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Clinical effects of oral theophylline in sick sinus syndrome
Clinical effects syndrome
of oral theophylline
in sick sinus
in 17 patients with symptomatic sinus bradycardia (age: 66 + 11 years), a resting electrocardiogram, a 24-hour Halter recording, and a treadmill test were performed both before and after administration of slow-release theophyiiine (700 mg daily). The drug increased resting heart rate (46 & 7 versus 62 + 16 beats/min, p < O.Ol), mean 24-hour rate (51 & 6 versus 64 + 16 beats/min, p < O.Ol), and minimal 24-hour heart rate (36 k 6 versus 43 k 10 beats/min, p < 0.05). Cardiac pauses >2.5 seconds were present in four patients during control recording, and disappeared after theophyiiine. The daily number of premature supraventricular and ventricular beats increased slightly after the drug. Exercise heart rate was higher after theophylline than during the control test (p < 0.01). Thirteen patients were followed for a period of 17 & 3 months. Suppression of symptoms was achieved in 12 patients. Asthenia and easy fatigue were reduced markedly by the drug. During long-term therapy, the sinus rate was similar to that observed at the steady-state evaluation. in 3 of the 17 patients theophyiline had to be discontinued because of gastric intolerance (in two at the end of the steady-state evaiuatlon and In one during long-term therapy). These data suggest that oral theophylline can represent an effective therapy in some patients with symptomatic sinus bradycardia. (AM HEART J lgg1;122:1361.)
Paolo Alboni, MD, Benedetto Ratto, MD, Riccardo Cappato, MD, Paolo Rossi, MD, Emilio Gatto, MD, and Gian Enrico Antonioli, MD. Cento., Ferrara, and Genoa, Italy
The current therapy for symptomatic sick sinus syndrome (SSS), if there are no removable causes, is based on permanent stimulation. However, though all the aspects of the clinical course of SSS have not been well investigated, some data suggest that implantation of a permanent pacemaker does not represent an ideal therapy: (1) SSSis a relatively benign condition since the overall survival rate of patients with an established sinoatrial disorder is similar to that of the normal population.1-4 (2) The course of symptoms in SSS is very variable from patient to patient. Syncope may not reappear for several years in about 30 % to 407%of the cases;moreover, not uncommonly, syncope represents an isolated manifestation.‘? 2l5For these reasons it is hard to evaluate the actual benefits of either permanent stimulation or pharmacologic therapy. (3) VVI stimulation does not appreciably reduce mortality, even in patients with From the Division of Cardiology, Ospedale Civile, Cento; Division of Cardiology, Arcispedale S. Anna, Ferrara; and Division of Cardiology, Ospedale S. Martino, Geneva. Received for publication Nov. 2, 1990; accepted May 17, 1991. Reprint requests: Dr. Paolo Alboni, Division of Cardiology, Ospedale Civile, 44042 Cento (Fe), Italy. 4/l/32179
symptoms, and AA1 (or DDD) stimulation seems to improve the survival rate in comparison with VVI stimulation only in patients with congestive heart failure.6-8 Controlled studies to compare the survival rate in unpaced patients and in patients with AA1 (or DDD) stimulation have not been carried out up to now. Because of the relatively benign prognosis of SSS and, above all, of the marked variability of the course of symptoms, a pharmacologic therapy appears particularly useful. The drugs used in the past+adrenergic and vagolytic agents-gave disappointing results, both in terms of efficacy and in the high incidence of side effects during long-term treatment. It has been reported that theophylline at therapeutic concentrations induces a modest increase in heart rate in subjects with a normal sinus rate.g*lo During long-term therapy, the drug suppressed symptoms in young patients with paroxysmal bradyarrhythmiasll Moreover, theophylline diminished the frequency and severity of bradycardia in newborn infants with apnea-bradycardia spells.12,l3 Recently, Ellenbogen et a1.14reported two patients with marked sinus bradycardia after orthotopic heart transplantation; oral theophylline increased donor heart rate by about 50%) avoiding pacemaker implantation. Up to now 1361
Alboni et al.
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Table
American
November 1991 Heart Journal
I. Steady-state: Effect of oral theophylline (700 mg daily) on examined parameters Control
RestingHR Mean24-hrHR Minimal 24-hrHR Maximal 24-hrHR No. of pauses>2.5 set (in four pts) LongestR-R interval ExerciseHR
62 i 18beatslmin 63.9+ 16beats/min 42.81?1 10beats/min 114 + 87 beats/min
47.3 rt 59 1962 I 394 msec
1590 I 258 msec
887 rt 1764 168 + 542
No. of VPBs rate; SPB, supraventricular
46 + 7 beats/min 51.2I 6 beatslmin 36 I 6 beats/min 89.6-t 20beats/min
77.4t 17beats/min 85.8+ 14beats/min
1st stage 2nd stage No. of SPBs
HR, Heart
Theophylline
premature
beats; VPB, ventricular
premature
the drug has not been investigated in detail in patients with SSS. We have undertaken a study to assess the effects of oral theophylline in patients with sinus bradycardia not related to drugs. METHODS Patients.
We selected17 patients with symptomatic sinus bradycardia not induced by drugs. We included subjects with: (1) mean resting sinusrate <55 beats/min constantly present for somedays in several resting standard electrocardiograms(ECG) recorded during diurnal hours; (2) symptoms attributable to sinus node dysfunction; (3) absence of paroxysmal atria1 fibrillation or flutter or sustainedatrial tachycardia (bradycardia-tachycardia syndrome). Criteria for exclusion included the following: recent myocardial infarction, acute diseaseof any type, significant renal or hepatic disease,congestive heart failure. The age ranged from 50 to 80 years (mean 66 & 11). Fourteen were menand three were women.Twelve patients had organic heart disease:five had ischemicheart disease, five had hypertensive cardiovascular disease,and two had mitral valve disease;the remaining five patients had no signsof structural heart disease.All patients were in New York Heart Association (NYHA) functional classI to II. Fifteen patients complained of syncopeor dizzinessbefore the hospitalization; four complained of marked asthenia and easy fatigue. No patient engaged in an exercise program. All subjectswere nonsmokersat the time of entry into the study. Electrolytes were within the normal range. No patient wastaking cardioactive medicationsor drugs known to interfere significantly with the autonomic system or adenosinemetabolism(dipyridamole or diazepam). Diuretics, converting enzyme inhibitors, and nitrates could be administered if the patient neededthem; in this case,the control evaluation wasdoneduring administration of these drugs, which were then maintained during the follow-up period, possibly at the samedosage. Procedures. Each subject gave informed consent. The steady-state evaluation wasperformed during hospitalization. Chest-x-ray examination, echocardiogram,and stan-
94.5t 28 beats/min 105.2t 23beats/min 1135rfr 2330 184& 271
p
beats.
dard laboratory tests for hematologic, thyroid, renal, and hepatic function were performed. Resting heart rate was measuredfrom a lo-second standard ECG strip after a 15 minute rest period. Electrophysiologic studies were performed in 16 patients using transesophagealpacing, as previously described,l5 both in the basal state and after autonomic blockade. The latter was achieved by intravenous administration of propranolol, 0.2 mg/kg, and atropine, 0.04 mg/kg. The predicted intrinsic heart rate was estimated for each patient using the linear regression equation derived by Jose et a1.,i6relating intrinsic heart rate to age. The following day, patients underwent a 24-hour Holter monitoring for two consecutive days using a two-channel recorder. The data were analyzed to obtain: mean 24-hour heart rate, minimal 24-hour heart rate, maximal 24-hour heart rate, mean heart rate every hour, number of cardiac pauses>2.5 seconds,longestR-R interval, number of premature supraventricular and ventricular beatsand of episodesof ventricular tachycardia (more than three consecutive wide QRS complexes). The following day, an exercisetest wasperformed using the treadmill according to the modified Bruce protocol. The heart rate was measured from a lo-second electrocardiographic (ECG) strip at the end of the first and secondstage. Oral theophylline therapy wasthen initiated at the dosageof 700mg daily in two divided dosesusinga slow-release tablet. Five days later, an electrophysiologic study, Holter recording, and exercise test were repeated with the same methods; in particular, treadmill tests were always performed at the sametime of the day for each patient. Both before and after theophylline treatment, the parameters were reported as the mean of the two consecutive 24-hour Holter recordings to reduce spontaneousvariability and therefore to better evaluate the effects of the drug. Serum theophylline level wasdetermined on the sameday asthe second24-hour Holter recording, 3 hours after the intake of the morning dose.The patients were then enrolled in a long-term phaseand were seenat the outpatient clinic 1 to 2 months later and every 3 to 4 months thereafter. A clinical history, physical examination, resting ECG, 24-hour Holter recording, and serumtheophylline level were done during eachvisit. Dosagemodifications were madeas nec-
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Oral theophylline on sick sinus syndrome
SINUS MEAN
BRADYCARDIA
SINUS
BRADYCARDIA
MINIMAL
RESTING
1363
24-h
MEAN 24-h
HEART RATE
‘*Or
HEART
RATE
80.-
P zco G & 40 30 1
70.z_ % 2 60.t 2 50.-
40*-
20 t
30.-
h
PC.01
$
1. Effects of oral theophylline on meanresting heart rate (evaluated in the standard electrocardiogram) are shown graphically. The meansrl: standard deviation are representedby the vertical bars on either side. C, Control evaluation; T, after theophylline therapy. Fig.
essaryto eliminate symptoms and cardiac pausesand to limit drug-related sideeffects. Statistical evaluations were doneusingthe Wilcoxon test (p value significant at ~0.05). Results are given as mean f standard deviation. RESULTS Steady-state.
The effects of theophylline are reported in Table I and in Figs. 1 to 5. Mean resting heart rate, evaluated in the standard ECG, increased in 16 patients during treatment with theophylline (A%: +36%, p < O.Ol), (Fig. 1). Mean 24-hour heart rate increased in 16 subjects during theophylline therapy (A%: +25%, p < O.Ol), (Fig. 2). The percentage increases in daytime heart rate and sleeping heart rate (between 10 PM and 6 AM) were very similar: +25.6% and +22.8%, respectively 03 = NS) (Fig. 3). Minimal 24-hour heart rate increased during theophylline therapy in 14 patients (A% : +19%, p <0.05), (Fig. 2), and maximal 24-hour heart rate increased in 15 (A%: +27%, p < 0.01). In four
L
f pc .05
I
A
T
PC.01
2. Effects of oral theophylline on minimal and mean 24-hour heart rate are reported graphically. Abbreviations as in Fig. 1. Fig.
patients cardiac pauses >2.5 seconds were present in the control recording; the daily number of these pauses was 36 f 53; they disappeared in all patients during theophylline treatment. The longest R-R interval decreased in 16 patients (A % : -23 % , p < 0.01) (Fig. 4). The daily number of premature supraventricular and ventricular beats increased after theophylline treatment, but the differences were not statistically significant (887 r 1764 versus 1135 + 2230 daily and 168 f 542 versus 184 + 271 daily, respectively). In one patient, who did not complain of palpitations, an “asymptomatic” nonsustained ventricular tachycardia was observed during theophylline therapy and therefore it could not be surely related to the drug. A treadmill test was performed in 15 patients; in the remaining two it was not done due to age difficulties. At the end of the first stage, the heart rate was higher in 13 patients after theophylline than during the control test (A% : +22%, p < 0.01). In one patient the exercise test was interrupted during the second stage for muscular exhaustion. In the 13 pa-
1364
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et al.
American
SINUS
80
November 1991 Heart Journai
HRADYCARDIA
t
8
10
12
14
16
18
TIME Fig.
20
22
24
2
4
6
(24 hr clock)
3. Mean hourly heart rate (in beats/min) during the control evaluation and after theophylline ther-
apy. tients in whom a comparison could be made at the end of the second stage, heart rate was higher after theophylline than during the control test (A % : +22 % , p < O.Ol), (Fig. 5). The electrophysiologic effects of oral theophylline have already been partly reported by usi and are not pertinent to the present clinical work. However, the intrinsic heart rate was normal in 3 patients and abnormal in 13. Because of the low prevalence of autonomic sinus node dysfunction in our patients, it is not possible to evaluate possible different effects of the drug on bradycardia related to intrinsic sinus node dysfunction or to autonomic dysfunction. Theophylline did not significantly change systolic and diastolic blood pressure either at rest or during exercise. Serum theophylline level ranged from 3.7 to 20 PgI ml (mean: 11.4 -t 4). There was no apparent correlation between serum theophylline level and the percentage change in mean 24-hour heart rate (r = O.lO), minimal 24-hour rate (r = 0.20), maximal 24-hour rate (r = 0.12), premature supraventricular beats (r = O.lO),andprematureventricularbeats (F = 0.02). Two patients reported nausea during theophylline therapy. Follow-up. Long-term theophylline therapy was initiated in 13 patients and not in the two who reported nausea during steady-state evaluation or in another two who preferred pacemaker implantation. The mean age was 67 z!z 10 years. Eight patients had organic heart disease. Four patients complained of syncope and dizziness, six of dizziness, and four of marked asthenia and easy fatigue. One patient died after 7 months of treatment for a pancreatic neoplasm. In the remaining 12 patients the follow-up period ranged from 12 to 23 months
(mean 17 + 3). Long-term therapy was initiated at a dosage of 500 to 700 mg daily (Theolair SR, Lirca Synthelabo, Limito, Italy or Theo-24, Schiapparelli Searle, Torino, Italy). In these 12 patients the mean resting heart rate was 45 ? 7 beats/min during the control evaluation, 59 rt 13 beats/min at the steadystate evaluation, and 56 f 7 beats/min during the last visit at the outpatient clinic. The mean 24-hour heart rate was 50 * 7 beats/min, 61 +- 11 beats/min, and 58 t- 6 beats/min, respectively. The minimal 24hour heart was 36 it 4 beats/min, 42 +- 6 beats/min, and 40 * 4 beats/min, respectively. The daily number of premature supraventricular beats was 891 + 1912 during the control evaluation, 1550 +- 2687 at the steady-state evaluation, and 834 + 1160 during the last visit. The daily number of ventricular premature beats was 243 f 616, 208 +_ 300, and 307 f 640, respectively. In no patient were there episodes of ventricular tachycardia. In four patients cardiac pauses >2.5 seconds were present at the control evaluation (mean: 36 -+ 53 daily); during longterm therapy they were observed in one patient only during one visit. At one visit in two patients the follow-up heart rate decreased to control values. In both patients the serum theophylline level was <4 pg/ml, and it is possible that they were noncompliant with their medication schedule for a period of time. In no patient did dizziness or syncope occur during Holter recording, either at the steady-state evaluation or during the follow-up period. The mean dosage of theophylline at the last visit was 438 2 132 mg daily (range: 300 to 700 mg), and the mean serum theophylline level was 8.6 + 3 pg/ml (range: 4.2 to 14.2). During long-term therapy, one patient complained of dizziness during one visit but
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Oral theophylline on sick sinus syndrome
SINUS LONGEST
BRADYCARDIA R-R
SINUS
INTERVAL
MEAN
1365
BRADYCARDIA
EXERCISE
1” STAGE
HEART
RATE
2”dSTAGE
160
/
t 140.-
2 120.> &n3-
8O.m
60.-
I/
Fig. 5. Effects of oral theophylline on the exerciseheart
rate evaluated at the end of the first and second stage (treadmill test). Abbreviations as in Fig. 1. p-co1 Fig. 4. Effects of oral theophylline on the duration of the longest R-R interval. Abbreviations as in Fig. 1.
not in subsequent follow-up visits; the remaining patients did not complain of syncope or dizzinessduring long-term treatment. Theophylline markedly reduced asthenia and easy fatigue in all four patients. Two patients reported nausea; in one it disappeared after a reduction of the dosage, whereas in the other theophylline treatment had to be discontinued at 15 months. DISCUSSION
Theophylline exerts positive chronotropic action.gplo An improvement in sinus nodal function has been reported after both intravenous and oral administration of the drug. lly 15yl7 Moreover, a reduction in symptoms during long-term treatment has been reported by Benditt et al.” in 10 young subjects with paroxysmal sinus bradyarrhythmias or atrioventricular (AV) block without structural heart disease.Recently, we18observed a marked positive dromotropic effect of oral theophylline in patients with atrial fibrillation and a slow ventricular response.
However, up to now, no systematic study has been carried out on the clinical effects of this drug in patients with SSS. There are several mechanisms by which theophylline might exert positive chronotropic and dromotropic action; however, several observations suggest that the primary action of theophylline at therapeutic concentrations is blockade of adenosine receptors.lgp2oAdenosine has been shown to slow sinus rate and depress AV nodal conduction in laboratory animals and in clinical patients21122Theophylline completely antagonizes the negative chronotropic and dromotropic action of adenosine by blocking extracellular adenosine receptors.lg In addition to antagonism of adenosine receptors, other mechanisms of theophylline have been postulated, in particular an adrenergic effect. 23 However, several observations suggest that this action of the drug appears at serum concentrations over the therapeutic range.24 In 15 patients with sinus bradycardia, by utilizing amethod previously adopted by us25-27that investigates the different modes of action of an antiarrhythmic drug in man, we15observed that the percentage decrease in sinus cycle length, corrected sinus node recovery time, and sinoatrial conduction time induced by oral theophylline were very similar with and without au-
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tonomic blockade. This seems to confirm that the positive chronotropic action of theophylline is not mediated by autonomic receptors. In the present study we have investigated the effects of oral theophylline in patients with sinus bradycardia only; we have not assessed the effects in patients with bradycardia-tachycardia syndrome, since an arrhythmogenic action of the drug has been described.28p 2g In our patients, as well, theophylline slightly increased premature supraventricular and ventricular beats; this increase was similar at the steady-state evaluation and during long-term therapy. At the steady-state evaluation, slow-release theophylline significantly increased resting heart rate by 36%) mean 24-hour heart rate by 25%) minimal 24hour heart rate by 19%) and exercise heart rate by 22%. Four patients showed cardiac pauses >2.5 seconds, no longer present after drug administration. The longest R-R interval decreased in all patients. The drug therefore exerts a marked positive chronotropic effect during both rest and exercise. Examination of data from individual patients at the steadystate evaluation shows that the increase in sinus node measures was excessive in several subjects (Figs. 1,2, and 5); for this reason we decreased the theophylline dosage in some subjects at the beginning of long-term therapy. During long-term therapy, the sinus rate was similar to that observed at the steady-state evaluation, despite the reduction in the daily dosage (700 mg at the steady-state evaluation and 438 f 132 mg at the last visit). This suggests that the chronotropic action of the drug does not decrease in time, at least for a period of about 2 years. During long-term therapy, only one patient complained of dizziness at one visit; the remaining patients have remained symptom-free. Our results therefore suggest a reduction in bradycardia-related symptoms in patients treated with theophylline; this observation seems to be strengthened by the marked reduction in the frequency of cardiac pauses and in the duration of the longest R-R interval. However, the course of symptoms in SSS is variable from patient to patient, and for this reason the interpretation of the results obtained after either pharmacologic therapy or pacemaker implantation is difficult. To better assess this point, a randomized study of long-term efficacy is required. The marked reduction in asthenia and easy fatigue during longterm treatment is interesting; it can be related both to the increase in sinus rate and to an effect on the central nervous system. 3o In 3 out of the 17 patients (17 % ) theophylline had to be discontinued because of nausea (in two at the end of the steady-state pe-
American
November 1991 Heart Journal
riod and in one during long-term therapy); it has already been widely reported that in 15% to 20% of subjects theophylline must be withdrawn because of gastric intolerance.30 Our data suggest that the initial dosage of the drug should be 500 to 600 mg daily, and it can be then slightly decreased or increased according to the clinical course. Serum theophylline level should be >5 pg/ml; for lower values the effects of the drug on heart rate are inconstant; besides, the serum concentration should not be more than 15 pg/ml to prevent side effects of the drug. 3o The results of the present study show for the first time that oral theophylline can represent an effective therapy in some patients with symptomatic sinus bradycardia. Because of the variable clinical course of SSS with frequent spontaneous remission of the symptoms, a pharmacologic treatment appears useful; when it is not efficacious or causes undesirable side effects, it does not prevent any pacemaker implantation. REFERENCES
1. Baldi N, Castelli M, Alberti E, Morgera T, Camerini F. La sindrome de1 seno malato: storia naturale. In: Consolo F, Arrigo F, Oreto G, eds. La sindrome de1 seno malato. Padova: Piccin Ed, 1979:133. 2. Gann D, Tolentino A, Samet P. Electrophysiologic evaluation of elderly patients with sinus bradycardia. A long term follow-up study. Ann Intern Med 1979;90:24-9. 3. Shaw DB, Holman RR, Gowers JI. Survival in sino-atria1 disorder (sick sinus syndrome). Br Med J 1980;280:139-41. 4. Alt E, Volker R, Wirtzfeld A, Ulm K. Survival and follow-up after pacemaker implantation: comparison of patients with sick sinus syndrome, complete heart block and atria1 fibrillation. PACE 1985;8:849-57. 5. Sasaki Y, Shimotori M, Akahane K, Yonekura H, Hirano K, Endoh R, Koike S, Kawa S, Furuta S, Homma T. Long term follow-up of patients with sick sinus syndrome: a comparison of clinical aspects among unpaced, ventricular inhibited paced and ohvsioloeicallv oaced aroun. PACE 1988:11:1575-83. 6. Alpert “MA, Curtis JJ, Sanfelippo JF, Flake; CC, Walls JT, Mukerji V, Villareal D, Katti SK, Medigan NP, Morgan RJ. Comparative survival following permanent ventricular and dual-chamber pacing for patients with chronic symptomatic sinus node dysfunction with and without heart failure. AM HEART J 1987;113:958-65. 7. Rosenqvist M, Brandt J, Schuller H. Long-term pacing in sinus node disease: effects of stimulation mode on cardiovascular morbidity and mortality. AM HEART J 1988;116:16-22. 8. Santini M, Alexidou G, Ansalone G, Cacciatore G, Cini R, Turitto G. Relation of prognosis in sick sinus syndrome disease to age, conduction defects and modes of permanent cardiac pacing. Am J Cardiol 1990;65:729-35. 9. Blinks JR, Olson CB, Jewel1 BR, Braveny P. Influence of caffeine and other methylxanthines on mechanical properties of isolated mammalian heart muscle. Circ Res 1972;30:367-92. 10. Vestal R, Eiriksson CE Jr, Musser B, Ozaki L, Halter JB. Effect of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Circulation 1983;67:162-71. 11. Benditt DG, Benson W Jr, Kreitt J, Dunnigan A, Pritzker MR, Crouse L, Scheinman MM. Electrophysiologic effects of theophylline in young patients with recurrent symptomatic bradyarrhythmias Am J Cardiol 1983;52:1223-9.
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12. Shannon DC, Gotay F, Stein IM, Roger MC, Todras ID, Moylan FMB. Prevention of apnea and bradycardia in low-birthweight infants. Pediatrics 1975;55:583-94. 13. Meyers TF, Milsap RL, Krauss AN, Adult PAM, Reidenberg MM. Low-dose theophylline therapy in idiopathic apnea of prematurity. J Pediatr 1980;96:99-103. 14. Ellenbogen KA, Szentpetery S, Katz MR. Reversibility of prolonged chronotropic dysfunction with theophylline following orthotopic cardiac transplantation. AM HEARTJ 1988;
110~202-6. 15. Alboni P, Rossi P, Ratto B, Pedroni P, Gatto E, Antonioli GE. 16. 17.
18.
19.
20. 21.
Electrophysiologic effects of oral theophylline in sinus bradycardia. Am J Cardiol 1990;65:1037-9. Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970;4:160-7. Eiriksson CE, Writer SL, Vestal RE. Theophylline-induced alterations in cardiac electrophysiology in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1987;135:322-6. Alboni P, Ratto B, Scarf6 S, Rossi P, Cappato R, Paparella N. Dromotropic effects of oral theophylline in patients with atria1 fibrillation and a slow ventricular response. Eur Heart J 1991;12:630-4. Belardinelli L, Fenton R, West A, Linden J, Althaus J, Berne RM. Extracellular action of adenosine and the antagonism by aminophylline on the atrioventricular conduction in isolated perfused guinea pig and rat hearts. Circ Res 1982;51:569-79. Rall TW. Evaluation of the mechanism of action of methylxanthines from calcium mobilizers to antagonist of adenosine receptors. Pharmacologist 1982;24:277-87. James TN, Bear ES, Frink RJ, Urthaler F. Pharmacologic production of atrioventricular block with and without initial bundle branch block. J Pharmacol Exp Ther 1971;179:338-46.
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22. Favale S, Di Biase M, Rizzo U, Belardinelli L, R&on P. Effect of adenosine and adenosine-5triphosphate on atrioventricular conduction in patients. J Am Co11 Cardiol 1985;5: 1212-9. 23. Westfall TC, Brasted M. Specificity of blockade of the nicotine-induced release of H3-norepinephrine from adrenergic neurons of the guinea pig heart by various pharmacological agents. J Pharmacol Exp Ther 1974;189:659-65. 24. Sollevi A, Ostergren J, Fagrell B, Hjemdahl P. Theophylline antagonizes cardiovascular response to dipyridamole in man without affecting increases in plasma adenosine. Acta Physiol Stand 1984;121:165-71. 25. Alboni P, Shantha N, Filippi L, Pirani R, Preziosi S, Tomasi AM, Masoni A. Clinical effects of digoxin on sinus node and atrioventricular node function after pharmacological autonomic blockade. AM HEART J 1984;108:1255-61. 26. Alboni P, Paparella N, Pirani R, Cappato R, Cucci AM, Ruffilli E, Tomasi AM. Different electrophysiological modes of action of oral quinidine in man. Eur Heart J 1985;6:946-53. 27. Alboni P, Paparella N, Cappato R, Candini GC. Direct and autonomically mediated effects of oral flecainide. Am J Cardiol 1988;61:759-63. 28. Banner AS, Sunderrajan EV, Agaral MK, Addington WW. Arrhythmogenic effects of orally administered bronchodilators. Arch Intern Med 1979;139:434-7. 29. Conradson T, Eklundh G, Olofsson B, Pahlm 0, Person G. Arrhythmogenicity from combined bronchodilator therapy in patients with obstructive lung disease and concomitant ischemic heart disease. Chest 1987;91:5-9. 30. Rall TW. The xanthines. In: Gilman AG, Goodman LS, Gilman A, eds. The pharmacological basis of the therapeutics. 6th ed. New York MacMillan Publishing Co, Inc, 1980:594.
of oral theophylline
in sick sinus
in 17 patients with symptomatic sinus bradycardia (age: 66 + 11 years), a resting electrocardiogram, a 24-hour Halter recording, and a treadmill test were performed both before and after administration of slow-release theophyiiine (700 mg daily). The drug increased resting heart rate (46 & 7 versus 62 + 16 beats/min, p < O.Ol), mean 24-hour rate (51 & 6 versus 64 + 16 beats/min, p < O.Ol), and minimal 24-hour heart rate (36 k 6 versus 43 k 10 beats/min, p < 0.05). Cardiac pauses >2.5 seconds were present in four patients during control recording, and disappeared after theophyiiine. The daily number of premature supraventricular and ventricular beats increased slightly after the drug. Exercise heart rate was higher after theophylline than during the control test (p < 0.01). Thirteen patients were followed for a period of 17 & 3 months. Suppression of symptoms was achieved in 12 patients. Asthenia and easy fatigue were reduced markedly by the drug. During long-term therapy, the sinus rate was similar to that observed at the steady-state evaluation. in 3 of the 17 patients theophyiline had to be discontinued because of gastric intolerance (in two at the end of the steady-state evaiuatlon and In one during long-term therapy). These data suggest that oral theophylline can represent an effective therapy in some patients with symptomatic sinus bradycardia. (AM HEART J lgg1;122:1361.)
Paolo Alboni, MD, Benedetto Ratto, MD, Riccardo Cappato, MD, Paolo Rossi, MD, Emilio Gatto, MD, and Gian Enrico Antonioli, MD. Cento., Ferrara, and Genoa, Italy
The current therapy for symptomatic sick sinus syndrome (SSS), if there are no removable causes, is based on permanent stimulation. However, though all the aspects of the clinical course of SSS have not been well investigated, some data suggest that implantation of a permanent pacemaker does not represent an ideal therapy: (1) SSSis a relatively benign condition since the overall survival rate of patients with an established sinoatrial disorder is similar to that of the normal population.1-4 (2) The course of symptoms in SSS is very variable from patient to patient. Syncope may not reappear for several years in about 30 % to 407%of the cases;moreover, not uncommonly, syncope represents an isolated manifestation.‘? 2l5For these reasons it is hard to evaluate the actual benefits of either permanent stimulation or pharmacologic therapy. (3) VVI stimulation does not appreciably reduce mortality, even in patients with From the Division of Cardiology, Ospedale Civile, Cento; Division of Cardiology, Arcispedale S. Anna, Ferrara; and Division of Cardiology, Ospedale S. Martino, Geneva. Received for publication Nov. 2, 1990; accepted May 17, 1991. Reprint requests: Dr. Paolo Alboni, Division of Cardiology, Ospedale Civile, 44042 Cento (Fe), Italy. 4/l/32179
symptoms, and AA1 (or DDD) stimulation seems to improve the survival rate in comparison with VVI stimulation only in patients with congestive heart failure.6-8 Controlled studies to compare the survival rate in unpaced patients and in patients with AA1 (or DDD) stimulation have not been carried out up to now. Because of the relatively benign prognosis of SSS and, above all, of the marked variability of the course of symptoms, a pharmacologic therapy appears particularly useful. The drugs used in the past+adrenergic and vagolytic agents-gave disappointing results, both in terms of efficacy and in the high incidence of side effects during long-term treatment. It has been reported that theophylline at therapeutic concentrations induces a modest increase in heart rate in subjects with a normal sinus rate.g*lo During long-term therapy, the drug suppressed symptoms in young patients with paroxysmal bradyarrhythmiasll Moreover, theophylline diminished the frequency and severity of bradycardia in newborn infants with apnea-bradycardia spells.12,l3 Recently, Ellenbogen et a1.14reported two patients with marked sinus bradycardia after orthotopic heart transplantation; oral theophylline increased donor heart rate by about 50%) avoiding pacemaker implantation. Up to now 1361
Alboni et al.
1362
Table
American
November 1991 Heart Journal
I. Steady-state: Effect of oral theophylline (700 mg daily) on examined parameters Control
RestingHR Mean24-hrHR Minimal 24-hrHR Maximal 24-hrHR No. of pauses>2.5 set (in four pts) LongestR-R interval ExerciseHR
62 i 18beatslmin 63.9+ 16beats/min 42.81?1 10beats/min 114 + 87 beats/min
47.3 rt 59 1962 I 394 msec
1590 I 258 msec
887 rt 1764 168 + 542
No. of VPBs rate; SPB, supraventricular
46 + 7 beats/min 51.2I 6 beatslmin 36 I 6 beats/min 89.6-t 20beats/min
77.4t 17beats/min 85.8+ 14beats/min
1st stage 2nd stage No. of SPBs
HR, Heart
Theophylline
premature
beats; VPB, ventricular
premature
the drug has not been investigated in detail in patients with SSS. We have undertaken a study to assess the effects of oral theophylline in patients with sinus bradycardia not related to drugs. METHODS Patients.
We selected17 patients with symptomatic sinus bradycardia not induced by drugs. We included subjects with: (1) mean resting sinusrate <55 beats/min constantly present for somedays in several resting standard electrocardiograms(ECG) recorded during diurnal hours; (2) symptoms attributable to sinus node dysfunction; (3) absence of paroxysmal atria1 fibrillation or flutter or sustainedatrial tachycardia (bradycardia-tachycardia syndrome). Criteria for exclusion included the following: recent myocardial infarction, acute diseaseof any type, significant renal or hepatic disease,congestive heart failure. The age ranged from 50 to 80 years (mean 66 & 11). Fourteen were menand three were women.Twelve patients had organic heart disease:five had ischemicheart disease, five had hypertensive cardiovascular disease,and two had mitral valve disease;the remaining five patients had no signsof structural heart disease.All patients were in New York Heart Association (NYHA) functional classI to II. Fifteen patients complained of syncopeor dizzinessbefore the hospitalization; four complained of marked asthenia and easy fatigue. No patient engaged in an exercise program. All subjectswere nonsmokersat the time of entry into the study. Electrolytes were within the normal range. No patient wastaking cardioactive medicationsor drugs known to interfere significantly with the autonomic system or adenosinemetabolism(dipyridamole or diazepam). Diuretics, converting enzyme inhibitors, and nitrates could be administered if the patient neededthem; in this case,the control evaluation wasdoneduring administration of these drugs, which were then maintained during the follow-up period, possibly at the samedosage. Procedures. Each subject gave informed consent. The steady-state evaluation wasperformed during hospitalization. Chest-x-ray examination, echocardiogram,and stan-
94.5t 28 beats/min 105.2t 23beats/min 1135rfr 2330 184& 271
p
beats.
dard laboratory tests for hematologic, thyroid, renal, and hepatic function were performed. Resting heart rate was measuredfrom a lo-second standard ECG strip after a 15 minute rest period. Electrophysiologic studies were performed in 16 patients using transesophagealpacing, as previously described,l5 both in the basal state and after autonomic blockade. The latter was achieved by intravenous administration of propranolol, 0.2 mg/kg, and atropine, 0.04 mg/kg. The predicted intrinsic heart rate was estimated for each patient using the linear regression equation derived by Jose et a1.,i6relating intrinsic heart rate to age. The following day, patients underwent a 24-hour Holter monitoring for two consecutive days using a two-channel recorder. The data were analyzed to obtain: mean 24-hour heart rate, minimal 24-hour heart rate, maximal 24-hour heart rate, mean heart rate every hour, number of cardiac pauses>2.5 seconds,longestR-R interval, number of premature supraventricular and ventricular beatsand of episodesof ventricular tachycardia (more than three consecutive wide QRS complexes). The following day, an exercisetest wasperformed using the treadmill according to the modified Bruce protocol. The heart rate was measured from a lo-second electrocardiographic (ECG) strip at the end of the first and secondstage. Oral theophylline therapy wasthen initiated at the dosageof 700mg daily in two divided dosesusinga slow-release tablet. Five days later, an electrophysiologic study, Holter recording, and exercise test were repeated with the same methods; in particular, treadmill tests were always performed at the sametime of the day for each patient. Both before and after theophylline treatment, the parameters were reported as the mean of the two consecutive 24-hour Holter recordings to reduce spontaneousvariability and therefore to better evaluate the effects of the drug. Serum theophylline level wasdetermined on the sameday asthe second24-hour Holter recording, 3 hours after the intake of the morning dose.The patients were then enrolled in a long-term phaseand were seenat the outpatient clinic 1 to 2 months later and every 3 to 4 months thereafter. A clinical history, physical examination, resting ECG, 24-hour Holter recording, and serumtheophylline level were done during eachvisit. Dosagemodifications were madeas nec-
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Oral theophylline on sick sinus syndrome
SINUS MEAN
BRADYCARDIA
SINUS
BRADYCARDIA
MINIMAL
RESTING
1363
24-h
MEAN 24-h
HEART RATE
‘*Or
HEART
RATE
80.-
P zco G & 40 30 1
70.z_ % 2 60.t 2 50.-
40*-
20 t
30.-
h
PC.01
$
1. Effects of oral theophylline on meanresting heart rate (evaluated in the standard electrocardiogram) are shown graphically. The meansrl: standard deviation are representedby the vertical bars on either side. C, Control evaluation; T, after theophylline therapy. Fig.
essaryto eliminate symptoms and cardiac pausesand to limit drug-related sideeffects. Statistical evaluations were doneusingthe Wilcoxon test (p value significant at ~0.05). Results are given as mean f standard deviation. RESULTS Steady-state.
The effects of theophylline are reported in Table I and in Figs. 1 to 5. Mean resting heart rate, evaluated in the standard ECG, increased in 16 patients during treatment with theophylline (A%: +36%, p < O.Ol), (Fig. 1). Mean 24-hour heart rate increased in 16 subjects during theophylline therapy (A%: +25%, p < O.Ol), (Fig. 2). The percentage increases in daytime heart rate and sleeping heart rate (between 10 PM and 6 AM) were very similar: +25.6% and +22.8%, respectively 03 = NS) (Fig. 3). Minimal 24-hour heart rate increased during theophylline therapy in 14 patients (A% : +19%, p <0.05), (Fig. 2), and maximal 24-hour heart rate increased in 15 (A%: +27%, p < 0.01). In four
L
f pc .05
I
A
T
PC.01
2. Effects of oral theophylline on minimal and mean 24-hour heart rate are reported graphically. Abbreviations as in Fig. 1. Fig.
patients cardiac pauses >2.5 seconds were present in the control recording; the daily number of these pauses was 36 f 53; they disappeared in all patients during theophylline treatment. The longest R-R interval decreased in 16 patients (A % : -23 % , p < 0.01) (Fig. 4). The daily number of premature supraventricular and ventricular beats increased after theophylline treatment, but the differences were not statistically significant (887 r 1764 versus 1135 + 2230 daily and 168 f 542 versus 184 + 271 daily, respectively). In one patient, who did not complain of palpitations, an “asymptomatic” nonsustained ventricular tachycardia was observed during theophylline therapy and therefore it could not be surely related to the drug. A treadmill test was performed in 15 patients; in the remaining two it was not done due to age difficulties. At the end of the first stage, the heart rate was higher in 13 patients after theophylline than during the control test (A% : +22%, p < 0.01). In one patient the exercise test was interrupted during the second stage for muscular exhaustion. In the 13 pa-
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et al.
American
SINUS
80
November 1991 Heart Journai
HRADYCARDIA
t
8
10
12
14
16
18
TIME Fig.
20
22
24
2
4
6
(24 hr clock)
3. Mean hourly heart rate (in beats/min) during the control evaluation and after theophylline ther-
apy. tients in whom a comparison could be made at the end of the second stage, heart rate was higher after theophylline than during the control test (A % : +22 % , p < O.Ol), (Fig. 5). The electrophysiologic effects of oral theophylline have already been partly reported by usi and are not pertinent to the present clinical work. However, the intrinsic heart rate was normal in 3 patients and abnormal in 13. Because of the low prevalence of autonomic sinus node dysfunction in our patients, it is not possible to evaluate possible different effects of the drug on bradycardia related to intrinsic sinus node dysfunction or to autonomic dysfunction. Theophylline did not significantly change systolic and diastolic blood pressure either at rest or during exercise. Serum theophylline level ranged from 3.7 to 20 PgI ml (mean: 11.4 -t 4). There was no apparent correlation between serum theophylline level and the percentage change in mean 24-hour heart rate (r = O.lO), minimal 24-hour rate (r = 0.20), maximal 24-hour rate (r = 0.12), premature supraventricular beats (r = O.lO),andprematureventricularbeats (F = 0.02). Two patients reported nausea during theophylline therapy. Follow-up. Long-term theophylline therapy was initiated in 13 patients and not in the two who reported nausea during steady-state evaluation or in another two who preferred pacemaker implantation. The mean age was 67 z!z 10 years. Eight patients had organic heart disease. Four patients complained of syncope and dizziness, six of dizziness, and four of marked asthenia and easy fatigue. One patient died after 7 months of treatment for a pancreatic neoplasm. In the remaining 12 patients the follow-up period ranged from 12 to 23 months
(mean 17 + 3). Long-term therapy was initiated at a dosage of 500 to 700 mg daily (Theolair SR, Lirca Synthelabo, Limito, Italy or Theo-24, Schiapparelli Searle, Torino, Italy). In these 12 patients the mean resting heart rate was 45 ? 7 beats/min during the control evaluation, 59 rt 13 beats/min at the steadystate evaluation, and 56 f 7 beats/min during the last visit at the outpatient clinic. The mean 24-hour heart rate was 50 * 7 beats/min, 61 +- 11 beats/min, and 58 t- 6 beats/min, respectively. The minimal 24hour heart was 36 it 4 beats/min, 42 +- 6 beats/min, and 40 * 4 beats/min, respectively. The daily number of premature supraventricular beats was 891 + 1912 during the control evaluation, 1550 +- 2687 at the steady-state evaluation, and 834 + 1160 during the last visit. The daily number of ventricular premature beats was 243 f 616, 208 +_ 300, and 307 f 640, respectively. In no patient were there episodes of ventricular tachycardia. In four patients cardiac pauses >2.5 seconds were present at the control evaluation (mean: 36 -+ 53 daily); during longterm therapy they were observed in one patient only during one visit. At one visit in two patients the follow-up heart rate decreased to control values. In both patients the serum theophylline level was <4 pg/ml, and it is possible that they were noncompliant with their medication schedule for a period of time. In no patient did dizziness or syncope occur during Holter recording, either at the steady-state evaluation or during the follow-up period. The mean dosage of theophylline at the last visit was 438 2 132 mg daily (range: 300 to 700 mg), and the mean serum theophylline level was 8.6 + 3 pg/ml (range: 4.2 to 14.2). During long-term therapy, one patient complained of dizziness during one visit but
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Oral theophylline on sick sinus syndrome
SINUS LONGEST
BRADYCARDIA R-R
SINUS
INTERVAL
MEAN
1365
BRADYCARDIA
EXERCISE
1” STAGE
HEART
RATE
2”dSTAGE
160
/
t 140.-
2 120.> &n3-
8O.m
60.-
I/
Fig. 5. Effects of oral theophylline on the exerciseheart
rate evaluated at the end of the first and second stage (treadmill test). Abbreviations as in Fig. 1. p-co1 Fig. 4. Effects of oral theophylline on the duration of the longest R-R interval. Abbreviations as in Fig. 1.
not in subsequent follow-up visits; the remaining patients did not complain of syncope or dizzinessduring long-term treatment. Theophylline markedly reduced asthenia and easy fatigue in all four patients. Two patients reported nausea; in one it disappeared after a reduction of the dosage, whereas in the other theophylline treatment had to be discontinued at 15 months. DISCUSSION
Theophylline exerts positive chronotropic action.gplo An improvement in sinus nodal function has been reported after both intravenous and oral administration of the drug. lly 15yl7 Moreover, a reduction in symptoms during long-term treatment has been reported by Benditt et al.” in 10 young subjects with paroxysmal sinus bradyarrhythmias or atrioventricular (AV) block without structural heart disease.Recently, we18observed a marked positive dromotropic effect of oral theophylline in patients with atrial fibrillation and a slow ventricular response.
However, up to now, no systematic study has been carried out on the clinical effects of this drug in patients with SSS. There are several mechanisms by which theophylline might exert positive chronotropic and dromotropic action; however, several observations suggest that the primary action of theophylline at therapeutic concentrations is blockade of adenosine receptors.lgp2oAdenosine has been shown to slow sinus rate and depress AV nodal conduction in laboratory animals and in clinical patients21122Theophylline completely antagonizes the negative chronotropic and dromotropic action of adenosine by blocking extracellular adenosine receptors.lg In addition to antagonism of adenosine receptors, other mechanisms of theophylline have been postulated, in particular an adrenergic effect. 23 However, several observations suggest that this action of the drug appears at serum concentrations over the therapeutic range.24 In 15 patients with sinus bradycardia, by utilizing amethod previously adopted by us25-27that investigates the different modes of action of an antiarrhythmic drug in man, we15observed that the percentage decrease in sinus cycle length, corrected sinus node recovery time, and sinoatrial conduction time induced by oral theophylline were very similar with and without au-
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tonomic blockade. This seems to confirm that the positive chronotropic action of theophylline is not mediated by autonomic receptors. In the present study we have investigated the effects of oral theophylline in patients with sinus bradycardia only; we have not assessed the effects in patients with bradycardia-tachycardia syndrome, since an arrhythmogenic action of the drug has been described.28p 2g In our patients, as well, theophylline slightly increased premature supraventricular and ventricular beats; this increase was similar at the steady-state evaluation and during long-term therapy. At the steady-state evaluation, slow-release theophylline significantly increased resting heart rate by 36%) mean 24-hour heart rate by 25%) minimal 24hour heart rate by 19%) and exercise heart rate by 22%. Four patients showed cardiac pauses >2.5 seconds, no longer present after drug administration. The longest R-R interval decreased in all patients. The drug therefore exerts a marked positive chronotropic effect during both rest and exercise. Examination of data from individual patients at the steadystate evaluation shows that the increase in sinus node measures was excessive in several subjects (Figs. 1,2, and 5); for this reason we decreased the theophylline dosage in some subjects at the beginning of long-term therapy. During long-term therapy, the sinus rate was similar to that observed at the steady-state evaluation, despite the reduction in the daily dosage (700 mg at the steady-state evaluation and 438 f 132 mg at the last visit). This suggests that the chronotropic action of the drug does not decrease in time, at least for a period of about 2 years. During long-term therapy, only one patient complained of dizziness at one visit; the remaining patients have remained symptom-free. Our results therefore suggest a reduction in bradycardia-related symptoms in patients treated with theophylline; this observation seems to be strengthened by the marked reduction in the frequency of cardiac pauses and in the duration of the longest R-R interval. However, the course of symptoms in SSS is variable from patient to patient, and for this reason the interpretation of the results obtained after either pharmacologic therapy or pacemaker implantation is difficult. To better assess this point, a randomized study of long-term efficacy is required. The marked reduction in asthenia and easy fatigue during longterm treatment is interesting; it can be related both to the increase in sinus rate and to an effect on the central nervous system. 3o In 3 out of the 17 patients (17 % ) theophylline had to be discontinued because of nausea (in two at the end of the steady-state pe-
American
November 1991 Heart Journal
riod and in one during long-term therapy); it has already been widely reported that in 15% to 20% of subjects theophylline must be withdrawn because of gastric intolerance.30 Our data suggest that the initial dosage of the drug should be 500 to 600 mg daily, and it can be then slightly decreased or increased according to the clinical course. Serum theophylline level should be >5 pg/ml; for lower values the effects of the drug on heart rate are inconstant; besides, the serum concentration should not be more than 15 pg/ml to prevent side effects of the drug. 3o The results of the present study show for the first time that oral theophylline can represent an effective therapy in some patients with symptomatic sinus bradycardia. Because of the variable clinical course of SSS with frequent spontaneous remission of the symptoms, a pharmacologic treatment appears useful; when it is not efficacious or causes undesirable side effects, it does not prevent any pacemaker implantation. REFERENCES
1. Baldi N, Castelli M, Alberti E, Morgera T, Camerini F. La sindrome de1 seno malato: storia naturale. In: Consolo F, Arrigo F, Oreto G, eds. La sindrome de1 seno malato. Padova: Piccin Ed, 1979:133. 2. Gann D, Tolentino A, Samet P. Electrophysiologic evaluation of elderly patients with sinus bradycardia. A long term follow-up study. Ann Intern Med 1979;90:24-9. 3. Shaw DB, Holman RR, Gowers JI. Survival in sino-atria1 disorder (sick sinus syndrome). Br Med J 1980;280:139-41. 4. Alt E, Volker R, Wirtzfeld A, Ulm K. Survival and follow-up after pacemaker implantation: comparison of patients with sick sinus syndrome, complete heart block and atria1 fibrillation. PACE 1985;8:849-57. 5. Sasaki Y, Shimotori M, Akahane K, Yonekura H, Hirano K, Endoh R, Koike S, Kawa S, Furuta S, Homma T. Long term follow-up of patients with sick sinus syndrome: a comparison of clinical aspects among unpaced, ventricular inhibited paced and ohvsioloeicallv oaced aroun. PACE 1988:11:1575-83. 6. Alpert “MA, Curtis JJ, Sanfelippo JF, Flake; CC, Walls JT, Mukerji V, Villareal D, Katti SK, Medigan NP, Morgan RJ. Comparative survival following permanent ventricular and dual-chamber pacing for patients with chronic symptomatic sinus node dysfunction with and without heart failure. AM HEART J 1987;113:958-65. 7. Rosenqvist M, Brandt J, Schuller H. Long-term pacing in sinus node disease: effects of stimulation mode on cardiovascular morbidity and mortality. AM HEART J 1988;116:16-22. 8. Santini M, Alexidou G, Ansalone G, Cacciatore G, Cini R, Turitto G. Relation of prognosis in sick sinus syndrome disease to age, conduction defects and modes of permanent cardiac pacing. Am J Cardiol 1990;65:729-35. 9. Blinks JR, Olson CB, Jewel1 BR, Braveny P. Influence of caffeine and other methylxanthines on mechanical properties of isolated mammalian heart muscle. Circ Res 1972;30:367-92. 10. Vestal R, Eiriksson CE Jr, Musser B, Ozaki L, Halter JB. Effect of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Circulation 1983;67:162-71. 11. Benditt DG, Benson W Jr, Kreitt J, Dunnigan A, Pritzker MR, Crouse L, Scheinman MM. Electrophysiologic effects of theophylline in young patients with recurrent symptomatic bradyarrhythmias Am J Cardiol 1983;52:1223-9.
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12. Shannon DC, Gotay F, Stein IM, Roger MC, Todras ID, Moylan FMB. Prevention of apnea and bradycardia in low-birthweight infants. Pediatrics 1975;55:583-94. 13. Meyers TF, Milsap RL, Krauss AN, Adult PAM, Reidenberg MM. Low-dose theophylline therapy in idiopathic apnea of prematurity. J Pediatr 1980;96:99-103. 14. Ellenbogen KA, Szentpetery S, Katz MR. Reversibility of prolonged chronotropic dysfunction with theophylline following orthotopic cardiac transplantation. AM HEARTJ 1988;
110~202-6. 15. Alboni P, Rossi P, Ratto B, Pedroni P, Gatto E, Antonioli GE. 16. 17.
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Electrophysiologic effects of oral theophylline in sinus bradycardia. Am J Cardiol 1990;65:1037-9. Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970;4:160-7. Eiriksson CE, Writer SL, Vestal RE. Theophylline-induced alterations in cardiac electrophysiology in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1987;135:322-6. Alboni P, Ratto B, Scarf6 S, Rossi P, Cappato R, Paparella N. Dromotropic effects of oral theophylline in patients with atria1 fibrillation and a slow ventricular response. Eur Heart J 1991;12:630-4. Belardinelli L, Fenton R, West A, Linden J, Althaus J, Berne RM. Extracellular action of adenosine and the antagonism by aminophylline on the atrioventricular conduction in isolated perfused guinea pig and rat hearts. Circ Res 1982;51:569-79. Rall TW. Evaluation of the mechanism of action of methylxanthines from calcium mobilizers to antagonist of adenosine receptors. Pharmacologist 1982;24:277-87. James TN, Bear ES, Frink RJ, Urthaler F. Pharmacologic production of atrioventricular block with and without initial bundle branch block. J Pharmacol Exp Ther 1971;179:338-46.
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22. Favale S, Di Biase M, Rizzo U, Belardinelli L, R&on P. Effect of adenosine and adenosine-5triphosphate on atrioventricular conduction in patients. J Am Co11 Cardiol 1985;5: 1212-9. 23. Westfall TC, Brasted M. Specificity of blockade of the nicotine-induced release of H3-norepinephrine from adrenergic neurons of the guinea pig heart by various pharmacological agents. J Pharmacol Exp Ther 1974;189:659-65. 24. Sollevi A, Ostergren J, Fagrell B, Hjemdahl P. Theophylline antagonizes cardiovascular response to dipyridamole in man without affecting increases in plasma adenosine. Acta Physiol Stand 1984;121:165-71. 25. Alboni P, Shantha N, Filippi L, Pirani R, Preziosi S, Tomasi AM, Masoni A. Clinical effects of digoxin on sinus node and atrioventricular node function after pharmacological autonomic blockade. AM HEART J 1984;108:1255-61. 26. Alboni P, Paparella N, Pirani R, Cappato R, Cucci AM, Ruffilli E, Tomasi AM. Different electrophysiological modes of action of oral quinidine in man. Eur Heart J 1985;6:946-53. 27. Alboni P, Paparella N, Cappato R, Candini GC. Direct and autonomically mediated effects of oral flecainide. Am J Cardiol 1988;61:759-63. 28. Banner AS, Sunderrajan EV, Agaral MK, Addington WW. Arrhythmogenic effects of orally administered bronchodilators. Arch Intern Med 1979;139:434-7. 29. Conradson T, Eklundh G, Olofsson B, Pahlm 0, Person G. Arrhythmogenicity from combined bronchodilator therapy in patients with obstructive lung disease and concomitant ischemic heart disease. Chest 1987;91:5-9. 30. Rall TW. The xanthines. In: Gilman AG, Goodman LS, Gilman A, eds. The pharmacological basis of the therapeutics. 6th ed. New York MacMillan Publishing Co, Inc, 1980:594.