(Circulation. 2000;101:624.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Antiarrhythmic Efficacy of Dipyridamole in Treatment of Reperfusion Arrhythmias
Evidence for cAMP-Mediated Triggered Activity as a Mechanism Responsible for Reperfusion Arrhythmias
Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998, and published in abstract form (Circulation. 1998;98[suppl I];I-166.).
From the Division of Cardiology (Y.Y., M.H., T.K., Y.I., M.A., H.S.), First Department of Internal Medicine, University of Nagoya School of Medicine, Nagoya; Cardiovascular Center (T.Y., Y.M., M.T., M.O., J.T.), Aichi Prefectural Owari Hospital, Ichinomiya; and the Cardiovascular Center (Y.T., N.T., H.H., T.I.), Nagoya Dai-ni Red Cross Hospital, Nagoya, Japan.
Correspondence to Yukihiko Yoshida, MD, Division of Cardiology, First Department of Internal Medicine, University of Nagoya School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. E-mail ykyoshi{at}wb3.so-net.ne.jp
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Abstract |
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Background—Intracellular calcium overload is believed to play an important role in development of reperfusion arrhythmias. Dipyridamole, an inhibitor of cellular uptake of adenosine, may prevent or terminate reperfusion arrhythmias by reducing intracellular calcium overload.
Methods and Results—First, we tested for a preventive effect of dipyridamole. Sixty-one patients who underwent primary PTCA for treatment of acute anterior wall myocardial infarction were enrolled in this prospective study. Patients were divided into dipyridamole (DP) and nondipyridamole (non-DP) groups. The 2 groups had similar baseline characteristics. In the DP group, dipyridamole 0.5 mg/kg was infused intravenously for 3 minutes immediately before reperfusion during primary PTCA. Arrhythmias after reperfusion were analyzed from continuous ECG recordings. None of the patients in the DP group (n=23) had accelerated idioventricular rhythms (AIVR) or ventricular tachycardia (VT). In contrast, 7 (18.4%) had AIVR and 3 (7.9%) had VT in the non-DP group (n=38; P<0.01). Second, we tested for a termination effect of dipyridamole. Dipyridamole 0.5 mg/kg was infused intravenously while continuous ECG recordings were obtained in 9 patients who had either sustained AIVR (n=7) or sustained VT (n=2) after reperfusion of occluded coronary artery. Arrhythmias were terminated in all patients.
Conclusions—These results indicate that administration of dipyridamole can prevent and terminate reperfusion arrhythmias such as AIVR and VT. cAMP-mediated triggered activity may, at least in part, be responsible for reperfusion-induced AIVR and VT.
Key Words: adenosine • arrhythmia • myocardial infarction • reperfusion
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Introduction |
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Reperfusion arrhythmias, such as accelerated idioventricular rhythm (AIVR) and ventricular tachycardia (VT), are frequently observed after reperfusion of an occluded coronary artery in the setting of acute myocardial infarction (AMI).1 2 3 Reperfusion arrhythmias, in addition to their importance as a marker of successful reperfusion of an occluded coronary artery, require special attention because hemodynamics may rapidly deteriorate during VT or ventricular fibrillation (Vfib). It is therefore important clinically to establish the mechanism and treatment of such reperfusion arrhythmias.
Intracellular calcium overload is believed to play a critical role in development of reperfusion arrhythmias.4 5 6 Furthermore, adenosine has been shown to suppress reperfusion injury7 and to terminate idiopathic VT caused by intracellular calcium overload.8 9 10 Dipyridamole, an inhibitor of cellular transport of adenosine, is thought to exert the same antiarrhythmic activity as adenosine by increasing interstitial myocardial concentration of adenosine.11 Although dipyridamole is expected to prevent or terminate reperfusion arrhythmias caused by intracellular calcium overload, its antiarrhythmic efficacy in treatment of reperfusion arrhythmias has not been clarified. The purpose of the present study was to determine the effect of dipyridamole on reperfusion arrhythmias in patients with AMI.
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Methods |
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Study Patients
One hundred twenty-three consecutive patients with AMI who presented within 6 hours of onset of symptoms were enrolled in the present study. Coronary angiography confirmed that the infarct-related artery was completely occluded. Primary PTCA was performed in all patients. Studies were approved by the institutional review committee, and informed consent was obtained from all patients before they entered the study.
Excluded from the study were patients with a prior history of MI,
insulin therapy for diabetes mellitus, or coronary artery
bypass surgery; with severe stenoses of 
90% that affected
arteries other than the infarct-related artery, pulmonary
edema, or cardiogenic shock; or who had undergone unsuccessful
reperfusion or had experienced no-reflow phenomenon at reperfusion.
The study population consisted of 91 men and 32 women aged 31 to 85 years (64±11 years). The infarct-related artery was the right coronary artery (RCA) in 45 patients, left main trunk (LMT) in 3, left anterior descending coronary artery (LAD) in 61, and left circumflex coronary artery (LCx) in 14. Primary PTCA was performed in all patients, and the occluded vessel was successfully reperfused in all.
Coronary Angiography and Primary PTCA
Coronary angiography and primary PTCA were performed
within 6 hours of onset of symptoms of AMI. Once the femoral artery was
catheterized, 10 000 IU of heparin was administered and additional
boluses of 1000 IU were given as needed to achieve an activated
clotting time of 350 s. Coronary angiograms were obtained in
2 projections. Intracoronary
nitroglycerin was administered before
diagnostic angiography and primary PTCA. LAD occlusions
were considered proximal if located before the origin of the first
well-developed septal branch, distal if located after the origin of the
third diagonal branch, and mid if located between these limits. Primary
PTCA was performed by use of a conventional catheter balloon technique.
Reperfusion was considered successful when flow in the infarct-related
artery was improved to Thrombolysis in Myocardial
Infarction (TIMI)12 grade 2 or 3.
Data Recording
Continuous recordings of 6- to 12-lead ECGs and
blood pressure were obtained simultaneously from the start
of coronary angiography until completion of PTCA at a paper
speed of 10 mm/s. When arrhythmias appeared,
recordings were obtained at a paper speed of 25 mm/s. ECG
and blood pressure recordings were analyzed by 3 of the
authors (Y.Y., M.H., N.T.). Differences of opinion were settled
through discussion.
Definitions
Rapid ventricular rhythms were divided by use of
heart rate into AIVR (>60 bpm but <120 bpm) and VT (120 bpm). AIVR
and VT were also classified by their duration: sustained (lasting 30
s) and nonsustained (lasting <30 s).
Effect of Dipyridamole on Prevention of
Reperfusion Arrhythmias
The ability of dipyridamole to prevent
reperfusion arrhythmias was investigated in a subset of
patients with AMI caused by a culprit lesion in the LAD. Patients were
prospectively divided into dipyridamole (DP) and
nondipyridamole (non-DP) groups. For patients in the DP
group, 0.5 mg/kg of dipyridamole (Persantine injection;
Behringer-Ingelheim, Japan) was administered intravenously
for 3 minutes immediately before reperfusion during primary PTCA.
Elimination half-life of dipyridamole administered
intravenously is 24.6 minutes.13 Type and
frequency of ventricular arrhythmias that occurred
during the 30 minutes after reperfusion were compared between
groups.
Effect of Dipyridamole on Termination of
Reperfusion Arrhythmias
The ability of dipyridamole to terminate
reperfusion arrhythmias was determined in patients with AIVR or
VT developed within 10 minutes after reperfusion. The DP group for the
prevention study was excluded from the termination study. As for
AIVR, if tachycardia continued for >30 s,
dipyridamole (0.5 mg/kg) was primarily infused
intravenously while continuous ECGs and blood pressure
recordings were obtained simultaneously. To assess
precisely the effect of dipyridamole on AIVR, patients
whose arrhythmias were nonsustained or terminated spontaneously
before infusion of dipyridamole were excluded. As for
VT, patients who had severe hemodynamic compromise were
cardioverted, and 100 mg of bolus intravenous lidocaine was
injected into the remaining patients with VT. If lidocaine injection
was ineffective, dipyridamole 0.5 mg/kg was infused
intravenously. Termination of sustained AIVR or sustained
VT during or for 1 minute after the infusion of
dipyridamole was defined as successful termination of
arrhythmia. If AIVR or VT resumed within 20 minutes after
cessation of the arrhythmia after dipyridamole
infusion, cessation of the arrhythmia was considered
unsuccessful.
Statistical Analysis
Data are expressed as mean±SD or number (percentage) of
patients. Differences between categorical variables were
analyzed by 
2 analysis or
Fisher’s Exact Test, and differences between continuous variables
were analyzed by Student’s t test.
P<0.05 was considered statistically significant.
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Results |
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Effect of Dipyridamole for Prevention of Reperfusion Arrhythmias
In 61 patients, the infarct-related artery was the LAD. These patients were divided into non-DP (first 38 patients) and DP (next 23 patients) groups to investigate the effects of dipyridamole for prevention of reperfusion arrhythmias. No significant differences existed between groups with respect to age, number of diseased vessels, lesion location, collateral flow grade, or time from onset to reperfusion (Table 1
). No patients in the DP group
had reperfusion-induced AIVR or VT, whereas 7 patients (18.4%) had
AIVR and 3 (7.9%) had VT (10 patients; 26.3%) in the non-DP group
(P<0.01). Vfib was noted in 2 patients (5.3%) in the
non-DP group and was preceded by monomorphic VT in both. Although Vfib
did not occur in the DP group, no significant statistical difference
existed in the incidence of Vfib between groups. Premature
ventricular complexes (PVC; 1 bpm) occurred at the same
frequency in the 2 groups (Table 2). No
patients developed chest pain, tachypnea, shortness of breath, or
hypotension as a result of dipyridamole administration.
In the DP group, no arrhythmias except sporadic PVCs were
observed for at least 60 minutes after dipyridamole
infusion.
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Effect of Dipyridamole on Termination of
Reperfusion Arrhythmias
Reperfusion arrhythmias developed in 52 (52%) of the 100
patients who had not received dipyridamole at the time
primary PTCA was performed, and 66 arrhythmic episodes were observed in
these patients. The infarct-related artery was the RCA in 45 patients,
LMT in 3, LAD in 38, and LCx in 14. Arrhythmias included sinus
bradycardia in 9 patients (9%), PVC in 33 (33%), AIVR in 12 (12%),
VT in 7 (7%), and Vfib in 5 (5%) (see Table 3). Sinus bradycardia tended to be
associated with RCA or LCx occlusion and AIVR with LAD occlusion. On
the other hand, PVC, VT, and Vfib occurred at similar frequencies for
infarctions in the 3 coronary arteries. The ability of
dipyridamole to terminate reperfusion
arrhythmias was investigated in 19 patients in whom AIVR (n=12)
or VT (n=7) developed.
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AIVR was nonsustained or subsided spontaneously before administration of dipyridamole in 5 (RCA, 2; LAD, 2; and LCx, 1) of the 12 patients with AIVR. Consequently, AIVR was sustained in 7 patients. VT degenerated into Vfib or was terminated with cardioversion because of hypotension in 4 (LMT, 1; LAD, 3) of the 7 patients with VT. In the other 3 patients with VT, 100 mg of lidocaine was injected intravenously. One patient with an occluded LCx received cardioversion, and the remaining 2 patients with RCA occlusions had sustained monomorphic VT. As a result, VT was sustained in 2 patients.
Dipyridamole was successfully administered to 9
patients with sustained AIVR (n=7) or sustained VT (n=2).
Arrhythmias terminated during or immediately after
administration of dipyridamole in all 9 patients (see
Figures 1 through 3). AIVR or VT cycle
length did not accelerate in any patient in response to
dipyridamole. Dipyridamole had minimal
effects on systolic and diastolic blood pressure
during AIVR or VT (
10 mm Hg). No resumption of
arrhythmia was observed until completion of PTCA (for at least
60 minutes after dipyridamole infusion) in all 9
patients.
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ventricular bigeminy). Vertical
arrow indicates end of dipyridamole injection. C,
Complete abolition of ventricular ectopy 
15 s after end
of dipyridamole.
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Discussion |
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Main Findings
In the present study, we investigated the efficacy of dipyridamole for treatment of reperfusion arrhythmias such as AIVR and VT in patients with AMI. To our knowledge, the present study is the first to demonstrate that dipyridamole can prevent or terminate AIVR and VT that develops at the time of reperfusion. AIVR has been reported not to require special treatment because this arrhythmia has minimal hemodynamic consequences.14 However, in some patients with depressed cardiac function, AIVR also may induce hypotension.15 In the setting of VT, blood pressure may quickly drop, and a high risk exists of degeneration to Vfib. Because of the widespread use of reperfusion therapy, management of reperfusion arrhythmias is an increasingly important clinical issue. The preventive effect of dipyridamole on reperfusion arrhythmias shown in the present study suggests that premedication with dipyridamole immediately before reperfusion can improve safety of reperfusion therapy.
Because AIVR occasionally terminates spontaneously and VT causes abrupt hypotension, few studies have been published on the use of antiarrhythmic drugs to terminate reperfusion-associated AIVR and VT.16 In the present study, only 9 patients with sustained AIVR (n=7) or sustained VT (n=2) could be treated with dipyridamole. However, because the tachyarrhythmias were terminated during or immediately after administration of dipyridamole in all 9 patients, we conclude that this agent may be efficacious for termination of reperfusion arrhythmias.
Antiarrhythmic Action of Adenosine and
Dipyridamole
Adenosine is thought to terminate idiopathic VT, which is
caused by intracellular calcium overload.8 9 10 This type
of VT is probably precipitated by cAMP-mediated triggered activity. The
mechanism of tachycardia is believed to be
catecholamine-induced delayed afterdepolarizations (DADs).
DADs have been reported to be dependent on intracellular calcium
overload that results from cAMP stimulation.17
Adenosine has no known direct electrophysiological effects on adult ventricular tissue or Purkinje fibers.9 However, it antagonizes the inotropic and electrophysiological effects of catecholamines that are mediated by stimulation of adenylate cyclase.18 19 20 Adenosine inhibits adenylate cyclase through activation of the adenosine A1 receptor. After the agonist binds to the adenosine A1 receptor, intracellular GTP binds to the GTP-dependent regulatory protein (Gi). This process results in dissociation of Gi from the A1 receptor and inhibition of the catalytic subunit of adenylate cyclase, thereby preventing cAMP formation,20 intracellular calcium overload, afterdepolarizations, and triggered activity. As a result, VT is terminated.8 9 10
Dipyridamole is an inhibitor of the cellular uptake of adenosine and exhibits the same antiarrhythmic actions as adenosine.10 11 21 However, dipyridamole has less negative chronotropic and dromotropic effects (atrioventricular blockade) and a longer half-life than adenosine. Because dipyridamole possesses a selective effect on tachyarrhythmias induced by cAMP-mediated triggered activity, the agent can be used to elucidate the mechanism of arrhythmias even in patients with acute coronary syndromes such as AMI. Dipyridamole may prevent or terminate reperfusion arrhythmias by reducing intracellular calcium overload. However, no studies have been published concerning efficacy of dipyridamole for prevention or termination of reperfusion arrhythmias. The present study is the first study to demonstrate the efficacy of dipyridamole for treatment of reperfusion arrhythmias.
Dipyridamole is also known to have a coronary vasodilating effect through activation of the adenosine A2 receptor on endothelial and vascular smooth muscle cells.22 Therefore, it is possible that the antiarrhythmic efficacy of dipyridamole is due to improved coronary flow. However, in the present study, intracoronary nitroglycerin showed little effect toward prevention of reperfusion arrhythmias. Furthermore, nicorandil, which improves coronary microvascular circulation in the same manner as adenosine, has been reported not to reduce the incidence of reperfusion arrhythmias.23 Therefore, although a coronary vasodilating effect might be a possible mechanism for antiarrhythmic action of dipyridamole, we believe that the antiarrhythmic efficacy of dipyridamole results mainly from inhibition of intracellular calcium overload through stimulation of the adenosine A1 receptor on cardiomyocytes.
Electrophysiological Mechanisms of
Reperfusion Arrhythmias
Electrophysiological mechanisms of reperfusion
arrhythmias are still being disputed. Arrhythmias in
experimental models of ischemia and reperfusion were previously
believed to be reentrant arrhythmias that resulted from
heterogeneous recovery of the refractory period and
conductivity.24 25 However, more recently, Kaplinsky et
al26 found that reperfusion arrhythmias after 30
minutes of ischemia consist of 2 types: an instantaneous
ventricular arrhythmia (onset at 0 to 1 minute) and
a delayed ventricular arrhythmia (onset at 2 to 7
minutes). They demonstrated that the former was a reentrant
arrhythmia caused by electrical inhomogeneity and associated
with a high frequency of Vfib. In contrast, the latter was caused by
increased ventricular automaticity and associated with a
low frequency of Vfib.26 On the other hand, Ferrier et
al5 reported that in isolated tissue preparation, DADs and
triggered rhythms occurred during conditions that mimicked reperfusion
after a 40-minute ischemic episode. Subsequently, this
mechanism has also attracted considerable attention as the underlying
mechanism of reperfusion arrhythmias, although this has not
been demonstrated clinically in patients who have undergone reperfusion
therapy because of AMI.
A great deal has been surmised from animal studies regarding the mechanism of AIVR and VT when occluded vessels were reperfused. Specifically, AIVR is believed to result from abnormal automaticity of the subendocardial Purkinje fibers.4 16 26 In contrast, VT is caused by either reentrant or nonreentrant mechanisms and in some cases by triggered activity as a result of DAD.4 5 However, the reperfusion arrhythmias found in the clinical setting may differ from those observed in experimental models, because factors such as lesion location, collateral flow grade, time to reperfusion, and coronary flow volume can vary. Even among clinical studies, varied incidence of reperfusion arrhythmias has been demonstrated.2 27 28 29 30 31 These results suggest that mechanisms responsible for AIVR and VT in clinical cases might be somewhat different from those observed in experimental models. In the present study, we clinically demonstrated for the first time that AIVR and VT that occur after reperfusion are probably cAMP-mediated arrhythmias and are therefore likely to be triggered arrhythmias.
The incidence of Vfib in clinical settings has been reported to be low.28 29 30 31 In the present study, Vfib occurred in only 2 patients (5.3%) in the non-DP (control) group. In both patients, acceleration of VT occurred before Vfib. These findings are consistent with the mechanism of Vfib described by Moe et al.32 No patients had Vfib in the DP group. This is thought to be attributable to the fact that, by preventing VT from developing immediately after reperfusion, dipyridamole may prevent the acceleration and degeneration of VT into Vfib. Furthermore, because triggered activity has been demonstrated as the mechanism responsible for Vfib,33 it is possible that dipyridamole prevents development of Vfib by suppressing intracellular calcium overload.
Study Limitations
The present study has several limitations. First, it was
not a randomized clinical study. However, the incidences of AIVR, VT,
and Vfib in the control group were similar or even lower than in
previous reports.2 28 29 30 31 Therefore, we believe that the
control group is representative and that the results of
the study have clinical significance even though the study was not
randomized. Second, dipyridamole is known to cause
coronary steal.34 No patients who received
dipyridamole in this study had stenosis
(90%) of any coronary artery other than the infarct-related
artery. In patients with severe stenoses in arteries other than
the infarct-related coronary artery, coronary steal
might occur and exert a proarrhythmic effect. This issue will require
additional study. Third, it remains to be clarified whether
administration of dipyridamole can prevent development
of Vfib. To define the antiarrhythmic efficacy of this agent against
reperfusion-induced Vfib, further studies that include greater numbers
of patients are needed.
Received June 23, 1999; revision received September 1, 1999; accepted September 15, 1999.
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