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BACKGROUND: Autonomic denervation is an ancillary phenomenon during thermal ablation of atrial fibrillation (AF), that may have synergistic effects on symptomatic improvement and long-term freedom from AF. Pulsed field ablation (PFA), a nonthermal ablation modality, was noninferior to thermal ablation in treating AF; however, PFA's relative myocardial selectivity may minimize autonomic effects. OBJECTIVES: This study sought to compare heart rate (HR) and heart rate variability (HRV) metrics as markers of autonomic function after ablation using PFA vs thermal ablation. METHODS: ADVENT (FARAPULSE ADVENT PIVOTAL Trial PFA System vs SOC Ablation for Paroxysmal Atrial Fibrillation) was a randomized pivotal study comparing PFA (pentaspline catheter) with thermal ablation (radiofrequency [RF] or cryoballoon [CB]) for treating paroxysmal AF. Baseline HR was acquired from a pre-ablation 12-lead electrocardiogram, whereas follow-up HRs, as well as HRV (standard deviation of all normal to normal RR intervals, standard deviation of 5-minute average RR intervals) metrics, were derived from 72-hour Holter monitors at 6 and 12 months. RESULTS: This study included 379 paroxysmal AF patients undergoing PFA (n = 194) or thermal ablation (n = 185; n = 102 RF, n = 83 CB) completing 6- and 12-month Holter monitoring. Compared with PFA, thermal patients had significantly greater increases in HR from baseline to 6 months (ΔHR; 10.1 vs 5.9 beats/min; P = 0.02) and 12 months (ΔHR; 8.8 vs 5.2 beats/min; P = 0.03). This increase in HR at 6 and 12 months was similar between CB and RF (P = 0.94 and 0.83, respectively). HRV, both standard deviation of all normal to normal RR intervals and standard deviation of 5-minute average RR intervals, were significantly lower at both 6 and 12 months after thermal ablation compared with PFA (P < 0.01). CONCLUSIONS: PFA's effect on the autonomic nervous system was attenuated compared with thermal ablation. Whether this affects long-term freedom from AF or symptomatic bradycardia/pauses after AF ablation requires further study.

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Problem alcohol drinking continues to be a substantial cost and burden. In addition, alcohol consumption in women has increased in recent decades, and women can have greater alcohol problems and comorbidities. Thus, there is a significant need for novel therapeutics to enhance sex-specific, individualized treatment. Heart rate (HR) and HR variability (HRV) are of broad interest because they may be both biomarkers for and drivers of pathological states. HRV reflects the dynamic balance between sympathetic (SNS, 'fight or flight') and parasympathetic (PNS, 'rest and digest') systems. Evidence from human studies suggest PNS predominance in women and SNS in men during autonomic regulation, indicating the possibility of sex differences in risk factors and physiological drivers of problem drinking. To better understand the association between HRV sex differences and alcohol drinking, we examined whether alcohol consumption levels correlated with time domain HRV measures (SDNN and rMSSD) at baseline, at alcohol drinking onset, and across 10 min of drinking, in adult female and male Wistar rats. In particular, we compared both HRV and HR measures under alcohol-only and compulsion-like conditions (alcohol + 10 mg/L quinine), because compulsion can often be a significant barrier to treatment of alcohol misuse. Importantly, previous work supports the possibility that different HRV measures could be interpreted to reflect PNS versus SNS influences. Here, we show that females with higher putative PNS indicators at baseline and at drinking onset had greater alcohol consumption. In contrast, male intake levels related to increased potential SNS measures at drinking onset. Once alcohol was consumed, HR predicted intake level in females, perhaps a pharmacological effect of alcohol. However, HRV changes were greater during compulsion-like intake versus alcohol-only, suggesting HRV changes (reduced SNS in females, reduced PNS and increased HR in males) specifically related to aversion-resistant intake. We find novel and likely clinically relevant autonomic differences associated with biological sex and alcohol drinking, suggesting that different autonomic mechanisms may promote differing aspects of female and male alcohol consumption.

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OBJECTIVE: This narrative review examines how speculative belief that the autonomic nervous system causes Meniere's Disease (MD) led otolaryngologists to adopt invasive surgical procedures and medical treatments still offered today. DATA SOURCES: Google Scholar, PubMed. REVIEW METHODS: A comprehensive literature review (1860-2022) was performed using the terms "Meniere AND (sympathetic OR sympathectomy OR vasomotor OR cervical ganglion)," returning 5360 items. All abstracts were briefly reviewed, relevant publications selected for further study, and key articles discussed by all authors. As it became clear that betahistine was related to the historical narrative, an additional search was performed using "Betahistine AND Meniere AND (vasomotor OR sympathetic OR sympathectomy OR cervical ganglion OR autonomic)," which yielded 336 results. RESULTS: In the 19th and 20th centuries, growing knowledge of human anatomy led the scientific community to speculate that autonomic dysregulation caused many medical conditions. Excessive sympathetic mediated vasomotor changes were thought to cause hypertension, ischemia, and tissue damage. Clinicians applied the hypothesis to MD, assigning the sympathetic nervous system responsible for vertigo secondary to paroxysmal vasospasm and for hearing loss to poor cochlear nutrition. Despite limited animal experiments and isolated clinical observations, otolaryngologists performed sympathectomies, and, in the 1970s, replaced the procedure with betahistine as an alternative medical treatment. CONCLUSION: Premature excitement about a plausible hypothesis led to unnecessary and unwarranted operations. Despite absent evidence of sympathetic overactivation in MD, surgeons eagerly adopted sympathectomies, and later betahistine. Rigorous evaluation of the validity of these treatment practices is needed. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:535-542, 2024.

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Introduction: Mental health conditions remain a substantial and costly challenge to society, especially in women since they have nearly twice the prevalence of anxiety disorders. However, critical mechanisms underlying sex differences remain incompletely understood. Measures of cardiac function, including heart rate (HR) and HR variability (HRV), reflect balance between sympathetic (SNS) and parasympathetic (PNS) systems and are potential biomarkers for pathological states. Methods: To better understand sex differences in anxiety-related autonomic mechanisms, we examined HR/HRV telemetry in food-restricted adult rats during novelty suppression of feeding (NSF), with conflict between food under bright light in the arena center. To assess HRV, we calculated the SDNN (reflective of both SNS and PNS contribution) and rMSSD (reflective of PNS contribution) and compared these metrics to behaviors within the anxiety task. Results: Females had greater HR and lower SNS indicators at baseline, as in humans. Further, females (but not males) with higher basal HR carried this state into NSF, delaying first approach to center. In contrast, males with lower SNS measures approached and spent more time in the brightly-lit center. Further, females with lower SNS indicators consumed significantly more food. In males, a high-SNS subpopulation consumed no food. Among consumers, males with greater SNS ate more food. Discussion: Together, these are congruent with human findings suggesting women engage PNS more, and men SNS more. Our previous behavior-only work also observed female differences from males during initial movement and food intake. Thus, high basal SNS in females reduced behavior early in NSF, while subsequent reduced SNS allowed greater food intake. In males, lower SNS increased engagement with arena center, but greater SNS predicted higher consumption. Our findings show novel and likely clinically relevant sex differences in HRV-behavior relationships.

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Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting millions of people worldwide. The cardiac autonomic nervous system (ANS) is widely recognized as playing a key role in both the initiation and propagation of AF. This paper reviews the background and development of a unique cardioneuroablation technique for the modulation of the cardiac ANS as a potential treatment for AF. The treatment uses pulsed electric field energy to selectively electroporate ANS structures on the epicardial surface of the heart. Insights from in vitro studies and electric field models are presented as well as data from both pre-clinical and early clinical studies.

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Renal nerves have been an attractive target for interventions aimed at lowering blood pressure; however, the specific roles of renal afferent (sensory) versus efferent sympathetic nerves in mediating hypertension are poorly characterized. A number of studies have suggested that a sympathoexcitatory signal conveyed by renal afferents elicits increases in blood pressure, whereas other studies identified sympathoinhibitory afferent pathways. These sympathoinhibitory pathways have been identified as protective against salt-sensitive increases in blood pressure through endothelin B (ETB) receptor activation. We hypothesized that ETB-deficient (ETB-def) rats, which are devoid of functional ETB receptors except in adrenergic tissues, lack appropriate sympathoinhibition and have lower renal afferent nerve activity following a high-salt diet compared with transgenic controls. We found that isolated renal pelvises from high salt-fed ETB-def animals lack a response to a physiological stimulus, prostaglandin E2, compared with transgenic controls but respond equally to a noxious stimulus, capsaicin. Surprisingly, we observed elevated renal afferent nerve activity in intact ETB-def rats compared with transgenic controls under both normal- and high-salt diets. ETB-def rats have been previously shown to have heightened global sympathetic tone, and we also observed higher total renal sympathetic nerve activity in ETB-def rats compared with transgenic controls under both normal- and high-salt diets. These data indicate that ETB receptors are integral mediators of the sympathoinhibitory renal afferent reflex (renorenal reflex), and, in a genetic rat model of ETB deficiency, the preponderance of sympathoexcitatory renal afferent nerve activity prevails and may contribute to hypertension.NEW & NOTEWORTHY Here, we found that endothelin B receptors are an important contributor to renal afferent nerve responsiveness to a high-salt diet. Rats lacking endothelin B receptors have increased afferent nerve activity that is not responsive to a high-salt diet.

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BACKGROUND: Vasovagal syncope (VVS) is the leading cause of syncope. The most frequent mechanism is that of a cardioinhibitory response, vasodepressor response, or mixture of both. Neural stimulation that negates or overcomes the effects of vagal tone may be used as a treatment strategy for VVS. METHODS: Six male canines were studied. Stimulation (10-Hz, 2 ms pulse duration, 2 min duration) of the cervical vagus (CV), thoracic vagus (TV), and stellate ganglia (SG) was performed using needle electrodes at 3 V, 5 V, and 10 V output. SG stimulation at an output of 10 V overlaying TV stimulation at the same output was performed. Heart rate (HR), blood pressure (BP), and cardiac output (CO) were measured before, during, and after stimulation. RESULTS: Right cervical vagal stimulation was associated with significant hemodynamic changes. HR, SBP, and DBP were reduced (107 ± 16 vs. 78 ± 15 bpm [P < 0.0001], 116 ± 24 vs. 107 ± 28 mmHg [P = 0.002] and 71 ± 18 vs. 58 ± 20 mmHg [P < 0.0001]), respectively, while left cervical vagal stimulation had minimal changes. CV stimulation was associated with greater hemodynamic changes than TV stimulation. Left and right SG stimulation significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR at 5 V and 10 V, which could be observed within 30 s after stimulation. An output-dependent increase in hemodynamic parameters was seen with both left and right SG stimulation. No difference between left and right SG stimulation was seen. SG stimulation overlay significantly increased HR, BP, and CO from baseline vagal stimulation bilaterally. CONCLUSIONS: Stellate ganglia stimulation leads to increased HR and BP despite significant vagal stimulation. This may be exploited therapeutically in the management of vasovagal syncope.

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Postural orthostatic tachycardia syndrome (POTS) is a common and therapeutically challenging condition affecting numerous people worldwide. Recent studies have begun to shed light on the pathophysiology of this disorder. At the same time, both non-pharmacologic and pharmacologic therapies have emerged that offer additional treatment options for those afflicted with this condition. This paper reviews new concepts in both the pathophysiology and management of POTS.

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Atrial fibrillation has a multifactorial pathophysiology influenced by cardiac autonomic innervation. Both sympathetic and parasympathetic influences are profibrillatory. Innovative therapies targeting the neurocardiac axis include catheter ablation or pharmacologic suppression of ganglionated plexi, renal sympathetic denervation, low-level vagal stimulation, and stellate ganglion blockade. To date, these therapies have variable efficacy. As our understanding of atrial fibrillation and the cardiac nervous system expands, our approach to therapeutic neuromodulation will continue evolving for the benefit of those with AF.

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OBJECTIVE: To evaluate the relationship between visit-to-visit systolic blood pressure variability (SBPv) and fatigue symptoms in Multiple Sclerosis (MS) patients. METHODS: This is a cross-sectional study using data for MS patients who completed the Fatigue Subscale in the Performance Scales (PS), a validated, self-reported measure of MS-related disability, between 2011 and 2015 at an academic medical center. Those who had at least 3 available SBP measures within the prior 12 months of the survey were included in the analysis. Ordinal logistic regression was used to model fatigue as a function of SBP variability, adjusting for demographic factors and mean SBP. RESULTS: Data for 91 MS subjects were analyzed. We found that, compared to those with the lowest SBP variability (Tertile 1), subjects in Tertile 2 had 2.2 times higher odds (OR = 2.19; 95% CI, 0.82-5.87; p = 0.120) and those in Tertile 3 (highest variability) 4.2 times higher odds (OR = 4.16; 95% CI, 1.56-11.13; p = 0.005) of being in a higher fatigue level group, independent of age, sex, race/ethnicity, and mean SBP. CONCLUSIONS: Our data show that MS patients with higher SBP variability had a greater degree of fatigue. Future research is needed to further explore this relationship and the potential for therapeutic opportunities to improve fatigue.

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Cardiac sympathetic denervation (CSD) is a valuable option in the setting of refractory ventricular arrhythmias in patient with structural heart disease. Since the procedure was introduced for non structural heart disease patients the techniques evolved and were modified to be adopted in several settings. In this state-of-the-art article we revised different techniques, their rationale, strengths, and pitfalls.

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The term "immuno-autonomics" has been coined to describe an emerging field evaluating the interaction between stress, autonomic nervous system (ANS), and inflammation. The field remains largely unknown among practicing rheumatologists. Our objective was to evaluate the perspectives of rheumatologists regarding the role of stress in the activity and management of rheumatoid arthritis (RA). A 31-item survey was conducted with 231 rheumatologists. Rheumatologists were asked to assess the role of stress in rheumatoid arthritis (RA) disease activity and were provided with information regarding immuno-autonomics. They were asked to consider how immuno-autonomics resonated with their patient management needs. The majority of rheumatologists are eager to better understand non-response, believe that stress biology and ANS dysfunction interfere with disease activity, and embrace the theory that measurement of ANS via next-generation HRV may be able to evaluate autonomic dysfunction and the biology of stress. Rheumatologists are open to the idea that quantitative measurement of ANS function using next-generation HRV can be a helpful tool to RA practice. The majority agree that ANS state influences RA disease control and that quantitative measures of ANS state are helpful to RA practice. Rheumatologists also agree that patients with poor ANS function may be at risk for not responding adequately to conventional, biologic, or targeted synthetic DMARDs. Almost all would use an in-office test to quantitatively measure ANS using next-generation HRV. This study shows that rheumatologists are open to embracing evaluation of ANS function as a possible tool in the management and treatment of RA.

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The effective management of cardiovascular diseases requires knowledge of intrinsic and extrinsic innervation of the heart and an understanding of how perturbations of said components affect cardiac function. The innate cardiac conduction system, which begins with cardiac pacemaker cells and terminates with subendocardial Purkinje fibers, is modulated by said systems. The intrinsic component of the cardiac autonomic nervous system, which remains incompletely elucidated, consists of intracardiac ganglia and interconnecting neurons that tightly regulate cardiac electrical activity. Extrinsic components of the autonomic nervous system, such as carotid baroreceptors and renin-angiotensin-aldosterone system, modulate sympathetic input to the heart through the stellate ganglion and parasympathetic input via the vagus nerve. There remains a need for additional therapies to treat conditions, such as advanced heart failure and refractory arrhythmias, and a better understanding of autonomics may be key to their development.

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PURPOSE: High-intensity interval training (HIIT) produces significant health benefits. However, the acute physiological responses to HIIT are poorly understood. Therefore, we aimed to measure the acute cardiac autonomic, haemodynamic, metabolic and left ventricular mechanical responses to a single HIIT session. METHODS: Fifty young, healthy participants completed a single HIIT session, comprising of three 30-s maximal exercise intervals on a cycle ergometer, interspersed with 2-min active recovery. Cardiac autonomics, haemodynamics and metabolic variables were measured pre-, during and post-HIIT. Conventional and speckle tracking echocardiography was used to record standard and tissue Doppler measures of left ventricular (LV) structure, function and mechanics pre- and post-HIIT. RESULTS: Following a single HIIT session, there was significant post-exercise systolic hypotension (126 ± 13 to 111 ± 10 mmHg, p < 0.05), parallel to a significant reduction in total peripheral resistance (1640 ± 365 to 639 ± 177 dyne⋅s⋅cm5, p < 0.001) and significant increases in baroreceptor reflex sensitivity and baroreceptor effectiveness index (9.2 ± 11 to 24.8 ± 16.7 ms⋅mmHg-1 and 41.8 ± 28 to 68.8 ± 16.2, respectively) during recovery compared to baseline. There was also a significant increase in the low- to high-frequency heart rate variability ratio in recovery (0.7 ± 0.48 to 1.7 ± 1, p < 0.001) and significant improvements in left ventricular global longitudinal strain (- 18.3 ± 1.2% to - 29.2 ± 2.3%, p < 0.001), and myocardial twist mechanics (1.27 ± 0.72 to 1.98 ± 0.72°·cm-1, p = 0.028) post-HIIT compared to baseline. CONCLUSION: A single HIIT session is associated with acute improvements in autonomic modulation, haemodynamic cardiovascular control and left ventricular function, structure and mechanics. The acute responses to HIIT provide crucial mechanistic information, which may have significant acute and chronic clinical implications.

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OBJECTIVES: This study aimed to describe the preliminary results of a modified sympathicotomy for cardiac sympathetic denervation (CSD), which may reduce the predictive risk and intraoperative surgical time of the procedure. BACKGROUND: CSD, in patients with refractory ventricular tachycardia (VT), is comprehensively recognized as an important treatment option for patients with structural heart disease as well as congenital inherited arrhythmia syndrome. METHODS: We consecutively enrolled 5 patients with refractory VT. Baseline demographic, medical, and surgical data as well as arrhythmia outcomes and procedural complications were evaluated. RESULTS: A total of 5 patients (mean age: 67.4 years) were enrolled for the treatment of refractory VT with a modified CSD technique. In 3 of 5 patients, an overall reduction in VT burden (ranging from 75% to 100%) and VT number was observed after the CSD despite an in-hospital early recurrence. CONCLUSIONS: A modified CSD (sympathicotomy T2-T5) with stellate ganglion sparing and the use of unipolar radiofrequency is feasible, effective, and safe in the setting of untreatable VT.

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Heart failure (HF) is characterized by asymmetrical autonomic balance. Treatments to restore parasympathetic activity in human heart failure trials have shown beneficial effects. However, mechanisms of parasympathetic-mediated improvement in cardiac function remain unclear. The present study examined the effects and underpinning mechanisms of chronic treatment with the cholinesterase inhibitor, pyridostigmine (PYR), in pressure overload HF induced by transverse aortic constriction (TAC) in mice. TAC mice exhibited characteristic adverse structural (left ventricular hypertrophy) and functional remodelling (reduced ejection fraction, altered myocyte calcium (Ca) handling, increased arrhythmogenesis) with enhanced predisposition to arrhythmogenic aberrant sarcoplasmic reticulum (SR) Ca release, cardiac ryanodine receptor (RyR2) hyper-phosphorylation and up-regulated store-operated Ca entry (SOCE). PYR treatment resulted in improved cardiac contractile performance and rhythmic activity relative to untreated TAC mice. Chronic PYR treatment inhibited altered intracellular Ca handling by alleviating aberrant Ca release and diminishing pathologically enhanced SOCE in TAC myocytes. At the molecular level, these PYR-induced changes in Ca handling were associated with reductions of pathologically enhanced phosphorylation of RyR2 serine-2814 and STIM1 expression in HF myocytes. These results suggest that chronic cholinergic augmentation alleviates HF via normalization of both canonical RyR2-mediated SR Ca release and non-canonical hypertrophic Ca signaling via STIM1-dependent SOCE.

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The potential benefits of autonomous systems are obvious. However, there are still major issues to be dealt with before developing such systems becomes a commonplace engineering practice, with accepted and trustworthy deliverables. We argue that a solid, evolving, publicly available, community-controlled foundation for developing next-generation autonomous systems is a must, and term the desired foundation "autonomics." We focus on three main challenges: 1) how to specify autonomous system behavior in the face of unpredictability; 2) how to carry out faithful analysis of system behavior with respect to rich environments that include humans, physical artifacts, and other systems; and 3) how to build such systems by combining executable modeling techniques from software engineering with artificial intelligence and machine learning.

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BACKGROUND: Clinical management of vaso-vagal syncope (VVS) remains challenging since no therapy has proven to completely prevent VVS recurrence. OBJECTIVE: The purpose of this study was to analyze the mid-term outcome of cryoballoon (CB) cardioneuroablation achieved by pulmonary vein isolation (PVI) in patients with VVS. METHODS: Patients who underwent CB cardioneuroablation in our centers between January 2014 to June 2018 were included. All patients had a history of VVS or pre-syncope despite therapeutic attempts with medical and/or pacing treatments. Patients were excluded in case of structural heart diseases, cerebrovascular diseases or suspected drug-related syncope. Both heart rate (HR) and atrio-ventricular (AV) interval were analyzed on the 12-lead electrocardiogram (ECG) the day before the procedure, the day after, and in the follow-up. RESULTS: In total, 26 patients (76.9% males, 37.5 ± 9.0 years old) were included. All patients underwent a successful procedure with the 28 mm second-generation Arctic Front Advance CB. No major complication occurred. At a mean follow-up of 20.1 ± 11.6 months the freedom from VVS or reflex pre-syncope was 83,7%, with 22 patients free from any clinical recurrence. Basal HR significantly increased the day after the procedure (57.2 bpm vs 78.3 bpm, p < 0.001), while at the final follow-up it stabilized at a value halfway between the 2 previous ones (69.8 bpm, p = 0.0086). The AV interval didn't modify significantly after the procedure. CONCLUSION: Endocardial autonomic denervation achieved by CB PVI appears to be an effective and safe treatment option for patients with refractory VVS and reflex pre-syncope.