Search

The approach introduced by Network Physiology intends to find and quantify connectedness between close- and far related aspects of a person’s Physiome. In this study I applied a Network-inspired analysis to a set of measurement data that had been assembled to detect prospective orthostatic intolerant subjects among people who were destined to go into Space for a two weeks mission. The advantage of this approach being that it is essentially model-free: no complex physiological model is required to interpret the data. This type of analysis is essentially applicable to many datasets where individuals must be found that “stand out from the crowd”. The dataset consists of physiological variables measured in 22 participants (4f/18 m; 12 prospective astronauts/cosmonauts, 10 healthy controls), in supine, + 30° and + 70° upright tilted positions. Steady state values of finger blood pressure and derived thereof: mean arterial pressure, heart rate, stroke volume, cardiac output, systemic vascular resistance; middle cerebral artery blood flow velocity and end-tidal pCO2 in tilted position were (%)-normalized for each participant to the supine position. This yielded averaged responses for each variable, with statistical spread. All variables i.e., the “average person’s response” and a set of %-values defining each participant are presented as radar plots to make each ensemble transparent. Multivariate analysis for all values resulted in obvious dependencies and some unexpected ones. Most interesting is how individual participants maintained their blood pressure and brain blood flow. In fact, 13/22 participants had all normalized Δ-values (i.e., the deviation from the group average, normalized for the standard deviation), both for +30° and +70°, within the 95% range. The remaining group demonstrated miscellaneous response patterns, with one or more larger Δ-values, however of no consequence for orthostasis. The values from one prospective cosmonaut stood out as suspect. However, early morning standing blood pressure within 12 h after return to Earth (without volume repletion) demonstrated no syncope. This study demonstrates an integrative way to model-free assess a large dataset, applying multivariate analysis and common sense derived from textbook physiology.

BACKGROUND: Glomerular hyperfiltration resulting from an elevated intraglomerular pressure (Pglom) is an important cause of CKD, but there is no feasible method to directly assess Pglom in humans. We developed a model to estimate Pglom in patients from combined renal arterial pressure and flow measurements. METHODS: We performed hemodynamic measurements in 34 patients undergoing renal or cardiac angiography under baseline conditions and during hyperemia induced by intrarenal dopamine infusion (30 μg/kg). For each participant during baseline and hyperemia, we fitted an adapted three-element Windkessel model that consisted of characteristic impedance, compliance, afferent resistance, and Pglom. RESULTS: We successfully analyzed data from 28 (82%) patients. Median age was 58 years (IQR, 52–65), median eGFR was 95 ml/min per 1.73 m(2) (IQR, 74–100) using the CKD-EPI formula, 30% had microalbuminuria, and 32% had diabetes. The model showed a mean Pglom of 48.0 mm Hg (SD=10.1) at baseline. Under hyperemia, flow increased by 88% (95% CI, 68% to 111%). This resulted in a 165% (95% CI, 79% to 294%) increase in afferent compliance and a 13.1-mm Hg (95% CI, 10.0 to 16.3) decrease in Pglom. In multiple linear regression analysis, diabetes (coefficient, 10.1; 95% CI, 5.1 to 15.1), BMI (0.99 per kg/m(2); 95% CI, 0.38 to 1.59), and renal perfusion pressure (0.42 per mm Hg; 95% CI, 0.25 to 0.59) were significantly positively associated with baseline Pglom. CONCLUSIONS: We constructed a model on the basis of proximal renal arterial pressure and flow velocity measurements that provides an overall estimate of glomerular pressure and afferent and efferent resistance in humans. The model provides a novel research technique to evaluate the hemodynamics of CKD on the basis of direct pressure and flow measurements. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Functional HEmodynamics in patients with and without Renal Artery stenosis (HERA), NL40795.018.12 at the Dutch national trial registry (toetsingonline.nl).

Background: A recently discovered sudden cardiac arrest (SCA) syndrome is linked to a risk haplotype that harbors the dipeptidyl-peptidase 6 (DPP6) gene as a plausible culprit. Objective: Because DPP6 impacts both cardiomyocyte and neuronal function, we hypothesized that ventricular fibrillation (VF) in risk haplotype carriers arises from functional changes in both the heart and autonomic nervous system. Methods: We studied 6 risk haplotype carriers with previous VF (symptomatic), 8 carriers without VF (asymptomatic), and 7 noncarriers (controls). We analyzed supine and standing heart rate variability, baroreflex sensitivity, pre-VF heart rate changes, and myocardial 123I-meta-iodobenzylguanide (123I-mIBG) scintigraphy. Results: Carriers had longer interbeat intervals than controls (1.03 ± 0.11 seconds vs 0.81 ± 0.07 seconds; P

This paper reviews the many functions of the vagus nerve, to understand how they interact in daily life and what might be accomplished by therapeutical electrical stimulation. A short historical introduction on the discovery and name-giving of the cranial nerves numbers 9-12 is followed by an overview of the functions that are under lower brain stem control: heart (rate, contractility), intestine (swallowing, peristalsis and glands secretions, feeling of satiety), lungs (bronchoconstriction, lung-irritant and stretch receptor signaling), blood pressure (by vascular wall stress sensing) and blood gases by specialized receptors. Key in the review is the physiology behind beat-by-beat heart rate variations, how everyday life is reflected in its variability, from exciting moments to quiet sleep, with the 'common faint' or vasovagal collapse as extreme example. Next, the recently proposed role of the vagus nerve in limiting inflammation is discussed. This has led to adoption of an earlier developed technique for epilepsy treatment, i.e., electrical stimulation of one vagus nerve bundle in the neck, but now for immune diseases like rheumatoid arthritis and the scope is even widening to depression and cluster headache. However, the problem in application of whole vagus nerve stimulation is the lack of specificity: there is no way to titrate the stimulation to an observable effect variable. All nerves in the bundle, incoming and outgoing, can be 'hit', leading to side-effects which limit the intended application.

The results of many medical measurements are directly or indirectly influenced by the autonomic nervous system (ANS). For example pupil size or heart rate may demonstrate striking moment-to-moment variability. This review intends to elucidate the physiology behind this seemingly unpredictable system. The review is split up into: 1. The peripheral ANS, parallel innervation by the sympathetic and parasympathetic branches, their transmitters and co-transmitters. It treats questions like the supposed sympatho/vagal balance, organization in plexuses and the 'little brains' that are active like in the enteric system or around the heart. Part 2 treats ANS-function in some (example-) organs in more detail: the eye, the heart, blood vessels, lungs, respiration and cardiorespiratory coupling. Part 3 poses the question of who is directing what? Is the ANS a strictly top-down directed system or is its organization bottom-up? Finally, it is concluded that the 'noisy numbers' in medical measurements, caused by ANS variability, are part and parcel of how the system works. This topical review is a one-man's undertaking and may possibly give a biased view. The author has explicitly indicated in the text where his views are not (yet) supported by facts, hoping to provoke discussion and instigate new research.

Introduction Baroreflex sensitivity (BRS) is often presented as a single number, but it is actually a frequency-dependent phenomenon whose value changes constantly due to internal and external stimuli. The standing posture, for instance, necessitates a changeover from vagal to sympathetic predominance for cardiovascular control. We present a wavelet cross-spectral analysis of blood pressure (BP) and interbeat interval (IBI) recordings in the search for variations in gain and phase between these signals. Additionally, we show how the lag in sympathetic response dictates BP-to-IBI phase relations. Methods Recordings in supine and head-up tilted (HUT) position, obtained earlier in 10 healthy subjects (4f/6m, aged 27-47 years) were used. BP and IBI were measured from the continuous finger pressure (by Finometer). The cross-wavelet analysis produced time- and frequency dependent gain (wBRS, wavelet derived BRS) and phase, using the MATLAB® wavelet toolbox. We also applied the wBRS method to model-generated BP- and IBI-data with known interrelations to test the results of this analysis technique. Finally, wBRS values were compared with the xBRS-approach, which is a time domain method for continuous BRS estimation in a sliding 10-s window. Results In resting supine conditions, wBRS fluctuates; more at respiratory frequencies than in the 0.1 Hz band. After HUT, wBRS at the respiratory frequency decreases from average 22.7 to 8.5 ms/mmHg, phase between BP and IBI increases from -30° to -54°; in the sympathetic 0.1 Hz range these numbers are 13.3→6.3 ms/mmHg and -54°→-59°. The values found by xBRS are intermediate between wBRS-resp and wBRS-0.1 Hz. The Appendix shows that for the simulated data the BRS and phase values as found by the wavelet technique can be explained from vector additions of vagal and sympathetic BRS contributions. Discussion During supine rest parasympathetic control of heart rate dominates BRS; after HUT this is diminished and less effective. Due to the reaction times of the autonomic effectors, the phase relations between the signals depend on the relative contribution of the sympathetics, which explains the larger phase shift. Conclusion Cross wavelet analysis allows to follow fast BRS changes in time and frequency, while the computed phase relations help understand sympathetic participation.

karel hendrik wesseling ([Fig. 1][1]), emeritus professor of biomedical instrumentation, was born in The Hague, The Netherlands, on April 23, 1935. He studied electrical engineering, in his words, from 1950 on, and since 1953 at the Delft University of Technology (DUT) from which he graduated with

Spontaneous oscillations of blood pressure (BP) and interbeat interval (IBI) may reveal important information on the underlying baroreflex control and regulation of BP. We evaluated the method of continuously measured instantaneous baroreflex sensitivity by cross correlation (xBRS) validating its mean value against the gold standard of phenylephrine (Phe) and nitroprusside (SNP) bolus injections, and focusing on its spontaneous changes quantified as variability around the mean. For this purpose, we analyzed data from an earlier study of eight healthy males (aged 25–46 years) who had received Phe and SNP in conditions of baseline and autonomic blocking agents: atropine, propranolol, and clonidine. Average xBRS corresponds well to Phe/SNP‐BRS, with xBRS levels ranging from 1.2 (atropine) to 102 msec/mmHg (subject asleep under clonidine). Time shifts from BP‐ to IBI‐signal increased from ≤1 sec (maximum correlations within the current heartbeat) to 3–5 sec (under atropine). Plotted on a logarithmic vertical scale, xBRS values show 40% variability (defined as SD/mean) over the whole range in the various conditions, except twice when the subjects had fallen asleep and it dropped to 20%. The xBRS oscillates at frequencies of 0.1 Hz and lower, dominant between 0.02–0.05 Hz. Although xBRS is the result of IBI/BP‐changes, no linear coherence was found in the cross‐spectra of the xBRS‐signal and IBI or BP. We speculate that the level of variability in the xBRS‐signal may act as a probe into the central nervous condition, as evidenced in the two subjects who fell asleep with high xBRS and only 20% of relative variation.

Standing up elicits a host of cardiovascular changes which all affect the cerebral circulation. Lowered mean arterial blood pressure (ABP) at brain level, change in the cerebral venous outflow path, lowered end‐tidal PCO 2 (PETCO 2), and intracranial pressure (ICP) modify cerebral blood flow (CBF). The question we undertook to answer is whether gravity‐induced blood pressure (BP) changes are compensated in CBF with the same dynamics as are spontaneous or induced ABP changes in a stable position. Twenty‐two healthy subjects (18/4 m/f, 40 ± 8 years) were subjected to 30° and 70° head‐up tilt (HUT) and sinusoidal tilts (SinTilt, 0°↨60° around 30° at 2.5–10 tilts/min). Additionally, at those three tilt levels, they performed paced breathing at 6–15 breaths/min to induce larger than spontaneous cardiovascular oscillations. We measured continuous finger BP and cerebral blood flow velocity (CBFv) in the middle cerebral artery by transcranial Doppler to compute transfer functions (TFs) from ABP‐ to CBFv oscillations. SinTilt induces the largest ABP oscillations at brain level with CBFv gains strikingly lower than for paced breathing or spontaneous variations. This would imply better autoregulation for dynamic gravitational changes. We demonstrate in a mathematical model that this difference is explained by ICP changes due to movement of cerebrospinal fluid (CSF) into and out of the spinal dural sack. Dynamic cerebrovascular autoregulation seems insensitive to how BP oscillations originate if the effect of ICP is factored in. CSF‐movement in‐and‐out of the spinal dural space contributes importantly to orthostatic tolerance by its effect on cerebral perfusion pressure.

Objectives: Early-life adversity has been shown to be associated with cardiovascular disease and mortality in later life, but little is known about the mechanisms that underlie this association. Prenatal undernutrition, a severe early-life stressor, is associated with double the risk of coronary heart disease and increased blood pressure responses to psychological stress. In the present study, we tested the hypothesis that prenatal undernutrition induces alterations in the autonomic nervous system, which may increase the risk of developing heart disease.Methods: We studied autonomic function in 740 men and women (mean [SD] age, 58 [0.9] years) who were members of the Dutch famine birth cohort. We compared those exposed to famine during early (n = 64), mid (n = 107), or late gestation (n = 127) to those unexposed to famine in utero (n = 442). Participants underwent a series of 3 psychological stressors (Stroop, mirror tracing, and speech) while their blood pressure and heart rate were recorded continuously.Results: Data had sufficient quality in 602 participants for derivation of autonomic function indices by spectral analysis. The stress protocol led to significant sample-level changes in systolic blood pressure, heart rate, and all cardiovascular control measures (all p values < .001). None of the autonomic function parameters, at rest or in response to stress, differed significantly (all p values > .050) according to prenatal famine exposure.Conclusions: Prenatal undernutrition was not associated with autonomic function in late adulthood. We conclude that altered autonomic function does not seem to explain our previous findings of increased coronary heart disease risk among those exposed to famine prenatally.

Objective During hypotension induced by tilt-table testing, low presyncopal blood pressure (BP) usually recovers within 1 min after tilt back. However, in some patients prolonged post faint hypotension (PPFH) is observed. We assessed the hemodynamics underlying PPFH in a retrospective study. Methods Seven patients (2 females, aged 31–72 years) experiencing PPFH were studied. PPFH was defined as a systolic BP below 85 mmHg for at least 2 min after tilt back. In 6 out of 7 presyncope was provoked by 0.4 mg sublingual NTG, administered in the 60° head-up tilt position following head-up tilt for 20 min. Continuous BP was monitored and stroke volume (SV) was computed from pressure pulsations. Cardiac output (CO) was calculated from SV × heart rate (HR); and total peripheral resistance (TPR) from mean BP/CO. Left ventricular contractility was estimated by dP/dtmax of finger pressure pulse. Results Systolic BP (SYS), diastolic BP (DIAS) and HR during PPFH were lower compared to baseline: SYS 75 ± 14 versus 121 ± 18 mmHg, DIAS 49 ± 9 versus 71 ± 9 mmHg and HR 52 ± 14 versus 67 ± 12 beats/min (p

Reconstruction of central aortic pressure from a peripheral measurement by a generalized transfer function (genTF) works well at rest and mild exercise at lower heart rates, but becomes less accurate during heavy exercise. Particularly, systolic and pulse pressure estimations deteriorate, thereby underestimating central pressure. We tested individualization of the TF (indTF) by adapting its resonance frequency at the various levels of exercise. In seven males (age 44-57) with coronary artery disease, central and peripheral pressures were measured simultaneously. The optimal resonance frequency was predicted from regression formulas using variables derived from the individual's peripheral pressure pulse, including a pulse contour estimation of cardiac output (pcCO). In addition, reconstructed pressures were calibrated to central mean and diastolic pressure at each exercise level. Using a genTF and without calibration, the error in estimated aortic pulse pressure was -7.5 ± 6.4 mmHg, which was reduced to 0.2 ± 5.7 mmHg with the indTFs using pcCO for prediction. Calibration resulted in less scatter at the cost of a small bias (2.7 mmHg). In exercise, the indTFs predict systolic and pulse pressure better than the genTF. This pilot study shows that it is possible to individualize the peripheral to aortic pressure transfer function, thereby improving accuracy in central blood pressure assessment during exercise.

Acute psychological stress challenges the cardiovascular system with an increase in BP (blood pressure), HR (heart rate) and reduced BRS (baroreflex sensitivity). β-adrenergic blockade enhances BRS during rest, but its effect on BRS during acute psychological stress is unknown. This study tested the hypothesis that BRS is higher during acute psychological stress in healthy subjects under β-adrenergic blockade. Twenty healthy novice male bungee jumpers were randomized and studied with (PROP, n=10) or without (CTRL, n=10) propranolol. BP and HR responses and BRS [cross-correlation time-domain (BRSTD) and cross-spectral frequency-domain (BRSFD) analysis] were evaluated from 30 min prior up to 2 h after the jump. HR, cardiac output and pulse pressure were lower in the PROP group throughout the study. Prior to the bungee jump, BRS was higher in the PROP group compared with the CTRL group [BRSTD: 28 (24–42) compared with 17 (16–28) ms·mmHg−1, P

A severe variant of vasovagal syncope, observed during tilt tests and blood donation has recently been termed "prolonged post-faint hypotension" (PPFH). A 49-year-old male with a life-long history of severe fainting attacks underwent head-up tilt for 20 min, and developed syncope 2 min after nitroglycerine spray. He was unconscious for 40 s and asystolic for 22 s. For the first 2 min of recovery, BP and HR remained low (65/45 mmHg and 40 beats/min) despite passive leg-raising. Blood pressure (and symptoms) only improved following active bilateral leg flexion and extension ("dynamic tension"). During PPFH, when vagal activity is extreme, patients may require central stimulation as well as correction of venous return.

Purpose To test the hypothesis that the sensitivity of near-infrared spectroscopy (NIRS) in reflecting the degree of (compensated) hypovolemia would be affected by the application site and probing depth. We simultaneously applied multi-site (thenar and forearm) and multi-depth (15–2.5 and 25–2.5 mm probe distance) NIRS in a model of simulated hypovolemia: lower body negative pressure (LBNP). Methods The study group comprised 24 healthy male volunteers who were subjected to an LBNP protocol in which a baseline period of 30 min was followed by a step-wise manipulation of negative pressure in the following steps: 0, −20, −40, −60, −80 and −100 mmHg. Stroke volume and heart rate were measured using volume-clamp finger plethysmography. Two multi-depth NIRS devices were used to measure tissue oxygen saturation (StO2) and tissue hemoglobin index (THI) continuously in the thenar and the forearm. To monitor the shift of blood volume towards the lower extremities, calf THI was measured by single-depth NIRS. Results The main findings were that the application of LBNP resulted in a significant reduction in stroke volume which was accompanied by a reduction in forearm StO2 and THI. Conclusions NIRS can be used to detect changes in StO2 and THI consequent upon central hypovolemia. Forearm NIRS measurements reflect hypovolemia more sensitively than thenar NIRS measurements. The sensitivity of these NIRS measurements does not depend on NIRS probing depth. The LBNP-induced shift in blood volume is reflected by a decreased THI in the forearm and an increased THI in the calf. Electronic supplementary material The online version of this article (doi:10.1007/s00134-010-2128-6) contains supplementary material, which is available to authorized users.

Di Rienzo M, Castiglioni P, Iellamo F, Volterrani M, Pagani M, Mancia G, Karemaker JM, Parati G. Dynamic adaptation of cardiac baroreflex sensitivity to prolonged exposure to microgravity: data from a 16-day spaceflight. J Appl Physiol 105: 1569-1575, 2008. First published August 28, 2008; doi:10.1152/japplphysiol.90625.2008.-This study explored the process of arterial baroreflex adaptation to microgravity, starting from the first day of flight, during the 16-day STS-107 Columbia Space Shuttle mission. Continuous blood pressure (BP), ECG, and respiratory frequency were collected in four astronauts on ground (baseline) and during flight at days 0-1, 6-7, and 12-13, both at rest and during moderate exercise (75 W) on a cycle ergometer. Sensitivity of the baroreflex heart rate control (BRS) was assessed by sequence and spectral alpha methods. Baroreflex effectiveness index (BEI); low-frequency (LF) power and high-frequency (HF) power of systolic BP (SBP), diastolic BP (DBP), and R-R interval (RRI); the RRI LF/HF ratio; and the RRI root mean square of successive differences (RMSSD) index were also estimated. We found that, at rest, BRS increased in early flight phase, compared with baseline (means +/- SE: 18.3 +/- 3.4 vs. 10.4 +/- 1.2 ms/mmHg; P

Postural stress requires immediate autonomic nervous action to maintain blood pressure. We determined time-domain cardiac baroreflex sensitivity (BRS) and time delay (tau) between systolic blood pressure and interbeat interval variations during stepwise changes in the angle of vertical body axis (alpha). The assumption was that with increasing postural stress, BRS becomes attenuated, accompanied by a shift in tau toward higher values. In 10 healthy young volunteers, alpha included 20 degrees head-down tilt (-20 degrees), supine (0 degree), 30 and 70 degrees head-up tilt (30 degrees, 70 degrees), and free standing (90 degrees). Noninvasive blood pressures were analyzed over 6-min periods before and after each change in alpha. The BRS was determined by frequency-domain analysis and with xBRS, a cross-correlation time-domain method. On average, between 28 (-20 degrees) to 45 (90 degrees) xBRS estimates per minute became available. Following a change in alpha, xBRS reached a different mean level in the first minute in 78% of the cases and in 93% after 6 min. With increasing alpha, BRS decreased: BRS = -10.1.sin(alpha) + 18.7 (r(2) = 0.99) with tight correlation between xBRS and cross-spectral gain (r(2) approximately 0.97). Delay tau shifted toward higher values. In conclusion, in healthy subjects the sensitivity of the cardiac baroreflex obtained from time domain decreases linearly with sin(alpha), and the start of baroreflex adaptation to a physiological perturbation like postural stress occurs rapidly. The decreases of BRS and reduction of short tau may be the result of reduced vagal activity with increasing alpha.

Noninvasive finger blood pressure has become a surrogate for central blood pressure under widely varying circumstances. We tested the validity of finger-aorta transfer functions (TF) to reconstruct aortic pressure in seven cardiac patients before, during, and after incremental bicycle exercise. The autoregressive exogenous model method was used for calculating finger-aorta TFs. Finger pressure was measured noninvasively using Finapres and aortic pressure using a catheter-tip manometer. When applying the individual TFs found during rest for reconstruction of aortic pressure during all workloads, systolic pressure was increasingly underestimated, with large variation between subjects: +4.0 to −18.1 mmHg. In most subjects, diastolic pressure was overestimated: −3.9 to +5.5 mmHg. Pulse pressure estimation varied between +4.5 and −21.9 mmHg. In all cases, wave distortion was present. Postexercise, error in reconstructed aortic systolic pressure slowly declined, and diastolic pressure was overestimated. During rest, the TF gain had a minimum between 3.65 and 4.85 Hz (Fmin). During exercise, Fmin shifted to frequencies between 4.95 and 7.15 Hz at the maximum workload, with no change in gain. Postexercise, gain in most subjects shifted to values closer to unity, whereas Fmin did not return to resting values. Within each subject, aorta-Finapres travel time was linearly related to mean pressure. During exercise, Fmin was linearly related to both delay and heart rate. We conclude that, during increasing exercise, rest TFs give an increasingly unreliable reconstruction of aortic pressure, especially at higher heart rates.

A dip in blood pressure (BP) in response to head-up tilt (HUT) or active standing might be due to rapid pooling in the veins below the heart (preload) or muscle activation-induced drop in systemic vascular resistance (afterload). We hypothesized that, in the cardiovascular response to passive HUT, where, in contrast to active standing, little BP dip is observed, features affecting the preload play a key role. We developed a baroreflex model combined with a lumped-parameter model of the circulation, including viscoelastic stress-relaxation of the systemic veins. Cardiac contraction is modeled using the varying-elastance concept. Gravity affects not only the systemic, but also the pulmonary, circulation. In accordance with the experimental results, model simulations do not show a BP dip on HUT; the tilt-back response is also realistic. If it is assumed that venous capacities are steady-state values, the introduction of stress-relaxation initially reduces venous pooling. The resulting time course of venous pooling is comparable to measured impedance changes. When venous pressure-volume dynamics are neglected, rapid (completed within 30 s) venous pooling leads to a drop in BP. The direct effect of gravity on the pulmonary circulation influences the BP response in the first ∼5 s after HUT and tilt back. In conclusion, the initial BP response to HUT is mainly determined by the response of the venous system. The time course of lower body pooling is essential in understanding the response to passive HUT.

Background— In patients with a malignant hypertension, immediate parenteral treatment with blood pressure–lowering agents such as intravenous sodium nitroprusside (SNP) is indicated. In this study, we evaluated static and dynamic cerebral autoregulation (CA) during acute blood pressure lowering with SNP in these patients. Methods and Results— In 8 patients with mean arterial pressure (MAP) >140 mm Hg and grade III or IV hypertensive retinopathy at hospital admission, middle cerebral artery blood velocity (MCA V) and blood pressure were monitored. Dynamic CA was expressed as the 0.1-Hz MCA V mean to MAP phase lead and static CA as the MCA V mean to MAP relationship during SNP treatment. Eight normotensive subjects served as a reference group. In the patients, the MCA V mean to MAP phase lead was lower (30±8° versus 58±5°, mean±SEM; P mean decrease was 22±4%, along with a 27±3% reduction in MAP (from 166±4 to 121±6 mm Hg; P −1 · % mm Hg −1 ; r =0.70±0.07). Conclusions— In patients with malignant hypertension, dynamic CA is impaired. An MCA V mean plateau was not detected during the whole SNP treatment, indicating loss of static CA as well. This study showed that during the whole rapid reduction in blood pressure with SNP, MCA V mean decreases almost one on one with MAP.

Internal jugular veins are the major cerebral venous outflow pathway in supine humans. In upright humans the positioning of these veins above heart level causes them to collapse. An alternative cerebral outflow pathway is the vertebral venous plexus. We set out to determine the effect of posture and central venous pressure (CVP) on the distribution of cerebral outflow over the internal jugular veins and the vertebral plexus, using a mathematical model. Input to the model was a data set of beat-to-beat cerebral blood flow velocity and CVP measurements in 10 healthy subjects, during baseline rest and a Valsalva manoeuvre in the supine and standing position. The model, consisting of 2 jugular veins, each a chain of 10 units containing nonlinear resistances and capacitors, and a vertebral plexus containing a resistance, showed blood flow mainly through the internal jugular veins in the supine position, but mainly through the vertebral plexus in the upright position. A Valsalva manoeuvre while standing completely re-opened the jugular veins. Results of ultrasound imaging of the right internal jugular vein cross-sectional area at the level of the laryngeal prominence in six healthy subjects, before and during a Valsalva manoeuvre in both body positions, correlate highly with model simulation of the jugular cross-sectional area (R(2) = 0.97). The results suggest that the cerebral venous flow distribution depends on posture and CVP: in supine humans the internal jugular veins are the primary pathway. The internal jugular veins are collapsed in the standing position and blood is shunted to an alternative venous pathway, but a marked increase in CVP while standing completely re-opens the jugular veins.

In man assuming the upright position, end-tidal PCO2 (PETCO2) decreases. With the rising interest in cerebral autoregulation during posture change, which is known to be affected by PETCO2, we sought to determine the factors leading to hypocapnia during standing up from the supine position. To study the contribution of an increase in tidal volume (VT) and breathing frequency, a decrease in stroke volume (SV), a ventilation–perfusion (V/Q) gradient and an increase in functional residual capacity (FRC) to hypocapnia in the standing position, we developed a mathematical model of the lung to follow breath-to-breath variations in PETCO2. A gravity-induced apical-to-basal V/Q gradient in the lung was modelled using nine lung segments. We tested the model using an eight-subject data set with measurements of VT, pulmonary O2 uptake and breath-to-breath lumped SV. On average, the PETCO2 decreased from 40 mmHg to 36 mmHg after 150 s standing. Results show that the model is able to track breath-to-breath PETCO2 variations (r2= 0.74, P < 0.05). Model parameter sensitivity analysis demonstrates that the decrease in PETCO2 during standing is due primarily to increased VT, and transiently to decreased SV and increased FRC; a slight gravity-induced V/Q mismatch also contributes to the hypocapnia. The influence of cardiac output on hypocapnia in the standing position was verified in experiments on human subjects, where first breathing alone, and then breathing, FRC and V/Q were controlled.

OBJECTIVES - We set out to determine the effect of sublingual nitroglycerin (NTG), as used during routine tilt testing in patients with unexplained syncope, on hemodynamic characteristics and baroreflex control of heart rate (HR) and systemic vascular resistance (SVR). BACKGROUND Nitroglycerin is used in tilt testing to elicit a vasovagal response. It is known to induce venous dilation and enhance pooling. Also, NTG is lipophilic and readily passes cell membranes, and animal studies suggest a sympatho-inhibitory effect of NTG on circulatory control. METHODS Routine tilt testing was conducted in 39 patients with suspected vasovagal syncope (age 36 16 years, 18 females). Patients were otherwise healthy and free of medication. Before a loss of consciousness set in, oncoming syncope was cut short by tilt-back or counter-maneuvers. Finger arterial pressure was monitored continuously (Finapres). Left ventricular stroke volume (SV) was computed from the pressure pulsations (Modelflow). Spontaneous baroreflex control of HR was estimated in the time and frequency domains. RESULTS During tilt testing, 22 patients developed presyncope. After NTG administration but before presyncope, SV and cardiac output (CO) decreased (p

Background and aim Analysis of heart rate variability (HRV) has recently become the playing field of mathematicians and physicists, losing its relation to physiology and the clinic. To set the record straight, a set of animal experiments is presented here, which was designed to test how vagus nerve traffic might produce beat to beat (b-t-b) heart rate (HR) control, like the baroreflex will do in vivo. Methods The response of HR to vagus nerve stimulation was tested after bilateral vagotomy in rabbits under anesthesia. Three protocols were followed: 1. Single burst stimulation at varying moments in one cardiac cycle; 2. B-t-b stimulation in each cycle, coupled to the P-wave with variable delays; in addition, testing the effects of one increased or decreased burst; 3. Tetanic stimulation, shortly interrupted or increased at varying moments in the cardiac cycle. Results and conclusions Sensitivity of the sinoatrial node to the timing of vagal bursts in its cycle from protocol 1 explains most of the observations. A single burst would be most effective when applied in late repolarization or early diastole of the sinoatrial node's action potential. In b-t-b stimulation the longest cardiac cycles occur when bursts are timed just before the end of the 'sensitive period'. Later coming bursts have their (diminished) effect on the next cycle; critically timed bursts induce an unstable HR, alternating between long and short cycles. This ran in synchrony with the respirator, thus producing a large respiratory sinus arrhythmia, even though the vagus nerves had been cut. HR-response to vagal burst activity shows two components: a fast one which is phase-sensitive and a slow one that builds up with longer lasting activity and also disappears slowly. Tetanic stimulation results in prolonged, but variable cycle lengths which are difficult to change by short-lasting manipulation of impulse frequency, be it up or down. Relevance for patients Measurement of heart rate variability (HRV) and baroreflex sensitivity (BRS) have become clinical tools in the cardiology clinic and in hypertension research. This study shows how the underlying vagus nerve to heart rate physiology is responsible for moment-to-moment variability in these numbers at almost unchanged underlying physiology. Programmed stimulation of the vagus nerves in acute animals (rabbits) demonstrates that the optimal mode of fast, beat-to-beat heart rate control by these nerves is by means of bursts of impulses arriving in every heart beat at well-timed moments. In vivo this is how the baroreflex stabilizes blood pressure at the expense of HRV.

Background — After experimental carotid sinus denervation in animals, blood pressure (BP) level and variability increase markedly but normalize to preoperative levels within 10 to 14 days. We investigated the course of arterial BP level and variability after bilateral denervation of the carotid sinus baroreceptors in humans. Methods and Results — We studied 4 women (age 41 to 63 years) who were referred for evaluation of arterial baroreflex function because of clinical suspicion of carotid sinus denervation attributable to bilateral carotid body tumor resection. The course of BP level and variability was assessed from repeated office and 24-hour ambulatory measurements (Spacelabs/Portapres) during 1 to 10 years of (retrospective) follow-up. Rapid cardiovascular reflex adjustments to active standing and Valsalva’s maneuver were assessed. Office BP level increased from 132/86 mm Hg (range, 118 to 148/80 to 92 mm Hg) before bilateral surgery to 160/105 mm Hg (range, 143 to 194/90 to 116 mm Hg) 1 to 10 years after surgery. During continuous 24-hour noninvasive BP recording (Portapres), a marked BP variability was apparent in all 4 patients. Initial symptomatic hypotension on change to the upright posture and abnormal responses to Valsalva’s maneuver were observed. Conclusions — Acute carotid sinus denervation, as a result of bilateral carotid body tumor resection, has a long-term effect on the level, variability, and rapid reflex control of arterial BP. Therefore, in contrast to earlier experimental observations, the compensatory ability of the baroreceptor areas outside the carotid sinus seems to be of limited importance in the regulation of BP in humans.

We tested the reliability of noninvasive cardiac output (CO) measurement in different body positions by pulse contour analysis (COpc) by using a transmission line model (K. H. Wesseling, B. De Wit, J. A. P. Weber, and N. T. Smith. Adv. Cardiol. Phys.5, Suppl. II: 16–52, 1983). Acetylene rebreathing (COrebr) was used as a reference method. Twelve subjects (age 21–34 yr) were studied: 1) six in whom COrebr and COpc were measured in the standing and 6° head-down tilt (HDT) postures and 2) six in whom CO was measured in the 30° HDT, supine, 30° head up-tilt (HUT), and 70° HUT postures on a tilt table. The COrebr-to-COpcratio in (near) the supine position during rebreathing was used as the calibration factor for COpcmeasurements. Calibrated COpc(COcal sup) consistently overestimated CO in the upright posture. The drop in CO with upright posture was underestimated by ∼50%. COcal sup and COrebr values did not differ in the 30° HDT position. Changes in the COrebr-to-COpcratio are highly variable among subjects in response to a change in posture. Therefore, COpc must be recalibrated for each subject in each posture.

Cardiovascular reflex tests remain the investigational cornerstone for the assessment of patients in the clinical autonomic laboratory. Three cardiovagal tests have been found suitable for testing: the instantaneous heart rate responses induced by deep breathing, Valsalva's manoeuvre and standing up. Suitable laboratory indices of adrenergic function include continuous monitoring of blood pressure responses induced by Valsalva's manoeuvre and standing up, which is now possible through tracking of beat-to-beat blood pressure changes at the finger. Spectral analysis of heart rate and blood pressure and pulse wave analysis for stroke volume changes are promising approaches to evaluate abnormalities in arterial baroreflex regulatory mechanisms in diabetic patients

Head-down tilted bedrest is a ground-based microgravity simulation model. Since in this position the influence of chief external determinants of circadian blood pressure variation, i.e. activity and posture, are reduced, it may reveal endogenous oscillatory factors. The effects of 42 days of 6 degrees head-down tilt on the circadian profiles of continuous finger blood pressure, heart rate, stroke volume, cardiac output and total peripheral resistance were analysed. In seven healthy volunteers (25-31 years) twelve 22 h Portapres registrations were performed: two in an ambulatory baseline period, eight during 42 days of head-down tilt, and two during recovery. Stroke volume was estimated by a pulse contour method ('Modelflow') from the finger arterial blood pressure tracing. Head-down tilt rapidly reduced circadian BP variation, especially for diastolic blood pressure. No effect of long-term head-down tilt on blood pressure level was observed. The day-night difference in heart rate was essentially unaffected. Cardiac output was maintained through an increase of heart rate and simultaneous decline of stroke volume. Our observations confirm the overriding importance of physical activity and orthostatic load on the diurnal variation of BP. The time-frame of the changes in stroke volume and heart rate during head-down tilt might point to a contribution of other factors besides a reduction of circulating blood volume affecting cardiovascular performance under these conditions.

The delay τ between rising systolic blood pressure (SBP) and baroreflex bradycardia has been found to increase when vagal tone is low. The α2-agonist clonidine increases cardiac vagal tone, and this study tested how it affects τ. In eight conscious supine human volunteers clonidine (6 μg/kg po) reduced τ, assessed both by cross correlation baroreflex sensitivity and sequence methods (both P < 0.05). Experiments on urethane-anaesthetized rats reproduced the phenomenon and investigated the underlying mechanism. Heart rate (HR) responses to increasing SBP produced with an arterial balloon catheter showed reduced τ ( P < 0.05) after clonidine (100 μg/kg iv). The central latency of the reflex was unaltered, however, as shown by the unchanged timing with which antidromically identified cardiac vagal motoneurons (CVM) responded to the arterial pulse. Testing the latency of the HR response to brief electrical stimuli to the right vagus showed that this was also unchanged by clonidine. Nevertheless, vagal stimuli delivered at a fixed time in the cardiac cycle (triggered from the ECG R-wave) slowed HR with a 1-beat delay in the baseline state but a 0-beat delay after clonidine ( n = 5, P < 0.05). This was because clonidine lengthened the diastolic period, allowing the vagal volleys to arrive at the heart just in time to postpone the next beat. Calculations indicate that naturally generated CVM volleys in both humans and rats arrive around this critical time. Clonidine thus reduces τ not by changing central or efferent latencies but simply by slowing the heart.

The enhanced heart rate and blood pressure soon after awaking increases cardiac oxygen demand, and has been associated with the high incidence of acute myocardial infarction in the morning. The behavior of cardiac oxygen supply is unknown. We hypothesized that oxygen supply decreases in the morning and to that purpose investigated cardiac oxygen demand and oxygen supply at night and after awaking. We compared hypertensive to normotensive subjects and furthermore assessed whether pressures measured non-invasively and intra-arterially give similar results. Aortic pressure was reconstructed from 24-h intra-brachial and simultaneously obtained non-invasive finger pressure in 14 hypertensives and 8 normotensives. Supply was assessed by Diastolic Time Fraction (DTF, ratio of diastolic and heart period), demand by Rate-Pressure Product (RPP, systolic pressure times heart rate, HR) and supply/demand ratio by A(dia)/A(sys), with A(dia) and A(sys) diastolic and systolic areas under the aortic pressure curve. Hypertensives had lower supply by DTF and higher demand by RPP than normotensives during the night. DTF decreased and RPP increased in both groups after awaking. The DTF of hypertensives decreased less becoming similar to the DTF of normotensives in the morning; the RPP remained higher. A(dia)/A(sys) followed the pattern of DTF. Findings from invasively and non-invasively determined pressure were similar. The cardiac oxygen supply/demand ratio in hypertensive patients is lower than in normotensives at night. With a smaller night-day differences, the hypertensives' risk for cardiovascular events may be more evenly spread over the 24 h. This information can be obtained noninvasively.

Summary Analysis of beat-to-beat fluctuations of heart rate and blood pressure is a promising new approach to the clinical diagnosis and management of alterations in cardiovascular regulation. We investigated the effects of three induction agents on beat-to-beat heart rate and blood pressure fluctuations in man. Beat-to-beat fluctuations were analysed by spectral analysis. Two spectral areas are of main interest. One area is centred on the respiratory frequency and shifts with changes in respiratory rate (High Frequency area). These high frequency flucuations in heart rate are caused by respiratory-induced blood pressure fluctuations, mediated by the vagus nerve through the baroreflex mechanism. Variability in the Low Frequency area, which occurs between 0.06 and 0.12 Hz is considered to be related to haemodynamic fluctuations due to the sympathetic baroreflex control loop of vasomotor activity and heart rate. Results from our study indicate that thiopentone, etomidate and propofol show considerable differences in their effects on beat-to-beat variability of heart rate and blood pressure. These differences can be explained by their specific effects on the cardiovascular system.

OBJECTIVE--To determine the long term effects of relaxation therapy on 24 hour ambulatory intra-arterial blood pressure in patients with mild untreated and uncomplicated hypertension. DESIGN--Four week screening period followed by randomisation to receive either relaxation therapy or non-specific counselling for one year. Ambulatory intra-arterial blood pressure was measured before and after treatment. SETTING--Outpatient clinic in Amsterdam's university hospital. SUBJECTS--35 Subjects aged 20-60 who were being treated by general practitioners for hypertension but were referred to take part in the study. At three consecutive screening visits all subjects had a diastolic blood pressure without treatment of 95-110 mm Hg. Subjects were excluded if they had damaged target organs, secondary hypertension, diabetes mellitus, a cholesterol concentration greater than 8 mmol/l, or a history of malignant hypertension. INTERVENTIONS--The group allocated to relaxation therapy was trained for eight weeks (one hour a week) in muscle relaxation, yoga exercises, and stress management and continued exercising twice daily for one year with monthly visits to the clinic. The control group had the same attendance schedule but had no training and were requested just to sit and relax twice a day. All subjects were asked not to change their diet or physical activity. MAIN OUTCOME MEASURE--Changes in ambulatory intra-arterial blood pressure after one year of relaxation therapy or non-specific counselling. RESULTS--Mean urinary sodium excretion, serum concentration of cholesterol, and body weight did not change in either group. Diastolic pressures measured by sphygmomanometry were 2 and 3 mm Hg lower in subjects in the relaxation group and control group respectively at the one year follow up compared with initial readings. The mean diastolic ambulatory intra-arterial pressure during the daytime had not changed after one year in either group, but small treatment effects could not be excluded: the mean change for the relaxation group was -1 mm Hg (95% confidence interval -6 to 3.9 mm Hg) and for the control group -0.4 mm Hg (-5.3 to 4.6 mm Hg). Mean ambulatory pressure in the evening also had not changed over the year, and in both groups nighttime pressure was 5 mm Hg higher. The variability in blood pressure was the same at both measurements. CONCLUSIONS--Relaxation therapy was an ineffective method of lowering 24 hour blood pressure, being no more beneficial than non-specific advice, support, and reassurance--themselves ineffective as a treatment for hypertension.

Wave reflections affect the proximal aortic pressure and flow waves and play a role in systolic hypertension. A measure of wave reflection, receiving much attention, is the augmentation index (AI), the ratio of the secondary rise in pressure and pulse pressure. AI can be limiting, because it depends not only on the magnitude of wave reflection but also on wave shapes and timing of incident and reflected waves. More accurate measures are obtainable after separation of pressure in its forward (P f ) and reflected (P b ) components. However, this calculation requires measurement of aortic flow. We explore the possibility of replacing the unknown flow by a triangular wave, with duration equal to ejection time, and peak flow at the inflection point of pressure (F tIP ) and, for a second analysis, at 30% of ejection time (F t30 ). Wave form analysis gave forward and backward pressure waves. Reflection magnitude (RM) and reflection index (RI) were defined as RM=P b /P f and RI=P b /(P f +P b ), respectively. Healthy subjects, including interventions such as exercise and Valsalva maneuvers, and patients with ischemic heart disease and failure were analyzed. RMs and RIs using F tIP and F t30 were compared with those using measured flow (F m ). Pressure and flow were recorded with high fidelity pressure and velocity sensors. Relations are: RM tIP =0.82RM mf +0.06 ( R 2 =0.79; n=24), RM t30 =0.79RM mf +0.08 ( R 2 =0.85; n=29) and RI tIP =0.89RI mf +0.02 ( R 2 =0.81; n=24), RI t30 =0.83RI mf +0.05 ( R 2 =0.88; n=29). We suggest that wave reflection can be derived from uncalibrated aortic pressure alone, even when no clear inflection point is distinguishable and AI cannot be obtained. Epidemiological studies should establish its clinical value.

Background and Purpose— We addressed whether dynamic cerebral autoregulation (dCA) is affected in middle cerebral artery (MCA) territory (MCAS) and lacunar ischemic stroke (LS). Methods— Blood pressure (MAP) and MCA velocity (V) were measured in 10 patients with large MCAS (National Institutes of Health Stroke score, 17±2; mean±SEM), in 10 with LS (score, 9±1), and in 10 reference subjects. dCA was evaluated in time (delay of the MCA V mean counter-regulation during changes in MAP) and frequency domains (cross-spectral MCA V mean -to-MAP phase lead). Results— In reference subjects, latencies for MAP increments (5.3±0.5 seconds) and decrements (5.6±0.5 seconds) were comparable, and low frequency MCA V mean -to-MAP phase lead was 56±5 and 59±5° (left and right hemisphere). In MCAS, these latencies were 4.6±0.7 and 5.6±0.5 seconds in the nonischemic hemisphere and not detectable in the ischemic hemisphere. In the unaffected hemisphere, phase lead was 61±6° versus 26±6° on the ischemic side ( P Conclusions— In large MCAS infarcts, dynamic cerebral autoregulation was impaired in the affected hemisphere. In LS, dynamic cerebral autoregulation was impaired bilaterally, a finding consistent with the hypothesis of bilateral small vessel disease in patients with lacunar infarcts.

Reduction in plasma volume is a major contributor to orthostatic tachycardia and hypotension after spaceflight. We set out to determine time- and frequency-domain baroreflex (BRS) function during preflight baseline and venous occlusion and postflight orthostatic stress, testing the hypothesis that a reduction in central blood volume could mimic the postflight orthostatic response. In five cosmonauts, we measured finger arterial pressure noninvasively in supine and upright positions. Preflight measurements were repeated using venous occlusion thigh cuffs to impede venous return and “trap” an increased blood volume in the lower extremities; postflight sessions were between 1 and 3 days after return from 10- to 11-day spaceflight. BRS was determined by spectral analysis and by PRVXBRS, a time-domain BRS computation method. Although all completed the stand tests, two of five cosmonauts had drastically reduced pulse pressures and an increase in heart rate of ∼30 beats/min or more during standing after spaceflight. Averaged for all five subjects in standing position, high-frequency interbeat interval spectral power or transfer gain did not decrease postflight. Low-frequency gain decreased from 8.1 (SD 4.0) preflight baseline to 6.8 (SD 3.4) postflight ( P = 0.033); preflight with thigh cuffs inflated, low-frequency gain was 9.4 (SD 4.3) ms/mmHg. There was a shift in time-domain-determined pulse interval-to-pressure lag, Tau, toward higher values ( P < 0.001). None of the postflight results were mimicked during preflight venous occlusion. In conclusion, two of five cosmonauts showed abnormal orthostatic response 1 and 2 days after spaceflight. Overall, there were indications of increased sympathetic response to standing, even though we can expect (partial) restoration of plasma volume to have taken place. Preflight venous occlusion did not mimic the postflight orthostatic response.

Contains fulltext : 59280.pdf (Publisher’s version ) (Open Access) The direct vasodilatory and negative chronotropic effects of adenosine in humans are counterbalanced by a reflex increase in sympathetic nerve traffic. A suggested mechanism for this reflex includes peripheral chemoreceptor activation. We, therefore, assessed the contribution of carotid chemoreceptors to sympatho-excitation by adenosine. Muscle sympathetic nerve activity was recorded during adenosine infusion (140 microg.kg(-1).min(-1) for 5 min) in five patients lacking carotid chemoreceptors after bilateral carotid body tumour resection (one male and four female, mean age 51 +/- 11 years) and in six healthy controls (two male and four female, mean age 50 +/- 7 years). Sympathetic responses to sodium nitroprusside injections were assessed to measure baroreceptor-mediated sympathetic activation. In response to adenosine, controls showed no change in blood pressure, an increase in heart rate (+48.2 +/- 13.2%; P

In man assuming the upright position, end-tidal P(CO(2)) (P(ETCO(2))) decreases. With the rising interest in cerebral autoregulation during posture change, which is known to be affected by P(ETCO(2)), we sought to determine the factors leading to hypocapnia during standing up from the supine position. To study the contribution of an increase in tidal volume (V(T)) and breathing frequency, a decrease in stroke volume (SV), a ventilation-perfusion (V/Q) gradient and an increase in functional residual capacity (FRC) to hypocapnia in the standing position, we developed a mathematical model of the lung to follow breath-to-breath variations in P(ETCO(2)). A gravity-induced apical-to-basal V/Q gradient in the lung was modelled using nine lung segments. We tested the model using an eight-subject data set with measurements of V(T), pulmonary O(2) uptake and breath-to-breath lumped SV. On average, the P(ETCO(2)) decreased from 40 mmHg to 36 mmHg after 150 s standing. Results show that the model is able to track breath-to-breath P(ETCO(2)) variations (r(2)= 0.74, P P 0.05). Model parameter sensitivity analysis demonstrates that the decrease in P(ETCO(2)) during standing is due primarily to increased V(T), and transiently to decreased SV and increased FRC; a slight gravity-induced V/Q mismatch also contributes to the hypocapnia. The influence of cardiac output on hypocapnia in the standing position was verified in experiments on human subjects, where first breathing alone, and then breathing, FRC and V/Q were controlled.

During standing, both the position of the cerebral circulation and the reductions in mean arterial pressure (MAP) and cardiac output challenge cerebral autoregulatory (CA) mechanisms. Syncope is most often associated with the upright position and can be provoked by any condition that jeopardizes cerebral blood flow (CBF) and regional cerebral tissue oxygenation (cO2Hb). Reflex (vasovagal) responses, cardiac arrhythmias, and autonomic failure are common causes. An important defense against a critical reduction in the central blood volume is that of muscle activity (“the muscle pump”), and if it is not applied even normal humans faint. Continuous tracking of CBF by transcranial Doppler-determined cerebral blood velocity ( Vmean) and near-infrared spectroscopy-determined cO2Hb contribute to understanding the cerebrovascular adjustments to postural stress; e.g., MAP does not necessarily reflect the cerebrovascular phenomena associated with (pre)syncope. CA may be interpreted as a frequency-dependent phenomenon with attenuated transfer of oscillations in MAP to Vmeanat low frequencies. The clinical implication is that CA does not respond to rapid changes in MAP; e.g., there is a transient fall in Vmeanon standing up and therefore a feeling of lightheadedness that even healthy humans sometimes experience. In subjects with recurrent vasovagal syncope, dynamic CA seems not different from that of healthy controls even during the last minutes before the syncope. Redistribution of cardiac output may affect cerebral perfusion by increased cerebral vascular resistance, supporting the view that cerebral perfusion depends on arterial inflow pressure provided that there is a sufficient cardiac output.

Item does not contain fulltext Experimental denervation in animals has shown that carotid baro- and chemoreceptors play an eminent role in maintaining blood pressure and blood gas homeostasis. Denervation of carotid sinus baro- and chemoreceptors in humans may occur as a complication of invasive interventions on the neck or after experimental surgical treatment in asthma. In this topical review, the short- and long-term effects of carotid baro- and chemoreceptor denervation on the control of circulation and ventilation in humans are discussed. Carotid baroreceptor denervation in humans causes a persistent decrease in vagal and sympathetic baroreflex sensitivity and an increase in blood pressure variability; however, carotid denervation does not lead to chronic hypertension. Therefore, although carotid baroreceptors contribute to short-term blood pressure control, other receptors are able to maintain normal chronic blood pressure levels in the absence of carotid baroreceptors. Conversely, carotid chemoreceptor denervation leads to permanent abolition of normocapnic ventilatory responses to hypoxia and reduced ventilatory responses to hypercapnia.

Bilateral carotid body tumor resection causes a permanent attenuation of vagal baroreflex sensitivity. We retrospectively examined the effects of bilateral carotid body tumor resection on the baroreflex control of sympathetic nerve traffic. Muscle sympathetic nerve activity was recorded in 5 patients after bilateral carotid body tumor resection (1 man and 4 women, 51±11 years) and 6 healthy control subjects (2 men and 4 women, 50±7 years). Baroreflex sensitivity was calculated from changes in R-R interval and muscle sympathetic nerve activity in response to bolus injections of phenylephrine and nitroprusside. In addition, sympathetic responses to the Valsalva maneuver and cold pressor test were measured. The integrated neurogram of patients and control subjects contained a similar pattern of pulse synchronous burst of nerve activity. Baroreflex control of both heart rate and sympathetic nerve activity were attenuated in patients as compared with control subjects [heart rate baroreflex sensitivity: 3.68±0.93 versus 11.61±4.72 ms/mm Hg (phenylephrine, P =0.011) and 2.53±1.36 versus 5.82±1.94 ms/mm Hg (nitroprusside, P =0.05); sympathetic baroreflex sensitivity: 3.70±2.90 versus 7.53±4.12 activity/100 beats/mm Hg (phenylephrine, P =0.10) and 3.93±4.43 versus 15.27±10.03 activity/100 beats/mm Hg (nitroprusside, P =0.028)]. The Valsalva maneuver elicited normal reflex changes in muscle sympathetic nerve activity, whereas heart rate responses were blunted in the patients with bilateral carotid body tumor resection. Maximal sympathetic responses to the cold pressor test did not differ between the two groups. Denervation of carotid sinus baroreceptors as the result of bilateral carotid body tumor resection produces chronic impairment of baroreflex control of both heart rate and sympathetic nerve activity. During the Valsalva maneuver, loss of carotid baroreflex control of heart rate is less well compensated for by the extra carotid baroreceptors than the control of muscle sympathetic nerve activity.

Orthostatic intolerance is common when astronauts return to Earth: after brief spaceflight, up to two-thirds are unable to remain standing for 10 min. Previous research suggests that susceptible individuals are unable to increase their systemic vascular resistance and plasma noradrenaline concentrations above pre-flight upright levels. In this study, we tested the hypothesis that adaptation to the microgravity of space impairs sympathetic neural responses to upright posture on Earth. We studied six astronauts ∼72 and 23 days before and on landing day after the 16 day Neurolab space shuttle mission. We measured heart rate, arterial pressure and cardiac output, and calculated stroke volume and total peripheral resistance, during supine rest and 10 min of 60 deg upright tilt. Muscle sympathetic nerve activity was recorded in five subjects, as a direct measure of sympathetic nervous system responses. As in previous studies, mean (± s.e.m.) stroke volume was lower (46 ± 5 vs. 76 ± 3 ml, P = 0.017) and heart rate was higher (93 ± 1 vs. 74 ± 4 beats min−1, P = 0.002) during tilt after spaceflight than before spaceflight. Total peripheral resistance during tilt post flight was higher in some, but not all astronauts (1674 ± 256 vs. 1372 ± 62 dynes s cm−5, P = 0.32). No crew member exhibited orthostatic hypotension or presyncopal symptoms during the 10 min of postflight tilting. Muscle sympathetic nerve activity was higher post flight in all subjects, in supine (27 ± 4 vs. 17 ± 2 bursts min−1, P = 0.04) and tilted (46 ± 4 vs. 38 ± 3 bursts min−1, P = 0.01) positions. A strong (r2 = 0.91–1.00) linear correlation between left ventricular stroke volume and muscle sympathetic nerve activity suggested that sympathetic responses were appropriate for the haemodynamic challenge of upright tilt and were unaffected by spaceflight. We conclude that after 16 days of spaceflight, muscle sympathetic nerve responses to upright tilt are normal.

In healthy humans blood pressure and heart periods fluctuate at respiratory and other frequencies. The extent of these fluctuations is situation and age dependent. Although literature concurs that most of these fluctuations are reflex driven, some insist on an exemption for the respiratory

Blood pressure (BP) and heart rate (HR) are continually varying. The nervous mechanisms behind this variability have been studied extensively in non-human animal models (for reviews, see Eckberg & Sleight, 1992). Since the 1980s, the combined availability of non-invasive blood pressure measurement by the Penaz-Wesseling Finapres, and more and more powerful computers in the laboratory, have revived research into prevalence and physiological meaning of this variability in humans. When Fourier analysis was applied to analysis of BP variability (BPV) and HR variability (HRV), two frequency peaks stood out: one around the respiratory frequency and one around 0.1 Hz, or one oscillation in 10 s. These frequencies had been observed in blood pressure recordings before, actually over 130 years ago: Traube-Hering waves (coupled to respiration) and Mayer waves, the 0.1 Hz and slower oscillations. In the earlier research it had been established that oscillating sympathetic activity causes the Mayer waves in blood pressure. The respiration-coupled blood pressure oscillations were partly explained by mechanical effects of respiration and possibly by the vagally induced heart period oscillations coupled to respiration, known as respiratory sinus arrhythmia (RSA) (Eckberg & Sleight, 1992). Due to the easy availability of ECG recordings, heart rate oscillations have extensively been studied, much more so than blood pressure oscillations. In this field of research the idea was put forward that the 0.1 Hz oscillation in HRV, also called low frequency or LF, might be used as indicator of sympathetic activity. The respiratory (high frequency or HF) frequency in HR must be due to vagal activity, the vagus nerve being the only one that can make HRV follow at the respiratory rate; atropine also completely blocks RSA. It was but one step to suggest that the relative amounts of LF and HF HRV gave an impression of the balance between sympathetic and parasympathetic (vagal) outflow to the heart. Indeed, on many occasions where one would expect the balance to shift either way, the LF/HF ratio shifted similarly, even though it is common knowledge that atropine not only blocks HF but most of LF as well, demonstrating that both peaks in HRV are due to (mainly) vagal activity. A review of this theory and the arguments is given by Camm et al. (1996). This leaves a discrepancy: why would the LF/HF HRV ratio have a relation to the sympathetic/vagal outflow at all? The answer lies in the baroreflex: LF HRV is riding on a blood pressure oscillation. That, too, explains the phase relationship: blood pressure is leading the HR wave. The basis of this particular oscillation is, still, an unsettled matter. In this issue of The Journal of Physiology, Cooke et al. (1999) have very carefully investigated the prevalence of LF oscillations in healthy test humans who were subjected to graded passive orthostatic tilt on a tilt table. Efferent sympathetic activity, measured directly from the peroneal nerve, increased in proportion to the orthostatic load. However, in spite of large changes in baroreceptor loading and accompanying nerve traffic, the frequency of the LF band did not change at all. In the view of the authors, this pleads against the current theory for the origin of LF: up until now, many shared the view that this oscillation found its origin in the slowness of the baroreflex feedback to changes in peripheral resistance (resonance theory). This was supported by computer simulations of the cardiovascular control system and by other supporting evidence (DeBoer et al. 1987). Cooke et al. (1999) are inclined to put the origin of LF oscillations in some pacemaker, possibly in the CNS, rather than in the baroreflex. A comparable, unsettled matter is the origin of RSA. One explanation has been to see it as a baroreflex phenomenon: BP changing mechanically by the respiratory act, and HR following at the speed of vagal control, within the same beat (DeBoer et al. 1987). Another explanation would place the origin of RSA in the CNS, where co-activity of the vagus nerve with respiratory activity would drive HR in the same frequency as respiration (Taylor & Eckberg, 1996). Careful analysis of the phase relationships between respiratory oscillations in HR and BP should give the answer: is HR leading, or is BP?Cooke et al. (1999) have dealt with this issue as well: their analysis yields a phase advance for HR compared with BP changes. A comparable phase advance had been found earlier, by slightly different (Fourier) analysis methods (DeBoer et al. 1987). However, this had led those authors to give the advantage to BP, favouring the baroreflex hypothesis. The basic problem here is how one turns essentially discontinuous signals (systolic pressure values, heart period durations) into continuous ones that are input into the Fourier analysis. This calls for a meta-analysis of methods and results, rather than more experiments. The study by Cooke et al. (1999) has been one of the most carefully executed experimental studies in literature to date, so the final answer should be at hand. Where does this leave the LF/HF ratio as a measure for sympatho-vagal balance? From the Cooke et al. (1999) paper we learn how LF BP increases at increasing orthostatic stress. At the same time respiration-related vagal activity decreases, resulting in less HF HRV and almost unchanged LF HRV. The net effect is that LF/HF HRV, indeed, would shift as predicted. But then, so what? One may wonder if we should put much more effort in to what is clearly an epiphenomenon of basic processes in central cardiovascular control. The paper by Cooke et al. (1999) has probably not put an end to LF/HF HRV computations, but sends a clear warning sign to all who take its physiology seriously.