Incoherent oscillations of respiratory sinus arrhythmia during acute mental stress in humans

Respiratory sinus arrhythmia (RSA) has been widely used as a measure of the cardiac vagal control in response to stress. However, RSA seems not to be a generalized indicator because of its dependency on respiratory parameter and individual variations of RSA amplitude (A(RSA)). We hypothesized that phase-lag variations between RSA and respiration may serve as a normalized index of the degree of mental stress. Twenty healthy volunteers performed mental arithmetic task (ART) after 5 min of resting control followed by 5 min of recovery. Breathing pattern, beat-to-beat R-R intervals, and blood pressure (BP) were determined using inductance plethysmography, electrocardiography, and a Finapres device, respectively. The analytic signals of breathing and RSA were obtained by Hilbert transform and the degree of phase synchronization (λ) was quantified. With the use of spectral analysis, heart rate variability (HRV) was estimated for the low-frequency (LF) and high-frequency (HF) bands. A steady-state 3-min resting period (REST), the first 3 min (ART1), and the last 3 min (ART2) of the ART period (ranged from 6- to 19 min) and the last 3 min of the recovery period (RCV) were analyzed separately. Heart rate, systolic BP, and breathing frequency (f(R)) increased and λ, A(RSA), and HF power decreased from REST to ART (P < 0.01). The λ was correlated with normalized A(RSA) and the HF power. The decrease in λ could not be explained solely by the increase in f(R). We conclude that mental stress exerts an influence on RSA oscillations, inducing incoherent phase lag with respect to breathing, in addition to a decrease in RSA.     

Microgravity alters respiratory sinus arrhythmia and short-term heart rate variability in humans

We studied heart rate (HR), heart rate variability (HRV), and respiratory sinus arrhythmia (RSA) in four male subjects before, during, and after 16 days of spaceflight. The electrocardiogram and respiration were recorded during two periods of 4 min controlled breathing at 7.5 and 15 breaths/min in standing and supine postures on the ground and in microgravity. Low (LF)- and high (HF)-frequency components of the short-term HRV (< or =3 min) were computed through Fourier spectral analysis of the R-R intervals. Early in microgravity, HR was decreased compared with both standing and supine positions and had returned to the supine value by the end of the flight. In microgravity, overall variability, the LF-to-HF ratio, and RSA amplitude and phase were similar to preflight supine values. Immediately postflight, HR increased by approximately 15% and remained elevated 15 days after landing. LF/HF was increased, suggesting an increased sympathetic control of HR standing. The overall variability and RSA amplitude in supine decreased postflight, suggesting that vagal tone decreased, which coupled with the decrease in RSA phase shift suggests that this was the result of an adaptation of autonomic control of HR to microgravity. In addition, these alterations persisted for at least 15 days after return to normal gravity (1G).     

Self-regulation of respiratory sinus arrhythmia

Respiratory sinus arrhythmia (RSA) — the peak-to-peak variations in heart rate caused by respiration — can be used as a noninvasive measure of parasympathetic cardiac control. In the present study four strategies to increase RSA amplitude are investigated: (1) biofeedback of RSA amplitude, (2) biofeedback of RSA amplitude plus respiratory instructions, (3) respiratory biofeedback, and (4) respiratory instructions only. All four procedures produce a significant increase of RSA amplitude from the first physiological control trial compared to baseline. This increase is faster for the groups that received respiratory biofeedback and respiratory instructions only than for the two groups that received biofeedback of RSA amplitude, the increases being equivalent for the four groups in the third session. All subjects of the group that received biofeedback of RSA amplitude only reported respiratory strategies in order to achieve the increase in RSA. Possible clinical implications of these results for parasympathetic cardiac control and cardiovascular disorders are discussed.This research was supported by a grant to the first author from the University of Granada (Spain).     

Individual differences in respiratory sinus arrhythmia

To investigate the interindividual differences in respiratory sinus arrhythmia (RSA), recordings of ventilation and electrocardiogram were obtained from 12 healthy subjects for five imposed breathing periods (T(TOT)) surrounding each individual's spontaneous breathing period. In addition to the spectral analysis of the R-R interval signal at each breathing period, RSA characteristics were quantified by using a breath-by-breath analysis where a sinusoid was fitted to the changes in instantaneous heart rate in each breath. The amplitude and phase (or delay = phase x T(TOT)) of this sinusoid were taken as the RSA characteristics for each breath. It was found that for each subject the RSA amplitude-T(TOT) relationship was linear, whereas the delay-T(TOT) relationship was parabolic. However, the parameters of these relationships differed between individuals. Linear correlation between the slopes of RSA amplitude versus T(TOT) regression lines and 1) mean breathing period and 2) mean R-R interval during spontaneous breathing were calculated. Only the correlation coefficient with breathing period was significantly different from zero, indicating that the longer the spontaneous breathing period the lesser the increase in RSA amplitude with increasing breathing period. Similarly, only the correlation coefficient between the curvature of the RSA delay-T(TOT) parabola and mean breathing period was significantly different from zero; the longer the spontaneous breathing period the larger the curvature of RSA delay. These results suggest that the changes in RSA characteristics induced by changing the breathing period may be explained partly by the spontaneous breathing period of each individual. Furthermore, a transfer function analysis performed on these data suggested interindividual differences in the autonomic modulation of the heart rate.     

Self-regulation of respiratory sinus arrhythmia.

Respiratory sinus arrhythmia (RSA)--the peak-to-peak variations in heart rate caused by respiration--can be used as a noninvasive measure of parasympathetic cardiac control. In the present study four strategies to increase RSA amplitude are investigated: (1) biofeedback of RSA amplitude, (2) biofeedback of RSA amplitude plus respiratory instructions, (3) respiratory biofeedback, and (4) respiratory instructions only. All four procedures produce a significant increase of RSA amplitude from the first physiological control trial compared to baseline. This increase is faster for the groups that received respiratory biofeedback and respiratory instructions only than for the two groups that received biofeedback of RSA amplitude, the increases being equivalent for the four groups in the third session. All subjects of the group that received biofeedback of RSA amplitude only reported respiratory strategies in order to achieve the increase in RSA. Possible clinical implications of these results for parasympathetic cardiac control and cardiovascular disorders are discussed.     

Direct effect of Pa(CO2) on respiratory sinus arrhythmia in conscious humans

Respiratory sinus arrhythmia (RSA) may improve the efficiency of pulmonary gas exchange by matching the pulmonary blood flow to lung volume during each respiratory cycle. If so, an increased demand for pulmonary gas exchange may enhance RSA magnitude. We therefore tested the hypothesis that CO2 directly affects RSA in conscious humans even when changes in tidal volume (V(T)) and breathing frequency (F(B)), which indirectly affect RSA, are prevented. In seven healthy subjects, we adjusted end-tidal PCO2 (PET(CO2)) to 30, 40, or 50 mmHg in random order at constant V(T) and F(B). The mean amplitude of the high-frequency component of R-R interval variation was used as a quantitative assessment of RSA magnitude. RSA magnitude increased progressively with PET(CO2) (P < 0.001). Mean R-R interval did not differ at PET(CO2) of 40 and 50 mmHg but was less at 30 mmHg (P < 0.05). Because V(T) and F(B) were constant, these results support our hypothesis that increased CO2 directly increases RSA magnitude, probably via a direct effect on medullary mechanisms generating RSA.     

Effects of hypercapnia and hypoxemia on respiratory sinus arrhythmia in conscious humans during spontaneous respiration

Normally, at rest, the amplitude of respiratory sinus arrhythmia (RSA) appears to correlate with cardiac vagal tone. However, recent studies showed that, under stress, RSA dissociates from vagal tone, indicating that separate mechanisms might regulate phasic and tonic vagal activity. This dissociation has been linked to the hypothesis that RSA improves pulmonary gas exchange through preferential distribution of heartbeats in inspiration. We examined the effects of hypercapnia and mild hypoxemia on RSA-vagal dissociation in relation to heartbeat distribution throughout the respiratory cycle in 12 volunteers. We found that hypercapnia, but not hypoxemia, was associated with significant increases in heart rate (HR), tidal volume, and RSA amplitude. The RSA amplitude increase remained statistically significant after adjustment for respiratory rate, tidal volume, and HR. Moreover, the RSA amplitude increase was associated with a paradoxical rise in HR and decrease in low-frequency-to-high-frequency mean amplitude ratio derived from spectral analysis, which is consistent with RSA-vagal dissociation. Although hypercapnia was associated with a significant increase in the percentage of heartbeats during inspiration, this association was largely secondary to increases in the inspiratory period-to-respiratory period ratio, rather than RSA amplitude. Additional model analyses of RSA were consistent with the experimental data. Heartbeat distribution did not change during hypoxemia. These results support the concept of RSA-vagal dissociation during hypercapnia; however, the putative role of RSA in optimizing pulmonary perfusion matching requires further experimental validation.     

Phase-averaged characterization of respiratory sinus arrhythmia pattern

A method for the accurate time-domain characterization of respiratory sinus arrhythmia (RSA) pattern is presented and applied to two groups of healthy subjects to lay the baseline of RSA patterns and to underlay their features: response to standing, stability in successive recordings, and individuality of the shape of RSA pattern. RSA pattern is evaluated by selective averaging of heart rate (HR) changes from multiple respiratory cycles over the respiratory phase and represents the complete modulating function of HR by respiration. The RSA pattern is evaluated with free respiration and even in cases of severe arrhythmia. Estimation error is 6-8% in magnitude, phase resolution is 0.2 rad, and sensitivity margin for respiratory-related HR variability (HRV) components is 1%. RSA magnitude, phase lag, and expiration-to-inspiration time ratio are derived in addition to the entire pattern. In a group of 10 healthy young adults, a phase lag difference of 11.4 +/- 8.5% (mean +/- SD, P < 0.004) was observed between supine and standing postures, possibly ascribed to breathing mechanics. A second group of 15 healthy young adults at supine rest showed stability of the RSA pattern in successive recordings (several weeks apart) as well as individuality among subjects. This may suggest a nonscalar individual long-term index for cardiorespiratory coupling. The method is complementary to the existing statistical and spectral methods. It allows the complete characterization of the primary RSA components and may provide new insight into the effects of vagal activity and changes in clinical conditions.     

Mechanisms of respiratory sinus arrhythmia in patients with mild heart failure

The high-frequency (HF) component of the heart rate variability (HRV) is regarded as an index of cardiac vagal responsiveness. However, when vagal tone is decreased, nonneural mechanisms could account for a significant proportion of the HF component. To test this hypothesis, we examined the HRV spectral power in 20 patients with mild chronic heart failure (CHF) and 11 controls before and during ganglion blockade with trimethaphan camsylate (3-6 mg/min iv). A small HF component was still present during ganglion blockade, and its amplitude did not differ between CHF patients and controls. The average contribution of nonneural oscillations to the HF component was 15% (range 1-77%) in patients with CHF and 3% (range 0. 7-30%) in healthy controls (P < 0.005). During controlled breathing at 0.16 Hz, however, it decreased to 1% (range 0.2-13%) in healthy controls and 5% (range 1-44%) in CHF patients. Our results indicate that the HF component can significantly overestimate cardiac vagal responsiveness in patients with mild CHF. This bias is improved by controlled breathing, since this maneuver increases the vagal contribution to HF without affecting its nonneural component.     

Augmentation of respiratory sinus arrhythmia in response to progressive hypercapnia in conscious dogs

Respiratory sinus arrhythmia (RSA) may serve to enhance pulmonary gas exchange efficiency by matching pulmonary blood flow with lung volume within each respiratory cycle. We examined the hypothesis that RSA is augmented as an active physiological response to hypercapnia. We measured electrocardiograms and arterial blood pressure during progressive hypercapnia in conscious dogs that were prepared with a permanent tracheostomy and an implanted blood pressure telemetry unit. The intensity of RSA was assessed continuously as the amplitude of respiratory fluctuation of heart rate using complex demodulation. In a total of 39 runs of hypercapnia in 3 dogs, RSA increased by 38 and 43% of the control level when minute ventilation reached 10 and 15 l/min, respectively (P < 0.0001 for both), and heart rate and mean arterial pressure showed no significant change. The increases in RSA were significant even after adjustment for the effects of increased tidal volume, respiratory rate, and respiratory fluctuation of arterial blood pressure (P < 0.001). These observations indicate that increased RSA during hypercapnia is not the consequence of altered autonomic balance or respiratory patterns and support the hypothesis that RSA is augmented as an active physiological response to hypercapnia.     

Respiratory sinus arrhythmia is associated with efficiency of pulmonary gas exchange in healthy humans

Respiratory sinus arrhythmia (RSA) may be associated with improved efficiency of pulmonary gas exchange by matching ventilation to perfusion within each respiratory cycle. Respiration rate, tidal volume, minute ventilation (.VE), exhaled carbon dioxide (.VCO(2)), oxygen consumption (.VO(2)), and heart rate were measured in 10 healthy human volunteers during paced breathing to test the hypothesis that RSA contributes to pulmonary gas exchange efficiency. Cross-spectral analysis of heart rate and respiration was computed to calculate RSA and the coherence and phase between these variables. Pulmonary gas exchange efficiency was measured as the average ventilatory equivalent of CO(2) (.VE/.VCO(2)) and O(2) (.VE/.VO(2)). Across subjects and paced breathing periods, RSA was significantly associated with CO(2) (partial r = -0.53, P = 0.002) and O(2) (partial r = -0.49, P = 0.005) exchange efficiency after controlling for the effects of age, respiration rate, tidal volume, and average heart rate. Phase between heart rate and respiration was significantly associated with CO(2) exchange efficiency (partial r = 0.40, P = 0.03). These results are consistent with previous studies and further support the theory that RSA may improve the efficiency of pulmonary gas exchange.     

CO2-dependent components of sinus arrhythmia from the start of breath holding in humans

A substantial portion of sinus arrhythmia in conscious humans appears to be caused by the CO2-dependent central respiratory rhythm. Under some circumstances, therefore, sinus arrhythmia might indicate the presence of the central respiratory rhythm. Humans can voluntarily modify their central respiratory rhythm (e.g., by pacing breathing or by delaying or advancing breaths), but it is not clear what happens to it from the start of breath holding. In this study, we show that sinus arrhythmia persists from the start of breath holds prolonged by preoxygenation. We also show that some of the frequency components of sinus arrhythmia start within each subject's eupneic frequency range and change when end-tidal Pco2 is lowered or raised, as we would expect if the central respiratory rhythm continues from the start of breath holding. We discuss whether sinus arrhythmia can indicate if the central respiratory rhythm continues from the start of breath holding.     

The relationship between respiratory sinus arrhythmia and heart rate during anesthesia in rat.

During inspiration the heart rate (HR) increases and during expiration it decreases. Contribution of respiratory sinus arrhythmia (RSA) to spontaneous heart rate variability (HRV) can be measured as the high frequency (HF) component of variation in consecutive R-R intervals on ECG. In conscious rats, slowing of HR is associated with an increase in HF. The aim of this study was to investigate whether this relationship between HF and HR is preserved during anesthesia in rat. A 15 minutes long ECG signal was recorded from rats (N=15) under moderate chloral hydrate (CHL) anesthesia. Recordings were extended with 45 minutes to investigate the effect of atropine (N=3), against controls (N=3). Short term HRV was investigated in 30 seconds long epochs. HF was considered the frequency band between 0.8 and 1.6 Hz. RSA was quantified as the relative spectral power of the HF. Respiratory frequency (RF) was quantified as the mean spectral frequency within the HF band. One minute estimates of HR, RSA and HF were calculated by averaging 3 epochs of 30 seconds overlapped 50%. The average HR was 427 +/- 3 bpm. The magnitude of RSA was 45 +/- 1% at a RF of 71 +/- 1 rpm. We found that: (1) the decrease in HR that occurs during CHL anesthesia in rat correlates with an increase in RSA; (2) atropine reduces RSA and the time-dependent decrease in HR; (3) the time-dependent increase in RSA is preserved after atropine. We conclude that the correlation between RSA and HR reflects the cardio-pulmonary coupling under parasympathetic control.     

Postural-induced phase shift of respiratory sinus arrhythmia and blood pressure variations: insight from respiratory-phase domain analysis

The purpose of this study is to evaluate the multiple effects of respiration on cardiovascular variability in different postures, by analyzing respiratory sinus arrhythmia (RSA) and respiratory-related blood pressure (BP) variations for systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) in the respiratory-phase domain. The measurements were conducted for 420 s on healthy humans in the sitting and standing positions, while the subjects were continuously monitored for heart rate and BP variability and instantaneous lung volume. The waveforms of RSA and respiratory-related BP variations were extracted as a function of the respiratory phase. In the standing position, the waveforms of the BP variations for SBP, DBP, and PP show their maxima at around the end of expiration (pi rad) and the minima at around the end of inspiration (2 pi rad), while the waveform of RSA is delayed by approximately 0.35 pi rad compared with the BP waveforms. On the other hand, in the sitting position, the phase of the DBP waveform (1.69 pi rad) greatly and significantly (P < 0.01) differs from that in the standing position (1.20 pi rad). Also, the phase of PP is delayed and that of RSA is advanced in the sitting position (P < 0.01). In particular, the phase shift of the DBP waveform is sufficiently large to alter whole hemodynamic fluctuations, affecting the amplitudes of SBP and PP variations. We conclude that the postural change associated with an altered autonomic balance affects not only the amplitude of RSA, but also the phases of RSA and BP variations in a complicated manner, and the respiratory-phase domain analysis used in this study is useful for elucidating the dynamic mechanisms of RSA.     

Contribution of the respiratory rhythm to sinus arrhythmia in normal unanesthetized subjects during positive-pressure mechanical hyperventilation

The precise contribution of the CO2-dependent respiratory rhythm to sinus arrhythmia in eupnea is unclear. The respiratory rhythm and sinus arrhythmia were measured in 12 normal, unanesthetized subjects in normocapnia and hypocapnia during mechanical hyperventilation with positive pressure. In normocapnia (41 +/- 1 mmHg), the respiratory rhythm was always detectable from airway pressure and inspiratory electromyogram activity. The amplitude of sinus arrhythmia (138 +/- 21 ms) during mechanical hyperventilation with positive pressure was not significantly different from that in eupnea. During the same mechanical hyperventilation pattern but in hypocapnia (24 +/- 1 mmHg), the respiratory rhythm was undetectable and the amplitude of sinus arrhythmia was significantly reduced (to 40 +/- 5 ms). These results show a greater contribution to sinus arrhythmia from the respiratory rhythm during hypocapnia caused by mechanical hyperventilation than previously indicated in normal subjects during hypocapnia caused by voluntary hyperventilation. We discuss whether the respiratory rhythm provides the principal contribution to sinus arrhythmia in eupnea.     

Human sinus arrhythmia: inconsistencies of a teleological hypothesis

Respiratory sinus arrhythmia (RSA) may serve an inherent function in optimizing pulmonary gas exchange efficiency via clustering and scattering of heart beats during the inspiratory and expiratory phases of the respiratory cycle. This study sought to determine whether physiological levels of RSA, enhanced by slow paced breathing, caused more heart beats to cluster in inspiration. In 12 human subjects, we analyzed the histogram distribution of heart beats throughout the respiratory cycle during paced breathing at 12, 9, and 6 breaths/min (br/min). The inspiratory period-to-respiratory period ratio was fixed at approximately 0.5. RSA and its relationship with respiration was characterized in the phase domain by average cubic-spline interpolation of electrocardiographic R wave-to-R wave interval fluctuations throughout all respiratory cycles. Although 6 br/min breathing was associated with a significant increase in RSA amplitude (P < 0.01), we observed no significant increase in the proportion of heart beats in inspiration (P = 0.34). Contrary to assumptions in the literature, we observed no significant clustering of heart beats even with high levels of RSA enhanced by slow breathing. The results of this study do not support the hypothesis that RSA optimizes pulmonary gas exchange efficiency via clustering of heart beats in inspiration.     

Limb venous tone and responsiveness in hypertensive humans

Hypertensive (HTN) animal models demonstrate lower venous compliance as well as increased venous tone and responsiveness compared with normotensive (NTN) controls. However, the extent to which findings in experimental animals can be extended to humans is unknown. Forearm and calf venous compliance were quantified in 9 NTN (23 +/- 1 yr) and 9 HTN (24 +/- 1 yr) men at baseline, after administration of nitroglycerin (NTG), during a cold pressor test (CP), and post-handgrip exercise ischemia (PEI). Individual pressure-volume relationships from a cuff deflation protocol (1 mmHg/s) were modeled with a quadratic regression. Regression parameters beta(1) and beta(2) were used to calculate compliance. A one-way ANOVA was used to compare the beta parameters and a repeated-measures ANOVA was used to compare volumes across all pressures (between groups at baseline and within groups during perturbations). Limb venous compliance was similar between groups (forearm: NTN beta(1) = 0.11 +/- 0.01 and beta(2) = -0.00097 +/- 0.0001, HTN beta(1) = 0.10 +/- 0.01 and beta(2) = -0.00088 +/- 0.0001; calf: NTN beta(1) = 0.12 +/- 0.01 and beta(2) = -0.00102 +/- 0.0001, HTN beta(1) = 0.11 +/- 0.01 and beta(2) = -0.00090 +/- 0.0001). However, at baseline, volume across all pressures (i.e., capacitance) was lower in the forearm (P < or = 0.01) and tended to be lower in the calf (P = 0.08) in HTN subjects. Venous compliance was not altered by any perturbation in either group. Forearm volume was increased during NTG in HTN subjects only. While venous compliance was similar between NTN and HTN adults, HTN adults have lower forearm venous capacitance (volume) which is increased with NTG. These data suggest that young HTN adults may have augmented venous smooth muscle tone compared with NTN controls.     

Nitric oxide regulates retinal vascular tone in humans

The purpose of the present study was to investigate the contribution of basal nitric oxide (NO) on retinal vascular tone in humans. In addition, we set out to elucidate the role of NO in flicker-induced retinal vasodilation in humans. Twelve healthy young subjects were studied in a three-way crossover design. Subjects received an intravenous infusion of either placebo or NG-monomethyl-L-arginine (L-NMMA; 3 or 6 mg/kg over 5 min), an inhibitor of NO synthase. Thereafter, diffuse luminance flicker was consecutively performed for 16, 32, and 64 s at a frequency of 8 Hz. The effect of L-NMMA on retinal arterial and venous diameter was assessed under resting conditions and during the hyperemic flicker response. Retinal vessel diameter was measured with a Zeiss retinal vessel analyzer. L-NMMA significantly reduced arterial diameter (3 mg/kg: -2%; 6 mg/kg: -4%, P < 0.001) and venous diameter (3 mg/kg: -5%; 6 mg/kg: -8%, P < 0.001). After placebo infusion, flicker induced a significant increase in retinal vessel diameter (P < 0.001). At a flicker duration of 64 s, arterial diameter increased by 4% and venous diameter increased by 3%. L-NMMA did not abolish these hyperemic responses but blunted venous vasodilation (P = 0.017) and arterial vasodilation (P = 0.02) in response to flicker stimulation. Our data indicate that NO contributes to basal retinal vascular tone in humans. In addition, NO appears to play a role in flicker-induced vasodilation of the human retinal vasculature.