODS: Finger arterial blood pressure (ABP) and right middle cerebral artery blood velocity (CBV) were recorded in 15 individuals diagnosed with VVS (n = 11 female, mean age: 40 ± 16 years, mean body mass index: 24.9 ± 4.0 kg/m2) at supine rest and during HUT (80 degree angle). Individual ABP and CBV waveforms during VVS were input into a modified Windkessel model to calculate Ci and ohmic CVR. Gosling\'s pulsatility index (Pi; pulse amplitude/mean CBV) was calculated.
RESULTS: Diastolic ABP, systolic ABP, mean ABP (72 ± 11 to 51 ± 12 mmHg), and CVR decreased progressively during presyncope (all P ≤ 0.04). As expected, systolic CBV was sustained (all P ≥ 0.29) while diastolic and mean CBV (51 ± 13 to 38 ± 13 mmHg) fell during presyncope (all P ≤ 0.04). Both Ci and Pi increased during presyncope (128 ± 97 and 60 ± 41%, respectively; all P ≤ 0.049) and were positively correlated (R2 = 0.79, P < 0.01). Increased Ci contributed to changes in mean CBV (P < 0.01) but decreased CVR did not (P = 0.28).
CONCLUSIONS: These data provide evidence that Ci increases during presyncope in patients with VVS and is likely involved in the maintenance of systolic CBV during a fall in diastolic CBV. However, this regulation is not sufficient to preserve CBV in the presence of such extreme and progressive reductions in ABP.

BACKGROUND: Neurocardiogenic syncope is a common condition with significant associated psychological and physical morbidity. The effectiveness of therapeutic options for neurocardiogenic syncope beyond placebo remains uncertain.
METHODS: The primary endpoint was the risk ratio (RR) of spontaneously recurring syncope following any therapeutic intervention. We also examined the effect of blinding on treatment efficacy. We identified all randomised trials which evaluated the effect of any pharmacological, device-based or supportive intervention on patients with a history of syncope. A systematic search was conducted on Medline, Embase, PubMed databases and Cochrane Central Register for Controlled Trials from 1950 to 25 April 2023. Event rates, their RRs and 95% CIs were calculated, and a random-effects meta-analysis was conducted for each intervention. Data analysis was performed in R using RStudio.
RESULTS: We identified 47 eligible trials randomising 3518 patients. Blinded trials assessing syncope recurrence were neutral for beta blockers, fludrocortisone and conventional dual-chamber pacing but were favourable for selective serotonin reuptake inhibitors (SSRIs) (RR 0.40, 95% CI 0.26 to 0.63, p<0.001), midodrine (RR 0.70, 95% CI 0.53 to 0.94, p=0.016) and closed-loop stimulation (CLS) pacing (RR 0.15, 95% CI 0.07 to 0.35, p<0.001). Unblinded trials reported significant benefits for all therapy categories other than beta blockers and consistently showed larger benefits than blinded trials.
CONCLUSIONS: Under blinded conditions, SSRIs, midodrine and CLS pacing significantly reduced syncope recurrence. Future trials for syncope should be blinded to avoid overestimating treatment effects.
UNASSIGNED: CRD42022330148.

BACKGROUND: Fasting before coronary procedures is currently recommended to reduce complications despite the lack of scientific evidence.
OBJECTIVE: The TONIC (Comparison Between Fasting and No Fasting Before Interventional Coronary Intervention on the Occurrence of Adverse Events) noninferiority trial investigated the safety and comfort of a nonfasting strategy (ad libitum food and drinks) vs traditional fasting (>6 hours for solid food and liquids) before coronary procedures.
METHODS: In this monocentric, prospective, single-blind randomized controlled trial, 739 patients undergoing coronary procedures were included and randomized to a fasting or a nonfasting strategy. Emergency procedures were excluded. The primary endpoint was a composite of vasovagal reaction, hypoglycemia (defined by blood sugar ≤0.7 g/L), and isolated nausea and/or vomiting. Noninferiority margin was 4%. Secondary endpoints were contrast-induced nephropathy and patients\' satisfaction.
RESULTS: Among the 739 procedures (697 elective and 42 semiurgent), 517 angiographies, and 222 angioplasties (including complex and high-risk procedures) were performed. The primary endpoint occurred in 30 of 365 nonfasting patients (8.2%) vs 37 of 374 fasting patients (9.9%), demonstrating noninferiority (absolute between-group difference, -1.7%; 1-sided 95% CI upper limit: 1.8%). No food-related adverse event occurred, and contrast-related acute kidney injuries were similar between groups. Overall, procedure satisfaction and perceived pain were similar in both groups, but nonfasting patients reported less hunger and thirst (P < 0.01). In case of redo coronary procedures, most patients (79%) would choose a nonfasting strategy.
CONCLUSIONS: The TONIC randomized trial demonstrates the noninferiority of a nonfasting strategy to the usual fasting strategy for coronary procedures regarding safety, while improving patients\' comfort.