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.

Role of Artificial Intelligence in Improving Syncope Management.

Syncope is common in the general population and a common presenting symptom in acute care settings. Substantial costs are attributed to the care of patients with syncope. Current challenges include differentiating syncope from its mimickers, identifying serious underlying conditions that caused the syncope, and wide variations in current management. Although validated risk tools exist, especially for short-term prognosis, there is inconsistent application, and the current approach does not meet patient needs and expectations. Artificial intelligence (AI) techniques, such as machine learning methods including natural language processing, can potentially address the current challenges in syncope management. Preliminary evidence from published studies indicates that it is possible to accurately differentiate syncope from its mimickers and predict short-term prognosis and hospitalisation. More recently, AI analysis of electrocardiograms has shown promise in detection of serious structural and functional cardiac abnormalities, which has the potential to improve syncope care. Future AI studies have the potential to address current issues in syncope management. AI can automatically prognosticate risk in real time by accessing traditional and nontraditional data. However, steps to mitigate known problems such as generalisability, patient privacy, data protection, and liability will be needed. In the past AI has had limited impact due to underdeveloped analytical methods, lack of computing power, poor access to powerful computing systems, and availability of reliable high-quality data. All impediments except data have been solved. AI will live up to its promise to transform syncope care if the health care system can satisfy AI requirement of large scale, robust, accurate, and reliable data.

Making certain that noninvasive therapy for vasovagal syncope has failed before proceeding to invasive interventions.

There is a perceived need to express concisely the advice of guidelines in the context of consideration of invasive management of highly symptomatic vasovagal syncope. In response to this need the table is presented as a checklist and the text adds explanation and details. It is anticipated that this will prove to be of value for clinicians.

Cardiovascular autonomic dysfunction in post-COVID-19 syndrome: a major health-care burden.

Cardiovascular autonomic dysfunction (CVAD) is a malfunction of the cardiovascular system caused by deranged autonomic control of circulatory homeostasis. CVAD is an important component of post-COVID-19 syndrome, also termed long COVID, and might affect one-third of highly symptomatic patients with COVID-19. The effects of CVAD can be seen at both the whole-body level, with impairment of heart rate and blood pressure control, and in specific body regions, typically manifesting as microvascular dysfunction. Many severely affected patients with long COVID meet the diagnostic criteria for two common presentations of CVAD: postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. CVAD can also manifest as disorders associated with hypotension, such as orthostatic or postprandial hypotension, and recurrent reflex syncope. Advances in research, accelerated by the COVID-19 pandemic, have identified new potential pathophysiological mechanisms, diagnostic methods and therapeutic targets in CVAD. For clinicians who daily see patients with CVAD, knowledge of its symptomatology, detection and appropriate management is more important than ever. In this Review, we define CVAD and its major forms that are encountered in post-COVID-19 syndrome, describe possible CVAD aetiologies, and discuss how CVAD, as a component of post-COVID-19 syndrome, can be diagnosed and managed. Moreover, we outline directions for future research to discover more efficient ways to cope with this prevalent and long-lasting condition.

Canadian Cardiovascular Society 2023 Guidelines on the Fitness to Drive.

Cardiovascular conditions are among the most frequent causes of impairment to drive, because they might induce unpredictable mental state alterations via diverse mechanisms like myocardial ischemia, cardiac arrhythmias, and vascular dysfunction. Accordingly, health professionals are often asked to assess patients' fitness to drive (FTD). The Canadian Cardiovascular Society previously published FTD guidelines in 2003-2004; herein, we present updated FTD guidelines. Because there are no randomized trials on FTD, observational studies were used to estimate the risk of driving impairment in each situation, and recommendations made on the basis of Canadian Cardiovascular Society Risk of Harm formula. More restrictive recommendations were made for commercial drivers, who spend longer average times behind the wheel, use larger vehicles, and might transport a larger number of passengers. We provide guidance for individuals with: (1) active coronary artery disease; (2) various forms of valvular heart disease; (3) heart failure, heart transplant, and left ventricular assist device situations; (4) arrhythmia syndromes; (5) implantable devices; (6) syncope history; and (7) congenital heart disease. We suggest appropriate waiting times after cardiac interventions or acute illnesses before driving resumption. When short-term driving cessation is recommended, recommendations are on the basis of expert consensus rather than the Risk of Harm formula because risk elevation is expected to be transient. These recommendations, although not a substitute for clinical judgement or governmental regulations, provide specialists, primary care providers, and allied health professionals with a comprehensive list of a wide range of cardiac conditions, with guidance provided on the basis of the level of risk of impairment, along with recommendations about ability to drive and the suggested duration of restrictions.

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.

Serotonin reuptake inhibition for the prevention of vasovagal syncope: a systematic review and meta-analysis.

PURPOSE: Vasovagal syncope is a common clinical condition that lacks effective medical therapies despite being associated with significant morbidity. Current guidelines suggest that serotonin-specific reuptake inhibitors might suppress vasovagal syncope but supporting studies have been small and heterogenous. The purpose of this study was to evaluate the efficacy of serotonin-specific reuptake inhibitors to prevent syncope in patients with recurrent vasovagal syncope by conducting a systematic review and meta-analysis of published studies. METHODS: Relevant randomized controlled trials were identified from the MEDLINE and Embase databases without language restriction from inception to August 2022, and ClinicalTrials.gov. All studies were conducted in clinical syncope populations and compared the benefit of serotonin versus placebo. Weighted relative risks were estimated using random effects meta-analysis techniques. RESULTS: Three studies (n = 204) met inclusion criteria. Patients were 42 ± 13 years of age and 51% female. Serotonin-specific reuptake inhibitors were found to substantially reduce the likelihood of a patient having at least one recurrence of vasovagal syncope [relative risk (RR) 0.34 (0.20-0.60), p < 0.01] with minimal between-study heterogeneity (I2 = 0%, p = 0.67). Serotonin-specific reuptake inhibitors in two reports provided significant protection against clinical presyncope [RR 0.43 (0.24-0.77), p < 0.01], with minimal between-study heterogeneity (I2 = 0%, p = 0.80). CONCLUSIONS: Serotonin-specific reuptake inhibitors may be effective in preventing syncope induced by head-up tilt testing and in syncope in the community in randomized, double-blinded clinical trials.

Twenty-five years of research on syncope.

Over the last 25 years, the Europace journal has greatly contributed to dissemination of research and knowledge in the field of syncope. More than 400 manuscripts have been published in the journal. They undoubtedly improved our understanding of syncope. This symptom is now clearly differentiated from other forms of transient loss of consciousness. The critical role of vasodepression and/or cardioinhibition as final mechanisms of reflex syncope is emphasized. Current diagnostic approach sharply separates between cardiac and autonomic pathways. Physiologic insights have been translated, through rigorously designed clinical trials, into non-pharmacological or pharmacological interventions and interventional therapies. The following manuscript is intended to give the reader the current state of the art of knowledge of syncope by highlighting landmark contributions of the Europace journal.

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.

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.

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.

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.