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 CO, finger arterial pressure, and muscle sympathetic nerve activity (MSNA) were measured simultaneously in 7 subjects during saline, atropine and propranolol infusion.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Heart rate variability biofeedback: effects of age on heart rate variability, baroreflex gain, and asthma.

Objectives: To present additional analysis of data from a previously published study showing that biofeedback training to increase heart rate variability (HRV) can be an effective component in asthma treatment. HRV and intervention-related changes in HRV are negatively correlated with age. Here we assess the effects of age on biofeedback effects for asthma.

Human vagal baroreflex sensitivity fluctuates widely and rhythmically at very low frequencies.

Arterial pressure fluctuates rhythmically in healthy supine resting humans, who, from all outward appearances, are in a 'steady-state'. Others have asked, If baroreflex mechanisms are functioning normally, how can arterial pressure be so variable? We reanalysed data from nine healthy young adult men and women and tested the hypotheses that during brief periods of observation, human baroreflex sensitivity fluctuates widely and rhythmically. We estimated vagal baroreflex sensitivity with systolic pressure and R-R interval cross-spectra measured over 15 s segments, moved by 2 s steps through 20-min periods of frequency- and tidal volume-controlled breathing.

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.

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.

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.

Cardiac size, autonomic function, and 5-year follow-up of chronic heart failure patients with severe prolongation of ventricular activation.

Background: Chronic heart failure is characterized by left ventricular dilation and abnormalities of cardiac autonomic function. Up to 20% of patients with chronic heart failure have QRS prolongation, which can lead to asynchronous left ventricular contraction. We tested the hypotheses that in patients with chronic heart failure, QRS > 150 ms is a risk factor for additional abnormalities of ventricular morphology, heart rate variability, and increased mortality.

The human respiratory gate.

Respiratory activity phasically alters membrane potentials of preganglionic vagal and sympathetic motoneurones and continuously modulates their responsiveness to stimulatory inputs. The most obvious manifestation of this 'respiratory gating' is respiratory sinus arrhythmia, the rhythmic fluctuations of electrocardiographic R-R intervals observed in healthy resting humans. Phasic autonomic motoneurone firing, reflecting the throughput of the system, depends importantly on the intensity of stimulatory inputs, such that when levels of stimulation are low (as with high arterial pressure and sympathetic activity, or low arterial pressure and vagal activity), respiratory fluctuations of sympathetic or vagal firing are also low.

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.

Cardiovascular and sympathetic neural responses to handgrip and cold pressor stimuli in humans before, during and after spaceflight.

Astronauts returning to Earth have reduced orthostatic tolerance and exercise capacity. Alterations in autonomic nervous system and neuromuscular function after spaceflight might contribute to this problem. In this study, we tested the hypothesis that exposure to microgravity impairs autonomic neural control of sympathetic outflow in response to peripheral afferent stimulation produced by handgrip and a cold pressor test in humans.

Does the menstrual cycle influence the sensitivity of vagally mediated baroreflexes?

The menstrual cycle provokes several physiological changes that could influence autonomic regulatory mechanisms. We studied the carotid-cardiac baroreflex in ten healthy young women on four occasions over the course of their menstrual cycles (days 0-8, 9-14, 15-20 and 21-25). We drew blood during each session for analysis of oestrogen, progesterone and noradrenaline (norepinephrine) levels, and assessed carotid-cardiac baroreflex function by analysing R-R interval responses to graded neck pressure sequences.