Julian M. Stewart

2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope

Robert S. Sheldon, Blair P. Grubb II, Brian Olshansky, Win-Kuang Shen, Hugh Calkins, Michele Brignole, Satish R. Raj, Andrew D. Krahn, Carlos A. Morillo, Julian M. Stewart, Richard Sutton, Paola Sandroni, Karen J. Friday, Denise Tessariol Hachul, Mitchell I. Cohen, Dennis H. Lau, Kenneth A. Mayuga, Jeffrey P. Moak, Roopinder K. Sandhu, Khalil Kanjwal

Autonomic Nervous System Dysfunction in Adolescents with Postural Orthostatic Tachycardia Syndrome and Chronic Fatigue Syndrome Is Characterized by Attenuated Vagal Baroreflex and Potentiated Sympathetic Vasomotion

The objective was to determine the nature of autonomic and vasomotor changes in adolescent patients with orthostatic tachycardia associated with the chronic fatigue syndrome (CFS) and the postural orthostatic tachycardia syndrome (POTS). Continuous electrocardiography and arterial tonometry was used to investigate the heart rate and blood pressure responses before and 3–5 min after head-up tilt in 22 adolescents with POTS and 14 adolescents with CFS, compared with control subjects comprising 10 healthy adolescents and 20 patients with simple faint. Heart rate and blood pressure variability, determined baroreceptor function using transfer function analysis, and measured cardiac vagal and adrenergic autonomic responses were calculated using timed breathing and the quantitative Valsalva maneuver. Two of 10 healthy controls and 14 of 20 simple faint patients experienced vasovagal syncope during head-up tilt. By design, all CFS and POTS patients experienced orthostatic tachycardia, often associated with hypotension. R-R interval and heart rate variability were decreased in CFS and POTS patients compared with control subjects and remained decreased with head-up tilt. Low-frequency (0.05–0.15 Hz) blood pressure variability reflecting vasomotion was increased in CFS and POTS patients compared with control subjects and increased further with head-up tilt. This was associated with depressed baroreflex transfer indicating baroreceptor attenuation through defective vagal efferent response. Only the sympathetic response remained. Heart rate variability declined progressively from normal healthy control subjects through syncope to POTS to CFS patients. Timed breathing and Valsalva maneuver were most often normal in CFS and POTS patients, although abnormalities in select individuals were found. Heart rate and blood pressure regulation in POTS and CFS patients are similar and indicate attenuated efferent vagal baroreflex associated with increased vasomotor tone. Loss of beat-to-beat heart rate control may contribute to a destabilized blood pressure resulting in orthostatic intolerance. The dysautonomia of orthostatic intolerance in POTS and in chronic fatigue are similar.

Orthostatic intolerance in adolescent chronic fatigue syndrome

Objectives. To demonstrate the association between orthostatic intolerance and the chronic fatigue syndrome (CFS) in adolescents and to delineate the form that orthostatic intolerance takes in these children. Study Design. We investigated the heart rate and blood pressure (BP) responses to head-up tilt (HUT) in 26 adolescents aged 11 to 19 years with CFS compared with responses in adolescents referred for the evaluation of simple faint and to responses in 13 normal healthy control children of similar age. Results. A total of 4/13 of the controls and 18/26 simple faint patients experienced typical faints with an abrupt decrease in BP and heart rate associated with loss of consciousness. One CFS patient had a normal HUT. A total of 25/26 CFS patients experienced severe orthostatic symptoms associated with syncope in 7/25, orthostatic tachycardia with hypotension in 15/25, and orthostatic tachycardia without significant hypotension in 3/25. Acrocyanosis, cool extremities, and edema indicated venous pooling in 18/25. None of the control or simple faint patients experienced comparable acral or tachycardic findings. Conclusions. We conclude that chronic fatigue syndrome is highly related to orthostatic intolerance in adolescents. The orthostatic intolerance of CFS often has heart rate and BP responses similar to responses in the syndrome of orthostatic tachycardia suggesting that a partial autonomic defect may contribute to symptomatology in these patients.

Pooling in chronic orthostatic intolerance : arterial vasoconstrictive but not venous compliance defects

Background—Orthostatic intolerance is characterized by postural tachycardia syndrome (POTS) with exaggerated tachycardia, orthostatic symptoms, and “pooling” (which comprises acrocyanosis and dependent edema when upright). My colleagues and I tested the hypothesis that pooling results from increased venous compliance in POTS patients. Methods and Results—Fifteen patients aged 13 to 19 years were compared with 11 healthy, age-matched controls. The POTS group was divided into patients with high venous pressure (Pv>20 mm Hg) and normal Pv on the basis of resting supine Pv obtained in previous work. Subjects were studied using strain gauge plethysmography to measure blood flow, Pv, and the venous compliance volume-pressure relation while supine and during incremental head-up tilt testing at −10°, 0°, 20°, and 35°. Volume-pressure relations of controls and POTS patients with normal Pv and high Pv were not different and were unchanged by orthostasis. Supine leg peripheral resistance was greater than control resistance in patients with high Pv (54±9 versus 30±6 mm Hg · mL−1 · 100 mL−1 · min−1) and less than control resistance in patients with normal Pv (17±2 mm Hg · mL−1 · 100 mL−1 · min−1). On upright tilt, resistance decreased in high Pv to approximate resistance in normal Pv. Resistance in controls increased throughout tilt. Leg Pv increased in patients with normal Pv and in controls but remained unchanged in the high Pv group. Conclusions—The findings suggest that pooling in POTS is due to blunted arterial vasoconstriction, which produces passive redistribution of blood within peripheral venous capacitance beds. Venous compliance in POTS is similar to that in control subjects.

Patterns of orthostatic intolerance: The orthostatic tachycardia syndrome and adolescent chronic fatigue

OBJECTIVES To describe the orthostatic tachycardia syndrome (OTS) in adolescents, similarities to and differences from chronic fatigue syndrome (CFS), and patterns of orthostatic intolerance during head-up tilt (HUT). STUDY DESIGN Using electrocardiography and arterial tonometry, we investigated the heart rate and blood pressure responses during HUT in 20 adolescents with OTS compared with 25 adolescents with CFS, 13 healthy control subjects, and 20 patients with simple faint. RESULTS Of the control subjects, 4 of 13 experienced typical vasovagal faints with an abrupt fall in blood pressure and heart rate, and 14 of 20 patients with simple faint experienced similar HUT responses. All patients with CFS (25/25) experienced severe orthostatic symptoms with syncope in 2 of 25, early orthostatic tachycardia during HUT in 16 of 23 (13/16 hypotensive), and delayed orthostatic tachycardia in 7 of 23 (6/7 hypotensive). Acrocyanosis and edema occurred in 18 of 25. Early orthostatic tachycardia occurred in 10 of 20 patients with OTS. Of these, 9 of 10 were hypotensive, but hypotension was delayed in 4 of 9. Delayed tachycardia occurred in 10 of 20 (all hypotensive). Acrocyanosis and edema occurred in most patients with CFS, fewer patients with OTS, and in one patient with simple faint. Orthostatic symptoms were similar but more severe in patients with CFS compared with patients with OTS. CONCLUSIONS Symptoms and patterns of orthostatic heart rate and blood pressure change in OTS overlap strongly with those of CFS. Orthostatic intolerance in OTS may represent an attenuated form of chronic fatigue pathophysiology.

Pathophysiology, Diagnosis, and Treatment of Orthostatic Hypotension and Vasovagal Syncope

Orthostatic hypotension (OH) occurs in 0.5% of individuals and as many as 7–17% of patients in acute care settings. Moreover, OH may be more prevalent in the elderly due to the increased use of vasoactive medications and the concomitant decrease in physiologic function, such as baroreceptor sensitivity. OH may result in the genesis of a presyncopal state or result in syncope. OH is defined as a reduction of systolic blood pressure (SBP) of at least 20 mm Hg or diastolic blood pressure (DBP) of at least 10 mm Hg within 3 minutes of standing. A review of symptoms, and measurement of supine and standing BP with appropriate clinical tests should narrow the differential diagnosis and the cause of OH. The fall in BP seen in OH results from the inability of the autonomic nervous system (ANS) to achieve adequate venous return and appropriate vasoconstriction sufficient to maintain BP. An evaluation of patients with OH should consider hypovolemia, removal of offending medications, primary autonomic disorders, secondary autonomic disorders, and vasovagal syncope, the most common cause of syncope. Although further research is necessary to rectify the disease process responsible for OH, patients suffering from this disorder can effectively be treated with a combination of nonpharmacologic treatment, pharmacologic treatment, and patient education. Agents such as fludrocortisone, midodrine, and selective serotonin reuptake inhibitors have shown promising results. Treatment for recurrent vasovagal syncope includes increased salt and water intake and various drug treatments, most of which are still under investigation.

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology

Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using 1H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross‐sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) 1H MRSI to measure CSF lactate; (ii) single‐voxel 1H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) 31P MRSI to measure brain high‐energy phosphates as objective indices of mitochondrial dysfunction. We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high‐energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology. Copyright

The postural tachycardia syndrome.

Postural tachycardia syndrome (POTS) is a disorder of unknown etiology, and patients with this condition exhibit orthostatic intolerance (OI) and excessive tachycardia. Excessive tachycardia with POTS has been defined as a rapid (within 10 minutes) increase in heart rate by more than 30 beats per minute or a heart rate that exceeds 120 beats per minute. Patients with POTS can experience difficulty with daily routines such as housework, shopping, eating, and attending work or school. The possibility exists that all forms of OI, including POTS, result from central hypovolemia even without tachycardia. The clinical findings of POTS are observed in an increasing number of patients who are usually female and aged 15 to 50 years. Adults with POTS do not have hypotension, whereas children may exhibit hypotension. Many patients with POTS are intolerant of exercise. “Idiopathic” POTS must be distinguished from other conditions that can reduce venous return to the heart and produce similar signs and symptoms such as dehydration, anemia, or hyperthyroidism. Therapies for POTS are directed at relieving the central hypovolemia or at compensating for the circulatory dysfunctions that may cause this disorder. Treatments have resulted in varying degrees of success and are often used in combination with each other.

Clinical and Physiological Effects of an Acute α-1 Adrenergic Agonist and a β-1 Adrenergic Antagonist in Chronic Orthostatic Intolerance

Background—Adrenergic agents are commonly used in the treatment of chronic orthostatic intolerance with postural tachycardia syndrome (POTS). POTS may be associated with increased limb blood flow (“high flow”) and defective orthostatic vasoconstriction or decreased limb blood flow (“low flow”) and potentially with small blood volume. Methods and Results—We investigated the consequences of short-term intravenous administration of an &agr;-1 adrenergic agonist, phenylephrine, and a &bgr;-1 adrenergic antagonist, esmolol, in 14 patients with POTS aged 13 to 19 years. Indices of heart rate and blood pressure variability, peripheral blood flow, and arterial resistance were assessed, and the capacitance relation was computed for every subject using venous occlusion plethysmography. Patients were tilted to 35° upright while medicated and while unmedicated, and measurements were repeated. Phenylephrine improved orthostatic tolerance and normalized hemodynamics and indices of heart rate/blood pressure variability while supine and while upright, producing significant peripheral vasoconstriction and venoconstriction (20% capacitance change). Esmolol did not improve orthostatic tolerance or hemodynamics. A subgroup of low-flow POTS patients had exaggerated venoconstriction to phenylephrine (50% capacitance change) but others had no response. Conclusions—Phenylephrine, but not esmolol, improves orthostatic tolerance and hemodynamics in POTS. This lends support to the use of oral &agr;-1 agonists in the treatment of patients with chronic orthostatic intolerance.

Neurally mediated hypotension and autonomic dysfunction measured by heart rate variability during head-up tilt testing in children with chronic fatigue syndrome.

Recent investigations suggest a role for neurally mediated hypotension (NMH) in the symptomatology of chronic fatigue syndrome (CFS) in adults. Our previous observations in children with NMH and syncope (S) unrelated to CFS indicate that the modulation of sympathetic and parasympathetic tone measured by indices of heart rate variability (HRV) is abnormal in children who faint during head-up tilt (HUT). In order to determine mine the effects of autonomic tone on HUT in children with CFS we performed measurements of HRV during HUT in 16 patients aged 11–19 with CFS. Data were compared to 26 patients evaluated for syncope and with 13 normal control subjects. After 30 minutes supine, patients were tilted to 80° for 40 minutes or until syncope occurred. Time domain indices included RR interval, SDNN, RMSSD, and pNN50. An autoregressive model was used to calculate power spectra. LFP (.04–.15 Hz), HFP (.15–.40Hz), and TP (.01–.40Hz). Data were obtained supine (baseline) and after HUT. Thirteen CFS patients fainted (CFS+, 5/13 pure vasodepressor syncope) and three patients did not (CFS-). Sixteen syncope patients fainted (S+, all mixed vasodepressor-cardioinhibitory) and 10 did not (S-). Four control patients fainted (Control+, all mixed vasodepressor-cardioinhibitory) and nine did not (Control-). Baseline indices of HRV were not different between Control+ and S+, and between Control- and S-, but were depressed in S+ compared to S-. HRV indices were strikingly decresed in CFS patients compared to all other groups. With tilt, SDNN, RMSSD, and pNN50 and spectral indices decreased in all groups, remaining much depressed in CFS compared to S or control subjects. With HUT, sympathovagal indices (LFP/HFP, nLFP, and nHFP) were relatively unchanged in CFS, which contrasts with the increase in nLFP with HUT in all other groups. With syncope RMSSD, SDNN, LFP, TP, and HFP increased in S+ (and Control+), suggesting enhanced vagal heart rate regulation. These increases were not observed in CFS+ patients. CFS is associated with NMH during HUT in children. All indices of HRV are markedly depressed in CFS patients, even when compared with already low HRV in S+ or Control+ patients. Sympathovagal balance does not shift toward enhanced sympathetic modulation of heart rate with HUT and there is blunting in the overall HRV response with syncope during HUT. Taken together these data may indicate autonomic impairment in patients with CFS.