1276 Spectral Analysis of Blood Pressure and Heart Rate Variability in Evaluating Cardiovascular Regulation A Critical Appraisal Gianfranco P: Abstract Blood pressure variability includes shythmic and ‘nonrhythmic fluctuations that, with the use of spectral analysis, appear as clear peaks or broadband power, respectively. This review offers concise and critical description of the spectral methods most commonly used (fast Fourier transform versus utoregressive modeling, time-varying versus broadband spec teal analysis) and an evaiuation of theie advantages and disad- ‘vantages. It also provides insight into the problems that stil alec the physiological and clinical interpretations of dat provided by spectral analysis of blood pressure and heart ra variability. In particular, the assessment of blood pressure and Ineatt rate spectra aimed at providing indexes af autonomic he regulation of blood pressure (BP) is tradition- ally described in terms of homeostasis." This word comes from the Greek homeo (similar) and stasis (steady) and indicates that BP, although being continuously perturbed by external stimulations, always displays the tendency to come back toward a reference set point. This dynamic behavior of BP implies thi attention should be directed not only to the average BP valuc, which can be regarded as the reference set point, but also to the BP and cardiovascular fluctuations oc ‘curring around this average. Data from a variety of sources indicate that these fluctuations are indeed much ‘more than undesirable noise. On the contrary, they esent a rich source of information that can provide ight into the mechanisms of cardiovas- cular control.** Cardiovascular fluctuations ean be stud ied through beat-to-beat BP and heart rate (HR) mon- itoring and calculation of the variance (or standard deviation) of their average values Recently, how- ever, frequency domain analysis has also been used to subdivide the variability of BP and HR into different Recvived September 8, 1994; fist deckion October 25, 1994 seibion accepted February 16,1995 From the Istituto Scientfico Ospedale §. Luca, Centro Auxo logico Italiano, Milano (G-P.,G.ML), Medicina Interna I. Ospedale S. Gerardo, Monza and Universita di Milano (G.P. G.M.) (lta. Children’s Hospital, Department of Cardiology, Havant Medica School, Boston (PS); Massachussetts Institute of Technolo, Health Sciences and ‘Technology, Cambridge (.PS.), Mass. ad LARG, Centro di Bioingegneria, Fondazione Pro Juventute, Mi- lao, italy (M. Di R), Correspondence to Gianfranco Parat, MD, Cento di Fisiologia linia © Ipertensions, Ospedale Maggiore and. Universit Milano, va F Stora, ati, J. Philip Saul, Marco Di Rienzo, Giuseppe Mancia cardiovascular modulation is discussed. Evidence is given that multivariate models—which allow evalvation of the inte ons between changes in blood pressure, heart rate, and other biological signals (uch as respiratory activity) in the time or frequency domains—offer 4 more comprehensive approach 10 the assessment of cardiovascular regulation than that repre sented by the separate analysis of fictuations in blood pressure fr heatt rate only. ypertension, 1995;25:1276-1286,) Key Words © blood pressure « heart rate * autonomic nervous system © hypertension, essential * sequence analysis frequency components and to quantify the variance or “power” at cach specific frequency." A wide variety of algorithms and models have been proposed in this context to study spontancous cardiovascular variability and to characterize the relation between the changes in HR, arterial BP, and respiration, However, the optimal ‘methods for extracting such information and the most appropriate interpretations of the results obtained are still matters of considerable debate." This article will focus on these issues. Rhythmic and Nonrhythmic Changes in BP and HR Rhythmic BP and HR oscillations related to respira- tory activity were first deseribed by Hales" and: von Haller," and their observations were confirmed by Lud- wig 80 years later.* After a few decades, Mayer reported that BP also oscillates at frequencies slower than the respiratory rhythm, suggesting that these oscillations are related to vasomotor activity."©"* More recently, techno- logical progress in the field of data collection and analysis HR recording, availability of low-cost eo gorithms for data process- ing, etc) has led to more sophisticated approaches 10 rhythmic circulatory phenomena and to their more frequent investigation by power spectrum analysis, Orig inally, three BP and HR rhythmic oscillations were identified, all with a period shorter than 1 minute and with the appearance in the spectrum as individual peaks (Fig 14). These peaks reflect (1) oscillations with Frequency around 0.2 to 0.4 Hz, a frequency similar to that of normal respiratory activity, defined as high- frequency (HF): ions with frequency of approximately 0.1 Hz, defined as mid-frequency (MF)Parati ct al Cardiovascular Control and Spectral Analysis 1277 Es Tine(ninowe) Frege er B ‘Time Series. ‘Spectre. eee is! z ae Fro 1. Pots show respiratory and heart rate time series (ot) and spectra (ight) for one subject with “peaky" heart rate ‘spectra (A) and one with broadband heart rate spectra (2). and corresponding in the case of BP to the classic Mayer ‘waves; and (3) oscillations with a frequency between 01.02 and 0.07 Hz, defined as low-frequency (LF) and pro bly related to a variety of cardiorespiratory phenomena and mechanisms." Subsequent studies, however, have made it clear that the amplitude and frequency of the above oscillations are by no means constant but vary a5 4 funtion of different behavioral conditions. This is the tse for the 0.3-Hz (HF) and 0.1-Hz (MF) oscillations. It ‘even more often the case for the 002 to 0.07-Hz oscillations (LE), which explains why investigators base 1 their analysis on peak detection models (see below) usually disregard these fluctuations and consider only two major components in the spectrum, around 0.1 and 03 Ha, defined as HF and LF, respectively Regardless of whether the spectrum is subdivided into two oF three components, an important issue is whether power special analysis should exclusively focus on spec- tral peaks. The peak detection approach is supported by 4a number of investigators who believe that a peak may fellect a specific mechanism of cardiovascular control that can thus be quantitatively assessed by the power or area of the peak. However, other observations suggest that (1) a peak may originate from more than a single cardiovascular control mechanism, and (2) a. single cardiovascular eontrol mechanism ‘may contribute. to different. peaks.*22* In addition, recent studies have shown that BP and HR variability includes not only rhythmic oscillations but also nonthythmic fluctuations that appear in the spectrum not as clearly defined peaks but as powers spread over a broad frequency region (Fig, 1B). It is now clear that these nonrhythmic fluctuations are also relevant to cardiovascular control mechanisms, 10" 10! 10 10 10 107 107 10" 1 Hz Fic 2. Plot shows broadband systolic blood pressure spectra ‘blaine from a fee-moving cat inthe intact cancion (dark lino) f’and 3 weeks after sinoaortc denervation (SAD, light in). Stood pressure was continuously recorded for 3 hours by means of an intra-arterial catheter (abdominal aorta Inarted through a fem- fra ator). Systolic pressure spectral components ranging from Approximately 0.5 to 0.0001 Hz are considered. (Modified from Di Fenzo et al by permission) As an example, in unanesthetized cats under continuous BP and HR monitoring, removal of baroreceptor re- straint of sympathetic activity by sinoaortic denervation is accompanied by systematic changes in nonpeaked BP and HIR powers in several frequency regions® (Fig 2) Furthermore, in normotensive and hypertensive sul jects, nonpeaked BP and HR powers are modified in systematic fashion by a condition of reduced sympathetic and inereased vagal activity such as sleep252" Thus, consideration of broadband powers rather than peaks only may offer a broader description of cardiovascular regulation, Fast Fourier Transform Versus Autoregressive Methods ‘The methods most commonly used for spectral analy~ sis are based on (1) the discrete Fourier transform, ‘usually implemented on the computeras the fast Fourier * and (2) autoregressive (AR) model- ing.!22°° The spectrum resulting from the FFT is de- rived from all the data present in the recorded sigy it includes the entire signal variance, regardless. of whether its frequency components apy specific spectral peaks or as nonpeaked broadband powers. In contrast, with the AR procedure, the raw data are used to identify a bestfiting model from which the final spectrum, consisting of the DC component and a vai able number of peaks, is derived. The components of the signal not fitting the model are treated as noise and partially or totally removed,!222" The above consid: ations identify the most important dillerences between the two methods (Fig 3) and their advantages and ‘ages in different conditions. When attention is focused only on BP or HR rhythmic fluctuations driven by a fixed-rate oscillator, AR methods are suitable ‘because of their ability to identify the central frequency Of the oscillation in an analytic way. Furthermore, the ‘AR approach is particularly appropriate when the num.1278 Hypertension Vol 25, No 6 June 1995 as. Fic 3, Plots show the same heart rate spectra of Fig 1A ight) and Fig 1B (of) obtained by means of diferent analysis moth- ‘ods. A, Data are plotted with an unsmoothed fast Fourier transform (FFT) algorithm; B, data are plotted with an autore- ‘gressive (AR) model, the order (=19) of which was determined by Akaiko entra: C, data are plotted with an FFT algorithm smoothed with a Gaussian window and appear lke those ‘obtained with the AR model having an order of 13 (8); D, data are plottad with an AR model with 3 high order (=30) and appear ike {hose obtained with the unsmoothed FFT algorthm (A). ber of samples available for the analysis is low, because the Frequency resolution of the AR-derived spectrum is not as dependent as the FFT method on the length of the recording. On the other hand, when the analysis is focused on broadband powers, the AR’ method suitably describes the spectrum only if an appropriately high model order is used. Unfortunately, the criteria to automaticaly determine the model order usually lead to seleetion of am order that tends to be tendentally love than that necessary to describe broadband spectra. Thus, the order so defined may need to be empirically corrected on the basis of the investigator's experts Under these conditions, the FFT method may be pref- erable. It should be emphasized that in several condi- tions, the results obtained by the FFT and AR methods may be very lose to each other. This occurs when (I) the ‘AR model order approaches the number of data points ‘or (2) the FFT-derived speetrum is used with method ological manipulation (eg, the Blackman-Tukey method ‘and a prewindowing and smoothing of the autocorrela- tion function?” Short- Versus Long-Lasting BP and HR Recordings Most studies on spectral analysis of BP and HR variability make use of data segments 3 to 5 minutes long. derived from recordings obtained under standardized laboratory conditions after removal of possible artifacts (an issue briefly dealt with in Appendix A). This pro- vides reliable results when spectral components with periods shorter than 1 minute are being considered, regardless of whether the subject has a low or high basal HR. On the other hand, such a spectral analysis cannot be appropriately performed if the recording segments are shorter than 3 minutes (LPS. unpublished data, 1994) unless the analysis focuses on components with frequencies equal to or greater than 0.1 Hz only. In the latter case, even a window of 1 minute in length may suffice, although in a bradycardic subject this would result in a low number of points available for the analysis and thus in a crtieal reduction of the frequency resolu- tion of the spectral estimate if the FFT method is used. ata collected in laboratory conditions, however, can- not reflect what happens in daily life, and to this aim, 24-hour BP and HR recordings performed in ambulant subjects have to be considered. Analysis ofthese record- ings may provide a description of the day-night modu- lation of fast (ie, 0.025 Hz) BP and HR spectral ‘components. This can be obtained by time-varying spec- tral analysis techniques, such as the sequential spectral approach or the Wigner-Ville technique,2*?" all of which track the time-varying features of BP and HR over the recording period. Use of these techniques allows the BP and HR spectral responses to behavioral and envi- ronmental factors to be identified (Fig 4). Through the analysis of 24-hour ambulatory BP and HR recordings, information on slower components of BP and HR variability can also be obtained. This can be achieved by using spectral techniques that provide a single speetrum from the entire 24-hour recording, thereby estimating spectral components over a broad range of frequencies (broadband spectral analysis, Fig 5).%+° This allows one to collect information on ultrasiow HR and BP changes and on their potential relevance to cardiovas- cular control mechanisms. The broadband approach, for example, has led to the important finding that 24-hour BP and HR spectra are characterized by a l/f trend"; je, the amplitudes of BP and HR fluctu tions increase progressively with the reduction in the frequency of such fluctuations. This spectral character- istic indicates that overall 24-hour BP and HR variabil- ities depend more on very low than on higher frequency components. The I/f trend of BP and HR spectra has also been shown to undergo marked changes indifferent pathophysiological conditions: Interpretation of Spectral Data Spectral analysis techniques used to quantify BP and HI variability usually focus on the variability compo- nents with frequencies ranging between 0.025 and 0.50 Hz, based on the evidence that in these frequency regions, BP and HR spectra are at least in part modu- lated by neural autonomic influences“ Despite the large number of studies available on this issue, however, the interpretation of the BP and HR spectra in this frequency region is still a matter of some debate Interpretation of HR Spectra ‘Vagal cardiac control operates like a low-pass filter with a relatively high cutoff frequency, effectively mod- ulating HR up to 1.0 Hz, while sympathetic cardiac control operates as a low-pass filter with a much lower cutoff frequency, capable of significantly modulating HR only at frequencies below 0.15 Hz. The results of a ‘number of studies support this view. In dogs, broadband electrical stimulations of the vagus are followed by HR changes with minimal dampening up to at least 0.7 Hz, whereas broadband electrical stimulation of the rightParati et al Cardiovascular Control and Spectral Analysis 1279 stellate ganglion is followed by TIR changes with a delay Of approximately 2 seconds and a dampening that leads to @ minimal response above 0.15 Hz" Second, in dogs and humans, parasympathetic blockade by atropine ‘eliminates most HR fluctuations above 0.15 Hz, while Teaving those below 0.15 Hz partly unaffected." 10! wo ot wo Brot So E10 10 1 10 0 ws rt tot 107 He Fic 5. Plot shows broadband spectrum of systolic pressure bbtained from the analysis of a 24-hour ambulatory intra-arterial blood pressure recording performed in a normotensive volun tect, Spectral components with fraquencies ranging from 1 to ‘ppronimately 0.000023 Hz (e, with periods ranging from 1 ‘Second fo 12 hours) are considered. The continuous line refers to the actual spectra; the discontinuous line is the 1/1 tine modeling the spectrum in the frequency region where the 1/F ‘model is suitably applicable. inours) Fred. Plots show soquentil power spectrum den- sities (PSD) of low-frequency (0.026 to 0.07 Hz}, mmid-frequency (0.07 to 0.14 Hz), and high ftequency (0.14 to 0.85 Hi) systolic blood pressure (SBP) oscillations computed over consecutive seq- ‘ments of 256 beats throughout a 24-hour period in ‘2 representative subject. SBP mean values and Standard deviations for each half hour ofthe recor ing are also shown. Data are derived trom a 24-hour intraartenal ambulatory blood pressure recording ‘of a representative subject. Dotted lines inthe right panel refer to sagments in which PSD could not be Estimated because of nonstationartios in the re ‘Corded signal. (From Paral eta" by permission) Third, cardiac sympathetic blockade with propranolol reduces HR fluctuations below 0.15 Hz, while leaving those above 0.15 Hz largely unalfected.=**3” Thus, HR changes at frequencies above 0.15 Hz seem to be primarily caused by modulation of cardiae vagal efferent activity. Also, since respiration usually occurs at frequen- ties greater than 9 breaths per minute (0.15 Hz), respi ratory fluctuations in HR are likely to be mediated primarily by parasympathetic efferent pathways. These ‘observations explain the use of respiratory sinus arrhyth- mia as a measure of cardiac vagal modulation.® 44” However, they also explain why respiratory sinus ar- rhythmia’ may not accurately reflect only vagal HR ‘modulation, since sympathetic modulation of respiratory- induced HR changes occurs when the respiratory aetivity is below 0.15 Hz. Finally, even at frequencies above 0.13 Hz, not all HR modulation is parasympathetically me- diated, A small respiratory sinus arrhythmia postulated to be caused by mechanical modulation of sinus rate by stretch persists after combined pharmacological sympa- thetic and parasympathetic blockade and alter cardiae transplantation2=!" One can thus conclude that HR power in the HF band, above 0. but incomplete measure of vagal cardiac control ‘The specificity of LF and MF HR powers for a single control mechanism is even lower because (1) in animals, HI fluctuations at frequencies below 0.15 Hz are af Vy ‘and sym- pathetic cardiac nerves™=*; (2) in humans, HR powers between 00.03 and 0.15 Hz are reduced by either para sympathetic or sympathetic pharmacological block- ‘ide229"; and (3) HR fluctuations in this region have been associated with a wide variety of stimuli, including1280 Hypertension Vol 25, No 6 June 1995 thermoregulation, periodic breathing, and hemody- namie instability.%5* Thus, HR spectra in the MF or LF regions are not invariably a specific sympathetic marker, it has been suggested,%= but may also depend on ‘vagal influences and other mechanisms. The reliability of these spectral indexes in reflecting cardiac sympathetic modulation can be enhanced, however, in a number of behavioral or experimental conditions in which the sympathetic system can be selectively activated.®+* Interpretation of BP Spectra ‘The observation that HF BP power is not substantially modified in patients with denervated donor hearts! 343 has led to the suggestion that this power is mainly caused by the mechanical effects of respiration on the pressure gradients, size, and functions of the heart and large thoracic vessels25 There are, however, conflicting findings on this issue. Actually, it has also been sug- ested that vagally mediated changes in HR and cardiac output play a role in determining HF BP powers However, the influence of vagal modulation on HF BP powers may be different in different species because in ‘conscious cats, sinoaortic denervation, ie, an interven- tion that markedly impairs cardiac vagal drive, markedly reduces HF HR powers with only a minor and nonsig- nificant reduction in HF BP powers.” ‘Autonomic modulation of HR is an even less impor- tant determinant of BP powers in the LF and MF regions because cardiac autonomic blockade by the combined administration of atropine and propranolol climinates only a fraction of BP variability at frequencies lower than 0.15 Hz2? It thus seems likely that LF and ME BP powers are predominantly caused by fluctuations in vasomotor tone and systemic vascular resistance. At frequencies between 0.25 and 0.07 Hz, the factors wolved in this vascular modulation have been regarded as being the renin-angiotensin system, endothelial fac- tors, local influences related to thermoregulation, and others.2"5%*! However, their precise role remains largely speculative. In contrasi, evidence has been collected that in the frequency region between 0.07 and 0.15 Hz (or between 0.05 and 0.15 Hz according to other authors), BP powers increase with laboratory stimuli that increase sympathetic cardiovascular influences (eg, head-up tlt- ing, mental stress) and decrease with conditions that decrease sympathetic cardiovascular influences (eg, sleep and a-adrenergic blockade).*”-» Thus, the hy- pothesis has been advanced that the BP spectral powers between 0.07 (or 0,05) and 0.15 Hz (defined as LF or MF by different investigators) represent a marker of sympa- thetic vasomotor tone. As mentioned above, the same type of evidence (increase and decrease in power during increase and decrease in sympathetic drive) has been used to conclude that HR powers in the same frequency region represent _a marker of sympathetic cardiac drive. However, as is the case with HR, LF (or MF) BP power may not invariably be a consistent marker of sympathetic vasomotor regulation. BP and HR Spectral Powers as Indexes of Autonomic Cardiovascular Modulation Markers capable of dynamically assessing sympathetic vasomotor and cardiac drive in daily life conditions would be important diagnostic tools" However, the reliability of BP (or HR) powers around 0.1 Hz as specific sympathetic markers has revently been ques- tioned by several investigators. Their data come not only from animal experiments, which have the problem of a safe extrapolation t0 humans, but also from healthy subjects and patients with cardiovascular disease. For example, Cohen et al® reported that in healthy volun- teers a reflex increase in sympathetic nerve trafic (mea- sured directly by microneurography) and in vascular resistance (measured by forearm venous oechision peth= ysmography) induced by lower body negative pressure ‘was not accompanied by a similar consistent increase in 0.1-Hz HR power. Saul et a found that in normoten- sive humans the reflex increase in sympathetic nerve trafic (microncurography) induced by intravenous infu- sion of nitroprusside was associated with an increased 0.1-Hz HR power but that no reduction in the 0.1-Hz HR power occurred during the reduction in sympathetic nerve trafic reflexly induced by intravenous infusion of phenylephrine. Kingwell et al showed that although i some clinical conditions (early heart transplantation and pure autonomic failure) cardiac norepinephrine. spill- over and 0.1-Hz HR power were concordant reduced, in other clinical conditions (late heart transplantation, ‘aged individuals, and congestive heart failure) they showed discordant changes. Kienzle etal observed that in heart failure patients there was an inverse correlation between different measures of HR variability, including 0.1- and 0.3-Hz powers, and indexes of sympathoexcita- tion such as muscle sympathetic nerve activity and plasma norepinephrine—ie, the higher the sympathoex- citation, the lower the powers of 0.05 to 0-15~ and 0.2 0 O.5-Hiz HR spectral components and the HR standard deviation. Daffonchio et al observed that in conscious rats destruction of the peripheral sympathetic nerves by ‘-hydroxydopamine reduced the 0.2 10 0.8-Hz BP pow- ers (ie, the powers corresponding to the powers around 0.1 Hz in humans) by 65% in normotensive rats and by only 20% in hypertensive rats, the remaining power boeing unalfected by the elimination of residual sympa- thetic activity and adrenal gland influences via additional awvacrenergic blockade. Finally, Adamopoulos et al®? also showed that in patients with congestive heart fail- ure, spectral indexes of autonomic activity correlate poorly with other measures of autonomic function ‘The important conclusion that can be drawn from these observations is that the level of sympathetic car- iovascular modulation cannot always be specifically reflected by the power of HR and BP spectral compo- nents around 0.1" Hz. ‘A further important issue to be considered is the reproducibility of these spectral indexes. Although some studies have teported that, in standardized conditions, O.1- and 03-Hz powers of BP and HR have a good reproducibility other studies have emphasized the Possible occurrence of a high random variability in BP ‘and FIR spectral powers even when derived from stan- dardized recordings.”:” Reproducibility of BP and HR spectral powers in the 0.025 to 05-Hez region is an even ‘more complex problem when these spectral components are quantified, in individual subjects, from the analysis of short-lasting segments derived from 24-hour ambulatory BP and HR recordings because of the influence of varying behavioral conditions 278 Other more general problems related to the use of spectral powers as tools for selective quantification ofParati et al Cardiovascular Control and Spectral Analysis 1281 autonomic cardiae or vascular influences are worth mentioning. First, neural modulation of both HR and BP is influenced by a large number of input signals and diversified interaction of central command and reflexes at various brain levels. Thus, it may be that an approach Which assumes that these complex mechanisms can be described by considering only BP and HR spectral powers within the narrow frequency regions around 0.1 and 0.3 Hz is too simplistic. Its more likely that a much wider frequency region, containing rhythmic and non- shythmic fluctuations, is under the modulation of these neural mechanisms, a hypothesis that has some support in the literature, When broadband spectral analysis has been used for the assessment of BP and HR variability in conscious cats and dogs, arterial baroreflex regulation of BP and HR fluctuations has been found to occur at all frequencies, from the very low to the very high." Second, the current interpretation of spectral data relies on the assumption that the responses of the system ‘under evaluation are approximately linear. Yet, neural regulation of the cardiovascular system is characterized by at least two orders of nonlinearity. There are system nonlinearities, present regardless of the operating point, such as the nonadditive nature of the interactions of cardiac sympathetic and parasympathetic responses,” the cardiac phase-dependent response of the slope of phase 4 depolarization to vagal stimuli’* and the possi ble nonlinear gating of vagal and sympathetic neural outflow by respiration.” In addition, there are nonli cartes that may originate in specific behavioral and experimental conditions, driving the cardiovascular sys- tem control mechanisms to operate out of their linear range. Virtually every physiological control system has steady-state responses that are sigmoidal and include a threshold, saturation point, and in between, a linear ‘operating regime” (Fig 6A and 6B). A typical example of this is represented by the arterial baroreflex control of HR, which has a sigmoidal stimulus (BP)-response (RR interval) curve. In this instance, both the steady-state and dynamic responses of the system are a function of the BP level. The dynamic response can be thought of as continuously moving up and down the sigmoid curve that describes the steady-state baroreflex gain, with ‘maximal gain usually equal to the instantaneous slope of | the sigmoid curve (Fig 6C and 6D). In addition, the system gain at any one mean operating point might depend on other factors, such as the frequeney with which the input varies (eg, low-pass filter responses to sympathetic modulation) or the rate of change of the input (eg, wiss differentiator properties of the arterial baroreceptors to phasic inputs).” Fig 6C shows clearly that an increase in the mean operating point of decrease, ‘or no change in the dynami depend ing on the initial operating point, a parameter that ‘annot be determined by means of a simple frequency domain analysis, This implies that changes in the activity Of cardiovascular control mechanisms (which, as already mentioned, are often intrinsically nonlinear) may not be lincarly related to changes in BP or HR variability. Thus, ‘a measure of BP or HR fluctuations may fail to qu alterations of autonomic cardiovascular influent several instances. OF course, this may be a problem of al measures of autonomic tone in relation to its modulating Static (Steady State) Gain aa} rg can, eS = BF ian BF Dynamic Gain je D RR Gain, eee (rnceci} maul mmHg) ome a Fic 6. Schematic drawing shows diferent features of the sen- sitivity (gain) of baroretex heat rate control. A, Sigmoid curve ‘escrbing the relationship between changes inthe Input (bI00d pressure, BP) and reflex changes in the output (RR interva). AS BP increases, RR interval also increases, approximating a sig- ‘moidal reationship wth threshold and saturation values at ether tend ofthe curve, Me gain of the heat rate baroreflex is defined fa the slope at any given point on the response curve. Admin= istration of vasaetve agents (nitroprusside [NP] or phenyloph- fine [PE induces changes in moan arterial pressure, moving the rormal baroreflex operating poi (baseline) into. a. diferent ‘perating range. This potentially may lead to diferent gains. B, Plot of baroreflex steady-state gain as a function of BP. As the ‘baroreflex stimulus-response curve s sigmoidal, maxim gains ‘observed inthe linear portion of the curve, occurring a interme bate BP values. At more extreme SP values, steady-state gains Cinished. C, Dynami (or “bea-to-beat) baroreflex gain as meaured by the autoregressive moving average (ARMIA) the Spectral and the sequence techniques at the mean operating pint in A may be higher or lower than the steady-state gain, Bepending on the characteristics of the BP signal. , in partic Ur, the dynamic gain will probably depend on the trequency Content of the Input signal because of either inherent fering Characteristics of the Barorellex response (e, low-pass, high- pase, band-pass) or dependence on a signal derived from the Input, such as the dervative or rato of change of the input signa Inthis case, maximal gain is found to occur around 0.15 Hz, wth ‘ocreased gain at both ends ofthe frequency range, suggesting band-pass characterstics. influences and to its effect on receptor, cardiac, and vascular responses. As_a somewhat separate issue, frequency domain techniques are particularly suitable for the measurement Of dyntamic responses. Thus they may not be appropriate for the assessment of mean operating conditions in the system under evaluation. This is particularly the ease in the evaluation of the sympathetic or parasympathetic ‘modulation of HR of BP, in which spectral analysis is unlikely to provide a measure of mean neural activity, This point is graphically demonstrated by the response of respiratory sinus arrhythmia to an elevation of mean arterial pressure induced by an infusion of phenyleph- rine (Fig 7). In this case, mean vagal activity almost certainly increases (HR decreases by approximately 18June 1995 ee Time (in) Time (in) Fia 7. Plots show time series of respiratory volume (top), heart rate (midland mean blood pressure (bottom) in one Subject. Data wore obtained in contr conditions (let) and {during intravenous phenylephrine infusion (ight), which do- termined an increase in blood pressure and a reflex bradycar- dia. Note that at the time of maximal reflex cardiac vagal stimulation under phenylephrine infusion, respiratory sinus arrhythmia disappeared. beats per minute), but respiratory. sinus arrhythmia isappears, probably secondary to the saturation of either the Vagal responses or the response of the heart to vagal activity (LPS, GP, unpublished observations, 1994). Finally, two further methodological issues deserve to iscussed in this context. First, proper interpretation is highly dependent on the presence of signal stationarity." This issue is more than a theoretical requirement for the use of spectral analysis any time the attention is focused on specific spectral peaks because the dynamic characteristics of the system are likely 0 be diferent during changes in the mean operating point Second, interpretation of the spectra also depends on the occurrence of an appropriate degree of spontancous fluctuations of the parameters that influence the signal under evaluation so that the risk of having no input data in the frequency range of interest is avoided.="08 A proper degree of variability in the input data can be obtained by recording the signal under changing external stimulations. As an example, this ean be done by using paced breathing over a wie frequency range as a means to elicit variations in the cardiovascular signals and in the engaged control mechanisms. Closing the Gaps ‘The most common attempt for improving the assess- ment of autonomic cardiovascular modulation by the spectral analysis approach is to couple the information obtained from the recorded biological signal with the information derived from physiological and mathemati- cal models. This may help the interpretation of the results, provided that the model (1) is used when its assumptions fit with the biological data and (2) is validated at least in part by experimental data indepen- dently obtained. An example is a model based on the assumption that sympathetic and vagal cardiac influ- fences are normally altered in opposite directions and that thus one can improve on the limited sensitivity of 0.1-Hz (LF or ME, according to different authors’ defi- nitions) and 0.3-Hz (HF) powers as respective markers of sympathetic and vagal cardiac drive by using their ratio as an index of sympathovagal balance. Such a model may provide useful information in a number of instances. However, there may be conlitions (eg, eX- ecise, diving) in which these two spectral components undergo not discordant but concordant changes of sim- ilar or different magnitude. In the latter ease, the resulting changes in the LF-HF ratio may be misinter- preted as indicating opposite changes in sympathetic and vagal drive Other more complex examples are the modeling ap- proaches that consider the relationship between fluctu- tions of two oF more cardiovascular signals physiolog cally related to each other. To date, these multivariate models have allowed evaluation of the baroreceptor-HR reflex using both time domain and frequency domain approaches. A time domain method described in the 1980s" is based on computer identification of se- quences of three or more consecutive beats character- ized either by a progressive increase in systolic BP followed by a linearly related lengthening in. pulse interval or by a progressive reduction in systolic BP followed by a linearly related shortening in pulse inter- val. The slope of the regression line between systolic BP and pulse interval changes is taken as an index of baroreflex sensitivity. A frequency domain method also used to assess baroreflex sensitivity is based on the computation of the squared ratio between the spectral powers of RR interval and systolic BP® or of the ‘modulus ofthe cross-spectrum between systolic BP and RR interval in the frequency regions (0.07 to 0.35 Hz) where these two signals show a significant coherence ** ‘The validity of either approach has been independently verified by the striking changes in the outputs of these models produced by sinoaortic denervation in ani- mals, which allows their use as a reliable index of baroreflex sensitivity in daily lie. Other multivariate models are (1) those addressing the relationships between BP and HR in a closed-loop fashion, by means of either autoregressive moving aver- age techniques (ARMA models)" or Fourier-based transfer function techniques, and (2) those quantifying the relations between respiration and either BP or HR. fluctuations using the same techniques." Inthe former instance, ARMA. models have been used to study not only the reflex effects of BP alterations on HR changes (reflex feedback) but abo the direct mechanical effects of alterations in HR on BP changes (mechanical feed- forward). On the other hand, with either technique, the evaluation of the relation between respiratory activity and BP or HR changes can be used to provide a quantification of the gain and phase relationship be- tween respiration and its cardiovascular effects as a function of the frequency of these changes. This ap- proach may be further improved if the analysis is not limited to spontaneous respiratory activity (which may have a limited frequency content) but makes use of paced breathing pattern to obtain a broadband or “whit- ened” input respiratory signal that contains all physio- logically relevant frequencies simultaneously (see above)” BP and HR Variability in Essential Hypertension Using short-lasting BP and HR recordings obtained in the laboratory environment, Guzzetti et al" reportedParati cs al Cardiovascular Control and Spectral Analysis 1283) that, compared with normotensive subjects, patients with essential hypertension are characterized by a greater LF power (defined as the power around 0.1 Hz) and a smaller HF power of RR interval during supine rest. ‘They also reported that these powers showed a smaller increase and decrease, respectively, during passive tilt ing. These observations were interpreted as indicating that cardiac sympathetic tone is incre vagal tone and modulation are decreased in esser hypertension, a conclusion in line with the previous studies in which autonomic cardiac modulation was investigated by different techniques." They also con- cluded, however, that sympathetic cardiac modulation ‘may be impaired in hypertension, wl agreement with previous reports showing unchanged and even enhanced HR responses to exercise, stress, and ‘autonomic cardiae drive. Comparison data are alo available on BP and HR, variability of normotensive and essential hypertensive subjects throughout the 24 hours. In a study that made use of 24-hour intra-arterial ambulatory BP ceconding, sively from normotensive subjects to pat derline, mild, and more severe essential hyper. ‘The HR standard deviation was similar in normotensive subjects and in borderline and mildly hypertensive pa- tients and decreased in severely hypertensive patients.? Further results were obtained in additional studies in which the 24-hour intra-arterial BP and HR signals of normotensive and hypertensive subjects were divided into contiguous segments of 5 to 6 minutes, and power spectral analysis was performed on all segments charac y ary signal.22” In all subjects, spectral powers displayed a large segment-to-segment variabil- ity over the entire frequency region considered, pre- sumably because of the effect of the changing bel ioral pattern, Spectral powers, however, also showed ematic fluctuations, which consisted of (1) a pro- nounced nocturnal reduction of the systolic and di stolic BP powers around 0.1 Hz and (2) a more slight nocturnal increase in the 0.3-Hz (HE) power of pulse interval. With the exception of a smaller increase in the HE power of pulse interval, average powers and power changes were similar in the normo- tensive and mildly hypertensive subgroups.2°2? Finally, the time domain and frequency domain tech- ‘niques for computer evaluation of the arterial baroreflex described above®?*5* have shown that the sensitivity of the baroreceptor-HR reflex is much lower in essential hypertensive than in normotensive subjects for each hhour of the 24 hours, thereby confirming previous con- clusions obtained by studying the baroreflex with labo- ratory techniques." Dynamic analysis of the baroreflex, however, has also shown that although in normotensive subjects baroreflex sensitivity shows a marked nocturnal increase, this feature is much less evident in hypertensive data obtained by quantification of BP and HR fluctuations in hypertensive pationts emphasize that, although interpretation of the results may not always be easy (mainly because of the composite nature of spectral powers), time domain and frequency domain analysis of HR and BP variability can provide inter. esting new insights into the daily life alterations of autonomic cardiovascular modulation in hyperten- sion. A striking finding appears to be a daily life impairment of the baroreceptor-HR reflex. There are also an increase in BP variability and to a lesser extent a reduction in HR variability. These alterations are more evident when overall measures of BP and HR variability rather than specific components of these phenomena are considered. Conclusions Available data unequivocally indicate that analysis of BP and HI variability by the spectral approach, as well as by time domain techniques, may provide interesting information and represent a useful tool for the study of the mechanisms involved in cardiovascular regulation in both normal and diseased conditions. The potential importance of these techniques is in particular related to the possibility they offer for information to be obtained on cardiovascular regulation in real life conditions, i, in conditions free from artificial laboratory stimulations. However, interpretation of BP and HR spectra is some- times controversial, particularly when signals recorded ‘outside of a standardized laboratory environment are considered, and there is evidence that specific spectral components may he related to different mec different conditions. In particular, although sympathetic vascular and cardiae modulation appears to be reflected by BP and HR powers around 0.1 Hz, the specifi sensitivity, and reprod dewes of mean sympathetic activity in different condi tions are not always optimal. Progress in the field is now oollered by multivariate models that allow interactions between BP, HR, and other biological signals to be cevaluated in the time or frequency domain, Application Of some of these models to the analysis of long-lasting BP and HR recordings obtained in ambulant subjects will also allow the problems arising from the use of laboratory data to predict what happens in daily life 10 be overcome. Appendix A Removal of Artifacts Recordings of BP, eleetrocardiographic, a " signals may inchude artifacts, such as dampening of the BP Signal, distortion of the pulse waveform by movements, pre {ure beats, ete. The likelihood of these urtifets being found in the recorded signals is obviously higher when Tongesting recordings are being considered, particulary if these record ings are obtained in smbulant subjects ‘ high frequency of arifets also must be expected when long-lasting recordings obtained by a Finapres measuring de- vice (Finapres 2300, Ohmeda) oF by’ iis portable version (Portapres, TNO) are considered because the site of BP measurement, atthe finger level, is associated with «high rate fof movement artifacts” and hecause the continuous BP recording is periodically interrupted by automatic calibration signals These artifacts must be removed to obtain reliable spectral ‘estimation, and signal editing is particulary crucial to avoid crtors in the quantification of faster HI and BP spectral components ‘Occasional ectopic beats can be removed by procedures: (1) Interpolated. cetopie beats removed, and the RRC interval corresponding to the missing beat will then be the sum of the intervaly preceding. and following the ectopic beat; (2) if a delay follows the ectopic beat, the RRC interval considered for analysis might be the1284 Hypertension Vol 25, No 6 June 1995 mean of the intervals preceding and following the removed ‘ectopic beat. Such a procedure is particularly suitable for ectopic beats followed by a compensatory delay. Obviously, recordings without arrhythmias should generally be preferred. Incase of long-lasting recordings (eg, 24-hour Holter tracings), fan acceptable riterion might be to consider for spectral analysis only subperiods during which the frequeney of ectopic beats is less than 1% of total beats, “The editing task can be efficiently performed through com- puter identification of aberrant waveforms. This is commonly obtained (1) by setting threshold values for specific fiducial poinis on the recorded waveform (eg, in the case of BP recordings, the maximal and minimal values for systolic and diastolic BPs, the maximal and minimal time lengths ofa given ‘waveform, rte of change of BP within the waveform, ete) and (@) by matching each recorded waveform with a template. ‘Once detected, artifacts can be either automatically deleted by the computer or visualized on a screen and interactively doleted by the operator. Appendix B Essential Glossary Autoregressive (AR) Modeling ‘Technique for the mathematical modeling of signals, This approach is based on the assumption that the value ofa signal depends only on the previous values of the same signal plus “noise.” Once the AR model of a signal i estimated, the spectrum ofthe input signal canbe computed from a manip- Ulation of the mathematical mode. Autoregressive Moving Average (ARMA) Modeling ‘Technique for the mathematical modeling of signals. I i based on the assumption that the value of the output signal depends on either the previous values of the same signal {autoregressive component) and on the present and previous values ofa diferent input signal (moving average component), withthe addition of "noise" factor. Broadband Spectral Analysis Speetal analysis proving a spectral estimation over a wide range of frequencies. By this approach, a single spectrum is obtained from a relatively long-lasting input data record Fourier Transform Decomposition of a given signal into a series of sine and cosine waves having frequencies that are multiples of the fundamental frequency (the reciprocal of the time length of the input data record). The spectral power ofthe input signal ean bbe derived from the magnitude of these sine and cosine waves. Fast Fourier Transform Algorithm fo the fast estimation of the Fourier transform. 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