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A study conducted by Dighton, from St. George's Hospital, London, investigating the autonomic influences on sinus bradycardia. The research involved 24 patients with sinus bradycardia and 16 control subjects, who were assessed using various autonomic reflex manoeuvres and drug response tests. The aim was to differentiate the physiological from the pathological type of bradycardia caused by atrial disease.
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From the Cardiac Department, St. George's Hospital, London
Two groups ofpatients are suggested by the results: i) Bradycardia due to atrial disease (sinoatrial^ diseasel
bradycardia are^ asymptomatic,^ some^ present^ with syncope or^ dizzy spells. Physiological bradycardia is
in association with vasomotor syncope. When^ a
The aim of the (^) present work has been to investi-
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
in (^) active form in the (^) sinoatrial node and atrium
Patients presenting with sinus bradycardia have
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.
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.
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).
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-
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
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-
history of both controls (^) and those with sinus
Seven patients presenting with sinus bradycardia were found to have P wave abnormalities; 4 having
o0i sec was seen in 5 patients each with right bundle-
activation times in these (^) patients.
Reflex tests
were not^ seen in the control group. In the sinus
range.
rate II (^) patients had responses below normal range
I3, 20).
(Table 2, Cases 2, 3, (^) 5, 6, 7, 8, I2, I6, 17, 20, (^) 2I,
I, 2, 3, 5, 6, 12, I3, i6, (^) 17, 20, 2I, 22, 23, 24). Four
drug responses (Cases 3, 6,8, (^) 13,i63, (^) I7, 20, 21, 23,
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
drug (^) responses, 5 had^ an^ abnormality of either P wave (^) voltage or (^) morphology (Cases 3, 8, I3, I7, (^) 23),
23). Of^ the^ I0^ cases^ with^ reduced^ responses, 4 had evidence (^) of (^) right bundle-branch block (^) with left
had (^) first-degree atrioventricular (^) block with a PR
I5, 22). One^ of^ these had abnormal P waves with
rhythm at^ times (^) (Cases I, I2, I5), 2 had (^) right bundle-branch block with left axis deviation (^) (Cases
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-
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
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-
tant in the production of Adams-Stokes syncope in these patients. Those with normal atrial pace- maker responses may have been subject to syncope
attacks.
with (^) Adams-Stokes attacks had evidence of reduced
have Adams-Stokes attacks, 4 had no^ electro-
others had both P wave abnormalities and atrio-
it remains to^ be^ shown^ that^ reduced^ responses to
atrial pathology. From the present work^ one^ may
evidence (^) suggests that sinus (^) arrest, atrioventricular
I969).
tion is unknown. In short-term atrial pacing it is characteristic for atrial rhythm to return within
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
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
it must be assumed that reduced responses to
disturbance of atrial pacemaker cells themselves. Nine of the patients with defective sinoatrial pacemaker function were found to have an atrio-
' sinoatrial disease' is part of a widespread conduct- ing tissue disease. As in complete heart block idio-
of sinoatrial disease.
opportunity afforded to^ observe^ the^ occurrence of
implying lesser automatic function in the atrial
results do not support the results of Mandel et al.
were much smaller however. Their^ method of con-
liable to cause prolonged symptoms and^ arrhythmia. The results of the^ present work^ agree with those of
have led to the conclusion that^ atrial^ responses to
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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Easley, R. M., and Goldstein, S. (197I). Sino-atrial syncope American Journal of Medicine, 50, I66. Eraut, D., and Shaw, D. B. (I97I). Sinus bradycardia.
Fielder, D. L., Nelson, D. C., Andersen, T. W., and Graven- stein, J. S. (i969). Cardiovascular effects of atropine and neostigmine in man. Anesthesiology, 30, 637. Grodner, A. S., Lahrtz, H.-G., Pool, P. E., and Braunwald, E. (I970). Neurotransmitter control of sino-atrial pacemaker frequency in isolated rat atria and in intact rabbits. Circu- lation Research, 27, 867. Hoffman, B. F., and Cranefield, P. (I960). Electrophysiology of the Heart. McGraw-Hill, New York. James, T. N. (I967). Cardiac innervation: anatomic and pharmacologic relations. Bulletin of the New York Academy of Medicine, 43, I041. James, T. N., and Nadeau, R.^ A.^ (I963). Sinus bradycardia during injections directly into^ the^ sinus node artery. American Journal of Physiology, 204, 9. James, T. N., and Spence, C. A. (I966). Distribution of cholinesterase within the sinus node and A-V node of the human heart. Anatomical Record, (^) ISS, I5I. Maliovanova, S.^ D.^ (I968). Cholinesterase^ activity^ of^ the ner- vous apparatus and myocardium of the^ rabbits^ heart during experimental diphtheritic myocarditis. Doklady Akademnit Nauk SSSR, 178, 2I3. Mandel, W. J., Hayakawa, H., Allen, H.^ N., Danzig, R., and Kermaier, A. I. (I972). The assessment of sinus node function in patients with the sick sinus syndrome. Circu- lation, 46, 76I. Mandel, W., Hayakawa, H., Danzig, R., and Marcus, H. S. (I97i). Evaluation of sino-atrial node function in man by overdrive suppression. Circulation, 44, 59. Rossi, L. (I969). Disturbances in impulse conduction, sino- atrial arrest, sinu-atrial^ block, sinus^ arrest^ and atrial stand- still. In Histopathologic Features^ of Cardiac^ Arrhythmias, pp. 126-I3I. Casa Editrice Ambrosiana, Milan. Shaw, D. B., and Eraut, D. (I969). Atrial^ bradycardia or the lazy sinus syndrome. Bristol Medico-Chirurgical J7ournal, 84, 213. Toda, N., and Shimamoto, K. (I968). The influence of sympathetic stimulation on transmembrane potentials in the S-A node. Journal of Pharmacology and Experimental Therapeutics, IS9, 298. Toda, N., and^ West, T. C.^ (I967). Interactions^ of^ K, Na, and vagal stimulation^ in^ the^ S-A node^ of^ the^ rabbit. American
Requests for^ reprints to^ Dr.^ D.^ H.^ Dighton, Depart-
Palace Road, London W6 8RF.