Glucose-sensitive hypothalamic nuclei traced through functional magnetic resonance imaging.

Introduction: Hypothalamic glucose-sensitive neural circuits, which regulate energy metabolism and can contribute to diseases such as obesity and type 2 diabetes, have been difficult to study in humans. We developed an approach to assess hypothalamic functional connectivity changes during glucose loading using functional magnetic resonance imaging (fMRI). Methods: To do so, we conducted oral glucose tolerance tests while acquiring functional images before, and 10 and 45 min after glucose ingestion in a healthy male and cross-sectionally in 20 healthy participants on two different diets. Results: At group level, 39 fMRI sessions were not sufficient to detect glucose-mediated connectivity changes. However, 10 repeated sessions in a single subject revealed significant intrinsic functional connectivity increases 45 min after glucose intake in the arcuate, paraventricular, and dorsomedial nuclei, as well as in the posterior hypothalamic area, median eminence, and mammillary bodies. Discussion: Our methodology allowed to outline glucose-sensitive hypothalamic pathways in a single human being and holds promise in delineating individual pathophysiology mechanisms in patients with dysglycemia.

Randomized Trial Comparing SGLT2 Inhibition and Hydrochlorothiazide on Sympathetic Traffic in Type 2 Diabetes.

Introduction: Reductions in sympathetic nervous system activity may contribute to beneficial effects of sodium glucose cotransporter 2 (SGLT2) inhibition on cardiovascular outcomes. Therefore, we tested the hypothesis that SGLT2 inhibition with empagliflozin (Empa) lowers muscle sympathetic nerve activity (MSNA) in patients with type 2 diabetes mellitus (T2DM) compared with hydrochlorothiazide (HCT) to discern SGLT2-specific actions from responses to increased natriuresis. Methods: We randomized patients with T2DM on metformin monotherapy to either 25 mg/d Empa (n = 20) or 25 mg/d HCT (n = 21) for 6 weeks in a parallel, double-blind fashion. We assessed MSNA by peroneal microneurography, blood pressure, cardiovascular and metabolic biomarkers at baseline and at the end of treatment. Results: Both drugs elicited volume depletion, as indicated by increased thoracic impedance. Compared with HCT, Empa caused 1.23 kg more body weight loss (P = 0.011) and improved glycemic control. Seated systolic blood pressure decreased with both treatments (P < 0.002). MSNA did not change significantly with either treatment; however, MSNA changes were negatively correlated with changes in body weight on Empa (P = 0.042) and on HCT(P = 0.001). The relationship was shifted to lower MSNA on Empa compared with HCT (P = 0.002). Conclusion: Increased renal sodium excretion eliciting body weight loss may promote sympathetic activation. However, sympathetic excitation in the face of increased sodium loss may be attenuated by SGLT2 inhibitor-specific actions.

Cerebral blood flow autoregulation assessment by correlation analysis between mean arterial blood pressure and transcranial doppler sonography or near infrared spectroscopy is different: A pilot study.

PURPOSE: Recently, cerebral autoregulation indices based on moving correlation indices between mean arterial pressure (MAP) and cerebral oximetry (NIRS, ORx) or transcranial Doppler (TCD)-derived middle cerebral artery flow velocity (Mx) have been introduced to clinical practice. In a pilot study, we aimed to evaluate the validity of these indices using incremental lower body negative pressure (LBNP) until presyncope representing beginning cerebral hypoperfusion as well as lower body positive pressure (LBPP) with added mild hypoxia to induce cerebral hyperperfusion in healthy subjects. METHODS: Five male subjects received continuous hemodynamic, TCD and NIRS monitoring. Decreasing levels of LBNP were applied in 5-minute steps until subjects reached presyncope. Increasing levels of LBPP were applied stepwise up to 20 or 25 mmHg. Normobaric hypoxia was added until an oxygen saturation of 84% was reached. This was continued for 10 minutes. ORx and Mx indices were calculated using previously described methods. RESULTS: Both Indices showed an increase > 0.3 indicating impaired cerebral autoregulation during presyncope. However, there was no significant difference in Mx at presyncope compared to baseline (p = 0.168). Mean arterial pressure and cardiac output decreased only in presyncope, while stroke volume was decreased at the last pressure level. Neither Mx nor ORx showed significant changes during LBPP or hypoxia. Agreement between Mx and ORx was poor during the LBNP and LBPP experiments (R2 = 0.001, p = 0.3339). CONCLUSION: Mx and ORx represent impaired cerebral autoregulation, but in Mx this may not be distinguished sufficiently from baseline. LBPP and hypoxia are insufficient to reach the upper limit of cerebral autoregulation as indicated by Mx and ORx.

Real-Time Magnetic Resonance Imaging to Study Orthostatic Intolerance Mechanisms in Human Beings: Proof of Concept.

Background Discerning the mechanisms driving orthostatic symptoms in human beings remains challenging. Therefore, we developed a novel approach combining cardiac and cerebral real-time magnetic resonance imaging, beat-to-beat physiological monitoring, and orthostatic stress testing through lower-body negative pressure (LBNP). We conducted a proof-of-concept study in a patient with severe orthostatic hypotension. Methods and Results We included a 46-year-old man with pure autonomic failure. Without and during -30 mmHg LBNP, we obtained 3T real-time magnetic resonance imaging of the cardiac short axis and quantitative flow measurements in the pulmonary trunk and middle cerebral artery. Blood pressure was 118/74 mmHg during supine rest and 58/35 mmHg with LBNP. With LBNP, left ventricular stroke volume decreased by 44.6%, absolute middle cerebral artery flow by 37.6%, and pulmonary trunk flow by 40%. Conclusions Combination of real-time magnetic resonance imaging, LBNP, and continuous blood pressure monitoring provides a promising new approach to study orthostatic intolerance mechanisms in human beings.

Effects of short-term hypercaloric nutrition on orthostatic tolerance in healthy individuals: a randomized controlled crossover study.

Reduced-caloric intake lowers blood pressure through sympathetic inhibition, and worsens orthostatic tolerance within days. Conversely, hypercaloric nutrition augments sympathetic activity and blood pressure. Because dietary interventions could be applied in patients with syncope, we tested the hypothesis that short-term hypercaloric dieting improves orthostatic tolerance. In a randomized crossover trial, 20 healthy individuals (7 women, 26.7 ± 8 years, 22.6 ± 2 kg/m2) followed a 4-day hypercaloric (25% increase of energy intake by fat) or normocaloric nutritional plan, with a washout period of at least 23 days between interventions. We then performed head-up tilt table testing with incremental lower body negative pressure while recording beat-by-beat blood pressure and heart rate. The primary endpoint was orthostatic tolerance defined as time to presyncope. Time to presyncope during combined head-up tilt and lower body negative pressure did not differ between hypercaloric and normocaloric dieting (median 23.19 versus 23.04 min, ratio of median 1.01, 95% CI of ratio 0.5-1.9). Heart rate, blood pressure, heart rate variability, and blood pressure variability in the supine position and during orthostatic testing did not differ between interventions. We conclude that 4 days of moderate hypercaloric nutrition does not significantly improve orthostatic tolerance in healthy individuals. Nevertheless, given the important interaction between energy balance and cardiovascular autonomic control in the brain, caloric intake deserves more attention as a potential contributor and treatment target for orthostatic intolerance.

Limited evidence for sympathetic neural overactivation in older patients with type 2 diabetes mellitus.

Introduction: Mechanistic studies suggested that excess sympathetic activity promotes arterial hypertension while worsening insulin sensitivity. Older patients with type 2 diabetes are at particularly high cardiovascular and metabolic risk. However, data on sympathetic activity in this population is scarce. Methods: We studied 61 patients with type 2 diabetes mellitus (22 women, 60.9 ± 1.4 years; 39 men, 60.9 ± 1.4 years). They had to have diabetes for at least 2 years, a hemoglobin A1c of 6.5-10%, a body-mass-index of 20-40 kg/m2, and had to be treated with stable doses of metformin only. We recorded ECG, finger and brachial blood pressure, and muscle sympathetic nerve activity (MSNA). Results: MSNA was 37.5 ± 2.5 bursts/min in women and 39.0 ± 2.0 bursts/min in men (p = 0.55). MSNA expressed as burst incidence was 52.7 ± 2.0 bursts/100 beats in women and 59.2 ± 3.1 bursts/100 beats in men (p = 0.21). Five out of 39 men (12.8%) and two out of 22 women (9.1%) exhibited resting MSNA measurements above the 95th percentile for sex and age. In the pooled analysis, MSNA was not significantly correlated with systolic blood pressure, diastolic blood pressure, body mass index, waist circumference, body composition, or HbA1c (r 2 < 0.02, p > 0.26 for all). Discussion: We conclude that relatively few older patients with type 2 diabetes mellitus exhibit increased MSNA. The large interindividual variability in MSNA cannot be explained by gender, blood pressure, body mass index, or glycemic control.

Endovascular baroreflex amplification and the effect on sympathetic nerve activity in patients with resistant hypertension: A proof-of-principle study.

BACKGROUND: First in human studies suggest that endovascular baroreflex amplification (EVBA) lowers blood pressure (BP). To explore potential mechanisms for BP reduction, this study examines the effects of EVBA on muscle sympathetic nerve activity (MSNA) and baroreceptor sensitivity (BRS). METHODS: In a single-center sub-study of the CALM-DIEM study (Controlling And Lowering blood pressure with the MobiusHD-Defining Efficacy Markers), 14 patients with resistant hypertension were treated with EVBA. Microneurography and non-invasive continuous BP measurements were performed at baseline and three months after MobiusHD implantation. The primary outcome was change in MSNA. Secondary outcomes were change in baroreflex sensitivity (BRS), cardiovascular responses to a sympathetic stimulus, BP, heart rate (HR) and heart rate variability (HRV). RESULTS: The primary endpoint was obtained in 10 of 14 patients enrolled in the sub-study. MSNA burst frequency and burst incidence decreased in 6 of 10 patients: mean change -4.1 bursts/min (95% confidence interval -12.2 to 4.0) and -3.8 bursts/100 heartbeats (-15.2 to 7.7). MSNA spike frequency and spike count decreased in 8 of 10 patients: mean change -2.8 spikes/sec (-7.3 to 1.8) and -3.0 spikes/heartbeat (-6.1 to 0.1). Change in MSNA and BP were not correlated. Office BP decreased by -14/-6 mmHg (-27 to -2/-15 to 3). We observed a trend towards decreased HR (-5 bpm, -10 to 1) and increased total power HRV (623 msec2, 78 to 1168). In contrast, BRS and cardiovascular responses remained unchanged after EVBA. CONCLUSIONS: In this proof-of-principle study, EVBA did not significantly decrease MSNA in patients with resistant hypertension. EVBA did not impair baroreflex function. TRIAL REGISTRATION: Clinical trial registration at NCT02827032.

Baroreflex Curve Fitting Using a WYSIWYG Boltzmann Sigmoidal Equation.

Arterial baroreflex assessment using vasoactive substances enables investigators to collect data pairs over a wide range of blood pressures and reflex reactions. These data pairs relate intervals between heartbeats or sympathetic neural activity to blood pressure values. In an X-Y plot the data points scatter around a sigmoidal curve. After fitting the parameters of a sigmoidal function to the data, the graph's characteristics represent a rather comprehensive quantitative reflex description. Variants of the 4-parameter Boltzmann sigmoidal equation are widely used for curve fitting. Unfortunately, their 'slope parameters' do not correspond to the graph's actual slope which complicates the analysis and bears the risk of misreporting. We propose a modified Boltzmann sigmoidal function with preserved goodness of fit whose parameters are one-to-one equivalent to the sigmoidal curve's characteristics.

Sympathetic vasoconstrictor activity before and after left ventricular assist device implantation in patients with end-stage heart failure.

AIMS: Sympathetic overactivity, which predicts poor outcome in patients with heart failure, normalizes following cardiac transplantation. We tested the hypothesis that haemodynamic improvement following left ventricular assist device (LVAD) implantation is also associated with reductions in centrally generated sympathetic activity. METHODS AND RESULTS: In eight patients with heart failure (two women, six men, age 44-66 years), we continuously recorded electrocardiogram, beat-to-beat finger blood pressure, respiration, and muscle sympathetic nerve activity (MSNA) before and after implantation of the continuous-flow LVAD devices HeartWare HVAD (n = 4) and HeartMate II (n = 2), and the non-continuous-flow device HeartMate 3 (n = 2). LVAD implantation increased cardiac output by 1.29 ± 0.88 L/min (P = 0.060) and mean arterial pressure by 16.2 ± 7.9 mmHg (P < 0.001), while reducing pulse pressure by 25.3 ± 9.8 mmHg (P < 0.001). LVAD implantation did not change MSNA burst frequency (-1.3 ± 7.5 bursts/min, P = 0.636), total activity (+0.62 ± 1.83 au, P = 0.369), or normalized activity (+0.63 ± 4.23, P = 0.685). MSNA burst incidence was decreased (-7.8 ± 9.3 bursts/100 heart beats, P = 0.049). However, cardiac ectopy altered MSNA bursting patterns that could be mistaken for sympatholysis. CONCLUSION: Implantation of current design LVAD does not consistently normalize sympathetic activity in patients with end-stage heart failure despite haemodynamic improvement.

Medullary and Hypothalamic Functional Magnetic Imaging During Acute Hypoxia in Tracing Human Peripheral Chemoreflex Responses.

[Figure: see text].

Deciphering the neural signature of human cardiovascular regulation.

Cardiovascular regulation is integral to life. Animal studies have identified both neural and endocrine pathways, by which the central nervous system adjusts cardiac output and peripheral vascular resistance to changing physiological demands. The outflow of these pathways is coordinated by various central nervous regions based on afferent information from baroreceptors, chemoreceptors, nociceptors, and circulating hormones, and is modulated by physiologic and behavioural state. In humans, however, knowledge on central cardiovascular regulation below the cortical level is scarce. Here, we show using functional MRI (fMRI) that at least three hypothalamic subsystems are involved in cardiovascular regulation in humans. The rhythmic behaviour of these systems corresponds to high and low frequency oscillations typically seen in blood pressure and heart rate variability.

Stand up too fast and you know what happens next. You will feel faint as the blood rushes away from your head. Gravity pulls the blood into your legs, and your blood pressure drops. To correct this imbalance, the brain sends nerve impulses telling the heart to beat faster and the outer blood vessels to tighten. This is the autonomic nervous system at work. It is how the brain adjusts cardiac output, and quietly controls other internal organs in the body. It involves two key regions of the brain, the hypothalamus and the brainstem, and stimulates smooth muscles and glands around the body. The cardiovascular system also responds to the demands of exercise, with the heart supplying fresh blood laden with oxygen and the blood clearing out waste materials as it flows around the body. Perhaps surprisingly, blood pressure and heart rate fluctuate even at rest. The heart beats faster when breathing in and slower when breathing out. People's blood pressure, the force that keeps blood moving through arteries, also oscillates in so-called Mayer waves that last about 10 seconds. Much of the current understanding of the inner workings of the cardiovascular system ­ and how it is regulated by the brain ­ stems from animal experiments. This is because few attempts have been made to simultaneously measure how a person's brain and cardiovascular system work with enough detail to see how brain waves and cardiac oscillations might interact. To achieve this, Manuel et al. have now measured the brain activity, pulse and blood pressure of twenty-two healthy people while they were lying down in an MRI machine. This revealed that three distinct parts of the hypothalamus regulate cardiovascular output in humans. These 'subsystems' communicate with each other and with the lower brainstem, which sits beneath the hypothalamus. Manuel et al. also observed that the rhythmic activity of these subsystems runs in sync with oscillations typically seen in heart rate and blood pressure. With this work, Manuel et al. have shown that it is feasible to measure different systems of cardiovascular control in humans. In time, with further experiments using this new approach, the understanding of chronic high blood pressure and heart failure may improve.

Testing individual baroreflex responses to hypoxia-induced peripheral chemoreflex stimulation.

INTRODUCTION: Baroreflexes and peripheral chemoreflexes control efferent autonomic activity making these reflexes treatment targets for arterial hypertension. The literature on their interaction is controversial, with suggestions that their individual and collective influence on blood pressure and heart rate regulation is variable. Therefore, we applied a study design that allows the elucidation of individual baroreflex-chemoreflex interactions. METHODS: We studied nine healthy young men who breathed either normal air (normoxia) or an air-nitrogen-carbon dioxide mixture with decreased oxygen content (hypoxia) for 90 min, with randomization to condition, followed by a 30-min recovery period and then exposure to the other condition for 90 min. Multiple intravenous phenylephrine bolus doses were applied per condition to determine phenylephrine pressor sensitivity as an estimate of baroreflex blood pressure buffering and cardiovagal baroreflex sensitivity (BRS). RESULTS: Hypoxia reduced arterial oxygen saturation from 98.1 ± 0.4 to 81.0 ± 0.4% (p < 0.001), raised heart rate from 62.9 ± 2.1 to 76.0 ± 3.6 bpm (p < 0.001), but did not change systolic blood pressure (p = 0.182). Of the nine subjects, six had significantly lower BRS in hypoxia (p < 0.05), two showed a significantly decreased pressor response, and three showed a significantly increased pressor response to phenylephrine in hypoxia, likely through reduced baroreflex buffering (p < 0.05). On average, hypoxia decreased BRS by 6.4 ± 0.9 ms/mmHg (19.9 ± 2.0 vs. 14.12 ± 1.6 ms/mmHg; p < 0.001) but did not change the phenylephrine pressor response (p = 0.878). CONCLUSION: We applied an approach to assess individual baroreflex-chemoreflex interactions in human subjects. A subgroup exhibited significant impairments in baroreflex blood pressure buffering and BRS with peripheral chemoreflex activation. The methodology may have utility in elucidating individual pathophysiology and in targeting treatments modulating baroreflex or chemoreflex function.

Efficacy of Electrical Baroreflex Activation Is Independent of Peripheral Chemoreceptor Modulation.

Arterial baroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of resistant hypertension. Previous studies suggested that the peripheral chemoreflex is tonically active in hypertensive patients and may inhibit baroreflex responses. We hypothesized that peripheral chemoreflex activation attenuates baroreflex efficacy evoked by electrical carotid sinus stimulation. We screened 35 patients with an implanted electrical carotid sinus stimulator. Of those, 11 patients with consistent acute depressor response were selected (7 men/4 women, age: 67±8 years, body mass index: 31.6±5.2 kg/m2, 6±2 antihypertensive drug classes). We assessed responses to electrical baroreflex stimulation during normoxia, isocapnic hypoxia (SpO2: 79.0±1.5%), and hyperoxia (40% end-tidal O2 fraction) by measuring heart rate, blood pressure, ventilation, oxygen saturation, end-tidal CO2 and O2 fractions, and muscle sympathetic nerve activity. During normoxia, baroreflex activation reduced systolic blood pressure from 164±27 to 151±25 mm Hg (mean±SD, P<0.001), heart rate from 64±13 to 61±13 bpm (P=0.002), and muscle sympathetic nerve activity from 42±12 to 36±12 bursts/min (P=0.004). Hypoxia increased systolic blood pressure 8±12 mm Hg (P=0.057), heart rate 10±6 bpm (P<0.001), muscle sympathetic nerve activity 7±7 bursts/min (P=0.031), and ventilation 10±7 L/min (P=0.002). However, responses to electrical carotid sinus stimulation did not differ between hypoxic and hyperoxic conditions: systolic blood pressure: -15±7 versus -14±8 mm Hg (P=0.938), heart rate: -2±3 versus -2±2 bpm (P=0.701), and muscle sympathetic nerve activity: -6±4 versus -4±3 bursts/min (P=0.531). We conclude that moderate peripheral chemoreflex activation does not attenuate acute responses to electrical baroreflex activation therapy in patients with resistant hypertension. These patients provided insight into human baroreflex-chemoreflex interactions that could not be gained otherwise.

Cardiac and Vascular Sympathetic Baroreflex Control during Orthostatic Pre-Syncope.

We hypothesized that sympathetic baroreflex mediated uncoupling between neural sympathetic discharge pattern and arterial pressure (AP) fluctuations at 0.1 Hz during baroreceptor unloading might promote orthostatic pre-syncope. Ten volunteers (32 ± 6 years) underwent electrocardiogram, beat-to-beat AP, respiratory activity and muscle sympathetic nerve activity (MSNA) recordings while supine (REST) and during 80° head-up tilt (HUT) followed by -10 mmHg stepwise increase of lower body negative pressure until pre-syncope. Cardiac and sympathetic baroreflex sensitivity were quantified. Spectrum analysis of systolic and diastolic AP (SAP and DAP) and calibrated MSNA (cMSNA) variability assessed the low frequency fluctuations (LF, ~0.1 Hz) of SAP, DAP and cMSNA variability. The squared coherence function (K2) quantified the coupling between cMSNA and DAP in the LF band. Analyses were performed while supine, during asymptomatic HUT (T1) and at pre-syncope onset (T2). During T2 we found that: (1) sympathetic baroreceptor modulation was virtually abolished compared to T1; (2) a progressive decrease in AP was accompanied by a persistent but chaotic sympathetic firing; (3) coupling between cMSNA and AP series at 0.1 Hz was reduced compared to T1. A negligible sympathetic baroreceptor modulation during pre-syncope might disrupt sympathetic discharge pattern impairing the capability of vessels to constrict and promote pre-syncope.

Effects of Prolonged Head-Down Bed Rest on Cardiac and Vascular Baroreceptor Modulation and Orthostatic Tolerance in Healthy Individuals.

Orthostatic intolerance commonly occurs after prolonged bed rest, thus increasing the risk of syncope and falls. Baroreflex-mediated adjustments of heart rate and sympathetic vasomotor activity (muscle sympathetic nerve activity - MSNA) are crucial for orthostatic tolerance. We hypothesized that prolonged bed rest deconditioning alters overall baroreceptor functioning, thereby reducing orthostatic tolerance in healthy volunteers. As part of the European Space Agency Medium-term Bed Rest protocol, 10 volunteers were studied before and after 21 days of -6° head down bed rest (HDBR). In both conditions, subjects underwent ECG, beat-by-beat blood pressure, respiratory activity, and MSNA recordings while supine (REST) and during a 15-min 80° head-up tilt (TILT) followed by a 3-min -10 mmHg stepwise increase of lower body negative pressure to pre-syncope. Cardiac baroreflex sensitivity (cBRS) was obtained in the time (sequence method) and frequency domain (spectrum and cross-spectrum analyses of RR interval and systolic arterial pressure - SAP, variability). Baroreceptor modulation of sympathetic discharge activity to the vessels (sBRS) was estimated by the slope of the regression line between the percentage of MSNA burst occurrence and diastolic arterial pressure. Orthostatic tolerance significantly decreased after HDBR (12 ± 0.6 min) compared to before (21 ± 0.6 min). While supine, heart rate, SAP, and cBRS were unchanged before and after HDBR, sBRS gain was slightly depressed after than before HDBR (sBRS: -6.0 ± 1.1 versus -2.9 ± 1.5 burst% × mmHg-1, respectively). During TILT, HR was higher after than before HDBR (116 ± 4 b/min versus 100 ± 4 b/min, respectively), SAP was unmodified in both conditions, and cBRS indexes were lower after HDBR (α index: 3.4 ± 0.7 ms/mmHg; BRSSEQ 4.0 ± 1.0) than before (α index: 6.4 ± 1.0 ms/mmHg; BRSSEQ 6.8 ± 1.2). sBRS gain was significantly more depressed after HDBR than before (sBRS: -2.3 ± 0.7 versus -4.4 ± 0.4 burst% × mmHg-1, respectively). Our findings suggest that baroreflex-mediated adjustments in heart rate and MSNA are impaired after prolonged bed rest. The mechanism likely contributes to the decrease in orthostatic tolerance.

What do we really know about supine hypertension in patients with orthostatic hypotension.

PURPOSE OF REVIEW: Patients with severe orthostatic hypotension due to autonomic failure may be hypertensive in the supine position. Until recently, there were no internationally recognized diagnostic criteria for supine hypertension. This review covers diagnostic criteria, mechanisms, and management of supine hypertension in autonomic failure patients. RECENT FINDINGS: Recently, an international consensus group defined supine hypertension in patients with neurogenic orthostatic hypotension as brachial SBP at least 140 mmHg and/or DBP at least 90 mmHg while supine. Using these criteria, a large proportion of patients with orthostatic hypotension is diagnosed with supine hypertension. Recent research supports the concept that the hypertension can be mediated through residual sympathetic nervous system function and independently from sympathetic activity, for example via mineralocorticoid receptor activation. SUMMARY: The clear definition of supine hypertension is an important step that will hopefully foster clinical research in this area. Supine hypertension promotes renal sodium excretion, thus, worsening orthostatic hypotension the next morning. Supine hypertension may promote cardiovascular and renal disease. Yet, long-term benefits of treating supine hypertension be it through non pharmacological or pharmacological means have not been proven by sufficiently large clinical trials.

Information-domain method for the quantification of the complexity of the sympathetic baroreflex regulation in healthy subjects and amyotrophic lateral sclerosis patients.

BACKGROUND: The sympathetic baroreflex (sBR) adjusts muscle sympathetic nerve activity (MSNA) in response to arterial pressure changes but the relevance of assessing sBR control complexity is unclear. OBJECTIVE: We propose a method for the evaluation of sBR control complexity. APPROACH: The approach comprises the quantification of complexity of the sBR latency regulation and the assessment of complexity of the relationship linking MSNA burst to R-wave peak regardless of the variability of the sBR latency. The Shannon entropy (SE) of the sBR latency distribution is taken as an estimate of complexity of the sBR latency regulation. The conditional entropy (CE) of the beat-to-beat binary series obtained by coding the presence/absence of the MSNA burst after an R-wave peak is taken as an estimate of complexity of the sBR control regardless of the sBR latency variability. Surrogate analysis was utilized to set the level of inactive or impaired sBR. The approach was applied to 10 young healthy subjects undergoing head-up tilt (HUT) followed by lower body negative pressure to evoke presyncope (preSYNC) before and after 21 d head-down bed rest (HDBR), and to five amyotrophic lateral sclerosis (ALS) patients undergoing HUT. MAIN RESULTS: In healthy subjects the surrogate analysis suggested that HUT and preSYNC significantly activated the sBR control but its response was weakened after 21 d HDBR. During preSYNC sBR latency increased significantly only after 21 d HDBR. In ALS patients the complexity of the sBR latency regulation was close to the level set by surrogate analysis and HUT did not trigger any sBR control response. SIGNIFICANCE: The proposed method for sBR control complexity quantification was useful in detecting the impairment of the sBR control after 21 d HDBR in healthy subjects and the dysfunction of the sBR regulation in ALS patients.