DOI 10.1378/chest.114.1.185 1998;114;185-191 Chest Andrea Passantino, Paolo Totaro, Cinzia Forleo and Paolo Rizzon Maria Vittoria Pitzalis, Filippo Mastropasqua, Francesco Massari, Normal Subjects Arrhythmia and Baroreflex Gain in -Blocker Effects on Respiratory Sinus β http://chestjournal.chestpubs.org/content/114/1/185 and services can be found online on the World Wide Web at: The online version of this article, along with updated information ISSN:0012-3692 ) http://chestjournal.chestpubs.org/site/misc/reprints.xhtml ( without the prior written permission of the copyright holder. No part of this article or PDF may be reproduced or distributed 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. Copyright1998by the American College of Chest Physicians, Physicians. It has been published monthly since 1935. is the official journal of the American College of Chest Chest 1998 by the American College of Chest Physicians by guest on July 21, 2011 chestjournal.chestpubs.org Downloaded from
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DOI 10.1378/chest.114.1.185 1998;114;185-191Chest
Andrea Passantino, Paolo Totaro, Cinzia Forleo and Paolo RizzonMaria Vittoria Pitzalis, Filippo Mastropasqua, Francesco Massari, Normal SubjectsArrhythmia and Baroreflex Gain in -Blocker Effects on Respiratory Sinusβ
without the prior written permission of the copyright holder.No part of this article or PDF may be reproduced or distributed3300 Dundee Road, Northbrook, IL 60062. All rights reserved. Copyright1998by the American College of Chest Physicians,Physicians. It has been published monthly since 1935.
is the official journal of the American College of ChestChest
1998 by the American College of Chest Physicians by guest on July 21, 2011chestjournal.chestpubs.orgDownloaded from
p-Blocker Effects on Respiratory SinusArrhythmia and Baroreflex Gain inNormal Subjects*Maria Vittoria Pitzalis, MD, PhD; Filippo Mastropasqua, MD;Francesco Massari, MD; Andrea Passantino, MD; Paolo Totaro, MD;Cinzia Forleo, MD; and Paolo Rizzon, MD
Study objective: The results of studies on the effect of p-adrenergie blockade on respiratory sinusarrhythmia (RSA) are discordant. The aim of this study was to verify whether chronic p-adren-ergic blockade is capable of increasing RSA, and therefore vagal outflow, and to analyze whetherthe mechanism of action is central or peripheral.Participants and design: Twenty normal subjects (28±2 years old) were randomized to receive a
hydrophilic (nadolol) p-blocker, a lipophilic (metoprolol) p-blocker, and placebo.Measurements: After 1 week of therapy, a spectral analysis was made of the variability in heartrate and systolic BP during controlled breathing at 16 breaths/min. The high-frequencycomponent was calculated for the RR interval (measure of RSA) and systolic pressure, and thesquared coherence and phase functions were assessed between RR and systolic pressurefluctuations in the respiratory band; a negative phase means that RR changes follow systolicpressure changes. The gain in the relationship between the two signal fluctuations was alsocalculated.Results: Both p-blockers increased the mean (±SD) RR interval (placebo=808±21, nado-lol=l,054±30, metoprolol= 1,031 ±27 ms; p<0.0001), RSA (placebo=542, nadolol=1,177, meto¬
prolol 1,316 ms2; p=0.002), and the gain (placebo= 13.6±1.5, nadolol=21.9±2.8, metopro-lol=24.5±3.6 ms/mm Hg; p<0.002), and both modified the phase function (placebo=.21.1 ±5.3,nadolol= 1.8±4.9, metoprolol=.2.9±4.2 degree; p<0.0001). No difference was found betweennadolol and metoprolol.Conclusions: Chronic P-adrenergic blockade enhanced both RSA and baroreflex gain andreduced the phase between the RR interval and systolic pressure oscillations. Since no differencewas found between the hydrophilic and the lipophilic P-blockers, these changes seem to be dueto a peripheral effect. (CHEST 1998; 114:185-191)
Key words: baroreflex sensitivity; cross-spectral analysis; humans; hydrophilic P-blockers; lipophilic p-blockers;metoprolol; nadolol; respiratory sinus arrhythmia; vagal activityAbbreviations: ctHF= alpha index in the high frequency band; CI=confidence interval; DBP=diastolic BP; HF=highfrequency; HF-RR.high-frequency component of the RR spectrum; HF-SBP=high-frequency component of the SBPspectrum; 4>HF=phase relation between RR and SBP fluctuations in the high-frequency band; K2= squared coherence;RESP= respiratory signal; RSA=respiratory sinus arrhythmia; SBP.systolic BP
TJ espiratory sinus arrhythmia (RSA) is a measure-" of vagal modulation of the sinus node.15 Respi¬ratory activity is able to modulate both parasympa-thetic and sympathetic cardiac outflow; however,when the breathing rate is more than nine breathsper minute (0.15 Hz), RSA is maximally dominated
*From the Institute of Cardiology (Drs. Pitzalis and Rizzon, Drs.Mastropasqua, Massari, Passantino, Totaro, and Forleo), Uni¬versity of Bari, Bari, Italy, and the "Salvatore Maugeri" Foun¬dation IRCCS, Cassano Medical Centre, Cassano, Italy.Supported in part by a Young Investigator Award from the ItalianSociety of Cardiology (Dr. Pitzalis).Manuscript received July 24, 1997; revision accepted November31, 1997.
by the modulation of parasympathetic outflow.6-7One explanation for respiratory RR interval fluctua¬tions is that respiration first affects arterial pressureand then heart rate fluctuations mechanically via thebaroreflex control.8 The role of baroreflex contribu¬tion in the origin of RSA in healthy humans has beenemphasized recently.910RSA is therefore a good parameter for analyzing
the effects of drugs or other interventions on vagaloutflow in man. The studies performed so far35-1119in order to evaluate whether p-adrenergic blockademodifies RSA have reached different conclusions.Some11-1518 have demonstrated the ability of
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P-blockers to enhance RSA, but it is not clear whatthe underlying mechanism is. It has been suggestedthat the increase may be due to central vagotonicactivity;1315 therefore, since their central effect isrelated to their ability to pass the blood-brain barri¬er,20-21 hydrophilic and lipophilic p-blockers shouldhave different effects on RSA.The aim of the present study was to test whether
hydrophilic and lipophilic P-blockers are capable ofmodifying vagal outflow differently as evaluated bymeans of RSA and the relationship between oscilla¬tions in the RR interval and systolic arterial pressureat the respiratory band.
years; range, 24 to 34 years; weight, 62±2 kg; and height, 171 ±3cm) were studied. None was a habitual cigarette smoker (18 hadnever smoked, and 2 had been mild smokers in the recent past),and all engaged in an average level of physical activity. The studywas approved by the institutional review boards for humanexperimentation of the local ethical committee, and all of thesubjects gave their informed consent.
Experimental Protocol
This was a randomized, single-blind, placebo-controlled, two-
period crossover trial. The subjects were randomly assigned toreceive a hydrophilic (nadolol, 80 mg/d) or a lipophilic (metopro¬lol, controlled release, 200 mg/d) P-blocker for 1 week; thesecond p-blocker was administered after a 14-day washoutperiod. Placebo was given for 1 week after a washout period of 14days following the second period of p-blocker administration.During the seventh day of administration of each treatment, all ofthe subjects underwent spectral analysis of heart rate and systolicblood pressure (SBP) variabilities. In a quiet and light-attenuatedroom, the subjects were asked to remain in the supine positionfor 30 min between 9 and 10 AM in order to allow theircardiovascular mechanisms to achieve steady state. They were
then asked to control their breathing with the aid of a metronomeat a rate of 16 breaths/min (approximately 0.27 Hz) for a periodof 5 min. Tidal volume was not controlled, in order to allow foradjustments in the acid-base balance.22
Data Collection and AnalysisSignal Acquisition: Surface ECG signals using a conventional
bedside monitor (Hewlett Packard model 78354C; Andover,Mass), respiratory signals (by means of the impedance pneumo-graph, Hewlett Packard model 78354C), and noninvasive BPsignals from the third finger at heart level (using a photoplethys-mographic transducer, Finapres model 2300, Ohmeda; Engle-wood, Colo) were continuously acquired throughout each periodby a personal computer with signal conditioning, an anti-aliasinglow-pass filter, and a 12-bit A/D interface. The ECG signals wereacquired at a sampling rate of 1 kHz, and the other signals wereacquired at a sampling rate of 250 Hz. A real-time program23detected the ECG R-wave signal and measured the beat-to-beatintervals and beat-to-beat SBP. When present, artifacts were
removed and corrected by linear interpolation with the previousand following beats. From the visual inspection time series of thetachogram, systogram, and respirogram, periods of 256 beatswere selected and considered eligible for successive analysis.
Time Domain Analysis: The mean values of RR interval (ms)and SBP and diastolic blood pressure (DBP) (mm Hg) were
calculated for each recording.Frequency Domain Analysis: Frequency domain analyses of
variability were made after the elimination of linear trends on
beat-to-beat RR intervals, beat-to-beat SBP, and respiratorysignals (RESP). Power spectral analysis was performed by au-
toregressive method; the model order was selected by the Akaikecriterion. RSA was computed by considering the component ofthe power spectrum in the high-frequency (HF) band. A spectraldecomposition algorithm was used to measure the area below thespectral peaks.24 The power of HF-RR component (centeredfrequency about 0.27 Hz) was expressed in absolute values (ms2)and normalized units;25 HF-SBP was expressed in absolute values(mm Hg2).The spectral analysis of heart rate provides a good estimate of
RSA,26 especially when breathing fluctuations are evaluatedtogether with the heart rate signal.7-22'27-29
Cross-Spectral Analysis: The squared coherence (K2) andphase (<S>) functions between the RR interval, RESP (RR-RESP),and SBP (RR-SBP) were assessed by means of bivariate spectralanalysis (Fig 1).30>31 The squared coherence K2(f) evaluates thedegree of linear correlation between the varibility in two signalsas a function of frequency. It assumes values between 0 (norelationship) and 1 (maximal relationship). The phase function,assuming values in the ±180° range, may be useful to indicatethe lead or lag of one signal with respect to the other as a functionof frequency.
In our transfer function analysis, we considered the SBP as
input and RR interval as output. The transfer phase was definedto yield a negative value of degrees and seconds.732A K2 value >0.75 between RESP and the RR interval was
required for a good estimate of RSA.27 When the K2 in cross-
spectrum between HF-RR and HF-SBP was >0.5, we analyzedthe OHF and calculated the aHF index (ie, the square root of theratio of the RR and SBP power in the HF band; aHF), whichrepresents the gain (ms/mm Hg) in the relationship between RRand SBP fluctuations.32-34
Statistical AnalysisThe results are given as means±SEM. The absolute values of
the power spectral components were transformed to their naturallogarithms because of their skewed distributions; the geometricmeans of these variables (ie, the antilogarithm of the mean
transformed data) are given, together with their 95% confidenceintervals (CIs). The comparisons between the p-blockers andplacebo were made by means of one-way analysis of variance(ANOVA) for repeated measures and the Student-Newman-Keuls test for multiple comparisons; the power spectral compo¬nents were analyzed on the basis of their transformed values. Atwo-sided p value <0.05 was considered significant.The statistical analysis was carried out using software (SPSS
Advanced Statistics Version 6.1; SPSS Inc; Chicago, 1995).
RESULTS
All of the subjects controlled their breathing well,as is demonstrated by the narrow range of therespiratory frequencies (Table 1).As shown in Table 1, both P-blockers significantly
186 Clinical Investigations
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Figure 1. Spectral analysis of the breathing (A), RR interval (B), and SBP (C) signals in a subjectbreathing at 16 breaths/min. As expected, the HF components of the spectra are centered at the same
frequency (near 0.27 Hz). In panel D, high degree of coherence (K2) between the two signals(RR-RESP) is present. Panel E shows that the phase angle (O) related to the highest degree ofcoherence found at the respiratory frequency is negative. In this example, the fact that the oscillationsof the cardiorespiratory signals were all at 0.27 Hz is not casual because cross-spectral analysis betweenthe signals (D, E) showed a high squared correlation indicating that they are strictly related. Thisrelation, as far as RR intervals and SBP is concerned, is characterized by a stable phase that is negativeand therefore suggests that RR interval oscillation follows SBP oscillation. K2=solid line; <$>=dottedline.
lengthened the RR cycles (p<0.01) and reduced thelevel of DRP (p<0.05); neither p-blocker signifi¬cantly modified SRP.RSA significantly increased after the administra¬
tion of both P-blockers, whether evaluated as bothabsolute (p= 0.002) (Table 1) or normalized units
(p^O.006) (Fig 2). During the three study periods(ie, the two P-blockers and placebo), the K valuesbetween the RR interval and respiration (RR-RESP)and between the RR interval and systolic pressure(RR-SBP) were very high (Table 2); this high corre¬
lation allowed us to exclude that the oscillations ofthe three analyzed signals are at the same frequencyby chance and suggest that they are related to eachother.
During placebo administration, cross-spectralanalysis performed on all the subjects showed a
negative <5HF value (-0.226±0.05 s) (Fig 3). Inother words, the value of <E> offers a quantification ofthe temporal delay between the two signals, and thefact that it is negative means that RR signal followsSBP signal.Both the hydrophilic and the lipophilic P-blocker
significantly enhanced aHF and reduced OHF (Ta¬ble 2): Figure 4 shows an example of the obtaineddata.No difference was found between the two
P-blockers.
Discussion
The present study of normal young subjects allowstwo major conclusions to be drawn. First, p-adren-
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*p<0.05 vs placebo.fp<0.01 vs placebo.nu=normalized unit.
ergic blockade leads to a significant increase in RSA(a measure of cardiac vagal activity) and affects thegain and phase between oscillations in BP and theRR interval at the respiratory frequency. Second, theabsence of any significant difference between hydro¬philic (nadolol) and lipophilic (metoprolol) p-block¬ers suggests that the effects of these drugs are more
probably mediated at a peripheral than at a centralsite.
Mechanisms of RSAThe spectral analysis of RR interval fluctuations in
relation to respiration7'28-29 makes it possible toobtain reproducible data on RSA,35-36 and it has to bemade during controlled respiration and/or the acqui¬sition of respiratory signal.2228Although nonneural other than neural mecha¬
nisms may play a role in the genesis of RSA, thecontribution of nonneural component to RSA is
100
Placebo Nadolol Metoprolol
Figure 2. Changes in the HF components of RR interval(HF-RR) expressed in normalized units (nu; percentage) afterP-blocker and placebo administration. The values are expressedas mean±SE. The asterisks and lines refer to statistical signifi¬cance (p<0.05).
negligible, being <1% at rest.37 Two principal mod¬els have been suggested to explain the interactionbetween respiration and both heart rate and SBP:the first, which is supported by animal experiments,suggests the existence of a central respiratory mod¬ulation that is capable of modifying heart rate vari¬ability and then BP variability (the Akselrod hypoth¬esis);38 the second is that respiration modulatescardiac output and therefore BP which, in turn,modifies heart rate by means of the vagal arm of thebaroreflex (the De Boer model).8
In our study, cross-spectral analysis performedduring placebo administration with the subjects in a
supine position showed that the phase betweensystolic pressure and the RR interval was negative at
high respiratory frequency (ie, RR interval fluctua¬tions appeared to follow systolic pressure fluctua¬tions), and this negative relationship may suggest a
baroreflex link (De Boer model). A negative <MFhas also been reported in two other studies,9-32although our <E>HF values are lower than those foundby Pagani et al32 (-21° vs -28°) and higher thanthose found by Blader and Hughson9 (.21° vs
14°); however, these differences may be due to thedifferent ages of the three study populations. How¬ever, Taylor and Eckberg39 found that phase esti¬mates made in the supine position suggest thatvariations in systolic pressure follow those in the RRinterval.
Table 2.Effects of fi-Blockers on aHF and Cross-Spectrum Phase and Coherence
Placebo Nadolol MetoprololRR-RESPK2
RR-SBPK2<I>HF, degreesaHF, ms/mm Hg
0.97±0.008 0.98±0.004 0.97±0.009
0.98±0.003-21.1±5.313.6±1.5
0.97±0.01-1.8±4.9*21.9±2.8*
0.98±0.009-2.9±4.2*24.5±3.6*
*p<0.01 vs placebo.
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Figure 3. Effects of nadolol and metoprolol on the phase (<MF)between the RR interval and SBP variabilities in the respiratoryband. Both shift the values towards zero. The values are
mean±SE. The asterisks refer to statistical significance vs pla¬cebo (p<0.05).
Effects of fi-BlockersIn the present study, both p-blockers increased
RSA. The conflicting results of previous studies inhumans seem to depend on whether the drugs were
administered acutely or chronically. In the formercase, only a slight effect on HF-RR or none at all was
tt o O
o O
0.40 Hz
Figure 4. Coherence (K2) and phase ($) relationships betweenthe RR interval and SBP variabilities in a subject during placebo(top) and nadolol administration (bottom). Under both condi¬tions, the K2 value in the respiratory band is near to 1 and the Oshifts after drug administration. The phase lines are darkenedwhere K2 exceeds 0.5.
observed;5'11-16-17'19'26 in the latter case, there was a
significant increase in this component.111518 Thereason for these different results remains unclear,although Bigger40 has hypothesized that the absenceof any acute effect could be due to the fact that themeasurements were made too soon after drug ad¬ministration. We have also demonstrated thatP-blockers can induce an increase in spectral barore¬flex gain in accordance with the findings of Luciniet al.12Only a few studies in humans have been designed
to evaluate whether the effects of P-blockers on theautonomic nervous system were due to their centralor peripheral activity, and none of these studiesinvolved healthy subjects. Our findings confirm theresults of a previous study of patients with coronaryartery disease41-42 that demonstrated the equal ef¬fects of lipophilic (metoprolol) and hydrophilic(atenolol) p-blockers on the average 24-h HF powerof heart rate variability. Floras et al43 sought toevaluate the effects of P-adrenergic blockade usingdrugs with different degrees of lipophilicity on reflexvagal activity (phenylephrine method) in patientswith essential hypertension; although they demon¬strated an increase in baroreflex sensitivity with all ofthe p-blockers used, they did not resolve the ques¬tion of the relative importance of lipophilicity. Re¬cently, Sanderson et al44 have demonstrated thesuperior effect of lipophilic P-blockers in restoringspectral baroreflex gain in patients with heart failureand concluded that this effect may be due to a directcentral effect of this drug.Our data excluded a direct central effect in normal
subjects because no difference was found betweenthe lipophilic and hydrophilic P-blockers; thesedrugs therefore seem to act at a peripheral level,although their precise site of action is not known.
P-adrenergic-blockers administered long termcould also act at the level of the sinus node, where a
peripheral interaction between sympathetic and va¬
gal activity has been demonstrated. In a recent work,Hedman et al45 have shown that sympathetic stimu¬lation in anesthetized dogs reduced the HF oscilla¬tions of the RR interval caused by vagal stimulation.This close interaction could also explain the results ofBloomfield et al46 who found a reduction in RSAafter the administration of isoprotenerol, as well as
those of Coker et al14 who showed that the increasein RSA after P-blocker administration was abolishedwhen an anticholinergic drug was administered. Onthe basis of these findings, the increase in vagalmodulation that we observed may have been due toa peripheral modulation of the sympatho-vagal inter¬action ("accentuated antagonism")47 In particular,P-blockers may eliminate presynaptic sympathetic
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inhibition by causing an increase in vagal outflow,which is represented by the increased values of RSA.
Clinical ImplicationsIn patients with previous myocardial infarction, a
depressed baroreflex sensitivity (ie, cardiac vagalreflex) has been associated with an increased inci¬dence of death and malignant arrhythmias.48-51 Theanalysis of the trials in which p-blockers have beenadministered to postmyocardial infarction patientsseems to show that the beneficial effect of reducingmortality is a characteristic of lipophilic P-blockers.52Experimental studies have suggested that the bene¬ficial effect of lipophilic P-blockers may be due to a
direct central effect.53This hypothesis has not been confirmed in patients
with coronary artery disease4142 or hypertension43 or
in normal subjects, as shown in the present study.Sanderson et al44 concluded that lipophilic p-block¬ers have a greater effect than hydrophilic p-blockersin patients with heart failure and depressed barore-ceptor function. Although these findings might havebeen influenced by the type of hydrophilic P-blockerused, ie, celiprolol, which has an intrinsic sympatho¬mimetic activity, these conclusions led us to thinkthat the hydrophilic or lipophilic properties ofP-blockers in modifying the parameters of auto-nomic nervous system balance may depend on theirbaseline values; in particular, it might be that inpatients with depressed baroreflex sensitivity, onlylipophylic P-blockers can be useful. Future studiescould be designed to test this hypothesis.Limitations of the StudyA limitation of the present study is represented by
the method used to assess baroreflex gain. In fact,the closed-loop nature of the cardiorespiratory sys¬tem makes it difficult to interpret any change occur¬
ring within it, and this interpretation becomes par¬ticularly arduous when attempting to define therelationships among respiration, SBP, and RR inter¬vals. It has been suggested that cross-spectral analy¬sis of these parameters clarifies these relationshipsand, although they offer only a gross index of timerelations, phase estimates have been widely used forthis purpose.8-9'31'32'34-39Another possible limitation of our study may be
related to the fact that the definition of the hydro¬philic and lipophilic nature of P-blockers is based on
their capacity or otherwise to pass the blood-brainbarrier; however, hydrophilic P-blockers (such as
nadolol) are also capable of crossing this barrier,albeit in small concentrations. It may be that even a
relatively low brain concentration of nadolol is suffi¬cient to increase vagal outflow, although this seems
to be unlikely because the peripheral effects ofhydrophilic P-blockers are maximal and occur at a
time when they are not detected in the brain.54In conclusion, chronic p-adrenergic blockade en¬
hances RSA (and therefore vagal outflow) by increas¬ing the gain and reducing the phase between the RRinterval and SBP oscillations. This effect seems to bedue to peripheral modulation since no differencewas found between hydrophilic and lipophilicP-blockers.ACKNOWLEDGMENTS: The authors wish to thank GiovannaPontraldolfo and Aldo Balducci for the technical assistance incollecting and analyzing data.
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DOI 10.1378/chest.114.1.185 1998;114; 185-191Chest
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