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Purpose: Exercise testing is often used to assess cardiac function during physical exertion to obtain diagnostic information. However, this procedure is limited to measuring the electrical activity of the heart using electrocardiography and intermittent blood pressure (BP) measurements and does not involve the continuous assessment of heart functioning. In this study, we compared continuous beat-to-beat pulse contour analysis to monitor noninvasive cardiac output (CO) during exercise with inert gas rebreathing and respired gas analysis.Methods: Nineteen healthy male volunteers were subjected to bicycle ergometry testing with increasing workloads. Cardiac output was deter- mined noninvasively by continuous beat-to-beat pulse contour analysis (Nexfin) and by inert gas rebreathing, and estimated using the respired gas analysis method. The effects of the rebreathing maneuver on heart rate (HR), stroke volume (SV), and CO were evaluated.Results: The CO values derived from the Nexfin- and inert gas rebreathing methods were well correlated (r = 0.88, P < 0.01) and the limits of agreement were 30.3% with a measurement bias of 0.4 ± 1.8 L/min. Nexfin- and respired gas analysis-derived CO values correlated even better (r = 0.94, P < 0.01) and the limits of agreement were 21.5% with a measurement bias of -0.70 ± 1.6 L/min. At rest, the rebreathing maneuver increased HR by 13 beats/min (P < 0.01), SV remained unaffected (P = 0.7), while CO increased by 1.0 L/min (P < 0.01). Rebreathing did not affect these parameters during exercise.Conclusions: Nexfin continuous beat-to-beat pulse contour analysis is an appropriate method for noninvasive assessment of CO during exercise. [ABSTRACT FROM AUTHOR]

Sympathovagal balance is important in the pathogenesis of hypertension and independently associated with mortality. We evaluated the value of automated analysis of cross-correlation baroreflex sensitivity (xBRS) and heart rate variability (HRV) and its relationship with clinical covariates in 13,326 participants from the multi-ethnic HELIUS study. Finger blood pressure (BP) was continuously recorded, from which xBRS, standard deviation of normal-to-normal intervals (SDNN), and squared root of mean squared successive difference between normal-to-normal intervals (RMSDD) were determined. A subset of 3356 recordings > 300 s was used to derive the minimally required duration by comparing shortened to complete recordings, defined as intraclass correlation (ICC) > 0.90. For xBRS and SDNN, 120 s and 180 s were required (ICC 0.93); for RMSDD, 60 s (ICC 0.94) was sufficient. We included 10,252 participants (median age 46 years, 54% women) with a recording > 180 s for the regression. xBRS, SDNN, and RMSDD decreased linearly up to 50 years of age. For xBRS, there was a signification interaction with sex, with for every 10 years a decrease of 4.3 ms/mmHg (95%CI 4.0-4.6) for men and 5.9 ms/mmHg (95%CI 5.6-6.1) for women. Using splines, we observed sex-dependent nonlinearities in the relation with BP, waist-to-hip-ratio, and body mass index. Future studies can help unravel the dynamics of these relations and assess their predictive value. Panel 1 depicts automatic analysis and filtering of finger BP recordings, panel 2 depicts computation of xBRS from interpolated beat to beat data of systolic BP and interbeat interval, and (IBI) SDNN and RMSDD are computed directly from the filtered IBI dataset. Panel 3 depicts the results of large-scale analysis and relation of xBRS with age, sex, blood pressure and body mass index., (© 2023. The Author(s).)

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., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Karemaker.)

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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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 123 I-meta-iodobenzylguanide ( 123 I-mIBG) scintigraphy., Results: Carriers had longer interbeat intervals than controls (1.03 ± 0.11 seconds vs 0.81 ± 0.07 seconds; P <.001), lower low-frequency (LF) and higher high-frequency (HF) activity, and lower LF/HF ratio (0.68 ± 0.50 vs 2.11 ± 1.10; P = .013) in the supine position. Upon standing up, carriers had significantly larger decrease in interbeat interval and increase in LF than controls (standing-to-supine ratio: 0.78 ± 0.07 vs 0.90 ± 0.07; P = .002; and 1.94 ± 1.03 vs 1.17 ± 0.34; P = .022, respectively), and nonsignificantly larger decrease in HF (0.62 ± 0.36 vs 0.97 ± 0.42; P = .065) and increase in LF/HF ratio (5.55 ± 6.79 vs 1.62 ± 1.24; P = .054). Sixteen of 17 VF episodes occurred at rest. Heart rate immediately before VF was 110 ± 25 bpm. Symptomatic carriers had less heterogeneous 123 I-mIBG distribution in the left ventricle than asymptomatic carriers (single-photon emission computed tomography score ≥3 in 7 asymptomatic and 1 symptomatic carrier; P = .008)., Conclusion: It can be speculated that these data are consistent with more labile autonomic tone in carriers, suggesting that the primary abnormalities may reside in both the heart and the autonomic nervous system., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The heart may be a mirror of the soul, but the human mind is more than its heart rate variability (HRV). Many techniques to quantify HRV promise to give a view of what is going on in the body or even the psyche of the subject under study. This "Hypothesis" paper gives, on the one hand, a critical view on the field of HRV-analysis and, on the other hand, points out a possible direction of future applications. In view of the inherent variability of HRV and the underlying processes, as lined out here, the best use may be found in serial analysis in a subject/patient, to find changes over time that may help in early discovery of developing pathology. Not every future possibility is bright and shining, though, as demonstrated in a fictional diary excerpt from a future subject, living in a society geared toward preventive medicine. Here implanted biochips watch over the health of the population and artificial intelligence (AI) analyses the massive data flow to support the diagnostic process., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Karemaker.)

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 μ g/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)., (Copyright © 2020 by the American Society of Nephrology.)

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.

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 P CO 2 (P ET CO 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., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

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., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

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.

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., Competing Interests: The authors declare no conflicts of interest;

Background: Heart rate variability (HRV) is a validated method to establish autonomic nervous system (ANS) activity. Rheumatoid arthritis (RA) is accompanied by ANS imbalance. We hypothesized that ANS dysfunction may precede the development of RA, which would suggest that it plays a role in its etiopathogenesis., Methods: First, we assessed HRV parameters in supine (resting) and upright (active) position in healthy subjects (HS, n=20), individuals at risk of developing arthritis (AR subjects, n=50) and RA patients (RA, n=20). Next, we measured resting heart rate (RHR), a parasympathetic HRV parameter, in an independent prospective cohort of AR subjects (n=45). We also evaluated expression levels of the parasympathetic nicotinic acetylcholine receptor type 7 (α7nAChR) on circulating monocytes., Findings: Both AR subjects (68 beats per minute (bpm), interquartile range (IQR) 68-73) and RA patients (68bpm, IQR 62-76) had a significantly higher RHR compared to HS (60bpm, IQR 56-63). RHR was significantly higher at baseline in individuals who subsequently developed arthritis. Expression levels of α7nAChR were lower in AR subjects with RHR ≥70bpm compared to those with RHR <70bpm, consistent with reduced activity of the parasympathetic cholinergic anti-inflammatory pathway., Interpretation: These data support the notion that autonomic dysfunction precedes the development of RA., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The author has no relevant disclosures to make. The experiments have been carried out in the former Dept. of Physiology at the Medical Faculty of the University of Amsterdam, where he worked as associate professor of Physiology.

Aims: Since many type 2 diabetes patients experience postprandial hypotension, the aim of this study was to unravel meal-related changes in systemic hemodynamics and autonomic nervous system (ANS)-balance., Methods: Forty-two age-matched males (15 type 2 diabetes; 12 metabolic syndrome; 15 controls) without overt autonomic neuropathy received a standardized high-fat mixed meal after an overnight fast. Hemodynamic variables were measured by finger plethysmography. Fourier analysis was used to calculate the low-/high-frequency (LF/HF)-ratio, a marker of autonomic nervous system-balance, and baroreceptor reflex sensitivity (BRS)., Results: Following the meal, diastolic blood pressure (DBP) decreased in type 2 diabetes patients only, paralleled by a significant decrement in systemic vascular resistance (SVR) and an increase in cardiac index. All groups showed an increase in postprandial heart rate. Controls, but not metabolic syndrome or type 2 diabetes patients, showed a meal-related increase in LF/HF-ratio. When combining all study subjects, homeostatic model assessment-insulin resistance (HOMA-IR) was inversely correlated with changes in DBP, SVR, LF/HF-ratio and BRS., Conclusions: Based on these data, we hypothesize that in patients with uncomplicated type 2 diabetes, insulin resistance hampers adequate meal-induced sympathetic activation, leading to a decrease in SVR and resulting in a postprandial drop in DBP., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: A sympathetic shift in heart rate variability (HRV) from high to lower frequencies may be an early signal of deterioration in a monitored patient. Most chronic heart failure (CHF) patients receive β-blockers. This tends to obscure HRV observation by increasing the fast variations. We tested which HRV parameters would still detect the change into a sympathetic state., Methods and Results: β-blocker (Carvedilol®) treated CHF patients underwent a protocol of 10 min supine rest, followed by 10 min active standing. CHF patients (NYHA Class II-IV) n = 15, 10m/5f, mean age 58.4 years (47-72); healthy controls n = 29, 18m/11f, mean age 62.9 years (49-78). Interbeat intervals (IBI) were extracted from the finger blood pressure wave (Nexfin®). Both linear and non-linear HRV analyses were applied that (1) might be able to differentiate patients from healthy controls under resting conditions and (2) detect the change into a sympathetic state in the present short recordings. Linear: mean-IBI, SD-IBI, root mean square of successive differences (rMSSD), pIBI-50 (the proportion of intervals that differs by more than 50 ms from the previous), LF, HF, and LF/HF ratio. Non-linear: Sample entropy (SampEn), Multiscale entropy (MSE), and derived: Multiscale variance (MSV) and Multiscale rMSSD (MSD). In the supine resting situation patients differed from controls by having higher HF and, consequently, lower LF/HF. In addition their longer range (τ = 6-10) MSE was lower as well. The sympathetic shift was, in controls, detected by mean-IBI, rMSSD, pIBI-50, and LF/HF, all going down; in CHF by mean-IBI, rMSSD, pIBI-50, and MSD (τ = 6-10) going down. MSD6-10 introduced here works as a band-pass filter favoring frequencies from 0.02 to 0.1 Hz., Conclusions: In β-blocker treated CHF patients, traditional time domain analysis (mean-IBI, rMSSD, pIBI-50) and MSD6-10 provide the most useful information to detect a condition change.

Aim: Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system., Design and Methods: A randomized, placebo-controlled, double-blind, dose-response intervention study was conducted in 32 healthy males (age: 21±2years; BMI: 21.9±1.7kg/m(2)). Participants were allocated to prednisolone 7.5mg once daily (n=12), prednisolone 30mg once daily (n=12), or placebo (n=8) for two weeks. Beta-cell function was measured by hyperglycemic clamp with arginine stimulation, glucagon levels were measured following a standardized meal test., Results: We found that prednisolone treatment dose-dependently reduced C-peptide secretion following arginine stimulation on top of hyperglycemia (ASI-iAUCCP): -2.8 (-5.2;0.2) and -3.1 (-8.8; -1.0) nmolL(-1)min(-1) for prednisolone 7.5mg and prednisolone 30mg, respectively (P=0.035 vs. placebo). Fasting glucagon levels increased dose-dependently (vs. placebo; P=0.001), whereas postprandial glucagon levels were only increased by prednisolone 30mg. Changes in parasympathetic activity related with changes in fasting glucose levels (r=-0.407; P=0.03) and showed a trend towards correlation with fasting glucagon concentrations (r=-0.337; P=0.07). The change in sympathovagal balance was inversely related to ASI-iAUCCP (r=-0.365; P=0.05)., Conclusion: We conclude that in addition to inducing insulin resistance, prednisolone treatment dose-dependently impaired islet-cell function. Altered sympathovagal balance may be related to these effects., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: The external pumping action in CPR should generate sufficient flow and pressure, but the pump must also be 'primed' by ongoing venous return. Different additions to standard CPR are in use just for this purpose. Active decompression of the thorax (ACD-CPR) to 'suck in' venous blood has proven successful, but, theoretically, compression of venous reservoirs in the abdomen should be even more effective. We compared different techniques for improved CPR with specific attention to the pulmonary circulation. We did our comparisons 'in silico' rather than 'in vivo' in a well-evaluated computer model., Methods: We used an adapted version of Babb's computer model for CPR, reprogrammed in Matlab(®). (1) We compared standard chest compression-only CPR (CO-CPR) and ACD-CPR to CPR with interposed abdominal compression (IAC-CPR). (2) Since the thorax/heart configuration differs between patients, and consequently the way blood is propelled by the chest compressions, we checked the influence of the ratio thoracic/cardiac pump effectiveness., Results: (1) Only IAC-CPR leads to physiological values for mean aortic pressure and cardiac output. (2) However, since the whole heart is in the pressure chamber of the compressed thorax, pulmonary artery pressure rises to about the same level as aortic pressure. In practice, this might lead to pulmonary edema during and after CPR, unless (3) intra-abdominal compression pressure is strictly limited; simulations indicate that intra-abdominal pressure should not exceed 30-40 mmHg., Conclusions: IAC-CPR outperforms the other techniques in achieving good aortic pressure and cardiac output. However, abdominal pressure should be limited., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.

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/dt (max) 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 < 0.05). Marked hypotension was associated with a 47% fall in CO 3.1 ± 0.6 versus 5.9 ± 1.3 L/min (p < 0.05) and decreases in dP/dt, 277 ± 77 versus 759 ± 160 mmHg/s (p < 0.05). The difference in TPR was not significant 1.1 ± 0.3 versus 1.0 ± 0.3 MU (p = 0.229). In four patients, we attempted to treat PPFH by 30° head-down tilt. This intervention increased SYS only slightly (to 89 ± 12 mmHg)., Interpretation: PPFH seems to be mediated by severe cardiac depression.

The objective of the present study was to test the hypothesis that controlled, adequately compensated, central hypovolemia in subjects with intact autoregulation would be associated with decreased peripheral microcirculatory diffusion and convection properties and, consequently, decreased tissue oxygen carrying capacity and tissue oxygenation. Furthermore, we evaluated the impact of hypovolemia-induced microcirculatory alterations on resting tissue oxygen consumption. To this end, 24 subjects were subjected to a progressive lower body negative pressure (LBNP) protocol of which 14 reached the end of the protocol. At baseline and at LBNP=-60 mm Hg, sidestream dark field (SDF) images of the sublingual microcirculation were acquired to measure microvascular density and perfusion; thenar and forearm tissue hemoglobin content (THI) and tissue oxygenation (StO2) were recorded using near-infrared spectroscopy (NIRS); and a vascular occlusion test (VOT) was performed to assess resting tissue oxygen consumption rate. SDF images were analyzed for total vessel density (TVD), perfused vessel density (PVD), the microvascular flow index (MFI), and flow heterogeneity (MFIhetero). We found that application of LBNP resulted in: 1) a significantly decreased microvascular density (PVD) and perfusion (MFI and MFIhetero); 2) a significantly decreased THI and StO2; and 3) an unaltered resting tissue oxygen consumption rate. In conclusion, using SDF imaging in combination with NIRS we showed that controlled, adequately compensated, central hypovolemia in subjects with intact autoregulation is associated with decreased microcirculatory diffusion (PVD) and convection (MFI and MFIhetero) properties and, consequently, decreased tissue oxygen carrying capacity (THI) and tissue oxygenation (StO2). Furthermore, using a VOT we found that resting tissue oxygen consumption was maintained under conditions of adequately compensated central hypovolemia., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Medical communication is goal oriented behavior. As such, it can be modeled as a chain of decisions, resulting from cognitive and emotional processes each potentially associated with psychophysiological reactions. Psychophysiological may be helpful to detect small changes in affect or arousal in the course of a consultation that would be difficult to detect by other evaluations of the process, like self-reports. The question is how psychophysiological communication research should be modeled for unraveling in more detail the cognitive, emotional and interpersonal processes which underlie physician and patient behavior., Methods: In the world of medical communication research the six-function model of medical communication reveals a number of fundamental perceptual, cognitive and emotional processes which may evoke psychophysiological responses. The world of psychophysiological research encompasses domains of perception, mental imagery, anticipation and action which all have close connections with fundamental tasks in communication., Conclusion: This paper discusses ten methodological issues in linking continuous psychophysiological data to verbal and nonverbal events in a medical consultation observed with the Verona coding system., Practice Implications: When linking the two worlds of research, the methodological challenges discussed need to be solved to obtain a valid and reliable application of psychophysiological measures in medical communication research., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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.

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.

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.

The delay τ between rising systolic blood pressure (SBP) and baroreflex bradycardia has been found to increase when vagal tone is low. The α(2)-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.

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<0.05; BRSFD: 27 (20-34) compared with 14 (9-19) ms·mmHg-1, P<0.05; values are medians (interquartile range)]. BP declined after the jump in both groups, and post-jump BRS did not differ between the groups. In conclusion, during acute psychological stress, BRS is higher in healthy subjects treated with non-selective β-adrenergic blockade with significantly lower HR but comparable BP.

Introduction: Medical communication can be a stressful experience for both doctors and patients. In particular, inexperienced doctors facing the demanding task of a bad news consultation may experience high levels of distress. The aim of this exploratory study is to test students' differential cardiovascular reactivity to history taking and bad news consultations with a simulated patient, and to test the relation between the students' self-reported stressfulness of the consultation and their cardiovascular response., Methods: Fourth and fifth year medical students (n=20) conducted a history taking (HT) and a bad news (BN) consultation in a randomized order with a standardized patient. Heart rate (HR), mean arterial pressure (MAP), cardiac output (CO) and systemic vascular resistance (SVR) were assessed by way of the Finapres-technique in four conditions: rest, reading aloud, and during both consultations. Self-reported stress was assessed before and after each interview using the State and Trait Anxiety Inventory (STAI), and a visual analogue scale (VAS)., Results: Both HT and BN provoked more cardiovascular stress than reading. Bad-news provoked the highest HR and CO responses compared to all other conditions, and had a greater impact when it was the student's first consultation. The STAI and VAS data showed some correlations with the cardiovascular stress measures and a comparable but less significant pattern in stress response., Discussion: The effect of order of the HT and BN consultations on the students' stress levels suggests an additional impact of novelty and habituation. Unfamiliarity with the patient may enhance the stressfulness of the task of breaking bad news., (2010 Elsevier B.V. All rights reserved.)

Inflight 24-h profiles of blood pressure (BP) and heart rate (HR) were recorded in 2 ESA-astronauts by automatic upper arm cuff measurements. In one astronaut this was combined with Portapres continuous finger blood pressure recordings. It was the intention to contrast the latter to 24-h recordings in an earlier Head-Down-Tilted (HDT) bed rest study [Voogel, A.J., Stok, W.J., Pretorius, P.J., Van Montfrans, G.A., Langewouters, G.J., Karemaker, J.M., 1997. Circadian blood pressure and systemic haemodynamics during 42 days of 6 degrees head-down tilt. Acta Physiol. Scand. 161, pp. 71-80]. BP-levels in Space were not very much changed from preflight; the circadian BP-rhythm seemed dampened. Only daytime diastolic pressures (both subjects) and nighttime HR (one subject) were significantly lower in Space. However, compared to the effect of a control tilt manoeuvre on the ground, even lower BP values might have been expected. Striking were the BP- and HR-surges during the working days in Space, often related to stressful moments like live appearances on public TV. Systemic vascular resistance (SVR) dropped during the night, unlike HDT. Thus, actual spaceflight refuted our earlier findings in HDT both for BP-levels and for daytime to nighttime changes. The combined observations lead to the hypothesis that short-lasting spaceflight may induce strong psychological stress in astronauts. When interpreting space-physiological observations this must be taken into account.

Introduction: Hypovolemia and hypovolemic shock are life-threatening conditions that occur in numerous clinical scenarios. Near-infrared spectroscopy (NIRS) has been widely explored, successfully and unsuccessfully, in an attempt to use it as an early detector of hypovolemia by measuring tissue oxygen saturation (StO2). In order to investigate the measurement site dependence and probe dependence of NIRS in response to hemodynamic changes, such as hypovolemia, we applied a simple cardiovascular challenge: a posture change from supine to upright, causing a decrease in stroke volume (as in hypovolemia) and a heart rate increase in combination with peripheral vasoconstriction to maintain adequate blood pressure., Methods: Multi-depth NIRS was used in nine healthy volunteers to assess changes in StO2 in the thenar and forearm in response to the hemodynamic changes associated with a posture change from supine to upright., Results: A posture change from supine to upright resulted in a significant increase (P < 0.001) in heart rate. Thenar StO2 did not respond to the hemodynamic changes following the posture change, whereas forearm StO2 did. Forearm StO2 was significantly lower (P < 0.001) in the upright position compared to supine for all probing depths., Conclusions: The primary findings in this study were that forearm StO2 is a more sensitive parameter to hemodynamic changes than thenar StO2 and that the depth at which StO2 is measured is of minor influence. Our data support the use of forearm StO2 as a sensitive parameter for the detection of central hypovolemia and hypovolemic shock in (trauma) patients.

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 < 0.05), and it tended to return to baseline in subsequent days. During exercise, BRS was lower than at rest, without differences between preflight and in-flight values. At rest, in the early flight phase, RMSSD and RRI HF power increased (P < 0.05) compared with baseline, whereas LF powers of SBP and DBP decreased. No statistical difference was found in these parameters during exercise before vs. during flight. These findings demonstrate that heart rate baroreflex sensitivity and markers of cardiac vagal modulation are enhanced during early exposure to microgravity, likely because of the blood centralization, and return to baseline values in subsequent flight phases, possibly because of the fluid loss. No deconditioning seems to occur in the baroreflex control of the heart.

Objective: The goal was to investigate cardiovascular responses to a psychosocial stressor in school-aged, formerly premature boys and girls who had been treated neonatally with dexamethasone or hydrocortisone because of chronic lung disease., Methods: We compared corticosteroid-treated, formerly preterm infants with formerly preterm infants who had not been treated neonatally with corticosteroids (reference group). Children performed the Trier Social Stress Test for Children, which includes a public speaking task and a mental arithmetic task. Blood pressure was recorded continuously before, during, and after the stress test. Plasma norepinephrine levels were determined before the test, directly after the stress task, and after recovery., Results: Overall, in response to stress, girls had significantly larger changes in systolic blood pressure and mean arterial pressure and in stroke volume and cardiac output, compared with boys. Boys exhibited larger total peripheral resistance responses, compared with girls. The hydrocortisone group did not differ significantly from the reference group in any of the outcome measures. However, dexamethasone-treated children had smaller stress-induced increases in systolic and mean arterial blood pressure than did hydrocortisone-treated children. In addition, the dexamethasone group showed smaller increases in stroke volume and blunted norepinephrine responses to stress, compared with children in the reference group. Correction for gender did not affect these results., Conclusions: The differences in cardiovascular stress responses between girls and boys are consistent with known gender differences in adult cardiovascular stress responses. Our data demonstrate that neonatal treatment with dexamethasone has long-term consequences for the cardiovascular and noradrenergic stress responses; at school age, the cardiovascular stress response was blunted in dexamethasone-treated children. Hydrocortisone-treated children did not differ from the reference group, which suggests that hydrocortisone might be a safe alternative to dexamethasone for treating chronic lung disease of prematurity.

Type 2 diabetes is associated with an increased risk of endothelial dysfunction and microvascular complications with impaired autoregulation of tissue perfusion. Both microvascular disease and cardiovascular autonomic neuropathy may affect cerebral autoregulation. In the present study, we tested the hypothesis that, in the absence of cardiovascular autonomic neuropathy, cerebral autoregulation is impaired in subjects with DM+ (Type 2 diabetes with microvascular complications) but intact in subjects with DM- (Type 2 diabetes without microvascular complications). Dynamic cerebral autoregulation and the steady-state cerebrovascular response to postural change were studied in subjects with DM+ and DM-, in the absence of cardiovascular autonomic neuropathy, and in CTRL (healthy control) subjects. The relationship between spontaneous changes in MCA V(mean) (middle cerebral artery mean blood velocity) and MAP (mean arterial pressure) was evaluated using frequency domain analysis. In the low-frequency region (0.07-0.15 Hz), the phase lead of the MAP-to-MCA V(mean) transfer function was 52+/-10 degrees in CTRL subjects, reduced in subjects with DM- (40+/-6 degrees ; P<0.01 compared with CTRL subjects) and impaired in subjects with DM+ (30+/-5 degrees ; P<0.01 compared with subjects with DM-), indicating less dampening of blood pressure oscillations by affected dynamic cerebral autoregulation. The steady-state response of MCA V(mean) to postural change was comparable for all groups (-12+/-6% in CTRL subjects, -15+/-6% in subjects with DM- and -15+/-7% in subjects with DM+). HbA(1c) (glycated haemoglobin) and the duration of diabetes, but not blood pressure, were determinants of transfer function phase. In conclusion, dysfunction of dynamic cerebral autoregulation in subjects with Type 2 diabetes appears to be an early manifestation of microvascular disease prior to the clinical expression of diabetic nephropathy, retinopathy or cardiovascular autonomic neuropathy.