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Effects of pharmacologic autonomic blockade on atrial electrophysiologic properties in normal subjects and in patients with sinus node disease
International Journal of Cardiology, 8 (1985) 437-445 Elsevier
431
IJC 00276
Effects of pharmacologic autonomic blockade on atria1 electrophysiologic properties in normal subjects and in patients with sinus node disease A. Michelucci, L. Padeletti, G.A. Fradella, D. Monizzi, A. Giomi and
F. Fantini Cardiology Unit, Uniuersi[v of Florence, Ita[v (Received
1 November
1984; revision accepted
8 January
1985)
Michelucci A, Padeletti L, Fradella GA, Monizzi D, Giomi A, Fantini F. Effects of pharmacologic autonomic blockade on atria1 electrophysiologic properties in normal subjects and in patients with sinus node disease. Int J Cardiol 1985;8:437-445. In order to elucidate the influence of autonomic nervous system on atrial electrophysiologic properties, we studied 10 patients with sinus node dysfunction and 10 age-matched normal subjects. In each of them effective and functional refractory periods of the right atrium (near its junction with the superior caval vein) were measured, during atria1 pacing (lOO/min) and using variable current strengths (2,3,4, 5, 7, 10, and 15 mA), before and after pharmacologic autonomic blockade (using intravenous propranolo10.2 mg/kg and atropine 0.04 mg/kg). Mean values of effective and functional refractory periods at each current strength were significantly higher in patients with sinus node disease than in normal subjects both before and after autonomic blockade. Blockade did not significantly modify mean values of effective and functional refractory periods at any current strength, either in patients with sinus node disease or in normal subjects. Furthermore, autonomic blockade did not change the effects of the increase of current strength on atrial refractoriness in either group. We conclude that our data indicate a prolonged refractoriness to be present in patients with sinus node disease even in the absence of influences from the autonomic nervous system. Thus, we can suggest a “primary” involvement of atrial fibers in this pathophysiological condition. Propranolol together with atropine did not induce changes of atrial refractoriness. Indeed, they probably exerted an opposite effect. The
Correspondence
to: Dr. Antonio
0167-5273/85/$03.30
Michelucci,
Via Bronzino,
0 1985 Elsevier Science Publishers
163. 50142 Firenze.
B.V. (Biomedical
Italy.
Division)
438
effects of the increase of current strength on atria1 excitability
do not seem to be
mediated by autonomic humoral agents. (Key words:
atrium;
atropine;
current
strength;
propranolol;
refractoriness)
Ictroduction Cardiac electrophysiological status is dependent upon a complex and delicately balanced interaction between “intrinsic” cardiac electrophysiological properties and factors outside the heart. Among the “extrinsic” factors capable of exerting modifying influences upon the myocardium, the role of the autonomic nervous system is most important. For this reason the diagnostic use of pharmacologic autonomic blockade (by intravenous propranolol together with atropine) has been recommended in clinical electrophysiology [1,2]. This method made possible a better definition of normal [l] and abnormal [2] “intrinsic” sinus node function. Little information is available, however, on the “intrinsic” behaviour of atria1 refractoriness in man. With this in mind, we performed an evaluation of this topic knowing that autonomic mediators are able to influence recovery of atria1 excitability [3-61, and that abnormalities in atria1 refractoriness have been shown in patients with sinus node dysfunction and/or atria1 tachyarrhythmias [7,8] without the role of autonomic mediators being evaluated on this behaviour. Furthermore, previous studies have shown the use of stimuli of different current strengths to have a more precise role in determining myocardial refractoriness [9-111, in this way producing a liberation of autonomic mediators [12,13]. On the basis of these previous investigations, our analysis was performed in normal subjects and in patients with sinus node disease by determining atria1 refractoriness measured, using stimuli of different current strengths before and after autonomic blockade.
Material and Methods We studied two groups of patients. The first group consisted of 10 subjects (6 males and 4 females), mean age 65 years (range 57-75 years) who underwent an electrophysiological study for unexplained dizziness. History, physical examination, chest X-ray, electrocardiography, echocardiography, ambulatory monitoring or maximal exercise treadmill test all proved to be normal in this group. The second group of subjects consisted of 10 patients (5 males and 5 females), mean age 69 years (range 53-77 years) with a clinical diagnosis of sinus node dysfunction. The diagnosis was suggested by the presence of sinus bradycardia and/or sinus arrest concomitant with symptoms of dizziness or vertigo (or both). The electrocardiographic abnormalities had been documented in the electrocardiogram or in 24-hr Holter ambulatory electrocardiographic tape recordings. Only one patient had a history of palpitations without instrumental documentation of tachyarrhythmias. Although five patients had a history of ischemic heart disease and two had hypertensive heart disease, none demonstrated congestive heart failure or cardiome-
439
galy. All patients were in New York Heart Association Class I. Excluded from these studies were patients with pulmonary disease, glaucoma or urinary retention. There was no significant age difference between the two groups. All studies were done in a postabsorptive, nonsedated state with the patient in the supine, resting position. The nature of the studies was explained to all subjects and a signed consent was obtained from all. All cardioactive drugs were withdrawn for at least 5 half-lives. All subjects were in sinus rhythm at the start of the study. Two catheters (number 6F USC1 quadripolar and number 6F USC1 tripolar) were inserted percutaneously via a right antecubital vein and the right femoral vein, respectively. The quadripolar catheter was positioned at the high right atrium near its junction with the superior caval vein. The distal pair of electrodes were used to stimulate the atrium and the proximal pair to record a high right atria1 electrogram. The tripolar catheter was positioned across the tricuspid valve and was used to record a His bundle electrogram. Effective and functional refractory periods were measured during atria1 pacing (lOO/min) using variable current strengths (2, 3, 4, 5, 7, 10, and 15 mA) and introducing an extrastimulus (at 5-10 msec decrements) after the eighth paced complex of the basic drive. The pulse width of both driven beats and premature extrastimuli was held constant (2 msec), while the current strength of stimuli of the basic paced rhythm and of premature extrastimuli increased in parallel. Intracardiac electrograms were recorded at filter frequency settings of 40 and 500 Hz. One or more surface electrocardiographic leads (I, II, III and V,) were also recorded. All traces were simultaneously displayed on a Hewlett-Packard eight-channel oscilloscope and were recorded on a Elema-Schonander Mingograph 62-6 channel ink-jet at a paper speed of 100 mm/set. Premature programmed atria1 stimulation was performed using an electrically isolated battery-powered Medtronics 5325 stimulator. The functional refractory period was the shortest coupling interval recorded on the high right atria1 electrogram. The effective refractory period was the longest interval between the stimulus artefact (atria1 pacing) and the extrastimulus which failed to propagate. Evaluation of refractoriness according to the above described protocol was repeated in each subject after autonomic blockade (using intravenous propranolol 0.2 mg/kg body weight, administered over a period of 3 min. followed 10 min later by atropine sulphate 0.04 mg/kg, administered over 1 mm). Measurements began after 5 min and were completed within 20 min of administration of atropine. In each subject we evaluated also the resting heart rate (from 10 consecutive sinus cycles, 10 min after the introduction of the catheters) and the intrinsic heart rate (from the shortest 10 consecutive sinus cycles after atropine). The normality of the latter value was established (according to Jose and Collison [14]) by calculating for each subject the predicted intrinsic heart rate and its 95% confidence limits. As all subjects of our study were older than 45 years, the 95% confidence limits (again according to Jose and Collison [14]) of predicted intrinsic heart rate were & 18%. Sinus node recovery time was then calculated before and after autonomic blockade by atria1 pacing at cycle lengths of 600, 500. 430, 370, and 330 msec. This was done for 2 min at each cycle length.
440
Corrected sinus node recovery time was calculated before and after autonomic blockade by deducting the mean of 10 consecutive spontaneous sinus node cycles immediately preceding each pacing run for sinus node recovery time. Its value was considered normal, according to our laboratory, if lower than 450 msec. The paired t-test was used to analyze changes in heart rate, sinus node recovery time, corrected sinus node recovery time and atria1 refractoriness (at each current strength) after autonomic blockade. The unpaired t-test was used to compare patients with sinus node disease and normal subjects before and after autonomic blockade. Values are expressed in msec and as mean f 1 SD. Significance was defined at the 90% level.
Results Normal Subjects Mean values of heart rate and of intrinsic heart rate were 69 _t 9 beats/mm and 83 _t 6 beats/mm, respectively. All values of intrinsic heart rate were within the normal range of predicted heart rate. Mean values of sinus node recovery time before and after autonomic blockade were 1167 f 117 and 1021 _t 131, respectively. Mean values of corrected sinus node recovery time before and after autonomic blockade were 288 + 63 and 294 + 82, respectively. All single values of corrected sinus node recovery time proved to be normal both before and after autonomic blockade. We did not observe any difference in the effects of current strength on atria1 refractoriness when comparing its behaviour before and after autonomic blockade. In each subject both before and after autonomic blockade the effective and functional refractoriness decreased with increasing current; the relation between atria1 refractoriness and current strength was nonlinear and large changes were observed at low current strengths both in effective and functional refractoriness. In contrast. at higher current strengths (a 7 mA) the changes in atria1 refractory periods were small and the strength-refractoriness curve became steep. The range of single values and the mean values of effective refractory period at each current strength before and after autonomic blockade are shown in Table 1. These same values in respect to functional refractory period are given in Table 2. There was no statistical difference at any current strength between the mean values of effective and of functional refractoriness before and after autonomic blockade. Patients with Sinus Node Disease Mean values of heart rate and of intrinsic heart rate were 60 + 10 beats/min and 64 + 10 beats/min, respectively. Single values of intrinsic heart rate were below the normal limit of the (predicted) normal range in 8 patients and within the (predicted) normal range in 2 patients. Mean values of heart rate and of intrinsic heart rate of sinus node disease patients were significantly lower than those of normal subjects ( P < 0.04 and P < 0.0005. respectively). Mean values of sinus node recovery time
1
ERP (msec) ufter AB N Range Mean SND Range Mean N vs. SND PC
ERP (msec) hefDre AB N Range Mean SND Range Mean N vs. SND PC
240-300 269 + 22 270-380 317k38 0.003
240-310 272 + 26
270-380 327 + 33
0.001
0.04
0.007
250-350 304 * 39 0.004
0.02
0.002
250-330 291 f 31
210-280 245 + 25
0.05
0.02
230-280 254 f 23
220-330 275 f 44
210-280 244+24
7
220-330 295k44
220-280 251 f 32
5
260-380 305 + 45
240-300 264 + 30
0.02
230-390 306 + 49
250-450 320 f 69
280-450 346 + 54
4
230-300 265 f 28
3
(mA)
220-310 271+ 33
strength
230-320 282? 34
2
Current
Range of single values. mean values of effective refractory period (ERP) at each current strength before and after autonomic (N) and of patients with sinus node disease (SND). Statistical significance between N and SND is shown.
TABLE
0.02
240-320 270 k 33 240-320 275 + 33 0.01
210-280 236 of-27
0.01 0.02
210-280 240 + 23
220-320 267 * 37
210-260 227 + 25
15
(AB) of normal
220- 340 276 & 44
210-270 239 f 22
10
blockade
subjects
2
FRP (msec) after A B N Range Mean SND Range Mean N vs. SND PC
FR P (msec) before A B N Range Mean SND Range Mean N vs. SND PC
260-310 289 f 20 280-410 347 * 48 0.003
290-430 358k50
0.001
0.04
0.01
260-320 29Of24
270-500 346 + 79
290-500 366 + 67
3
(mA)
250-320 295 _+25
strength
260-330 301_+ 29
2
Current
280-400 328 k43 0.004
0.009
240-310 275 + 24
0.04
250-500 331 k 80
0.003
270-360 311 f 31
240-290 270 + 21
250-510 322 f 85
230-300 266 _+25
7
0.002
250-360 307 * 33
230-290 260 f 23
0.03
240-500 320 f 87
230-280 259 _+20
10
strength, before and after autonomic N and SND is shown.
240-300 276 _+23
5
270-420 337+51
250-310 284 + 24
0.02
260-510 327 k 54
240-320 282 f 27
4
Range of single values, mean values of functional refractory period (FRP) at each current subjects (N) and of patients with sinus node disease (SND). Statistical significance between
TABLE blockade
250-360 300 * 36
230-290 255 k 25
0.01
240-360 295 + 45
230-270 252_+20
15
(AB), of normal
443
before and after autonomic blockade were 1964 & 354 and 2150 t- 554, respectively. They were significantly higher than those of normal subjects both before (P -e 0.003) and after (P < 0.006) autonomic blockade. Mean values of corrected sinus node recovery time before and after the two drugs were 940 * 326 and 1187 + 522, respectively. All single values of corrected sinus node recovery time were abnormally prolonged both before and after autonomic blockade. Moreover, mean values of corrected sinus node recovery time were significantly higher than those of normal subjects both before (P < 0.007) and after (P < 0.01) autonomic blockade. As with the normal subjects, we did not observe any obvious difference in the effects of current strength on atria1 refractoriness in patients with sinus node disease when comparing their behavior before and after autonomic blockade. In this regard, the observations noted for normal subjects were valid in the patients with sinus node disease (Tables 1 and 2). There was no statistical difference at any current strength between the mean values of effective and of functional refractoriness before and after autonomic blockade. The comparison between the patients with sinus node disease and the normal subjects showed that mean values of effective and functional refractoriness at each current strength were significantly higher in the former both before and after autonomic blockade. Statistical significances between the groups are shown in Tables 1 and 2.
Discussion It has been suggested that the determination of the refractory period at multiple current strengths (rather than at one current strength) provides a more accurate measure of excitability [9,10,11]. Thus, in order to evaluate atria1 excitability, we measured refractoriness at different current strengths. Moreover, in order to evaluate the influence of autonomic nervous system on atria1 electrophysiologic properties, the measurements were made before and after the administration of propranolol plus atropine. The use of these two drugs and their doses have been assessed in previous studies [1,2,14]. We cannot deny, however, that some methodological problems could exist concerning the validity of this approach. Nonetheless, there is indirect evidence that alpha-adrenergic receptors are present in the myocardium even if their role in clinical electrophysiology remains to be evaluated [15]. Moreover, a direct effect of propranolol on myocardial excitability could be supposed, even if the used dose (0.2 mg/kg) is considered much smaller than that required to induce an effect on membrane stability [16,17]. In our study the combined effect of the two drugs was unable to modify atria1 refractoriness either in normal subjects or in patients with sinus node disease. We can try to explain our data in the light of some previous results. Atropine is able to reduce [3,4] and propranolol to increase [5] atria1 refractoriness. Thus, atropine and propranolol can exert opposite effects, and the result might be no significant changes. It should be noted, however, that we performed measurements of refractoriness at the junction of the right atrium with the superior caval vein (i.e.
444
near the sinus node). This area has a high concentration of cholinesterase [18,19], together with autonomic nerves and ganglia [20]. It is possible that vagal influence and beta-receptor activity are both particularly active at this site, so conditioning our results. Mean control values of effective and functional refractoriness as measured at each current strength were significantly higher in our study in patients with sinus node disease than in normal subjects. The existence of an abnormally prolonged atria1 refractoriness in the presence of sinus node disease has been noted in previous studies [7,8]. To evaluate if this behaviour could be conditioned by vagal influence and sympathetic activity, we compared mean values of refractoriness in each group after the administration of propranolol and atropine. This showed that the mean values of effective and functional atria1 refractoriness remained higher in the presence of sinus node disease than in the normal subjects. On this basis, we can suggest the existence of an abnormal “intrinsic” atria1 excitability in patients with sinus node disease. This concept should not be surprising, when it is considered that sinus node disease in its broadest sense encompasses atria1 disease [21,22]. Previous studies in animals suggest that the increase in stimulus strength results in liberation of autonomic mediators [12,13,23] which then condition the electrophysiologic properties of atria1 fibers [23]. Our results do not support this conclusion. We found that the combined effect of atropine and propranolol was unable to modify the effects of the increase in strength of stimulus. Because of this, we should reconsider the link between current strength and autonomic mediators. Probably there is a more complex interaction between current strength and local properties of atria1 myocardium, even if it cannot be assessed easily in clinical electrophysiology. In conclusion, we have demonstrated prolonged atria1 refractoriness in patients with sinus node disease even if vagal influence and beta-receptor activity are excluded. Thus, we can propose the existence of a “primary” involvement of atria1 fibers in this pathophysiological condition.
References 1 Alboni P. Malacarne C, Pedroni P. Masoni A, Narula OS. Electrophysiology of normal sinus node with and without autonomic blockade. Circulation 1982;65:1236-1242. 2 Kang P, Gomes JAC. El-Sherif N. Differential effects of functional autonomic blockade on the variables of sinus nodal automaticity in sick sinus syndrome. Am J Cardiol 1982;49:273-282. 3 Dhingra RC, Amat-y-Leon F, Wyndham C, et al. Electrophysiologic effects of atropine on human sinus node and atrium. Am J Cardiol 1976;38:429-434. 4 Michelucci A, Padeletti L. Fradella GA, et al. Effects of atropine on atria1 refractoriness and its dispersion in humans. Int J Clin Pharmacol Ther Toxic 1984;22:254-258. 5 Damato AN, Caracta AR, Akhtar M, Lau SH. The effects of commonly used cardiovascular drugs on AV conduction and refractoriness. In: Narula OS, ed. His bundle electrocardiography and clinical electrophysiology. Philadelphia: FA Davis Company, 1975;105-125. 6 De Elio FJ. The action of acetylcholine. adrenaline and other substances on the refractory period of the rabbit auricle. Br J Pharmacol 1947;2:131-142. 7 Monivi D. Michelucci A, Padeletti L. Fradella GA, Fantini F. Effects of current strength and of length of basic drive on atrial excitability. Eur Heart J 1983:4:51.
445 8 Luck J, Engel TR. Dispersion of atrial refractoriness in patients with sinus node dysfunction. Circulation 1979;60:404-412. 9 Michelucci A. Padeletti L. Fradella GA, et al. Influence of current strength and length of basic drive on atria) refractoriness in man. In: Steinbach K. Glogar D. Lasckovics A. Scheibelhofer W. Weber H, eds. Proceedings of the VII World Symposium on Cardiac Pacing. Darmstadt: Steinkopff Verlag. 1983;671--676. 10 Greenspan AM, Camardo JS. Horowitz LN, Spielman SR. Josephson ME. Human ventricular refractoriness: effects of increasing current. Am J Cardiol 1981:47:244-250. 11 Simpson RJ Jr. Foster JR. Gettes LS. Atria) excitability and conduction in patients with interatrial conduction defects. Am J Cardiol 1982;50:1331-1337. 12 Whalen WJ. Apparent exception to the “all or none” law in cardial muscle. Science 1958:127:468-469. 13 Furchgott RF, De Gubareff T, Grossman A. Release of autonomic mediators in cardiac tissue by suprathreshold stimulation. Science 1959;129:328-329. 14 Jose AD. Collison D. The normal range and determinants of the intrinsic heart rate in man, Cardiovasc Res 1970;4:160-167. 15 Govier WC, Mosal NC, Whittington P, Broom AH. Myocardial alpha and beta adrenergic receptors as demonstrated by atria1 functional refractory period changes. J Pharmacol Exp Ther 1966:154:255-263. 16 Lucchesi BR, Whitsett S, Stickney JL. Antiarrhythmic effects of beta-adrenergic blocking agents. Ann NY Acad Sci 1967;139:940-951. 17 Fitzgerald JD. Perspectives in adrenergic beta-receptor blockade. Clin Pharmacol Ther 1969:10:292-306. 18 Carbonell LM. Esterases of the conductive system of the heart. J Histochem Cytochem 1956:4:87-95. 19 James TN. Spence CA. Distribution of cholinesterase within the sinus node and A-V node of the human heart. Anat Ret 1966;155:151-161. 20 James TN. Anatomy of the human sinus node. Anat Ret 1961:141:109-139. 21 Demoulin JC. Kulbertus HE. Histopathological correlates of sino-atria1 disease. Br Heart J 1978;40:1384-1389. 22 Shaw DB. The etiology of sinoatrial disorder (sick sinus syndrome). Am Heart J 1976;92:539-548. 23 Azuma T. Hayashi H, Kanno T. Matsuda K. Effects of intensity of driving stimulus on the shape of membrane action potential of the heart. Nature (London) 1961;192:1295-1296.
431
IJC 00276
Effects of pharmacologic autonomic blockade on atria1 electrophysiologic properties in normal subjects and in patients with sinus node disease A. Michelucci, L. Padeletti, G.A. Fradella, D. Monizzi, A. Giomi and
F. Fantini Cardiology Unit, Uniuersi[v of Florence, Ita[v (Received
1 November
1984; revision accepted
8 January
1985)
Michelucci A, Padeletti L, Fradella GA, Monizzi D, Giomi A, Fantini F. Effects of pharmacologic autonomic blockade on atria1 electrophysiologic properties in normal subjects and in patients with sinus node disease. Int J Cardiol 1985;8:437-445. In order to elucidate the influence of autonomic nervous system on atrial electrophysiologic properties, we studied 10 patients with sinus node dysfunction and 10 age-matched normal subjects. In each of them effective and functional refractory periods of the right atrium (near its junction with the superior caval vein) were measured, during atria1 pacing (lOO/min) and using variable current strengths (2,3,4, 5, 7, 10, and 15 mA), before and after pharmacologic autonomic blockade (using intravenous propranolo10.2 mg/kg and atropine 0.04 mg/kg). Mean values of effective and functional refractory periods at each current strength were significantly higher in patients with sinus node disease than in normal subjects both before and after autonomic blockade. Blockade did not significantly modify mean values of effective and functional refractory periods at any current strength, either in patients with sinus node disease or in normal subjects. Furthermore, autonomic blockade did not change the effects of the increase of current strength on atrial refractoriness in either group. We conclude that our data indicate a prolonged refractoriness to be present in patients with sinus node disease even in the absence of influences from the autonomic nervous system. Thus, we can suggest a “primary” involvement of atrial fibers in this pathophysiological condition. Propranolol together with atropine did not induce changes of atrial refractoriness. Indeed, they probably exerted an opposite effect. The
Correspondence
to: Dr. Antonio
0167-5273/85/$03.30
Michelucci,
Via Bronzino,
0 1985 Elsevier Science Publishers
163. 50142 Firenze.
B.V. (Biomedical
Italy.
Division)
438
effects of the increase of current strength on atria1 excitability
do not seem to be
mediated by autonomic humoral agents. (Key words:
atrium;
atropine;
current
strength;
propranolol;
refractoriness)
Ictroduction Cardiac electrophysiological status is dependent upon a complex and delicately balanced interaction between “intrinsic” cardiac electrophysiological properties and factors outside the heart. Among the “extrinsic” factors capable of exerting modifying influences upon the myocardium, the role of the autonomic nervous system is most important. For this reason the diagnostic use of pharmacologic autonomic blockade (by intravenous propranolol together with atropine) has been recommended in clinical electrophysiology [1,2]. This method made possible a better definition of normal [l] and abnormal [2] “intrinsic” sinus node function. Little information is available, however, on the “intrinsic” behaviour of atria1 refractoriness in man. With this in mind, we performed an evaluation of this topic knowing that autonomic mediators are able to influence recovery of atria1 excitability [3-61, and that abnormalities in atria1 refractoriness have been shown in patients with sinus node dysfunction and/or atria1 tachyarrhythmias [7,8] without the role of autonomic mediators being evaluated on this behaviour. Furthermore, previous studies have shown the use of stimuli of different current strengths to have a more precise role in determining myocardial refractoriness [9-111, in this way producing a liberation of autonomic mediators [12,13]. On the basis of these previous investigations, our analysis was performed in normal subjects and in patients with sinus node disease by determining atria1 refractoriness measured, using stimuli of different current strengths before and after autonomic blockade.
Material and Methods We studied two groups of patients. The first group consisted of 10 subjects (6 males and 4 females), mean age 65 years (range 57-75 years) who underwent an electrophysiological study for unexplained dizziness. History, physical examination, chest X-ray, electrocardiography, echocardiography, ambulatory monitoring or maximal exercise treadmill test all proved to be normal in this group. The second group of subjects consisted of 10 patients (5 males and 5 females), mean age 69 years (range 53-77 years) with a clinical diagnosis of sinus node dysfunction. The diagnosis was suggested by the presence of sinus bradycardia and/or sinus arrest concomitant with symptoms of dizziness or vertigo (or both). The electrocardiographic abnormalities had been documented in the electrocardiogram or in 24-hr Holter ambulatory electrocardiographic tape recordings. Only one patient had a history of palpitations without instrumental documentation of tachyarrhythmias. Although five patients had a history of ischemic heart disease and two had hypertensive heart disease, none demonstrated congestive heart failure or cardiome-
439
galy. All patients were in New York Heart Association Class I. Excluded from these studies were patients with pulmonary disease, glaucoma or urinary retention. There was no significant age difference between the two groups. All studies were done in a postabsorptive, nonsedated state with the patient in the supine, resting position. The nature of the studies was explained to all subjects and a signed consent was obtained from all. All cardioactive drugs were withdrawn for at least 5 half-lives. All subjects were in sinus rhythm at the start of the study. Two catheters (number 6F USC1 quadripolar and number 6F USC1 tripolar) were inserted percutaneously via a right antecubital vein and the right femoral vein, respectively. The quadripolar catheter was positioned at the high right atrium near its junction with the superior caval vein. The distal pair of electrodes were used to stimulate the atrium and the proximal pair to record a high right atria1 electrogram. The tripolar catheter was positioned across the tricuspid valve and was used to record a His bundle electrogram. Effective and functional refractory periods were measured during atria1 pacing (lOO/min) using variable current strengths (2, 3, 4, 5, 7, 10, and 15 mA) and introducing an extrastimulus (at 5-10 msec decrements) after the eighth paced complex of the basic drive. The pulse width of both driven beats and premature extrastimuli was held constant (2 msec), while the current strength of stimuli of the basic paced rhythm and of premature extrastimuli increased in parallel. Intracardiac electrograms were recorded at filter frequency settings of 40 and 500 Hz. One or more surface electrocardiographic leads (I, II, III and V,) were also recorded. All traces were simultaneously displayed on a Hewlett-Packard eight-channel oscilloscope and were recorded on a Elema-Schonander Mingograph 62-6 channel ink-jet at a paper speed of 100 mm/set. Premature programmed atria1 stimulation was performed using an electrically isolated battery-powered Medtronics 5325 stimulator. The functional refractory period was the shortest coupling interval recorded on the high right atria1 electrogram. The effective refractory period was the longest interval between the stimulus artefact (atria1 pacing) and the extrastimulus which failed to propagate. Evaluation of refractoriness according to the above described protocol was repeated in each subject after autonomic blockade (using intravenous propranolol 0.2 mg/kg body weight, administered over a period of 3 min. followed 10 min later by atropine sulphate 0.04 mg/kg, administered over 1 mm). Measurements began after 5 min and were completed within 20 min of administration of atropine. In each subject we evaluated also the resting heart rate (from 10 consecutive sinus cycles, 10 min after the introduction of the catheters) and the intrinsic heart rate (from the shortest 10 consecutive sinus cycles after atropine). The normality of the latter value was established (according to Jose and Collison [14]) by calculating for each subject the predicted intrinsic heart rate and its 95% confidence limits. As all subjects of our study were older than 45 years, the 95% confidence limits (again according to Jose and Collison [14]) of predicted intrinsic heart rate were & 18%. Sinus node recovery time was then calculated before and after autonomic blockade by atria1 pacing at cycle lengths of 600, 500. 430, 370, and 330 msec. This was done for 2 min at each cycle length.
440
Corrected sinus node recovery time was calculated before and after autonomic blockade by deducting the mean of 10 consecutive spontaneous sinus node cycles immediately preceding each pacing run for sinus node recovery time. Its value was considered normal, according to our laboratory, if lower than 450 msec. The paired t-test was used to analyze changes in heart rate, sinus node recovery time, corrected sinus node recovery time and atria1 refractoriness (at each current strength) after autonomic blockade. The unpaired t-test was used to compare patients with sinus node disease and normal subjects before and after autonomic blockade. Values are expressed in msec and as mean f 1 SD. Significance was defined at the 90% level.
Results Normal Subjects Mean values of heart rate and of intrinsic heart rate were 69 _t 9 beats/mm and 83 _t 6 beats/mm, respectively. All values of intrinsic heart rate were within the normal range of predicted heart rate. Mean values of sinus node recovery time before and after autonomic blockade were 1167 f 117 and 1021 _t 131, respectively. Mean values of corrected sinus node recovery time before and after autonomic blockade were 288 + 63 and 294 + 82, respectively. All single values of corrected sinus node recovery time proved to be normal both before and after autonomic blockade. We did not observe any difference in the effects of current strength on atria1 refractoriness when comparing its behaviour before and after autonomic blockade. In each subject both before and after autonomic blockade the effective and functional refractoriness decreased with increasing current; the relation between atria1 refractoriness and current strength was nonlinear and large changes were observed at low current strengths both in effective and functional refractoriness. In contrast. at higher current strengths (a 7 mA) the changes in atria1 refractory periods were small and the strength-refractoriness curve became steep. The range of single values and the mean values of effective refractory period at each current strength before and after autonomic blockade are shown in Table 1. These same values in respect to functional refractory period are given in Table 2. There was no statistical difference at any current strength between the mean values of effective and of functional refractoriness before and after autonomic blockade. Patients with Sinus Node Disease Mean values of heart rate and of intrinsic heart rate were 60 + 10 beats/min and 64 + 10 beats/min, respectively. Single values of intrinsic heart rate were below the normal limit of the (predicted) normal range in 8 patients and within the (predicted) normal range in 2 patients. Mean values of heart rate and of intrinsic heart rate of sinus node disease patients were significantly lower than those of normal subjects ( P < 0.04 and P < 0.0005. respectively). Mean values of sinus node recovery time
1
ERP (msec) ufter AB N Range Mean SND Range Mean N vs. SND PC
ERP (msec) hefDre AB N Range Mean SND Range Mean N vs. SND PC
240-300 269 + 22 270-380 317k38 0.003
240-310 272 + 26
270-380 327 + 33
0.001
0.04
0.007
250-350 304 * 39 0.004
0.02
0.002
250-330 291 f 31
210-280 245 + 25
0.05
0.02
230-280 254 f 23
220-330 275 f 44
210-280 244+24
7
220-330 295k44
220-280 251 f 32
5
260-380 305 + 45
240-300 264 + 30
0.02
230-390 306 + 49
250-450 320 f 69
280-450 346 + 54
4
230-300 265 f 28
3
(mA)
220-310 271+ 33
strength
230-320 282? 34
2
Current
Range of single values. mean values of effective refractory period (ERP) at each current strength before and after autonomic (N) and of patients with sinus node disease (SND). Statistical significance between N and SND is shown.
TABLE
0.02
240-320 270 k 33 240-320 275 + 33 0.01
210-280 236 of-27
0.01 0.02
210-280 240 + 23
220-320 267 * 37
210-260 227 + 25
15
(AB) of normal
220- 340 276 & 44
210-270 239 f 22
10
blockade
subjects
2
FRP (msec) after A B N Range Mean SND Range Mean N vs. SND PC
FR P (msec) before A B N Range Mean SND Range Mean N vs. SND PC
260-310 289 f 20 280-410 347 * 48 0.003
290-430 358k50
0.001
0.04
0.01
260-320 29Of24
270-500 346 + 79
290-500 366 + 67
3
(mA)
250-320 295 _+25
strength
260-330 301_+ 29
2
Current
280-400 328 k43 0.004
0.009
240-310 275 + 24
0.04
250-500 331 k 80
0.003
270-360 311 f 31
240-290 270 + 21
250-510 322 f 85
230-300 266 _+25
7
0.002
250-360 307 * 33
230-290 260 f 23
0.03
240-500 320 f 87
230-280 259 _+20
10
strength, before and after autonomic N and SND is shown.
240-300 276 _+23
5
270-420 337+51
250-310 284 + 24
0.02
260-510 327 k 54
240-320 282 f 27
4
Range of single values, mean values of functional refractory period (FRP) at each current subjects (N) and of patients with sinus node disease (SND). Statistical significance between
TABLE blockade
250-360 300 * 36
230-290 255 k 25
0.01
240-360 295 + 45
230-270 252_+20
15
(AB), of normal
443
before and after autonomic blockade were 1964 & 354 and 2150 t- 554, respectively. They were significantly higher than those of normal subjects both before (P -e 0.003) and after (P < 0.006) autonomic blockade. Mean values of corrected sinus node recovery time before and after the two drugs were 940 * 326 and 1187 + 522, respectively. All single values of corrected sinus node recovery time were abnormally prolonged both before and after autonomic blockade. Moreover, mean values of corrected sinus node recovery time were significantly higher than those of normal subjects both before (P < 0.007) and after (P < 0.01) autonomic blockade. As with the normal subjects, we did not observe any obvious difference in the effects of current strength on atria1 refractoriness in patients with sinus node disease when comparing their behavior before and after autonomic blockade. In this regard, the observations noted for normal subjects were valid in the patients with sinus node disease (Tables 1 and 2). There was no statistical difference at any current strength between the mean values of effective and of functional refractoriness before and after autonomic blockade. The comparison between the patients with sinus node disease and the normal subjects showed that mean values of effective and functional refractoriness at each current strength were significantly higher in the former both before and after autonomic blockade. Statistical significances between the groups are shown in Tables 1 and 2.
Discussion It has been suggested that the determination of the refractory period at multiple current strengths (rather than at one current strength) provides a more accurate measure of excitability [9,10,11]. Thus, in order to evaluate atria1 excitability, we measured refractoriness at different current strengths. Moreover, in order to evaluate the influence of autonomic nervous system on atria1 electrophysiologic properties, the measurements were made before and after the administration of propranolol plus atropine. The use of these two drugs and their doses have been assessed in previous studies [1,2,14]. We cannot deny, however, that some methodological problems could exist concerning the validity of this approach. Nonetheless, there is indirect evidence that alpha-adrenergic receptors are present in the myocardium even if their role in clinical electrophysiology remains to be evaluated [15]. Moreover, a direct effect of propranolol on myocardial excitability could be supposed, even if the used dose (0.2 mg/kg) is considered much smaller than that required to induce an effect on membrane stability [16,17]. In our study the combined effect of the two drugs was unable to modify atria1 refractoriness either in normal subjects or in patients with sinus node disease. We can try to explain our data in the light of some previous results. Atropine is able to reduce [3,4] and propranolol to increase [5] atria1 refractoriness. Thus, atropine and propranolol can exert opposite effects, and the result might be no significant changes. It should be noted, however, that we performed measurements of refractoriness at the junction of the right atrium with the superior caval vein (i.e.
444
near the sinus node). This area has a high concentration of cholinesterase [18,19], together with autonomic nerves and ganglia [20]. It is possible that vagal influence and beta-receptor activity are both particularly active at this site, so conditioning our results. Mean control values of effective and functional refractoriness as measured at each current strength were significantly higher in our study in patients with sinus node disease than in normal subjects. The existence of an abnormally prolonged atria1 refractoriness in the presence of sinus node disease has been noted in previous studies [7,8]. To evaluate if this behaviour could be conditioned by vagal influence and sympathetic activity, we compared mean values of refractoriness in each group after the administration of propranolol and atropine. This showed that the mean values of effective and functional atria1 refractoriness remained higher in the presence of sinus node disease than in the normal subjects. On this basis, we can suggest the existence of an abnormal “intrinsic” atria1 excitability in patients with sinus node disease. This concept should not be surprising, when it is considered that sinus node disease in its broadest sense encompasses atria1 disease [21,22]. Previous studies in animals suggest that the increase in stimulus strength results in liberation of autonomic mediators [12,13,23] which then condition the electrophysiologic properties of atria1 fibers [23]. Our results do not support this conclusion. We found that the combined effect of atropine and propranolol was unable to modify the effects of the increase in strength of stimulus. Because of this, we should reconsider the link between current strength and autonomic mediators. Probably there is a more complex interaction between current strength and local properties of atria1 myocardium, even if it cannot be assessed easily in clinical electrophysiology. In conclusion, we have demonstrated prolonged atria1 refractoriness in patients with sinus node disease even if vagal influence and beta-receptor activity are excluded. Thus, we can propose the existence of a “primary” involvement of atria1 fibers in this pathophysiological condition.
References 1 Alboni P. Malacarne C, Pedroni P. Masoni A, Narula OS. Electrophysiology of normal sinus node with and without autonomic blockade. Circulation 1982;65:1236-1242. 2 Kang P, Gomes JAC. El-Sherif N. Differential effects of functional autonomic blockade on the variables of sinus nodal automaticity in sick sinus syndrome. Am J Cardiol 1982;49:273-282. 3 Dhingra RC, Amat-y-Leon F, Wyndham C, et al. Electrophysiologic effects of atropine on human sinus node and atrium. Am J Cardiol 1976;38:429-434. 4 Michelucci A, Padeletti L. Fradella GA, et al. Effects of atropine on atria1 refractoriness and its dispersion in humans. Int J Clin Pharmacol Ther Toxic 1984;22:254-258. 5 Damato AN, Caracta AR, Akhtar M, Lau SH. The effects of commonly used cardiovascular drugs on AV conduction and refractoriness. In: Narula OS, ed. His bundle electrocardiography and clinical electrophysiology. Philadelphia: FA Davis Company, 1975;105-125. 6 De Elio FJ. The action of acetylcholine. adrenaline and other substances on the refractory period of the rabbit auricle. Br J Pharmacol 1947;2:131-142. 7 Monivi D. Michelucci A, Padeletti L. Fradella GA, Fantini F. Effects of current strength and of length of basic drive on atrial excitability. Eur Heart J 1983:4:51.
445 8 Luck J, Engel TR. Dispersion of atrial refractoriness in patients with sinus node dysfunction. Circulation 1979;60:404-412. 9 Michelucci A. Padeletti L. Fradella GA, et al. Influence of current strength and length of basic drive on atria) refractoriness in man. In: Steinbach K. Glogar D. Lasckovics A. Scheibelhofer W. Weber H, eds. Proceedings of the VII World Symposium on Cardiac Pacing. Darmstadt: Steinkopff Verlag. 1983;671--676. 10 Greenspan AM, Camardo JS. Horowitz LN, Spielman SR. Josephson ME. Human ventricular refractoriness: effects of increasing current. Am J Cardiol 1981:47:244-250. 11 Simpson RJ Jr. Foster JR. Gettes LS. Atria) excitability and conduction in patients with interatrial conduction defects. Am J Cardiol 1982;50:1331-1337. 12 Whalen WJ. Apparent exception to the “all or none” law in cardial muscle. Science 1958:127:468-469. 13 Furchgott RF, De Gubareff T, Grossman A. Release of autonomic mediators in cardiac tissue by suprathreshold stimulation. Science 1959;129:328-329. 14 Jose AD. Collison D. The normal range and determinants of the intrinsic heart rate in man, Cardiovasc Res 1970;4:160-167. 15 Govier WC, Mosal NC, Whittington P, Broom AH. Myocardial alpha and beta adrenergic receptors as demonstrated by atria1 functional refractory period changes. J Pharmacol Exp Ther 1966:154:255-263. 16 Lucchesi BR, Whitsett S, Stickney JL. Antiarrhythmic effects of beta-adrenergic blocking agents. Ann NY Acad Sci 1967;139:940-951. 17 Fitzgerald JD. Perspectives in adrenergic beta-receptor blockade. Clin Pharmacol Ther 1969:10:292-306. 18 Carbonell LM. Esterases of the conductive system of the heart. J Histochem Cytochem 1956:4:87-95. 19 James TN. Spence CA. Distribution of cholinesterase within the sinus node and A-V node of the human heart. Anat Ret 1966;155:151-161. 20 James TN. Anatomy of the human sinus node. Anat Ret 1961:141:109-139. 21 Demoulin JC. Kulbertus HE. Histopathological correlates of sino-atria1 disease. Br Heart J 1978;40:1384-1389. 22 Shaw DB. The etiology of sinoatrial disorder (sick sinus syndrome). Am Heart J 1976;92:539-548. 23 Azuma T. Hayashi H, Kanno T. Matsuda K. Effects of intensity of driving stimulus on the shape of membrane action potential of the heart. Nature (London) 1961;192:1295-1296.