Low-frequency Blood Pressure Oscillations Research Articles

Predicting Vasovagal Responses: A Model-Based and Machine Learning Approach.

Vasovagal syncope (VVS) or neurogenically induced fainting has resulted in falls, fractures, and death. Methods to deal with VVS are to use implanted pacemakers or beta blockers. These are often ineffective because the underlying changes in the cardiovascular system that lead to the syncope are incompletely understood and diagnosis of frequent occurrences of VVS is still based on history and a tilt test, in which subjects are passively tilted from a supine position to 20° from the spatial vertical (to a 70° position) on the tilt table and maintained in that orientation for 10–15 min. Recently, is has been shown that vasovagal responses (VVRs), which are characterized by transient drops in blood pressure (BP), heart rate (HR), and increased amplitude of low frequency oscillations in BP can be induced by sinusoidal galvanic vestibular stimulation (sGVS) and were similar to the low frequency oscillations that presaged VVS in humans. This transient drop in BP and HR of 25 mmHg and 25 beats per minute (bpm), respectively, were considered to be a VVR. Similar thresholds have been used to identify VVR's in human studies as well. However, this arbitrary threshold of identifying a VVR does not give a clear understanding of the identifying features of a VVR nor what triggers a VVR. In this study, we utilized our model of VVR generation together with a machine learning approach to learn a separating hyperplane between normal and VVR patterns. This methodology is proposed as a technique for more broadly identifying the features that trigger a VVR. If a similar feature identification could be associated with VVRs in humans, it potentially could be utilized to identify onset of a VVS, i.e, fainting, in real time.

Study of heart rate recovery and cardiovascular autonomic modulation in healthy participants after submaximal exercise

Heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS) provide important information on cardiovascular autonomic control. However, little is known about the reorganization of HRV, BPV, and BRS after aerobic exercise. While there is a positive relationship between heart rate (HR) recovery rate and cardiorespiratory fitness, it is unclear whether there is a relationship between cardiorespiratory fitness and reorganization of cardiovascular autonomic modulation during recovery. Thus, this study aimed to investigate whether cardiorespiratory fitness influences the cardiovascular autonomic modulation recovery, after a cardiopulmonary exercise test. Sixty men were assigned into groups according to their cardiorespiratory fitness: low cardiorespiratory fitness (LCF = VO2: 22–38 mL kg−1 min−1), moderate (MCF = VO2: 38–48 mL kg−1 min−1), and high (HCF = VO2 > 48 mL kg−1 min−1). HRV (linear and non-linear analysis) and BPV (spectral analysis), and BRS (sequence method) were performed before and after a cardiopulmonary exercise test. The groups with higher cardiorespiratory fitness had lower baseline HR values and HR recovery time after the cardiopulmonary exercise test. On comparing rest and recovery periods, the spectral analysis of HRV showed a decrease in low-frequency (LF) oscillations in absolute units and high frequency (HF) in absolute and normalized units. It also showed increases in LF oscillations of blood pressure. Nonlinear analysis showed a reduction in approximate entropy (ApEn) and in Poincare Plot parameters (SD1 and SD2), accompanied by increases in detrended fluctuation analysis (DFA) parameters α1 and α2. However, we did not find differences in cardiovascular autonomic modulation parameters and BRS in relation to cardiorespiratory fitness neither before nor after the cardiopulmonary test. We concluded that cardiorespiratory fitness does not affect cardiovascular autonomic modulations after cardiopulmonary exercise test, unlike HR recovery.

Low-frequency blood pressure oscillations and inotrope treatment failure in premature infants.

The underlying mechanism as to why some hypotensive preterm infants do not respond to inotropic medications remains unclear. For these infants, we hypothesize that impaired vasomotor function is a significant factor and is manifested through a decrease in low-frequency blood pressure variability across regulatory components of vascular tone. Infants born ≤28 wk estimated gestational age underwent prospective recording of mean arterial blood pressure for 72 h after birth. After error correction, root-mean-square spectral power was calculated for each valid 10-min data frame across each of four frequency bands (B1, 0.005-0.0095 Hz; B2, 0.0095-0.02 Hz; B3, 0.02-0.06 Hz; and B4, 0.06-0.16) corresponding to different components of vasomotion control. Forty infants (twenty-nine normotensive control and eleven inotrope-exposed) were included with a mean ± SD estimated gestational age of 25.2 ± 1.6 wk and birth weight 790 ± 211 g. 9.7/11.8 Million (82%) data points were error-free and used for analysis. Spectral power across all frequency bands increased with time, although the magnitude was 20% less in the inotrope-exposed infants. A statistically significant increase in spectral power in response to inotrope initiation was noted across all frequency bands. Infants with robust blood pressure response to inotropes had a greater increase compared with those who had limited or no blood pressure response. In this study, hypotensive infants who require inotropes have decreased low-frequency variability at baseline compared with normotensive infants, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure.NEW & NOTEWORTHY In this study, we examine patterns of low-frequency oscillations in blood pressure variability across regulatory components of vascular tone in normotensive and hypotensive infants exposed to inotropic medications. We found that hypotensive infants who require inotropes have decreased low-frequency variability at baseline, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure.

Vestibular Activation Habituates the Vasovagal Response in the Rat.

Vasovagal syncope is a significant medical problem without effective therapy, postulated to be related to a collapse of baroreflex function. While some studies have shown that repeated static tilts can block vasovagal syncope, this was not found in other studies. Using anesthetized, male Long–Evans rats that were highly susceptible to generation of vasovagal responses, we found that repeated activation of the vestibulosympathetic reflex (VSR) with ±2 and ±3 mA, 0.025 Hz sinusoidal galvanic vestibular stimulation (sGVS) caused incremental changes in blood pressure (BP) and heart rate (HR) that blocked further generation of vasovagal responses. Initially, BP and HR fell ≈20–50 mmHg and ≈20–50 beats/min (bpm) into a vasovagal response when stimulated with Sgv\\S in susceptible rats. As the rats were continually stimulated, HR initially rose to counteract the fall in BP; then the increase in HR became more substantial and long lasting, effectively opposing the fall in BP. Finally, the vestibular stimuli simply caused an increase in BP, the normal sequence following activation of the VSR. Concurrently, habituation caused disappearance of the low-frequency (0.025 and 0.05 Hz) oscillations in BP and HR that must be present when vasovagal responses are induced. Habituation also produced significant increases in baroreflex sensitivity (p < 0.001). Thus, repeated low-frequency activation of the VSR resulted in a reduction and loss of susceptibility to development of vasovagal responses in rats that were previously highly susceptible. We posit that reactivation of the baroreflex, which is depressed by anesthesia and the disappearance of low-frequency oscillations in BP and HR are likely to be critically involved in producing resistance to the development of vasovagal responses. SGVS has been widely used to activate muscle sympathetic nerve activity in humans and is safe and well tolerated. Potentially, it could be used to produce similar habituation of vasovagal syncope in humans.

Arterial Pressure, Heart Rate, and Cerebral Hemodynamics Across the Adult Life Span.

Age-related alterations in systemic and cerebral hemodynamics are not well understood. The purpose of this study is to characterize age-related alterations in beat-to-beat oscillations in arterial blood pressure (BP), heart rate (HR), cerebral blood flow (CBF), cardiac baroreflex sensitivity, and dynamic cerebral autoregulation across the adult life span. We studied 136 healthy adults aged 21 to 80 years (60% women). Beat-to-beat BP, HR, and CBF velocity were measured at rest and during sit-stand maneuvers to mimic effects of postural changes on BP and CBF. Transfer function analysis was used to assess baroreflex sensitivity and dynamic cerebral autoregulation. Carotid-femoral pulse wave velocity was measured to assess central arterial stiffness. Advanced aging was associated with elevated carotid-femoral pulse wave velocity, systolic and pulse BP, cerebrovascular resistance, and CBF pulsatility, but reduced mean CBF velocity. Compared with the young and middle-aged, older adults had lower beat-to-beat BP, HR, and CBF variability in the low-frequency ranges at rest, but higher BP and CBF variability during sit-stand maneuvers. Baroreflex sensitivity was reduced, whereas dynamic cerebral autoregulation gain was elevated at rest in older adults. Multiple linear regression analysis indicated that systolic BP variability is correlated positively with carotid-femoral pulse wave velocity independent of HR variability. In conclusion, advanced aging is associated with elevated pulsatility in BP and CBF; reduced beat-to-beat low-frequency oscillations in BP, HR, and CBF; and impaired baroreflex sensitivity and dynamic cerebral autoregulation at rest. The augmented BP and CBF variability in older adults during sit-stand maneuvers indicate diminished cardiovascular regulatory capability and increased hemodynamic stress on the cerebral circulation with aging.

Cardiovascular variability is similarly altered in coronary patients with normal left ventricular function and in heart failure patients.

After myocardial infarction (MI), baroreflex function is impaired and heart rate (HR) variability is reduced. An impaired baroreflex has been observed also in coronary patients with no previous MI, leading to hypothesize alterations of HR variability also in these patients. The aim of the present work was, therefore, to study whether and to what extent cardiovascular variability is altered in coronary patients with no previous MI. Thirty-two individuals were studied: eleven patients with coronary artery disease but no previous MI [coronary artery disease (CAD)], eleven patients with a reduced left ventricular ejection fraction [congestive heart failure (CHF)] and ten age-matched controls (CNT). Overall HR variability was significantly and similarly reduced in CAD (630 ± 272 ms) and CHF patients (594 ± 395 ms) with respect to CNT (1405 ± 837 ms), this being the case also for the low and high frequency spectral components. Low-frequency oscillations of blood pressure (BP) were also significantly and similarly less pronounced in CAD (0.7 ± 0.7 mmHg) and CHF patients (0.7 ± 0.7 mmHg) compared with CNT (1.8 ± 1.4 mmHg). Moreover, both CAD and CHF patients showed a significantly reduced baroreflex function and an increased pulse-wave velocity with respect to CNT. Our study shows that in coronary patients with no MI and no left ventricular dysfunction, there is a profound alteration of both HR and BP variability as in CHF patients, presumably because of a marked impairment of the autonomic modulation of the heart and blood vessels.

Relationship of Heart Rate Variability to Sleepiness in Patients with Obstructive Sleep Apnea with and without Heart Failure

Many patients with severe obstructive sleep apnea (OSA) do not complain of excessive daytime sleepiness (EDS), possibly due to increased sympathetic nervous activity (SNA) and accompanying heightened alertness. We hypothesized that in patients with OSA, those without subjective EDS (Epworth Sleepiness Scale, ESS score < 11) would have higher very low frequency (VLF) heart rate variability (HRV) during sleep, reflecting greater sympathetic heart rate modulation than patients with an ESS score ≥ 11. Patients with severe OSA (AHI ≥ 30: 26 with and 65 without heart failure) were divided into those with and without EDS. Heart rate (HR) signals were acquired in stage 2 sleep during periods of recurrent apneas and hypopneas and submitted to coarse graining spectral analysis, which extracts harmonic, neurally mediated contributions to HRV from total spectral power. Because the apnea-hyperpnea cycle entrains muscle SNA at VLF (0 to 0.04 Hz), VLF power was our principal between-group comparison. Subjects without EDS had higher harmonic VLF power (944 ± 839 vs 447 ± 461 msec(2), p = 0.003) than those with EDS, irrespective of the presence or absence of heart failure (1218 ± 944 vs 426 ± 299 msec(2), p = 0.043, and 1029 ± 873 vs 503 ± 533 msec(2), p = 0.003, respectively). ESS scores correlated inversely with VLF power in all (r = -0.294, p = 0.005) and in heart failure subjects (r = -0.468, p = 0.016). Patients with severe OSA but without EDS have higher VLF-HRV than those with EDS. This finding suggests that patients with severe OSA but without EDS have greater sympathetic modulation of HRV than those with EDS that may reflect elevated adrenergically mediated alertness. Taranto Montemurro L; Floras JS; Picton P; Kasai T; Alshaer H; Gabriel JM; Bradley TD. Relationship of heart rate variability to sleepiness in patients with obstructive sleep apnea with and without heart failure.

Reply from K. L. Ryan, C. A. Rickards, C. Hinojosa‐Laborde, W. H. Cooke and V. A. Convertino

We thank Pagani et al. for their interest in our recent paper (Ryan et al. 2011)) and for their kind comments concerning our work. We appreciate the opportunity for further dialogue about the issue of whether low-frequency (LF) blood pressure oscillations can be used as an accurate non-invasive surrogate of direct measurements of sympathetic nerve activity. In the Letter to the Editor, Pagani et al. rightfully point out that there were minor differences in techniques used in our study versus their previous work. While we used fast Fourier transfer (FFT) to perform our spectral analysis, autoregression (AR) was used for spectral analysis in the studies that Pagani et al. cite and which form the primary literature on which our work was based. Both techniques, however, have been used in studies investigating autonomic function, with comparable results (Persson 1997; Badilini et al. 1998)). While we cannot discount the possibility that utilization of a different technique might yield slightly different quantitative values, the results derived using these techniques, if truly reflective of autonomic control, should reliably reflect the underlying physiology and should therefore be qualitatively similar. Concerning normalization of spectral powers, what does this mean physiologically? As cautioned previously, ‘normalizing the oscillations to each other can uncouple their amplitudes from the physiology’ (Taylor & Studinger, 2006)). Clearly, this is dangerous territory for a measure purporting to track autonomic nerve activity. Importantly, it should also be noted that Pagani et al. (1997) reported significant correlations between both absolute low-frequency oscillations of systolic arterial pressure (SAPLF) and normalized SAPLF with muscle sympathetic nerve activity (MSNA). Based on the evidence, it is unlikely that differences in the techniques used to quantify the amplitude of blood pressure oscillations could be res- ponsible for our findings that challenge the use of SAPLF as a non-invasive surrogate of MSNA. We also agree that, like any analytical technique, interpretations of MSNA measurements must be informed by an appreciation of the technical limitations of microneurography. Over the past 45 years, however, microneurography has become a well-accepted technique that has driven entirely new understandings of the control of autonomic function in humans in both health and disease (Vallbo et al. 2004; Fatouleh & Macefield, 2011)). When continuous MSNA measurements are collected in the same subject in the same experimental session without a shift in baseline (conditions met in our work), issues such as electrode tip placement, damage and electronic settings are minimized if not abrogated. Indeed, the concept that SAPLF might serve as a non-invasive means of assessing sympathetic nerve activity was put forward based on results of studies in which MSNA was measured (Pagani et al. 1997; Furlan et al. 2000)), suggesting that we all agree that direct measurement of MSNA has value in answering this research question. Furthermore, as discussed in our paper (Ryan et al. 2011)), results from animal studies measuring renal (Tsai et al. 2009)) or splanchnic (Persson et al. 1992; Stauss et al. 1995)) sympathetic nerve activity have shown that LF oscillations of blood pressure are not a marker of levels of sympathetic nerve activity, indicating that our conclusion is not a function of the measurement of MSNA per se but represents a more global relationship. We also agree with Pagani et al. that, generally speaking, SAPLF increases during sympathetic activation and that it may reflect oscillatory patterns of sympathetic nerve firing; the results of all of the studies to date are in concordance with this concept. While we appreciate the desire for a convenient and non-invasive biomarker of sympathetic nerve activity, our concern is that SAPLF might be used inappropriately to assess autonomic function in individual patients, as our data do not show a direct relationship between SAPLF and MSNA in all individuals. These healthy subjects were drawn from a fairly homogeneous population and studied in a controlled laboratory setting with a well-accepted experimental model that produces progressively increasing sympathetic activation. If such large interindividual variability in the SAPLF–MSNA relationship exists in these healthy subjects under these conditions, how can one define what a ‘normal’ relationship is for the population as a whole? If we cannot reliably define ‘normal’, how then can we define what is abnormal or indicative of dysautonomia in patient populations? While convenience is an attractive feature, it cannot replace efficacy. We would never advocate throwing the baby out with the bath water. But should we not objectively assess whether the baby is able to perform effectively in the situation in which he or she has been placed?

Extracting autonomic information from oscillations in MSNA

Extracting autonomic information from oscillations in MSNA

Caveat utilitor: take measure of your marker

Caveat utilitor: take measure of your marker

Serotonin nerve terminals in the dorsomedial medulla facilitate sympathetic and ventilatory responses to hemorrhage and peripheral chemoreflex activation

Serotonin neurons of the caudal raphe facilitate ventilatory and sympathetic responses that develop following blood loss in conscious rats. Here, we tested whether serotonin projections to the caudal portion of the dorsomedial brain stem (including regions of the nucleus tractus solitarius that receive cardiovascular and chemosensory afferents) contribute to cardiorespiratory compensation following hemorrhage. Injections of the serotonin neurotoxin 5,7-dihydroxytryptamine produced >90% depletion of serotonin nerve terminals in the region of injection. Withdrawal of ∼21% of blood volume over 10 min produced a characteristic three-phase response that included 1) a normotensive compensatory phase, 2) rapid sympathetic withdrawal and hypotension, and 3) rapid blood pressure recovery accompanied by slower recovery of heart rate and sympathetic activity. A gradual tachypnea developed throughout hemorrhage, which quickly reversed with the advent of sympathetic withdrawal. Subsequently, breathing frequency and neural minute volume (determined by diaphragmatic electromyography) declined below baseline following termination of hemorrhage but gradually recovered over time. Lesioned rats showed attenuated sympathetic and ventilatory responses during early compensation and later recovery from hemorrhage. Both ventilatory and sympathetic responses to chemoreceptor activation with potassium cyanide injection were attenuated by the lesion. In contrast, the gain of sympathetic and heart rate baroreflex responses was greater, and low-frequency oscillations in blood pressure were reduced after lesion. Together, the data are consistent with the view that serotonin innervation of the caudal dorsomedial brain stem contributes to sympathetic compensation during hypovolemia, possibly through facilitation of peripheral chemoreflex responses.

α-Adrenergic effects on low-frequency oscillations in blood pressure and R-R intervals during sympathetic activation

The present study was designed to address the contribution of α-adrenergic modulation to the genesis of low-frequency (LF; 0.04-0.15 Hz) oscillations in R-R interval (RRi), blood pressure (BP) and muscle sympathetic nerve activity (MSNA) during different sympathetic stimuli. Blood pressure and RRi were measured continuously in 12 healthy subjects during 5 min periods each of lower body negative pressure (LBNP; -40 mmHg), static handgrip exercise (HG; 20% of maximal force) and postexercise forearm circulatory occlusion (PECO) with and without α-adrenergic blockade by phentolamine. Muscle sympathetic nerve activity was recorded in five subjects during LBNP and in six subjects during HG and PECO. Low-frequency powers and median frequencies of BP, RRi and MSNA were calculated from power spectra. Low-frequency power during LBNP was lower with phentolamine versus without for both BP and RRi oscillations (1.6 ± 0.6 versus 1.2 ± 0.7 ln mmHg(2), P = 0.049; and 6.9 ± 0.8 versus 5.4 ± 0.9 ln ms(2), P = 0.001, respectively). In contrast, the LBNP with phentolamine increased the power of high-frequency oscillations (0.15-0.4 Hz) in BP and MSNA (P < 0.01 for both), which was not observed during saline infusion. Phentolamine also blunted the increases in the LBNP-induced increase in frequency of LF oscillations in BP and RRi. Phentolamine decreased the LF power of RRi during HG (P = 0.015) but induced no other changes in LF powers or frequencies during HG. Phentolamine resulted in decreased frequency of LF oscillations in RRi (P = 0.004) during PECO, and a similar tendency was observed in BP and MSNA. The power of LF oscillation in MSNA did not change during any intervention. We conclude that α-adrenergic modulation contributes to LF oscillations in BP and RRi during baroreceptor unloading (LBNP) but not during static exercise. Also, α-adrenergic modulation partly explains the shift to a higher frequency of LF oscillations during baroreceptor unloading and muscle metaboreflex activation.

Resting state functional connectivity of the whole head with near-infrared spectroscopy.

Resting state connectivity aims to identify spontaneous cerebral hemodynamic fluctuations that reflect neuronal activity at rest. In this study, we investigated the spatial-temporal correlation of hemoglobin concentration signals over the whole head during the resting state. By choosing a source-detector pair as a seed, we calculated the correlation value between its time course and the time course of all other source-detector combinations, and projected them onto a topographic map. In all subjects, we found robust spatial interactions in agreement with previous fMRI and NIRS findings. Strong correlations between the two opposite hemispheres were seen for both sensorimotor and visual cortices. Correlations in the prefrontal cortex were more heterogeneous and dependent on the hemodynamic contrast. HbT provided robust, well defined maps, suggesting that this contrast may be used to better localize functional connectivity. The effects of global systemic physiology were also investigated, particularly low frequency blood pressure oscillations which give rise to broad regions of high correlation and mislead interpretation of the results. These results confirm the feasibility of using functional connectivity with optical methods during the resting state, and validate its use to investigate cortical interactions across the whole head.

Impact of α1-adrenoceptor expression on contractile properties of vascular smooth muscle cells

Low-frequency blood pressure oscillations (Mayer waves) are discussed as a marker for sympathetic modulation of vascular tone. However, the factors that determine the frequency response of the vasculature to sympathetic stimuli are not fully understood. Possible mechanisms include functions related to alpha(1)-adrenergic receptors (alpha(1)-AR) and postreceptor processes involved in the vascular contractile response. The purpose of the present study was to examine the hypothesis that expression levels of alpha(1)-AR and their subtype distribution determine velocity and magnitude of alpha(1)-AR-mediated vascular smooth muscle cell (VSMC) contraction. alpha(1A)-, alpha(1B)-, and alpha(1D)-AR subtypes were transfected into VSMCs from rat aorta and characterized immunocytochemically via confocal microscopy. Functional studies in isolated cells were performed using video microscopy. The alpha(1)-AR agonist phenylephrine produced dose-dependent contractions of VSMCs. All transfected groups were more sensitive to phenylephrine compared with controls. Maximal contraction velocity almost doubled in transfected cells. However, no differences in observed parameters were found between the three transfected groups. Contractile properties in response to membrane depolarization with KCl were similar in all groups. In conclusion, alpha(1)-AR density determines velocity and sensitivity of alpha(1)-AR-mediated contraction in VSMCs. alpha(1)-AR subtype distribution does not appear to influence vasoconstriction to sympathetic stimuli.

Adrenergic origin of very low-frequency blood pressure oscillations in the unanesthetized rat

Spectral analysis of cardiovascular signals has been extensively used to investigate circulatory homeostatic mechanisms. However, the nature of very low-frequency (VLF) fluctuations remains unclear. Because we previously observed enhanced VLF fluctuations in blood pressure (BP) in the sympathectomized rat (a model characterized by markedly increased plasma epinephrine levels), the aims of our study were to assess whether the genesis of VLF fluctuations in BP depends on circulating catecholamines and to determine which adrenergic receptor(s) and which membrane ion channel(s) are involved. We used continuous intra-arterial BP recordings from unanesthetized unrestrained rats to compute the power of VLF fluctuations in BP in the intact condition, during acute ganglionic blockade with hexamethonium, and after restoration of BP levels by infusion (in addition to hexamethonium) of adrenergic agonists (epinephrine, norepinephrine, and clonidine) or nonadrenergic vasoconstrictors (vasopressin). Effects of infusion of specific adrenergic receptor blockers (propranolol, prazosin, and yohimbine) with hexamethonium and catecholamines and infusion of various membrane ion channel blockers on VLF fluctuations in BP were also evaluated. Our results are as follows. 1) Ganglionic blockade drastically reduced BP levels and VLF fluctuations. 2) All vasoconstrictors restored BP levels, but only adrenergic vasoconstrictors generated striking VLF fluctuations in BP. 3) Catecholamine-induced fluctuations were abolished by alpha2-, but not alpha1- or beta-, adrenergic receptor blockade and by Ba2+-sensitive K+ channel or L-type Ca2+ channel, but not by other ion channel, blockers. We conclude that, in the conscious, unrestrained ganglion-blocked rat, catecholamine infusion generates VLF fluctuations in BP through stimulation of alpha2-receptors and activation of Ba2+-sensitive K+ channels. These fluctuations may have (patho)physiological relevance under conditions of disrupted circulatory homeostasis.

Paradoxical effect of sibutramine on autonomic cardiovascular regulation in obese hypertensive patients

Sibutramine, a serotonin and norepinephrine transporter blocker, is a common adjunctive obesity treatment. Acute studies in healthy subjects suggested that an inhibitory central nervous mechanism might attenuate the peripheral stimulatory effect on the sympathetic nervous system. This notion has not been tested in overweight and obese patients. We conducted a randomized, controlled clinical study in hypertensive patients with BMI > or = 27 to < 40 kg/m(2). After 4 week placebo run-in period patients were randomized to four different antihypertensive treatments or placebo. After 4 weeks of antihypertensive therapy, patients were additionally treated with sibutramine 15 mg o. d. for 3 months. Patients underwent cardiovascular autonomic reflex testing and a graded head-up tilt test at the end of each phase. Mean body weight decreased from 98.5+/-4 to 94.7+/-4 kg (p<0.05) between end of placebo run-in and end of sibutramine treatment. Supine blood pressure was 154+/-3/80+/-2, 145+/-3/76+/-2 and 150+/-3/79+/-2mmHg at the end of placebo run-in, after antihypertensive titration (ns) and end of sibutramine treatment (ns), respectively. Blood pressure was affected similarly during head up tilt testing. The systolic blood pressure response to cold pressor testing was diminished with sibutramine (p<0.01). Sibutramine decreased low frequency systolic blood pressure oscillations in the supine position (p<0.01). Resting blood pressure tends to increase with sibutramine, whereas blood pressure during sympathetic stimulation and low frequency blood pressure oscillations are decreased. These paradoxical changes are consistent with previous studies in healthy subjects and suggest a combination of peripheral and central nervous system mechanisms.

PREDICTION OF LOW FREQUENCY BLOOD PRESSURE OSCILLATIONS VIA A COMBINED HEART/RESISTANCE MODEL

Low frequency oscillations in blood pressure (BP) can occur due to a feedback pathway between the sensing of BP and the central nervous system (CNS), often termed the baroreflex, affecting both cardiac output (heart-rate and stroke volume) and peripheral resistance. In this paper, an integrated model of both these subsystems is assembled and an analysis technique developed, which shows the conditions under which a limit cycle oscillation can occur. In particular, the role of mean levels of cardiac output and peripheral resistance, previously thought to be relatively unimportant, in establishing and maintaining sustained oscillations, is highlighted. The ultimate aim of this analysis is to assist in the development of diagnostic tests based on measurement of low-frequency blood pressure oscillations.

Dynamic baroreflex control of blood pressure: influence of the heart vs. peripheral resistance.

The aim in the present experiments was to assess the dynamic baroreflex control of blood pressure, to develop an accurate mathematical model that represented this relationship, and to assess the role of dynamic changes in heart rate and stroke volume in giving rise to components of this response. Patterned electrical stimulation [pseudo-random binary sequence (PRBS)] was applied to the aortic depressor nerve (ADN) to produce changes in blood pressure under open-loop conditions in anesthetized rabbits. The stimulus provided constant power over the frequency range 0-0.5 Hz and revealed that the composite systems represented by the central nervous system, sympathetic activity, and vascular resistance responded as a second-order low-pass filter (corner frequency approximately 0.047 Hz) with a time delay (1.01 s). The gain between ADN and mean arterial pressure was reasonably constant before the corner frequency and then decreased with increasing frequency of stimulus. Although the heart rate was altered in response to the PRBS stimuli, we found that removal of the heart's ability to contribute to blood pressure variability by vagotomy and beta(1)-receptor blockade did not significantly alter the frequency response. We conclude that the contribution of the heart to the dynamic regulation of blood pressure is negligible in the rabbit. The consequences of this finding are examined with respect to low-frequency oscillations in blood pressure.

Inconsistent link between low-frequency oscillations: R-R interval responses to augmented Mayer waves.

Low-frequency oscillations in arterial blood pressure (Mayer waves) and R-R interval are thought to be linked through the arterial baroreflex. To delve into this relationship, we applied low (10 mmHg) and moderate (30 mmHg) lower body negative pressure (LBNP) in 10-s cycles to 18 healthy young male subjects. They showed no change in average blood pressure with this oscillatory stimulus but did show a significant decrease in R-R interval (P < 0.05) during both levels of LBNP. In addition, we succeeded in augmenting low-frequency blood pressure oscillations in a graded response to oscillatory LBNP level (P < 0.05) while significantly increasing low-frequency R-R interval oscillations (P < 0.05). However, cross-spectral coherence between these increased oscillations was highly variable across individuals and stimulus level. Although nearly all subjects showed significant coherence during basal conditions (n = 17), only seven subjects maintained significant coherence during both levels of LBNP. These results suggest that a complex interaction of regulatory mechanisms determines the link between low-frequency oscillations and the responses to even low levels of LBNP.

Low-Frequency Blood Pressure Oscillations in Mesenteric Vessels in Conscious Rats

Low-Frequency Blood Pressure Oscillations in Mesenteric Vessels in Conscious Rats