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International Journal of Cardiology 87 (2003) 231–236
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Electrocardiographic criteria for vagotonia—validation with
pharmacological parasympathetic blockade in healthy subjects
´
Jose´ Kawazoe Lazzoli, Pedro Paulo da Silva Soares, Antonio Claudio Lucas da Nobrega,
´ *
Claudio Gil Soares de Araujo
´ , Brazil
Departments of Morphology, Physiology and Pharmacology, Universidade Federal Fluminense, Niteroi
Received 4 February 2002; received in revised form 22 May 2002; accepted 24 May 2002
Abstract
Background: The importance of vagal tone on cardiac function and cardiovascular mortality is well established. Although the presence
of an enhanced cardiac vagal tone (CVT) is frequently diagnosed using the 12-lead resting electrocardiogram (ECG) in daily practice,
most of the proposed criteria have been determined on an empirical basis. Our objective was to evaluate the effects of pharmacological
blockade of the parasympathetic component of the autonomic nervous system on resting ECG tracings. Methods: Nine healthy young
adults (2465 year-old) underwent parasympathetic blockade with atropine sulfate i.v. (0.04 mg kg 21 ) and resting ECGs were obtained
before and 15 min thereafter. CVT was assessed by a dimensionless index, which measures the RR interval reduction caused by the vagal
withdrawal induced by a 4-s exercise test performed on a cycle ergometer where the subjects pedal as fast as possible with no added
resistance. Results: This index was 1.6360.24 and 1.0360.03, before and after atropine, respectively (P,0.0001). Atropine reduced the
R–R intervals (P,0.0001), and the amplitude of T-waves in several leads (DII: P50.03; V4: P50.04; V5: P50.03; V6: P50.01), and
abolished the appiculation of T-waves, J-point and ST-segment elevations (P,0.05), and U-waves (P,0.05), which were present in
baseline ECG in all subjects in at least two leads. The R-wave amplitude in leads V4, V5, and V6 (all P$0.10) was not modified by
atropine infusion. Conclusion: The duration of the R-R intervals and the amplitude of T-waves in leads DII, V4, V5, and V6, and the
presence of T-wave appiculation, U-waves, and elevation of J-point and ST-segment should be used to detect enhanced cardiac vagal tone
in healthy subjects.
 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Atropine sulfate; Electrocardiography; Parasympathetic blockade; Vagotonia
1. Introduction
Diminished cardiac vagal tone (CVT), associated
with an enhanced sympathetic drive in the presence
of induced myocardial ischemia, reduces the ventricular fibrillation threshold, thus facilitating the
occurrence of life-threatening arrhythmias [1–3]. On
the other hand, enhanced vagal activity produced by
* Corresponding author. Clınica
´
´
de Medicina do Exercıcio,
R. Siqueira
Campos, 93 / 101, 22031-070 Rio de Janeiro, RJ, Brazil.
´
E-mail address: [email protected] (C.G.S. de Araujo).
pharmacological means [4,5] or by direct electrical
neurostimulation [6,7] reduces the occurrence of
arrhythmias. In the clinical setting, a preserved CVT
is a positive prognostic factor in patients with coronary heart disease [8–10] and with heart failure
[11].
In daily cardiology practice, the diagnosis of
vagotonia is based on the 12-lead resting electrocardiogram (ECG). However, there has been no study
determining the experimental basis for detecting
enhanced CVT in the ECG. Actually, a previous
study [12] has demonstrated the lack of consensus
0167-5273 / 02 / $ – see front matter  2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S0167-5273( 02 )00330-3
232
J.K. Lazzoli et al. / International Journal of Cardiology 87 (2003) 231–236
among specialists in electrocardiography and cardiac
arrhythmias on the ECG variables to be considered
for the diagnosis of vagotonia.
Acute controlled interventions that inhibit the endorgan effects of vagal tone, such as pharmacological
blockade, may provide a single opportunity to evaluate the influence of CVT on ECG. In this study, we
have analyzed the ECG modifications caused by the
pharmacological suppression of CVT by atropine
infusion in healthy volunteers.
2. Materials and methods
2.1. Subjects
Asymptomatic healthy young adults (six male;
three female; age52465 years old) underwent a
pharmacological blockade of the parasympathetic
component of autonomic nervous system. All subjects were considered healthy on basis of clinical
examination, blood testing (hemogram, biochemistry
and electrolytes), maximal exercise testing, and Doppler echocardiogram. Also, none of them had taken
any medications in the 7 days preceding the study.
All subjects signed an informed consent after detailed
explanation of the procedures and potential discomforts. The study had been approved by the Institutional Review Board.
2.2. Procedures
Following a 5-min rest period on the supine
position after a 3-h fast, a standard 12-lead ECG was
performed, and the subjects sat on a cyclergometer
and had the ECG monitored by one single lead (CC5)
in order to perform the 4-s exercise test (4-sET), to
estimate CVT. In each occasion, two maneuvers were
performed, and the highest CVT index (see below)
was considered for analysis. The 4-sET is a validated
procedure [13,14], which consists in pedaling as fast
as possible a cycle ergometer without added resistance (with ‘zero load’), between the fourth and the
eighth second of a 12-s long maximal inspiratory
apnea. From the ECG tracing (lead CC5), two
specific R–R intervals were measured in milliseconds: the one immediately before exercise or the
first into exercise, whichever is the largest; and the
shortest one during exercise. Thus, we obtained a
dimensionless index, the CVT index, which reflects
the heart rate (HR) response at the onset of the
exercise, which mechanism has been demonstrated to
correspond predominantly to a vagal withdrawal,
without sympathetic influence [13,14]. In addition,
this chronotropic response is not changed if an
eventual non-voluntary Valsalva maneuver is performed [15]. A CVT index equal to 1.00 indicates the
absence of heart rate response and would theoretically correspond to the absence of CVT. This
procedure has also been used to evaluate CVT in
different experimental approaches [16].
A superficial venous access was then obtained, and
parasympathetic blockade was performed with the
infusion of atropine sulfate (0.04 mg kg 21 ) within 5
min [17]. After atropine administration, we performed a resting 12-lead ECG followed by two 4sET, both repeated at intervals thereafter (5, 15, 30,
60, 90 and 120 min after atropine infusion).
We selected two ECG tracings for analysis: the
baseline ECG, performed immediately before venous
puncture; and the ECG tracing obtained 15 min after
the end of the atropine infusion, occasion in which
the CVT index would tend to be 1.00, meaning
absence of CVT.
2.3. Data analysis
The following ECG variables were measured
(mean of three complexes or waves without interference and with a stable baseline): R-wave amplitude in
leads V4 (RV4), V5 (RV5), and V6 (RV6); T-wave
amplitude in leads DII (TDII), V4 (TV4), V5 (TV5),
and V6 (TV6); sum of the amplitudes of R-waves in
leads V4, V5, and V6 (Rtot); sum of the amplitudes
of T-waves in leads V4, V5, and V6 (Ttot); duration
of R–R interval (R–R), presence of U-waves (U),
and presence of ST-segment elevation (STelev). The
amplitudes were measured in millimeters, the R–R
duration was measured in milliseconds, and the
presence of U-waves and STelev was registered as to
the number of leads in which these characteristics
were observed.
This ECG analysis was performed twice by one of
the authors, with a 30-day interval, and the analysis
was based on the mean results. The Student paired
t-test or the Wilcoxon test for discrete variables was
J.K. Lazzoli et al. / International Journal of Cardiology 87 (2003) 231–236
Table 1
Results of the correlation analyses between the ECG variables and the
CVT index, before the venous infusion of atropine sulfate
RV4
RV5
RV6
TV4
TV5
TV6
U
R-R
TDII
STelev
Rtot
Ttot
r or rs
P-value
0.70*
0.58
0.52
0.69*
0.70*
0.74*
0.48
0.81*
0.67*
0.55
0.65
0.74*
0.036
0.104
0.153
0.040
0.037
0.022
0.191
0.008
0.048
0.125
0.057
0.022
r5Pearson correlation coeficient;
coeficient; * significant correlations.
rs5Spearman-rank
correlation
applied to compare the pre- and post-atropine values.
We also calculated the correlation between baseline
CVT index values and each of the variables of
baseline ECG with the Pearson or the SpearmanRank procedure, when appropriate. A 5% probability
level was accepted for statistical significance.
Table 2
Values of the ECG variables before (PRE) and after (POST) the venous
infusion of atropine sulfate
ECG variable
PRE
POST
P-value
RV4
RV5
RV6
TV4
TV5
TV6
U
R–R
TDII
STelev
Rtot
Ttot
17.062.6
16.262.3
12.061.3
5.660.9
5.061.0
3.760.6
561
1070673
3.260.3
361
45.265.9
14.362.3
17.362.9
15.062.3
11.261.3
4.160.7*
3.160.5*
2.260.4*
060*
487640*
1.860.2*
060*
43.466.2
9.561.6*
0.781
0.098
0.097
0.040
0.027
0.010
,0.05
,0.0001
0.003
,0.05
0.372
0.015
RV4, R-wave amplitude in lead V4; RV5, R-wave amplitude in lead
V5; RV6, R-wave amplitude in lead V6; TV4, T-wave amplitude in lead
V4; TV5, T-wave amplitude in lead V5; TV6, T-wave amplitude in lead
V6; U, presence of U-waves; R–R, R–R interval duration, em milliseconds; TDII, T-wave amplitude in lead DII; STelev, presence of
ST-segment elevation; Rtot, sum of the R-wave amplitudes in leads V4,
V5, and V6; Ttot, sum of the T-wave amplitudes in leads V4, V5, and V6.
The amplitudes were measured in millimeters and the presence of Uwaves and STelev were registered as to the number of leads where the
characteristic was present. Values are mean6standard error. * Significant
differences vs. PRE.
233
3. Results
The atropine infusions were performed without any
unexpected complication. All subjects reported dry
mouth and mild visual disturbances after atropine
infusion. However, no subject reported a major
discomfort that would cause the interruption of the
procedure. All symptoms were absent 6 h after the
onset of the procedure.
As expected and according to previously published
results [13,14], the results of the CVT index tended to
1.00 in the 4-sET performed 15 min after atropine
administration (mean and S.D.: 1.0360.03), with
values differing from baseline (1.6360.24; P,
0.0001). Table 1 shows the results of the linear
correlation analysis between CVT measures and ECG
variables and Table 2 shows the ECG variables and
the respective levels of probability.
4. Discussion
In the present study, the selective pharmacological
parasympathetic blockade was produced to determine
how the presence of this component influences the
resting ECG. The results demonstrate a significant
reduction in the R–R interval; a reduction in T-wave
amplitude in leads DII, V4, V5, and V6; and the
consistent disappearance of U-waves, and ST-segment elevations. In the baseline ECG we also observed a significant association between CVT index
and the following ECG variables: amplitude of Rwaves in lead V4; amplitude of T-waves in leads DII,
V4, V5, and V6; and the R–R interval; with the
exception of R-waves in lead V4, the same variables
were significantly modified with the parasympathetic
blockade.
The internal control of the study was the use of the
4-sET to evaluate CVT. It has been shown that CVT
index reflects CVT without any measurable sympathetic influence [13,14]. Our data confirm this concept, since the acceleration of the HR with dynamic
exercise was abolished in the subjects after atropine
infusion.
CVT has been also studied extensively by different
measures of HR variability, which carries prognostic
value in coronary artery disease [18] and in heart
failure patients [19]. Wennerblom et al. [20] has
234
J.K. Lazzoli et al. / International Journal of Cardiology 87 (2003) 231–236
investigated a particular aspect of HR variability, the
rate and velocity of change in HR during Holter 24-h
recordings, as a measure of vagal withdrawal and
sympathetic activation.
The CVT index used in the present study is
analogous to this strategy as it also measures the HR
increase caused by vagal withdrawal [13,14]. Although HR variability has been used to assess CVT,
there are many controversial issues to be resolved,
related to methodological aspects as well as to
physiological interpretations [21]. Therefore, there is
still a place for determination of CVT by means of
simple, low-cost, widely available and established
methods, such as the standard ECG.
An important methodological concept in the present study is the use of pharmacological blockade to
study the ECG changes. This strategy must consider
the theoretical features of Rosenblueth and Simeone
model [22], which validity depends on a series of
factors: first, on its applicability in humans, because it
was proposed from experimental studies on cats. This
evaluation is sometimes difficult, since various
studies performed pharmacological blockade in anesthetized animals, and it is known that anesthesia
modifies the activity of the parasympathetic component [23]. Second, the doses of atropine sulfate
must block completely the parasympathetic component of the autonomic nervous system. Third, it is
assumed that the blockade of one component does not
interfere with the activity of the other one.
The dose of atropine sulfate was the same as
suggested by Jose [17], and further demonstrated by
Jose and Taylor [24] as adequate to promote a
complete blockade of the parasympathetic efference
to the heart. This dose—and even lower doses of
atropine—have been frequently used in studies on
HR control by autonomic nervous system [25–30].
Another methodological issue refers to the pharmacokynetics of the autonomic blocking agent we
employed. It has been demonstrated that 2–3 min
after the atropine infusion the HR reaches a stable
value [17,24]. Maciel et al. [31] demonstrated that the
dose of 0.04 mg kg 21 was enough to completely
block, for 1 h, the acceleration of the HR induced by
a static upper limbs exercise of maximal intensity,
sustained by 10 s. Although the authors have employed an inhibitory parasympathetic stimulus, we
have no reason to believe that during this study there
has been an attenuation of the parasympathetic
blocking capacity of atropine in the 15 min after the
end of venous infusion. Actually, the CVT index
values tended to 1.00, 5 min after the end of atropine
infusion, and thus continued until 90 min after the
infusion. Therefore, the moment we decided to
analyze the ECG seemed adequate. Nevertheless,
even considering the dose and the duration of atropine action, it is not possible to warrant a complete
blocking effect, because atropine sulfate is a competitive blocking agent. From a pharmacological point of
view, the competitive inhibitors only reduce the
possibility of the natural agonist to interact with the
receptor in the cell membrane, but once there is a
determined concentration of the natural agonist in the
synapses, one cannot discard the possibility of some
degree of post-synaptic stimulation [32].
In spite of these difficulties, atropine sulfate
produces definite effects on parasympathetic activity
and on sinus node, and its use as a single agent is still
the best non-invasive method to study the parasympathetic control on HR [33], on the heart, and
consequently on ECG. Even considering the number
of factors that interfere on the heart electrical activity,
and influence its surface ECG registration, we found
in this study some considerably consistent data.
First, we observed a consistent and somewhat
presumable reduction of the R–R intervals. This
finding is according to the literature [34], and to a
previous study from our group [12] that pointed out
sinus bradycardia as the preferred criterion by
specialists in electrocardiography and cardiac arrhythmias.
The lack of consistent modifications on R-waves in
leads V4, V5, and V6 is not surprising, as a number of
cardiac and extra-cardiac factors influence their amplitude. Although a significant association between
the CVT index and RV4 has been observed, we have
not observed consistent changes in R-waves amplitudes with the parasympathetic blockade. In fact,
the behavior of the R-waves was inconsistent: the
RV4 was taller in six subjects and lower in three; the
RV5 was taller in three subjects and lower in six; and
the RV6 was taller in three subjects, lower in five,
and remained unmodified in one. These data suggest
that other uncontrolled factors may be responsible for
these variations.
A relevant finding was the consistent reduction of
J.K. Lazzoli et al. / International Journal of Cardiology 87 (2003) 231–236
T-waves in leads DII, V4, V5, and V6, that was
observed in eight of the nine subjects. Another
interesting observation was the consistent disappearance of the appiculation of T-waves in all subjects
who had the T-waves with this characteristic. Also,
T-wave amplitude in these leads had a significant
association with CVT index. This is also in accordance with the literature [34–36], that empirically
consider tall and peaked T-waves as a criterion for
vagotonia.
Seven subjects had a J-point elevation with at least
0.1 mV of amplitude, accompanied by a ST-segment
elevation with superior concavity, in at least 2 leads.
This pattern completely disappeared in six of the
seven subjects (83%), having remained in only one
lead of the seventh subject, who presented this
pattern in 6 leads in the baseline tracing.
All subjects presented U-waves in the baseline
ECG in at least 2 leads, and the subject with the
higher CVT indexes had U-waves in eight leads. The
U waves consistently disappeared in all subjects, in
all leads, with the atropine infusion. In the ECG
tracings after atropine infusion, one may observe the
horizontal T–P interval showing very clearly the
absence of the U-wave where it was present before.
The present results should be interpreted in light of
some limitations. This study cannot distinguish if
these changes were consequence of the CVT blockade; if they were consequence of the HR acceleration that accompanied the CVT suppression; or if
they were due to both. The CVT reduction is
generally accompanied by HR acceleration, as in the
situation of the pharmacological blockade performed
in this study, and in the physiological situation
observed during dynamic exercise, with a concomitant stimulation of the sympathetic tone. In physiological situations, these two phenomena are tightly
connected. Experimentally, even the induction of a
HR acceleration with a pacemaker, without any type
of autonomic handling or without any type of dynamic or static exercise, would not warrant that the
efferent impulses of the parasympathetic component
to the heart would be unchanged. An experimental
study, in unanesthetized animals, inducing HR acceleration with a pacemaker, with the monitoring of
the efference by parasympathetic and sympathetic
nerves to the heart could elucidate this question. Even
with these limitations, our approach seemed to be the
235
most appropriate strategy so far to study the influences of CVT in the resting ECG.
In conclusion, the blockade of cardiac vagal tone
reduced the R–R intervals and the amplitude of
T-waves in leads DII, V4, V5, and V6, with disappearance of T-wave appiculation, J-point and STsegment elevations, and U-waves, suggesting that
these criteria should be used to detect vagotonia on
the ECG.
Acknowledgements
˜
This work was supported by grants from Fundaçao
de Amparo a` Pesquisa do Estado do Rio de Janeiro
˜ de Aperfeiçoamento de
(FAPERJ); Coordenaçao
´
Pessoal de Nıvel
Superior (CAPES), and Conselho
´
Nacional de Desenvolvimento Cientıfico
e Tecno´
logico
(CNPq).
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