Methylxanthine derivatives, such as theophylline, antagonize the cardiac actions of adenosine in a competitive manner [12]. We previously showed that in the presence of clinically significant concentrations of adenosine in humans, theophylline reverses A₁-mediated atrioventricular block more readily than it reverses A₂-mediated coronary vasodilation [13]. In this report, we provide evidence to show that second- or third-degree atrioventricular block occurring as an early complication of acute inferior myocardial infarction is probably mediated by endogenous adenosine. This is shown by the fact that this atrioventricular block can be promptly converted to a normal sinus rhythm by using theophylline.

Methods

Top Methods Results Discussion Author & Article Info References

Patients admitted to the Gainesville Veterans Affairs Hospital with a diagnosis of acute inferior myocardial infarction were monitored for clinically significant and persistent atrioventricular conduction delay. When such a dysrhythmia was seen, the primary care physician was instructed to treat the patient with intravenous atropine according to the 1992 Emergency Cardiac Care/American Heart Association guidelines [14]. If this therapy failed to restore 1:1 atrioventricular nodal conduction and normal sinus rhythm, or if it was not used, 150 to 250 mg of theophylline were given as a slow intravenous injection at a rate of 100 mg/min. The patient's heart rhythm was monitored for recurrent arrhythmias using 2-lead cardiac telemetry for at least 24 hours. No patient had a previous history of cardiac arrhythmias, and the electrocardiogram done for each patient at study entry showed a normal sinus rhythm. Patients were treated with oral aspirin (325 mg/d), intravenous heparin, and nitroglycerin. No patient had received ß-blockers or calcium antagonists before the onset of the bradyarrhythmia.

Results

Top Methods Results Discussion Author & Article Info References

During a 6-month period, 11 men who were hospitalized with acute inferior myocardial infarction developed persistent and clinically significant atrioventricular conduction delay within 4 hours of the onset of symptoms. Eight patients either failed to respond to the initial standard treatment with atropine or were directly treated, at the discretion of the primary physician, with theophylline. No bradyarrhythmia converted to a sinus rhythm before the administration of theophylline. Six of the 8 patients had received thrombolytic therapy before the onset of the atrioventricular conduction delay. Three patients developed hemodynamically significant third-degree atrioventricular block, and 5 developed high-grade second-degree atrioventricular block (Table 1).

All patients developed clinically significant atrioventricular nodal conduction delays 30 to 240 minutes (mean ±SD, 69 ± 72 minutes) after the onset of myocardial infarction symptoms. All had symptoms or signs of hypoperfusion (six had dizziness; one had fatigue; five had cool, clammy skin; three had changes in mental status; and the mean systolic blood pressure was 74 ± 13 mm Hg). Two of the three patients who developed third-degree atrioventricular block and four of the five patients who developed second-degree atrioventricular block were initially treated unsuccessfully with atropine (1 mg given intravenously). Patients received theophylline (mean dose, 218 ± 37 mg) as a slow intravenous injection. Figure 1 shows electrocardiographic recordings from a patient with third-degree atrioventricular block who converted to normal sinus rhythm after receiving 150 mg of theophylline and who remained in normal sinus rhythm with 1:1 atrioventricular conduction for 36 hours of observation. In all patients, 1:1 atrioventricular nodal conduction and normal sinus rhythm were restored within 1.8 ± 0.7 minutes after the injection of theophylline. In association with the resumption of sinus rhythm and 1:1 atrioventricular conduction, the mean systolic blood pressure increased from 74 ± 13 mm Hg to 112 ± 6 mm Hg (n = 8), and all signs and symptoms of hypoperfusion subsided after administration of theophylline. No patient had worsening of anginal pain, and three patients reported a noticeable decrease in anginal pain.

View larger version (122K): [in this window] [in a new window]   Figure 1. Electrocardiographic recordings from leads II and aVF. Top. New-onset third-degree heart block (p waves are marked by arrows) that began 45 minutes after the patient was hospitalized for an acute inferior myocardial infarction. The patient had accompanying dizziness and on physical examination had cool, clammy skin and a systolic blood pressure of 68 mm Hg. Bottom. After the administration of theophylline, 150 mg, an immediate conversion to normal sinus rhythm with 1:1 atrioventricular conduction occurred. The patient's systolic blood pressure increased to 110 mm Hg, and all symptoms abated. The normal sinus rhythm persisted for more than 36 hours of observation.

Discussion

Top Methods Results Discussion Author & Article Info References

Our findings in this uncontrolled and observational but hypothesis-driven study show that theophylline, an adenosine-receptor antagonist, can convert ischemia-related atrioventricular nodal conduction disturbances to normal sinus rhythm. Because each of the eight patients converted to 1:1 atrioventricular nodal conduction with normal sinus rhythm within 3 minutes (1.8 ± 0.7 minutes) of the administration of theophylline, it is unlikely that the dysrhythmias resolved spontaneously. The relevance of these findings is greatly enhanced by the fact that theophylline antagonizes the negative chronotropic and dromotropic effect of adenosine in humans [13]. Additionally, in the doses administered, the primary action of theophylline is adenosine antagonism and not sympathomimetic stimulation [15]. Atropine would not be expected to potentiate the effects of theophylline. These results indicate that, under conditions in which excessive depression of cardiac function (such as bradyarrhythmia) is secondary to an increased production of adenosine by the heart, A₁ adenosine-receptor antagonists may prove to be useful.

Patients with acute inferior myocardial infarctions are more likely than patients with anterior-wall myocardial infarctions to develop atrioventricular block because the blood supply to the atrioventricular node is usually supplied by the right coronary artery [16]. Patients with "early" atrioventricular block (occurring less than 24 hours into their hospital course) are less likely to respond to atropine, more likely to require temporary pacing, and more likely to have a morbid or mortal event than are similar patients who develop "late" atrioventricular block (occurring more than 24 hours into their hospital course) [17]. Because of the poor prognosis associated with "early" atrioventricular block and the ineffectiveness of the current therapy for it, the efficacy of alternative therapies, such as A₁ 1 adenosine-receptor antagonists, should be investigated. Our results are the first to suggest that theophylline can be used as primary or rescue therapy for "early" bradyarrhythmias associated with myocardial infarction.

One of the limitations of our study is that the administration of theophylline was neither blinded nor directly compared with other standard therapy. Another is that the number of patients studied was relatively small. Nevertheless, our results provide strong circumstantial evidence to show that theophylline is useful in bradyarrhythmias related to myocardial infarction, and they provide the rationale for future evaluation of the role that endogenous adenosine plays in ischemia-related rhythm disturbances.

In conclusion, adenosine produced by the ischemic myocardium may induce significant atrioventricular blockade. These arrhythmias—which may be resistant to conventional therapy, such as atropine—appear to respond to the adenosine antagonist theophylline. In light of present and previous observations, theophylline can be considered as an alternative when standard front-line antiarrhythmic therapy has failed. By promptly converting dysrhythmia to normal sinus rhythm, theophylline may make invasive and risky procedures, such as temporary pacemaker placement, unnecessary. A₁ adenosine-receptor antagonists more potent, specific, and selective than theophylline may prove to be valuable in the short- and long-term management of cardiac arrhythmias associated with excess endogenous adenosine production.

@copy; 1995 American College of Physicians