Massimo Pagani

Cardiovascular neural regulation explored in the frequency domain.

A consistent link appears to exist between predominance of vagal or sympathetic activity and predominance of HF or LF oscillations, respectively: RR variability contains both of these rhythms, and their relative powers appear to subserve a reciprocal relation like that commonly found in sympathovagal balance. In this respect, it is our opinion that rhythms and neural components always interact, just like flexor and extensor tones or excitatory and inhibitory cardiovascular reflexes, and that it is misleading to separately consider vagal and sympathetic modulations of heart rate. In humans and experimental animals, functional states likely to be accompanied by an increased sympathetic activity are characterized by a shift of the LF-HF balance in favor of the LF component; the opposite occurs during presumed increases in vagal activity. In addition, LF oscillation evaluated from SAP variability appears to be a convenient marker of the sympathetic modulation of vasomotor activity. Although based on indirect markers, the exploration in the frequency domain of cardiovascular neural regulation might disclose a unitary vision hard to reach through the assemblage of more specific but fragmented pieces of information.

Power spectrum analysis of heart rate variability to assess the changes in sympathovagal balance during graded orthostatic tilt.

BACKGROUND The powers of the low-frequency (LF) and high-frequency (HF) oscillations characterizing heart rate variability (HRV) appear to reflect, in their reciprocal relationship, changes in the state of the sympathovagal balance occurring during numerous physiological and pathophysiological conditions. However, no adequate information is available on the quantitative resolution of this methodology. METHODS AND RESULTS We studied 22 healthy volunteers (median age, 46.5 years) who were subjected after a rest period to a series of passive head-up tilt steps randomly chosen from the following angles: 15 degrees, 30 degrees, 45 degrees, 60 degrees, and 90 degrees. From the continuous ECG, after appropriate analog-to-digital conversion, a personal computer was used to compute, with an autoregressive methodology, time and frequency domain indexes of RR interval variability. Spectral and cross-spectral analysis with the simultaneously recorded respiratory signal excluded its contribution to LF. Age was significantly correlated to variance and to the absolute values in milliseconds squared of very-low-frequency (VLF), LF, and HF components. The tilt angle was correlated to both LF and HF (expressed in normalized units [nu]) and to the LF-to-HF ratio (r = .78, -.72, and .68; respectively). Lower levels of correlation were found with HF (in ms2) and RR interval. No correlation was present between tilt angle and variance, VLF, or LF (in ms2). Individual analysis confirmed that the use of nu provided the greatest consistency of results. CONCLUSIONS Spectral analysis of HRV, using nu or LF-to-HF ratio, appears to be capable of providing a noninvasive quantitative evaluation of graded changes in the state of the sympathovagal balance.

Relationship Between Spectral Components of Cardiovascular Variabilities and Direct Measures of Muscle Sympathetic Nerve Activity in Humans

BACKGROUND Spectral analysis of RR interval and systolic arterial pressure variabilities may provide indirect markers of the balance between sympathetic and vagal cardiovascular control. METHODS AND RESULTS We examined the relationship between power spectral measurements of variabilities in RR interval, systolic arterial pressure, and muscle sympathetic nerve activity (MSNA) obtained by microneurography over a range of blood pressures. In eight healthy human volunteers, MSNA, RR interval, intra-arterial pressure, and respiration were measured during blood pressure reductions induced by nitroprusside and during blood pressure increases induced by phenylephrine. Both low-frequency (LF; 0.10 +/- 0.01 Hz) and high-frequency (HF; 0.23 +/- 0.01 Hz) components were detected in MSNA variability. Increasing levels of MSNA were associated with a shift of the spectral power toward its LF component. Decreasing levels of MSNA were associated with a shift of MSNA spectral power toward the HF component. Over the range of pressure changes, the LF component of MSNA variability was positively and tightly correlated with LF components of RR interval (in normalized units; P < 10(-6)) and of systolic arterial pressure variability (both in millimeters of mercury squared and normalized units; P < 5 x 10(-5) and P < 5 x 10(-6), respectively). The HF component of MSNA variability was positively and tightly correlated with the HF component (in normalized units) of RR-interval variability (P < 3 x 10(-4)) and of systolic arterial pressure variability (P < .01). CONCLUSIONS During sympathetic activation in normal humans, there is a predominance in the LF oscillation of blood pressure, RR interval, and sympathetic nerve activity. During sympathetic inhibition, the HF component of cardiovascular variability predominates. This relationship is best seen when power spectral components are normalized for total power. Synchronous changes in the LF and HF rhythms of both RR interval and MSNA during different levels of sympathetic drive are suggestive of common central mechanisms governing both parasympathetic and sympathetic cardiovascular modulation.

Continuous 24-hour assessment of the neural regulation of systemic arterial pressure and RR variabilities in ambulant subjects.

In this study, we tested the hypothesis that the neural control of circulation in humans undergoes continuous but in part predictable changes throughout the day and night. Dynamic 24-hour recordings were obtained in two groups of ambulant subjects. In 18 hospitalized patients free to move, direct high-fidelity arterial pressures and electrocardiograms were recorded, and in an additional 28 nonhospitalized subjects, only electrocardiograms were obtained. Spectral analysis of systolic arterial pressure and of RR interval variabilities provided quantitative markers of sympathetic and vagal control of the sinus node and of sympathetic modulation of vasomotor tone. With this approach, the low-frequency (approximately 0.1 Hz) component of RR interval and systolic arterial pressure variabilities is considered a marker primarily of sympathetic activity, whereas the high-frequency (approximately 0.25 Hz) component of RR interval variability, related to respiration, seems to be a marker primarily of vagal activity. We observed a pronounced and consistent reduction in the markers of sympathetic activity and an increase in those of vagal activity during the night. In the invasive studies, while the subjects were still lying in bed after waking up, the markers of sympathetic activity rose rapidly and concomitantly with a simultaneous vagal withdrawal. Noninvasive studies confirmed the early morning rise of the markers of sympathetic activity and the circadian pattern of sympathovagal balance. These data indicate that the ominously increased rate of cardiovascular events in the morning hours may reflect the sudden rise of sympathetic activity and the reduction of vagal tone.

Sympathetic predominance in essential hypertension: A study employing spectral analysis of heart rate variability

In this study on 91 subjects we tested the hypothesis of an enhanced sympathetic activity in uncomplicated essential hypertension employing spectral analysis of heart rate variability. With this technique the tonic sympathetic and vagal activities and their changes are respectively assessed by the power of approximately 0.1 Hz (low frequency, LF) and approximately 0.25 Hz (respiratory linked, high frequency, HF) components of the spectrum of the beat by beat variability of RR interval. When comparing the 40 subjects with diastolic blood pressure consistently greater than 95 mmHg (hypertensives, Ht), with 35 age-matched controls (diastolic arterial pressure less than 90 mmHg, Nt), we observed that LF was greater and HF smaller in Ht as compared to Nt, thus suggesting an enhanced sympathetic activity and a reduce vagal activity in Ht. Additionally, passive tilt, which in Nt enhances LF [delta = 26 +/- 2 normalized units (nu)] and reduces HF (delta = -22 +/- 2, nu), produced smaller (P less than 0.05) changes in Ht (delta LF = 6.3 +/- 2.7 and delta HF = -7.5 +/- 2.3 nu). Furthermore, the values of LF at rest and the altered effects of tilt on LF and HF were significantly correlated with the degree of the hypertensive state. Chronic beta-adrenergic blockade (atenolol 100 mg once daily for 2 weeks, n = 13) reduced heart rate and blood pressure (from 162/103 to 136/88 mmHg) together with a significant diminution of LF and an increase of HF. Thus, spectral analysis of RR variability appears to be a convenient non-invasive technique to follow the progressive alterations in sympatho-vagal balance present in essential hypertension.

Absence of Low-Frequency Variability of Sympathetic Nerve Activity in Severe Heart Failure

BACKGROUND In normal humans, variability of blood pressure, RR interval, and sympathetic activity occurs predominantly at a low frequency (LF; 0.04 to 0.14 Hz) and a high frequency (HF; +/-0.25 Hz). In conditions that increase sympathetic activation in normal humans, the LF component is increased relative to the HF component. Patients with heart failure have high levels of sympathetic activity. We tested the hypothesis that the LF component of sympathetic nerve activity variability is increased in heart failure. METHODS AND RESULTS We performed spectral analysis of simultaneous recordings of resting muscle sympathetic nerve activity (MSNA) and RR interval in 21 patients with chronic heart failure and 12 age-matched control subjects. MSNA was higher in patients with heart failure (62 +/- 4 bursts per minute) than in the normal subjects (39 +/- 4 bursts per minute; P < .01). LF components of RR interval and MSNA variability were lower in the heart failure patients versus the control subjects (P < .01). HF variability of RR interval and MSNA was preserved, at least in part, in heart failure. There was close coherence between variability patterns of RR interval and MSNA. Furthermore, in 14 heart failure patients who had no LF variability in MSNA compared with 7 heart failure patients who did manifest LF variability in MSNA, RR interval was shorter, the variance of RR interval was lower, MSNA was higher, respiratory rate was faster, and left ventricular ejection fraction was lower (all P < .05). At a median follow-up of 12 months, 4 heart failure patients had died, all of whom had had absent LF oscillations in MSNA and RR interval. CONCLUSIONS The LF variability of sympathetic nerve activity is absent in patients with severe heart failure. This disturbed pattern of variability is closely coherent with the abnormal variability of RR interval. These disturbances of rhythmic oscillations of autonomic outflow, evident in both RR interval and MSNA, suggest a central autonomic regulatory impairment in heart failure and may have important prognostic implications.

Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy

We studied heart rate variability in 49 uncomplicated diabetics (27 with insulin therapy; 22 with oral hypoglycemic agents) and in 40 age-matched controls. An automatic autoregressive algorithm was used to compute the power spectral density (PSD) of beat by beat RR variability derived from the surface ECG. The PSD contains two major components (a low frequency approximately 0.1 Hz (LF) and a high frequency, respiratory linked, approximately 0.25 Hz (HF] that provide, respectively, quantitative markers of sympathetic and vagal modulatory activities and of their balance. As compared to controls, in diabetics, besides a reduced RR variance at rest (2722 +/- 300 and 1436 +/- 241 ms2, respectively), we observed during passive tilt an altered response of spectral indices of sympathetic activation and vagal withdrawal, suggestive of a complex modification in the neural control activities. In addition, we compared this approach to the commonly used clinical tests score, and observed that the latter provides overall results similar to those obtained with spectral changes induced by tilt (r = 0.42; P less than 0.01). Of potential clinical importance is that the data obtained with spectral analysis appear more thoroughly quantifiable and do not require the active collaboration of the patients.

Entropy, entropy rate, and pattern classification as tools to typify complexity in short heart period variability series

An integrated approach to the complexity analysis of short heart period variability series (/spl sim/300 cardiac beats) is proposed and applied to healthy subjects during the sympathetic activation induced by head-up tilt and during the driving action produced by controlled respiration (10, 15, and 20 breaths/min, CR10, CR15, and CR20 respectively). The approach relies on: 1) the calculation of Shannon entropy (SE) of the distribution of patterns lasting three beats; 2) the calculation of a regularity index based on an entropy rate (i.e., the conditional entropy); 3) the classification of frequent deterministic patterns (FDPs) lasting three beats. A redundancy reduction criterion is proposed to group FDPs in four categories according to the number and type or of heart period changes: a) no variation (0V); b) one variation (1V); and c) two like variations (2LV); 4) two unlike variations (2UV). The authors found that: 1) the SE decreased during tilt due to the increased percentage of missing patterns; 2) the regularity index increased during tilt and CR10 as patterns followed each other according to a more repetitive scheme; and 3) during CR10, SE and regularity index were not redundant as the regularity index significantly decreased while SE remained unchanged. Concerning pattern analysis the authors found that: a) at rest mainly three classes (0V, 1V, and 2LV) were detected; b) 0V patterns were more likely during tilt; c) 1V and 2LV patterns were more frequent during CR10; and d) 2UV patterns were more likely during CR20. The proposed approach based on quantification of complexity allows a full characterization of heart period dynamics and the identification of experimental conditions known to differently perturb cardiovascular regulation.

Conversion From Vagal to Sympathetic Predominance With Strenuous Training in High-Performance World Class Athletes

Background—Benefits of moderate endurance training include increases in parasympathetic activity and baroreflex sensitivity (BRS) and a relative decrease in sympathetic tone. However, the effect of very intensive training load on neural cardiovascular regulation is not known. We tested the hypothesis that strenuous endurance training, like in high-performance athletes, would enhance sympathetic activation and reduce vagal inhibition. Methods and Results—We studied the entire Italian junior national team of rowing (n=7) at increasing training loads up to 75% and 100% of maximum, the latter ∼20 days before the Rowing World Championship. Autoregressive power spectral analysis was used to investigate RR interval and blood pressure (BP) variabilities. BRS was assessed by the sequences method. Increasing training load up to 75% of maximum was associated with a progressive resting bradycardia and increased indexes of cardiac vagal modulation and BRS. However, at 100% training load these effects were reversed, with increases in resting heart rate, diastolic BP, low-frequency RR interval, and BP variabilities and decreases in high-frequency RR variability and BRS. Three athletes later won medals in the World Championship. Conclusions—This study indicates that very intensive endurance training shifted the cardiovascular autonomic modulation from a parasympathetic toward a sympathetic predominance. This finding should be interpreted within the context of the substantial role played by the sympathetic nervous system in increasing cardiovascular performance at peak training. Whether the altered BP and autonomic function shown in this study might be in time hazardous to human cardiovascular system remains to be established.

A Cardiocardiac Sympathovagal Reflex in the Cat

The reflex changes in single cardiac vagal efferent fibers elicited by excitation of afferent cardiac sympathetic fibers were studied in cats anesthetized with chloralose and urethane. Efferent vagal and sympathetic units were dissected from the end of a cardiac nerve cut at its junction with the right atrium. In some cases, efferent vagal units were dissected from the cervical vagus. Excitation always evoked a clear reduction in the discharge of cardiac vagal units and a clear increase in the discharge of cardiac sympathetic fibers. The effects on cervical vagal efferents were variable. Hence, excitation of afferent cardiac sympathetic fibers could simultaneously elicit inhibition of the vagal outflow to the heart and excitation of the sympathetic outflow. By contrast, stimulation of the cut central end of the contralateral vagus produced the opposite effects. Convergence of afferent fibers in the vagi and the cardiac sympathetic nerves on the same cardiac vagal and cardiac sympathetic postganglionic neurons was demonstrated. Convergence from carotid sinus baroreceptors was also observed.