O. Rimoldi

Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog.

In 57 normal subjects (age 20–60 years), we analyzed the spontaneous beat-to-beat oscillation in R-R interval during control recumbent position, 90° upright tilt, controlled respiration (n = 16) and acute (n = 10) and chronic (n = 12) β-adrenergic receptor blockade. Automatic computer analysis provided the autoregressive power spectral density, as well as the number and relative power of the individual components. The power spectral density of R-R interval variability contained two major components in power, a high frequency at ∼0.25 Hz and a low frequency at ∼0.1 Hz, with a normalized low frequency: high frequency ratio of 3.6 ± 0.7. With tilt, the low-frequency component became largely predominant (90 ± 1%) withalow frequency: high frequency ratio of 21 ± 4. Acute β-adrenergic receptor blockade (0.2 mg/kg IV propranolol) increased variance at rest and markedly blunted the increase in low frequency and low frequency: high frequency ratio induced by tilt. Chronic β-adrenergic receptor blockade (0.6 mg/kg p.o. propranolol, t.i.d.), in addition, reduced low frequency and increased high frequency at rest, while limiting the low frequency: high frequency ratio increase produced by tilt. Controlled respiration produced at rest a marked increase in the high-frequency component, with a reduction of the low-frequency component and of the low frequency: high frequency ratio (0.7 ± 0.1); during tilt, the increase in the low frequency: high frequency ratio (8.3 ± 1.6) was significantly smaller. In seven additional subjects in whom direct high-fidelity arterial pressure was recorded, simultaneous R-R interval and arterial pressure variabilities were examined at rest and during tilt. Also, the power spectral density of arterial pressure variability contained two major components, with a relative low frequency: high frequency ratio at rest of 2.8 ± 0.7, which became 17 ± 5 with tilt. These power spectral density components were numerically similar to those observed in R-R variability. Thus, invasive and noninvasive studies provided similar results. More direct information on the role of cardiac sympathetic nerves on R-R and arterial pressure variabilities was derived from a group of experiments in conscious dogs before and after bilateral stellectomy. Under control conditions, high frequency was predominant and low frequency was very small or absent, owing to a predominant vagal tone. During a 9% decrease in arterial pressure obtained with IV nitroglycerin, there was a marked increase in low frequency, as a result of reflex sympathetic activation. Bilateral stellectomy prevented this low-frequency increase in R-R but not in arterial pressure autospectra, indicating that sympathetic nerves to the heart are instrumental in the genesis of low-frequency oscillations in R-R interval.

Model for the assessment of heart period and arterial pressure variability interactions and of respiration influences

A model which assesses the closed-loop interaction between heart period (HP) and arterial pressure (AP) variabilities and the influence of respiration on both is applied to evaluate the sources of low frequency (LF∼0·1 Hz) and high frequency (HF, respiratory rate ∼0·25 Hz) in conscious dogs (n=18) and humans (n=5). A resonance of AP closed-loop regulation is found to amplify LF oscillations. In dogs, the resonance gain increases slightly during baroreceptor unloading (mild hypotension obtained with nitroglycerine (NTG) i.v. infusion, n=8) and coronary artery occlusion ((CAO), n=6), and it is abolished by ganglionic transmission blockade ((ARF), Arfonad i.v. infusion, n=3). In humans, this gain is considerably increased by passive tilt. Different, possibly central, sources of LF oscillations are also evaluated, finding a strong rhythmic modulation of HP during CAO. At HF, a direct respiratory arrhythmia is dominant in dogs at control, while it is considerably reduced during CAO. On the contrary, in humans, a strong influence of respiration on AP is shown which induces a reflex respiratory arrhythmia. An index of the gain of baroreceptive response, αcl, was decreased by NTG and CAO, and virtually abolished by chronic arterial baroreceptive denervation (TABD, n=4) and ARF.

Quantifying the strength of the linear causal coupling in closed loop interacting cardiovascular variability signals

Abstract. The coherence function measures the amount of correlation between two signals x and y as a function of the frequency, independently of their causal relationships. Therefore, the coherence function is not useful in deciding whether an open-loop relationship between x and y is set (x acts on y, but the reverse relationship is prevented) or x and y interact in a closed loop (x affects y, and vice versa). This study proposes a method based on a bivariate autoregressive model to derive the strength of the causal coupling on both arms of a closed loop. The method exploits the definition of causal coherence. After the closed-loop identification of the model coefficients, the causal coherence is calculated by switching off separately the feedback or the feedforward path, thus opening the closed loop and fixing causality. The method was tested in simulations and applied to evaluate the degree of the causal coupling between two variables known to interact in a closed loop mainly at a low frequency (LF, around 0.1 Hz) and at a high frequency (HF, at the respiratory rate): the heart period (RR interval) and systolic arterial pressure (SAP). In dogs at control, the RR interval and the SAP are highly correlated at HF. This coupling occurs in the causal direction from the RR interval to the SAP (the mechanical path), while the coupling on the reverse causal direction (the baroreflex path) is not significant, thus pointing out the importance of the direct effects of respiration on the RR interval. Total baroreceptive denervation, by opening the closed loop at the level of the influences of SAP on RR interval, does not change these results. In elderly healthy men at rest, the RR interval and SAP are highly correlated at the LF and the HF. At the HF, a significant coupling in both causal directions is found, even though closed-loop interactions are detected in few cases. At the LF, the link on the baroreflex pathway is negligible with respect to that on the reverse mechanical one. In heart transplant recipients, in which SAP variations do not cause RR interval changes as a result of the cardiac denervation, the method correctly detects a significant coupling only on the pathway from the RR interval to the SAP.

Assessment of the neural control of the circulation during psychological stress

In this study, we used spectral analysis of short-term R-R and systolic arterial pressure (SAP) variabilities to estimate the changes in neural control of the circulation produced by psychological stress. The 0.1 Hz low-frequency (LF) component of R-R and SAP variabilities provided a quantitative index of the sympathetic activity controlling heart rate and vasomotion. Conversely the high-frequency (HF) respiratory component of R-R variability provided an index of vagal tone. In conscious dogs we used the seemingly stressful situation of being accompanied for the first time to the experimental laboratory as a stimulus. In human subjects we used mental arithmetic. In both cases LF of R-R and SAP variabilities increased significantly suggesting enhanced sympathetic activity both to the SA node and the vasculature. In man, the index alpha, a measure of the overall gain of baroreceptor mechanisms, was found to be reduced during mental arithmetic. Spectral analysis of cardiovascular variabilities thus suggests that in man and in conscious dogs psychological challenges induce a profound re-arrangement of neural control of the circulation, which appears to be characterised by sympathetic predominance and which can be monitored by this technique.

Analysis of the pressor sympathetic reflex produced by intracoronary injections of bradykinin in conscious dogs.

The reflex hemodynamic effects of intracoronary bradykinin were tested in 20 conscious instrumented dogs. When the experiments were performed after full recovery from surgery and anesthesia, graded doses (10–300 ng/kg) of bradykinin always produced graded pressor responses, in the absence of any pain reaction. At the maximum pressor response obtained with 100 ng/kg, mean arterial pressure rose 28 ± 3% from 89 ± 4 mm Hg, left ventricular pressure 20 ± 3% from 121 ± 2 mm Hg, heart rate 30 ± 4% from 88 ± 5 beats/min, rate of change of left ventricular pressure 18 ± 3% from 2812 ± 65 mm Hg/sec (P < 0.01). Higher doses of bradykinin did not produce greater responses. The magnitude of the response was similar when the injection was performed in either the left anterior descending (change in mean arterial pressure 29 ± 3%) or circumflex (change in mean arterial pressure 27 ± 2%) coronary artery. The reflex nature of the response was proved by its disappearance after appropriate pharmacological blockades; moreover, after vagotomy, the pressor rise was maintained, the heart rate response was reduced (change in heart rate 10 ± 2%), and the inotropic response was enhanced (rate of change of left ventricular pressure 24 ± 3%). This suggested that the afferent pathway of the pressor reflex was in the sympathetic nerves and that a subordinate vagal depressor reflex was also operative. No pain reaction was obtained even when injecting very large amounts (1000–2000 ng/kg) of bradykinin, which, instead, induced arterial hypotension. Pain reactions (as inferred by agitation and vocalization) were observed in three out of nine dogs studied during the first week after surgery. This reaction was no longer present when the same animals were tested later on, at the time of complete recovery. In five of the nine dogs studied during the first week after surgery, the intracoronary injection of bradykinin produced a depressor (change in mean arterial pressure −31 ± 6%) response, which, however, reverted to a pressor effect (change in mean arterial pressure 22 ± 4%) later, when recovery was complete. In five additional dogs, the pressor response observed after full recovery from surgery was no longer present when the injection of bradykinin was repeated under anesthesia. The present experiments in conscious dogs show that the chemical stimulation of the fully innervated heart with intracoronary bradykinin can initiate pressor reflexes independent of pain and in the presence of intact buffering mechanisms.

Causal relationship between heart rate and arterial blood pressure variability signals

A method is described which allows the determination of the causal relationship existing between two biological signals (heart rate and arterial blood pressure variability signals) which carry information about the role of control elicited by the autonomic nervous system. This method assumes an autoregressive (AR) model for the two signals to check the cross-correlation of the two residuals after AR identification. This information, together with the classical parameters of the spectral analysis (mean, variance, frequency and power in two typical bands, gain, phase and coherence) may provide a more precise evaluation of the complex mechanisms involved in the control of heart rate and blood pressure in numerous physiopathological situations.

Sympathetic activation during treadmill exercise in the conscious dog: Assessment with spectral analysis of heart period and systolic pressure variabilities

We studied in seven conscious dogs the dynamic rearrangements in neural control of heart rate and left ventricular pressure during treadmill exercise as assessed by spectral analysis. The presence, at rest, of a major high-frequency component (HF), an indicator of vagal tone, was reverted during exercise to a major low-frequency component (LF), an indicator of sympathetic activation. These changes were blunted by chronic beta and alpha 1 adrenergic receptor blockade.

Spectral Analysis of Cardiovascular Variables as a Tool to Quantify Neural Cardiovascular Control in the Laboratory and Real Life Conditions

The neural control of the circulation depends upon a continuous interaction between opposite, i.e. negative and positive, feed-back mechanisms, mediated respectively by vagal/baroreceptive and sympathetic circuits.

Neuro Humoral Control

The notion that the arterial tree is a very complex branching system (Bergel, 1972) is a very old one. Most likely such a complexity has contributed to hamper the studies of its mechanical properties. Early studies highlighted both the behavior of the vessel wall and the volume properties of individual arteries. In general, these studies were based on several simplifying assumptions, including an assumption of similarity between regional arteries. However important regional differences have been shown whenever such was sought experimentally (Cox, 1978).