A telemetric study of physiologic changes in mice with induced autoimmune encephalomyelitis

Dysfunction of the autonomic nervous system may be an important component of disease progression in multiple sclerosis (MS), a paralytic inflammatory autoimmune disease of the central nervous system. Using the experimental autoimmune encephalomyelitis mouse model of MS, the authors carried out a pilot study to investigate whether telemetric monitoring might be a feasible approach for detecting disturbances in the autonomic control of heart rate and blood pressure after disease induction. Telemetric monitoring devices that were implanted in mice provided useful information regarding the physiologic changes that accompanied disease induction and progression. Changes were observed in heart rate, blood pressure, heart rate variability and diurnal rhythm immediately before and after disease onset. The device implantation procedure did not seem to alter the course of disease. Further investigation may establish these methods as a system for studying the relationships between MS progression and autonomic regulation of physiological status.     

Involvement of the central adrenomedullin peptides in the baroreflex

The peptides derived from post-translational processing of preproadrenomedullin are produced in and act on areas of the autonomic nervous system important for blood pressure regulation. We examined the role of endogenous, brain-derived adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in the central nervous system arm of the baroreflex by using passive immunoneutralization to block the actions of the endogenous peptides. Our results indicate that the preproadrenomedullin-derived peptides do not play a role in sensing changes in blood pressure (baroreflex sensitivity), but the adrenomedullin peptides do regulate the speed with which an animal returns to a normal, stable blood pressure. These findings suggest that endogenous, brain-derived AM and PAMP participate in the regulation of autonomic activity in response to baroreceptor activation and inactivation.     

Human cerebrovascular and autonomic rhythms during vestibular activation

Otolith activation increases muscle sympathetic nerve activity (MSNA), and MSNA activation may alter associations among autonomic oscillators, including those modulating cerebral hemodynamics. The purpose of this study was to determine the influence of vestibulosympathetic activation on cerebral and autonomic rhythms. We recorded the ECG, finger arterial pressure, end-tidal CO(2), respiration, cerebral blood flow velocity, and MSNA in eight subjects. Subjects breathed at 0.25 Hz for 5 min in the prone and head-down positions. We analyzed data in time and frequency domains and performed cross-spectral analyses to determine coherence and transfer function magnitude. Head-down rotation increased MSNA from 7 +/- 1.3 to 12 +/- 1.5 bursts/min (P = 0.001) but did not affect R-R intervals, arterial pressures, mean cerebral blood flow velocities (V(mean)), or their power spectra. Vestibular activation with head-down rotation had no effect on mean arterial pressure and V(mean) transfer function magnitude. The two new findings from this study are 1) head-down rotation independently activates the sympathetic nervous system with no effect on parasympathetic activity or V(mean); and 2) frequency-dependent associations between arterial pressures and V(mean) are independent of vestibular activation. These findings support the concept that vestibular-autonomic interactions independently and redundantly serve to maintain steady-state hemodynamics.     

The investigation of the synchronization between rhythms in the human cardiovascular system from time series of R-R-intervals

We demonstrated that, from the sequence of R-R intervals, it is possible to calculate the instantaneous phases and instantaneous frequencies of the main rhythmic processes governing the cardiovascular dynamics in humans, namely, the main heart rhythm, respiration, and the process of slow regulation of blood pressure with basic frequency close to 0.1 Hz. For the cases of spontaneous respiration and paced respiration with a fixed frequency, the synchronization between the rhythms of the cardiovascular system was investigated based on the analysis of only the time series of R-R intervals. It is shown that the main heart rhythm and the rhythm of low-frequency regulation of blood pressure can be synchronized with respiration.     

Spectrum analysis of blood pressure and cardiac rate in the conscious rat

Intrafemoral pulsatile blood pressure of conscious rats was computed to generate evenly spaced signals (systolic, diastolic, mean blood pressure, heart rate) at 200 ms intervals. This equidistant sampling allowed a direct spectral analysis using a Fast Fourier Transform algorithm. Systolic blood pressure and heart rate exhibited low frequency oscillations (Mayer waves, 20-605 mHz) and a high frequency peak related to respiration (1,765 mHz). The diastolic blood pressure and the mean blood pressure only exhibited low frequency oscillations. This procedure could be useful to analyze the various components of blood pressure variability.     

Quantitative Autonomic Testing

Disorders associated with dysfunction of autonomic nervous system are quite common yet frequently unrecognized. Quantitative autonomic testing can be invaluable tool for evaluation of these disorders, both in clinic and research. There are number of autonomic tests, however, only few were validated clinically or are quantitative. Here, fully quantitative and clinically validated protocol for testing of autonomic functions is presented. As a bare minimum the clinical autonomic laboratory should have a tilt table, ECG monitor, continuous noninvasive blood pressure monitor, respiratory monitor and a mean for evaluation of sudomotor domain. The software for recording and evaluation of autonomic tests is critical for correct evaluation of data. The presented protocol evaluates 3 major autonomic domains: cardiovagal, adrenergic and sudomotor. The tests include deep breathing, Valsalva maneuver, head-up tilt, and quantitative sudomotor axon test (QSART). The severity and distribution of dysautonomia is quantitated using Composite Autonomic Severity Scores (CASS). Detailed protocol is provided highlighting essential aspects of testing with emphasis on proper data acquisition, obtaining the relevant parameters and unbiased evaluation of autonomic signals. The normative data and CASS algorithm for interpretation of results are provided as well.     

Localized real time blood flow measurements

A novel method for real time, localized, flow measurements is applied to blood flow in human fingers. Results for arterial and venous flow in normal subjects and patients with abnormal blood circulation are presented. Effects of blood flow regulation by the autonomic nervous system have been observed. Stricture of the digital arteries could be clearly demonstrated in a patient with Raynaud's phenomenon. Experimental signals due to pulsatile flow in a model system can be simulated in a quantitative way. The calibration, however, depends on the actual spin-spin relaxation time and the shape of the pulsatile flow vs. time curve. Due to these limitations, the volume flow rate can be measured with a relative error of approximately +/- 25%.     

Phase Synchronization of Hemodynamic Variables at Rest and after Deep Breathing Measured during the Course of Pregnancy

Background

The autonomic nervous system plays a central role in the functioning of systems critical for the homeostasis maintenance. However, its role in the cardiovascular adaptation to pregnancy-related demands is poorly understood. We explored the maternal cardiovascular systems throughout pregnancy to quantify pregnancy-related autonomic nervous system adaptations.

Methodology

Continuous monitoring of heart rate (R-R interval; derived from the 3-lead electrocardiography), blood pressure, and thoracic impedance was carried out in thirty-six women at six time-points throughout pregnancy. In order to quantify in addition to the longitudinal effects on baseline levels throughout gestation the immediate adaptive heart rate and blood pressure changes at each time point, a simple reflex test, deep breathing, was applied. Consequently, heart rate variability and blood pressure variability in the low (LF) and high (HF) frequency range, respiration and baroreceptor sensitivity were analyzed in resting conditions and after deep breathing. The adjustment of the rhythms of the R-R interval, blood pressure and respiration partitioned for the sympathetic and the parasympathetic branch of the autonomic nervous system were quantified by the phase synchronization index γ, which has been adopted from the analysis of weakly coupled chaotic oscillators.

Results

Heart rate and LF/HF ratio increased throughout pregnancy and these effects were accompanied by a continuous loss of baroreceptor sensitivity. The increases in heart rate and LF/HF ratio levels were associated with an increasing decline in the ability to flexibly respond to additional demands (i.e., diminished adaptive responses to deep breathing). The phase synchronization index γ showed that the observed effects could be explained by a decreased coupling of respiration and the cardiovascular system (HF components of heart rate and blood pressure).

Conclusions/Significance

The findings suggest that during the course of pregnancy the individual systems become increasingly independent to meet the increasing demands placed on the maternal cardiovascular and respiratory system.     

Low-frequency component of photoplethysmogram reflects the autonomic control of blood pressure

The question of how much information the photoplethysmogram (PPG) signal contains on the autonomic regulation of blood pressure (BP) remains unsolved. This study aims to compare the low-frequency (LF) and high-frequency components of PPG and BP and assess their correlation with oscillations in interbeat (RR) intervals at similar frequencies. The PPG signal from the distal phalanx of the right index finger recorded using a reflective PPG sensor at green light, the BP signal from the left hand recorded using a Finometer, and RR intervals were analyzed. These signals were simultaneously recorded within 15 min in a supine resting condition in 17 healthy subjects (12 males and 5 females) aged 33 ± 9 years (mean ± SD). The study revealed the high coherence of LF components of PPG and BP with the LF component of RR intervals. The high-frequency components of these signals had low coherence. The analysis of the signal instantaneous phases revealed the presence of high-phase coherence between the LF components of PPG and BP. It is shown that the LF component of PPG is determined not only by local myogenic activity but also reflects the processes of autonomic control of BP.     

Blood pressure and blood flow variation during postural change from sitting to standing: model development and validation.

Short-term cardiovascular responses to postural change from sitting to standing involve complex interactions between the autonomic nervous system, which regulates blood pressure, and cerebral autoregulation, which maintains cerebral perfusion. We present a mathematical model that can predict dynamic changes in beat-to-beat arterial blood pressure and middle cerebral artery blood flow velocity during postural change from sitting to standing. Our cardiovascular model utilizes 11 compartments to describe blood pressure, blood flow, compliance, and resistance in the heart and systemic circulation. To include dynamics due to the pulsatile nature of blood pressure and blood flow, resistances in the large systemic arteries are modeled using nonlinear functions of pressure. A physiologically based submodel is used to describe effects of gravity on venous blood pooling during postural change. Two types of control mechanisms are included: 1) autonomic regulation mediated by sympathetic and parasympathetic responses, which affect heart rate, cardiac contractility, resistance, and compliance, and 2) autoregulation mediated by responses to local changes in myogenic tone, metabolic demand, and CO(2) concentration, which affect cerebrovascular resistance. Finally, we formulate an inverse least-squares problem to estimate parameters and demonstrate that our mathematical model is in agreement with physiological data from a young subject during postural change from sitting to standing.     

Early autonomic malfunction in normotensive individuals with a genetic predisposition to essential hypertension

One of the primary pathologies associated with hypertension is a complex autonomic dysfunction with evidence of sympathetic hyperactivity and/or vagal withdrawal. We investigated the possibility for early detection of essential hypertension on the basis of the analysis of heart rate (HR) and blood pressure fluctuations, which reflect autonomic control. Young adult normotensive offspring of one hypertensive parent (KHT; n = 12) and normotensive offspring of two normotensive parents (YN; n = 14) participated in this study. ECG, continuous blood pressure, and respiration were recorded during steady-state conditions and under various autonomic challenges. Time-frequency decomposition of these signals was performed with the use of a continuous wavelet transform. The use of the wavelet transform enables the extension of typical HR variability analysis to non-steady-state conditions. This time-dependent spectral analysis of HR allows time-dependent quantification of different spectral components reflecting the sympathetic and parasympathetic activity during rapid transitions, such as an active change in posture (CP). During an active CP from the supine to standing position, KHT demonstrated a significantly greater increase in the low-frequency fluctuations in HR than YN, indicating enhanced sympathetic involvement in the HR response to CP, and a reduced alpha-index, indicating decreased baroreceptor sensitivity. On recovery from handgrip, vagal reactivation was more sluggish in KHT. These results indicate the early existence of malfunctions in both branches of autonomic control in individuals at increased risk of hypertension.     

Respiratory modulation of the autonomic nervous system during Cheyne-Stokes respiration

Cheyne-Stokes respiration (CSR) is associated with increased mortality among patients with heart failure. However, the specific link between CSR and mortality remains unclear. One possibility is that CSR results in excitation of the sympathetic nervous system. This review relates evidence that CSR exerts acute effects on the autonomic nervous system during sleep, and thereby influences a number of cardiovascular phenomena, including heart rate, blood pressure, atrioventricular conduction, and ventricular ectopy. In patients in sinus rhythm, heart rate and blood pressure oscillate during CSR in association with respiratory oscillations, such that both peak heart rate and blood pressure occur during the hyperpneic phase. Inhalation of CO2 abolishes both CSR and the associated oscillations in heart rate and blood pressure. In contrast, O2 inhalation sufficient to eliminate hypoxic dips has no significant effect on CSR, heart rate, or blood pressure. In patients with atrial fibrillation, ventricular rate oscillates in association with CSR despite the absence of within-breath respiratory arrhythmia. The comparison of RR intervals between the apneic and hyperpneic phases of CSR indicates that this breathing disorder exerts its effect on ventricular rate by inducing cyclical changes in atrioventricular node conduction properties. In patients with frequent ventricular premature beats (VPBs), VPBs occur more frequently during the hyperpneic phase than the apneic phase of CSR. VPB frequency is also higher during periods of CSR than during periods of regular breathing, with or without correction of hypoxia. In summary, CSR exerts multiple effects on the cardiovascular system that are likely manifestations of respiratory modulation of autonomic activity. It is speculated that the rhythmic oscillations in autonomic tone brought about by CSR may ultimately contribute to the sympatho-excitation and increased mortality long observed in patients with heart failure and CSR.     

Altered Orcadian Rhythms of Blood Pressure and Heart Rate in Non-Hemodialysis Chronic Renal Failure

The extended use of ambulatory monitoring has permitted the identification of many conditions in which the circadian rhythm of blood pressure is altered. The common denominator seems to be an impairment of the autonomic nervous system function. We examined whether the circadian blood pressure rhythm is altered in chronic renal failure (where autonomic dysfunction is usually present) by using a standardized chronobiological inferential statistical method in hospitalized subjects. For this purpose, a group of 30 non-hemodialysis hypertensive patients with chronic renal failure was compared with a second group of 30 patients affected by uncomplicated mild-to-moderate essential hypertension. The two groups were matched by age, sex and circadian mesors of blood pressure. Diet, meal times, sleep and activity logs were standardized. Blood pressure and heart rate recordings were obtained by using an automatic oscillometric recorder and subsequently analyzed according to the cosinor method. A mean circadian rhythm of blood pressure was documented in both groups, but while the mean acrophases occurred between 2 and 3 p.m. in essential hypertension, in renal failure they were between 11 p.m. and midnight for blood pressure and around 7 p.m. for heart rate. In addition, the mean circadian amplitudes were significantly lower in renal failure, while the mean circadian mesor of heart rate was significantly higher. Our data demonstrate that the circadian rhythms of blood pressure and heart rate are altered also in hypertension due to chronic renal failure.     

Altered Orcadian Rhythms of Blood Pressure and Heart Rate in Non-Hemodialysis Chronic Renal Failure

The extended use of ambulatory monitoring has permitted the identification of many conditions in which the circadian rhythm of blood pressure is altered. The common denominator seems to be an impairment of the autonomic nervous system function. We examined whether the circadian blood pressure rhythm is altered in chronic renal failure (where autonomic dysfunction is usually present) by using a standardized chronobiological inferential statistical method in hospitalized subjects. For this purpose, a group of 30 non-hemodialysis hypertensive patients with chronic renal failure was compared with a second group of 30 patients affected by uncomplicated mild-to-moderate essential hypertension. The two groups were matched by age, sex and circadian mesors of blood pressure. Diet, meal times, sleep and activity logs were standardized. Blood pressure and heart rate recordings were obtained by using an automatic oscillometric recorder and subsequently analyzed according to the cosinor method. A mean circadian rhythm of blood pressure was documented in both groups, but while the mean acrophases occurred between 2 and 3 p.m. in essential hypertension, in renal failure they were between 11 p.m. and midnight for blood pressure and around 7 p.m. for heart rate. In addition, the mean circadian amplitudes were significantly lower in renal failure, while the mean circadian mesor of heart rate was significantly higher. Our data demonstrate that the circadian rhythms of blood pressure and heart rate are altered also in hypertension due to chronic renal failure.     

Age dependency of cardiovascular autonomic responses to head-up tilt in healthy subjects.

In elderly subjects, heart rate responses to postural change are attenuated, whereas their vascular responses are augmented. Altered strategy in maintaining blood pressure homeostasis during upright position may result from various cardiovascular changes, including age-related cardiovascular autonomic dysfunction. This exploratory study was conducted to evaluate impact of age on cardiovascular autonomic responses to head-up tilt (HUT) in healthy subjects covering a wide age range. The study population consisted of 63 healthy, normal-weight, nonsmoking subjects aged 23-77 yr. Five-minute electrocardiogram and finger blood pressure recordings were performed in the supine position and in the upright position 5 min after 70 degrees HUT. Stroke volume was assessed from noninvasive blood pressure signals by the arterial pulse contour method. Heart rate variability (HRV) and systolic blood pressure variability (SBPV) were analyzed by using spectral analysis, and baroreflex sensitivity (BRS) was assessed by using sequence and cross-spectral methods. Cardiovascular autonomic activation during HUT consisted of decreases in HRV and BRS and an increase in SBPV. These changes became attenuated with aging. Age correlated significantly with amplitude of HUT-stimulated response of the high-frequency component (r = -0.61, P < 0.001) and the ratio of low-frequency to high-frequency power of HRV (r = -0.31, P < 0.05) and indexes of BRS (local BRS: r = -0.62, P < 0.001; cross-spectral baroreflex sensitivity in the low-frequency range: r = -0.38, P < 0.01). Blood pressure in the upright position was maintained well irrespective of age. However, the HUT-induced increase in heart rate was more pronounced in the younger subjects, whereas the increase in peripheral resistance was predominantly observed in the older subjects. Thus it is likely that whereas the dynamic capacity of cardiac autonomic regulation decreases, vascular responses related to vasoactive mechanisms and vascular sympathetic regulation become augmented with increasing age.     

Changes in cardiohemodynamic parameters,cardiointervalography, and microcirculation observed in local cold test in young men born in northern regions

The cardiohemodynamic and blood microcirculation parameters at rest and under local cold exposure in young male subjects have been estimated. It has been found that the subjects with the initially low velocity of erythrocytes (blood flow) in their nail bed capillaries have higher blood pressure, stroke volume, cardiac output, and cardiac index, which proves that these subjects have the hyperkinetic type of blood flow with the pronounced hypertensive reaction. At the same time, the shift of heart rate variability values under the cold exposure indicates that the activation of the sympathetic autonomic nervous system is more statistically significant than that in those subjects who originally had a higher velocity of erythrocytes. In the subjects of this group, no changes were observed in either heart rate autonomic regulation or index of tension under the local cold exposure, which proved that these subjects had the enhanced functional reserves of the cardiovascular system and autonomic regulation. They also had a fairly pronounced reactivity of the parameters of systemic hemodynamics, which manifested itself in changes in their blood filling parameters against the background of decrease in total peripheral vascular resistance and coefficient of integral tonicity.     

Vav3 is involved in GABAergic axon guidance events important for the proper function of brainstem neurons controlling cardiovascular, respiratory, and renal parameters

Vav3 is a phosphorylation-dependent activator of Rho/Rac GTPases that has been implicated in hematopoietic, bone, cerebellar, and cardiovascular roles. Consistent with the latter function, Vav3-deficient mice develop hypertension, tachycardia, and renocardiovascular dysfunctions. The cause of those defects remains unknown as yet. Here, we show that Vav3 is expressed in GABAegic neurons of the ventrolateral medulla (VLM), a brainstem area that modulates respiratory rates and, via sympathetic efferents, a large number of physiological circuits controlling blood pressure. On Vav3 loss, GABAergic cells of the caudal VLM cannot innervate properly their postsynaptic targets in the rostral VLM, leading to reduced GABAergic transmission between these two areas. This results in an abnormal regulation of catecholamine blood levels and in improper control of blood pressure and respiration rates to GABAergic signals. By contrast, the reaction of the rostral VLM to excitatory signals is not impaired. Consistent with those observations, we also demonstrate that Vav3 plays important roles in axon branching and growth cone morphology in primary GABAergic cells. Our study discloses an essential and nonredundant role for this Vav family member in axon guidance events in brainstem neurons that control blood pressure and respiratory rates.     

Blood pressure regulation and cardiac autonomic control in mice overexpressing alpha- and gamma-melanocyte stimulating hormone

Melanocyte stimulating hormones (MSH) derived from pro-opiomelanocortin have been demonstrated to participate in the central regulation of cardiovascular functions. The aim of the present study was to elucidate the chronic effects of increased melanocortin activation on blood pressure regulation and autonomic nervous system function. We adapted telemetry to transgenic mice overexpressing alpha- and gamma-MSH and measured blood pressure, heart rate and locomotor activity, and analyzed heart rate variability (HRV) in the frequency-domain as well as baroreflex function by the sequence technique. Transgenic (MSH-OE) mice had increased systolic blood pressure but their heart rate was similar to wild-type (WT) controls. The 24-h mean of systolic blood pressure was 132+/-7mmHg in MSH-OE and 113+/-4mmHg in WT mice. Locomotor activity was decreased in the MSH-OE mice. Furthermore, MSH-OE mice showed slower adaptation to mild environmental stress in terms of blood pressure changes. The low frequency (LF) power of HRV tended to be higher in MSH-OE mice compared to WT mice, without a difference in overall variability. The assessment of baroreflex function indicated enhanced baroreflex effectiveness and more frequent baroreflex operations in MSH-OE mice. Baseline heart rate, increased LF power of HRV and increased baroreflex activity may all reflect maintenance of baroreflex integrity and an increase in cardiac vagal activity to counteract the increased blood pressure. These results provide new evidence that long-term activation of the melanocortin system elevates blood pressure without increasing heart rate.     

Longitudinal studies on the effect of hypertension on circadian hemodynamic and autonomic rhythms in telemetered rats

This study dealt with the long-term effects of hypertension on circadian rhythms of hemodynamic and cardiovascular autonomic functions in radiotelemetered rats. Blood pressure (BP), heart rate (HR), spontaneous locomotor activity, and respiration.were monitored in spontaneously hypertensive rats (SHRs), a model of human hypertension, from 14 to 27 weeks of age and in Wistar-Kyoto rats (WKY) as controls. Cardiovascular autonomic changes were determined by time-domain analysis of the variability of BP (standard deviation of mean arterial pressure, SDMAP) and HR (standard deviation of R-R intervals, SDRR, and the root mean square of successive differences in R-R intervals, rMSSD). Compared with WKY rats, the 24-hr MAP and SDMAP were higher at week 14 in SHRs and showed stepwise increases over the study duration, suggesting progressive increases in vasomotor sympathetic activity in hypertensive rats. Also, higher SDRR, rMSSD, and activity and lower HR and respiration were demonstrated in SHRs. Normal circadian rhythms (higher dark-time values) of MAP, HR, SDMAP, and SDRR were evident in WKY rats at week 20 and continued thereafter. Compared with WKY rats, the circadian BP and HR patterns were abolished and inverted, respectively, in SHRs. Lower dark-time, compared with light-time, SDMAP values were observed in SHRs that were associated with temporal increases in HR variability indices. These findings demonstrate that hypertension elicits significant alterations in circadian autonomic and hemodynamic profiles. Further, the steady increases in BP, average level and oscillations, in SHRs may explain the reported progressive age-related vascular and cardiac hypertrophy in these rats.     

Changes in the autonomic balance of the regulation of the rate of heart contractions during physical loading in chronic suppression or potentiation of the endogenous opioidergic system in rats

The influence of endogenous opioid system on the rat's mean blood pressure (BP) and heart rate (HS) has been studied under the chronic infusion of the opioid receptor antagonist naloxone (1 mg/kg intraperitoneally, twice a day, during 6 days) or an inhibitor of captorile enkephalinases (20 mg/kg subcutaneously). Naloxone caused a significant decrease and captorile--increase of maximum meanings of HR during exercises (the running on the treadmill during 3.5 min by the velocity of 30 m/min), both compounds didn't exert a considerable effect on BP at rest and during exercises. It has been concluded that the endogenous opioid system plays an important role in the autonomic HR regulation during exercise.