Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation

Results of a prospective and controlled study

Kwo-Chang Uenga,*, Tsung-Po Tsaia, Wen-Chung Yub, Chin-Feng Tsaia, Ming-Cheng Lina, Kuei-Chuan Chana, Chung-Yin Chenb, Der-Jinn Wua, Chung-Sheng Lina and Shih-Ann Chenb

a Division of Cardiology and Cardiovascular Surgery, Institute of Medicine, Chung-Shan Medical University Hospital, Taichung, Taiwan
b National Yang-Ming University, School of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

* Correspondence to: Kwo-Chang Ueng, MD, Division of Cardiology, Chung-Shan Medical University Hospital, Taichung, 110, Sec. 1, Chien-Kuo N. Rd., Taichung, Taiwan. Tel: 886-4-2253-2603; Fax: 886-4-2252-3626
E-mail address: ueng.kc{at}msa.hinet.net

Received 28 April 2003; revised 22 July 2003; accepted 14 August 2003

Abstract

Aims This study aimed to assess whether enalapril could improve cardioversion outcome and facilitate sinus rhythm maintenance after conversion of chronic atrial fibrillation (AF).

Methods and results Patients with chronic AF for more than 3 months were assigned to receive either amiodarone (200mg orally 3 times a day; group I: n=75) or the same dosage of amiodarone plus enalapril (10mg twice a day; group II: n=70) 4 weeks before scheduled external cardioversion. The end-point was the time to first recurrence of AF. In 125 patients (86.2%), AF was converted to sinus rhythm. Group II had a trend to a trend to a lower rate of immediate recurrence of AF than group I did (4.3% vs 14.7%, P=0.067). Kaplan–Meier analysis demonstrated a higher probability of group II remaining in sinus rhythm at 4 weeks (84.3% vs 61.3%, P=0.002) and at the median follow-up period of 270 days (74.3% vs 57.3%, P=0.021) than in group II.

Conclusion The addition of enalapril to amiodarone decreased the rate of immediate and subacute arrhythmia recurrences and facilitated subsequent long-term maintenance of sinus rhythm after cardioversion of persistent AF.

Key Words: Atrial fibrillation • Remodelling • Angiotensin-convertingenzyme inhibitor

1. Introduction

Atrial fibrillation (AF), the most common sustained arrhythmia in the elderly, increases the risk of stroke and it and also itis an independent predictor of mortality.1–3Transthoracic electrical cardioversion of AF is one of the most widely used and effective treatments for restoration of sinus rhythm.4,5However, it it has a limited success rate and a high recurrence rate, which is only partially affected by anti-arrhythmic treatment.6,7Clinical observations have demonstrated that the recurrence of AF is frequently clustered within the first month after cardioversion.8,9Most of the recurrences are probably due to electrical and structural remodelling, caused by changes in the refractory period of atrial muscle8,10,11and atrial fibrosis with intra-atrial conduction disturbances.

Recently, several studies12–14have demonstrated that the atrial angiotensin system may play an important role as a mediator of atrial remodelling in AF. A recent study15supporting this notion showed that there was a lower recurrence rate of AF and a longer time to first arrhythmia recurrence in patients with AF lasting more than 7 days who were treated with amiodarone and irbesartan. However, the effect of angiotensin converting enzyme (ACE) inhibitor on cardioversion outcome and subsequent maintenance of sinus rhythm in patients with persistent AF lasting more than 3 months is not known. Therefore, the aim of the current study was to investigate in a prospective, controlled fashion whether the ACE inhibitor enalapril facilitates maintenance of sinus rhythm in patients receiving electrical cardioversion of chronic AF.

2. Methods

2.1. Patient population
From May 2001 to January 2003, 180 consecutive patients with persistent AF for more than 3 months by serial electrocardiograms (ECG) were prospectively included. All of the patients were in stable cardiac condition. Written informed consent was obtained from all patients before they entered the study. Underlying heart disease was determined from the patient's history, physical examination, chest X-ray film, transthoracic and/or transoesophageal echocardiogram and, if available, coronary angiography. Patients with any of the following conditions were excluded from the study: age younger than 18 years; significant rheumatic stenosis; a left atrium size larger than 6.0cm in long axis view; myocardial infarction within 6 months or unstable angina; severe uncontrolled heart failure (New York Heart Association functional class IV); heart surgery within the last 6 months; a previous adverse reaction to amiodarone or enalapril; significant thyroid, pulmonary, hepatic or renal disease; a history of thromboembolism within 6 months; pregnancy or fertile female; significant electrolyte imbalance; QT prolongation (i.e. corrected QT more than 0.45s); sick sinus syndrome; significant alterations of the atrioventricular conduction; an implanted pacing device.

2.2. Study protocol and follow-up (Fig. 1)
Patients with AF lasting more than 3 months were admitted to the hospital for external cardioversion after at least 4 weeks of adequate treatment with warfarin at a dosage adjusted to achieve an international normalized ratio of two or more. Patients were randomized in an open-label fashion into two groups. Patients received either oral amiodarone 200mg three times daily alone or amiodarone 200mg three times daily plus enalapril 10mg twice daily 4 weeks before electrical cardioversion. To control blood pressure, enalapril 10mg was administered at twice daily and could be increased to 20mg twice daily in patients with hypertension. Electrical cardioversion was scheduled after 4 weeks of randomization.



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Fig. 1 Trial profile.

 
Details of the external cardioversion procedure in our laboratory have been described previously.10In brief, it was performed with the patient in the fasting state. After obtaining a 12-lead ECG and measurement of arterial pressure, the patients were attached to an external defibrillator (CodeMaster XL+, Hewlett-Packard). Then, the patients were adequately anesthetized with propofol (1.5mg/kg, i.v.), and a direct current shock synchronized to the R wave was delivered. The location of the paddle was oriented in the apex-sternum direction and shocks were delivered with a step-up (100, 200, 300 and 360J) protocol until any of the following conditions were achieved: sinus rhythm or immediate recurrence of AF (IRAF) (defined as recurrence of AF within 2min after at least one sinus beat achieved by external shock). Supplemental oxygen was provided to ensure oxygen saturation more than 90%. Careful registration of a continuous 12-lead ECG rhythm started before the first shock and continued for 2min after the last shock to look for all atrial premature beats (APBs), any IRAF episodes and their mode of onset. After successful electrical cardioversion, a daily maintenance dose of 200mg of amiodarone was given for all patients. Enalapril was either maintained at the same dose as before in those patients randomized to enalapril or increased to 20mg twice daily if the patient had high blood pressure. Patients were discharged 24 to 48h after cardioversion. Anticoagulation was continued for at least 4 weeks after electrical cardioversion. Before hospital discharge, the patients were instructed in using an event recorder (Sentinel, Del Mar, CA USA). They were requested to make a 90-s recording every morning immediately after they woke up. All patients were seen at an outpatient clinic at each week in during the first month, then monthly thereafter, and at any time the patient complained of palpitations or other symptoms. Standard 12-lead ECG and inquiry about any recurrence of palpitation were done at each visit. A 24-h Holter recording was performed at 1, 6 and 12 months, and at any time the patient had any symptoms such as palpitations, dyspnoea, or chest congestion suggestive of recurrence of AF.

2.3. Definition of terms
Cardioversion was deemed successful if sinus rhythm was established and maintained for at least 2min. Total shock failure was defined as no any sinus beat emerges throughout the course of electrical cardioversion. After the ultra-short IRAF period, relapses of AF within 4 weeks were deemed as subacuterecurrences.

2.4. End-point of the study
The end-point was the length of time to a first electrocardiographically confirmed recurrence of AF or atrial flutter. Only episodes lasting longer than 10min (as indicated by the history) were considered to be clinically significant. For the purpose of the end-point, the beginning of the follow-up was considered to be the day of the scheduled electrical cardioversion (day 0). Patients in whom sinus rhythm was not achieved were classified as having had a recurrence on day 0.

2.5. Statistics
The sample size was calculated to provide the study with 80% power for a two-sided alpha level of 0.05, assuming a 50% relapse free rate in the amiodarone group and a 70% relapse free rate in the amiodarone plus enalapril group within 1 year after cardioversion.

Parametric data are expressed as the mean±SD or numbers and percentages of patients. Continuous variables were compared between two treatment groups using the unmatched t- test, and categorical data by the chi-square test with Yates’ correction or Fisher's exact test as appropriate. Estimates of the proportion of patients remaining in sinus rhythm over time were constructed using the method of Kaplan–Meier and compared using the log-rank test. To find variables possibly related to recurrence of AF, log-rank comparisons of Kaplan–Meier curves were also used for an univariate assessment of the prognostic value of potential risk factors, such as age, sex, left atrial size, left ventricular ejection fraction, the presence or absence of underlying cardiac disease, and the duration of AF prior to cardioversion, measured at study entry. Subsequently, variables with a P value <0.20 were selected for multivariate Cox proportional hazards regression analysis. The assumption of proportional hazards was checked by estimating plots of the logarithm of the cumulative hazard. The risk reductions of AF relapse after electrical cardioversion were calculated in the form of hazard ratios and 95% CIs from Cox's proportional hazards models. The risk reduction for amiodarone plus enalapril against amiodarone alone was calculated as 100x (1-hazard ratio). The principal evaluation of efficacy of both treatment modalities in the prevention of AF recurrence after cardioversion was made from all patients who received electrical cardioversion. For patients who were lost to follow-up, events were censored at the last visit. A P value less than 0.05 was considered statistically significant.

3. Results

3.1. Patients characteristics
Among the 180 patients, 159 patients were randomized to participate in the present study. Within 4 weeks after randomization, eight patients (two in the amiodarone group, six in the amiodarone plus enalapril group) were withdrawn from the study because of pharmacological side effects (slow ventricular response in three patients with treatment of amiodarone and dry cough in six patients with treatment of enalapril). In six patients, sinus rhythm was documented at the time of the scheduled electrical cardioversion, of whom three were in the amiodarone group and three were in the amiodarone plus enalapril group. These patients were excluded from analysis. Finally, 145 patients wereanalyzed. Among these patients, 75 were assigned to amiodarone, and 70 to amiodarone and enalapril. The baseline demographic and clinical characteristics and the concomitant cardiovascular medications are shown in Table 1. The median duration of AF before attempted cardioversion was 34 months (range, 4 to 144), with no differences among the groups. For patients treated with enalapril, the daily dose of enalapril ranged from 20 to 40mg, with 27.1% of the patients receiving 40mg. Final systolic blood pressure values were similar between the amiodarone group and amiodarone plus enalapril group (129±15 vs 127±18mmHg, P=0.553).


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Table 1 Baseline characteristics of study patientsa

 
3.2. Results of electrical cardioversion
Electrical cardioversion converted AF to sinus rhythm in 125 patients (86.2%). Patients in the amiodarone plus enalapril group had a trend to a higher success rate of restoring sinus rhythm than those patients in the amiodarone group did (91.4% vs 81.3%, P=0.128), although it did not reach statistical significance. Table 2summarizes the results of electrical cardioversion in two groups. The mean electrical energy and number of shocks required for successful cardioversion were similar in the two groups (amiodarone group vs amiodarone plus enalapril group: 219±85 vs 212±86J, and 2.2±0.9 vs 2.1±0.9 shocks; P=0.629 and 0.536, respectively). Of these patients, sinus rhythm could not be achieved in six patients because of total shock failure (three in the amiodarone group and three in the amiodarone plus enalapril group, P=0.931).


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Table 2 Cardioversion results

 
3.3. Immediate recurrence of atrial fibrillation
Overall, 14 episodes of spontaneous AF reinitiation (11 in the amiodarone group and three in the amiodarone plus enalapril group) within 2min, which accounts for 70% of ineffective cardioversion, were observed at a median duration of 22s (range, 4 to 88) immediately after electrical cardioversion. All IRAF episodes were initiated by APBs with preceding normal sinus rate or cycle length oscillation. Furthermore, patients receiving enalapril had significantly fewer APBs within 2min after cardioversion than those not receiving enalapril (9±8 vs 19±13 APBs/2min after cardioversion, P=0.001). Patients in the amiodarone plus enalapril group had a non-significant trend to a trend to a lower rate of IRAF than those patients in the amiodarone group did (4.3% vs 14.7%, P=0.067).

3.4. Subacute recurrence of atrial fibrillation
At the 4-week follow-up visit, 40 patients had a recurrence of AF. Recurrence of AF within 4 weeks occurred in 11 patients of the amiodarone plus enalapril group, as compared with 29 patients in the amiodarone group. Kaplan–Meier analysis demonstrated that the probability of remaining in sinus rhythm at 4 weeks was higher among the patients assigned to amiodarone plus enalapril (84.3%) than among those assigned to amiodarone alone (61.3%, P=0.002). For the patients treated with enalapril, the hazard ratio for a recurrence of AF was 0.31, reflecting a 69% reduction in the risk of subacute recurrence of AF within 4 weeks after cardioversion (95% CI 0.11 to 0.87; P=0.026). After the Cox proportional model was applied, correcting for those confounding factors (i.e. left atrial size, or the left ventricular ejection fraction), the hazard ratio was 0.37, reflecting a 63% reduction (95% CI 0.12 to 1.15; P=0.041). In addition, APBs count was significantly fewer in patients receiving enalapril during 24-h Holter recording at 4-week follow-up than those not receiving enalapril (80±176 vs 205±414 APBs, P=0.038).

3.5. Long-term outcome
After a median follow-up period of 270 days (range, 61 to 575), Kaplan–Meier analysis (Fig. 2A) showed that the amiodarone plus enalapril group had a higher incidence of patients remaining in sinus rhythm (74.3% vs 57.3%,P=0.021). Moreover, the most important variable shown to independently influence late outcome by multivariate analysis was left atrial size >40mm prior to cardioversion. Fig. 2B and Fig. 2C clearly show that enalapril plus amiodarone was superior to amiodarone alone after cardioversion in subgroup patients with left atrial size >40mm (hazard ratio 0.48; 95% CI 0.25 to 0.91; P=0.026).



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Fig. 2 Kaplan–Meier plots depicting the percentage of patients remaining free from recurrence of atrial fibrillation. Panel A shows the estimates of the proportion of patients with no recurrence of atrial fibrillation in the two groups; Panel B and C show the results of treatment with enalapril on time to recurrence of atrial fibrillation for subgroup patients with left atrial dimension > or <=40mm.

 
3.6. Complications of electrical cardioversion and adverse effects during follow-up
Overall, 314R wave synchronized shocks were delivered without cardioversion-related thromboembolic event. Transient sinus bradycardia (less than 50beats/min) occurred in 19 (25.3%) amiodarone group patients and 15 (21.4%) amiodarone plus enalapril group patients respectively within 2min after cardioversion, but in all cases it was well tolerated and short-lasting (less than 60s). However, one patient required permanent pacemaker implantation because of sick sinus syndrome during follow-up. There were no ventricular proarrhythmic effects, defined as the new onset of sustained ventricular tachycardia, ventricular fibrillation or torsades de pointes, either in patients treated with amiodarone or in those treated with amiodarone plus enalapril. However, four patients had typical atrial flutter and underwent radiofrequency catheter ablation during follow-up. Adverse clinical events resulted in discontinuation in four patients (5.3%) treated with amiodarone and seven patients (10.0%) treated with amiodarone plus enalapril. Four patients discontinued enalapril because of dry cough or increased serum concentration of creatinine and/or potassium. Adverse events requiring the discontinuation of amiodarone occurred in four patients treated with amiodarone alone and three patients treated with amiodarone plus enalapril. Pulmonary toxicity was suspected in one male patient in whom pulmonary fibrosis developed 3 months after starting amiodarone and enalapril. This patient had persistent cough and progressive dyspnoea, and infiltration pattern in chest X-ray. After amiodarone was discontinued, the symptoms disappeared. Treatment with amiodarone was discontinued in two patients because of hypothyroidism, and in one because of hyperthyroidism.

4. Discussion

4.1. Major findings
This study has demonstrated that treatment with enalapril decreased the rate of immediate and subacute arrhythmia recurrences and could significantly enhance long-term outcome in patients with long-standing AF after cardioversion. The combination of enalapril and amiodarone was well tolerated and did not increase the risk of electrical cardioversion complications.

4.2. Atrial premature beats and relapse of arrhythmia
The present study and previous studies9,16have found that all IRAF episodes were triggered by APBs. Atrial ectopy clearly remained potentially important as a trigger for reinitiation of AF. The ability of APBs to induce AF depends on their timing and location relative to electrical heterogeneity gradients.17,18The potential importance of ectopic activity in AF has acquired great significance with the recent recognition of the important role of ectopic beats originating from the great venous tissues.19–21When a vulnerable substrate exists, the occurrence of AF requires a trigger, generally provided by ectopic beats. Enalapril might may suppress the APBs, probably by its modifying the sympathetic tone22,23and/or decreasing Na+/Ca2+exchanger activity.24–26Webster et al.27also observed that ACE inhibition was associated with a trend toward reduction of the frequency of APBs over time in addition to a decrease in atrial pressure. In the present study, we showed that patients treated with enalapril had significantly fewer APBs within 2min following cardioversion and at the 4-week follow-up, and also, these patients had less recurrences of AF.

4.3. ACE inhibitors and immediate relapse of atrial fibrillation
The natural history of AF is characterized by a gradual worsening with time. Atrial fibrillation itself alters atrial electrophysiology (termed atrial electrical remodelling, mainly shortening of atrial effective refractory period), and causes atrial dilatation (structural remodelling), which facilitates the perpetuation of AF itself.7,28–30Nakashima et al.12reported that captopril prevented atrial electrical modelling induced by a relatively brief period (6h) of rapid atrial pacing in a dog model. However, a recent manuscript by Shinagawa et al.31have has already shown that enalapril has no effect on longer-term (7 days) electrical remodelling, as might occur with persistent AF. In the present study, patients were in AF for more than 3 months before cardioversion. Thus, it is unlikely that the electrophysiologic effects of ACE inhibitors on electrical remodelling have contributed to the beneficial outcome. In the present study, the finding that treatment with enalapril only resulted in marginal effect on IRAF may be explained as a net result by the persistence of electrical remodelling despite treatment of enalapril and positive effect of enalapril on structural remodelling and fewer APBs during this period.

4.4. ACE inhibitors and subacute recurrence of atrial fibrillation
Most of the benefit of enalapril occurred during the first 4 weeks after conversion. After that, the two curves seem to be parallel. The mechanisms of treatment with enalapril causing this result remain to be understood. In a goat model of AF, changes in atrial refractory periods were no longer evident 1 week after recovery of sinus rhythm.11Everett et al.32demonstrated that complete reversal of electrical remodelling occurred 7 to 14 days after cardioversion of persistent AF in a canine model. However, gross and ultrastructural changes persisted, as did vulnerability to induce AF. Our previous work33also demonstrated that complete reversal of atrial electrical remodelling following cardioversion of chronic AF in humans happened on the third day after cardioversion. However, the present study, as well as previous clinical observation,8has demonstrated that the persistence of atrial vulnerability to fibrillation after cardioversion continues to increase within 2 to 4 weeks after reversal of electrical remodelling. Thus, subacute recurrence of AF within first 4 weeks after electrical cardioversion must be due to a distinct arrhythmogenic mechanism other than electrical remodelling.

Atrial fibrosis could cause circumscribed electrophysiological inhomogeneities of the atria allowing the induction of AF. A recent study by Shi et al.13has shown that experimental congestive heart failure induced by right ventricular pacing creates dilatation of both atria and atrial fibrosis (structural remodelling), which is correlated with vulnerability to AF. In this work, they demonstrated the ability of enalapril to regress atrial fibrosis and reduce associated AF promotion in the setting of congestive heart failure. These findings, suggestinged that the blockade of the atrial tissue ACE is associated with inhibition of collagen type I synthesis. Enalapril has been shown to attenuate arrhythmogenic atrial structural remodelling in an experimental heart failure model.14The ACE inhibitor trandolapril reduced the incidence of AF in post-myocardial infarction patients with left ventricular dysfunction.34However, most patients included in the present study had a nearly normal left ventricular ejection fraction and were predominantly in the New York Heart Association class I–II. Thus, the results from heart failure models may not allow to really allow to explain the findings in patients without overt heart failure.

Recent studies have demonstrated changes in atrial expression/activity of ACE,35angiotensin II receptors,36and bradykinin metabolism37in persistent AF patients with normal left ventricular function. An ACE-dependent change in the amounts of activated extracellular signal-regulated kinases and bradykinin in atrial interstitial cells contributes to the development of atrial fibrosis, which provides a pathophysiologic substrate for AF. Atrial dilatation is another example of structural remodelling. It is an important independent factor to predict the early recurrence of AF, potentially promoting AF by activating stretch-operated channels and/or by increasing atrial mass. Previous report indicated that atrial dilatation increased the vulnerability of AF and opposed the successful maintenance of sinus rhythm.28A recent study by our group38also showed that the increased inhomogeneity in atrial electrophysiological properties during atrial dilatation contributed to the inducibility of AF. Thus, atrial dilatation could play an important role in arrhythmogenesis in clinical settings. In the current study, we demonstrated that the patients with left atrial dimension larger than 40mm was the only clinical parameter to predict of relapse into AF. Treatment with enalapril significantly reduced the recurrence of AF in these patients. These findings suggested potential reversibility of structural remodelling as a therapeutic benefit of ACE inhibition to reduce relapse into AF.

In patients after who have had successful cardioversion, recovery of normal atrial mechanical function was reported to occur from 1 to 4 weeks following after restoration of sinus rhythm.39,40Shi et al.13reported that experimental congestive heart failure causes mechanical abnormalities of both atria, which are correlated with atrial fibrosis. In this study, they demonstrated that enalapril significantly restored atrial emptying function and also reduced the vulnerability to AF. Regardless of the length of time course of the electrophysiological remodelling, it is likely that once a patient is restored to sinus rhythm, the time required for structural remodelling of the atria will likely be much slower than the electrophysiological remodelling of the individual atrial myocytes. We, therefore, believe that recurrence of AF after cardioversion is mostly attributed to atrial electrical and structural remodelling in different time courses, respectively. This may account for the different favourable effects of enalapril on IRAF and subacute recurrences after cardioversion of persistent AF. Besides, the finding that the beneficial role of enalapril seems to be weaning after 4 weeks may be in part attributed to arrhythmia relapse in three out of four patients with withdrawal of enalapril during late follow-up.

Although blood pressure control could be an important part of the mechanism for the benefit of enalapril on AF recurrence, there was similar proportion of hypertension and left ventricular hypertrophy. Also, there was no significant difference in blood pressure between the two groups at the randomization and after the follow-up. Therefore, it is less likely that lowering of blood pressure may play a role in the result of this study. Enalapril could have antiarrhythmic activity by means of other mechanisms. These include decrease of wall stress, improvement of left ventricular systolic function, decrease of end-diastolic left ventricular pressure and subsequently left atrial pressure, ß-blocking properties, and stabilization of electrolyte concentrations.

Recent multicentre, randomized studies41,42reveal that rhythm control offers no advantage over rate control in AF. The rhythm control strategy involved use of a wide range of potentially toxic antiarrhythmic drugs. These results reflect the limitations of current sinus rhythm maintenance therapy. However, novel approaches that may modify adverse structural remodelling were not investigated in these studies. Given the results from the present study and the study by Madrid et al.,15the addition of enalapril or irbesartan to amiodarone can achieve better maintenance of sinus rhythm than those with amiodarone alone during long-term follow-up. Of note, there is accumulating evidence that ACE inhibitor or angiotensin II type 1 receptor blocker treatmentimproves the prognosis in patients with underlyingcardiac disease. Therefore, the development of a new therapeutic target directed against the development of the AF substrate and atrial remodelling is likely to greatly alter the management strategy for these patients. However, further study must show whether such combination treatment can achieve lower complication, better quality of life, and better prevention of stroke and death than rate control can.

4.5. Limitations of the study
The study has several potential limitations: (1) Although combination therapy was superior to amiodarone alone, we cannot define the effects of monotherapy with enalapril because of study design; (2) We cannot exclude the possibility of a distortion in the estimate of the treatment effect (due to not including patients who spontaneously restored to sinus rhythm) in both groups; (3) The median follow-up period of the study was only 270 days that did not reach our presumed long-term follow up within 1 year. However, the Kaplan–Meier curves for both groups appeared to be parallel 6 months after cardioversion. Therefore, there is a reason to make our conclusion regarding the effect of enalapril on long-term follow-up; (4) Although a recovery from structural remodelling has been proposed as the major mechanism by which enalapril reduces subacute AF recurrences, no attempt was made to assess changes in atrial size and fibrosis in the current study, and further studies are necessary to address this question; (5) Hypertension may be associated with renin-angiotensin system activation. Many antihypertensive drugs can modify renin-angiotensin secretion. Diuretics could cause a rise in plasma renin activity, and the ß-blockers depress renin activity. Calcium channel blockade could have some effects on acute electrical remodelling. However, the percentage of patients using these agents was low and similar in both groups. It is unlikely that they may have played a role in the benefit of enalapril on AF recurrence.

5. Conclusion

Concomitant use of enalapril with amiodarone enhances cardioversion outcome in patients with long-lasting AF possibly mainly by attenuating adverse structural remodelling process and reducing APBs, thus reducing subsequent immediate and subacute arrhythmia relapses, and allowing more patients to remain in sinus rhythm.

Acknowledgments

We gratefully acknowledge the expert secretarial work of Wei-Heng Chi.

References

  1. Furberg CD, Pasty BM, Manolio TA et al. Prevalence of atrial fibrillation in elderly subjects. Am J Cardiol. 1994;74:236–241.[Medline]
  2. Sage JI, Van Uitert RL. Risk of recurrent stroke in patients with atrial fibrillation and non-valvular heart disease. Stroke. 1983;14:537–540.[Abstract]
  3. Benjamin EJ, Wolf PA, D'Agostino RB et al. Impact of atrial fibrillation on the risk of death. The Framingham Heart Study. Circulation. 1998;98:946–952.[Abstract/Free Full Text]
  4. Lown B. Electrical reversion of cardiac arrhythmias. Br Heart J. 1976;29:469–489.
  5. Ewy GA, Ulters L, Hager HD et al. Response of atrial fibrillation to therapy: role of etiology and left atrial diameter. J Electrocardiol. 1980;13:119–124.[Medline]
  6. Van Gelder IC, Crijns HJ, Van Gilst WH et al. Prediction of uneventful cardioversion and maintenance of sinus rhythm from direct-current electrical cardioversion of chronic atrial fibrillation and flutter. Am J Cardiol. 1991;68(1):41–46.[Medline]
  7. Crijns HJ, Van Gelder IC, Van Gilst WH et al. Serial antiarrhythmic drug treatment to maintain sinus rhythm after electrical cardioversion for chronic atrial fibrillation or atrial flutter. Am J Cardiol. 1991;68:335–341.[Medline]
  8. Tieleman RG, Van Gelder IC, Crijns HJ et al. Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillation-induced electrical remodeling of the atria? J Am Coll Cardiol. 1998;31(1):167–173.[Medline]
  9. Yu WC, Lin YK, Tai CT et al. Early recurrence of atrial fibrillation after external cardioversion. Pacing Clin Electrophysiol. 1999;22(11):1614–1619.[Medline]
  10. Allessie MA. Atrial electrophysiological remodeling: another vicious circle? J Cardiovasc Electrophysiol. 1998;9:1378–1393.[Medline]
  11. Wijffels MC, Kirchhof CJ, Dorland R et al. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation. 1995;92:1954–1968.[Abstract/Free Full Text]
  12. Nakashima H, Kumagai K, Urata H et al. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation. 2000;101:2612–2617.[Abstract/Free Full Text]
  13. Shi Y, Li D, Tardif JC, Nattel S. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure. Cardiovasc Res. 2002;54(2):456–461.[CrossRef][Medline]
  14. Li D, Shinagawa K, Pang L et al. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation. 2001;104:2608–2614.[Abstract/Free Full Text]
  15. Madrid AH, Bueno MG, Rebollo JM et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation. 2002;106(3):331–336.[Abstract/Free Full Text]
  16. Tse HF, Lau CP, Ayers GM. Incidence and modes of onset of early reinitiation of atrial fibrillation after successful internal cardioversion, and its prevention by intravenous sotalol. Heart. 1999;82(3):319–324.[Abstract/Free Full Text]
  17. Lammers WJ, Schalij MJ, Kirchhof CJ et al. Quantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias. Am J Physiol. 1990;259(4 Pt 2):H1254–H1263.[Medline]
  18. Wang J, Liu L, Feng J, Nattel S. Regional and functional factors determining induction and maintenance of atrial fibrillation in dogs. Am J Physiol. 1996;271(1 Pt 2):H148–H158.[Medline]
  19. Haïssaguerre M, Jaïs P, Shah DC et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339(10):659–666.[Abstract/Free Full Text]
  20. Chen SA, Hsieh MH, Tai CT et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation. 1999;100(18):1879–1886.[Abstract/Free Full Text]
  21. Tsai CF, Tai CT, Hsieh MH et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation. 2000;102(1):67–74.[Abstract/Free Full Text]
  22. Dibner-Dunlap ME, Smith ML, Kinugawa T et al. Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure. J Am Coll Cardiol. 1996;27(2):358–364.[CrossRef][Medline]
  23. Lombardi F, Colombo A, Basilico B et al. Heart rate variability and early recurrence of atrial fibrillation after electrical cardioversion. J Am Coll Cardiol. 2001;37(1):157–162.[CrossRef][Medline]
  24. Chen YJ, Chen SA, Chen YC et al. Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins: implication in initiation of atrial fibrillation. Circulation. 2001;104(23):2849–2854.[Abstract/Free Full Text]
  25. Touyz RM, Sventek P, Lariviere R et al. Cytosolic calcium changes induced by angiotensin II in neonatal rat atrial and ventricular cardiomyocytes are mediated via angiotensin II subtype 1 receptors. Hypertension. 1996;27(5):1090–1096.[Abstract/Free Full Text]
  26. Benardeau A, Hatem SN, Rucker-Martin C et al. Contribution of Na+/Ca2+ exchange to action potential of human atrial myocytes. Am J Physiol. 1996;271(3 Pt 2):H1151–H1161.[Medline]
  27. Webster MW, Fitzpatrick MA, Nicholls MG et al. Effect of enalapril on ventricular arrhythmias in congestive heart failure. Am J Cardiol. 1985;56(8):566–569.[Medline]
  28. Ewy G, Ulfers L, Hager WD et al. Response of atrial fibrillation to therapy: role of etiology and left atrial diameter. J Electrocardiol. 1980;13:119–124.[Medline]
  29. Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation: time course and mechanisms. Circulation. 1996;94:2968–2974.[Abstract/Free Full Text]
  30. Yu WC, Chen SA, Lee SH et al. Tachycardia-induced change of atrial refractory period in humans: rate dependency and effects of antiarrhythmic drugs. Circulation. 1998;97(23):2331–2337.[Abstract/Free Full Text]
  31. Shinagawa K, Mitamura H, Ogawa S et al. Effects of inhibiting Na(+)/H(+)-exchange or angiotensin converting enzyme on atrial tachycardia-induced remodeling. Cardiovasc Res. 2002;54(2):438–446.[CrossRef][Medline]
  32. Everett TH 4th, Li H, Mangrum JM et al. Electrical, morphological, and ultrastructural remodeling and reverse remodeling in a canine model of chronic atrial fibrillation. Circulation. 2000;102(12):1454–1460.[Abstract/Free Full Text]
  33. Yu WC, Lee SH, Tai CT et al. Reversal of atrial electrical remodeling following cardioversion of long-standing atrial fibrillation in man. Cardiovasc Res. 1999;42(2):470–476.[CrossRef][Medline]
  34. Pedersen OD, Bagger H, Kober L et al. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation. 1999;100:376–380.[Abstract/Free Full Text]
  35. Goette A, Staack T, Rocken C et al. Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation. J Am Coll Cardiol. 2000;35(6):1669–1677.[CrossRef][Medline]
  36. Goette A, Arndt M, Rocken C et al. Regulation of angiotensin II receptor subtypes during atrial fibrillation in humans. Circulation. 2000;101(23):2678–2681.[Abstract/Free Full Text]
  37. Lendeckel U, Arndt M, Wrenger S et al. Expression and activity of ectopeptidases in fibrillating human atria. J Mol Cell Cardiol. 2001;33(6):1273–1281.[CrossRef][Medline]
  38. Huang JL, Tai CT, Chen JT et al. Effect of atrial dilatation on electrophysiologic properties and inducibility of atrial fibrillation. Basic Res Cardiol. 2003;98(1):16–24.[CrossRef][Medline]
  39. Van Gelder IC, Crijns HJ, Blanksma PK et al. Time course of hemodynamic changes and improvement of exercise tolerance after cardioversion of chronic atrial fibrillation unassociated with cardiac valve disease. Am J Cardiol. 1993;72(7):560–566.[Medline]
  40. Manning WJ, Silverman DI, Katz SE et al. Impaired left atrial mechanical function after cardioversion: relation to the duration of atrial fibrillation. J Am Coll Cardiol. 1994;23(7):1535–1540.[Medline]
  41. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825–1833.[Abstract/Free Full Text]
  42. Van Gelder IC, Hagens VE, Bosker HA et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347(23):1834–1840.[Abstract/Free Full Text]

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