O. Oz

Spectral analysis of heart rate fluctuations. A non-invasive, sensitive method for the early diagnosis of autonomic neuropathy in diabetes mellitus.

Early detection and a quantitative evaluation of the degree of diabetic autonomic neuropathy were performed in 23 diabetic patients and 22 controls by computerized spectral analysis of beat-to-beat R-R interval variations on a continuous electrocardiogram. Simultaneous recording of cardiac and respiratory activity, R-wave detection by a fast peak detection algorithm and spectrum computation by Fast Fourier transform enabled the study of the power spectrum of heart rate fluctuations. The power of fluctuations at different frequencies is the result of sympathetic and vagal input into the sinoatrial node: this input is derived from vasomotor, baroreceptor and respiratory control loops. A marked reduction in the power of heart rate (HR) fluctuations, at all frequencies, was found in the diabetic patients as compared to controls. This indicates a depression of both parasympathetic and sympathetic activity. The difference was especially pronounced in subjects below age 65. The lowest activity was found in diabetics with concomitant peripheral neuropathy. The method described here is simple, objective, quantitative and very sensitive. It may facilitate the screening of diabetic patients for autonomic neuropathy and enable a convenient quantitative follow-up.

Spectral Analysis of Fluctuations in Heart Rate: An Objective Evaluation of Autonomic Nervous Control in Chronic Renal Failure

A quantitative, noninvasive method of assessing autonomic control, based on the spectral analysis of beat-to-beat fluctuations in heart rate (HR), was applied to patients with chronic renal failure (RF). Since the power spectrum of HR fluctuations measures the dynamic nervous control of HR, it can be used to quantitate a normal control system as opposed to a disturbed or depressed system. Indeed, in RF patients, a strong reduction in the HR power spectrum was observed in all frequency ranges, both sympathetically and parasympathetically mediated. A similar depression in autonomic control was demonstrated in patients on hemodialysis or peritoneal dialysis. RF patients not yet undergoing dialysis show a lesser degree of depression. Spectral analysis of HR fluctuations in RF patients makes it possible to quantitate autonomic dysfunction and to reliably measure its development as a function of time, and requires only a 10-min standard electrocardiogram recording.

Autonomic response to change of posture among normal and mild-hypertensive adults: investigation by time-dependent spectral analysis.

In this study, we applied the time-dependent spectral analysis approach (SDA) to investigate the autonomic changes occurring during a transition from supine to standing position (CP), in normal and unmedicated mild hypertensive subjects. The SDA method enables an accurate follow-up of the instantaneous changes in autonomic activity, even during the unsteady phase of the transition, where sudden changes in heart rate (HR) and arterial blood pressure (ABP) are observed. We were able to quantify the vagal withdrawal (reflected in the high frequency component of the time-dependent spectrum of HR fluctuations) in the immediate response to CP and the more slowly following sympathetic increase (reflected in the low frequency component of ABP). This general pattern was observed in both groups. In addition, our results identified an altered sympathetic response to CP in mild-hypertensives, as compared to normal adults. Their basal sympathetic activity is enhanced (higher mean HR and increased low frequency fluctuations in ABP) and their response to CP is reduced, as reflected only in the LF content of ABP fluctuations, relative to normals. No difference was observed in HR fluctuations, showing that there is no parasympathetically mediated alteration of the baroreflex control of HR in mild-hypertension.

Insight into blood-pressure control in SHR via the response to acute hemorrhage: a spectral analysis approach

In this study we investigated, by means of the spectral analysis approach, the possible alterations in the activity of the pressor-control mechanisms in relation to the development of essential hypertension. Since the maintenance of controlled arterial blood pressure (ABP) levels is achieved by a continuously fluctuating control system, instantaneous ABP varies continuously in direct correlation with the activation of various control branches. The power spectrum of ABP fluctuations thus provides a quantitative measure of the activity of the various controlling mechanisms. Two strains of rats, Spontaneously Hypertensive Rats (SHR) and Wistar-Kyoto normotensive rats (WKY), were subjected to acute hemorrhage, a procedure known to trigger a strong response, of both the neural (autonomic nervous system) and the hormonal (renin-angiotensin and vasopressin) systems. ABP was continuously recorded from the caudal artery in conscious, 1-month-old SHR and WKY. Three groups of rats were studied. Group 1, acute 2-ml hemorrhage; Groups 2, injection of prazosin (2.5 mg/kg) or Group 3, captopril (4 mg/kg), each followed by bleeding as in the group 1. Spectral analysis of ABP fluctuations was performed on time traces of 20 min duration. The low-frequency part of the power spectrum was analyzed. Three frequency bands were investigated: 0.004-0.04 Hz, 0.04-0.07 Hz and 0.07-0.1 Hz. In SHR, although the baseline mean ABP levels were similar to those of WKY, ABP fluctuations were significantly dampened in SHR in each of the three frequency ranges. Hemorrhage induced, in both strains, a similar fall in mean ABP accompanied by an increase in the slow ABP fluctuations. However, in SHR, the response was significantly greater that that of WKY. The steepest response was observed in the slowest, 0.004-0.04 Hz frequency band, 8.7 +/- 1.7 vs. 1.5 +/- 0.4 times the baseline levels. However, this intense increase in power after hemorrhage brought the two strains to similar levels. The difference in the response to bleeding was eliminated, in the three frequency ranges, by alpha 1 blockade. Captopril reduced the response to bleeding in SHR, to the level observed in WKY in all three frequency bands. Spectral analysis of the spontaneous oscillations in ABP unmasks abnormalities which conventional blood pressure measurements cannot detect in 1-month-old, still normotensive SHR. It thus, provides a tool to study the dynamics of the abnormalities which precede the development of hypertension. Bleeding amplifies the malfunction observed in SHR under baseline conditions, since the mean ABP levels were similar in both strains before and after bleeding, SHR seem to retain the ability to respond to a fall in blood volume by requiring a greater recruitment of the control mechanisms than WKY.

Correlation dimension estimation: can this nonlinear description contribute to the characterization of blood pressure control in rats?

The application of correlation dimension estimation to the study of cardiovascular control, via the blood pressure (BP) time series was investigated. The authors chose to calculate the Grassberger-Procaccia (GP) correlation dimension. In order to obtain a reliable estimate of the correlation dimension, they studied impact of various parameters such as the appropriate sampling rate, the time delays, the embedding dimension, the minimal trace length required, and the number of points needed as reference points. The authors developed a recipe for the reliable treatment of the continuous BP signal in rats, their animal model, and discussed the possible pitfalls which demand special attention. Next, they applied the surrogate data method to a BP time series, looking for the existence of nonlinear components, in order to test whether the nonlinear modeling is necessary for accurately describing the system. The authors found that, indeed, the correlation dimension does reveal information which cannot be unveiled by the commonly used power spectral technique, thus, making the nonlinear modeling an important approach, providing additional insight into the cardiovascular control system.

Beat-to-beat fluctuations in the BP related signals in rats: can it contribute to the understanding of the development of hypertension?

The goal of this study was to investigate the alterations in blood pressure control in young spontaneously hypertensive rats (SHR), as reflected in the power distribution of blood pressure fluctuations. We studied six SHR preceding the onset of overt hypertension, compared to six age matched control rats, the normotensive Wistar-Kyoto rats (WKY), and analyzed the power density distribution of several blood pressure related signals, namely: arterial blood pressure (ABP), systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) and heart rate (HR). ABP fluctuations exhibited a basic difference in the power distribution pattern between the strains: at low frequencies (< 0.15 Hz) more power was observed in WKY than in SHR, while in the (0.35-1.00 Hz) range, more power was observed in SHR. These significant differences in patterns which existed at baseline, were abolished by prazosin (2.5 mg/kg). Observing the power distribution in the BP related signals, the patterns were different from that found in the ABP itself. At baseline, in SBP and DBP, the most dominant power was located at low frequencies < 0.04 Hz, like in ABP. However, unlike ABP, the remainder of the power was located in the high frequency region (HF: 1.5-3.0 Hz), mainly in SHR. Prazosin had a marked effect on PP power spectra; it shifted the power to the HF region in both strains. In PP, power spectra differences observed between the strains at baseline in HF were eliminated by prazosin. This seems to indicate that, in SHR compared to WKY, respiratory fluctuations which are low at baseline in PP, are a mechanical reflection of the higher sympathetic tone in SHR before alpha1 sympathetic blockade. This study supports previous findings in which differences in cardiovascular control occur in SHR already at the prehypertensive stage. The above results suggest that alpha1 sympathetic control is altered in the SHR strain, and therefore, when this limb is blocked, some of the differences between the strains disappear. Furthermore, the analysis of the BP related signals enable us to identify alterations existing in the control mechanisms in SHR, which involve adjunct control mechanisms enhanced under alpha1 sympathetic blockade. Finally, an important result is, that for all BP related signals under study, excluding HR, the response to alpha1-blockade reduces the power density in the 0.07-0.15 Hz region indicating that this region is directly associated with the activity of alpha control.

Nonlinear dynamics applied to blood pressure control

Hypertension is a very frequent disease, known to trigger a range of severe cardiovascular problems. The elucidation of its pathophysiology requires investigation of the mechanisms responsible for the maintenance of blood pressure in the normal system, and their possible failure in hypertension. Some of these control mechanisms display nonlinear features, indicating that the blood pressure signal might be characterized by nonlinear dynamics. Our aim was thus to investigate the nonlinear properties of the blood pressure signal under normal conditions, and in a cardiovascular system prone to hypertension. Blood pressure was investigated in young spontaneously hypertensive rats (SHR), versus their age-matched normotensive progenitors (WKY). The correlation dimension was computed as quantification of blood pressure control complexity. The parameters required for the calculation procedure of the correlation dimension were carefully determined. The results were tested with surrogate data statistics. assuming linear autocorrelated Gaussian noise as the null hypothesis. Non-integer correlation dimension values were found in both strains, with lower values for SHR than for WKY, in particular following alpha-blockade. In all cases, a statistically significant difference was found between the real and surrogate data. These results show that the nonlinear dynamics parameter D, can be used to detect differences in BP control between prehypertensive SHR and WKY rats as early as 6-7 weeks after birth.

The effect of changes in blood volume on low frequency blood pressure fluctuations in spontaneously hypertensive rats

This study is based on the hypothesis that the development of essential hypertension is due to a defect in cardiovascular control. Young, prehypertensive, spontaneously hypertensive (SHR) rats were compared with normotensive Wistar Kyoto (WKY) rats. Spectral analysis of blood pressure (ABP) fluctuations previously demonstrated that baseline low-frequency fluctuations (0.04-0.1 Hz) are reduced in the SHR rats even before they develop hypertension. In the present study, 20-min-long ABP traces were sampled with the focus on frequencies as low as 0.004 Hz. The effect caused by a perturbation in blood pressure was investigated in young SHR versus WKY rats. A sudden drop in blood volume (2-ml bleeding) caused a clear increase in low-frequency ABP fluctuations, more pronounced in SHR than in WKY rats. The decrease in mean ABP was larger in SHR (-42%) than in WKY rats (-21%). Alpha/sub 1/-blockade (prazosin) affected the reaction of both species to bleeding differently. The results indicate that the SHR rats exhibit an abnormal nervous response ( alpha -sympathetic) to a drop in blood pressure, which might be at the basis of the development of hypertension.<<ETX>>

The diastolic decay constant in spontaneously hypertensive rats versus WKY rats as an indicator for vasomotor control

This research uses the diastolic decay constant (tau) to investigate the short term mechanism responsible for vasomotor control, mainly the alpha-sympathetic control system. Previous studies have shown that vasomotor control is altered in spontaneously hypertensive rats (SHR) preceding the phase of overt hypertension. The diastolic decay, according to the two element Windkessel model, displays an exponential shape with a decay constant, tau, depending on both the vascular resistance and the compliance. In our experiments, we used tau to characterize vasomotor activity and its control in the normotensive rats as well as in the spontaneously hypertensive rats (SHR) prone to hypertension. The beat to beat value of tau was evaluated from a continuous arterial blood pressure (ABP) signal, measured in the tail artery of the conscious, unrestrained rat. Four months old prehypertensive SHR were compared to their age matched normotensive controls (WKY). To study vasomotor regulation, we computed gains and delay times by investigating the compensatory response in tau to changes in mean ABP (MBP). These parameters are expected in the short term to be neurally controlled by the sympathetic system, mainly alpha-sympathetic. Our set of experiments consisted of changing MBP by performing successive injections in bolus of increasing doses of the vasoconstrictor angiotensin II. This procedure was repeated under double cardiac autonomic blockade of the vagal and beta 1 = sympathetic limbs. Our results show that, under baseline conditions, the absolute gain and delay times of tau are reduced in SHR compared to WKY. Double cardiac blockade decreases the absolute gain in both strains, while abolishing the baseline strain differences. These results reinforce our assumption that, in SHR, the alpha-sympathetic system is in a basic state of excitation even prior to the onset of overt hypertension and therefore reacting with reduced sensitivity (lower gain) to changes in MBP.

BP fluctuations in the normotensive versus the hypertensive cardiovascular system: simulation and experiment

A computerised model has been designed in order to simulate blood pressure (BP) control and mean BP (MBP) fluctuations in the normal and the hypertensive cardiovascular system. The purpose of this model is to compare between the two systems by allowing their control limbs to function naturally, hoping to obtain the BP fluctuations as experimentally observed in the two strains. In experimental studies performed on normotensive (WKY) vs. spontaneously hypertensive rats (SHR), the authors detected basic differences in the pattern of BP fluctuations. When introducing the respective control parameters of the vagal and beta-sympathetic limbs (experimentally measured) for the two strains of rats, the differences between WKY and SHR cause the low-frequency BP fluctuations to be slightly, but consistently, reduced in SHR. Among other findings, these experiments showed a clearly reduced beta -sympathetic gain in SHR as compared to WKY.<<ETX>>