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Purpose: Long-coronavirus disease (long-COVID) is associated with initial orthostatic hypotension and postural orthostatic tachycardia syndrome. Whether altered autonomic tone underlies these abnormalities is unknown. We compared autonomic function between patients with long-COVID and healthy controls, and within patients with long-COVID with different orthostatic hemodynamic phenotypes., Methods: Patients with long-COVID (n = 94; F = 76; 42 years [36, 53 years] with initial orthostatic hypotension: n = 40; F = 32; 49 years [39, 57 years]; postural orthostatic tachycardia syndrome: n = 29; F = 26; 39 years [33, 47 years]; or no abnormalities: n = 25; F = 18; 42 years [35, 49 years]), and healthy controls (n = 33; F = 25; 49 years [30, 62 years]) completed a 10-min active stand with beat-to-beat hemodynamics. Heart rate variability, blood pressure variability, and baroreflex sensitivity were calculated as indirect measures of cardiovascular autonomic health. Continuous data (median [95% confidence interval]) were analyzed with Mann-Whitney U tests or Kruskal-Wallis tests with Dunn's corrections., Results: Patients with long-COVID had lower upright high frequency heart rate variability (p = 0.04) and low frequency blood pressure variability (p = 0.001) than controls. Patients with initial orthostatic hypotension had lower supine baroreflex sensitivity compared with patients without abnormalities (p = 0.01), and lower supine baroreflex sensitivity (p = 0.001) and high frequency heart rate variability (p = 0.03) than patients with postural orthostatic tachycardia syndrome. Patients with postural orthostatic tachycardia syndrome had lower upright high frequency heart rate variability (p < 0.001) and baroreflex sensitivity (p < 0.001) compared with patients without abnormalities and lower upright low frequency blood pressure variability (p = 0.04) compared with controls., Conclusions: Patients with long-COVID have attenuated cardiac autonomic function. Patients with initial orthostatic hypotension have lower supine baroreflex sensitivity. Patients with postural orthostatic tachycardia syndrome have lower upright vascular sympathetic and cardiac parasympathetic modulation. Long-COVID subgroups do not present with homogeneous pathophysiology, necessitating targeted treatment strategies., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: This study was approved by the Conjoint Health Research Ethics Board at the University of Calgary (REB21-1188). Prior to participating, all study participants provided their written informed consent., (© 2025. Springer-Verlag GmbH Germany.)

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., (© 2024. Springer-Verlag GmbH Germany.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: Postural tachycardia syndrome (POTS) and vasovagal syncope (VVS) are two disorders of orthostatic intolerance which are often misdiagnosed as the other. In each case, patients experience a reduced health-related quality of life (HRQoL) compared to healthy populations. This study was conducted to test the hypothesis that HRQoL is worse in POTS., Methods: POTS patients were recruited from the Dysautonomia International Annual Patient and Caregiver Conference. VVS patient data came from those enrolled in the Second Prevention of Syncope Trial. Participants aged ≥ 18 years (177 POTS and 72 VVS) completed the RAND 36-Item Health Survey, a generic and coherent health-related quality of life survey., Results: POTS patients reported reduced HRQoL compared to VVS patients in physical functioning (42.5 ± 1.7 vs. 76.5 ± 2.9, p < 0.001), role limitations due to physical health (11.4 ± 1.9 vs. 33.0 ± 5.0, p < 0.001), energy and fatigue (27.2 ± 1.3 vs. 50.7 ± 2.6, p < 0.001), social functioning (45.2 ± 1.8 vs. 71.2 ± 2.9, p < 0.001), pain (48.8 ± 1.9 vs. 67.7 ± 2.9, p < 0.001), and general health (31.2 ± 1.5 vs. 60.5 ± 2.6, p < 0.001) domains. Scores did not differ significantly in the role limitations due to emotional health (p = 0.052) and emotional well-being (p = 0.271) domains. Physical and general health composite scores were lower in the POTS population, while mental health composite scores were not different., Conclusion: Differences in HRQoL exist between these patient populations. POTS patients report lower scores in physical and general health domains than VVS patients, but emotional health domains do not differ significantly. Targeting physical functioning in these patients may help improve quality of life.

Purpose: Vasovagal syncope (VVS) is a chronic debilitating condition seen mostly in young women of reproductive age. There are anecdotal reports of increased syncope and presyncope around menstruation. This case-control study assessed the effects of the menstrual cycle on lightheadedness episodes and compared the gynecological and pregnancy history of VVS patients to healthy subjects., Methods: A custom-designed gynecological and menstrual cycle questionnaire was previously developed for patients with orthostatic intolerance. This questionnaire was administered to female patients with VVS (n = 128) as a part of the multicenter Second Prevention of Syncope Trial, and to gender-matched healthy subjects (n = 92)., Results: VVS patients and healthy subjects reported significant variability in self-reported lightheadedness throughout the menstrual cycle. Both cohorts experienced greatest lightheadedness during menses (53 ± 2 vs. 56 ± 4), which decreased during the follicular phase (44 ± 2 vs. 41 ± 4). VVS patients reported less severity in premenstrual symptoms (Fisher's method P = 2.7E-06) compared to healthy controls. There is no difference in the incidence of gynecological abnormalities (Fisher's exact P = 0.193) and pregnancy complications (P = 1.0) between the two cohorts. VVS patients have similar pregnancy rates compared to healthy subjects (P = 0.674)., Conclusion: The severity of lightheadedness varies during the menstrual cycle and is similar in both VVS patients and healthy controls. VVS patients have no greater risk of gynecological abnormalities and pregnancy complications than healthy subjects.

Background: Vasovagal syncope is a common problem associated with a poor quality of life, which improves when the frequency of syncope is reduced. Effective pharmacological therapies for vasovagal syncope have been elusive. Midodrine is a pro-drug whose primary metabolite is an alpha-1 adrenoreceptor agonist. A few studies have suggested that it may be beneficial in syncope, but all have had significant methodological limitations. A placebo-controlled clinical trial of midodrine for the prevention of vasovagal syncope is needed., Structure of Study: The prevention of syncope trial IV (POST 4) is a multicenter, international, randomized, placebo-controlled study of midodrine in the prevention of vasovagal syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive midodrine 10-30 mg/day or matching placebo, and followed for 1 year. Secondary end points include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention-to-treat approach, with a secondary on-treatment analysis., Power Calculations: A total sample size of 112, split equally between the two groups, achieves 85 % power to detect a 50 % relative risk reduction when the event rates are 55 and 27.5 % in the placebo and midodrine arms. Allowing for 20 % dropout, we propose to enroll 140 patients., Registration: POST 4 is registered with http://www.clinicaltrials.gov (NCT01456481)., Implications: This study will be the first adequately powered trial to determine whether midodrine is effective in preventing vasovagal syncope. If it is effective, then midodrine may become the first-line pharmacological therapy for this condition.

We investigated the effect of ovarian hormones and aging on breathing pattern [pulmonary minute ventilation (V(E))], tidal volume (V(T)), breathing frequency (F(b)), and respiratory sinus arrhythmia (RSA) in women. Recordings of V(E) and electrocardiogram (ECG) were obtained from 23 healthy women (10 premenopausal, 13 postmenopausal) under resting, isocapnic hypoxia (IH), and euoxic hypercapnia (EH) conditions. Premenopausal women were tested on three different days, each day corresponding to a specific phase of the menstrual cycle (follicular, mid-cycle, and luteal); postmenopausal women (PMW) were tested on 1 day only. On each test day, subjects were challenged with IH and EH. The order of the two tests was randomized and separated by at least 1 hour. Due to the low F (b) of several PMW, the band limits for RSA analysis had to be adjusted. The spectral coherence between respiratory flow and ECG RR-interval was used to determine the spectral band. Within the spectral band, there was a consistent phase relationship between the two variables where high values of spectral coherence indicate a well-defined phase relationship between respiratory flow and RR-interval variability. The main findings in this study for RSA are fourfold. First, RSA did not change with different levels of ovarian hormones (progesterone, serum 17beta-estradiol) during the menstrual cycle. Second, RSA was not influenced by hormone replacement therapy. Third, RSA did not change with age. Fourth, RSA did not change with IH and EH-induced changes in breathing patterns. Finally, high individual variability of average RR-interval change per breath was found.