Diagnostic and societal impact of implementing the syncope guidelines of the European Society of Cardiology (SYNERGY study).

BACKGROUND: Syncope management is fraught with unnecessary tests and frequent failure to establish a diagnosis. We evaluated the potential of implementing the 2018 European Society of Cardiology (ESC) Syncope Guidelines regarding diagnostic yield, accuracy and costs. METHODS: A multicentre pre-post study in five Dutch hospitals comparing two groups of syncope patients visiting the emergency department: one before intervention (usual care; from March 2017 to February 2019) and one afterwards (from October 2017 to September 2019). The intervention consisted of the simultaneous implementation of the ESC Syncope Guidelines with quick referral routes to a syncope unit when indicated. The primary objective was to compare diagnostic accuracy using logistic regression analysis accounting for the study site. Secondary outcome measures included diagnostic yield, syncope-related healthcare and societal costs. One-year follow-up data were used to define a gold standard reference diagnosis by applying ESC criteria or, if not possible, evaluation by an expert committee. We determined the accuracy by comparing the treating physician's diagnosis with the reference diagnosis. RESULTS: We included 521 patients (usual care, n = 275; syncope guidelines intervention, n = 246). The syncope guidelines intervention resulted in a higher diagnostic accuracy in the syncope guidelines group than in the usual care group (86% vs.69%; risk ratio 1.15; 95% CI 1.07 to 1.23) and a higher diagnostic yield (89% vs. 76%, 95% CI of the difference 6 to 19%). Syncope-related healthcare costs did not differ between the groups, yet the syncope guideline implementation resulted in lower total syncope-related societal costs compared to usual care (saving €908 per patient; 95% CI €34 to €1782). CONCLUSIONS: ESC Syncope Guidelines implementation in the emergency department with quick referral routes to a syncope unit improved diagnostic yield and accuracy and lowered societal costs. TRIAL REGISTRATION: Netherlands Trial Register, NTR6268.

A novel and practical method to add video monitoring to tilt table testing.

AIMS: We describe a novel, practical, and inexpensive method to add video recording during tilt table testing (TTT): Open-Access-Video-TTT. METHODS AND RESULTS: The Open-Access-Video-TTT set-up uses a personal computer (PC) to capture screen video data from a non-invasive-beat-to-beat (NIBTB) haemodynamic blood pressure (BP) device, combined with video recording of a patient, using Open Broadcaster Software (OBS®). The new Open-Access-Video-TTT set up was tested with both the Finometer (model Finapres Nova®, Medical Systems, the Netherlands) and the Task Force® Touch Cardio monitor (CNSystems, Austria). For this, the Finapres Nova® was enabled in 'remote' mode and Real Video Network Computing (RealVNC®) was installed on the PC/laptop. The Task Force® has a DisplayPort (DP) port, for which a DP/ high-definition multimedia interface (HDMI) cable and a video capture card is used to merge the signals to the PC/laptop. With this method the combined images are stored as a new video signal. TTT can be performed with any routine protocol. CONCLUSIONS: Open Access-Video-TTT worked well for both the Finapres NOVA® and the Task Force Monitor ®. This novel method can be used easily by all physicians who wish to add video recording during TTT who do not have access to an electroencephalogram machine.

Variability of cardioinhibition in vasovagal syncope: differences between subgroups during cardioinhibition and beyond.

PURPOSE: We compared hemodynamic parameters between subjects with marked, intermediate and minimal cardioinhibition during vasovagal syncope. METHODS: The study included subjects with a decrease in heart rate while experiencing a complete vasovagal syncope during tilt-table testing. The subjects were classified as having marked, intermediate or minimal cardioinhibition, based on tertile values of the decrease in heart rate. Hemodynamic parameters between these groups were compared before tilt in the supine position, shortly after tilt and during cardioinhibition. RESULTS: A total of 149 subjects with a median age of 43 (interquartile range 24-60) years were included in the study. Among the three groups with different levels of cardioinhibition, the highest heart rate was observed in subjects with marked cardioinhibition both before and shortly after tilt and at the start of cardioinhibition. The heart rate decrease in these subjects was both larger and faster compared to subjects with minimal and intermediate cardioinhibition. CONCLUSION: Subjects with marked cardioinhibition have both a larger and faster decrease in heart rate compared to subjects with intermediate and minimal cardioinhibition, as early as from the start of cardioinhibition. Marked cardioinhibition is related to differences in hemodynamic profiles already present well before the start of cardioinhibition.

Dynamic changes in T-wave and QTc interval during tilt table testing: Innocent until proven otherwise.

A16-year-old female underwent tilt table testing, which resulted positive for reflex vasodepressive syncope. 12­lead ECG during syncope showed T-wave inversion in infero-lateral leads, along with QTc interval increase >100 msec compared to baseline. These abnormalities rapidly disappeared in supine position with resumption of consciousness. Complete cardiac evaluation excluded heart disease. T-wave changes and moderate QTc prolongation are relatively common in young (mainly female) patients undergoing tilt table testing and they appear benign in nature. However, in a minority of cases, on the basis of the clinical context and after an accurate ECG analysis, further examinations may be warranted.

Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Background and Objectives: During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF). The relationship between this CBF reduction and symptom severity has not been examined in detail. Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing. Materials and Methods: First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test. Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published. Results: 71 patients were retested because of worsening symptoms. The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up (p < 0.0001). The %CBF reduction changed from initially 19% to 31% at follow-up (p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns. The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively (p < 0.0001). Conclusions: Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction. The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms.

Leg pain in neuropathic postural tachycardia syndrome is associated with altered muscle membrane properties.

PURPOSE: In neuropathic postural tachycardia syndrome, peripheral sympathetic dysfunction leads to excessive venous blood pooling during orthostasis. Up to 84% of patients report leg pain and weakness in the upright position. To explore possible pathophysiological processes underlying these symptoms, the present study examined muscle excitability depending on body position in patients with neuropathic postural tachycardia syndrome and healthy subjects. METHODS: In ten patients with neuropathic postural tachycardia syndrome and ten healthy subjects, muscle excitability measurements were performed repeatedly: in the supine position, during 10 min of head-up tilt and during 6 min thereafter. Additionally, lower leg circumference was measured and subjective leg pain levels were assessed. RESULTS: In patients with neuropathic postural tachycardia syndrome, muscle excitability was increased in the supine position, decreased progressively during tilt, continued to decrease after being returned to the supine position, and did not completely recover to baseline values after 6 min of supine rest. The reduction in muscle excitability during tilt was paralleled by an increase in lower leg circumference as well as leg pain levels. No such changes were observed in healthy subjects. CONCLUSIONS: This study provides evidence for the occurrence of orthostatic changes in muscle excitability in patients with neuropathic postural tachycardia syndrome and that these may be associated with inadequate perfusion of the lower extremities. Insufficient perfusion as a consequence of blood stasis may cause misery perfusion of the muscles, which could explain the occurrence of orthostatic leg pain in neuropathic postural tachycardia syndrome.

Recommendations for tilt table testing and other provocative cardiovascular autonomic tests in conditions that may cause transient loss of consciousness : Consensus statement of the European Federation of Autonomic Societies (EFAS) endorsed by the American Autonomic Society (AAS) and the European Academy of Neurology (EAN).

An expert committee was formed to reach consensus on the use of tilt table testing (TTT) in the diagnosis of disorders that may cause transient loss of consciousness (TLOC) and to outline when other provocative cardiovascular autonomic tests are needed. While TTT adds to history taking, it cannot be a substitute for it. An abnormal TTT result is most meaningful if the provoked event is recognised by patients or eyewitnesses as similar to spontaneous events. The minimum requirements to perform TTT are a tilt table, a continuous beat-to-beat blood pressure monitor, at least one ECG lead, protocols for the indications stated below and trained staff. This basic equipment lends itself to the performance of (1) additional provocation tests, such as the active standing test, carotid sinus massage and autonomic function tests; (2) additional measurements, such as video, EEG, transcranial Doppler, NIRS, end-tidal CO2 or neuro-endocrine tests; and (3) tailor-made provocation procedures in those with a specific and consistent trigger of TLOC. TTT and other provocative cardiovascular autonomic tests are indicated if the initial evaluation does not yield a definite or highly likely diagnosis, but raises a suspicion of (1) reflex syncope, (2) the three forms of orthostatic hypotension (OH), i.e. initial, classic and delayed OH, as well as delayed orthostatic blood pressure recovery, (3) postural orthostatic tachycardia syndrome or (4) psychogenic pseudosyncope. A therapeutic indication for TTT is to teach patients with reflex syncope and OH to recognise hypotensive symptoms and to perform physical counter manoeuvres.

A higher proportion of men than of women fainted in the phase without nitroglycerin in tilt-induced vasovagal syncope.

PURPOSE: Vasovagal syncope (VVS) affects more women than men. We determined whether this sex ratio affects tilt table test (TTT) results. METHODS: We retrospectively studied TTT outcomes in suspected VVS. TTT consisted of supine rest, a maximum 20 min of head-up tilt without and, if nitroglycerin was needed, a further maximum 20 min after nitroglycerin administration. TTT was terminated if VVS occurred. We used binary logistic regression for the entire TTT and for each phase, with VVS as outcome and age and sex as predictors. RESULTS: TTT provoked vasovagal (pre)syncope in 494 out of 766 tests (64%). The proportion of men and women who fainted during the entire TTT did not differ significantly between the sexes (p = 0.13, corrected for age). A lower proportion of women than men had VVS in the phase without nitroglycerin (odds ratio 0.54; 95% confidence interval 0.37-0.79; p = 0.002, corrected for age), whereas a higher proportion of women than men fainted after nitroglycerin (odds ratio 1.58; 95% confidence interval 1.13-2.21; p = 0.008, corrected for age). These sex differences remained significant after correction for a history of orthostatic versus emotional triggers. The effect of sex on TTT outcome was closely associated with differences of blood pressure change upon tilt-up (lower in men in both TTT phases: without nitroglycerin p = 0.003; with nitroglycerin p = 0.05), but not with heart rate changes. CONCLUSION: Men were more susceptible to induction of VVS without nitroglycerin and women after it. The unexpected findings may be due to sex-specific pathophysiological differences.

Utility of Diagnostic Studies for Upper Gastrointestinal Symptoms in Children with Orthostatic Intolerance.

OBJECTIVE: To assess the utility of gastrointestinal (GI) diagnostic studies in the evaluation of patients with orthostatic intolerance. STUDY DESIGN: Medical records of 103 consecutive children/young adults with orthostatic intolerance and gastrointestinal symptoms were reviewed. All patients had undergone antroduodenal manometry in conjunction with the tilt table test, autonomic testing, and upper gastrointestinal endoscopy (EGD). A gastric emptying study (GES) was performed in 81 patients. RESULTS: The median age of the cohort was 17 years (IQR, 15-19) with a female predominance (females:males, 3:1). As expected, the tilt table test was abnormal in all patients. Antroduodenal manometry was abnormal in 83 of 103 patients (81%), showing neurogenic intestinal dysmotility in 50%, rumination in 20%, and visceral hyperalgesia in 10%. The GES results were abnormal in 23 of 81 patients (28.4%), mostly (21 of 23) with delayed GES. None of the tilt table test or autonomic results were predictive of abnormal antroduodenal manometry or GES. Analysis of EGD biopsy samples revealed nonspecific esophagitis and/or gastritis in 16 of 103 patients (15%). CONCLUSIONS: Antroduodenal manometry with the tilt table test were the most insightful investigations in adolescents and young adults with orthostatic intolerance and gastrointestinal symptoms. GES and EGD provided limited information. Gastrointestinal symptoms were related more to functional rather than mucosal or organic etiologies, suggesting a limited role of endoscopy alone in evaluating patients with orthostatic intolerance presenting with gastrointestinal symptoms.

Autonomic uprising: the tilt table test in autonomic medicine.

This perspective piece on head-up tilt table testing is part of a series on autonomic function testing. The tilt table can be a useful diagnostic test, but methodologies vary, and the results are sometimes misinterpreted. The intent here is not to review comprehensively the utility of various tilt table testing protocols but to convey a number of general points that may give perspective and have practical clinical value, based on an understanding of autonomic physiology and our long clinical and research experience in the evaluation of autonomic disorders. The goals of tilt table testing are to assess orthostatic hypotension (OH), chronic orthostatic intolerance (COI), and unexplained syncope. The testing is useful for distinguishing neurogenic from non-neurogenic OH, identifying failure of the sympathetic noradrenergic system in autonomic neuropathies and ganglionopathies, and assessing baroreflex-sympathoneural function in α-synucleinopathies. For COI, the testing can provide objective data related to the patient's symptoms, diagnose postural tachycardia syndrome (POTS), and distinguish POTS from other causes of tachycardia. Provocative tilt table testing can help understand bases for recurrent transient loss of consciousness in patients with syncope, distinguish neurally mediated syncope from psychogenic pseudosyncope, and separate syncope-related convulsion from epileptic seizures. For each of these purposes, the goals, formats, endpoints, and clinical utility are different. As for any autonomic test, tilt table findings must be interpreted in the context of the patient's clinical presentation.

[Differential diagnostics of unclear syncope]. / Differenzialdiagnostik unklarer Synkopen.

The clarification of syncope is a diagnostic challenge as possible causes often occur only intermittently. Therefore, a detailed and standardized anamnesis is essential as it 1) differentiates syncope from other transient losses of consciousness (TLOC) and 2) directly clarifies possible causes of syncope. The risk stratification plays a central and very important role in order to avoid unnecessary examinations in patients with benign syncope and to provide patients with life-threatening, mostly cardiac syncopal episodes with timely diagnostics and treatment. In cases where the cause of syncope is still unclear, a standardized approach is indicated using extended diagnostics, such as a tilt table examination, a carotid sinus pressure test, prolonged telemetric monitoring or clarification with an implantable loop recorder (ILR).

High incidence of ST-T changes in women during tilt-table testing.

INTRODUCTION: We have observed electrocardiographic (ECG) changes primarily in women during tilt table testing. METHODS: We reviewed 12 lead ECGs during tilt studies between 2012 and 2016 for changes in ST segments and T waves during tilt table testing. Patients with distinctly abnormal baseline ECGs were excluded. RESULTS: Of the 180 tilt studies, 117 (65%) were in women. There were 32 patients with ECG changes during tilting. Of these, 28 (87.5%) were in women with an average age of 45years. None had a history of CAD or exertional chest pain. Echocardiograms were available in 21 of the 28 women with tilt induced ECG changes and all were normal. ECG changes during tilt table testing were found in 4/64 (6.25%) of men. The occurrence of ST-T wave changes during tilt testing was significantly higher among women compared to men, with a p value of 0.008. Of the 28 women with ECG changes during tilt, 11 had T wave inversions alone. ST segment depression alone was noted in 7 women. There were 10 women who had both ST segment depression and T wave inversions. Changes occurred immediately upon tilting in 6. In the remaining, they occurred at an average of 4.8±4min after tilting. The slight increase in heart rate in patients with ECG changes was similar to that in the patients without new ECG changes. The ECG changes were not related to the presence of syncope. CONCLUSIONS: ECG changes during the testing was observed at a relatively high incidence primarily in women. The clinical significance of these repolarization changes during tilt testing is unknown. These ECG changes during tilt testing may correlate with the high incidence of false positive ECGs in women during exercise testing but do not necessarily indicate the presence of ischemic coronary disease. Additional research is needed to explain this phenomenon.

Clinical characteristics of supine hypertension in de novo Parkinson disease.

PURPOSE: Supine hypertension is frequently associated with autonomic failure. However, its clinical characteristics in patients with Parkinson disease (PD) remain unclear. The present study aimed to clarify the characteristics of supine hypertension in patients with de novo PD. METHODS: The subjects were 72 patients with de novo PD. We studied blood pressure and plasma norepinephrine levels after the patients rested for 20 min in the supine position. Changes in blood pressure were also examined on head-up tilt-table testing. RESULTS: The disease duration was 1.7 ± 1.6 years (average ± SD). Thirty-three (45.8 %) patients had supine hypertension (defined as a blood pressure of ≥140/90 mmHg). Supine blood pressure positively correlated with the degree of orthostatic hypotension. Age and the proportion of patients with akinetic-rigid motor subtype or preexisting hypertension were higher among patients with supine hypertension than among those without supine hypertension. The Mini-Mental State Examination score was lower in patients with supine hypertension than in those without supine hypertension. Sex, disease duration, disease severity, and peripheral sympathetic nervous activity as evaluated by the cardiac uptake of (123)I-metaiodobenzylguanidine and the plasma norepinephrine level did not differ between patients with and those without supine hypertension. CONCLUSION: Older age, akinetic-rigid motor subtype, and preexisting hypertension are independent risk factors for supine hypertension. Supine hypertension alone may be associated with milder peripheral sympathetic nervous denervation than orthostatic hypotension alone. As for global cognitive decline, supine hypertension is a far riskier comorbidity of early-stage PD than is orthostatic hypotension.

Clinical context and outcome of carotid sinus syndrome diagnosed by means of the 'method of symptoms'.

AIMS: The prevalence and outcome of carotid sinus syndrome (CSS) reported in the literature vary owing to differences in indications and methods of carotid sinus massage (CSM). METHODS AND RESULTS: We performed CSM on all patients aged 40 years and above with unexplained syncope after the initial evaluation. Carotid sinus massage was performed in the supine and standing positions on both sides for 10 s during continuous electrocardiogram and blood pressure monitoring; CSS was diagnosed in the event of an abnormal response to CSM in association with reproduction of spontaneous symptoms ('method of symptoms'). From July 2005 to July 2012, CSS was found in 164 (8.8%) of 1855 patients (mean age 77 ± 9 years, 73% males): 81% had an asystolic reflex (mean pause 7.6 ± 2.2 s) and 19% a vasodepressor reflex (mean lowest systolic blood pressure 65 ± 15 mmHg). Potential multifactorial causes of syncope (orthostatic hypotension, bundle branch block, bradycardia, tachyarrhythmias) were found in 74% of patients. One hundred forty-one patients received the proper care [advice on lifestyle measures in all, discontinuation (#40) or reduction (#17) of antihypertensive drugs, pacemaker implantation (#57)] and were followed up for 39 ± 25 months. Syncope recurred in 23 patients; the actuarial syncopal recurrence rate was 7% at 1 year and 26% at 5 years. Total syncopal episodes decreased from 91 per year during the 2 years before evaluation to 21 episodes per year during follow-up (P = 0.001). On Cox proportional-hazards regression, a mixed or vasodepressor response to tilt testing was the only independent predictor of syncopal recurrence (hazard ratio = 1.8; P = 0.01). CONCLUSION: Carotid sinus massage by means of the 'method of symptoms' indentifies a clinical syndrome with definite features and outcome. A treatment strategy involving lifestyle measures, reduction of antihypertensive drugs and cardiac pacing when appropriate is effective in reducing the syncopal recurrence rate.

Predictive value of isolated very low QRS voltage in tilt-table test for neurally mediated syncope.

Objective: The cause of syncope is generally determined based on clinical manifestations. There has been little discussion about the value of electrocardiograms for diagnosing neurally mediated syncope. The aim of this study was to test the predictive value of the isolated very low QRS voltage in tilt-table testing for suspected neurally mediated syncope in a Chinese population. Methods: This retrospective study enrolled patients with suspected neurally mediated syncope. Tilt-table testing was a part of the diagnostic examination. Each patient underwent echocardiography and electrocardiogram. isolated very low QRS voltage referred to a voltage of ⩽0.3 mV for the QRS complex in an isolated frontal lead or ⩽0.7 mV for the QRS complex in an isolated precordial lead. Results: In total, 157 patients were included in the tilt-table testing positive group, and 242 patients were included in the tilt-table testing negative group. Compared with the testing negative group, the testing positive group had more patients with isolated very low QRS voltage in the frontal leads (p < 0.001). Moreover, for patients with isolated very low QRS voltage in the precordial leads, no significant difference was noted between the testing positive group and testing negative group (p = 0.289). Isolated very low QRS voltage in the frontal leads demonstrated 84.08% sensitivity and 74.38% specificity for a positive tilt-table testing response. The area under the curve of isolated very low QRS voltage for a positive tilt-table testing response in frontal leads was 0.806 (p < 0.0001). Conclusion: In patients with suspected neurally mediated syncope, isolated very low QRS voltage in the frontal leads is a parameter that can predict a positive tilt-table testing response. The presence of isolated very low QRS voltage in frontal leads can serve as a parameter for evaluating syncope patients.

Tilt-table test: its role in modern practice.

Syncope is a major healthcare problem with significant morbidity, mortality and healthcare cost. It is a common symptom with a complex pathophysiology and, therefore, several aetiologies. Tilt-table testing (TTT) is an important, yet perhaps not widely-used, test that forms part of the management of syncope. We sought to assess the utilisation of this test in our institution for the investigation of patients with syncope, to study the referral patterns and the outcomes and usefulness of the TTT in a real-life setting. We undertook a retrospective study of all the TTT that were performed in our institution between January 2009 and October 2009. Of the 69 patients in which TTT was performed, 14 (20%) presented with presyncope, 24 (35%) with a single episode of syncope and 24 (44%) with multiple episodes. The average age was 57.2 years and 64% were female. Of the total patients, 35 (51%) had an abnormal TTT. Of the patients with normal TTT, four had internal loop recorders and six were referred to other medical specialities. The remaining patients (49%) had no formal diagnosis and were referred back to their general practitioner. TTT remains a common test modality and has great value when undertaken in the correct clinical context. This underlines the importance of a detailed clinical history. The European Society of Cardiology guidelines ensure a methodical and rational approach to syncopal patients and aide in choosing the right patient for the right test.

Comparison of a 20 degree and 70 degree tilt test in adolescent myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients.

Introduction: During a standard 70-degree head-up tilt test, 90% of adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develop an abnormal reduction in cerebral blood flow (CBF). A 70-degree test might not be tolerated by young ME/CFS patients because of the high incidence of syncopal spells. This study examined whether a test at 20 degrees would be sufficient to provoke important reductions in CBF in young ME/CFS patients. Methods: We analyzed 83 studies of adolescent ME/CFS patients. We assessed CBF using extracranial Doppler measurements of the internal carotid and vertebral arteries supine and during the tilt. We studied 42 adolescents during a 20 degree and 41 during a 70 degree test. Results: At 20 degrees, no patients developed postural orthostatic tachycardia (POTS), compared to 32% at 70 degrees (p = 0.0002). The CBF reduction during the 20 degree tilt of -27(6)% was slightly less than during the reduction during a 70 degree test [-31(7)%; p = 0.003]. Seventeen adolescents had CBF measurements at both 20 and 70 degrees. The CBF reduction in these patients with both a 20 and 70 degrees test was significantly larger at 70 degrees than at 20 degrees (p < 0.0001). Conclusions: A 20 degree tilt in young ME/CFS patients resulted in a CBF reduction comparable to that in adult patients during a 70 degree test. The lower tilt angle provoked less POTS, emphasizing the importance of using the 70 degree angle for that diagnosis. Further study is needed to explore whether CBF measurements during tilt provide an improved standard for classifying orthostatic intolerance.

Orthostatic chronotropic incompetence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Background: Orthostatic intolerance (OI) is a core diagnostic criterion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The majority of ME/CFS patients have no evidence of hypotension or postural orthostatic tachycardia syndrome (POTS) during head-up tilt, but do show a significantly larger reduction in stroke volume index (SVI) when upright compared to controls. Theoretically a reduction in SVI should be accompanied by a compensatory increase in heart rate (HR). When there is an incomplete compensatory increase in HR, this is considered chronotropic incompetence. This study explored the relationship between HR and SVI to determine whether chronotropic incompetence was present during tilt testing in ME/CFS patients. Methods: From a database of individuals who had undergone tilt testing with Doppler measurements for SVI both supine and end-tilt, we selected ME/CFS patients and healthy controls (HC) who had no evidence of POTS or hypotension during the test. To determine the relation between the HR increase and SVI decrease during the tilt test in patients, we calculated the 95% prediction intervals of this relation in HC. Chronotropic incompetence in patients was defined as a HR increase below the lower limit of the 95th % prediction interval of the HR increase in HC. Results: We compared 362 ME/CFS patients with 52 HC. At end-tilt, tilt lasting for 15 (4) min, ME/CFS patients had a significantly lower SVI (22 (4) vs. 27 (4) ml/m2; p < 0.0001) and a higher HR (87 (11) vs. 78 (15) bpm; p < 0.0001) compared to HC. There was a similar relationship between HR and SVI between ME/CFS patients and HC in the supine position. During tilt ME/CFS patients had a lower HR for a given SVI; 37% had an inadequate HR increase. Chronotropic incompetence was more common in more severely affected ME/CFS patients. Conclusion: These novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing in ME/CFS patients.

Dysautonomia: Diagnosis and Management.

Dysautonomias are a heterogenous group of disorders that can cause variable symptoms ranging from isolated impairment of one autonomic function to multisystem failure. The causes are also diverse and can be central or peripheral and primary (owing to an intrinsic neurologic cause) or secondary (owing to a disorder that secondarily causes damage to the autonomic nervous system). This review covers common phenotypes of dysautonomias, primary and secondary causes, initial clinical workups, interpretation of common autonomic tests, and first-line treatments. A brief review of autonomic impairment associated with acute and long-COVID is also presented.

Cardiovascular Response to Posture Changes: Multiscale Modeling and in vivo Validation During Head-Up Tilt.

In spite of cardiovascular system (CVS) response to posture changes have been widely studied, a number of mechanisms and their interplay in regulating central blood pressure and organs perfusion upon orthostatic stress are not yet clear. We propose a novel multiscale 1D-0D mathematical model of the human CVS to investigate the effects of passive (i.e., through head-up tilt without muscular intervention) posture changes. The model includes the main short-term regulation mechanisms and is carefully validated against literature data and in vivo measures here carried out. The model is used to study the transient and steady-state response of the CVS to tilting, the effects of the tilting rate, and the differences between tilt-up and tilt-down. Passive upright tilt led to an increase of mean arterial pressure and heart rate, and a decrease of stroke volume and cardiac output, in agreement with literature data and present in vivo experiments. Pressure and flow rate waveform analysis along the arterial tree together with mechano-energetic and oxygen consumption parameters highlighted that the whole system approaches a less stressed condition at passive upright posture than supine, with a slight unbalance of the energy supply-demand ratio. The transient dynamics is not symmetric in tilt-up and tilt-down testing, and is non-linearly affected by the tilting rate, with stronger under- and overshoots of the hemodynamic parameters as the duration of tilt is reduced. By enriching the CVS response to posture changes, the present modeling approach shows promise in a number of applications, ranging from autonomic system disorders to spaceflight deconditioning.