Reduced Stroke Volume and Brain Perfusion Drive Postural Hyperventilation in Postural Orthostatic Tachycardia Syndrome.

Postural hyperventilation has been implicated as a cause of postural orthostatic tachycardia syndrome (POTS), yet the precise mechanisms underlying the heightened breathing response remain unclear. This study challenges current hypotheses by revealing that exaggerated peripheral chemoreceptor activity is not the primary driver of postural hyperventilation. Instead, significant contributions from reduced stroke volume and compromised brain perfusion during orthostatic stress were identified. These findings shed light on our understanding of POTS pathophysiology, emphasizing the critical roles of systemic hemodynamic status. Further research should explore interventions targeting stroke volume and brain perfusion for more effective clinical management of POTS.

Serotonin and vasovagal syncope.

PURPOSE: 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. CONCLUSION: Multiple lines of evidence implicate serotonin neurotransmission in the cause of vasovagal syncope.

The Role of the Autonomic Nervous System in Vasovagal Syncope.

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 for the treatment of reflex syncope and functional bradyarrhythmias: A Scientific Statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS) and the Latin American Heart Rhythm Society (LAHRS).

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.

Hemodynamic Effects of the Osmopressor Response: A Systematic Review and Meta-Analysis.

Background Rapidly consuming water may offer practical orthostatic hypotension therapy. However, its efficacy across disorders remains uncertain. This study aims to assess the impact of rapid 350- to 500-mL water intake on systolic and diastolic blood pressure (BP) and heart rate (HR) through a systematic review and meta-analysis. Methods and Results We systematically reviewed MEDLINE and Embase up to June 2023, including randomized controlled trials and prospective cohort studies. Using random-effects meta-analysis, we calculated pooled mean differences (MDs) for maximum hemodynamic effects of rapid 350- to 500-mL water bolus consumption. Participants with orthostatic hypotension experienced increased systolic BP (MD, 24.18 [95% CI, 15.48-32.88]) and diastolic BP (MD, 11.98 [95% CI, 8.87-15.09]) with decreased HR (MD, -3.46 [95% CI, -5.21 to -1.71]). Similar results were observed in multiple system atrophy and pure autonomic failure subgroup analysis. Healthy participants showed modest increases in systolic BP (MD, 2.33 [95% CI, 1.02-3.64]) and diastolic BP (MD, 2.73 [95% CI, 1.15-4.30]), but HR changes were not significant (MD, -2.06 [95% CI, -5.25 to 1.13]). Water had no significant hemodynamic effects in patients with seated or supine postural tachycardia syndrome, although standing effects were unassessed. Our data do not exclude water's potential standing effect in postural tachycardia syndrome. Conclusions In patients with orthostatic hypotension, rapid water intake elevated short-term systolic BP and diastolic BP, with mild HR reduction when seated or supine. Healthy participants exhibited similar but milder effects. However, patients with postural tachycardia syndrome did not experience these changes in seated or supine positions. Further research is needed to evaluate the promising impact of rapid water ingestion on patients with postural tachycardia syndrome in a standing position, which was not addressed in our study.

Adrenal gland response to adrenocorticotropic hormone is intact in patients with postural orthostatic tachycardia syndrome.

BACKGROUND: Many patients with postural orthostatic tachycardia syndrome (POTS) are hypovolemic with plasma volume deficits of 10-30 %. Some also have low levels of aldosterone and diminished aldosterone-renin ratios despite elevations in angiotensin II, pointing to potential adrenal dysfunction. To assess adrenal gland responsiveness in POTS, we measured circulating levels of aldosterone and cortisol following adrenocorticotropin hormone (ACTH) stimulation. METHODS: While on a low Na+ diet (∼10 mEq/day), 8 female patients with POTS and 5 female healthy controls (HC) received a low dose (1 µg) ACTH bolus following a baseline blood sample. After 60 min, a high dose (249 µg) infusion of ACTH was administered to ensure maximal adrenal response. Venous aldosterone and cortisol levels were sampled every 30 min for 2 h. RESULTS: Aldosterone increased in both groups in response to ACTH but was not different between POTS vs. HC at 60 min (53.5 ng/dL [37.8-61.8 ng/dL] vs. 46.1 ng/dL [36.7-84.9 ng/dL]; P = 1.000) or maximally (56.4 ng/dL [49.2-67.1 ng/dL] vs. 49.5 ng/dL [39.1-82.8 ng/dL]; P = 0.524). Cortisol increased in both groups in response to ACTH but was not different in patients with POTS vs. HC at 60 min (39.9 µg/dL [36.1-47.7 µg/dL] vs. 39.3 µg/dL [35.4-46.6 µg/dL]; P = 0.724) or maximally (39.9 µg/dL [33.9-45.4 µg/dL] vs. 42.0 µg/dL [37.6-49.7 µg/dL]; P = 0.354). CONCLUSIONS: ACTH appropriately increased the aldosterone and cortisol levels in patients with POTS. These findings suggest that the response of the adrenal cortex to hormonal stimulation is intact in patients with POTS.

The Seventh Prevention of Syncope Trial (POST VII)-A randomized clinical trial of atomoxetine for the prevention of vasovagal syncope: Rationale and study design.

BACKGROUND: Vasovagal syncope (VVS) is common, recurs, and is associated with markedly reduced quality of life, anxiety, and frequent injuries. The few pharmacological therapies for VVS proven to have a moderate benefit in reducing recurrences are limited to patients without coexisting conditions such as hypertension or heart failure. Although there is some data to suggest Atomoxetine, a norepinephrine reuptake transport inhibitor (NET), may be a promising treatment option, an adequately powered randomized placebo-controlled trial is needed. STUDY DESIGN: POST VII is a multicenter, randomized, double-blind, placebo-controlled, crossover study that will randomize 180 patients with VVS and at least 2 syncopal spells in the preceding year to a target daily dose of atomoxetine 80 mg daily or to a matching placebo, with an observation period of 6 months in each phase and with a 1-week washout period between phases. The primary end point will be the proportion of patients with at least one syncope recurrence in each arm analyzed with an intention-to-treat approach. The secondary end points include total syncope burden, quality of life, cost, and cost-effectiveness. POWER CALCULATIONS: Assuming a 33% relative risk reduction in syncope recurrence with atomoxetine, and a dropout rate of 16%, the enrollment of 180 patients will give an 85% power of reaching a positive conclusion about atomoxetine, with P = .05. CONCLUSIONS: This will be the first adequately powered trial to determine whether atomoxetine is effective in preventing VVS. If proven effective, atomoxetine might become the first-line pharmacological treatment for recurrent VVS.

Symptoms of postural orthostatic tachycardia syndrome in pregnancy: a cross-sectional, community-based survey.

OBJECTIVE: To evaluate the relationship between postural orthostatic tachycardia syndrome (POTS) and pregnancy. DESIGN: Cross-sectional survey. SETTING: International. SAMPLE: A total of 8941 female patients with a diagnosis of POTS. METHODS: Data from the survey were analysed using descriptive measures and stratified for comparisons. MAIN OUTCOME MEASURES: Symptom course of POTS during pregnancy. Secondary outcomes included pregnancy loss, POTS onset during pregnancy and the impacts of a comorbid diagnosis of Ehlers-Danlos syndrome or an autoimmune disorder on symptoms during pregnancy. RESULTS: Overall, 40.8% (n = 3652) of participants reported one or more pregnancies. Most participants experienced worsening of symptoms in the first (62.6%) and third (58.9%) trimesters and 3 months after pregnancy (58.7%), and 81.1% experienced worsening symptoms at any point in their pregnancy. Most participants with worsening symptoms in the first trimester also experienced worsening symptoms in the second (61.6%) and third (68.1%) trimesters, but if they improved in the first trimester then this improvement persisted in the second and third trimesters. Of participants who reported that POTS was triggered by a specific event (41.3%), 8.1% reported pregnancy as the trigger for the onset. CONCLUSIONS: Postural orthostatic tachycardia syndrome symptoms in the first trimester of pregnancy may help predict symptom course throughout the duration of pregnancy. Some individuals may experience an initial onset of POTS during pregnancy. This novel information may guide clinicians in counselling patients with POTS who are planning pregnancy.

Complications related to pacemakers and other cardiac implantable electronic devices: essentials for internists and emergency physicians.

With the aging population, improving technology, and expanding indications for diagnosing and treating arrhythmias and heart failure, many patients are receiving cardiac implantable electronic devices (CIEDs) such as pacemakers and implantable cardioverter defibrillators. Consequently, patients with CIEDs are frequently encountered in the emergency department and in the wards. It is imperative that emergency physicians and internists have a strong foundation on CIEDs and their potential complications. This review aims to help physicians develop a framework in approaching CIEDs and to recognize and manage clinical scenarios that may arise from CIED complications.

Atomoxetine for suppression of vasovagal syncope.

OBJECTIVE: Vasovagal syncope (VVS) is a common clinical condition with few effective medical therapies. The study aimed to evaluate the effectiveness of atomoxetine in suppressing syncope in patients with recurrent VVS. METHODS: This was a retrospective, open-label, observational case series of 12 patients taking atomoxetine for suppression of recurrent vasovagal syncope. We compared syncope frequency in the 1 year before atomoxetine and while subjects were taking atomoxetine. We used novel applications of the Poisson distribution to describe the results as a collection of n = 1 studies. RESULTS: There were 12 subjects, eight female, with a mean age 47 ± 22 years and a mean Calgary Syncope Symptom Score of 2 (diagnostic of vasovagal syncope). The patients received a mean dose of atomoxetine of 66 ± 16 mg (1.06 ± 0.21 mg/kg). The mean follow-up period was 1.21 ± 1.01 years. While taking atomoxetine, 11/12 patients appeared to improve and 7/12 had no syncope in follow-up (p = 0.0046). The annualized syncope frequency decreased from a median 5.5 (IQR 4, 6.75) syncope per year to 0 (IQR 0, 0.88) syncope per year (p = 0.002, Wilcoxon rank-sum test). According to the Poisson distribution, 7/12 subjects significantly improved with p values of < 0.0001 to 0.0235, 3/12 did not faint but had too brief follow-up times to detect significance, and 2/12 did not improve significantly. CONCLUSIONS: In this case series, atomoxetine was a promising oral agent for the prevention of vasovagal syncope. The Poisson distribution permits individual patient-level assessment of improvement and detects insufficient follow-up despite apparent improvement.

Objective Hemodynamic Cardiovascular Autonomic Abnormalities in Post-Acute Sequelae of COVID-19.

BACKGROUND: Many COVID-19 patients are left with symptoms several months after resolution of the acute illness; this syndrome is known as post-acute sequalae of COVID-19 (PASC). We aimed to determine the prevalence of objective hemodynamic cardiovascular autonomic abnormalities (CAA), explore sex differences, and assess the prevalence of CAA among hospitalized vs nonhospitalized patients with PASC. METHODS: Patients with PASC (n = 70; female [F] = 56; 42 years of age; 95% confidence interval [CI], 40-48) completed standard autonomic tests, including an active stand test 399 days (338, 455) after their COVID-19 infection. Clinical autonomic abnormalities were evaluated. RESULTS: Most patients with PASC met the criteria for at least 1 CAA (51; 73%; F = 43). The postural orthostatic tachycardia syndrome hemodynamic (POTSHR) criterion of a heart rate increase of > 30 beats per minute within 5 to 10 minutes of standing was seen in 21 patients (30%; F = 20; P = 0.037 [by sex]). The initial orthostatic hypotension hemodynamic (IOH40) criterion of a transient systolic blood pressure change of > 40 mm Hg in the first 15 seconds of standing was seen in 43 (61%) patients and equally among female and male patients (63% vs 57%; P = 0.7). Only 9 (13%) patients were hospitalized; hospitalized vs nonhospitalized patients had similar frequencies of abnormalities (67% vs 74%; P = 0.7). CONCLUSIONS: Patients with PASC have evidence of CAA, most commonly IOH40, which will be missed unless an active stand test is used. Female patients have increased frequency of POTSHR, but IOH40 is equally prevalent between sexes. Finally, even nonhospitalized "mild" infections can result in long-term CAAs.

Can Artificial Intelligence Enhance Syncope Management?: A JACC: Advances Multidisciplinary Collaborative Statement.

Syncope, a form of transient loss of consciousness, remains a complex medical condition for which adverse cardiovascular outcomes, including death, are of major concern but rarely occur. Current risk stratification algorithms have not completely delineated which patients benefit from hospitalization and specific interventions. Patients are often admitted unnecessarily and at high cost. Artificial intelligence (AI) and machine learning may help define the transient loss of consciousness event, diagnose the cause, assess short- and long-term risks, predict recurrence, and determine need for hospitalization and therapeutic intervention; however, several challenges remain, including medicolegal and ethical concerns. This collaborative statement, from a multidisciplinary group of clinicians, investigators, and scientists, focuses on the potential role of AI in syncope management with a goal to inspire creation of AI-derived clinical decision support tools that may improve patient outcomes, streamline diagnostics, and reduce health-care costs.

Sleep syncope-A systematic review.

Background: Sleep syncope is a subtype of vasovagal syncope in which patients experience syncope after awakening from their sleep. The aim was to investigate the association of clinical characteristics and gastrointestinal symptoms with syncope, as well as the body position in which symptoms began. Methods: A systematic search of studies was performed in MEDLINE and EMBASE without language restrictions, from inception to 9 January 2022. Studies were included if they reported data on the proportion of patients who experienced symptoms (nausea, vomiting, abdominal pain, and diarrhea) associated with syncope. Results: Data were included for 116 patients in 13 studies. Patients were 46.9 ± 4.3 years and 61.4% were female. In 52.5% of patients, a supine body position at the time of syncope was reported. A history of phobias was reported by 67.6% of patients, and 96.5% of patients also had typical daytime vasovagal syncope. In the 5 studies reporting the results of head-up tilt testing (n = 77), 90.9% of patients had positive tests. Gastrointestinal symptoms were present in the majority of patients with reported rates of 65.6% for upper gastrointestinal symptoms and 86.0% for lower gastrointestinal symptoms. Conclusion: Patients with sleep syncope patients are predominantly female with a history of daytime vasovagal syncope. Gastrointestinal symptoms are present in the majority of patients and is therefore an important feature of sleep syncope.