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Pathophysiological mechanisms of postural tachycardia syndrome. Cartoon representation of how 3 major neuronal and hormonal abnormalities and their immediate effects may cause symptoms commonly associated with POTS.
Source publication
The Postural Tachycardia Syndrome (POTS) is the most common disorder seen in autonomic clinics. Cardinal hemodynamic feature of this chronic and debilitating disorder of orthostatic tolerance is an exaggerated orthostatic tachycardia (≥30 bpm increase in HR with standing) in the absence of orthostatic hypotension. There are multiple pathophysiologi...
Contexts in source publication
Context 1
... is a heterogeneous syndrome with several different patho- physiological mechanisms that can result in the typical POTS presentation, and a few more common ones are highlighted in this manuscript (Figure 1) (Raj, 2013). Neuropathic POTS is a condition with a partial neuropathy where there is pref- erential denervation of sympathetic nerves in the lower limbs that may account for local/regional blood flow abnormalities including venous pooling ( Jacob et al., 2000;Stewart et al., 2003). ...Context 2
... few patients in one family have a specific genetic abnormality linked to a single point mutation in the nore- pinephrine transporter with subsequent diminished clearance of norepinephrine ( Shannon et al., 2000). This hyperadrener- gic state is thought to drive the orthostatic tachycardia in these patients (Figure 1). The different pathophysiological mechanisms are not mutually exclusive, and POTS patients will often have Table 1 | Some pathophysiological mechanisms of POTS and related treatments. ...Context 3
... et al. conducted a trial before-after exercise training to 3 months of an exercise regimen consisting of 4 sessions per week, each lasting 30-45 min (n = 19) (Fu et al., 2011). The 3 month exercise program was able to increase the aldosterone:renin ratios well as the plasma volumes and blood volumes in these POTS patients. ...Similar publications
Introduction
On March 11, 2020, the World Health Organization sounded the COVID-19 pandemic alarm. While efforts in the first few months focused on reducing the mortality of infected patients, there is increasing data on the effects of long-term infection (Post-COVID-19 condition). Among the different symptoms described after acute infection, those...
Postural orthostatic tachycardia syndrome (POTS), a disorder of the autonomic nervous system characterized by a rise in heart rate of at least 30 bpm from supine to standing position, has been traditionally viewed as a dysfunction of the peripheral nervous system. However, recent studies and evidence from overlapping conditions suggest that in addi...
Puberty is initiated by hormonal changes in the adolescent body that trigger physical and behavioral changes to reach adult maturation. As these changes occur, some adolescents experience concerning pubertal symptoms that are associated with dysfunction of the autonomic nervous system (ANS). Vasovagal syncope (VVS) and Postural Orthostatic Tachycar...
Background
Patients with postural tachycardia syndrome (POTS) experience chronic symptoms of orthostatic intolerance. There is minimal data detailing the demographics, clinical features, and clinical course of this condition. This online, community‐based survey highlights patients’ experience with POTS. It consists of the largest sample of POTS pat...
Chronic orthostatic intolerance (COI) is defined by changes in heart rate (HR), blood pressure (BP), respiration, symptoms of cerebral hypoperfusion and sympathetic overactivation. Postural tachycardia syndrome (POTS) is the most common form of COI in young adults and is defined by an orthostatic increase in heart rate (HR) of ≥ 30 bpm in the absen...
Citations
... Abnormal autonomic nervous system response to orthostatism, in addition to exaggerated levels of epinephrine and norepinephrine, contributes to the pathophysiological spectrum of mechanisms in OI that may be further accentuated by multiple factors such as excessive venous pooling in the lower extremities, volume dysregulations, autoimmunity and hyperadrenergic status [89]. Earlier reports emphasized a downregulation of renin activity and abnormal levels of angiotensin II in POTS patients [90][91][92][93]. This is further intensified in COVID-19 infection, as previous studies reported [94,95]. ...
At the beginning of 2020, coronavirus disease 2019 (COVID-19) emerged as a new pandemic, leading to a worldwide health crisis and overwhelming healthcare systems due to high numbers of hospital admissions, insufficient resources, and a lack of standardized therapeutic protocols. Multiple genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been detected since its first public declaration in 2020, some of them being considered variants of concern (VOCs) corresponding to several pandemic waves. Nevertheless, a growing number of COVID-19 patients are continuously discharged from hospitals, remaining symptomatic even months after their first episode of COVID-19 infection. Long COVID-19 or ‘post-acute COVID-19 syndrome’ emerged as the new pandemic, being characterized by a high variability of clinical manifestations ranging from cardiorespiratory and neurological symptoms such as chest pain, exertional dyspnoea or cognitive disturbance to psychological disturbances, e.g., depression, anxiety or sleep disturbance with a crucial impact on patients’ quality of life. Moreover, Long COVID is viewed as a new cardiovascular risk factor capable of modifying the trajectory of current and future cardiovascular diseases, altering the patients’ prognosis. Therefore, in this review we address the current definitions of Long COVID and its pathophysiology, with a focus on cardiovascular manifestations. Furthermore, we aim to review the mechanisms of acute and chronic cardiac injury and the variety of cardiovascular sequelae observed in recovered COVID-19 patients, in addition to the potential role of Long COVID clinics in the medical management of this new condition. We will further address the role of future research for a better understanding of the actual impact of Long COVID and future therapeutic directions.
... Previous studies have suggested that lower renin activity, lower estimated angiotensinconverting enzyme-2 activity [13] and lower aldosterone levels [14] observed in POTS may contribute to the dysregulation of sodium re-uptake, reduced blood volume, and impaired blood pressure control. Pathophysiological mechanisms underlying this phenomenon are unclear though it is believed that autoimmunity may play a crucial role through inappropriate activation of adrenergic and angiotensin receptors [15][16][17][18]. ...
Background: Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous condition predominantly affecting autonomic control of the cardiovascular system. Its extensive symptom diversity implies multi-organ involvement that interacts in ways still requiring full exploration. Current understanding of POTS pathophysiology suggests alterations in the renin–angiotensin–aldosterone system as a possible contributing factor. Therefore, we investigated the relationship between the activity of the renin–angiotensin–aldosterone system and hemodynamic parameters in a cohort of POTS patients and controls recruited at a tertiary referral center.
Methods: The case-control study included 46 patients with POTS (27 ± 9 years), and 48 healthy controls (30 ± 9 years) without orthostatic intolerance. Plasma renin activity, expressed as angiotensin I generation, and plasma aldosterone were measured by enzyme-linked immunosorbent assay and were correlated with hemodynamic parameters obtained during active standing tests.
Results: Renin activity was significantly downregulated in POTS patients compared to healthy individuals (median, 3406 ng/mL vs. 9949 ng/mL, p < 0.001), whereas aldosterone concentration did not differ between POTS and healthy controls (median, 218 pmol/L vs. 218 pmol/L, p = 0.26). A significant inverse correlation between renin activity and supine and orthostatic blood pressure levels was observed in healthy individuals (p < 0.05 for all), but not in POTS patients.
Conclusions: Renin activity, but not aldosterone concentration, is downregulated in patients with POTS. Moreover, renin activity in POTS is dissociated from supine and standing blood pressure levels in contrast to healthy individuals. These findings suggest impaired renin function in POTS, which may direct future therapeutic approaches.
... Commonly, patients with POTS have increased catecholamine levels than healthy controls [8]. Studies have found that patients with POTS have, on average, higher levels of plasma angiotensin II and lower levels of plasma renin and aldosterone [9]. Correspondingly, higher levels of angiotensin II may reflect a deficiency in the vasodilatory effects of endothelial nitric oxide also found in some POTS patients [10]. ...
Postural orthostatic tachycardia syndrome (POTS) is a disorder characterized by orthostatic intolerance and, by definition, includes clinical symptoms of lightheadedness, palpitations, and tremulousness among others. It is considered a relatively rare condition that affects approximately 0.2% of the general population, and it is estimated that between 500,000 to 1,000,000 individuals in the United States have the condition and recently has been linked to post-infectious (viral) etiologies. We present a case of a 53-year-old woman who was diagnosed with POTS following extensive autoimmune workup, who was also status post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The post-coronavirus disease 2019 (COVID-19) cardiovascular autonomic dysfunction can affect global circulatory control, which describes increased heart rate even at resting states, and local circulatory disorders, such as coronary microvascular disease leading to vasospasm, as described by the patient's chest pain, and venous retention leading to pooling and reduced venous return after standing. Along with tachycardia with orthostatic intolerance, other symptoms can also accompany the syndrome. In the majority of patients, intravascular volume is reduced, leading to decreased venous return to the heart and causing reflex tachycardia and orthostatic intolerance. Management varies from lifestyle modifications to pharmacologic therapy, to which patients generally show a good response. POTS should be a differential on the cards, especially in patients post-COVID-19 infection, as these symptoms can be misdiagnosed as having psychological etiologies.
... POTS (Postural Orthostatic Tachycardia Syndrome) refers to the development of orthostatic symptoms associated with an increase in heart rate greater than or equal to 30 (from normal resting heart rate) but not associated with orthostatic hypotension [12]. The mechanisms proposed to explain POTS include autonomic neuropathy, increased sympathetic tone, a hypovolemic state with an altered renin-angiotensin-aldosterone system, and autoimmunity [13][14][15][16][17]. With the reporting of an increasing number of cases, POTS is gaining recognition in patients with COVID-19 in the post-infectious stage [8]. ...
... Neuroendocrine dysfunction: As compared to healthy people, POTS patients have evidence of higher levels of catecholamines [28] and angiotensin II [29] and lower levels of plasma renin and aldosterone [14,17,23] at baseline. There is also evidence that with standing POTS, patients have an increase in norepinephrine levels. ...
POTS (Postural Orthostatic Tachycardia Syndrome) is a multisystem disorder characterized by the abnormal autonomic response to an upright posture, causing orthostatic intolerance and excessive tachycardia without hypotension. Recent reports suggest that a significant percentage of COVID-19 survivors develop POTS within 6 to 8 months of infection. Prominent symptoms of POTS include fatigue, orthostatic intolerance, tachycardia, and cognitive impairment. The exact mechanisms of post-COVID-19 POTS are unclear. Still, different hypotheses have been given, including autoantibody production against autonomic nerve fibers, direct toxic effects of SARS-CoV-2, or sympathetic nervous system stimulation secondary to infection. Physicians should have a high suspicion of POTS in COVID-19 survival when presented with symptoms of autonomic dysfunction and should conduct diagnostic tests like the Tilt table and others to confirm it. The management of COVID-19-related POTS requires a comprehensive approach. Most patients respond to initial non-pharmacological options, but when the symptoms become more severe and they do not respond to the non-pharmacological approach, pharmacological options are considered. We have limited understanding and knowledge of post-COVID-19 POTS, and further research is warranted to improve our understanding and formulate a better management plan.
... Clinically, POTS presents with a range of symptoms of orthostatic intolerance, such as headache, dizziness, cardiopalmus, thoracic discomfort, blurring of vision, anhelation, and occasionally syncope. However, despite this condition being discovered three decades ago, its universal pathophysiologic mechanism has not yet been unambiguously identified (Streeten et al., 1988;Mar and Raj, 2014). Nevertheless, Zhang et al. reported significantly elevated plasma H 2 S, which is considered to be associated with dysfunction of peripheral vasoconstriction in patients with POTS (Zhang et al., 2012). ...
Objective
The aim of the study was to establish whether whole-blood microRNA (miRNA) profiles differ between postural tachycardia syndrome (POTS) sufferers and control subjects and to identify the miRNA that regulates plasma H 2 S.
Study Design
High-throughput sequencing was used to obtain whole-blood miRNA expression profiles for 20 POTS sufferers and 20 normal children.The thresholds for defining differentially expressed miRNAs (DEmiRNAs) were an adjusted DESeq P of <0.05 and a log2 fold variation of ≥3. The DEmiRNA target genes were identified using RNAhybrid and miRanda, and only those identified by both were considered. The combined effects of the DEmiRNAs were determined using KEGG pathway analysis. Another 40 POTS and 20 normal patients were used as validation subjects. Plasma H 2 S was determined with a sulfide electrode, and flow-mediated vasodilation (FMD) was performed with a color Doppler ultrasound system. miRNAs were analyzed using qRT-PCR.
Results
Totally, 13 DEmiRNAs were identified through high-throughput sequencing. In the 60-member validation group, the 13 miRNAs were verified again, and it turned out that miR-21 was significantly elevated and could diagnose POTS with a 100% specificity and 92.5% sensitivity. Overall, 198 and 481 genes, respectively, were shown to be targeted by the 13 DEmiRNAs when P values of 0.01 and 0.05 were used. The target gene of hsa-miR-21-5p was SP1 when the P -value is <0.01. DEmiRNAs were significantly enriched in 36 pathways ( P < 0.05), in which PI3K/Akt signaling was closely related to vascular function. In the validation subjects, the plasma H 2 S and FMD were higher in the POTS sufferers ( P < 0.05).
Conclusion
Elevated whole-blood miR-21 levels serve as an indicator for POTS and may explain the increased plasma H 2 S observed in POTS sufferers.
... Postural orthostatic tachycardia syndrome (POTS), a common disorder characterized by an unexplained and exaggerated heart rate (HR) increase during upright posture, is frequently associated with other autonomic symptoms including gastroparesis, severe fatigue, migraine headaches, and left chest pain [1]. No distinct etiopathophysiology has been established for this entity, although a number of intermediary mechanisms have been proposed, including hypovolemia, inadequate vasoconstriction and excessive venous pooling, peripheral denervation, and abnormalities in central sympathetic tone [2][3][4]. POTS occurs more frequently in young females and one-third of cases are associated with a preceding viral illness, vaccination, or stressful event [1], suggesting a possible autoimmune-mediated cause for POTS in some patients. Moreover, non-specific serological markers of autoimmunity are also prevalent in POTS. ...
... There is also evidence that decreased parasympathetic activity may contribute to the tachycardia in POTS [4,12]. This leads to consideration for the presence of autoantibodies to the M2 muscarinic acetylcholine receptor (M2R) in POTS. ...
Purpose
Previous studies demonstrated M2 muscarinic acetylcholine receptor-activating autoantibodies (M2R-AAb) were present in some patients with postural tachycardia syndrome (POTS). This study examines how these autoantibodies might contribute to the pathophysiology of POTS, and whether low-level tragus stimulation (LLTS) can ameliorate autoantibody-mediated autonomic dysregulation in the rabbit.
Methods
Five New Zealand white rabbits were immunized with a M2R second extracellular loop peptide to produce cholinomimetic M2R-AAb. Tilt test and infusion studies were performed on conscious rabbits before immunization, 6 weeks after immunization, and 8 weeks after immunization with 2-week daily LLTS treatment. Each rabbit served as its own control.
Results
Compared to preimmune state, an enhanced heart rate increase and decreased parasympathetic activity upon tilting were observed in immunized rabbits. Furthermore, these rabbits demonstrated an attenuated heart rate-slowing response to infusion of the M2R orthosteric agonist arecaidine propargyl ester (APE), suggesting an inhibitory allosteric effect of M2R-AAb. There was also a significant increase in serum inflammatory cytokines in immunized rabbits. LLTS treatment suppressed the postural tachycardia, improved the sympathovagal balance with increased acetylcholine secretion, reduced the levels of inflammatory cytokines, and reversed the attenuated heart rate response to APE in immunized rabbits. No suppression of M2R-AAb expression by LLTS was found during this short-term study period. Receptor-modulating activity of M2R-AAb produced in immunized rabbits was confirmed with in vitro bioassay.
Conclusions
Autoantibody inhibition of cholinergic ligand activity may be involved in the development of cardiovagal dysfunction and inflammation associated with POTS, both of which can be improved by vagal stimulation.
... In the "neuropathic" subtype, clinical features of small fiber neuropathy may be present while reduced cardiac preload may lead to a compensatory HR increase during orthostatic challenge. Many POTS patients have a blood volume that is lower than expected for their size and sex, suggesting that hypovolemia may underlie some of the hemodynamic findings of POTS (Fu et al., 2010;Mar and Raj, 2014;Raj et al., 2005). ...
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.
... POTS has been related to deconditioning in a number of studies [6][7][8]54], and all these studies advocate exercise training as part of the treatment, implying that deconditioning is at least a contributor to the pathophysiology of POTS. However, alternative explanations for POTS include blood volume reduction [55], mast cell activation disorders [56], peripheral autonomic neuropathy [55,[57][58][59][60][61], high levels of norepinephrine while standing [62], and genetic abnormalities [63]. Importantly, in the present study 11% of the ME/CFS patients with POTS had no signs of deconditioning and 33% had mild deconditioning (see Table 4). ...
Background
Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO 2 ) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO 2 during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).
Methods and results
In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO 2 ≥ 85% = no deconditioning, %peak VO 2 65–85% = mild deconditioning, and %peak VO 2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.
Conclusion
This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO 2 results on cardiopulmonary exercise testing.
... The syndrome was first described by Schondorf and Low in 1993 and included a heterogeneous group of similar clinical physiological presentations [1,2]. Postural orthostatic tachycardia syndrome affects as many as 3 million people in the United States [3], predominantly young women of child bearing age [4,5]. The etiology of the disorder remains unknown. ...
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 (IL1β, 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.
... Finally, a small subset of patients has an elevated level of angiotensin II without concomitant hypertension. It is thought that this group of patients is insensitive to the vasoconstrictive effects of angiotensin II [5]. A more detailed account of pathophysiology and therapy will be outlined in the Discussion section. ...
Dizziness can be protean with multiple phenotypes. One common phenotype in the young population is postural orthostatic tachycardia syndrome (POTS). POTS has a unique cardiovascular signature with a fascinating range of etiologies and pharmacodynamic substrates. This condition can pass undiagnosed for many years and is often mistaken as an anxiety disorder due to some of its hyperadrenergic manifestations. We present one such case and then flesh out the treatment strategies, both conservative and pharmacologic. We finally describe the various underlying pathophysiologic mechanisms of POTS and its sub-types and outline the various aberrant cardiovascular reflexes. We also describe the power spectra of the heart rate variability frequency bands and their underlying physiologic basis.
