Download Nonselective beta-adrenergic blocking agent, carvedilol

Journal of the American College of Cardiology
© 2000 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 36, No. 5, 2000
ISSN 0735-1097/00/$20.00
PII S0735-1097(00)00900-1
Nonselective Beta-Adrenergic Blocking
Agent, Carvedilol, Improves Arterial
Baroflex Gain and Heart Rate Variability in
Patients With Stable Chronic Heart Failure
Andrea Mortara, MD, Maria Teresa La Rovere, MD, Gian Domenico Pinna, BE,
Roberto Maestri, BE, MD, Soccorso Capomolla, MD, Franco Cobelli, MD
Pavia, Italy
The purpose of this study was to investigate in a case-controlled study whether carvedilol
increased baroreflex sensitivity and heart rate variability (HRV).
BACKGROUND In chronic heart failure (CHF), beta-adrenergic blockade improves symptoms and ventricular
function and may favorably affect prognosis. Although beta-blockade therapy is supposed to
decrease myocardial adrenergic activity, data on restoration of autonomic balance to the heart
and, particularly, on vagal reflexes are limited.
METHODS
Nineteen consecutive patients with moderate, stable CHF (age 54 ⫾ 7 years, New York
Heart Association [NYHA] class II to III, left ventricular ejection fraction [LVEF] 24 ⫾
6%), treated with optimized conventional medical therapy, received carvedilol treatment.
Controls with CHF were selected from our database on the basis of the following matching
criteria: age ⫾ 3 years, same NYHA class, LVEF ⫾ 3%, pulmonary wedge pressure ⫾
3 mm Hg, peak volume of oxygen ⫾ 3 ml/kg/min, same therapy. All patients underwent
analysis of baroreflex sensitivity (phenylephrine method) and of HRV (24-h Holter
recording) at baseline and after six months.
RESULTS
Beta-blockade therapy was associated with a significant improvement in symptoms (NYHA
class 2.1 ⫾ 0.4 vs. 1.8 ⫾ 0.5, p ⬍ 0.01), systolic and diastolic function (LVEF 23 ⫾ 7 vs.
28 ⫾ 9%, p ⬍ 0.01; pulmonary wedge pressure 17 ⫾ 8 vs. 14 ⫾ 7 mm Hg, p ⬍ 0.05) and
mitral regurgitation area (7.0 ⫾ 5.1 vs. 3.6 ⫾ 3.0 cm2, p ⬍ 0.01). No significant differences
were observed in either clinical or hemodynamic indexes in control patients. Phenylephrine
method increased significantly after carvedilol (from 3.7 ⫾ 3.4 to 7.1 ⫾ 4.9 ms/mm Hg, p ⬍
0.01) as well as RR interval (from 791 ⫾ 113 to 894 ⫾ 110 ms, p ⬍ 0.001), 24-h standard
deviation of normal RR interval and root mean square of successive differences (from 56 ⫾
17 to 80 ⫾ 28 ms and from 12 ⫾ 7 to 18 ⫾ 9 ms, all p ⬍ 0.05), while all parameters remained
unmodified in controls. During a mean follow-up of 19 ⫾ 8 months a reduced number of
cardiac events (death plus heart transplantation, 58% vs. 31%) occurred in those patients
receiving beta-blockade.
CONCLUSIONS Besides the well-known effects on ventricular function, treatment with carvedilol in CHF
restores both autonomic balance and the ability to increase reflex vagal activity. This
protective mechanism may contribute to the beneficial effect of beta-blockade treatment on
prognosis in CHF. (J Am Coll Cardiol 2000;36:1612– 8) © 2000 by the American College
of Cardiology
OBJECTIVES
In controlled clinical trials, long-term treatment of patients
with chronic heart failure (CHF) with the third generation
nonselective beta-adrenergic blocking agent, carvedilol, improves symptoms, slows progression of the disease and may
reduce morbidity and mortality (1–3). Several mechanisms
may contribute to the beneficial effect of carvedilol (4),
including a direct effect on beta-adrenoreceptors with inhibition of sympathetic overactivity. Since neurohormonal
activation has been reported to be one of the major causes in
the progression of heart failure and ventricular dysfunction,
its restraint by beta-blockers might be an important tool in
the treatment of CHF.
From the Department of Cardiology, Centro Medico di Montescano, “S. Maugeri”
Foundation, IRCCS, Pavia, Italy. Supported directly by “S. Maugeri” Foundation,
IRCCS, Pavia, Italy.
Manuscript received July 29, 1999; revised manuscript received April 10, 2000,
accepted June 15, 2000.
Autonomic nervous system integrity may be quantified
noninvasively in the clinical setting by analysis of heart rate
variability (HRV) and arterial baroreceptor function (5–7).
It has been shown that the two measures, although related
to sympathovagal activity, reflect different physiological
mechanisms. While HRV is considered a marker of tonic
sympathetic and vagal outflow, baroreflex sensitivity (BRS)
represents the capability of the cardiovascular regulatory
system to increase vagal activity by reflex. Both parameters
are depressed in CHF (5,8,9) and may identify patients at
higher risk of cardiac death and unfavorable outcome
(10,11). Beta-blockers have been shown to modulate HRV
and vagal reflexes in normal subjects, hypertensive and
postmyocardial infarction patients (12–22), but sparse and
inconsistent data have been reported for patients with CHF
(23–25). The aim of our study was to demonstrate in a
case-controlled study whether treatment with the nonselec-
JACC Vol. 36, No. 5, 2000
November 1, 2000:1612–8
Abbreviations and Acronyms
ANOVA ⫽ analysis of variance
BRS
⫽ baroreflex sensitivity
CHF
⫽ chronic heart failure
HRV
⫽ heart rate variability
LVEF
⫽ left ventricular ejection fraction
NYHA ⫽ New York Heart Association
rMSSD ⫽ root mean square of successive differences
SAP
⫽ systolic arterial pressure
SDNN ⫽ 24-h standard deviation of normal RR
interval
tive beta-blocker, carvedilol, improves vagal reflexes to the
heart and reduces sympathetic overactivity as evaluated by
assessment of arterial baroreceptor function and HRV
analysis.
METHODS
Study protocol and population. A case-controlled study
was a predefined choice to minimize in a limited number of
patients any possible differences in the level of ventricular
dysfunction between treated and nontreated patients.
Twenty consecutive subjects with moderate to severe CHF
in a clinical stable phase and optimized conventional medical treatment with angiotensin-converting enzyme inhibitors, digoxin and diuretics underwent a one-month betablocker titration period with carvedilol. Dosage of the drug
started from 3.25 mg twice daily and was progressively
increased until the maximum tolerated dose (max 25 mg
twice a day). During this time other drug therapies were
kept constant with the exception of diuretics, which were
adjusted according to the appearance of signs of fluid
retention.
Twenty patients selected from those enrolled in the heart
failure database of Montescano Medical Center (n ⫽ 640)
were retrospectively matched with the patients treated with
beta-blockers. The following clinical and hemodynamic
baseline matching criteria were used: age ⫾ 3 years, same
etiology, same New York Heart Association (NYHA) class,
left ventricular ejection fraction (LVEF) ⫾ 3%, pulmonary
wedge pressure ⫾ 3 mm Hg, max volume of oxygen exercise
capacity ⫾ 3 ml/kg/min. Patients who were treated with
amiodarone and beta-blockers were excluded from the
matching analysis. None had a history of pulmonary or
neurological disease or an acute myocardial infarction and
cardiac surgery within the previous six months. In order to
be entered into the database, all CHF patients had to have
been in a stable condition with no changes in signs or
symptoms in the two weeks preceding the study. At the first
assessment and at the end of follow-up, all patients underwent echocardiography with Doppler ultrasound examination, right heart catheterization, cardiopulmonary exercise
test, 24-h Holter recording with HRV analysis and BRS
assessment. All patients gave informed consent for the
Mortara et al.
Effect of Carvedilol on Autonomic Nervous System in CHF
1613
study, and the study was approved by the local ethical
committee.
Baroreflex sensitivity assessment. Arterial baroreceptor
function was evaluated by administration of the vasoactive
drug, phenylephrine, according to the well-established
method proposed by Smyth et al. (26). Baroreflex sensitivity
studies were analyzed by two independent and experienced
observers (A.M. and M.T.L.R.), as previously described
(7,11). Briefly, one electrocardiogram lead and systolic
arterial pressure obtained noninvasively via a photoplethysmographic transducer (Finapres, Ohmeda) were continuously recorded. Phenylephrine HCl (starting dosage 3 to
4 ␮g/kg) was given to raise the systolic arterial pressure
(SAP) by 15 to 30 mm Hg. The RR intervals were plotted
against the preceding arterial systolic peak, and a linear
regression analysis was performed for those points included
between the beginning and the end of the first significant
increase in SAP. Regression lines with a statistically significant correlation coefficient (p ⬍ 0.05) were accepted for
analysis; only for BRS near to zero (⫾ 0.5 ms/mm Hg), if
the increase of SAP was adequate (above 15 mm Hg), the
coefficients of regression were accepted independent of the
p value. This approach is justified by the fact that if SAP
increase causes no reflex changes (or small erratic changes)
of RR interval, the correlation between delta values of SAP
and RR would be necessarily poor with a regression line
running along the horizontal axis. A final slope was obtained by calculating the mean value of the injections
performed at the optimal phenylephrine dose. This value
was then considered as representing BRS (ms of RR
change/1 mm Hg of SAP increase).
Ambulatory electrocardiogram monitoring. Patients underwent 24-h Holter monitoring using a three-channel
Oxford recorder (Oxford Medical Instruments, United
Kingdom). All tapes were analyzed using the Oxford Excell
II Holter system for QRS labeling and arrhythmia detection. The tapes were manually reviewed by an independent
observer who was blind to the patient’s identity and study
treatment. Measurements of HRV were: standard deviation
of normal RR interval (SDNN) and root mean square of
successive differences (rMSSD). These time-domain parameters were chosen because they appear to be stable and
reproducible not only in normal subjects but also in various
subsets of patients with cardiovascular diseases, including
CHF failure (27).
Hemodynamic and Doppler echocardiographic evaluation. Right-sided heart catheterization was performed using a 7F Swan-Gantz balloon-tipped catheter inserted into
the right internal jugular vein and advanced through the
right heart into the pulmonary artery. Baseline standard
hemodynamic measurements, including pulmonary artery
pressure, mean pulmonary artery wedge pressure and mean
right atrial pressure, were made with the patients in a supine
position using a Hewlett Packard transducer (Andover,
Massachusetts) connected with a 7005 Marquette polygraph
(Marquette Electronic, Milwaukee, Wisconsin) and re-
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Mortara et al.
Effect of Carvedilol on Autonomic Nervous System in CHF
corded at a speed of 50 mm/s on a scale calibrated from 0 to
50 mm Hg. Cardiac output was measured by the thermodilution method as the mean of three consecutive measurements not varying by more than 10%.
A Hewlett Packard 1000 ultrasound system with 2.5 and
3.5 MHz probes was used to perform Doppler and twodimensional echocardiographic examinations, which were
obtained with the patients lying in a supine or slightly left
lateral decubitus position. Examinations were recorded on a
super-VHS videotape and analyzed by an experienced cardiologist. Left ventricular volumes and left ventricular ejection fraction (LVEF) were assessed by two-dimensional
apical 2- and 4-chamber views using the modified Simpson’s rule. Mitral regurgitation was diagnosed and semiquantitatively graded by color-flow Doppler from the apical
view.
Statistical methods. Comparisons between groups at baseline were performed by analysis of variance (ANOVA) for
continuous variables and by the chi-square test for categorical variables, whereas analyses before and after treatment
were performed by two-way ANOVA for repeated measures. Regression analysis was employed to assess the
relation between changes in LVEF and autonomic nervous
system parameters. Because of the skewed distribution of
BRS, Wilcoxon’s signed-rank test, Kruskal-Wallis
ANOVA and Spearman’s rank correlation procedure were
used when appropriate. All the analyses were performed
using the STATISTICA/W statistical package (Tulsa,
Oklahoma). Differences were considered significant when a
p value of ⬍ 0.05 was observed. All results are reported as
mean ⫾ SD.
RESULTS
Nineteen patients tolerated treatment with beta-blockers,
and the mean dosage at the end of follow-up was 40 ⫾ 18
mg/day. One subject experienced worsening of heart failure
that required extensive modification of the treatment and
was excluded from the analysis. Clinical and hemodynamic
characteristics and autonomic nervous system parameters of
the final 19 treated patients and of the 19 controls at
baseline are reported in Tables 1 and 2. The two groups
were almost identical in terms of level of ventricular dysfunction, and no significant differences were present in
either HRV or BRS.
Figure 1 shows the changes of matching variables in
treated and control patients. Beta-blockade therapy was
associated with a significant improvement in symptoms and
signs of ventricular impairment, while no differences were
observed in control subjects. Moreover, carvedilol caused a
significant reduction of the mitral regurgitation area (Fig.
1). The effect of treatment on autonomic parameters is
shown in Table 2. After beta-blockade, the RR interval
lengthened significantly, and both BRS and HRV indexes
showed a marked improvement. In contrast, all autonomic
nervous system parameters remained unmodified in control
JACC Vol. 36, No. 5, 2000
November 1, 2000:1612–8
Table 1. Baseline Clinical and Hemodynamic Characteristics in
Controls and in Patients Treated With Beta-blockers
Matching criteria
Age (yrs)
Etiology (%)
Ischemic
Idiopathic
Valvular
NYHA (class)
LVEF (%)
CI (L/min/m2)
PWP (mm Hg)
VO2 max (ml/kg/min)
Not matching Criteria
Duration of symptoms (months)
Na⫹ (mEq/L)
Echo deceleration time (s)
Mitral regurgitation 3–4⫹ (%)
RAP (mm Hg)
Therapy
ACE-inhibitors (%)
Diuretics (%)
Nitrates (%)
Digoxin (%)
Other vasodilators (%)
Controls
(n ⴝ 19)
Beta blockade
(n ⴝ 19)
53 ⫾ 8
53 ⫾ 8
47.5
47.5
5
2.1 ⫾ 0.4
23.6 ⫾ 5.8
2.3 ⫾ 0.5
17.7 ⫾ 8.9
14.8 ⫾ 4.0
47.5
47.5
5
2.1 ⫾ 0.4
23.8 ⫾ 7.3
2.4 ⫾ 0.5
17.4 ⫾ 8.4
14.5 ⫾ 3.8
25 ⫾ 18
138 ⫾ 4
121 ⫾ 30
53
5.8 ⫾ 4
24 ⫾ 11
138 ⫾ 3
127 ⫾ 37
47.5
3.9 ⫾ 3
89
94
57
89
5
94
94
63
84
5
ACE ⫽ angiotensin-converting enzyme; CI ⫽ cardiac index; LVEF ⫽ left ventricular
ejection fraction; Na⫹ ⫽ serum sodium concentration; NYHA ⫽ New York Heart
Association functional class; PWP ⫽ mean pulmonary wedge pressure; RAP ⫽ mean
right atrial pressure; VO2 max ⫽ maximum O2 consumption during exercise. Values
are mean ⫾ SD.
subjects. Individual data on BRS and SDNN changes after
beta-blockade are displayed in Figure 2; the mean delta
increase was 3.8 ⫾ 4 ms/mm Hg and 24 ⫾ 16 ms,
respectively. In treated patients there was a significant
relation between the delta changes in BRS and SDNN (r ⫽
0.59, p ⬍ 0.01), while neither measure was related to the
changes in mean 24-h RR interval (r ⫽ 0.16 for BRS and
r ⫽ 0.32 for SDNN, both NS). In addition, a significant
association was found between delta changes in LVEF and
delta changes in BRS or SDNN (Fig. 3).
During a subsequent period of follow-up of 19 ⫾ 8
months, five patients underwent cardiac transplantation,
and six cardiac deaths occurred in the control group, while
three cardiac deaths and three cardiac transplantations were
registered in those patients treated with carvedilol, thus
confirming a reduced prevalence of total cardiac events
(from 58% to 31%).
DISCUSSION
This case-controlled study clearly demonstrates that in mild
to severe stable patients with CHF with optimized medical
treatment, additional therapy with the nonselective betablocker, carvedilol, improves baseline vagal activity and the
baroreflex control of heart rate. This finding has clinically
relevant implications since in these patients the restoration
of more physiological dynamics of baroreceptor reflexes and
Mortara et al.
Effect of Carvedilol on Autonomic Nervous System in CHF
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November 1, 2000:1612–8
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Table 2. Autonomic Nervous System Parameters at Baseline and at the End of Follow-up in
Controls and in Patients Treated With Beta-blockers
Controls (n ⴝ 19)
Baroreflex sensitivity
BRS slope (ms/mm Hg)
Baseline SBP (mm Hg)
Baseline RR interval (ms)
Delta SBP increase (mm Hg)
Delta RR interval increase (ms)
Heart rate variability
RR interval (ms)
SDNN (ms)
rMSSD (ms)
Beta-blockade (n ⴝ 19)
Baseline
6-month
Baseline
6-month
4.0 ⫾ 3.7
109 ⫾ 15
848 ⫾ 157
18.8 ⫾ 5.1
95 ⫾ 66
4.2 ⫾ 3.1
110 ⫾ 14
852 ⫾ 145
18.5 ⫾ 4.0
94 ⫾ 64
3.7 ⫾ 3.4
108 ⫾ 11
802 ⫾ 128
18.1 ⫾ 5.0
88 ⫾ 83
7.1 ⫾ 4.9*†
114 ⫾ 8*†
981 ⫾ 131*†
19.4 ⫾ 5.9
210 ⫾ 170*†
807 ⫾ 121
57 ⫾ 16
15 ⫾ 9
782 ⫾ 117
61 ⫾ 13
14 ⫾ 12
791 ⫾ 113
56 ⫾ 17
12 ⫾ 7
894 ⫾ 110*†
80 ⫾ 28*†
18 ⫾ 9*
BRS ⫽ baroreflex sensitivity; rMSSD ⫽ root mean square of successive differences, SBP ⫽ systolic blood pressure; SDNN ⫽
standard deviation of 24-h normal RR interval.
*denotes p ⬍ 0.05 vs. baseline; †denotes p ⬍ 0.05 vs. controls at 6 months.
a more favorable sympathovagal balance to the heart may
protect against arrhythmogenic mechanisms and contribute
to a better outcome. After an observation period of six
months, hemodynamic and autonomic measures remained
stable in control patients thus confirming that the beneficial
improvement in functional and autonomic indexes observed
in treated patients was related only to the additive effect of
carvedilol.
Carvedilol in heart failure. Recent meta-analyses focused
on the results of randomized trials with beta-blockers in
CHF (1–3) have emphasized that carvedilol is highly
effective in reducing symptoms of heart failure, limiting
hospitalization and increasing survival. Moreover, carvedilol
improves LVEF and positively affects ventricular remodel-
ing by reducing left ventricular volumes and preventing
progressive ventricular dilation (4). In accordance with these
data, we observed a significant improvement of both systolic
and diastolic functions with a marked reduction of mitral
regurgitation. Since only stable CHF patients were enrolled
in this study, carvedilol was well tolerated and only in one
subject was treatment interrupted due to the worsening of
heart failure. The mechanisms involved in the positive effect
of carvedilol, particularly on systolic function, are still
uncertain. One proposal is that heart rate slowing with a
beneficial effect on diastolic times may be involved, as might
be a direct protective action on the myocytes against
cathecolamine excess. Moreover, a combined effect of carvedilol at different sites through adrenoreceptor blockade
Figure 1. Bar graph showing changes at six months of clinical and hemodynamic parameters in controls and in patients treated with beta-blockers. A
significant improvement of all indexes is shown after beta-blockade, while they remain unmodified in controls. LVEF ⫽ left ventricular ejection fraction;
NYHA ⫽ New York Heart Association.
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Effect of Carvedilol on Autonomic Nervous System in CHF
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November 1, 2000:1612–8
Figure 2. Individual changes of BRS (upper panels) and SDNN (lower panels) at six months in controls and in patients treated with carvedilol. BRS ⫽
baroreflex sensitivity; SDNN ⫽ 24-h standard deviation of normal RR interval.
and reduction of norepinephrine content (28,29) may cause
a significant increase in the sarcoplasmic Ca2⫹ content of
ventricular myocytes with a consequent improvement in
contractile performance (30). We found a significant correlation between changes in LVEF and autonomic nervous
system parameters (Fig. 3). Although the causality of this
association could not be established in the context of this
study, this relation does confirm a parallel improvement of
neural and hemodynamic indexes.
In this limited subset of patients, it is confirmed that
beta-blockade treatment is associated with a reduced number of cardiac events in CHF (mortality was double in
control patients). It is suggested that, among the mechanisms involved in this beneficial effect of carvedilol, a
restorative change of the autonomic function is likely to play
a significant role.
Effects of carvedilol on HRV and baroreflex sensitivity.
The effect of beta-blockade therapy on autonomic measures
has been extensively analyzed in healthy subjects and in
patients with hypertension or recent myocardial infarction
(12–22) but only few data have been reported in CHF
(23–25). It is generally accepted that beta-blocker treatment
increases mean RR interval and all HRV measures strictly
related to vagal activity. In CHF all parameters of HRV are
markedly reduced, and this has been interpreted as being the
result of a shift of autonomic balance towards a sympathetic
predominance (5). The mechanisms and clinical implications of reduced HRV in CHF and the occurrence of
possible confounding factors in the analysis of HRV have
been recently reviewed (5,8). Indeed, it has been reported
that SDNN during 24-h recording probably reflects the sum
of multiple neural and nonneural effects on the sinus node,
which also include chemoreceptor influences, fluctuations in
tidal volumes and other slow neurohormonal modulators of
cardiac rhythm (8). In this context, the UK-Heart prospective study (10) has recently demonstrated in more than 400
outpatients with mild to moderate heart failure that reduced
SDNN was the best noninvasive independent predictor of
cardiac death. In this study, carvedilol significantly improved SDNN, and this was not accounted for by the
increase in RR interval. This finding confirms that betablocker treatment exerts a positive effect on the mechanisms
that sustain the harmful hyperadrenergic state and affect
prognosis.
As far as arterial baroreflex gain is concerned, it has been
known since 1970 that beta-blockers can improve the reflex
response of heart rate to both blood pressure increase (31)
and the direct stimulation of baroreceptors by neck suction
(32). In normal subjects (18 –20) and in a limited number of
patients with hypertension (20,21), it was shown that
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November 1, 2000:1612–8
Figure 3. Scatterplots illustrating the relation between changes in LVEF
and changes in BRS (top panel) or SDNN (bottom panel) after betablockade. A significant relation between LVEF and both autonomic
indexes is shown. BRS ⫽ baroreflex sensitivity; LVEF ⫽ left ventricular
ejection fraction; SDNN ⫽ 24-h standard deviation of normal RR interval.
beta-blockers significantly increase baroreflex gain and that
this effect is independent of the beta-blocker used. We
previously demonstrated (11) in a large group of patients
with stable chronic heart failure that: 1) BRS as measured by
the phenylephrine technique is markedly depressed in CHF,
2) the relation of BRS with all indexes of ventricular
function, although significant, is fairly weak, and 3) BRS
quantification adds prognostic information to the predictive
accuracy of other established risk factors such as age, LVEF
and maximum oxygen consumption during exercise (11).
The mechanism of this arterial baroreflex dysfunction in
CHF has been described in detail elsewhere (9,11,33,34). It
is probably multifactorial, may be located in all components
of the reflex arc and includes central and peripheral effects of
high levels of angiotensin II.
In this study, we observed a marked improvement of BRS
after carvedilol treatment, and this was fully dependent on
enhancement of the RR reflex response since the blood
pressure increase induced by phenylephrine (the stimulus
evoking the reflex) was identical at baseline and after
therapy. Different possible explanations may be considered
for the effectiveness of carvedilol on baroreflex control of
heart rate, and these include hemodynamic mediated effects
and direct effects related to beta-receptor blockade. Arterial
Mortara et al.
Effect of Carvedilol on Autonomic Nervous System in CHF
1617
baroreceptors are sensitive to carotid distending pressure,
and their firing increases in response to small increments of
pressure (6,9). In this study, carvedilol significantly improved LVEF and reduced mitral regurgitation thus causing
an increase in both the absolute value and slope of the stroke
volume. This is confirmed by the study of Metra et al. (35)
who found that four months of carvedilol therapy produced
a significant increase in resting and exercise stroke volume
and stroke volume index. It is unquestionable that such
profound changes of systolic function and, consequently, in
carotid pressure could be responsible, at least in part, for the
restoration of baroreflex function. Moreover, because the
bradycardia that occurs in response to the hypertensive
stimulus is mediated largely by an increase in parasympathetic tone and is affected by adrenergic hyperactivity, any
changes in sympathetic and vagal efferent outflow to the
sinus node that resulted from modulation of other reflexogenic areas by beta-blockade treatment would interfere with
the assessment of BRS. Our data are in agreement with a
previous report that has clearly demonstrated that carvedilol
lowered other indexes of cardiac adrenergic activity, namely
coronary sinus and transmyocardial norepinephrine levels (29).
Theoretically, variations in SDNN and BRS could be
dependent on the same mechanisms influenced by carvedilol
therapy. However, the significant correlation we observed
between changes of the two measures may support either a
noncausal or a causal relationship, indicating a possible
direct effect of baroreflex improvement on HRV indexes.
Indeed, it has been demonstrated that arterial baroreceptors
are important modulators of respiratory and nonrespiratory
fluctuations of heart rate (5,36,37). As a consequence, it
would not be surprising if changes in BRS were found to
affect changes in HRV.
Study limitations. A possible limitation of our study is the
small sample size and the retrospective comparison with a
control group. However, because noninvasive evaluation of
autonomic nervous system analysis in CHF can be markedly
dependent on the level of hemodynamic dysfunction and
because possible differences in baseline clinical characteristics can persist in a limited number of randomized patients,
a case-controlled study was preferred to a randomized one.
Patients were consecutively allocated to the treatment arm,
and the controls were obtained after specific matching for
the most important clinical and hemodynamic variables.
This allowed us to have two identical groups at baseline,
such that any changes in ventricular function or autonomic
parameters could be ascribed only to the carvedilol treatment.
Spectral parameters (low- and high-frequency components, low-frequency/high-frequency ratio) were deliberately not used for the purposes of the present study since: 1)
recordings were not performed under resting controlled
conditions, and 2) it is well known that in CHF, lowfrequency and high-frequency powers are of limited value
for assessing autonomic modulation of heart rate (38 – 40).
In conclusion, this study shows that therapy with the
Mortara et al.
Effect of Carvedilol on Autonomic Nervous System in CHF
JACC Vol. 36, No. 5, 2000
November 1, 2000:1612–8
nonselective beta-blocker, carvedilol, significantly modifies
arterial baroreflex control of heart rate and the sympatheticparasympathetic interaction to the heart. This positive effect
on autonomic nervous system parameters is accompanied by
favorable changes in systolic and diastolic dysfunction and
suggests that carvedilol in CHF patients has the potential to
produce greater cardioprotection from harmful adrenergic
overactivity.
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