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British Heart,Journal, I974, 36, 79I-797.
Sinus bradycardia
Autonomic influences and clinical assessment
David H. Dighton
From the Cardiac Department, St. George's Hospital, London
Twenty-four patients with sinus bradycardia and i6^ control^ subjects were^ investigated using various^ autonomic
reflex manoeuvres and drug response tests.
Two groups ofpatients are suggested by the results: i) Bradycardia due to atrial disease (sinoatrial^ diseasel
sick sinus) -^ poor autonomic reponses, I6 patients. Of those with poor autonomic responses, 9 had additional
AV conduction defects, and half had experienced Adams-Stokes syncope. 2) Bradycardia of physiological
origin -^ normal or supernormal autonomic responses. a) Those with normal autonomic function, 7 cases. The
dominant atrial pacemaker in this group is possibly set at a lower rate than normal. Such patients were not
found to^ be^ liable to^ Adams-Stokes^ syncope,^ but^ may^ have^ vasomotor^ syncope.^ b) Vagotonia,^ I^ case.^ On^ the
basis of one patient it is suspected that^ sinus bradycardia may be^ due^ to^ 'vagotonia'^ or^ due^ to^ an^ unusual
sensitivity of the atrium to vagal influence. All autonomic responses were supernormal. Such patients, though
probably rare, may be especially liable to vasomotor syncope.
It is suggested that the investigations presented are useful in the routine assessment of patients presenting
with syncope and sinus bradycardia. Those patients with symptoms and poor autonomic responses may require
pacing while those^ with^ physiological^ responses^ may^ need^ no^ treatment^ or may^ be helped^ by^ drugs.
Although most patients presenting with sinus
bradycardia are^ asymptomatic,^ some^ present^ with syncope or^ dizzy spells. Physiological bradycardia is
usually of^ no^ clinical^ significance except when^ seen
in association with vasomotor syncope. When^ a
patient presents with Adams-Stokes syncope and
sinus bradycardia the problem is to differentiate
the bradycardia of physiological origin from that
which may be associated with some atrial pathology.
The aim of the (^) present work has been to investi-
gate the autonomic influences^ acting in sinus^ brady-
cardia and to^ develop routine^ tests^ useful^ in^ differ-
entiating the physiological from the^ pathological
type of bradycardia caused by atrial disease. The
tests described have developed from the need to
assess the clinical^ significance of^ sinus^ bradycardia
in patients with syncopal attacks.
The sinoatrial node and atrium are^ richly inner-
vated by both sympathetic and^ parasympathetic
nerve fibres (Grodner et^ al., I970; James, I967), the
pacemaker cells^ being directly affected^ by the
release of^ the^ acetylcholine and^ catecholamines
(James and^ Nadeau, I963; Hoffman^ and^ Cranefield,
I960; Toda^ and^ Shimamoto, I968;^ Toda^ and^ West,
Received 5 March (^) I
I967; Grodner et al., I970). The presence of the enzyme cholinesterase may be of importance in the control of the heart rate since it is responsible for the
hydrolysis of acetylcholine and can be demonstrated
in (^) active form in the (^) sinoatrial node and atrium
(James and Spence, I966).
Patients presenting with sinus bradycardia have
been investigated by using various reflex tests and
by infusion of drugs acting on the autonomic system
and atrial pacemaking sites.
Selection of subjects and methods Sixteen healthy adults volunteered as control subjects after being fully informed about the nature of the in- vestigation. Twenty-four patients with^ a^ persistent bradycardia at rest of less than 55 a minute were investigated after giving fully informed consent. No patient was ad- mitted to the investigation if the bradycardia could be related to drug therapy, untreated hypothyroidism, raised intracranial^ pressure, recent^ cardiac infarction, or cerebrovascular accident. Some patients presented with symptoms while others were found to have a persistent resting sinus bradycardia on routine electrocardio- graphy. Patients with fixed rate pacemakers were ex- cluded while some with demand pacemakers were
792 David H.^ Dighton
included. This selection was necessary since^ only demand pacemakers may be externally inhibited allowing the underlying spontaneous rhythm to manifest itself. All subjects were examined and weighed before in- vestigation. Those with demand pacemakers had their units inhibited by an external pulse generator attached at least IS minutes before investigation.
a) Reflex tests
With a continuous electrocardiographic recording (lead chosen to show largest P waves), all subjects performed simple manoeuvres designed to stimulate the dominant atrial pacemaker by autonomic reflexes. Recording started io to (^) i5 seconds before the reflex test and was continued throughout and for I0 seconds after each manoeuvre. Recordings were made with (^) quiet res- piration, forced inspiration (with breath held in in- spiration for a minimum of I5 seconds), a (^) Valsalva manoeuvre, using a^ sphygmanometer blown up to 40 mmHg, for a minimum of iS seconds and continued for as long as possible; right and left carotid sinus pressure continued until maximum response was ob- tained (up to I0 seconds usually); and (^) straight leg raising for 30 seconds. All the tests were (^) performed in the sitting position on a couch or (^) bed. The (^) electrocardio- grams obtained were (^) analysed for atrial rate using a standard rate (^) calculating ruler averaging two consecutive PP (^) intervals. The control rate was taken as the average ofthree measurements. Tne maximum or minimum rates during and after the manoeuvres were noted and ex- pressed as the rate difference above or below the control rate. Any changes in P wave morphology or changes in rhythm were noted. As far as possible recordings were made only during regular sinus (^) rhythm. Recordings with nodal (^) rhythm or some (^) irregular rhythm were re- jected and the^ manoeuvre^ repeated.
b) Drug tests
After the reflex tests, with the patient supine and at rest, intravenous bolus injections of the following (^) drugs were made into a normal saline intravenous infusion. i) (^) 5 ,Lg isoprenaline per 70 kg body weight (prepared in 2 ml (^) vials, (^5) jig/ml containing sodium metabisulphate); ii) 0-02 mg atropine sulphate per kg body weight; iii) o-8 mg prostigmine per 70 kg body weight given 20 minutes after the dose of atropine. The drugs were given in the order shown and flushed in with not more than 2 ml normal saline. A period of approximately I0 minutes elapsed between the doses of isoprenaline and atropine while the heart rate returned to previous control level. Only one dose of each (^) drug was given. The (^) doses given were chosen (^) to give an easily measur- able (^) response without (^) resulting in (^) undue side effects. The dose of (^) prostigmine was (^) suggested by the work of Fielder et al. (^) (I969).
Electrocardiograms were^ made^ continuously, io
seconds before and I minute after the dose of isoprena-
line. Only regular sinus (^) rhythm was (^) accepted as suitable during the control period. The same (^) procedure was followed for the atropine dose but further electrocardio-
grams (5 to I0 second strips) were taken every 5 minutes
until 20 minutes after injection. At 20 minutes after atro- pine the dose of prostigmine was given. After the dose of prostigmine, io-second recordings were made every minute for I0 minutes. The electrocardiograms were analysed for atrial rate with a standard rate (^) calculating ruler. The control (^) rates were taken as an average of five measurements (^) during the control period before each dose, only regular sinus rhythm being acceptable during this period. In the case of both atropine and isoprenaline the atrial rate was analysed with one measurement at every 3-second inter- val during the first minute. Further measurements were made at is-second intervals for a further (^2) minutes. Thereafter, in the case ofatropine, (^) measurements of atrial
rate were made at 5-minute intervals until prostigmine
was (^) given. During this analysis changes in rhythm or P wave morphology were noted. During the prostigmine re- sponse an average of five measurements was made at one minute intervals. The results were plotted as atrial rate against time in each case. Atrial response was assessed in two ways: i) the maximum or minimum (^) rate obtained above or below the mean control rate, and ii) the maximum rate of rise or fall in atrial rate during the response. This was estimated from a gradient drawn through the steepest four points on the response curve.
Results The ages, sex, mean resting heart rates, (^) electro-
cardiographic features, clinical features, and past
history of both controls (^) and those with sinus
bradycardia are given in Table i.
Seven patients presenting with sinus bradycardia were found to have P wave abnormalities; 4 having
flat or bifid P waves (voltage less than Oi mV) with
3 others having P waves of greater duration than
normal (o-i6 sec). A PR interval greater than 02 sec
was seen in 8 patients, no higher degrees of AV
block being seen. A QRS duration greater than
o0i sec was seen in 5 patients each with right bundle-
branch block and left axis deviation. His bundle
electrograms showed normal His to ventricular
activation times in these (^) patients.
Reflex tests
The changes in atrial rate with the various reflex
manoeuvres are shown in Table 2. No significant
quantitative difference could be shown between the
control responses to quiet breathing, forced inspira-
tion or straight leg raising, and those presenting with
sinus bradycardia. While the increase in rate during
a Valsalva manoeuvre was not significant, the total
drop in rate after the manoeuvre was significantly
less in the sinus bradycardia group.
Qualitative changes during the reflex responses
were not^ seen in the control group. In the sinus
bradycardia group various changes were seen.
794 David H. Dighton
patient (Case 14) the rate achieved was above control
range.
On the basis of decreased rate of change of atrial
rate II (^) patients had responses below normal range
(Cases I, 3, 5, 6, I2, I13, 15, i6, 17, I9, 23). One had
an above normal response (Case I4), the remaining
responses falling within control range.
In 2 patients frequent change in P wave shape
occurred (Cases I I, 23), with atrioventricular nodal
rhythm occurring at times in 5 (Cases 6, II, I2,
I3, i6). Supraventricular ectopics were frequently
observed in three (Cases I, 3, 6).
2) Atropine responses No significant difference
(P > o02) was found with either the increase in
atrial rate or in the maximum rate of change of
atrial rate between the control and sinus brady-
cardia groups. Only one patient had a response
below the normal range (Table 2) (Case I2) and
one had a response above normal range (Case 14).
With respect to the rate of change of atrial rate with
atropine, 5 patients had responses below the control
range (Table 2) (Cases I, I3, I5, 20, 24), 3 of whom
exhibited atrioventricular nodal takeover (Cases I,
I3, 20).
In the control group atrioventricular nodal take-
over occurred in one subject. In most subjects the
PR interval decreased by o0o4 sec. Nodal takeover
was observed in 8 patients (Cases I, 3, 6, I2, I4,
i6, I9, 20), with P wave variation occurring in one
case (Case 23).
3) Prostigmine responses Prostigmine was seen
to return the atrial rate to preatropine levels only.
When those with sinus bradycardia are compared
with controls, the differences between the drop in
atrial rate and the rate of change of atrial rate
fail to reach significant levels (P > o I).
In I3 of the sinus bradycardia group the decrease
in atrial rate observed was below the normal range
(Table 2, Cases 2, 3, (^) 5, 6, 7, 8, I2, I6, 17, 20, (^) 2I,
23, 24). One patient (Case 14) decreased his atrial
rate greater than any control subject.
Fourteen patients had a decrease in the rate of
change of atrial rate below the control range (Cases
I, 2, 3, 5, 6, 12, I3, i6, (^) 17, 20, 2I, 22, 23, 24). Four
patients had responses greater than the control
range in this respect (Cases 4, 9, 14, I9).
Results and clinical features
Of the io patients that had both reduced reflex and
drug responses (Cases 3, 6,8, (^) 13,i63, (^) I7, 20, 21, 23,
24), 5 had a history of Adams-Stokes attacks (Cases
3, 6, I3, I7, 20) and 2 a history of fainting attacks
(Cases 3, 8), with 5 requiring pacing (Cases 6, 13,
17, 20, 23). Two^ were^ satisfactorily controlled with long-acting (^) isoprenaline (Cases 3, i6). These patients all^ had^ below^ normal^ atrial^ responses and are (^) therefore (^) likely to have (^) sinoatrial disease or
'sick sinus syndrome'.
Of the I0 patients with both reduced reflex and
drug (^) responses, 5 had^ an^ abnormality of either P wave (^) voltage or (^) morphology (Cases 3, 8, I3, I7, (^) 23),
2 had evidence of sinoatrial block (Cases 6, i6), 2
of sinus arrest (Cases 8, 17), one of paroxysmal
atrial fibrillation (Case 13), and 4 had atrioven-
tricular nodal rhythm at times (Cases, i6, I7, 21,
23). Of^ the^ I0^ cases^ with^ reduced^ responses, 4 had evidence (^) of (^) right bundle-branch block (^) with left
axis deviation but no prolongation of His to ven-
tricular activation time. There was, therefore, no
electrophysiological evidence of trifascicular bundle-
branch disease in these cases. Since one patient also
had (^) first-degree atrioventricular (^) block with a PR
interval of 0-32 to 0'4 sec, 5 of the I0 patients with
reduced reflex and drug responses had evidence of
abnormal atrioventricular conduction.
There were 6 patients with reduced drug re-
sponses but^ normal^ reflex^ tests (Cases I, 2, 5, I2,
I5, 22). One^ of^ these had abnormal P waves with
intermittent sinus arrest (Case 5), 3 had nodal
rhythm at^ times (^) (Cases I, I2, I5), 2 had (^) right bundle-branch block with left axis deviation (^) (Cases
I, I5), and^2 had^ prolonged PR intervals (Cases 5,
22). None^ was^ seen to have either sinoatrial block or
atrial fibrillation. Of these 6, 5 had a history of
Adams-Stokes attacks (Cases 2, 5, I2, I5, 22), with 3
requiring pacing (Cases 5, I2, 22). This association
makes it likely that these patients have sinoatrial
disease or 'sick sinus syndrome'. One was con-
trolled with long-acting isoprenaline (Saventrine).
One only had a history of fainting episodes.
Eight patients (Cases 4, 7, 9, I0, II, I4, i8, I9)
were found to have no evidence of reduced atrial
pacemaker function. Of these, 3 had syncope which
was thought to be vasomotor in type (Cases 4, II,
14) rather than Adams-Stokes syncope. Three had
paroxysmal atrial^ fibrillation, one had occasional
atrioventricular nodal rhythm, and one other had
periods of^ sinus^ arrest^ (Case II). While 2 of these
patients had^ first-degree atrioventricular block, none
had evidence of bundle-branch block. These
patients have^ either^ physiological sinus bradycardia
or undetectable sinoatrial disease.
Discussion
Several workers have found that there may be re-
duced reflex and drug responses of heart rate in
patients with^ slow atrial arrhythmias or sick sinus
syndrome (Brasil, I955; Shaw and Eraut, I969;
Sinus bradycardia 795
Eraut and Shaw,^ I97I; Easley and Goldstein,^ I97I;
Mandel et al., 1972). Whether the responses so defined were reduced relative to normal is less definite since no control group data have been pub-
lished. Mandel et al. (I97I) did however use post-
pacing suppression to confirm subnormal atrial pacemaker function in their patients. After atrial pacing, good sinoatrial function is attended by early atrial takeover and poor function by delayed take- over. The results of the present work show that there are two groups of patients with sinus bradycardia, those with normal reflex and drug responses and those with (^) reduced responses. When these tests are used to differentiate two groups the inclusion of
patients with probable physiological bradycardia has
perhaps tended to reduce the statistical significance of some results. The results of this work suggest that those with the (^) presented evidence of reduced atrial pacemaker function are^ liable^ to^ Adams-Stokes^ attacks.^ In-
adequacy of lower pacemaking sites may be^ impor-
tant in the production of Adams-Stokes syncope in these patients. Those with normal atrial pace- maker responses may have been subject to syncope
of vasomotor origin, but not to Adams-Stokes
attacks.
On the basis of drug responses alone, all patients
with (^) Adams-Stokes attacks had evidence of reduced
sinoatrial automaticity. Of the^8 patients found^ to
have Adams-Stokes attacks, 4 had no^ electro-
cardiographic evidence other than sinus brady-
cardia to suggest reduced atrial pacemaker function.
One other had a P wave abnormality alone while 3
others had both P wave abnormalities and atrio-
ventricular nodal rhythm at^ times.
P wave abnormalities, atrial fibrillation, sinoatrial
block, and sinus arrest have been found^ to^ occur
commonly in association with defective sinoatrial
pacemaker function. The same abnormalities were
found, however, in some with normal atrial func-
tion, suggesting either the physiological origin of
these arrhythmias or defects not detected by the
present investigations.
Since no^ pathological data^ are^ available^ at^ present,
it remains to^ be^ shown^ that^ reduced^ responses to
autonomic stimuli are associated with recognizable
atrial pathology. From the present work^ one^ may
deduce only that there^ is^ a^ disturbance^ of atrial
pacemaker function^ in^ some^ patients. The^ available
evidence (^) suggests that sinus (^) arrest, atrioventricular
nodal rhythm, etc. (sick sinus syndrome) are asso-
ciated with atrial pathology (Brasil, I955; Rossi,
I969).
Some patients in this series were paced up to I
minutes before investigation. The^ influence of^ long-
term ventricular pacing on atrial pacemaker func-
tion is unknown. In short-term atrial pacing it is characteristic for atrial rhythm to return within
seconds after^ the^ cessation of^ pacing^ (Mandel^ et^ al.,
197I). In this series those paced for syncope due to a sinoatrial problem were the most likely to have an abnormality. One paced patient was^ found^ to^ have
supernormal autonomic^ responses^ whereas^ others
had only minor^ abnormalities of^ function.^ The find- ing of reduced responses in unpaced patients shows that the phenomenon is not solely pacing in- duced. In the absence of any known mechanism for
atrial pacemaker suppression by ventricular pacing
it must be assumed that reduced responses to
autonomic stimuli are^ most^ probably caused^ by^ a
disturbance of atrial pacemaker cells themselves. Nine of the patients with defective sinoatrial pacemaker function were found to have an atrio-
ventricular conduction defect, suggesting that
' sinoatrial disease' is part of a widespread conduct- ing tissue disease. As in complete heart block idio-
pathic fibrosis may possibly be the commonest cause
of sinoatrial disease.
The benefit of^ performing reflex^ tests^ lay in the
opportunity afforded to^ observe^ the^ occurrence of
arrhythmias. During these tests, nodal escape,
implying lesser automatic function in the atrial
pacemaking sites, sinus arrest, and supraventricular
tachycardias were occasionally seen, often with re-
production of the patients' symptoms. Some clue
as to the mechanism of the patients' dizzy spells,
palpitations, or^ syncope was^ thus^ discovered.^ In
some cases many hours^ of^ ward^ monitoring had
failed to reveal a significant arrhythmia.
Isoprenaline infusion, as a bolus infusion, proved
to be the most useful quantitative discriminating test
of atrial pacemaker function. With the dose given
occasional ectopics were seen and then only for a
short period. The response lasted 2 tO 3 minutes and
at worst caused only brief palpitation. The present
results do not support the results of Mandel et al.
(I972), i.e. that^ good responses^ are^ obtained^ in all
patients with^ sinoatrial disease^ or^ sick^ sinus^ syn-
drome. The doses of^ isoprenaline used in this study
were much smaller however. Their^ method of con-
tinuous drip infusion of isoprenaline was not em-
ployed since it is difficult to standardize and is more
liable to cause prolonged symptoms and^ arrhythmia. The results of the^ present work^ agree with those of
Brasil (I955) and of Eraut and Shaw (I97I) in
showing that^ patients with sick sinus^ syndrome^ have
reduced responses to isoprenaline.
The lack of control data in previous work may
have led to the conclusion that^ atrial^ responses to
atropine are reduced in^ 'sick^ sinus^ syndrome'. In
the control subjects studied^ the range of^ normal
Sinus bradycardia 797
autonomic influence. This group might, therefore, be regarded as having a physiological bradycardia and probably form the commonest naturally occur- ring group. As with other normal persons, they may be subject to vasomotor syncope, but not to Adams- Stokes syncope. The atrioventricular nodal rhythm and sinus arrest in these cases may be physiological in origin and caused by a spontaneous mechanism involving vagal stimulation (Hoffnan and^ Crane- field, i960). Some patients in this group may have sinoatrial disease, but with normal function in the dominant atrial pacemaker. Long-term follow-up may answer this question. Widespread atrial damage is probably necessary to produce an abnormality in the results of the tests described.
b) Vagotonia: one case (Case 14) One patient was seen to^ have^ 'supernormal' reflex^ and^ drug^ re- sponses. Since the^ vagal tone^ usually predominates at rest, this patient may have^ truly increased^ vagal tone accounting for his bradycardia. This^ type is probably rare.
It is suggested that the evaluation of^ atrial^ pace- maker function is of clinical value in^ patients pre- senting with bradycardia and syncope. The tests presented are at present in routine use for both^ inpatients and^ outpatients of^ this^ depart- ment.
The author is indebted'^ to^ Dr.^ Aubrey Leatham^ for^ his help, criticism, and^ advice; to^ Dr.^ Brian^ Robinson for his help during the planning stage of this^ work; and^ to^ Dr. Alan Harris and Mr. H.^ Siddons^ for^ their^ advice^ and comments.
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Requests for^ reprints to^ Dr.^ D.^ H.^ Dighton, Depart-
ment of Cardiology, Charing Cross^ Hospital, Fulham
Palace Road, London W6 8RF.
