Human baroreflex rhythms persist during handgrip and muscle ischaemia.

AIM: To determine whether physiological, rhythmic fluctuations of vagal baroreflex gain persist during exercise, post-exercise ischaemia and recovery. METHODS: We studied responses of six supine healthy men and one woman to a stereotyped protocol comprising rest, handgrip exercise at 40% maximum capacity to exhaustion, post-exercise forearm ischaemia and recovery. We measured electrocardiographic R-R intervals, photoplethysmographic finger arterial pressures and peroneal nerve muscle sympathetic activity. We derived vagal baroreflex gains from a sliding (25-s window moved by 2-s steps) systolic pressure-R-R interval transfer function at 0.04-0.15 Hz. RESULTS: Vagal baroreflex gain oscillated at low, nearly constant frequencies throughout the protocol (at approx. 0.06 Hz - a period of about 18 s); however, during exercise, most oscillations were at low-gain levels, and during ischaemia and recovery, most oscillations were at high-gain levels. CONCLUSIONS: Vagal baroreflex rhythms are not abolished by exercise, and they are not overwhelmed after exercise during ischaemia and recovery.

Perfusion heterogeneity in human skeletal muscle: fractal analysis of PET data.

Muscle blood flow has been shown to be heterogeneous at the voxel by voxel level in positron emission tomography (PET) studies using oxygen-15 labelled water. However, the limited spatial resolution of the imaging device does not allow direct measurement of true vascular flow heterogeneity. Fractal dimension (D) obtained by fractal analysis describes the relationship between the relative dispersion and the size of the region studied, and has been used for the assessment of perfusion heterogeneity in microvascular units. This study was undertaken to evaluate fractal characteristics of PET perfusion data and to estimate perfusion heterogeneity in microvascular units. Skeletal muscle blood flow was measured in healthy subjects using [15O]water PET and the fractal characteristics of blood flow in resting and exercising skeletal muscle were analysed. The perfusion heterogeneity in microvascular units was estimated using the measured heterogeneity (relative dispersion, RD = SD/mean) and D values. Heterogeneity due to methodological factors was estimated with phantoms and subtracted from the flow data. The number of aggregated voxels was inversely correlated with RD both in phantoms (Pearson r = -0.96-0.97) and in muscle (Pearson r = -0.94) when both parameters were expressed using a logarithmic scale. Fractal dimension was similar between exercising (1.13) and resting (1.14) muscles and significantly lower than the values in the phantoms with different activity levels (1.27-1.29). Measured flow heterogeneity values were 20% +/- 6% (exercise) and 27% +/- 5% (rest, P < 0.001), whereas estimated flow heterogeneity values in microvascular units (1 mm3) were 35% +/- 14% (exercise) and 49% +/- 14% (rest, P < 0.01). In conclusion, these results show that it is feasible to apply fractal analysis to PET perfusion data. When microvascular flow heterogeneity is estimated using fractals, perfusion appears to be more heterogeneous in microvascular units than when obtained by routine spatial analysis of PET data. Analysis of flow heterogeneity using PET and fractals could provide new insight into physiological conditions and diseases associated with changes in peripheral vascular function.

Comparison of vagal baroreflex function in nonpregnant women and in women with normal pregnancy, preeclampsia, or gestational hypertension.

OBJECTIVE: Our aim was to compare baroreflex function among nonpregnant women and among women with normal pregnancy, preeclampsia, or gestational hypertension. STUDY DESIGN: Baroreflex function was tested in 20 women with preeclampsia, in 20 age- and gestational age-matched normotensive gravid women, in 20 age-matched nonpregnant women, and in 20 nonmatched women with gestational hypertension. The baroreflex was measured by several modalities. RESULTS: Vagal baroreflex gain measured by cross-spectral analysis of parallel spontaneous heart rate and blood pressure changes is significantly decreased in normal pregnancy (15.8 +/- 7.2 vs 10.8 +/- 4.1 ms/mm Hg; P = 0.001), in comparison with vagal baroreflex gain in nonpregnant women. Baroreflex gain is further reduced in preeclamptic pregnancy (10.8 +/- 4.1 vs 7.2 +/- 2.6 ms/mm Hg; P = 0.003) and in gestational hypertension (10.8 +/- 4.1 vs 6.5 +/- 2.7 ms/mm Hg; P = 0.001), compared with that in normal pregnancy. Similar differences were seen with other baroreflex testing modalities. CONCLUSIONS: The normal reduction of baroreflex gain in pregnancy is further depressed in subjects with hypertensive disorders of pregnancy.

Respiratory modulation of human autonomic rhythms.

We studied the influence of three types of breathing [spontaneous, frequency controlled (0.25 Hz), and hyperventilation with 100% oxygen] and apnea on R-R interval, photoplethysmographic arterial pressure, and muscle sympathetic rhythms in nine healthy young adults. We integrated fast Fourier transform power spectra over low (0.05-0.15 Hz) and respiratory (0.15-0.3 Hz) frequencies; estimated vagal baroreceptor-cardiac reflex gain at low frequencies with cross-spectral techniques; and used partial coherence analysis to remove the influence of breathing from the R-R interval, systolic pressure, and muscle sympathetic nerve spectra. Coherence among signals varied as functions of both frequency and time. Partialization abolished the coherence among these signals at respiratory but not at low frequencies. The mode of breathing did not influence low-frequency oscillations, and they persisted during apnea. Our study documents the independence of low-frequency rhythms from respiratory activity and suggests that the close correlations that may exist among arterial pressures, R-R intervals, and muscle sympathetic nerve activity at respiratory frequencies result from the influence of respiration on these measures rather than from arterial baroreflex physiology. Most importantly, our results indicate that correlations among autonomic and hemodynamic rhythms vary over time and frequency, and, thus, are facultative rather than fixed.

Effects of noradrenaline on human vagal baroreflexes.

BACKGROUND: Baroreflex sensitivity (BRS) is depressed in conditions associated with high sympathetic nerve activity in proportion to circulating noradrenaline (NA) levels. Despite the prognostic importance of measurements of BRS in patients, there is little information on how high NA levels affect arterial baroreflex function. AIM: To understand better the role of NA in cardiovascular homeostasis. METHODS: We gave incremental intravenous NA infusions (at 50 and 100 ng/kg/min) to 12 healthy young men. We measured RR intervals and photoplethysmographic arterial pressures and estimated BRS with cross-spectral and sequence methods during metronome-guided respiration at 0.25 Hz. RESULTS: The high NA infusion rate significantly increased respiratory-frequency (0.15-0.40 Hz) RR interval spectral power and decreased low-frequency (0.04-0.15 Hz) systolic pressure spectral power compared with baseline levels (P < 0.05 for both). Cross-spectral BRS increased from an average (+/- SD) baseline level of 17.3+/-6.6 to 34.1+/-20.8 ms/mmHg at the high NA infusion rate (P < 0.05). Sequence BRS values did not increase significantly during NA infusions. The percentage of sequences with parallel changes in systolic pressures and RR intervals decreased progressively from a baseline level of 16.0+/-12.9 to 10.1+/-7.4 during the low NA infusion rate and to 6.2+/-6.2% during the high rate (P < 0.05 and 0.01, respectively). CONCLUSIONS: Increases in circulating NA to high physiological levels do not depress BRS but interfere with the close baroreflex-mediated coupling that is usually present between arterial pressure and heart rate.

Nine months in space: effects on human autonomic cardiovascular regulation.

We studied three Russian cosmonauts to better understand how long-term exposure to microgravity affects autonomic cardiovascular control. We recorded the electrocardiogram, finger photoplethysmographic pressure, and respiratory flow before, during, and after two 9-mo missions to the Russian space station Mir. Measurements were made during four modes of breathing: 1) uncontrolled spontaneous breathing; 2) stepwise breathing at six different frequencies; 3) fixed-frequency breathing; and 4) random-frequency breathing. R wave-to-R wave (R-R) interval standard deviations decreased in all and respiratory frequency R-R interval spectral power decreased in two cosmonauts in space. Two weeks after the cosmonauts returned to Earth, R-R interval spectral power was decreased, and systolic pressure spectral power was increased in all. The transfer function between systolic pressures and R-R intervals was reduced in-flight, was reduced further the day after landing, and had not returned to preflight levels by 14 days after landing. Our results suggest that long-duration spaceflight reduces vagal-cardiac nerve traffic and decreases vagal baroreflex gain and that these changes may persist as long as 2 wk after return to Earth.

Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine.

We evaluated a method of baroreflex testing involving sequential intravenous bolus injections of nitroprusside followed by phenylephrine and phenylephrine followed by nitroprusside in 18 healthy men and women, and we drew inferences regarding human sympathetic and vagal baroreflex mechanisms. We recorded the electrocardiogram, photoplethysmographic finger arterial pressure, and peroneal nerve muscle sympathetic activity. We then contrasted least squares linear regression slopes derived from the depressor (nitroprusside) and pressor (phenylephrine) phases with 1) slopes derived from spontaneous fluctuations of systolic arterial pressures and R-R intervals, and 2) baroreflex gain derived from cross-spectral analyses of systolic pressures and R-R intervals. We calculated sympathetic baroreflex gain from integrated muscle sympathetic nerve activity and diastolic pressures. We found that vagal baroreflex slopes are less when arterial pressures are falling than when they are rising and that this hysteresis exists over pressure ranges both below and above baseline levels. Although pharmacological and spontaneous vagal baroreflex responses correlate closely, pharmacological baroreflex slopes tend to be lower than those derived from spontaneous fluctuations. Sympathetic baroreflex slopes are similar when arterial pressure is falling and rising; however, small pressure elevations above baseline silence sympathetic motoneurons. Vagal, but not sympathetic baroreflex gains vary inversely with subjects' ages and their baseline arterial pressures. There is no correlation between sympathetic and vagal baroreflex gains. We recommend repeated sequential nitroprusside followed by phenylephrine doses as a simple, efficientmeans to provoke and characterize human vagal and sympathetic baroreflex responses.

Human responses to upright tilt: a window on central autonomic integration.

1. We examined interactions between haemodynamic and autonomic neural oscillations during passive upright tilt, to gain better insight into human autonomic regulatory mechanisms. 2. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, respiration and peroneal nerve muscle sympathetic activity in nine healthy young adults. Subjects breathed in time with a metronome at 12 breaths min-1 (0.2 Hz) for 5 min each, in supine, and 20, 40, 60, 70 and 80 deg head-up positions. We performed fast Fourier transform (and autoregressive) power spectral analyses and integrated low-frequency (0.05-0.15 Hz) and respiratory-frequency (0. 15-0.5 Hz) spectral powers. 3. Integrated areas of muscle sympathetic bursts and their low- and respiratory-frequency spectral powers increased directly and significantly with the tilt angle. The centre frequency of low-frequency sympathetic oscillations was constant before and during tilt. Sympathetic bursts occurred more commonly during expiration than inspiration at low tilt angles, but occurred equally in expiration and inspiration at high tilt angles. 4. Systolic and diastolic pressures and their low- and respiratory-frequency spectral powers increased, and R-R intervals and their respiratory-frequency spectral power decreased progressively with the tilt angle. Low-frequency R-R interval spectral power did not change. 5. The cross-spectral phase angle between systolic pressures and R-R intervals remained constant and consistently negative at the low frequency, but shifted progressively from positive to negative at the respiratory frequency during tilt. The arterial baroreflex modulus, calculated from low-frequency cross-spectra, decreased at high tilt angles. 6. Our results document changes of baroreflex responses during upright tilt, which may reflect leftward movement of subjects on their arterial pressure sympathetic and vagal response relations. The intensity, but not the centre frequency of low-frequency cardiovascular rhythms, is modulated by the level of arterial baroreceptor input. Tilt reduces respiratory gating of sympathetic and vagal motoneurone responsiveness to stimulatory inputs for different reasons; during tilt, sympathetic stimulation increases to a level that overwhelms the respiratory gate, and vagal stimulation decreases to a level below that necessary for maximal respiratory gating to occur.

Altered cardiovascular autonomic regulation after salmeterol treatment in asthmatic children.

The effects of therapeutic 4 weeks' inhaled salmeterol treatment on the cardiovascular and respiratory autonomic nervous regulation was studied in 11 asthmatic children using inhaled corticosteroid medication. The study followed a randomized, double-blind, placebo-controlled cross-over design. The salmeterol dose was 50 micrograms twice daily. The 4-week salmeterol treatment increased baseline heart rate, low-frequency/high-frequency (LF/HF) variability ratio of R-R intervals, LF variability of systolic arterial pressure (SAP) and maximum tidal volume during the deep breathing test, as well as morning and evening peak expiratory flow (PEF) values. The 4-week salmeterol treatment decreased baseline HF variability of R-R intervals. As a response to the acute 600 micrograms of salbutamol, the changes in heart rate, HF variability of R-R intervals and diastolic blood pressure were significantly smaller after 4 weeks' salmeterol treatment. In conclusion, 4 weeks' therapeutic salmeterol treatment decreases basal cardiovagal reactivity, increases sympathetic dominance in the cardiovascular autonomic balance and improves pulmonary function. A tolerance develops in the cardiovascular response but not in the bronchodilatory response.

Low-dose transdermal scopolamine decreases blood pressure in mild essential hypertension.

BACKGROUND: Increasing cardiovascular parasympathetic nervous activity could have antihypertensive effects. Low-dose transdermal scopolamine increases vagal-cardiac modulation of sinus node and baroreflex sensitivity in healthy subjects and in cardiac patients. OBJECTIVE: To study the short-term effects of transdermal scopolamine on blood pressure and cardiovascular autonomic control in patients with mild essential hypertension. DESIGN: A randomized, double-blind, placebo-controlled crossover trial with 12 untreated middle-aged [aged 39+/-5 years (mean+/-SD)] patients with mild essential hypertension. METHODS: We recorded the electrocardiogram, auscultatory sphygmomanometric and continuous photoplethysmographic finger arterial pressure, and spirometry signals with patients supine and 70 degrees tilted during controlled (0.25 Hz) breathing. Cardiovascular autonomic regulation was analyzed with power spectrum analysis of R-R interval and arterial pressure variability and a spontaneous sequence method for baroreflex sensitivity. In addition, a deep-breathing test was performed to assess maximal breathing-related sinus arrhythmia. RESULTS: Transdermal scopolamine treatment significantly decreased blood pressure both when patients lay supine and when they were in the 70 degrees tilted position. Scopolamine also slowed heart rate and increased baroreflex sensitivity and R-R interval high-frequency variability for both body positionings. In addition, scopolamine accentuated respiratory sinus arrhythmia during deep breathing and blunted the tilt-induced increase in heart rate. Scopolamine did not affect blood pressure variability. CONCLUSIONS: Transdermal scopolamine decreases arterial pressure, increases baroreflex sensitivity and accentuates vagal-cardiac modulation of sinus node in patients with mild hypertension. Our study supports the hypothesis that increasing cardiovascular parasympathetic activity could have antihypertensive effects in essential hypertension.

The dose-response effects of terbutaline on the variability, approximate entropy and fractal dimension of heart rate and blood pressure.

AIMS: To study the dose-response effects of intravenous terbutaline on the cardiovascular and respiratory autonomic nervous regulation. METHODS: The study followed a randomized, placebo-controlled crossover design in six healthy adult volunteers. The terbutaline dose ranged from 10 to 30 microg min(-1) We continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry in supine and upright positions at baseline and during 3 h drug infusion. The periodic variability components of R-R intervals (time between successive heart beats) and SAP in relation to respiration were assessed using spectral analysis techniques. The regularity of the time series was assessed by approximate entropy (ApEn) and the convolutedness by fractal dimension (FD). RESULTS: Terbutaline dose-dependently decreased total variability of R-R intervals, low frequency (LF) variability of R-R intervals (10 s waves), high frequency (HF) variability of R-R intervals (respiratory variability), total variability of SAP, HF variability of SAP, baroreflex sensitivity, plasma potassium concentration, approximate entropy of R-R interval and of SAP as well as fractal dimension of R-R interval. Terbutaline dose-dependently increased heart rate, LF/HF ratios of R-R intervals and of SAP, LF variability of SAP, minute ventilation and plasma terbutaline concentration. CONCLUSIONS: Terbutaline infusion decreases parasympathetic cardiovascular reactivity, baroreflex sensitivity, dimensionality of heart rate and plasma potassium concentration; it increases sympathetic dominance in cardiovascular autonomic balance, minute ventilation, and the regularity of heart rate and blood pressure time series.

Altered cardiovascular autonomic regulation after 2-week inhaled salbutamol treatment in asthmatic children.

UNLABELLED: We studied the effects of therapeutic 2-week inhaled salbutamol treatment on the cardiovascular and respiratory autonomic nervous regulation in eight children with asthma. In this randomized, double-blind, placebo-controlled crossover study our test subjects inhaled 200 microg salbutamol or placebo thrice daily for 14 days. After the 14-day treatment we continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry at baseline and the response to a single 600 microg salbutamol inhalation. The periodic variability components of R-R intervals (the time between successive heart beats) and SAP in relation to respiration were assessed using spectral analysis. Two-week salbutamol treatment increased baseline low frequency (LF) variability (P < 0.05) and low frequency/high frequency (LF/HF) variability ratio of R-R intervals (P < 0.05) when compared to the placebo treatment. As a response to the single salbutamol inhalation the increase in LF/HF ratio of R-R intervals was smaller after the 2-week salbutamol treatment (P < 0.01). No significant differences were found in the bronchodilatory response after the treatment period. CONCLUSION: Two-week salbutamol treatment shifts the cardiovascular autonomic regulation to a new level characterized by greater sympathetic responsiveness and slight beta2-receptor tolerance. Because these effects were evident 18 h after cessation of the therapy they are likely to reflect the adaptation of organ responses to regular therapy or altered central autonomic regulation rather than direct drug effect. A slight tolerance developed in the sympathovagal cardiac response but not in the bronchodilatory response.

Baroreflex sensitivity in drug-treated systemic hypertension.

Baroreflex sensitivity is impaired in patients with systemic hypertension. The persistence of abnormal baroreflex sensitivity despite adequate blood pressure control may be one of the reasons why the effect of antihypertensive therapy on coronary artery disease mortality has been less than expected on the basis of the achieved blood pressure levels.

Vagal and sympathetic mechanisms in patients with orthostatic vasovagal syncope.

BACKGROUND: Autonomic and particularly sympathetic mechanisms play a central role in the pathophysiology of vasovagal syncope. We report direct measurements of muscle sympathetic nerve activity in patients with orthostatic vasovagal syncope. METHODS AND RESULTS: We studied 53 otherwise healthy patients with orthostatic syncope. We measured RR intervals and finger arterial pressures and in 15 patients, peroneal nerve muscle sympathetic activity before and during passive 60 degree head-up tilt, with low-dose intravenous isoproterenol if presyncope did not develop by 15 minutes. We measured baroreflex gain before tilt with regression of RR intervals or sympathetic bursts on systolic or diastolic pressures after sequential injections of nitroprusside and phenylephrine. Orthostatic vasovagal reactions occurred in 21 patients, including 7 microneurography patients. Presyncopal and nonsyncopal patients had similar baseline RR intervals, arterial pressure, and muscle sympathetic nerve activity. Vagal baroreflex responses were significantly impaired at arterial pressures below (but not above) baseline levels in presyncopal patients. Initial responses to tilt were comparable; however, during the final 200 seconds of tilt, presyncopal patients had lower RR intervals and diastolic pressures than nonsyncopal patients and gradual reduction of arterial pressure and sympathetic activity. Frank presyncope began abruptly with precipitous reduction of arterial pressure, disappearance of muscle sympathetic nerve activity, and RR interval lengthening. CONCLUSIONS: Patients with orthostatic vasovagal reactions have impaired vagal baroreflex responses to arterial pressure changes below resting levels but normal initial responses to upright tilt. Subtle vasovagal physiology begins before overt presyncope. The final trigger of human orthostatic vasovagal reactions appears to be the abrupt disappearance of muscle sympathetic nerve activity.

Cross spectral analysis in assessment of baroreflex gain in patients with coronary artery disease.

BACKGROUND: Interest in determination of baroreflex sensitivity in clinical practice is growing because of its prognostic information in patients with heart disease. The purpose of the present study was to assess the feasibility of cross spectral analysis in the determination of baroreflex gain from spontaneous RR interval and systolic pressure fluctuations, and to compare the results to the traditional pharmacological method in patients with coronary artery disease. Methods. We measured the gain and time lag between RR interval and systolic pressure variabilities in the frequency domain, and compared baroreflex indexes obtained by this technique with standard phenylephrine tests in 32 patients with coronary artery disease. Results. Cross spectral analysis by fast Fourier transform techniques yielded acceptable (> 0.5) coherence between systolic pressure and RR interval in the mid- (0.07-0.15 Hz) and in the respiratory-frequency (0.15-0.40 Hz) band fluctuations in 30 patients (94%), with mean coherences of 0.69 and 0.74. The mean phase difference in the mid-frequency hand was greater than in the respiratory-frequency band (-83 vs -23 degrees, P < 0.001), suggesting that the mid-frequency fluctuations of RR intervals followed nearly 2 seconds after pressure changes, while respiratory-frequency fluctuations of RR intervals occurred nearly concomitantly with systolic pressure. The mean baroreflex slope derived from the bolus phenylephrine technique was 6.2 ms/mmHg (range 1.6-16.0), 5 patients had an abnormally low (<3 ms/mmHg) baroreflex sensitivity. Baroreflex gain determined by cross spectral analysis from the mid-frequency band correlated significantly (r = 0.60, P < 0.001, n = 27) with the baroreflex gain determined by the phenylephrine test, while the correlation in the respiratory-frequency band was not significant (r = 0.35, P = 0.09, n = 26). Conclusions. Baroreflex slopes derived from cross spectral techniques provide reliable (but not perfect) information regarding baroreflex gain derived from the clasic phenylephrine technique, even in patients with depressed baroreflex responses. Cross correlation calculation of spontaneous baroreflex slopes should be limited to data in the mid-frequency range, where the slopes are likely to reflect simple baroreflex physiology.

Effects of low-dose transdermal scopolamine on autonomic cardiovascular control in healthy young subjects.

We studied how posture influences the effects of transdermal scopolamine on autonomic cardiovascular regulation in a randomized, double-blind, placebo-controlled crossover study of 10 healthy young volunteers. We recorded the electrocardiogram and auscultatory sphygmomanometric and continuous non-invasive finger arterial pressure (Finapres device) to obtain signals for the beat-by-beat R-R interval and systolic, mean and diastolic pressures. R-R interval and arterial pressure variabilities were characterized by power spectral analysis. Scopolamine increased the mean R-R intervals and reduced arterial pressure in both the supine and the standing positions, but did not affect blood pressure variability. Scopolamine increased the total variability of R-R interval and its mid- (0.07-0.15 Hz) and high- (0.15-0.40 Hz) frequency band power in the standing position during controlled breathing at 0.25 Hz. In the supine position, scopolamine did not affect R-R interval variability. In the deep breathing test, scopolamine increased the maximal expiratory-inspiratory R-R interval ratio. This study showed that low-dose scopolamine increases vagal cardiac inhibition in both supine and standing positions in healthy volunteers. However, scopolamine increases heart rate variability only in the standing position during partial vagal withdrawal. The study also demonstrates that transdermal scopolamine decreases blood pressure in healthy young subjects.

Cardiovascular autonomic regulation in asthmatic children evidenced by spectral analysis of heart rate and blood pressure variability.

The objective of the study was to investigate the features of cardiovascular and respiratory autonomic nervous regulation in asthmatic and control children. Cardiorespiratory reactivity was studied by continuous and non-invasive recording of the electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry in supine and upright positions and during a deep breathing test in 19 children with bronchial asthma and 10 healthy control children (age 8-11 years). The periodic variability components of R-R intervals (the time between successive heart beats) and SAP in relation to respiration were assessed using spectral analysis techniques. Nine asthmatic children without beta2-agonist medication had a lower respiratory rate and larger high frequency (HF) variability of SAP than the controls, and 10 asthmatic children with beta2-agonist medication had greater low-frequency (LF) variability of SAP and LF/HF ratio of R-R intervals, but their respiratory rate did not differ from the controls. No intergroup differences were found in the postural change of variables. Stable bronchial asthma appears to increase respiratory-induced alterations in systolic blood pressure in children. Beta2-agonist medication, on the other hand, increases sympathetic cardiovascular activity in children with asthma.