Respiratory modulation of human autonomic function on Earth.

KEY POINTS: We studied healthy supine astronauts on Earth with electrocardiogram, non-invasive arterial pressure, respiratory carbon dioxide concentrations, breathing depth and sympathetic nerve recordings. The null hypotheses were that heart beat interval fluctuations at usual breathing frequencies are baroreflex mediated, that they persist during apnoea, and that autonomic responses to apnoea result from changes of chemoreceptor, baroreceptor or lung stretch receptor inputs. R-R interval fluctuations at usual breathing frequencies are unlikely to be baroreflex mediated, and disappear during apnoea. The subjects' responses to apnoea could not be attributed to changes of central chemoreceptor activity (hypocapnia prevailed); altered arterial baroreceptor input (vagal baroreflex gain declined and muscle sympathetic nerve burst areas, frequencies and probabilities increased, even as arterial pressure climbed to new levels); or altered pulmonary stretch receptor activity (major breathing frequency and tidal volume changes did not alter vagal tone or sympathetic activity). Apnoea responses of healthy subjects may result from changes of central respiratory motoneurone activity. ABSTRACT: We studied eight healthy, supine astronauts on Earth, who followed a simple protocol: they breathed at fixed or random frequencies, hyperventilated and then stopped breathing, as a means to modulate and expose to view important, but obscure central neurophysiological mechanisms. Our recordings included the electrocardiogram, finger photoplethysmographic arterial pressure, tidal volume, respiratory carbon dioxide concentrations and peroneal nerve muscle sympathetic activity. Arterial pressure, vagal tone and muscle sympathetic outflow were comparable during spontaneous and controlled-frequency breathing. Compared with spontaneous, 0.1 and 0.05 Hz breathing, however, breathing at usual frequencies (∼0.25 Hz) lowered arterial baroreflex gain, and provoked smaller arterial pressure and R-R interval fluctuations, which were separated by intervals that were likely to be too short and variable to be attributed to baroreflex physiology. R-R interval fluctuations at usual breathing frequencies disappear during apnoea, and thus cannot provide evidence for the existence of a central respiratory oscillation. Apnoea sets in motion a continuous and ever changing reorganization of the relations among stimulatory and inhibitory inputs and autonomic outputs, which, in our study, could not be attributed to altered chemoreceptor, baroreceptor, or pulmonary stretch receptor activity. We suggest that responses of healthy subjects to apnoea are driven importantly, and possibly prepotently, by changes of central respiratory motoneurone activity. The companion article extends these observations and asks the question, Might terrestrial responses to our 20 min breathing protocol find expression as long-term neuroplasticity in serial measurements made over 20 days during and following space travel?

Respiratory modulation of human autonomic function: long-term neuroplasticity in space.

KEY POINTS: We studied healthy astronauts before, during and after the Neurolab Space Shuttle mission with controlled breathing and apnoea, to identify autonomic changes that might contribute to postflight orthostatic intolerance. Measurements included the electrocardiogram, finger photoplethysmographic arterial pressure, respiratory carbon dioxide levels, tidal volume and peroneal nerve muscle sympathetic activity. Arterial pressure fell and then rose in space, and drifted back to preflight levels after return to Earth. Vagal metrics changed in opposite directions: vagal baroreflex gain and two indices of vagal fluctuations rose and then fell in space, and descended to preflight levels upon return to Earth. Sympathetic burst frequencies (but not areas) were greater than preflight in space and on landing day, and astronauts' abilities to modulate both burst areas and frequencies during apnoea were sharply diminished. Spaceflight triggers long-term neuroplastic changes reflected by reciptocal sympathetic and vagal motoneurone responsiveness to breathing changes. ABSTRACT: We studied six healthy astronauts five times, on Earth, in space on the first and 12th or 13th day of the 16 day Neurolab Space Shuttle mission, on landing day, and 5-6 days later. Astronauts followed a fixed protocol comprising controlled and random frequency breathing and apnoea, conceived to perturb their autonomic function and identify changes, if any, provoked by microgravity exposure. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, tidal carbon dioxide concentrations and volumes, and peroneal nerve muscle sympathetic activity on Earth (in the supine position) and in space. (Sympathetic nerve recordings were made during three sessions: preflight, late mission and landing day.) Arterial pressure changed systematically from preflight levels: pressure fell during early microgravity exposure, rose as microgravity exposure continued, and drifted back to preflight levels after return to Earth. Vagal metrics changed in opposite directions: vagal baroreflex gain and two indices of vagal fluctuations (root mean square of successive normal R-R intervals; and proportion of successive normal R-R intervals greater than 50 ms, divided by the total number of normal R-R intervals) rose significantly during early microgravity exposure, fell as microgravity exposure continued, and descended to preflight levels upon return to Earth. Sympathetic mechanisms also changed. Burst frequencies (but not areas) during fixed frequency breathing were greater than preflight in space and on landing day, but their control during apnoea was sharply altered: astronauts increased their burst frequencies from already high levels, but they could not modulate either burst areas or frequencies appropriately. Space travel provokes long-lasting sympathetic and vagal neuroplastic changes in healthy humans.

Human sympathetic outflows to skin and muscle target organs fluctuate concordantly over a wide range of time-varying frequencies.

Frequency-domain analyses of simultaneously recorded skin and muscle sympathetic nerve activities may yield unique information on otherwise obscure central processes governing human neural outflows. We used wavelet transform and wavelet phase coherence methods to analyse integrated skin and muscle sympathetic nerve activities and haemodynamic fluctuations, recorded from nine healthy supine young men. We tested two null hypotheses: (1) that human skin and muscle sympathetic nerve activities oscillate congruently; and (2) that whole-body heating affects these neural outflows and their haemodynamic consequences in similar ways. Measurements included peroneal nerve skin and tibial nerve muscle sympathetic activities; the electrocardiogram; finger photoplethysmographic arterial pressure; respiration (controlled at 0.25 Hz, and registered with a nasal thermistor); and skin temperature, sweating, and laser-Doppler skin blood flow. We made recordings at ∼27°C, for ∼20 min, and then during room temperature increases to ∼38°C, over 35 min. We analysed data with a wavelet transform, using the Morlet mother wavelet and wavelet phase coherence, to determine the frequencies and coherences of oscillations over time. At 27°C, skin and muscle nerve activities oscillated coherently, at ever-changing frequencies between 0.01 and the cardiac frequency (∼1 Hz). Heating significantly augmented oscillations of skin sympathetic nerve activity and skin blood flow, arterial pressure, and R-R intervals, over a wide range of low frequencies, and modestly reduced coordination between skin and muscle sympathetic oscillations. These results suggest that human skin and muscle sympathetic motoneurones are similarly entrained by external influences, including those of arterial baroreceptors, respiration, and other less well-defined brainstem oscillators. Our study provides strong support for the existence of multiple, time-varying central sympathetic neural oscillators in human subjects.

Beyond the Baroreflex: A New Measure of Autonomic Regulation Based on the Time-Frequency Assessment of Variability, Phase Coherence and Couplings.

For decades the role of autonomic regulation and the baroreflex in the generation of the respiratory sinus arrhythmia (RSA) - modulation of heart rate by the frequency of breathing - has been under dispute. We hypothesized that by using autonomic blockers we can reveal which oscillations and their interactions are suppressed, elucidating their involvement in RSA as well as in cardiovascular regulation more generally. R-R intervals, end tidal CO2, finger arterial pressure, and muscle sympathetic nerve activity (MSNA) were measured simultaneously in 7 subjects during saline, atropine and propranolol infusion. The measurements were repeated during spontaneous and fixed-frequency breathing, and apnea. The power spectra, phase coherence and couplings were calculated to characterise the variability and interactions within the cardiovascular system. Atropine reduced R-R interval variability (p < 0.05) in all three breathing conditions, reduced MSNA power during apnea and removed much of the significant coherence and couplings. Propranolol had smaller effect on the power of oscillations and did not change the number of significant interactions. Most notably, atropine reduced R-R interval power in the 0.145-0.6 Hz interval during apnea, which supports the hypothesis that the RSA is modulated by a mechanism other than the baroreflex. Atropine also reduced or made negative the phase shift between the systolic and diastolic pressure, indicating the cessation of baroreflex-dependent blood pressure variability. This result suggests that coherent respiratory oscillations in the blood pressure can be used for the non-invasive assessment of autonomic regulation.

Human vagal baroreflex mechanisms in space.

Although astronauts' cardiovascular function is normal while they are in space, many have altered haemodynamic responses to standing after they return to Earth, including inordinate tachycardia, orthostatic hypotension, and uncommonly, syncope. Simulated microgravity impairs vagal baroreceptor-cardiac reflex function and causes orthostatic hypotension. Actual microgravity, however, has been shown to either increase, or not change vagal baroreflex gain. In this study, we tested the null hypothesis that spaceflight does not impair human baroreflex mechanisms. We studied 11 American and two German astronauts before, during (flight days 2-8), and after two, 9- and 10-day space shuttle missions, with graded neck pressure and suction, to elicit sigmoid, vagally mediated carotid baroreflex R-R interval responses. Baseline systolic pressures tended to be higher in space than on Earth (P = 0.015, repeated measures analysis of variance), and baseline R-R intervals tended to be lower (P = 0.049). Baroreceptor-cardiac reflex relations were displaced downward on the R-R interval axis in space. The average range of R-R interval responses to neck pressure changes declined from preflight levels by 37% on flight day 8 (P = 0.051), maximum R-R intervals declined by 14% (P = 0.003), and vagal baroreflex gain by 9% (P = 0.009). These measures returned to preflight levels by 7-10 days after astronauts returned to Earth. This study documents significant increases of arterial pressure and impairment of vagal baroreflex function in space. These results and results published earlier indicate that microgravity exposure augments sympathetic, and diminishes vagal cardiovascular influences.

Fractal properties of human heart period variability: physiological and methodological implications.

Fractal frequency scaling of heart period variability is used as a concise index of overall cardiac control. However, no prior study has assessed within-individual reproducibility of fractal indices of heart period, or reported how the estimated indices respond to autonomic blockade. Therefore, we examined fractal properties of the heart period from ten young, healthy individuals during three separate experimental sessions under control (saline) conditions and twice under combined autonomic blockade (atenolol and atropine sulfate) conditions. Under each condition, R-R intervals were recorded with the subject in the supine and the 40 deg upright tilt positions during 20 min of controlled breathing in each position. We calculated the fractal scaling exponent using detrended fluctuation analysis and estimated confidence intervals of the scaling exponents for each R-R interval time series within each individual. In the control condition, upright tilt significantly increased the scaling exponents (from 0.73 +/- 0.11 (+/-S.D., session 1), 0.72 +/- 0.10 (session 2) and 0.75 +/- 0.13 (session 3) to 0.82 +/- 0.12, 0.82 +/- 0.11 and 0.84 +/- 0.10; Student's paired t-test, t = 2.79, P = 0.02; t = 2.80, P = 0.02; and t = 2.07, P = 0.07). However, neither the absolute scaling exponents nor their change in response to upright tilt were reproducible (Lin's concordance coefficient less than 0.9, P > 0.1 for all comparisons). Following autonomic blockade, the scaling exponents were significantly increased (supine: 1.08 +/- 0.13 and 1.08 +/- 0.14; tilt: 1.07 +/- 0.21 and 1.08 +/- 0.14) for both experimental sessions (two-way repeated-measures ANOVA; F(17,1) = 40.89, P < 0.001 and F(17,1) = 42.72, P < 0.001) regardless of position. However, within individuals, the scaling exponents failed to distinguish between control and blockade for half of the subjects in at least one experimental session. Thus, fractal scaling exponents are not reproducible within individuals and do not reliably reflect the autonomic mechanisms responsible for heart period variability. In fact, data from combined blockade suggest that physiological effects of autonomic outflow may mask intrinsic fractal behaviour of the sinoatrial node.

Cerebral blood flow velocity declines before arterial pressure in patients with orthostatic vasovagal presyncope.

OBJECTIVES: We studied hemodynamic changes leading to orthostatic vasovagal presyncope to determine whether changes of cerebral artery blood flow velocity precede or follow reductions of arterial pressure. BACKGROUND: Some evidence suggests that disordered cerebral autoregulation contributes to the occurrence of orthostatic vasovagal syncope. We studied cerebral hemodynamics with transcranial Doppler recordings, and we closely examined the temporal sequence of changes of cerebral artery blood flow velocity and systemic arterial pressure in 15 patients who did or did not faint during passive 70 degrees head-up tilt. METHODS: We recorded photoplethysmographic arterial pressure, RR intervals (electrocardiogram) and middle cerebral artery blood flow velocities (mean, total, mean/RR interval; Gosling's pulsatility index; and cerebrovascular resistance [mean cerebral velocity/mean arterial pressure, MAP]). RESULTS: Eight men developed presyncope, and six men and one woman did not. Presyncopal patients reported light-headedness, diaphoresis, or a sensation of fatigue 155 s (range: 25 to 414 s) before any cerebral or systemic hemodynamic change. Average cerebral blood flow velocity (CBFV) changes (defined by an iterative linear regression algorithm) began 67 s (range: 9 to 198 s) before reductions of MAP. Cerebral and systemic hemodynamic measurements remained constant in nonsyncopal patients. CONCLUSIONS: Presyncopal symptoms and CBFV changes precede arterial pressure reductions in patients with orthostatic vasovagal syncope. Therefore, changes of cerebrovascular regulation may contribute to the occurrence of vasovagal reactions.

Predicting death due to progressive heart failure in patients with mild-to-moderate chronic heart failure.

OBJECTIVES: The aim of this study was to explore the value of noninvasive predictors of death/mode of death in ambulant outpatients with chronic heart failure (HF). BACKGROUND: Mortality in chronic HF remains high, with a significant number of patients dying of progressive disease. Identification of these patients is important. METHODS: We recruited 553 ambulant outpatients age 63 +/- 10 years with symptoms of chronic HF (New York Heart Association functional class, 2.3 +/- 0.5) and objective evidence of left ventricular dysfunction (ejection fraction <45%, cardiothoracic ratio >0.55, or pulmonary edema on chest radiograph). After 2,365 patient-years of follow-up, 201 patients had died, with 76 events due to progressive HF. RESULTS: Independent predictors of all-cause mortality assessed with the Cox proportional hazards model were as follows: a low standard deviation of all normal-to-normal RR intervals (SDNN); lower serum sodium and higher creatinine levels; higher cardiothoracic ratio; nonsustained ventricular tachycardia; higher left ventricular end-systolic diameter; left ventricular hypertrophy; and increasing age. Independent predictors of death specific to progressive HF were SDNN, serum sodium and creatinine levels. The hazard ratio of progressive HF death for a 10% decrease in SDNN was 1.06 (95% confidence interval [CI], 1.01 to 1.12); for a 2 mmol/l decrease in serum sodium, 1.22 (95% CI, 1.08 to 1.38); and for a 10 micromol/l increase in serum creatinine, 1.14 (95% CI, 1.09 to 1.19) (all p < 0.01). CONCLUSIONS: In ambulant outpatients with chronic HF, low serum sodium and SDNN and high serum creatinine identify patients at increased risk of death due to progressive HF.

Heart rate variability biofeedback increases baroreflex gain and peak expiratory flow.

OBJECTIVE: We evaluated heart rate variability biofeedback as a method for increasing vagal baroreflex gain and improving pulmonary function among 54 healthy adults. METHODS: We compared 10 sessions of biofeedback training with an uninstructed control. Cognitive and physiological effects were measured in four of the sessions. RESULTS: We found acute increases in low-frequency and total spectrum heart rate variability, and in vagal baroreflex gain, correlated with slow breathing during biofeedback periods. Increased baseline baroreflex gain also occurred across sessions in the biofeedback group, independent of respiratory changes, and peak expiratory flow increased in this group, independently of cardiovascular changes. Biofeedback was accompanied by fewer adverse relaxation side effects than the control condition. CONCLUSIONS: Heart rate variability biofeedback had strong long-term influences on resting baroreflex gain and pulmonary function. It should be examined as a method for treating cardiovascular and pulmonary diseases. Also, this study demonstrates neuroplasticity of the baroreflex.

A prognostic index to predict long-term mortality in patients with mild to moderate chronic heart failure stabilised on angiotensin converting enzyme inhibitors.

BACKGROUND: Mortality in patients with mild to moderate chronic heart failure remains high. At present there is no easy way of identifying patients within this population at increased risk of death in the medium to long term. AIMS: To develop a prognostic index to identify outpatients with mild to moderate chronic heart failure at increased risk of death. METHODS AND RESULTS: Five hundred and fifty-three outpatients mean (S.D.) age 63(+/-10) years with symptoms of chronic heart failure (mean New York Heart Association functional class, 2.3(+/-0.5)), were recruited between December 1993 and April 1995. By April 2000, 201 patients had died. Using data from non-invasive measurements of cardiac size, electrical and autonomic function, renal function and plasma biochemistry we identified eight independent predictors of mortality (all P<0.01). To develop a prognostic index, predictors were dichotomised by group median and awarded 0 or 1 point accordingly. Serum sodium /=111 micromol/l (1 point), cardiothoracic ratio >/=0.52 (1 point), SDNN /=487 ms (1 point), QRS dispersion>/=42.7 ms (1 point), the presence of non-sustained ventricular tachycardia (1 point) and voltage criteria for left ventricular hypertrophy on 12-lead ECG (1 point). We calculated risk scores for patients by adding the points of each independent risk factor. In the low-risk group (0-3 points) mortality at 5 years was 20% and in the high-risk group (4-8 points) 53%. The area under the receiver-operator characteristic curve using dichotomised variables was 0.74 and for continuous model 0.78. CONCLUSIONS: Our prognostic index which uses eight non-invasive measurements and a straightforward additive points system, has good discrimination and stratifies outpatients with chronic heart failure into high and low risk. This index may be useful in clinical care and risk stratification.

Spontaneous 'baroreflex sequences' occur as deterministic functions of breathing phase.

Parallel increases or decreases of systolic pressures and R-R intervals occur spontaneously in healthy resting humans, and are thought to be expressions of vagal baroreflex physiology. We studied ten healthy supine young adults, and tested the null hypothesis that spontaneous baroreflex sequences are distributed uniformly throughout the breathing cycle. We recorded the electrocardiogram, photoplethysmographic arterial pressure, respiration (pneumobelt), and peroneal nerve muscle sympathetic activity in supine subjects who breathed spontaneously, or held their breaths in inspiration after 2 min of hyperventilation with 100% oxygen. We analysed pairs of three or more increasing or decreasing systolic pressures and R-R intervals with linear regression, and related the gain and timing of the onset of such sequences to the phase of respiration, and to preceding muscle sympathetic nerve activity. We found that baroreflex sequences occur erratically, at a frequency about one-third that of breathing. However, when baroreflex sequences do occur, the timing of their onset is dictated by the phase of respiration. Parallel increases of systolic pressures and R-R intervals ('up' sequences) begin just before and after the beginning of expiration, and parallel decreases of systolic pressures and R-R intervals ('down' sequences) begin during late expiration and inspiration. Average gains of up and down baroreflex sequences triggered by muscle sympathetic bursts are comparable during breathing and apnoea. However, the latencies between sympathetic bursts and baroreflex sequences are less during breathing than during apnoea. We propose that parallel systolic pressure--R-R interval sequences are expressions of arterial baroreflex physiology, and that the nearly fixed timing of such sequences within breaths reflects simply respiratory gating of muscle sympathetic bursts.

Time-frequency methods and voluntary ramped-frequency breathing: a powerful combination for exploration of human neurophysiological mechanisms.

We experimentally altered the timing of respiratory motoneuron activity as a means to modulate and better understand otherwise hidden human central neural and hemodynamic oscillatory mechanisms. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, tidal carbon dioxide concentrations, and muscle sympathetic nerve activity in 13 healthy supine young men who gradually increased or decreased their breathing frequencies between 0.05 and 0.25 Hz over 9-min periods. We analyzed results with traditional time- and frequency-domain methods, and also with time-frequency methods (wavelet transform, wavelet phase coherence, and directional coupling). We determined statistical significance and identified frequency boundaries by comparing measurements with randomly generated surrogates. Our results support several major conclusions. First, respiration causally modulates both sympathetic (weakly) and vagal motoneuron (strongly) oscillations over a wide frequency range-one that extends well below the frequency of actual breaths. Second, breathing frequency broadly modulates vagal baroreflex gain, with peak gains registered in the low frequency range. Third, breathing frequency does not influence median levels of sympathetic or vagal activity over time. Fourth, phase relations between arterial pressure and sympathetic and vagal motoneurons are unaffected by breathing, and are therefore likely secondary to intrinsic responsiveness of these motoneurons to other synaptic inputs. Finally, breathing frequency does not affect phase coherence between diastolic pressure and muscle sympathetic oscillations, but it augments phase coherence between systolic pressure and R-R interval oscillations over a limited portion of the usual breathing frequency range. These results refine understanding of autonomic oscillatory processes and those physiological mechanisms known as the human respiratory gate.

Baroreflex physiology studied in healthy subjects with very infrequent muscle sympathetic bursts.

Because it is likely that, in healthy human subjects, baroreflex mechanisms operate continuously, independent of experimental interventions, we asked the question, In what ways might study of unprovoked, very infrequent muscle sympathetic bursts inform baroreflex physiology? We closely examined arterial pressure and R-R interval responses of 11 supine healthy young subjects to arterial pressure ramps triggered by large isolated muscle sympathetic bursts. We triggered data collection sweeps on the beginnings of sympathetic bursts and plotted changes of arterial pressure (finger volume clamp or intra-arterial) and R-R intervals occurring before as well as after the sympathetic triggers. We estimated baroreflex gain from regression of R-R intervals on systolic pressures after sympathetic bursts and from the transfer function between cross-spectra of systolic pressure and R-R intervals at low frequencies. Isolated muscle sympathetic bursts were preceded by arterial pressure reductions. Baroreflex gain, calculated with linear regression of R-R intervals on systolic pressures after bursts, was virtually identical to baroreflex gain, calculated with the cross-spectral modulus [mean and (range): 24 (7-43) vs. 24 (8-45) ms/mmHg], and highly significant, according to linear regression (r(2) = 0.91, P = 0.001). Our results indicate that 1) since infrequent human muscle sympathetic bursts are almost deterministically preceded by arterial pressure reductions, their occurrence likely reflects simple baroreflex physiology, and 2) the noninvasive low-frequency modulus reliably reproduces gains derived from R-R interval responses to arterial pressure ramps triggered by infrequent muscle sympathetic bursts.

Chaotic signatures of heart rate variability and its power spectrum in health, aging and heart failure.

A paradox regarding the classic power spectral analysis of heart rate variability (HRV) is whether the characteristic high- (HF) and low-frequency (LF) spectral peaks represent stochastic or chaotic phenomena. Resolution of this fundamental issue is key to unraveling the mechanisms of HRV, which is critical to its proper use as a noninvasive marker for cardiac mortality risk assessment and stratification in congestive heart failure (CHF) and other cardiac dysfunctions. However, conventional techniques of nonlinear time series analysis generally lack sufficient sensitivity, specificity and robustness to discriminate chaos from random noise, much less quantify the chaos level. Here, we apply a 'litmus test' for heartbeat chaos based on a novel noise titration assay which affords a robust, specific, time-resolved and quantitative measure of the relative chaos level. Noise titration of running short-segment Holter tachograms from healthy subjects revealed circadian-dependent (or sleep/wake-dependent) heartbeat chaos that was linked to the HF component (respiratory sinus arrhythmia). The relative 'HF chaos' levels were similar in young and elderly subjects despite proportional age-related decreases in HF and LF power. In contrast, the near-regular heartbeat in CHF patients was primarily nonchaotic except punctuated by undetected ectopic beats and other abnormal beats, causing transient chaos. Such profound circadian-, age- and CHF-dependent changes in the chaotic and spectral characteristics of HRV were accompanied by little changes in approximate entropy, a measure of signal irregularity. The salient chaotic signatures of HRV in these subject groups reveal distinct autonomic, cardiac, respiratory and circadian/sleep-wake mechanisms that distinguish health and aging from CHF.

Arterial baroreflexes and cardiovascular modeling.

Many cardiovascular models involve prediction of changes that occur when a subject is perturbed in some way, to move from one state to another. A successful, predictive model should involve at least two elements: First, the model should include some index of the intensity of the perturbation that elicits the response; effective responses should, in some fashion, be linearly or nonlinearity related to perturbations. Second, the model should factor in subjects' abilities to meet the challenges posed by the perturbations. This review indicates that these two basic components of a successful model may be difficult to incorporate. In the simple case of passive upright tilt, blood pressure measurements may not accurately indicate the stimulus, because blood pressure reductions are reversed by rapidly occurring reflex blood pressure increases. Since not all subject populations respond identically to hemodynamic challenges, it also may be important to characterize baroreflex responsiveness, and include such a term in a model. Although vagal and sympathetic baroreflex responses to stereotyped challenges can be measured accurately, recent research points to extraordinary variability of baroreflex responsiveness. The complexities discussed in this review should be considered, whether they are, or even can be incorporated into cardiovascular models.

Heart rate chaos as a mortality predictor in mild to moderate heart failure.

Linear and nonlinear indices of heart rate variability (HRV) have been shown to predict mortality in congestive heart failure (CHF). However, most nonlinear indices describe only the fractality or complexity of HRV but not the intrinsic chaotic properties. In the present study, we performed linear (time- and frequency-domain), complexity (sample entropy), fractal (detrended fluctuation analysis) and chaos (numerical titration) analyses on the HRV of 50 CHF patients from the United Kingdom heart failure evaluation and assessment of risk trial database. Receiver operating characteristic and survival analysis yielded the chaos level to be the best predictor of mortality (followed by low/high frequency power ratio, LF/HF), such that these indices were significant in both univariate and multivariate models. These results indicate the power of heart rate chaos analysis as a potential prognostic tool for CHF.

Human cerebral autoregulation before, during and after spaceflight.

Exposure to microgravity alters the distribution of body fluids and the degree of distension of cranial blood vessels, and these changes in turn may provoke structural remodelling and altered cerebral autoregulation. Impaired cerebral autoregulation has been documented following weightlessness simulated by head-down bed rest in humans, and is proposed as a mechanism responsible for postspaceflight orthostatic intolerance. In this study, we tested the hypothesis that spaceflight impairs cerebral autoregulation. We studied six astronauts approximately 72 and 23 days before, after 1 and 2 weeks in space (n = 4), on landing day, and 1 day after the 16 day Neurolab space shuttle mission. Beat-by-beat changes of photoplethysmographic mean arterial pressure and transcranial Doppler middle cerebral artery blood flow velocity were measured during 5 min of spontaneous breathing, 30 mmHg lower body suction to simulate standing in space, and 10 min of 60 deg passive upright tilt on Earth. Dynamic cerebral autoregulation was quantified by analysis of the transfer function between spontaneous changes of mean arterial pressure and cerebral artery blood flow velocity, in the very low- (0.02-0.07 Hz), low- (0.07-0.20 Hz) and high-frequency (0.20-0.35 Hz) ranges. Resting middle cerebral artery blood flow velocity did not change significantly from preflight values during or after spaceflight. Reductions of cerebral blood flow velocity during lower body suction were significant before spaceflight (P < 0.05, repeated measures ANOVA), but not during or after spaceflight. Absolute and percentage reductions of mean (+/- s.e.m.) cerebral blood flow velocity after 10 min upright tilt were smaller after than before spaceflight (absolute, -4 +/- 3 cm s(-1) after versus -14 +/- 3 cm s(-1) before, P = 0.001; and percentage, -8.0 +/- 4.8% after versus -24.8 +/- 4.4% before, P < 0.05), consistent with improved rather than impaired cerebral blood flow regulation. Low-frequency gain decreased significantly (P < 0.05) by 26, 23 and 27% after 1 and 2 weeks in space and on landing day, respectively, compared with preflight values, which is also consistent with improved autoregulation. We conclude that human cerebral autoregulation is preserved, and possibly even improved, by short-duration spaceflight.