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.

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.

Comparison of methods for editing of ectopic beats in measurements of short-term non-linear heart rate dynamics.

Non-linear heart rate (HR) dynamics characterizes the fractal properties and complexity of the variations in HR. Ventricular and supraventricular ectopic beats might introduce a mathematical artefact to the analyses on sinus rhythm. We therefore evaluated the effects of different editing practices for ectopic beats such that 753 40-min ECG recordings were (i) not edited for the ectopic beats, or the ectopic beats were edited with (ii) an interpolation or with (iii) a deletion method before the analyses of non-linear HR dynamics. The non-linear HR dynamics analyses included detrended fluctuation analysis (DFA), approximate entropy, symbolic dynamics (SymDyn), fractal dimension and return map (RM). We found that the short-term scaling exponent (alpha1) of DFA, forbidden words of SymDyn and RM were sensitive measurements to the ectopic beats and there were strong correlations between these measurements and the number of ectopic beats. In addition, the unedited ectopic beats significantly lowered the stability of these measurements. However, the editing either with interpolation or deletion method corrected the measurements for the bias caused by the ectopic beats. On the contrary, the entropy measurements were not as sensitive to the ectopic beats. In conclusion, the ectopic beats affect the non-linear HR dynamics of sinus rhythm differently, causing a more marked bias in fractal than in complexity measurements of non-linear HR dynamics. This erroneous effect of ectopic beats can be corrected with a proper editing of these measurements. Therefore, there is an obvious need for standardized editing practices for ectopic beats before the analysis of non-linear HR dynamics.

Prolongation of QT interval by terbutaline in healthy subjects.

In a double-blind, randomized placebo-controlled crossover study, we characterized how terbutaline prolonged cardiac corrected QT interval (QTc). The study was carried out in six young and healthy male subjects in supine position. Escalating terbutaline doses were administered intravenously at infusion rates of 6 mL/h (10 microg terbutaline/min), 12 mL/h (20 microg terbutaline/min), and 18 mL/h (30 microg terbutaline/min). Terbutaline maximally prolonged QTc intervals on average by 60%, from 358 milliseconds (SD 28) to 456 milliseconds (SD 19). The effect was closely associated with a simultaneous decrease in plasma potassium concentration from 4.0 mmol/L (SD 0.1) to 2.5 mmol/L (SD 0.1). The final phase of slow ventricular repolarization, the interval between the apex and the end of T wave, was proven to be highly sensitive to the hypokalemic terbutaline actions, whereas the earlier repolarization phases were not strongly affected by terbutaline. Estimated by using the classic Nernst equation for membrane potentials, terbutaline-induced hypokalemia hyperpolarized ventricular myocardium from the resting level of -90 mV to -110 mV. The prolongation of QTc interval was related to ventricular hyperpolarization with a Pearson correlation coefficient of 0.91. Terbutaline-induced prolongation of QTc interval in healthy volunteers is in conformity with repolarization studies carried out in isolated canine heart ventricular preparations in which the cardiac ventricular cell membrane potential determines the duration of the final phase of slow ventricular repolarization.

Effects of terbutaline on peripheral vascular resistance and arterial compliance.

In a double blind, randomized placebo-controlled crossover study we characterized how terbutaline affects the mean and short-term fluctuations of peripheral vascular resistance and arterial compliance. The study was carried out in six young and healthy male subjects in the supine and upright positions by recording continuously electrocardiography and finger arterial blood pressure. On average, large intravenous terbutaline doses reduce maximally by 50% the mean systolic-diastolic pressure decay time (windkessel time), by 30% the mean vascular resistance, and by 20% the mean arterial compliance. Terbutaline reduces differently the beat-to-beat variability of peripheral vascular resistance and arterial compliance. The effects can be explained by beta-adrenoceptor activation that mediates smooth muscle relaxation in small resistance arteries and large conduit arteries. Differences between vascular resistance and compliance lowering actions could be explained by differences in the beta-adrenoceptor-mediated vascular relaxation and sympathetically mediated vascular contraction between small and large arteries.

Diabetes and haemodynamic reactions to acute coronary occlusion.

BACKGROUND: The risk of early sudden death before hospital admission is higher in diabetic than non-diabetic men with acute myocardial infarction and autonomic nervous activity may modify the clinical outcome of abrupt coronary occlusion. Since diabetes mellitus may interfere with autonomic and myocardial function, we decided to study whether diabetes alters autonomic and haemodynamic responses to acute coronary occlusion. METHODS: We analyzed the changes in heart rate, heart rate variability and blood pressure, and the occurrence of ventricular ectopy during a 2-min coronary occlusion in 238 non-diabetic and 32 diabetic patients referred for single vessel coronary angioplasty. The ranges of non-specific responses were determined by analyzing a control group of 19 patients with no ischaemia during a 2-min balloon inflation in a totally occluded coronary artery. RESULTS: Diabetic patients were more often (p<0.05) female, but there were no significant differences in the occluded vessel or incidence of ST changes or chest pain during coronary occlusion between the groups. Incidence of significant heart rate reactions and ventricular arrhythmias was comparable in both groups. Systolic blood pressure decreased (p=0.01) in the diabetic patients during coronary occlusion, but did not change significantly in the non-diabetic group. Coronary occlusion caused more often (34% vs. 14%, p<0.01) a significant decrease in blood pressure in diabetic patients. Logistic regression models developed to analyze the significance of diabetes while controlling for baseline variables and signs of ischaemia identified diabetes to be an independent predictor of hypotensive reactions (odds ratio [OR] 2.9, 95% confidence intervals 1.1-7.8, p<0.05), while female gender and high short-term heart rate variability were other independent predictors of hypotensive reactions. CONCLUSIONS: Diabetic patients often develop significant hypotension during the early phase of acute coronary occlusion. This abnormality may be related to diabetic cardiomyopathy and impairment of baroreflex-mediated regulation of circulation. Predisposition to hypotension may contribute to the observed differences in the clinical presentation and outcome of acute coronary events.

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.

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.

Effects of exercise training on cardiovagal and sympathetic responses to Valsalva's maneuver.

PURPOSE: We tested the hypothesis that a strictly-controlled program of aerobic conditioning would increase vagal and decrease sympathetic responses to Valsalva straining. METHODS: Eleven young men performed a maximal aerobic capacity test, controlled frequency breathing (0.25 Hz), and three Valsalva maneuvers before and after 4 wk of exercise training on a cycle ergometer (30 min at > or = 70% max heart rate, 3 sessions. week-1). During controlled breathing and Valsalva straining, we recorded the electrocardiogram, noninvasive beat-by-beat arterial pressure, and peroneal nerve muscle sympathetic traffic at the popliteal fossa (pre- and postexercise sympathetic recordings were obtainable in 7 of 11 subjects). Vagal-cardiac tone was estimated from R-R interval standard deviations during controlled frequency breathing. Cardiovagal baroreflex sensitivity was derived from increases of R-R intervals as functions of increases in systolic pressures with linear regression analysis during phase IV pressure increases, and sympathetic sensitivity was derived from the quotient of total muscle sympathetic nerve activity and diastolic pressure changes during phase II pressure reductions. RESULTS: Exercise training increased VO2 max (3.38 +/- 0.10 pre-, and 3.64 +/- 0.11 L. min-1 postexercise; mean +/- SE; P = 0.04), R-R interval standard deviations (75 +/- 0.12 pre- and 94 +/- 0.14 ms postexercise; mean +/- SE; P = 0.03), and cardiovagal baroreflex sensitivity (15.0 +/- 1.1 pre-, and 25.0 ms. mm Hg-1 +/- 4.0 postexercise; mean +/- SE; P = 0.03). Exercise training did not change baseline sympathetic traffic (P = 0.31) or sympathetic nerve responses to diastolic pressure reductions (P = 0.12). CONCLUSIONS: Exercise training affects vagal and sympathetic mechanisms differently: cardiovagal baroreflex sensitivity is increased, but sympathetic responses to arterial pressure decreases are unchanged.

Influence of microgravity on astronauts' sympathetic and vagal responses to Valsalva's manoeuvre.

When astronauts return to Earth and stand, their heart rates may speed inordinately, their blood pressures may fall, and some may experience frank syncope. We studied brief autonomic and haemodynamic transients provoked by graded Valsalva manoeuvres in astronauts on Earth and in space, and tested the hypothesis that exposure to microgravity impairs sympathetic as well as vagal baroreflex responses. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, respiration and peroneal nerve muscle sympathetic activity in four healthy male astronauts (aged 38-44 years) before, during and after the 16 day Neurolab space shuttle mission. Astronauts performed two 15 s Valsalva manoeuvres at each pressure, 15 and 30 mmHg, in random order. Although no astronaut experienced presyncope after the mission, microgravity provoked major changes. For example, the average systolic pressure reduction during 30 mmHg straining was 27 mmHg pre-flight and 49 mmHg in flight. Increases in muscle sympathetic nerve activity during straining were also much greater in space than on Earth. For example, mean normalized sympathetic activity increased 445% during 30 mmHg straining on earth and 792% in space. However, sympathetic baroreflex gain, taken as the integrated sympathetic response divided by the maximum diastolic pressure reduction during straining, was the same in space and on Earth. In contrast, vagal baroreflex gain, particularly during arterial pressure reductions, was diminished in space. This and earlier research suggest that exposure of healthy humans to microgravity augments arterial pressure and sympathetic responses to Valsalva straining and differentially reduces vagal, but not sympathetic baroreflex gain.

Nonlinear methods of biosignal analysis in assessing terbutaline-induced heart rate and blood pressure changes.

The aim of this study was to characterize how different nonlinear methods characterize heart rate and blood pressure dynamics in healthy subjects at rest. The randomized, placebo-controlled crossover study with intravenous terbutaline was designed to induce four different stationary states of cardiovascular regulation system. The R-R interval, systolic arterial blood pressure, and heart rate time series were analyzed with a set of methods including approximate entropy, sample entropy, Lempel-Ziv entropy, symbol dynamic entropy, cross-entropy, correlation dimension, fractal dimensions, and stationarity test. Results indicate that R-R interval and systolic arterial pressure subsystems are mutually connected but have different dynamic properties. In the drug-free state the subsystems share many common features. When the strength of the baroreflex feedback loop is modified with terbutaline, R-R interval and systolic blood pressure lose mutual synchrony and drift toward their inherent state of operation. In this state the R-R interval system is rather complex and irregular, but the blood pressure system is much simpler than in the drug-free state.