British HeartJournal, I975, 37, 32I-325. Br J: first published as 10.1136/hrt.37.3.321 on 1 March 1975. Downloaded from Sinoatrial block Autonomic influences and clinical assessment

David H. Dighton' From Cardiac Department, St. George's Hospital, Hyde Park Corner, London

Seventeen patients with sinoatrial block and i6 healthy volunteers were investigated with recently developed autonomic tests of atrial pacemakerfunction. Only one patient wasfound to be entirely normal in comparison with normal subjects, while another patient had supernormal responses. Fifteen patients had reduced responses relative to the controls implying impaired atrial pacemaker function or sinoatrial disease. It is suggested that while in some cases sinoatrial block may be ofphysiological origin, it is more often due to sinoatrial disease. The latter group are liable to Adams-Stokes syncope and may have additional atrio- ventricular conduction abnormalities. The possible mechanisms and treatment of sinoatrial block are dis- cussed relative to the autonomic and pacemakerfunction abnormalities described.

Sinoatrial block is an uncommon dysrhythmia of Those with demand pacemakers were included since unknown mechanism, characterized by the omission their units could be 'switched off' by external means, of P waves in the setting of a basic regular rhythm thus making the underlying rhythm apparent and avail- (Greenwood and Finkelstein, I964). It is found able for study. For this purpose an external pulse gen- erator was attached to the skin overlying the implanted incidentally in normal asymptomatic subjects and pacemaker and set to stimulate the skin at a rate in some dizzy or syncope. It may occur greater having spells than the pacemaker takeover rate. http://heart.bmj.com/ as an isolated dysrhythmia or in association with No patient was admitted to the investigation if the sinus (Easley and Goldstein, I97I), sinoatrial block could be related to drug therapy, un- (Short, 1954) or, sometimes, with treated hypothyroidism, raised intracranial pressure, atrioventricular conduction disorders. recent cardiac infarction, or cerebrovascular accident. A group of patients with sinoatrial block has been A history was obtained from each subject with par- investigated using autonomic reflex and pharmaco- ticular attention to the occurrence and character of logical tests of atrial pacemaker function. The aim syncope. The differentiation of 'vasomotor syncope' of the study has been to define the mechanism of from 'Adams-Stokes attacks' can be established from a detailed history or observation and is of great clinical on October 6, 2021 by guest. Protected copyright. the dysrhythmia and to assess its clinical significance importance. In the vasomotor attack consciousness is in individual subjects. lost gradually with dimming of vision, nausea, and sub- jective feelings of temperature change. The onset of an Subjects and methods Adams-Stokes attack is more abrupt though there may Sixteen healthy adults volunteered as control subjects be time for the subject to subside into a chair or onto after full explanation of the nature of the investigation. the floor before losing consciousness. The essential The age range of the controls was 2i to 68 years (mean: feature of the attack is the absence of the pulse, and 44 years). flushing on recovery is often remembered by the patient From 987 symptomatic patients referred to the Pacing as well as observed by witnesses. Unit of this hospital, 47 were found to have recorded All subjects were examined and weighed before in- evidence of sinoatrial block using the criteria of Green- vestigation. Those with demand pacemakers had their woodand Finkelstein (i964). Of these 47, 17 gave their units inhibited by the external pulse generator attached fully informed consent to the investigation. The age for at least I5 minutes before investigation. range of the patients was i8 to 82 years (mean 60 years). Patients with fixed-rate pacemakers were excluded. Received i8 September 1974. (a) Reflex tests 'Present address: Cardiac Department, Charing Cross Hos- With a continuous electrocardiographic recording (lead pital Fulham Palace Road, London W6 8RF. chosen to show largest P waves), all subjects performed Br Heart J: first published as 10.1136/hrt.37.3.321 on 1 March 1975. Downloaded from 322 David H. Dighton simple reflex manoeuvres designed to stimulate the of both and isoprenaline the atrial rate was dominant atrial pacemaker through the autonomic nerve analysed with one estimate at every 3-second intervals supply. Recording started I0 to i5 seconds before the during the first minute. Further estimates were made at reflex test and was continued throughout and for I0 15-second intervals for a further 2 minutes. Thereafter, seconds after each manoeuvre. Recordings were made in the case of atropine, estimates of atrial rate were with quiet respiration, forced inspiration (with breath made at 5-minute intervals until prostigmine was given. held in inspiration for a minimum of I5 seconds), a During this analysis changes in rhythm or P wave mor- Valsalva manoeuvre, using a sphygmanometer blown up phology were noted. During the prostigmine response to 40 mmHg (5.3 kPa), for a minimum of i5 seconds and an average of 5 estimations was made at each minute. continued for as long as possible, right and left carotid The results were plotted as atrial rate against time in sinus pressure continued until maximum response each case. From these graphs two parameters of atrial obtained (up to I0 seconds usually), and straight leg response were noted. (i) The maximum or minimum rate raising for 30 seconds. All the tests were performed in obtained above or below the mean control rate; and (ii) the sitting position on a couch or bed. The electro- the maximum rate of rise or fall in atrial rate during the cardiograms obtained were analysed for atrial rate using response. a standard rate calculating ruler averaging two consec- This was estimated from a gradient drawn through the utive PP intervals. The control rate was taken as the steepest four points on the response curve. average of three estimates. The maximum or minimum rates during and after the manouevres were noted and Results expressed as the rate difference above or below the con- trol rate. Any changes in P wave morphology or changes The clinical features of the patients are presented in rhythm were noted. As far as possible recordings were in Table i. made only during regular sinus rhythm. Recordings The electrocardiographic features are presented in with or some totally irregular rhythm Table 2. during either the control or test period were rejected and the manoeuvre repeated. TABLE I Clinical features of 17 patients with (b) Drug tests sinoatrial block Following the reflex tests, with the patient supine and at rest, intravenous bolus injections of the following drugs Symptoms No. Past history No. were made through a normal saline infusion into an antecubital vein. Dizzy spells 8 Cardiac infarction 4 (i) S ,ug isoprenaline per 70 kg Vasomotor syncope 5 Hypertension 3 body weight (BW) Adams-Stokes syncope 7 Diabetes I (using a freshly prepared solution in 2 ml vials, 5 mg/ml Palpitation 6 Myxoedema I http://heart.bmj.com/ containing sodium metabisulphate). Cardiac pain 4 I (ii) 0.02 mg atropine sulphate per kg BW. Diphtheria o (iii) o.8 mg prostigmine per 70 kg BW, given 20 minutes following 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 TABLE 2 Electrocardiographicfeatures in I7patients approximately io minutes elapsed between the doses of with isoprenaline and atropine while the heart rate retumed sinoatrial block to previous control level. Only one dose of each drug was given. No. on October 6, 2021 by guest. Protected copyright. The doses given were chosen to give an easily mea- surable response without resulting in undue side effects. Atrial rate < 50/min 3 All with AV nodal The dose of prostigmine was suggested by the work of rhythm at times Fielder et al. (I969). Abnormal P waves 4 PR>0.20s 5 (i with Wenckebach Electrocardiograms were recorded continuously, from periodicity) I0 seconds before to i minute after the dose of isoprena- Right bundle-branch block 3 line. The same procedure was followed for the atropine Left bundle-branch block 0 dose but further electrocardiograms (5 to io second T wave: flat/inverted strips) were taken every 5 minutes until 20 minutes after (no bundle-branch block) 4 the injection. Twenty minutes after the atropine injec- ST segments: flat/depressed 4 (2 with : I tion the dose of prostigmine was given. After the dose of previous infarct) prostigmine, i0-second recordings were made every Second degree sinoatrial block I0 minute for I0 minutes. Sinus arrest I0 Transient nodal rhythm 7 The electrocardiograms were analysed for atrial rate Nodal escape 8 with a standard rate calculating ruler. The control rates Atrial 4 (including 2 with were taken as an average of five estimates during the ischaemic heart control period before each dose, only regular sinus disease) rhythm being acceptable during this period. In the case Sinoatrial block 323 Br Heart J: first published as 10.1136/hrt.37.3.321 on 1 March 1975. Downloaded from

TABLE 3 Results of reflex and pharmacological tests in sinoatrial block

Investigation Change in atrial rate relative to control (beats/min) Controls (N= I6) Sinoatrial block (N= 17) P Mean Range Mean Range t-test (A) Reflex tests Respiratory 9.2 3, i8 9.I 4, 20 0.2 Forced inspiration -4.6 -2, +7 -1.9 -I, +I5 0.2 Valsalva: (during) +23.6 + IO, +47 + I5, 19 +2, +38 <0.05 (after) -38.9 -I9, -78 -20.4 0, -48 < 0.02 Right carotid sinus pressure -22.4 -2, -47 -I3-7 o, Sinus 0.I arrest Left carotid sinus pressure: -I4.7 0, -32 -8.6 o, Sinus 0. I arrest Straight leg raising +i6.6 +2, +30 +17.7 +2, +45

(a) Increase in atrial rate (beats/min). (b) Rate of change of atrial rate in beats min' s' (unless otherwise stated).

The i6 control subjects were fit and free from (i) Isoprenaline responses In the control sub- cardiovascular abnormalities. jects the increase above control resting rate was at

least 22 beats a minute, but in 9 of the patients with http://heart.bmj.com/ (a) Reflex results sinoatrial block this increase in rate was not achieved. The results are shown in Table 3. The responses by Similarly the acceleration of rate was less than in the sinoatrial block patients and the control sub- controls in 6 of the patients. jects to forced inspiration and straight leg raising Both the increase in rate and the acceleration of were not distinguishable. However, there was a rate in response to isoprenaline were reduced in the significant difference in the two groups to the Val- patients with sinoatrial block compared with the salva manoeuvre, the rate changes being less in the controls (P < o.oi). group with sinoatrial block. The responses to During the isoprenaline responses junctional on October 6, 2021 by guest. Protected copyright. carotid pressure were varied and there was a change rhythm occurred in one patient with change of P in rhythm in some of the group with sinoatrial block wave shape occurring in another. No similar changes group but not in the controls. were seen in the control subjects though T wave Right carotid pressure produced diminished flattening was seen in 2 controls. responses in 3; 4 had increased responses to right (ii) Atropine responses One patient had a dim- carotid pressure, i.e. 2 developed second degree inished rate response while 7 others had a reduced sinoatrial block and 2 sinus arrest. With left carotid rate of change response. The difference between the sinus pressure I patient developed transient com- controls and those with sinoatrial block, however, plete : this patient had developed second was not found to reach a level of statistical signifi- degree sinoatrial block with right carotid pressure. cance. Junctional rhythm was seen during the re- One patient developed second degree sinoatrial sponse of 2 patients, and during the response of i block with left carotid sinus pressure, while one control subject. Sinoatrial block occurring regu- other developed sinus arrest. larly before atropine was seen to disappear soon after the drug was given to 2 patients. (b) Pharmacological tests (iii) Prostigmine responses Compared to the The results are shown in Table 3. controls 6 patients had a diminished drop in atrial Br Heart J: first published as 10.1136/hrt.37.3.321 on 1 March 1975. Downloaded from 324 David H. Dighton

rate with this drug and 9 patients had a reduced rate associated with the arrhythmia. Cardiac ischaemia of change response. All the patients with a reduced and previous rheumatic fever were found to be rate response also had reduced rate of change re- major causes. One-third of the patients were fit sponses. No significant difference could be shown young adults thought to be clinically normal. The between the group with sinoatrial block and the natural occurrence of sinoatrial block is suggested controls. One patient had a response to prostigmine by the finding of only 5 asymptomatic cases in an that was greater than that of any control subject. electrocardiographic survey of 67375 American servicemen aged 20 to 24 years (Hiss, Averill, and Results and clinical features Lamb, I960). In the series of I7 patients with sino- atrial block reported here, 6 had evidence of ischae- Only one patient was entirely normal to all tests, mic heart disease, and i of rheumatic valve disease. with one other responding supernormally. Of the There was no evidence of heart disease in the other reflex responses only the Valsalva manoeuvre was patients though i gave a definite history of rheu- significantly different from those of the controls. matic fever and i had treated myxoedema. Ten patients had reduced Valsalva responses, with 8 The mechanism of sinoatrial block has been in of the I0 having reduced responses to isoprenaline, question (Scherf, I969) since it was described by 5 to prostigmine, and 3 to atropine. Wenckebach (I907). There is no evidence that true Five patients had either sinoatrial block (2 cases) 'block' occurs at the sinoatrial nodal level. On the or sinus arrest (3 cases), in response to carotid sinus basis of experimental work (Eyster and Meek, 1917; pressure. Only one of these patients had a reduced Scherf, I946) it seems unlikely that a pathological Valsalva response while 2 had reduced responses to process could reversibly block the transmission of prostigmine and one to isoprenaline. impulses from the to . The Nine patients had reduced responses to isoprena- term sinoatrial 'block' may, therefore, be unjustified, line: 5 of them had reduced Valsalva responses, 5 a view supported by the present work which sug- had reduced prostigmine responses, and 4 had re- gests defective atrial pacemaker function in most of duced atropine responses. Of the 7 patients with the patients. The sinoatrial node in sinoatrial block Adams-Stokes attacks, 4 had reduced isoprenaline possibly produces impulses which are regular but at responses. times subthreshold and unable to conduct to the Of the 7 patients with Adams-Stokes syncope, 2 atrium. This mechanism, previously suggested by had very reduced responses to both reflex and drug Resnik would the of an the by (I925), explain omission tests, i.e. Valsalva manoeuvre, isoprenaline, and exact number of cycles in otherwise regular rhythm http://heart.bmj.com/ prostigmine tests. Three others had reduced re- - a criterion that has been used to define sinoatrial sponses to one or two of these responses while the block (Greenwood and Finkelstein, I964). remaining 2 had abnormal but borderline responses The majority of patients investigated were shown to the three tests. No patient with Adams-Stokes to have defective sinoatrial function suggesting that attacks was found to be entirely normal to testing. some pathological process in the atrium was respons- Of the 3 patients with vasomotor syncope only ible for the dysrhythmia in most cases. The patho- one could be regarded as responding normally to logical process in the atrium has presumably to be both reflex and pharmacological challenge. Of the 2 widespread to account for the lack of takeover by on October 6, 2021 by guest. Protected copyright. patients with pronounced dizzy spells or near syn- surrounding atrial pacemakers. Additional disease cope, I responded supernormally to prostigmine of the atrioventricular conducting tissue might while the other had reduced reflex and isoprenaline account for the lack of atrioventricular nodal take. responses. over and subsequent in some cases. It is All 5 patients with a prolonged PR interval had possible that diminished pacemaker function in the reduced reflex and drug responses, as did the 3 patients with and lower sites might be pre- right bundle-branch block. Both sent before conduction defects are apparent with patients with paroxysmal had routine . abnormal responses, while the one patient with low Although only i patient was entirely normal to voltage P waves had reduced reflex and drug testing there were 4 with borderline responses - responses. just below normal range to one drug test. Sinoatrial block in some patients may be caused, therefore, Discussion by a transient physiological depression of sinoatrial In a survey from the literature of over 200 cases of function rather than by significant sinoatrial disease. sinoatrial block, Greenwood and Finkelstein (I964) Since carotid sinus pressure can produce the found that two-thirds of the patients had some arrhythmia in some cases a vagal mechanism is evidence of cardiac pathology or drug toxicity possible. Rather than continuous vagal stimulation a Br Heart J: first published as 10.1136/hrt.37.3.321 on 1 March 1975. Downloaded from Sinoatrial block 325 transient or phasic type (Dong and Reitz, I970) is a probably require a pacemaker whereas asympto- possible cause. 'Vagal epilepsy' caused by an un- matic patients with reduced responses alone should stable cerebral focus is an unproven but possible be observed closely. Those with normal or border- cause of sinus arrest in some patients. line responses may need no treatment if asympto- One case in this series had a response to vagally matic. Symptomatic patients with normal responses mediated reflexes and prostigmine in excess of the may respond to drug treatment, but pacing may be normal response. This patient may represent a required if drug treatment fails. It is suggested that group of patients with a hypersensitivity to normal the investigation of atrial pacemaker function as phasic vagal stimulation. presented is useful in the assessment and further Some patients in this series were paced up to 15 management of patients with sinoatrial block. They minutes before investigations. The influence of have so far been in use in this department for the long-term ventricular pacing on atrial pacemaker past 3 years. function is unknown. Certainly in short-term atrial pacing it is characteristic for atrial rhythm to return References within seconds after the cessation of pacing (Mandel Dong, E., and Reitz, B. A. (I970). Effect of timing of vagal et al., 197I). stimulation on heart rate in the dog. Circulation Research, 27, 635. It is suggested that there are two groups of sub- Easley, R. M., and Goldstein, S. (I97I). Sino-atrial syncope. jects with sinoatrial block, those that have symptoms American Journal of Medicine, So, i66. due to sinoatrial disease who may also have other Eyster, J. A. E., and Meek, W. J. (I9I7). Experiments on the evidence of heart disease, and those that are fit and origin and conduction of the cardiac impulse. Sino- ventricular and sino-auricular heart block. Archives of free from other cardiac pathology. Though the Internal Medicine, I9, 117. majority of patients were shown to have some defect Fielder, D. L., Nelson, D. C., Andersen, T. W., and Graven- of atrial pacemaker function there were 4 borderline stein, J. S. (I969). Cardiovascular effects of atropine and normal patients, i entirely normal patient, and neostigmine in man. Anesthesiology, 30, 637. Greenwood, R. J., and Finkelstein, D. (I964). Sino-atrial another who, in some respects, had greater than Heart Block. Charles C. Thomas, Springfield, Illinois. normal responses. The lack of evidence of signifi- Hiss, R. G., Averill, K. H., and Lamb, L. E. (I960). Electro- cantly reduced pacemaker function in these patients cardiographic findings in 67,375 asymptomatic subjects. suggests a transient physiological depression of the American 'ournal of , 6, I78. Mandel, W., Hayakawa, H., Danzig, R., and Marcus, H. S. atrial pacemakers, possibly vagally mediated, as a (I971). Evaluation of sinoatrial node function in man by cause of their dysrhythmia. Simultaneous vagal overdrive suppression. Circulation, 44, 59. stimulation of the atrioventricular node could also Resnik, W. H. (1925). The nature of so-called sino-auricular explain the absence of atrioventricular nodal take- block. Archives of Internal Medicine, 36, 788. http://heart.bmj.com/ Scherf, D. (I946). Experimental sinoauricular block. Pro- over. ceedings of the Society for Experimental Biology and Medi- A clinical value of these investigations is sug- cine, 6i, 286. gested by the fact that 5 of the 7 patients having Scherf, D. (I969). The mechanism of sinoatrial block. Adams-Stokes syncope had definitely reduced drug American Journal of Cardiology, 23, 769. Short, D. S. (I954). The syndrome of alternating bradycardia responses, while 2 had borderline responses. Others and tachycardia. British Heart Jrournal, I6, 208. with reduced responses had either dizzy spells or Wenckebach, K. F. (I907). Beitrage zur Kenntnis der men- faint attacks resulting in near syncope. Palpitations schlichen Herztatigkeit. Zweiter Teil. Archives of Anatomy occurred in patients who were both normal and and Physiology, i. on October 6, 2021 by guest. Protected copyright. abnormal to testing. Angina of effort occurred in 4 patients, all of whom had evidence of reduced atrial Requests for reprints to Dr. David H. Dighton, function. Symptomatic patients with Department, Charing Cross Hospital, Fulham Palace reduced atrial responses to the tests described will Road, London W6 8RF.