Long COVID: lights and shadows on the clinical characterization of this emerging pathology.

More than 800 million individuals have contracted SARSCOV2 infection worldwide. It was estimated that almost 10-20% of these might suffer from Long COVID. It is a multisystemic syndrome, which negatively affects the quality of life with a significant burden of health loss compared to COVID negative individuals. Moreover, the risk of sequelae still remains high at 2 years in both nonhospitalized and hospitalized individuals. This review summarizes studies regarding long COVID and clarifies the definitions, the risk factors and the management of this syndrome. Finally, it delves into the most frequent long-term outcomes, especially postural orthostatic tachycardia syndrome" (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), brain fog, and their therapeutical possibilities.

The Contribution of Psychological Symptoms to Cognitive Difficulties in Youth With Postural Orthostatic Tachycardia Syndrome and Chronic Pain.

INTRODUCTION: Subjectively experienced cognitive difficulties are common in youth with postural orthostatic tachycardia syndrome. The pathophysiological and psychological contributions of these cognitive impairments remain unclear. METHOD: Participants were 96 adolescents and young adults diagnosed with postural orthostatic tachycardia syndrome and admitted to an intensive pain treatment program. Participants completed cognitive assessment and measures of postural orthostatic tachycardia syndrome symptoms, pain intensity, pain catastrophizing, anxiety, depression, and functional disability. RESULTS: Self-reported autonomic symptom intensity, but not severity of heart rate change, was associated with cognitive performance. Symptoms of depression were associated with decreases in most measures of cognitive functioning. Pain intensity, pain catastrophizing, and depression but not cognitive scores and physiological measures, were significant predictors of disability. CONCLUSION: Depression appears to be a significant contributor to the cognitive difficulties in youth with postural orthostatic tachycardia syndrome. These findings highlight the importance of assessing and treating affective symptoms in this population along with medical and lifestyle approaches to treating postural orthostatic tachycardia syndrome symptoms.

Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome.

BACKGROUND: High sodium intake is recommended for the treatment of postural tachycardia syndrome (POTS) to counteract the hypovolemia and elevated plasma norepinephrine that contribute to excessive orthostatic tachycardia, but evidence of its efficacy is not available. OBJECTIVES: This study tested whether a high sodium (HS) diet reduces orthostatic tachycardia (Δ heart rate) and upright heart rate compared with a low sodium (LS) diet in POTS patients, and secondarily its effect on plasma volume (PV) and plasma norepinephrine. METHODS: A total of 14 POTS patients and 13 healthy control subjects (HC), age 23 to 49 years, were enrolled in a crossover study with 6 days of LS (10 mEq sodium/day) or HS (300 mEq sodium/day) diet. Supine and standing heart rate, blood pressure, serum aldosterone, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine were measured. RESULTS: In POTS, the HS diet reduced upright heart rate and Δ heart rate compared with the LS diet. Total blood volume and PV increased, and standing norepinephrine decreased with the HS compared with the LS diet. However, upright heart rate, Δ heart rate, and upright norepinephrine remained higher in POTS than in HC on the HS diet (median 117 beats/min [interquartile range: 98 to 121 beats/min], 46 beats/min [interquartile range: 32 to 55 beats/min], and 753 pg/ml [interquartile range: 498 to 919 pg/ml] in POTS vs. 85 beats/min [interquartile range: 77 to 95 beats/min], 19 beats/min [interquartile range: 11 to 32 beats/min], and 387 pg/ml [interquartile range: 312 to 433 pg/ml] in HC, respectively), despite no difference in the measured PV. CONCLUSIONS: In POTS patients, high dietary sodium intake compared with low dietary sodium intake increases plasma volume, lowers standing plasma norepinephrine, and decreases Δ heart rate. (Dietary Salt in Postural Tachycardia Syndrome; NCT01547117).

Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients.

OBJECTIVE: To describe clinical features, diagnostic findings, treatments, and outcomes in patients with new-onset postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders following SARS-CoV-2 infection (COVID-19). METHODS: We retrospectively reviewed medical records for patients who presented with persistent neurologic and cardiovascular complaints between April and December 2020 following COVID-19 infection. RESULTS: Twenty patients (70% female) were included in this study.Fifteen had POTS, 3 had neurocardiogenic syncope, and 2 had orthostatic hypotension. Six patients had abnormalities on cardiac or pulmonary testing, and 4 had elevated autoimmune or inflammatory markers. All patients were treated with non-pharmacologic therapies, and most required pharmacologic therapies. Six to 8 months after COVID-19, 17 (85%) patients had residual autonomic symptoms, with 12 (60%) unable to return to work. CONCLUSIONS: POTS can follow COVID-19 in previously healthy patients. Appropriate diagnostic investigations and therapies are necessary to identify and treat autonomic dysfunction after COVID-19.

Cutaneous alpha-synuclein deposition in postural tachycardia patients.

OBJECTIVE: To report a case series of patients with neuropathic POTS and cutaneous phosphorylated alpha-synuclein (P-SYN) deposition on skin biopsy and compare these to neuropathic POTS patients without P-SYN deposition. METHODS: The medical history, physical examination findings, autonomic function testing, and skin biopsy neuropathology of patients under the age of 50 with a postural tachycardia and a diagnosis of POTS were retrospectively reviewed. Included patients completed the composite autonomic severity score (COMPASS 31), the Wood Mental Fatigue Inventory, the Epworth Sleepiness scale, the REM Behavior Disorder Questionnaire, the Patient-Reported Outcomes Measurement Information System (PROMIS-10), and the Gastroparesis Cardinal Symptom Index. RESULTS: Of 296 patients seen with POTS, 22 patients with suspected neuropathic POTS had skin biopsies performed during their evaluation. Seven of 22 patients had P-SYN present on skin biopsy, while 15 individuals did not. Those with P-SYN on biopsy: (1) were more likely to be male; (2) had features of REM sleep behavioral disorder; (3) reported less sleepiness and cognitive impairment; and (4) noted greater symptoms of gastroparesis. On autonomic testing, the group with P-SYN deposition was more likely to have a hypertensive response to tilt-table testing and abnormal QSART responses. INTERPRETATION: Phosphorylated alpha-synuclein deposition is present in some postural tachycardia patients with neuropathic features. Individuals with a postural tachycardia and cutaneous phosphorylated alpha-synuclein deposition may be distinguished from other patients with neuropathic POTS.

The Postural Tachycardia Syndrome (PoTS) Bladder-Urodynamic Findings.

OBJECTIVE: To evaluate the urodynamics (UDS) of patients with postural tachycardia syndrome (PoTS). METHODS: Patients with a confirmed diagnosis of PoTS referred by the department of neuro-cardiology to the neuro-urology were identified and their UDS were retrospectively reviewed. RESULTS: In total, 50 patients (47 = 94.0% female) with confirmed PoTS and available UDS were identified. Mean age of females and males was 32.4 and 28.2 years, P = .15. Intermittent self-catheterisation was being used by 15/47 (31.9%) females at assessment. Detrusor overactivity was observed in 6 females (12.8%) (all at end fill and associated with urgency). In total, 14 (29.8%) females had no sensation of filling. No patients had an "unsafe" bladder. In total, 15/47 (31.9%) of women were unable to void with UDS catheters. Straining was reported in 22/35 (68.8%) of females. The female bladder outflow obstruction index = PDetQmax - 2.2(Qmax) was over 5 in 10/28 (35.7%) and over 18 in 5 (17.9%). The bladder contractility index = PDetQmax + 5Qmax was under 100 in 18/28 (28.6%) women. CONCLUSION: The UDS of patients with "PoTS bladder" often demonstrate a poorly sensate but stable and safe bladder with functional obstruction and impaired bladder contractility that may necessitate straining or intermittent self-catheterisation.

Decreased Stroke Volume and Venous Return in School Children with Postural Tachycardia Syndrome.

In postural tachycardia syndrome (POTS), a subtype of orthostatic intolerance, the changes in hemodynamics due to postural changes are poorly understood. We speculated that inappropriate venous return, which may occur in the upright position in patients with school-aged POTS, could be detected by echocardiography. Our prospective study was conducted with 100 POTS patients (45 boys and 55 girls), aged 13.1 ± 1.5 years and 52 age- and sex-matched healthy subjects (control). Echocardiography was performed in the supine and sitting positions. Cardiac parameters [stroke volume index, cardiac index, heart rate, and the maximum inferior vena cava diameter (max IVC)] were evaluated in addition to pulse pressure. Unlike the control subjects, POTS patients demonstrated decreased stroke volume index (P = 0.02) and max IVC (P < 0.01) irrespective of posture. The rates of max IVC change did not differ between control and POTS groups. The enrolled POTS patients were divided into two subgroups [dilatation (n = 57) and contraction (n = 43)] based on whether the change rate of max IVC was less than zero or not. The contraction group showed a significantly higher heart rate than the dilatation group with respect to posture (P = 0.03), indicating the poor response of peripheral vessels in the lower limbs only in the contraction group. In conclusion, echocardiographic assessment detected decreased stroke volume and venous return in POTS. The changes in max IVC in response to postural changes may indicate an underlying pathophysiology in POTS.

gAChR antibodies in children and adolescents with acquired autoimmune dysautonomia in Japan.

OBJECTIVE: Patients with acquired autonomic dysfunction may have antibodies specific to the ganglionic nicotinic acetylcholine receptor (gAChR). However, the clinical features of children and adolescents with acquired autonomic dysfunction (AAD) remain unclear. This study aimed to determine the clinical features of pediatric patients with acquired autonomic dysfunction. METHODS: This study retrospectively examined a series of patients of AAD with serum gAChR antibodies who were referred to our laboratory for antibody testing between January 2012 and April 2019. The study included 200 patients (<20 years, 20 cases; ≥20 years, 175 cases) with clinical features of AAD. RESULTS: Upon comparing pediatric and adult patients, we found that antecedent infection and autonomic symptoms at onset with gastrointestinal symptoms occurred more frequently in children with AAD. We confirmed that four children (20.0%) met the diagnostic criteria for postural orthostatic tachycardia syndrome (POTS). A significantly higher number of children than adults had POTS (P = 0.002). In addition, upper GI dysfunction was more prevalent in children than in adults (P = 0.042). In particular, nausea and vomiting occurred in 60.0% of children with AAD and in 21.1% of adults (P < 0.001). The frequency of paralytic ileus was significantly higher in children with AAD (20.0%) relative to adults (6.3%) (P = 0.030). Regarding extra-autonomic manifestations, encephalopathy was more frequent in children (15.0%) than in adults (1.1%) (P < 0.001). INTERPRETATION: Pediatric AAD patients have their own clinical characteristics, and these features may be unique to children and adolescents.

Supine Parasympathetic Withdrawal and Upright Sympathetic Activation Underly Abnormalities of the Baroreflex in Postural Tachycardia Syndrome: Effects of Pyridostigmine and Digoxin.

[Figure: see text].

Regional Gastrointestinal Transit and Contractility Patterns Vary in Postural Orthostatic Tachycardia Syndrome (POTS).

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is an autonomic disorder that affects multiple organs, including the gastrointestinal system. These patients often have multiple GI complaints with a severe impact on their quality of life. GI dysmotility patterns in POTS remains poorly understood and difficult to manage. AIMS: The aim of this study was to investigate the diagnostic yield of wireless motility capsule in patients with gastrointestinal symptoms and POTS, with use of a symptomatic control group without POTS as a reference. METHODS: We retrospectively reviewed the charts of patients who had both autonomic testing and wireless motility capsule between 2016 and 2020. The two groups were divided into those with POTS and those without POTS (controls) as diagnosed through autonomic testing. We compared the regional transit times and motility patterns between the two groups using the data collected from wireless motility capsule. RESULTS: A total of 25% of POTS patients had delayed small bowel transit compared to 0% of non-POTS patients (p = 0.047). POTS patients exhibited hypo-contractility patterns within the small bowel, including decreased contractions/min (2.95 vs. 4.22, p = 0.011) and decreased motility index (101.36 vs. 182.11, p = 0.021). In multivariable linear regression analysis, migraine predicted faster small bowel transit (p = 0.007) and presence of POTS predicted slower small bowel transit (p = 0.044). CONCLUSIONS: Motility abnormalities among POTS patients seem to affect mostly the small bowel and exhibit a general hypo-contractility pattern. Wireless motility capsule can be a helpful tool in patients with POTS and GI symptoms as it can potentially help guide treatment.

Impaired Endothelial Function in Patients With Postural Tachycardia Syndrome.

The purpose of this study is to evaluate endothelial function in postural tachycardia syndrome (PoTS), a poorly understood chronic condition characterized by a state of consistent orthostatic tachycardia (delta heart rate ≥30 beats per minute) upon standing without orthostatic hypotension. Nineteen patients with PoTS and 9 healthy controls were studied after 3 days of a fixed, caffeine-free, normal sodium (150 milliequivalents/day) diet. All participants underwent autonomic function testing, including sinus arrhythmia, valsalva maneuver, hyperventilation, cold pressor, handgrip, and a standing test with catecholamine measurements, followed by endothelial function testing. We analyzed 3 measures of endothelial function: percent brachial flow-mediated dilation, digital pulsatile arterial tonometry, and postischemic percent leg blood flow. Flow-mediated dilation was significantly lower in patients with PoTS (6.23±3.54% for PoTS) than in healthy controls (10.6±4.37% for controls versus, P=0.014). PoTS and controls had similar digital pulsatile arterial tonometry (1.93±0.40 arbitrary units for controls versus 2.13±0.63 arbitrary units for PoTS). PoTS had similar but suggestive percent leg blood flow to controls (313±158% for PoTS versus 468±236% for controls, P=0.098). Patients with PoTS have significantly reduced flow-mediated dilation compared with healthy controls, suggesting that PoTS is characterized by endothelial dysfunction in conduit arteries. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01308099.

Cardiovascular exercise as a treatment of postural orthostatic tachycardia syndrome: A pragmatic treatment trial.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous disorder of orthostatic intolerance with few proven treatments. OBJECTIVE: The purpose of this study was to determine the efficacy of an unsupervised at-home training regimen for the treatment of POTS. METHODS: We reviewed the medical records including autonomic function testing, symptom scores, and activities of daily living in individuals with POTS who were invited to participate in a 6-month outpatient cardiovascular exercise program. RESULTS: Seventy-seven individuals were invited (invited group), 48 of 77 (62%) participated (treated group) and 43 of 77 (56%) of those completed. Twenty-nine of 77 (38%) did not participate (control group). After 6 months, 11 of 48 (23%) individuals in the treated group met heart rate criteria for POTS compared with 27 of 29 (93%) in the control group (χ2 test, P < .0001). Supine heart rate (68 ± 8 beats/min vs 77 ± 10 beats/min; P < .001) and standing heart rate (95 ± 11 beats/min vs 115 ± 10 beats/min; P < .001) decreased in the treated group compared with the control group. The frequency of syncope decreased in the treated group (P < .001). An improvement in the EuroQol perceived quality of life scale score was detected in the treated group (61 ± 15 vs 71 ± 12 after 6 months, P < .001) compared with the control group (64 ± 9 vs 66 ± 8 after 6 months; P = .52). CONCLUSION: In this study, we report a successful pragmatic clinical trial of an outpatient exercise protocol in a tertiary care referral population that significantly improved cardiovascular function and quality of life in patients with POTS.

Extracardiac Abnormalities of Preload Reserve: Mechanisms Underlying Exercise Limitation in Heart Failure with Preserved Ejection Fraction, Autonomic Dysfunction, and Liver Disease.

While many of the cardiac limitations to exercise performance are now well-characterized, extracardiac limitations to exercise performance have been less well recognized but are nevertheless important. We propose that abnormalities of cardiac preload reserve represents an under-recognized but common cause of exercise limitations. We further propose that mechanistic links exist between conditions as seemingly disparate as heart failure with preserved ejection fraction, nonalcoholic fatty liver disease, and pelvic venous compression/obstruction syndromes (eg, May-Thurner). We conclude that extracardiac abnormalities of preload reserve serve as a major pathophysiologic mechanism underlying these and other disease states.

Cerebral Blood Flow and Cognitive Performance in Postural Tachycardia Syndrome: Insights from Sustained Cognitive Stress Test.

Background The physiology underlying "brain fog" in the absence of orthostatic stress in postural tachycardia syndrome (POTS) remains poorly understood. Methods and Results We evaluated cognitive and hemodynamic responses (cardiovascular and cerebral: heart rate, blood pressure, end-tidal carbon dioxide, and cerebral blood flow velocity (CBFv) in the middle cerebral artery at baseline, after initial cognitive testing, and after (30-minutes duration) prolonged cognitive stress test (PCST) whilst seated; as well as after 5-minute standing in consecutively enrolled participants with POTS (n=22) and healthy controls (n=18). Symptom severity was quantified with orthostatic hypotensive questionnaire at baseline and end of study. Subjects in POTS and control groups were frequency age- and sex-matched (29±11 versus 28±13 years; 86 versus 72% women, respectively; both P≥0.4). The CBFv decreased in both groups (condition, P=0.04) following PCST, but a greater reduction in CBFv was observed in the POTS versus control group (-7.8% versus -1.8%; interaction, P=0.038). Notably, the reduced CBFv following PCST in the POTS group was similar to that seen during orthostatic stress (60.0±14.9 versus 60.4±14.8 cm/s). Further, PCST resulted in greater slowing in psychomotor speed (6.1% versus 1.4%, interaction, P=0.027) and a greater increase in symptom scores at study completion (interaction, P<0.001) in the patients with POTS, including increased difficulty with concentration. All other physiologic responses (blood pressure and end-tidal carbon dioxide) did not differ between groups after PCST (all P>0.05). Conclusions Reduced CBFv and cognitive dysfunction were evident in patients with POTS following prolonged cognitive stress even in the absence of orthostatic stress.

The incidence of postural orthostatic tachycardia syndrome in the population of Zagreb, Croatia.

AIM: To estimate the incidence of postural orthostatic tachycardia syndrome (POTS) in the population of Zagreb, Croatia, and to determine the patients' demographic and clinical characteristics. METHODS: From 2012-2017, we identified patients with POTS by a retrospective analysis of medical records at University Hospital Center Zagreb. Crude incidence rates were directly standardized by age according to the European and World Standard Population. RESULTS: Out of 385 patients with suspected POTS, 23 had a definitive POTS diagnosis. The annual incidence ranged from 3.3 to 14.8 per 1000000 for both sexes combined. The highest incidence rates were in the age groups 18-29 and 30-39 years, with female predominance. The mean age at diagnosis was 30.7 years (standard deviation ±9.2, range 18-52). The median duration of symptoms at diagnosis was 7.5 months (range 3-180 months). Regarding associated comorbidities, two patients had chronic gastritis and one patient had each of the following: epilepsy, prior subarachnoid hemorrhage, anxiety, mitral insufficiency, obstructive sleep apnea, hypothyreosis, and irritable bowel syndrome. In patients not fulfilling the criteria for POTS, the most common alternative diagnoses were autonomic dysfunction due to multiple sclerosis in 22, anxiety disorder in 17, epilepsy in 16, and orthostatic tachycardia due to deconditioning in 13 patients. CONCLUSION: The data obtained in this study can be used to optimize disease surveillance in population, comprehensive assessment of disease burden, and organization of health care services.

Mechanisms and management of gastrointestinal symptoms in postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a disorder of orthostatic intolerance associated with many GI manifestations that can be broadly classified into two different categories: those present all the time (non-positional) and those that occur with orthostatic position change. There are also many conditions that can co-exist with POTS such as mast cell activation syndrome and the hypermobile form of Ehlers-Danlos syndrome (hEDS) that are also oftentimes associated with GI symptoms. In the current issue of Neurogastroenterology and Motility, Tai et al. explored the relationship between functional GI disorders among hEDS patients with and without concomitant POTS and showed that the hEDS-POTS cohort was more likely to have more than one GI organ involved compared to the cohort with hEDS alone, and certain GI symptoms were also more common in the hEDS-POTS cohort. In this review article, we will briefly review the literature surrounding putative mechanisms responsible for GI symptoms in POTS with an emphasis on the contributory role of concomitant hEDS and then discuss management strategies for GI symptoms in POTS.

Work Ability Assessment and Its Relationship with Cardiovascular Autonomic Profile in Postural Orthostatic Tachycardia Syndrome.

Postural orthostatic tachycardia syndrome (POTS) negatively impacts quality of life. The excessive increase in cardiac sympathetic modulation during standing, which characterizes POTS patients, leads to many symptoms and signs of orthostatic intolerance. Little is known about the consequences of the disease on work performance and its relationship with individual autonomic profiles. Twenty-two POTS patients regularly engaged in working activity (20 females, age 36 ± 12 years) and 18 gender- and age-matched controls underwent a clinical evaluation and filled out the Work Ability Index (WAI) questionnaire. POTS patients completed the Composite Autonomic Symptom Score (COMPASS31) questionnaire, underwent continuous electrocardiogram, blood pressure and respiratory activity recordings while supine and during a 75° head-up tilt (HUT). A power spectrum analysis provided the index of cardiac sympatho-vagal balance (LF/HF). WAI scores were significantly reduced in POTS patients (29.84 ± 1.40) compared to controls (45.63 ± 0.53, p < 0.01). A significant inverse correlation was found between individual WAI and COMPASS31 scores (r = -0.46; p = 0.03), HUT increase in heart rate (r = -0.57; p = 0.01) and LF/HF (r = -0.55; p = 0.01). In POTS patients, the WAI scores were inversely correlated to the intensity of autonomic symptoms and to the excessive cardiac sympathetic activation induced by the gravitational stimulus.

Circadian rhythms of blood pressure and rate pressure product in children with postural tachycardia syndrome.

OBJECTIVE: To investigate circadian rhythms of blood pressure (BP) and rate pressure product (RPP) in children with postural tachycardia syndrome (POTS) by performing 24-hour ambulatory blood pressure monitoring (24-h ABPM). METHODS: 103 POTS children and 84 age- and gender-matched healthy children were enrolled and they got 24-h ABPM under usual routine of diurnal activity and nocturnal sleep. RESULTS: Although the mean awake systolic BP (SBP), 24-h diastolic BP (DBP), awake DBP, asleep heart rate (HR) did not differ between two groups (P > 0.05), the mean 24-h and asleep SBP, asleep DBP, 24-h and awake HR, 24-h, awake and asleep RPP were significantly higher in POTS children (P < 0.01). Non-dipping BP was more prevalent in POTS children (67.0% vs. 46%, P < 0.001). The RPP of POTS and control children showed 24-h circadian variations with peak roughly occurring approximately 2 h after waking from nocturnal sleep. Compared with controls, the RPP values of POTS children were significantly higher during 2 h before and 3 h after waking (P < 0.05). For the RPP value of 1 h after waking, a cutoff value of 8995.6 bpm·mmHg yielded a sensitivity of 75.8% and a specificity of 65.4% for predicting POTS. CONCLUSIONS: Abnormal circadian BP regulation is prevalent in POTS children. POTS children present with daily sympathetic hyperactivity, especially during nocturnal sleep and within 3 h after waking. And the excessive morning surge in RPP parallels with the morning surge of orthostatic HR increments and OI symptoms.