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BACKGROUND: Postural Orthostatic Tachycardia Syndrome (POTS) is a chronic form of autonomic nervous system dysfunction primarily affecting premenopausal females. POTS patients experience chronic orthostatic symptoms, and a heart rate (HR) increase of ≥30 bpm within 10 min of standing in the absence of orthostatic hypotension (>20/10 mmHg decrease in blood pressure [BP]). On standing, patients can exhibit increased ventilation (VE) with subsequent reductions in end-tidal CO2 (i.e., hypocapnia). Hypocapnia exacerbates tachycardia and symptoms. Previous research has suggested exaggerated peripheral chemoreceptor (pChR) activity drives postural hyperventilation in POTS. OBJECTIVE: We explored exaggerated pChR activity in the pathophysiology of postural hyperventilation in POTS. HYPOTHESIS: We hypothesized that POTS patients have a greater VE reduction during pChR inhibition compared to healthy controls. METHODS: We conducted a randomized crossover trial of hyperoxia vs. normoxia while supine and during head-up tilt (HUT) in 25 POTS patients (F=25; age: 31±8 years) and 12 healthy controls (HC) (F=12; age: 31±6 years; p=0.8). To inhibit pChR, participants breathed 5x30sec bouts of normocapnic hyperoxia (O2: ~400mmHg). Continuous respiratory (VE, ETO2, ETCO2) and hemodynamics (HR, BP, stroke volume, cardiac output, systemic vascular resistance) were measured. Data are reported as mean±SD. Continuous variables were compared using a 3-factor mixed-effects model: [Group: Control vs. Patient] x [Position (repeated measure): supine vs. HUT] x [Gas (repeated measure): ON vs. OFF). RESULTS During normoxic HUT, VE increased relative to supine baseline in both POTS (Supine: 10.3±2.3 L/min, HUT: 15.2±4.2; pE in response to HUT was significantly greater in POTS (4.8±3.3 L/min) vs. HC (1.8±1.6 L/min; p=0.001). During HUT, hyperoxia reduced VE in both POTS (pE relative to HC. During pChR inhibition with hyperoxia, VE was reduced in both HC and POTS, and the magnitude of ventilatory inhibition in response to hyperoxia was the same in both groups. These findings suggest pChR activity is not exaggerated in POTS patients, and thus is not the primary driver of postural hyperventilation observed in POTS. This work was supported by Standing up to POTS. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is characterized by chronic orthostatic intolerance and significantly impacts quality of life of patients. POTS predominantly affects women of child-bearing age with an estimated prevalence of up to 1%. POTS is defined by an excessive increase in heart rate (HR) of ≥30 bpm within 10 minutes of upright posture, in the absence of orthostatic hypotension. POTS is associated with chronic symptoms (≥6 months) including hyperventilation (HV) in the form of hyperpnea. HV reduces arterial CO2 (hypocapnia) and worsens tachycardia in POTS. Whether it is hypocapnia that increases HR in these patients is unclear. Studies have not investigated the effects of CO2 on HR due to the confounding effects of posture and ventilation. Objective: We aimed to determine if hypocapnia exacerbates tachycardia in POTS patients. Hypothesis: We hypothesize that hypocapnia will increase HR in POTS. Methods: We conducted a randomized crossover trial of hypocapnic HV vs. eucapnic HV in 13 female POTS patients (34±9 y). Participants completed the supine breathing protocol: 1) HV with resultant hypocapnia, and 2) HV (with end-tidal CO2 (ETCO2) clamped at baseline). Breath-by-breath respiratory (ventilation (VE), tidal volume (VT), ETCO2, end-tidal O2 (ETO2)) and beat-to-beat hemodynamics (HR, stroke volume (SV), cardiac output (CO)) were measured. Data are reported as mean±SD. Paired t-tests were used to compare respiratory and hemodynamic parameters between hypocapnic HV vs. eucapnic HV. Results: During HV, ETCO2 was significantly lower during hypocapnia vs. eucapnia (19.6±3.7 mmHg vs. 37.4±3.5 mmHg; p2 was greater during hypocapnia vs eucapnia (117.4±4.7 mmHg vs. 114.6±3.1 mmHg; pE (22.2±6.5 L/min vs. 22.0±5.1 L/min; p=0.8) or VT (1.4±0.4 L vs. 1.4±0.3 L; p=0.9) between hypocapnia and eucapnia. HR was significantly greater during hypocapnia vs. eucapnia (99±12 bpm vs 82±10 bpm; p This work was supported by Standing up to POTS. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

BACKGROUND: The novel coronavirus (SARS-CoV-2) has negatively impacted the health and economy of the world. While most patients recover, many are suffering from symptoms several months after resolution of the acute illness (“Post-Acute Sequalae of COVID-19” [PASC]). Symptoms include fatigue, light-headedness, and tachycardia/palpitations, similar to symptoms of cardiovascular autonomic disorders such as Postural Orthostatic Tachycardia Syndrome (POTS), Initial Orthostatic Hypotension (IOH), Orthostatic Hypotension (OH), and Inappropriate Sinus Tachycardia (IST). We have previously shown a high prevalence of autonomic abnormalities among PASC patients. We currently do not know if these autonomic abnormalities are chronic and persist in PASC patients over time. OBJECTIVE: We aimed to determine if the autonomic abnormalities seen in patients after COVID-19 infection are persistent or transient, by comparing hemodynamic criterion between baseline and follow-up visits. We hypothesize that patients will recover, and abnormalities will not persist between the visits. METHODS: PASC patients (n=64; F=51; 46±12y) completed baseline visits 411±133 days after their initial COVID-19 infection and follow-up visits 97±9 days later. Patients underwent autonomic function testing with beat-to-beat hemodynamics during 10min supine rest followed by a 10min active stand. Patients were evaluated for hemodynamic criterion for POTS (­­­­↑HR≥30bpm within 10min), IOH (transient ↓SBP≥40mmHg within 15s), OH (↓SBP≥20mmHg within 3min), and IST (supine HR>100bpm). Categorical data were analyzed with a McNemar’s test. RESULTS: 19 (30%) participants met POTS criterion at baseline vs. 15 (23%) at follow-up (p=0.1). 43 (67%) participants met IOH criterion at baseline vs. 37 (58%) at follow-up (p=0.08). The OH criterion was seen in 2 (3.1%) vs 5 (7.8%) patients (p=0.2) and IST was seen in 1 patient at both visits (1.6%). Overall, 48 (75%) patients met the hemodynamic criterion for at least one autonomic disorder at baseline and 43 (67%) patients met at least one criterion at follow-up (p=0.09). CONCLUSION: Many patients with PASC have evidence of cardiovascular autonomic abnormalities, most commonly IOH, followed by POTS. The prevalence of these abnormalities does not decrease over time. These findings suggest patients with PASC are not recovering from autonomic complications due to their COVID-19 infections. Treatment and management strategies for autonomic abnormalities are needed to improve the quality of life for these patients. Funding: Canadian Institutes of Health Research (CIHR) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The autonomic nervous system maintains homeostasis of cardiovascular, respiratory, gastrointestinal, urinary, immune, and thermoregulatory function. Homeostasis involves a variety of feedback mechanisms involving peripheral afferents, many of which contain molecular receptors sensitive to mechanical deformation, termed mechanosensors. Here, we focus on the molecular identity of mechanosensors involved in the baroreflex control of the cardiovascular system. Located within the walls of the aortic arch and carotid sinuses, and/or astrocytes in the brain, these mechanosensors are essential for the rapid moment-to-moment feedback regulation of blood pressure (BP). Growing evidence suggests that these mechanosensors form a co-existing system of peripheral and central baroreflexes. Despite the importance of these molecules in cardiovascular disease and decades of research, their precise molecular identity remains elusive. The uncertainty surrounding the identity of these mechanosensors presents a major challenge in understanding basic baroreceptor function and has hindered the development of novel therapeutic targets for conditions with known arterial baroreflex impairments. Therefore, the purpose of this review is to (i) provide a brief overview of arterial and central baroreflex control of BP, (ii) review classes of ion channels currently proposed as the baroreflex mechanosensor, namely Transient Receptor Potential (TRP), Epithelial Sodium Channel (ENaC), Acid Sensing Ion Channel (ASIC), and Piezo, along with additional molecular candidates that serve mechanotransduction in other organ systems, and (iii) summarize the potential clinical implications of impaired baroreceptor function in the pathophysiology of cardiovascular disease.

Measuring the retinal microvasculature at high altitude provides a surrogate for cerebral microvasculature, offering potential insight into consequence of cerebral hypoxia in critical illness. This study demonstrates dynamic regulation of the retina during rapid ascent and prolonged exposure to high altitude and is the first to demonstrate sex-specific differences in retinal microvasculature at high altitude. The ability to dynamically assess intact microvasculature contiguous with the brain has widespread research and clinical applications.

Coronavirus-19 (COVID-19), the infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has wreaked havoc across the globe since its emergence in December 2019. Reports of patients presenting with syncope and pre-syncope, as well as hypoxemia without symptoms of dyspnea ("silent hypoxemia"), have led researchers to speculate whether SARS-CoV-2 can alter autonomic nervous system function. As viral infections are commonly reported triggers of altered autonomic control, we must consider whether SARS-CoV-2 can also interfere with autonomic activity, at least in some patients. As we are still in the early stages of understanding COVID-19, we still do not know whether syncope and silent hypoxemia are more strongly associated with COVID-19 compared to any other viral infections that severely compromise gas exchange. Therefore, in this perspective we discuss these two intriguing clinical presentations, as they relate to autonomic nervous system function. In our discussion, we will explore COVID-specific, as well as non-COVID specific mechanisms that may affect autonomic activity and potential therapeutic targets. As we move forward in our understanding of COVID-19, well-designed prospective studies with appropriate control and comparator groups will be necessary to identify potential unique effects of COVID-19 on autonomic function.

The autonomic nervous system (ANS) is highly integrated with virtually all organs and systems of the human body. The ANS functions autonomously to regulate many internal processes including, but not limited to, heart rate (HR), breathing, blood pressure (BP), sweating, digestion, sexual functioning, respiration, urination, and defecation. Due to the systemic nature of the autonomic network, the impacts of autonomic dysfunction and failure can be extensive. Therefore, tests for reliably measuring autonomic health are of utmost importance. Several clinically standardized and validated tests of autonomic functioning are widely available, noninvasive, and easily performed in an awakened state, including the battery of tests that comprise the autonomic reflex screen and sympathetic skin responses. Additionally, a plethora of non-clinically validated tests exist, but still provide important and insightful information regarding healthy autonomic functioning. Some tests, which will be discussed herein, include direct measures of sympathetic function, via microneurography, tests of sympathetic nerve integrity and tests that evoke reproducible influences on cardiovascular responses. Finally, mammals, including humans, operate on a 24-hour circadian cycle. Many physiological systems demonstrate measurable shifts between a wakeful versus a sleep state, and the physiological processes under autonomic control are no exception. Therefore, techniques for objectively evaluating basic physiological phenomena, including, but not limited to, respiration, thermoregulation, neuroendocrine modulation, and cardiovascular functioning, provide key insight into autonomic neural function during sleep. Common techniques for measuring these variables will be reviewed here.

To assess the ability of the Orthostatic Discriminant and Severity Scale (ODSS) to distinguish symptoms of orthostatic intolerance from non-orthostatic symptoms. Clinical evaluations and questionnaire responses were collected in 73 healthy controls and 132 patients referred to the Autonomic Disorders Clinic from September 1, 2016, through April 30, 2018, for queries regarding autonomic dysfunction. A receiver operating characteristic (ROC) curve analysis was used to interpret sensitivity and specificity and to determine cutoff scores for symptom assessment. Inter-item reliability was assessed using Cronbach’s alpha. To calculate positive and negative predictive powers, patient data were collected in a single-blinded fashion where the researcher collecting questionnaire data was blinded to the clinical evaluation and diagnosis. Predictive powers were calculated using a chi-squared cross-tabulation. The orthostatic and non-orthostatic symptoms scores produced ROC curves with an area under the curve of 0.89 and 0.79, respectively. The orthostatic scores yielded a positive and negative predictive power value of 73% and 81%, respectively. Combined, the ODSS identified patients with and without orthostatic symptoms with an overall accuracy of 76%. The reliability of the ODSS was significant, with a Cronbach’s alpha of 0.88, and all dichotomous items were deemed worthy of retention following an inter-item reliability assessment. The ODSS demonstrated a strong ability to distinguish patients with and without orthostatic intolerance and demonstrated sensitivity and specificity equivalent to that of other standardized measures. Overall, the ODSS produces symptom scores that are both reliable and useful for both research and clinical practice.

Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic dysfunction. The cortical autonomic network (CAN) is a network of brain regions associated with autonomic function. Therefore, our objective was to investigate whether impairment of CAN structures is involved in the pathophysiology of NOH. Fifteen controls (63 ± 13 yr) and 15 NOH patients (67 ± 6 yr; P = 0.2) with peripheral autonomic dysfunction completed standard tests of parasympathetic [deep breathing (DB)] and sympathetic [Valsalva maneuver (VM)] activation during a functional MRI. Blood-oxygen-level dependent (BOLD) contrasts were obtained and contrasted. Compared with controls, patients had significantly smaller heart rate responses to DB (control: 15.23 ± 9.6 vs. NOH: 5.7 ± 2.1) and Valsalva ratios (control: 2.1 ± 0.47 vs. NOH: 1.2 ± 0.1; P < 0.001). NOH patients had absent adrenergic phases (late phase II and phase IV) during VM as per a qualitative analysis. During VM, controls had greater activation in the right hippocampus (T-value: 8.03), left posterior cingulate (TL: 7.6), and bilateral thalamus (TR: 7.41, TL: 8.45; P < 0.05). During phase IV, controls had greater activation in the right hippocampus (TR: 5.78l P < 0.05). Following subtraction analysis, no significant differences were evident during DB. In conclusion, NOH patients have significantly less CAN activation during sympathetic, but not parasympathetic, activation. Impaired CANs associated with sympathetic activation may be involved in the pathophysiology of NOH. NEW & NOTEWORTHY Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic dysfunction characterized by failure of reflexive sympathetic activation. Our result reveal that patients with autonomic dysfunction caused by postganglionic sympathetic impairment also have impaired activation of structures within the cortical autonomic network. Impaired activation is evident during a test of sympathetic, but not parasympathetic, activation. Impaired cortical autonomic networks associated with sympathetic activation may be involved in the pathophysiology of NOH.

Cardiovascular diseases account for approximately one-third of all deaths each year. Of this, hypertension accounts for approximately 9.4 million deaths. Melatonin, the primary circadian hormone, has been substantiated as an effective and safe adjunct anti-hypertensive agent. In support of this, melatonin receptors have been identified within the central and peripheral nervous system, as well as the cardiovascular system, including various vascular tissues. Therefore, it is not surprising that recent research has emerged highlighting a key role of melatonin in autonomic regulation of blood pressure. In animals, pinealectomies elicit peripheral vasoconstriction and hypertension. In studies involving humans, both healthy controls and patient populations of essential and nocturnal hypertension, melatonin administration demonstrates significant hypotensive effects that yield clinically significant results. However, the precise mechanism by which melatonin elicits its hypotensive effects in humans require further investigation. This review focuses on melatonin, its role within the cardiovascular system and the emerging implications for its use as an anti-hypertensive agent. Additionally, this review will discuss the current thinking on potential mechanisms behind the hypotensive effects of melatonin including: endothelium-dependent vasodilation, anti-oxidant defence mechanisms and sympatho-vagal autonomic regulation.

To develop a scale to quantify and discriminate orthostatic from non-orthostatic symptoms. In the current study, we present validation and reliability of orthostatic and non-orthostatic symptom scores taken from the orthostatic discriminate and severity scale (ODSS). Validity and reliability were assessed in participants with and without orthostatic intolerance. Convergent validity was assessed by correlating symptoms scores with previously validated tools [autonomic symptom profile (ASP) and the orthostatic hypotension questionnaire (OHQ)]. Clinical validity was assessed by correlating scores against standardized autonomic testing. Test–retest reliability was calculated using an intra-class correlation coefficient. Convergent validity: orthostatic (OS) and non-orthostatic (NS) symptom scores from 77 controls and 67 patients with orthostatic intolerance were highly correlated with both the orthostatic intolerance index of the ASP (OS: r = 0.903; NS: r = 0.651; p

The objective of the current study was to investigate whether patients with neurogenic orthostatic hypotension (NOH) secondary to autonomic failure have impaired functional connectivity between the cerebellum and central autonomic structures during autonomic challenges. Fifteen healthy controls (61 ± 14 years) and 15 NOH patients (67 ± 6 years; p = 0.12) completed the following tasks during a functional brain MRI: (1) 5 min of rest, (2) 5 min of lower-body negative pressure (LBNP) performed at − 35 mmHg, and (3) Three, 15-s Valsalva maneuvers (VM) at 40 mmHg. Functional connectivity (Conn Toolbox V18) between central autonomic structures and discrete cerebellar regions involved in cardiovascular autonomic control, including the vermis and posterior cerebellum, was assessed using a regions-of-interest approach during rest, LBNP and VM. Functional connectivity was contrasted between controls and patients with autonomic failure. At rest, controls had significantly more intra-cerebellar connectivity and more connectivity between cerebellar lobule 9 and key central autonomic structures, including: bilateral anterior insula (TR-value: 4.84; TL-value: 4.51), anterior cingulate cortex (T-value: 3.41) and bilateral thalamus (TR-value: 3.95; TL-value: 4.51). During autonomic maneuvers, controls showed significantly more connectivity between cardiovascular cerebellar regions (lobule 9 and anterior vermis) and important autonomic regulatory sites, including the brainstem, hippocampus and cingulate: vermis-brainstem (T-value: 4.31), lobule 9-brainstem (TR-value, 5.29; TL-value, 4.53), vermis-hippocampus (T-value, 4.63), and vermis-cingulate (T-value, 4.18). Anatomical and functional studies in animals and humans substantiate a significant role for the cerebellum in cardiovascular autonomic control during postural adjustments. In the current study, patients with NOH related to autonomic failure showed evidence of reduced connectivity between cardiovascular cerebellar regions and several important central autonomic structures, including the brainstem. The cerebellum is an established structure in cardiovascular autonomic control; therefore, evidence of impaired cerebellar connectivity to other autonomic structures may further contribute to the inability to properly regulate blood pressure during postural changes in NOH patients.

Autonomic homeostasis is dependent upon several brainstem nuclei, as well as several cortical and subcortical structures. Together, these sites make up, in part, the central autonomic network. Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic failure that occurs due to a failure to increase sympathetic efferent activity in response to postural changes. Therefore, the purpose of the current study was to investigate brainstem functional connectivity in NOH patients with peripheral autonomic lesions resulting in autonomic failure. Fifteen controls (63 ± 13 years) and fifteen Neurogenic Orthostatic Hypotension patients (67 ± 6 years; p = .2) with peripheral autonomic dysfunction completed 5-min of rest and three Valsalva maneuvers during a functional brain scan. Functional connectivity from the brainstem to cortical and subcortical structures were contrasted between patients and controls. At rest controls had significantly greater brainstem connectivity to the anterior cingulate cortex (T-value: 4.29), left anterior insula (T-value:3.31), left putamen (T-value:3.31) and bilateral thalamus (TRIGHT-value: 3.83; TLEFT-value:4.25) (p-FDR, Highlights • NOH patients show reduced brainstem connectivity at rest and during Valsalva. • Brainstem connectivity was reduced to central autonomic network structures. • Brainstem-cerebellum connectivity was negatively correlated with autonomic function.

In evaluating autonomic dysfunction, the autonomic reflex screen (ARS) is an established set of standardized tests to evaluate the presence and severity of autonomic dysfunction. Our laboratory previously reported normative data on 121 healthy individuals; however, the sample size in older individuals was reduced compared with other age groups. Therefore, the objective of the current study was to provide updated normative values representative of young, middle-aged, and older individuals from Southwestern Ontario. Two hundred and fifty-two healthy individuals completed quantitative sudomotor axon reflex testing, heart rate responses to deep breathing (HRDB), and Valsalva maneuver using standard protocols of the ARS. All 4 sweat sites demonstrated a significant effect of sex (p < 0.001). In addition, the proximal leg, distal leg, and foot were all significantly affected by age (p < 0.001). Cardiovagal parameters, measured via HRDB and Valsalva ratio revealed a significant regression with age (p < 0.001). These results show similar trends with previously reported normative data sets. All normative data as a function of age and sex, where appropriate, are expressed as percentiles (2.5th, 5th, 95th, 97.5th). The current study provides updated normative data describing autonomic functioning in healthy individuals obtained from the sudomotor and cardiovagal components of the ARS.

Objective Compare activation patterns within the cortical autonomic network in patients with neurogenic orthostatic hypotension (NOH) versus healthy age-matched controls during an orthostatic challenge. Methods Fifteen health controls and 15 NOH patients performed 3 Valsalva maneuvers, and 5-min of lower-body negative pressure (LBNP) during a functional brain MRI. Results Compared to controls, NOH patients had significantly less activation within the cerebellum during both LBNP and VM. Both groups had significant activation of the bilateral insula and left thalamus during LBNP. No significant differences were found during the recovery phase of LBNP. Conclusions The cerebellum, which plays an important role in vestibulo-sympathetic reflexes, important for blood pressure adjustments during postural changes, appear to be affected in patients with NOH. The cerebellum also appears to be affected during other baroreflex mediated stressors such as the VM. Significance Orthostatic reflexes mediated by the cerebellum may be impaired in patients with NOH. The results suggest an additional pathological pathway in patients with autonomic failure.

The objective of this study was to assess hemodynamic responses and baroreflex sensitivity (BRS) indexes during Valsalva maneuver (VM) and head-up tilt (HUT) testing in orthostatic intolerance (OI). Patients with neurogenic orthostatic hypotension (NOH, n = 26), postural tachycardia syndrome ( n = 26) and symptomatic OI ( n = 14) were compared with healthy population (control, n = 107) and inappropriate sinus tachycardia ( n = 7). Hemodynamic assessment included patterning and quantification with vagal and adrenergic BRS (BRSa/BRSa1). In NOH, cardiovagal systolic blood pressure (SBP) decrements in VM and HUT were correlated ( r = 0.660, P < 0.001); a “V” pattern of VM indicated α-BRSa failure. Yet BRSa1 did not reveal changes vs. control ( P > 0.05) or was not applicable in 60% of NOH. In symptomatic OI, compared with control, cardiovagal SBP decrements were larger ( P < 0.05); higher BRSa1 contradicted higher adrenergic index (Composite Autonomic Severity Score). Overshoot in phase IV dipped below baseline or dropped ≥ 10 mmHg over 8 s in postural tachycardia syndrome (“N” pattern), but by 3 s in inappropriate sinus tachycardia (“M” pattern). Visualization of distinct VM patterns allows primary evaluation of autonomic dysfunction and differentiation of the various forms of OI. BRSa1 evaluation is compromised by pathological SBP patterns. VM patterning is a valuable nonpostural supplement to HUT capable of detecting and differentiating OI.

Objective To investigate hemodynamic trans-phasic fluctuations in Valsalva maneuver (VM) and relate them to adrenergic baroreflex sensitivity (BRSa) indices. Methods In a healthy population ( n =107) with a young age predominance (32±15years) systolic blood pressure (SBP) and BRSa indices in VM were studied. Results Augmented and Suppressed Autonomic Responses (AAR, 28%; SAR, 15%, respectively), in addition to Balanced Autonomic Response (BAR, 40%), were found. There was a predominance for an unbalanced SBP response (67% in AAR, 69% in SAR, vs. 53% in BAR) in subjects ages 20–29. Compared to BAR and AAR, SAR had insignificant female predominance (51% and 47% vs. 75% respectively, p >0.05). AAR had the highest alternative BRSa (BRSa 1 ) compared to SAR and BAR (26.73±17.97mmHg/s vs. 8.64±5.33mmHg/s and 15.68±10.40mmHg/s respectively, p Conclusions Qualitative evaluation revealed three distinct patterns in response to VM. Late phase II was found to be a key factor in VM patterns and as such, argues to include late phase II parameters such as hemodynamic and time indices in BRSa evaluation. Significance These findings may be of use in future evaluations when identifying mild autonomic dysfunction and/or distinguishing typical and atypical SBP patterns in a healthy population.

PURPOSE The clinical significance of heart rate variability in the context of autonomic dysfunction continues to be a matter of debate. A consensus is lacking on the best heart rate variability measures for clinical purposes. Therefore, the purpose of this study was to investigate the utility of heart rate variability parameters in healthy versus autonomic dysfunction. METHODS Healthy young (n = 134), healthy older (n = 32), and patients with mild (postural tachycardia syndrome; n = 25) and severe (neurogenic orthostatic hypotension; n = 34) autonomic dysfunction were included. Time and frequency parameters during baseline, head-up tilt (HUT), and heart rate response to deep breathing (HRDB) were compared. RESULTS Cardiovagal time parameters were significantly reduced during HUT in healthy young and postural tachycardia syndrome (P < 0.001). Healthy young had significantly higher time parameters during baseline, HUT, and HRDB (P < 0.01). This was reflected by a significantly lower resting heart rate (HR) (61.4 ± 9.0 bpm vs. 76.8 ± 13.6 bpm; P < 0.001) and a smaller [INCREMENT]HR during HUT (32.8 ± 10.5 bpm vs. 44.4 ± 13.3 bpm; P < 0.001). Time parameters increased in young and postural tachycardia syndrome during HRDB, which was characterized by a nonsignificant difference in [INCREMENT]HR between both groups. Time parameters were significantly higher in healthy old versus neurogenic orthostatic hypotension at rest and during HRDB (P < 0.05). During HUT, only the SD of all normal RR intervals remained significantly higher. Heart rate changes corroborated these findings. Resting HR was significantly lower in healthy older (62.6 ± 11.0 bpm vs. 70.7 ± 12.4 bpm), and [INCREMENT]HR during HRDB was significantly higher (15.9 ± 9.2 bpm vs. 3.9 ± 4.2 bpm; P < 0.001). During HUT, [INCREMENT]HR showed no significant differences. CONCLUSIONS Time domain parameters of heart rate variability have a greater utility than frequency parameters in clinical autonomic disorders.

PURPOSE The clinical significance of heart rate variability (HRV) in the context of autonomic dysfunction continues to be a matter of debate. Therefore, the purpose of the current study was to investigate the clinical relevance of HRV in the context of autonomic dysfunction. METHODS Heart rate variability data from 225 volunteers consisting of controls (n = 166) and patients with mild (n = 25) and severe (n = 34) autonomic dysfunction were retrospectively analyzed. Time and frequency parameters were correlated against baseline and standardized tests of autonomic function. RESULTS During baseline, resting HR was negatively correlated with time (SD of all normal RR interval, r = -0.511; RMSSD, r = -0.585; pNN50, r = -0.545) and frequency (low-frequency, r = -0.362; high-frequency, r = -0.421) parameters (P < 0.01). Resting systolic blood pressure demonstrated similar significant correlations (P < 0.01). During head-up tilt, SD of all normal RR intervals was positively correlated with [INCREMENT]HR and change in systolic blood pressure (r = 0.340; r = 0.538, respectively; P < 0.01). Similarly, low-frequency, high-frequency, and low-frequency/high-frequency ratios were correlated with [INCREMENT]HR (r = 0.422, r = 0.176, r = 0.470) and change in systolic blood pressure (r = 0.451, r = 0.407, and r = 0.185) (P < 0.01). Time parameters (SD of all normal RR intervals, RMSSD, and pNN50) were all significantly correlated with deep breathing (r = 0.600; r = 0.556; r = 0.516; P < 0.01, respectively). Low-frequency and high-frequency power were also correlated (r = 0.596; r = 0.580, respectively) (P < 0.01). CONCLUSIONS Time and frequency parameters showed significant negative correlations with baseline hemodynamics. During a test of sympathetic activation and parasympathetic withdrawal, this relationship shifted to reveal significant positive correlations between HRV parameters and hemodynamics. Last, during a test of parasympathetic activation, there were significant positive correlations with cardiovagally mediated HRV parameters. Overall, these results suggest broader clinical relevance for HRV parameters within the spectrum of autonomic functioning.

Neurogenic orthostatic hypotension (NOH) can be present in a number of disorders, including synucleinopathies, autoimmune disorders, and various genetic disorders. All are characterized by defective norepinephrine release from sympathetic terminals upon standing, resulting in impaired vasoconstriction. NOH is defined as a drop in systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg, or both, within 3 minutes of standing or head up-tilt at a minimum of 60°. However, approximately 50% of patients have associated supine hypertension, which greatly complicates treatment. Supine hypertension not only is a common side effect of many anti-hypotensive agents but is also present in untreated patients, suggesting it is, in part, innate to the pathophysiology of autonomic dysfunction. Pathological mechanisms differ depending on the underlying autonomic disorder. In central neurodegenerative disorders, residual post-ganglionic sympathetic activity is likely the primary mechanism, whereas plasma angiotensin, aldosterone, and inappropriate mineralocorticoid receptor activity may contribute in peripheral autonomic lesions. Baroreflex failure/loss of baroreflex buffering is common to both. More work is required. Clinically, there is much dispute regarding the treatment of supine hypertension when there is a risk of exacerbating orthostatic hypotension. However, given the similar levels of end-organ damage (i.e., heart attack and stroke) seen with transient hypertension, it seems clear that treatment is important. Current therapies for both NOH and supine hypertension include a combination of pharmacological and conservative measures. However, in addition to the current standard of care, protocols may consider 24-h blood pressure monitoring and potential future examination of the peripheral post-ganglionic sympathetic nerves in order to apply individualized adjunct therapies. Finally, no anti-hypertensive agents are currently approved for use in this patient population, and development of novel therapies should focus on short-acting agents, selective to the supine position, that act primarily at night when hypertension is most severe/prolonged.

To evaluate alpha and beta components of adrenergic baroreflex sensitivity (BRSa) in Valsalva maneuver (VM).BRSa was studied in 89 healthy subjects aged 30±13 [16-75] years. Subjects were divided into three groups per blood pressure (BP) patterns associated with relatively balanced or increased alpha-adrenergic modulation: (1) BAR (n=43) - Balanced Autonomic Response with a BP dip below baseline in late phase II (IIL) and recovery in phase IV; (2) SAR (n=16) - Suppressed Autonomic Response with a non-dipping BP; and (3) AAR (n=30) - Augmented Autonomic Response with a BP recovery in phase IIL. Discrete (alpha and beta) BRSa formulae were produced using alpha- or beta-adrenergic phases: α-BRSa (phase IIL) and β-BRSa (phase IV), respectively. Discrete BRSa were studied to determine potential correlations to BRSa1 (validated BRSa evaluation) and evaluated for reliability.Patterns with higher α-adrenergic influence showed correlation between α-BRSa and BRSa1 (AAR: r=0.447, p0.05; SAR: r=0.774, p0.01). BAR showed correlation between β-BRSa and BRSa1 (r=-0.566, p0.01), and α- and β-adrenergic coefficients (r=-0.381, p0.05). Discrete BRSa were more reliable than BRSa1 (n=33; p0.05).Discrete BRSa are reproducible and correlated with BRSa1.If validated, discrete BRSa may differentiate physiologic variances and vague dysautonomia.

Background: Background: High-dose intravenous immunoglobulin (IV-Ig) is an evidence-based treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). Recently, subcutaneous Ig (SC-Ig) has received increasing attention. We performed a meta-analysis to assess the efficacy of SC-Ig versus IV-Ig. Methods: Methods: We searched PubMed, Embase, and Scopus from January, 1990 to December, 2015 for publications comparing IV-Ig vs. SC-Ig in patients with CIDP or MMN. We performed fixed-effects meta-analyses for strength changes as measured by the Medical Research Council sum score changes (MRC-SS). Results: Results: A total of 8 studies comprising 138 patients (88 with CIDP and 50 with MMN) were included in the meta-analysis. Considering the total population the use of SC-Ig showed slightly better results for MRC-SS (ES=-1.78, 95%CI=-3.45 to -0.11, I222Conclusions: Conclusions: We found comparable efficacy between SC and IV-Ig administrations for CIDP and MMN. These results suggest that SC-Ig is a suitable alternative treatment method, especially when other situations (e.g. convenience, safety profile) warrant its use. Further studies are needed to explore the efficacy of SC-Ig for CIDP and MMN.

Purpose Healthy subjects with asymptomatic postural tachycardia at baseline were evaluated over a one year period to determine whether they developed non-postural versus orthostatic symptoms that could predispose them to develop Postural Tachycardia Syndrome (POTS). Methods Participants ( n = 30) were recruited for a 1-year follow-up (FUP) study if at baseline they demonstrated a heart rate increment of ≥ 30 bpm on head-up tilt (HUT). At FUP, HUT was repeated and four self-report questionnaires were used to assess symptoms. Results Heart rate (HR) increment was reduced in 19 subjects (− 11.8 ± 7.4 bpm) and increased in 11 subjects (8.3 ± 6.1 bpm) at FUP versus baseline. Heart rate increment at FUP demonstrated no correlation to general fatigue ( r = 0.006), body vigilance ( r = 0.195), or the component scores for physical ( r = − 0.087) and mental ( r = − 0.137) health of the SF-36. Similarly, there was no correlation between HR increment at FUP and orthostatic scores ( r = 0.04). However, orthostatic scores did show a significant positive correlation with general fatigue and body vigilance scores ( r = 0.374, r = 0.392, respectively; p Conclusions Despite meeting the heart rate criteria for POTS, these findings further support that the majority of young individuals express benign orthostatic tachycardia. In addition, after one year this patient population showed no predisposition to develop non-postural or postural symptoms that could lead to the full syndrome of POTS. These data further argue for the re-evaluation of the heart rate criteria for diagnosing POTS in young populations.

Cardiac and peripheral vasomotor factors contribute to the rapid pressor response at the onset of isometric handgrip exercise. We tested the hypothesis that age enhances the sympathetic and vasoconstrictor response at the onset of isometric handgrip exercise so that the pressor response is maintained, despite a diminished cardiac function. Twelve young and twelve older (24 ± 3 and 63 ± 8 yr) individuals performed 20-s isometric handgrip exercise at 30, 40, or 50% of maximal voluntary contraction force. Muscle sympathetic nerve activity (MSNA) was measured using microneurography. Mean arterial pressure (MAP) and cardiac output (Q̇) were assessed continuously by finger plethysmography and total peripheral resistance was calculated. MAP increased with the onset of handgrip; this increase was associated with handgrip intensity and was similar in both groups. Heart rate and Q̇ increased with increasing handgrip intensity in both groups, but increases were greater in young vs. older individuals (age × handgrip intensity interaction, P < 0.05). MSNA burst frequency increased ( P < 0.01), while MSNA burst incidence tended to increase ( P = 0.06) with increasing handgrip intensity in both groups. The change in MSNA between baseline and handgrip, for both frequency and incidence, increased with increasing handgrip intensity for both groups. There was no effect of handgrip intensity or age on total peripheral resistance. The smaller heart rate and Q̇ response during the first 20 s of handgrip exercise in older individuals was not accompanied by a greater sympathetic activation or vasoconstrictor response. However, increases in MAP were similar between groups, indicating that the pressor response at the onset of handgrip exercise is preserved with aging.

Background: Orthostatic symptoms including dizziness, light-headedness and syncope can be major causes of disability in patients with dysautonomia. Currently there is no validated tool capable of discriminating orthostatic from non-orthostatic constitutional symptoms. Therefore, we developed the Orthostatic Discriminant and Severity Scale (ODSS) to help make this distinction. Objective: Demonstrate validity and reliability of the ODSS. Methods: Convergent and clinical validity were assessed by correlating Orthostatic scores with previously validated tools (Autonomic Symptom Profile (ASP), composite scores of the Orthostatic Hypotension Questionnaire and the total Composite Autonomic Severity Score (tCASS), respectively). Test-retest reliability was calculated using an intra-class correlation coefficient. Results: Orthostatic scores from 23 controls and 5 patients were highly correlated with both the Orthostatic Intolerance index of the ASP (r=0.724;pConclusions: Our results, though preliminary, provide empiral evidence that the ODSS is capable of producing a valid and reliable orthostatic score.

Background: Valsalva maneuver (VM) is a simple and non-invasive technique extensively utilized clinically to detect dysautonomia. VM provides detailed information of baroreflex sensitivity (BRS) which is an important cardiovascular and autonomic marker. However, the current approach for calculating its adrenergic component (BRSa1) is moderately reliable and fails to evaluate atypical VM patterns. Methods: We analyzed typical and atypical VM patterns of 89 young, healthy individuals (30 ±13 years) with the aim of improving BRSa evaluation. Objectives: 1) To determine a new BRSa calculation (BRSa2) applicable to different VM patterns; 2) correlate BRSa2 to BRSa1; 3) compare the internal consistency (ICC) between BRSa1 and BRSa2. Results: The BRSa2 calculation is a complex hemodynamic and time assessment equivalent to the slope in vagal BRS. In contrast to BRSa1, BRSa2 operates with hemodynamic indices easily detectable in any VM pattern. In atypical VM patterns, BRSa2 correlated with BRSa1: “flat-top responses” (r = 0.774, p < 0.01); rapid hemodynamic recovery (r = 0.461, p < 0.05). Most importantly, BRSa2 was more reliable than BRSa1 (ICC= 0.759 versus 0.469). Conclusion: BRSa2 is more reliable and allows atypical responses to VM to be analyzed, which clinically, could help differentiate natural physiological variances and mild adrenergic dysfunction.