Creating a data dictionary for pediatric autonomic disorders.

PURPOSE: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders. METHODS: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition. RESULTS: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses. CONCLUSION: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary.

Postural orthostatic tachycardia syndrome: New concepts in pathophysiology and management.

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.

Sinus Tachycardia: a Multidisciplinary Expert Focused Review.

Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current medical condition that precipitates an increase in the sinus rate, but ST at rest without physiological triggers may also represent a spectrum of normal. In other cases, ST may not have an easily explainable cause but may represent serious underlying pathology and can be associated with intolerable symptoms. The classification of ST, consideration of possible etiologies, as well as the decisions of when and how to intervene can be difficult. ST can be classified as secondary to a specific, usually treatable, medical condition (eg, pulmonary embolism, anemia, infection, or hyperthyroidism) or be related to several incompletely defined conditions (eg, inappropriate ST, postural tachycardia syndrome, mast cell disorder, or post-COVID syndrome). While cardiologists and cardiac electrophysiologists often evaluate patients with symptoms associated with persistent or paroxysmal ST, an optimal approach remains uncertain. Due to the many possible conditions associated with ST, and an overlap in medical specialists who see these patients, the inclusion of experts in different fields is essential for a more comprehensive understanding. This article is unique in that it was composed by international experts in Neurology, Psychology, Autonomic Medicine, Allergy and Immunology, Exercise Physiology, Pulmonology and Critical Care Medicine, Endocrinology, Cardiology, and Cardiac Electrophysiology in the hope that it will facilitate a more complete understanding and thereby result in the better care of patients with ST.

Platelet Storage Pool Deficiency and Elevated Inflammatory Biomarkers Are Prevalent in Postural Orthostatic Tachycardia Syndrome.

A significant number of postural orthostatic tachycardia syndrome (POTS) patients have platelet delta granule storage pool deficiency (δ-SPD). The etiology of POTS is unknown but a number of laboratories, including ours, have reported elevations of G-protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies in POTS patients, detected by a variety of techniques, suggesting that the disorder is an autoimmune condition. Thus, it could also be considered an inflammatory disease. In a pilot study, we investigated a limited number of platelet-related cytokines and chemokines and discovered many that were elevated. This case−control study validates our pilot study results that POTS patients have an activated innate immune system. Plasma of 35 POTS patients and 35 patients with unexplained bleeding symptoms and categorized as "non-POTS" subjects was analyzed by multiplex flow cytometry to quantify 16 different innate immune system cytokines and chemokines. Electron microscopy was used to quantify platelet dense granules. Ten of 16 biomarkers of inflammation were elevated in plasma from POTS patients compared to non-POTS subjects, with most of the differences extremely significant, with p values < 0.0001. Of particular interest were elevations of IL-1ß and IL-18 and decreased or normal levels of type 1 interferons in POTS patients, suggesting that the etiology of POTS might be autoinflammatory. All POTS patients had δ-SPD. With a growing body of evidence that POTS is an autoimmune disease and having elevations of the innate immune system, our results suggest a potential T-cell-mediated autoimmunity in POTS characteristic of a mixed-pattern inflammatory disease similar to rheumatoid arthritis.

Inappropriate sinus tachycardia: a review.

Inappropriate sinus tachycardia (IST) has been defined as a resting heart rate of >100 beats per minute and an average 24-hour heart rate >90 bpm with distressing symptoms resulting from the persistent tachycardia. IST is prevalent in 1% of the middle-aged population, mostly females. Rarely can elderly patients also present with IST. Possible mechanisms of IST include intrinsic sinus node abnormality, beta-adrenergic receptor stimulating autoantibody, beta-adrenergic receptor supersensitivity, muscarinic receptor autoantibody, or hyposensitivity, impaired baroreflex control, depressed efferent parasympathetic/vagal function, nociceptive stimulation, central autonomic overactivity, aberrant neurohumoral modulation, etc. Symptoms associated with IST are palpitations, chest pain, fatigue, shortness of breath, presyncope, and syncope. Despite these distressing symptoms, IST has not been associated with tachycardia-associated cardiomyopathy or increased major cardiovascular events. Various treatment options for patients with IST are ivabradine, beta-adrenergic blockers, calcium channel blockers, psychiatric evaluation, and exercise training. Although, endocardial radiofrequency ablation targeting the sinus node has been used as a treatment modality for otherwise treatment-refractory IST, the results have been dismal. The other modalities used for refractory IST treatment are endocardial modification of the sinus node using radiofrequency energy, combined endo and epicardial ablation of the sinus node, thoracoscopic epicardial ablation of the sinus node, sinus node sparing thoracoscopic and endocardial hybrid ablation. The goal of this review is to provide the readership with the pathophysiological basis of IST and its management options.

Management strategies for vasovagal syncope.

Vasovagal syncope (VVS) (or neurocardiogenic syncope) is a common clinical condition that is challenging to both physicians and patients alike. Severe episodes of recurrent syncope can result in physical injury as well as psychological distress. This article provides a brief overview of current management strategies and a detailed overview of therapeutic modalities such as closed loop stimulation (CLS) and cardioneuroablation (CNA).

Postural orthostatic tachycardia syndrome (POTS): Priorities for POTS care and research from a 2019 National Institutes of Health Expert Consensus Meeting - Part 2.

The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area.

Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1.

Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.

Sick Sinus Syndrome Can Be Associated with Postural Tachycardia Syndrome and Inappropriate Sinus Tachycardia Syndrome.

As a known phenomenon, crossover between sinus node dysfunction and common atrial tachyarrhythmias-most notably, atrial fibrillation and atrial flutter-in older individuals has previously been seen. Here, we present one of the first case series demonstrating a similar relationship between sinus node dysfunction and much rarer etiologies of tachyarrhythmia-that is, postural tachycardia syndrome and inappropriate sinus tachycardia. The exact pathological mechanisms behind these arrhythmias as well as the observation of concurrent nodal dysfunction are poorly understood. Here, we propose both potential mechanistic pathways as well as an initial treatment algorithm for sinus node dysfunction based upon the existing evidence.

Further Observations on the Use of Pacemakers in Patients with Postural Orthostatic Tachycardia Syndrome with Demonstrated Asystole.

A subgroup of postural orthostatic tachycardia syndrome (POTS) patients may also have features of neurocardiogenic syncope (NCS). Syncope and presyncope are predominant clinical features in this subgroup of patients. Asystole has been reported as the cause of some recurrent syncopal episodes following evaluation with an implantable loop recorder (ILR). We present our experience of pacing in a group of patients with POTS and NCS, which resulted in the complete elimination of syncope. We reviewed the charts of 500 patients at the University of Toledo Medical Center from 2003 to 2013 and identified 40 patients who were eligible for inclusion in this study. Patients were included in this study if they had clinical features of POTS and unusually frequent episodes of syncope. All study participants subsequently underwent ILR implantation. Forty patients, including 32 (80%) women, aged 33 ± 13 years were included in this study. All patients demonstrated prolonged asystole (> 6 seconds) or severe bradycardia (heart rate < 30 bpm) during their syncope. Ten patients demonstrated an asystole of more than 10 seconds and also had prolonged and convulsive syncope. All patients had abrupt syncope without any warning signs. All 40 patients underwent dual-chamber pacemaker implantation. Syncope was eliminated in all 40 patients following pacemaker implantation; however, they continued to experience orthostatic tachycardia. Our findings support that dual-chamber pacing may help to eliminate syncope in a subgroup of POTS patients with recurrent syncope and prolonged asystole on ILR.

Inflammatory Biomarkers in Postural Orthostatic Tachycardia Syndrome with Elevated G-Protein-Coupled Receptor Autoantibodies.

A growing body of evidence suggests that postural orthostatic tachycardia syndrome (POTS) may be an autoimmune disorder. We have reported in a previous manuscript that 89% of POTS patients (n = 55) had elevations in G-protein-coupled adrenergic A1 receptor autoantibodies and 53% had elevations in muscarinic acetylcholine M4 receptor autoantibodies, as assessed by ELISA. Patients with autoimmune disorders have been reported with a variety of elevated cytokines and cytokines (such as rheumatoid arthritis); thus, we evaluated a limited number of cytokines/chemokines in POTS patients with elevated adrenergic and muscarinic receptor autoantibodies. We utilized the plasma of 34 patients from a previous study; all of the patients (100%) had autoantibodies against the A1 adrenergic receptor and 55.9% (19/34) had autoantibodies against the M4 muscarinic acetylcholine receptor. In particular, the plasma cytokine/chemokine levels were measured as biomarkers of inflammation by Quantibody® technology (Raybiotech, Peachtree Corners, GA, USA). We also evaluated the platelet dense granule numbers, as these patients frequently complain of symptoms related to platelet dysfunction. Patients were predominantly young females who displayed a multitude of co-morbidities but generally reported viral-like symptoms preceding episodes of syncope. Eighty five percent (29/34) had platelet storage pool deficiency. Patients had elevations in five of ten cytokine/chemokines biomarkers (IL1ß, IL21, TNFα, INFγ, and CD30), whereas two biomarkers had decreased levels (CD40L and RANTES). Our observations demonstrate that POTS patients known to have autoantibodies against the G-protein-coupled adrenergic A1 receptor have abnormal plasma concentrations of inflammatory cytokines.

Risks of adverse events in patients with orthostatic intolerance undergoing surgery with general anesthesia.

INTRODUCTION: Orthostatic intolerance (OI) is a group of disorders characterized by symptoms that occur upon standing and resolve with recumbence. Although well established but not widely recognized, these diagnoses may create uncertainty for clinicians dealing with a patient affected by OI and requiring a surgical procedure. OBJECTIVES: To determine the rate of intra- and postoperative major adverse events in patients with OI undergoing surgery with general anesthesia. METHODS: The study was a retrospective study of patients with orthostatic intolerance who underwent surgery requiring general anesthesia from 1 January 2000 to 31 December 2018. RESULTS: A total 171 patients with OI underwent 190 surgeries. In patients with POTS and orthostatic-induced VVS, there were no major significant adverse events. There was one episode of AVNRT in a patient with POTS and one episode of bradycardia secondary to vasovagal reflex in a patient with orthostatic-induced VVS. Moreover, there were 13 (6.8%) episodes of postoperative hypotension. However, the majority of these episodes were related to bleeding, volume depletion or sepsis. All cases of hypotension responded well to appropriate therapy. In patients with OH, the rate of postoperative major adverse cardiac events was 4.7%, and the 30-day mortality rate was 6.1%. This is not significantly different from the calculated risk for patients without OH. There were no myocardial infarctions or deaths at 30 days in patients with POTS or orthostatic-induced VVS. CONCLUSION: Patients with OI may not experience higher rates of perioperative complications compared with patients without OI syndromes.

New-onset Postural Orthostatic Tachycardia Syndrome Following Coronavirus Disease 2019 Infection.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. We report a case of new-onset postural orthostatic tachycardia syndrome in an otherwise healthy female patient following COVID-19 infection. The patient presented with fatigue, orthostatic palpitations, dizziness, and presyncope. She underwent head-up tilt-table testing and the findings were suggestive of postural orthostatic tachycardia syndrome.

Ivabradine in children with postural orthostatic tachycardia syndrome: a retrospective study.

BACKGROUND: Ivabradine is a unique medication that reduces the intrinsic heart rate by specifically blocking the inward funny current that controls the pacemaker activity of the sinus node. We conducted a retrospective cohort study to assess the efficacy of ivabradine in children suffering from postural orthostatic tachycardia syndrome. METHODS: A chart review was conducted of patients less than 18 years of age who were diagnosed with postural orthostatic tachycardia syndrome who had received ivabradine as treatment from January 2015 to February 2019 at our institution. Twenty-seven patients (25 females, 92.5%) were identified for the study. The outcomes which were assessed included a change in the severity and frequency of symptoms, heart rate, and blood pressure before and after starting ivabradine. RESULTS: There was an improvement in the symptoms of 18 (67%) out of 27 patients. The most notable symptom affected was syncope/presyncope with a reduction in 90%, followed by lightheadedness (85%) and fatigue (81%). The vital signs of the patients showed an overall significant lowering of the heart rate during sitting (89.7 ± 17.9 versus 73.2 ± 12.1; p-value <0.05) and standing (100.5 ± 18.1 versus 80.9 ± 10.1; p-value <0.05) without a significant change in the blood pressure. Two patients had visual disturbances (luminous phenomena). Severe bradycardia and excessive flushing were seen in two patients, respectively. Another one patient reported joint pain and fatigue. CONCLUSION: This study indicates that 67% of children treated with ivabradine report an improvement in symptoms.

Postural Orthostatic Tachycardia Syndrome Is Associated With Elevated G-Protein Coupled Receptor Autoantibodies.

Background The etiology of postural orthostatic tachycardia syndrome (POTS) is yet to be established. The disorder is often misdiagnosed as chronic anxiety or a panic disorder because the autonomic failure in these patients is not severe. A growing body of evidence suggests that POTS may be an autoimmune disorder. Antinuclear antibodies and elevations of ganglionic, adrenergic, and muscarinic acetylcholine receptor antibodies have all been reported. Methods and Results We collected detailed clinical symptoms of 55 patients diagnosed with POTS. We also evaluated serum levels of autoantibodies against 4 subtypes of G-protein coupled adrenergic receptors and 5 subtypes of G-protein coupled muscarinic acetylcholine receptors by ELISA. Our patients had a multitude of comorbidities, were predominantly young females, and reported viral-like symptoms preceding episodes of syncope. We detected a significant number of patients with elevated levels of autoantibodies against the adrenergic alpha 1 receptor (89%) and against the muscarinic acetylcholine M4 receptor (53%). Surprisingly, elevations of muscarinic receptor autoantibodies appeared to be dependent upon elevation of autoantibodies against the A1 adrenergic receptor! Four patients had elevations of G-protein coupled autoantibodies against all 9 receptor subtypes measured in our study. Five POTS patients had no elevation of any autoantibody; similarly, controls were also negative for autoantibody elevations. There was a weak correlation of clinical symptom severity with G-protein coupled autoantibodies. Conclusions Our observations provide further evidence that, in most cases, POTS patients have at least 1 elevated G-protein coupled adrenergic autoantibody and, in some instances, both adrenergic and muscarinic autoantibodies, supporting the hypothesis that POTS may be an autoimmune disorder.

The benefit of closed loop stimulation in patients with cardioinhibitory vasovagal syncope confirmed by head-up tilt table testing: a systematic review and meta-analysis.

PURPOSE: A proportion of patients with vasovagal syncope (VVS) experience recurrence despite appropriate management. Closed loop stimulation (CLS) pacing is a promising treatment for a subgroup of patients with cardioinhibitory response on head-up tilt table test (HUTT). Nonetheless, its efficacy remains uncertain. We sought to assess the efficacy of CLS pacing in patients with cardioinhibitory VVS. METHODS: We searched PubMed, Google Scholar, and the Cochrane Central Register of controlled trials for relevant studies (last search date April 23, 2018). Data were pooled using the Mantel-Haenszel fixed-effects model. For cohort studies, we used a Freeman-Tukey transformation to calculate the weighted summary proportion. Primary outcomes are syncope and presyncope. RESULTS: Eight studies were included in the final analyses (two single-blinded and one double-blinded RCT, two prospective observational studies, and three retrospective observational studies). Two hundred ninety-one patients included, with an average age of 57 years. Quality of evidence is moderate. Use of CLS pacing was associated with reduced risk of syncope (OR 0.08; 95% CI 0.03-0.18; I2 32%) and presyncope (OR 0.34; 95% CI 0.18-0.63; I2 0.00%). Using proportion meta-analysis, the summary estimate of the proportion of cases that developed syncope during CLS pacing was similar between RCTs and prospective studies (3.2% and 3.1%), respectively. This is much lower than the rate of recurrence in the control arm of RCTs at 33.7%. Sensitivity analyses yielded similar results. CONCLUSION: CLS pacing is beneficial for patients with recurrent vasovagal syncope who demonstrate a cardioinhibitory response on HUTT.

Role of implantable loop recorders in patients with postural orthostatic tachycardia syndrome.

INTRODUCTION: We previously reported on a subgroup of postural orthostatic tachycardia syndrome (POTS) patients who may also have features of neurocardiogenic syncope as well. In this subgroup of patients, we found syncope and presyncope were predominant clinical features. To understand the mechanism of syncope in this subgroup, we identified 39 patients who underwent loop recorder insertion. METHODS: We reviewed charts of 450 patients who had POTS and syncope seen at the University of Toledo Medical Center from 2003 to 2017. Thirty-nine patients had at least four episodes of syncope in the last 6 months and were included for this study. All of these patients had a prior evaluation with a Holter and an event monitor which were inconclusive. RESULTS: Thirty-nine patients, 33 (85%) women, aged 20-46 years, were included in this study. All patients demonstrated prolonged asystole (>6 seconds) or severe bradycardia (heart rate < 30 beats/min) during their syncope on implantable loop recorder (IRL). Fifteen patients demonstrated an asystole of >10 seconds and also had prolonged and convulsive syncope. All patients had abrupt syncope without any warning sign. All patients underwent dual-chamber pacemaker implantation using a closed loop stimulation algorithm. Syncope were completely eliminated in all patients following pacemaker implantation; however, they continued to have orthostatic tachycardia. CONCLUSION: POTS patients with unusually frequent syncope should be considered for ILR implantation if other monitoring modalities like 48-hour Holter monitor or event recorder are inconclusive. ILR may identify a subgroup of POTS patients who may benefit from pacemaker implantations.