© 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
Does treatment with ACE inhibitors or angiotensin II receptor antagonists prevent atrial fibrillation after dual chamber pacemaker implantation?
The Cardiothoracic Centre Thomas Drive, Liverpool L14 3PE, UK
Manuscript submitted 10 July 2004. Accepted after revision 20 June 2005.
*Corresponding author. South Manchester University Hospitals Trust, Cardiac Transplant Unit, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. Tel.: +44 151 228 1616; fax: +44 151 293 254. E-mail address: simongwilliams{at}hotmail.co.uk
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Abstract |
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AIMS: A retrospective observational study was performed to test the hypothesis that a lower incidence of atrial fibrillation (AF) would be observed in patients treated with either angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists (AIIRAs) than those without these drugs, 1-year following implantation of a dual chamber pacemaker for all indications.
METHODS: One hundred and sixty consecutive patients who underwent implantation of a dual chamber pacemaker between January and August 2002 were identified and their case notes were retrospectively analysed. The primary endpoint was the presence of persistent AF (confirmed by 12-lead ECG recorded from the visit to the pacemaker clinic) at 12-month follow-up.
RESULTS: Overall, 8% patients developed new onset persistent AF at 1-year follow-up. The incidence of AF at 1-year was 4% in patients treated with ACE inhibitors, 8% in patients taking AIIRAs or 5% on either drug. Although a trend towards a higher incidence of AF was observed at 1-year (10%) in patients not receiving either of these drugs, this was not statistically significant (P = 0.21, drug vs. no drug). The incidence of AF in patients with a previous history of paroxysmal AF or cardioversion was significantly higher (23%) than those patients without (5%), P < 0.0001. An odds ratio (95% CI) of 7.9 (2.3–27.8) was obtained.
CONCLUSION: To confirm these interesting initial results and to investigate this important relationship further, larger prospective randomised controlled studies are required.
Key Words: angiotensin II, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, dual chamber pacemakers, atrial fibrillation
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Introduction |
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Atrial fibrillation (AF) is the most commonly encountered chronic cardiac arrhythmia affecting 5% of the United Kingdom's population above 65 years and rising to 10% above 75 years[1]
. It is associated with an increased risk of systemic embolization[2], haemodynamic dysfunction and tachycardia mediated cardiomyopathy [3]–[5]. Recent randomised studies [6],[7] have shown dual chamber pacing (with or without rate response, DDD ± R) to be associated with a significant incidence of AF in the initial 2–3 years following pacemaker implantation. The exact mechanism for this is unknown, but as both DDD(R) and VVI(R) modes of pacing increase the incidence of AF compared with AAI(R), the likely mechanism, is thought to be right ventricular (RV) pacing causing an increase in left atrial (LA) size. Cumulative percent ventricular paced (Cum%VP) has an almost linear relationship with development of AF[6]. The incidence of new onset AF in DDD pacing can be as high as 24% at 3-year follow-up[7].
Collagen formation in atrial tissue may contribute to structural remodelling and fibrosis leading to the development of AF [8],[9]. Angiotensin II is one of the substances responsible for collagen formation. Previous work has shown increased atrial expression of angiotensin converting enzyme (ACE) and angiotensin II in fibrillating human tissue[10]. In experimental models of AF both ACE inhibitors and angiotensin receptor blockade appear to have a useful role in reducing AF [11],[12]. This mechanism is complex and thought to be involved in the prevention of atrial electrical and structural remodelling that promotes AF[11]–[14].
In a clinical setting, both ACE inhibition and specific antagonism at the angiotensin II receptor level decrease the recurrence of AF following cardioversion[15],[16]. ACE inhibition also reduces the incidence of AF following myocardial infarction (MI)[17] and in patients with left ventricular (LV) systolic dysfunction[18]. Similar data in hypertensive patients have shown a reduction in new onset AF in patients treated with ACE inhibitors[19] or angiotensin II receptor antagonists[20].
This retrospective observational study tested the hypothesis that a lower incidence of AF would be observed in patients treated with either ACE inhibitors or AIIRAs than those without these drugs, 1-year following DDD ± R pacing for all indications.
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Methods |
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One hundred and sixty consecutive patients undergoing dual chamber pacing for all indications at a regional cardiothoracic centre in United Kingdom between January and August 2002 were identified. Case notes were analysed retrospectively. Information including patient details, past medical history (including hypertension and history of previous arrhythmia), indication for pacemaker and baseline electrocardiogram (ECG) were recorded before pacemaker implantation. Patients in AF condition at the time of implant were excluded from the analysis. The primary endpoint was the presence of persistent AF (confirmed by 12-lead ECG recorded from the visit to the pacemaker clinic) at 12-month follow-up.
Data are expressed as mean ± SD for continuous variables, and frequencies were measured for categorical variables. The effect of the treatment groups (drug [ACE inhibitor, ARIIA or either drug] vs. no drug) on the development of AF was compared using the Chi-squared test. Logistic regression was used to identify significant independent predictors of AF and odds ratios were constructed for these predictors. P < 0.05 was considered statistically significant.
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Results |
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Baseline clinical characteristics of study population
Baseline characteristics of the study group are shown in Table 1. All patients underwent successful implantation of a dual chamber pacemaker without lead displacement complications at or around the time of implant. Indications for pacing were as follows: 110 (69%) for evidence of A-V block, 15 (9%) for sinoatrial disease, 19 (12%) for implantable cardiac defibrillator (ICD) implantation and 16 (10%) for other indications, e.g. carotid sinus syndrome. Mean (±SD) age was 74 ± 13 (range 20–95) years and 93 patients (58%) were male. Forty-seven (29%) patients were taking ACE inhibitors and 13 (8%) patients were on AIIRAs, 60 (38%) patients were therefore on either drug. Fourteen (9%) patients were taking amiodarone and 25 (16%) were prescribed beta-blockers. Forty-eight (30%) patients had a history of hypertension and 30 (19%) had a past history of AF, either previously cardioverted or paroxysmal.
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Incidence of AF and effect of drug treatment
Overall, 13 (8%) patients developed new onset persistent AF at 1-year follow-up. Fig. 1a illustrates the incidence of AF according to treatment with either ACE inhibitors or AIIRAs. The incidence of AF at 1-year was 4% in patients treated with ACE inhibitors, 8% in patients taking AIIRAs or 5% on either drug. Although a trend towards a higher incidence of AF was observed at 1-year in 10% of patients not receiving either of these drugs, this was not statistically significant (P = 0.21, drug vs. no drug). There was no significant difference in the incidence of AF in patients taking beta-blockers (12%) or not (7%), P = 0.56, or amiodarone (7%) or not (8%), P = 0.82. These data are demonstrated in Fig. 1b.
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Influence of hypertension and previous AF
In hypertensive patients, the incidence of AF was 10% vs. 7% in patients who were normotensive (P = 0.42). However, the incidence of AF in patients with a previous history of paroxysmal AF or cardioversion was significantly higher (23%) than those patients without (5%), P < 0.0001. These data are illustrated in Fig. 1c. Logistic regression identified previous history of AF to be an independent predictor of AF at 1-year with an odds ratio (95% CI) of 7.9 (2.3–27.8). Of the 130 (81%) patients who did not have a previous history of AF, the incidence of AF at 1-year was 3%. Fifty (38%) patients in this subgroup were taking either ACE inhibitors or AIIRAs. There was a lower incidence of AF at 1-year in patients taking drug treatment (2%) vs. no drug treatment (5%), although this was not statistically significant (P = 0.24).
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Discussion |
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The results from this retrospective study show that there is a trend, although not statistically significant, towards a lower incidence of AF 1-year following dual chamber pacemaker implantation in patients receiving treatment with either an ACE inhibitor or an ARIIA (5%) than in those patients who were not on either of these medications (10%). Not surprisingly, the only clinical factor shown to be significantly associated with the development of AF was a previous history of AF.
The overall incidence of new onset AF in our study, 1-year following pacemaker implantation was 8%, which is similar to previous reports [6],[7]. A previous study of elderly (>65 years) patients receiving pacemakers for a range of indications showed an AF incidence of 17% with dual chamber pacing at 30 months of follow-up[21]. Studies of patients with sinus node dysfunction having dual chamber pacing found the incidence of AF during follow-up ranging from 15.2%[22] to 23%[7] over 33 months. Although the exact mechanism whereby pacing increases the risk of AF is unknown, AF is more common with increasing amounts of ventricular pacing [6],[7],[22]. In addition, hospital admissions for heart failure occurred in 10.3% of patients in one study[6], and were related to the amount of ventricular pacing. The likely role of ventricular pacing in promoting heart failure (CHF) and AF in these patients is supported by echocardiographic data demonstrating that right ventricular pacing results in LA dilatation and reduced left ventricular fractional shortening[7].
Further evidence for the adverse effect of ventricular pacing on left ventricular function is seen in studies of ICD patients. In the MADIT II study[23] there was an increase in heart failure hospitalisations in those patients receiving ICDs, which has been linked to a reduction in ventricular function secondary to pacing. Right ventricular apical pacing resulting in deterioration in heart failure symptoms has also been noted by other investigators[24]. Minimising right ventricular pacing by programming dual chamber ICDs to VVI, 40/min, has previously been shown to be associated with less heart failure than with conventional dual chamber pacing[25].
This is the first study to examine whether treatment with drugs that block the effects of angiotensin II might reduce the higher incidence of AF seen in patients receiving dual chamber pacemakers. Although the result shows no significant differences in the incidence of AF at 1-year between the two groups, the trend to a slightly lower incidence is noteworthy. In this non-randomised, retrospective study one could argue that patients treated with ACE inhibitors and AIIRAs might be expected to have a higher incidence of AF than those patients not taking these. This is on the basis that the principal indications for treatment with these drugs (hypertension and cardiac failure) are also potent risk factors for the development of AF.
Previously, larger studies have shown that ACE inhibitors lower the incidence of AF in patients with congestive heart failure (CHF)[18], post-MI LV dysfunction[17] and hypertension[19]. Although the initial studies of ACE inhibitors in patients with LV dysfunction were not specifically designed to investigate their effects on the incidence of AF, subsequent analysis of the data from these studies support the use of ACE inhibitors in the prevention of AF. Follow-up data from the TRACE study[17] showed a reduction in new onset AF from 5.3% on placebo to 2.8% on trandolapril over 3 years of follow-up. The reduction in new onset AF in a group of patients at a single centre treated with enalapril in the SOLVD study was even more impressive, with a new onset AF rate on placebo of 24% vs. 5.4% on enalapril over 3 years of follow-up[18]. Data on the use of ACE inhibitors and AIIRAs to prevent recurrent AF following DC cardioversion are also emerging. The addition of lisinopril[15] or irbesartan[16] to amiodarone in the pericardioversion period has been shown to reduce the risk of recurrent AF post-cardioversion. Further evidence for the use of these drugs was provided by Madrid and colleagues[26], who performed a meta-analysis of seven trials consisting of 24,849 patients with a wide variety of cardiovascular diseases (hypertension, CHF, ischaemic heart disease and diabetes mellitus). Treatment with ACE inhibitors or AIIRAs significantly reduced the development or recurrence of AF (odds ratio 0.57; 95% CI, 0.39–0.82, P = 0.003) compared with either placebo or conventional treatment.
A lower, although not statistically significant, incidence of AF (5%) was observed in patients treated with either ACE inhibitors or AIIRAs than those without these drugs (10%) in our study is therefore consistent with previous clinical data. There are good theoretical reasons to believe that drugs that inhibit angiotensin II may be of use in preventing AF in patients undergoing dual chamber pacing, especially in the setting of LV dysfunction. The experimental induction of heart failure in dogs by rapid ventricular pacing promotes the induction and maintenance of AF[9]. The underlying mechanism of increased susceptibility to AF is considered to be changes in atrial conduction, secondary to atrial fibrosis. Treatment of dogs with enalapril during induction of heart failure by rapid ventricular pacing reduces atrial fibrosis and the duration of induced episodes of AF[2]. Coupled with these effects, enalapril was shown to reduce atrial tissue concentrations of angiotensin II and mitogen-activated protein kinases (MAPK), important mediators of angiotensin II induced tissue changes[27]. Echocardiographic data from the same group have demonstrated that part of the beneficial effects of enalapril may be mediated by attenuation of left atrial enlargement in this animal model[28]. Furthermore, AIIRAs have been shown to have direct electrophysiological effects on potassium currents (e.g. Kv 1.5, Kv 4.3) involved in cardiac repolarisation [13], [14].
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Study limitations |
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The small number of patients in this analysis may have limited the statistical power needed to determine a significant difference in the incidence of new onset AF between those patients taking ACE inhibitors or AIIRAs and those patients not taking these drugs. To confirm these interesting initial results, larger prospective randomised controlled studies are required.
Left ventricular function data were not available for all patients and this may have affected and influenced the incidence of AF. However, assessment of left ventricular function by echocardiography or other means is often difficult and not always accurate in patients with bradyarrhythmias prior to pacemaker implantation. Cumulative percent ventricular paced data were also not available in all patients and this would need to be corrected for a future study.
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Conclusions |
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Previous studies have shown that the drugs that inhibit angiotensin II (ACE inhibitors and AIIRAs) reduce the incidence of AF in patients with LV systolic dysfunction, following MI and electrical cardioversion. This is the first study to examine whether treatment with these drugs reduces the incidence of AF seen in patients receiving dual chamber pacemakers. We observed a trend, although not statistically significant, towards a lower incidence of AF 1-year following dual pacemaker implantation in those patients receiving treatment with either an ACE inhibitor or an ARIIA (5%) than in patients who were not on either of these medications (10%). To confirm these interesting initial results and to investigate this relationship further, larger prospective randomised controlled studies are required. Following the disappointing results of therapies designed to modify atrial electrical remodelling, the blockade of angiotensin II and prevention of atrial structural remodelling represent a new area of hope in the battle against AF.
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Footnotes |
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This work was presented in abstract form at Cardiostim in Nice, June 2004. 
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References |
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[1] Final consensus statement: consensus conference on atrial fibrillation in hospital and general practice. Proceedings of Royal College of Physicians supplement July 1999; vol. 29:.
[2] Halperin J.L. and Hart R.G. Atrial fibrillation and stroke: new ideas, persisting dilemmas. Stroke 1988; 19: 937–941.
[3] Prystowsky E.N. and Katz A.M. Atrial fibrillation. In Topol E.S. (Ed.). Textbook of cardiovascular medicine 1998; Philadelphia Lippincott-Raven pp. 1827–1861.
[4] Morillo C.A., Klein G.J., Jones D.L., Guiraudon C.M. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation 1995; 91: 1588–1595.
[5] Packer D.L., Bardy G.H., Worley S.J., et al. Tachycardia induced cardiomyopathy: a reversible form of left ventricular dysfunction. Am J Cardiol 1986; 57: 563–570.[CrossRef][Web of Science][Medline]
[6] Sweeney M.O., Hellkamp A.S., Ellenbogen K.A., et al. Adverse effects of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003; 107: 2932–2937.
[7] Nielsen J.C., Kristensen L., Andersen H.R., et al. A randomized comparison of atrial and dual chamber pacing in 177 consecutive patients with sick sinus syndrome. J Am Coll Cardiol 2003; 42: 614–623.
[8] Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002; 415: 219–226.[CrossRef][Medline]
[9] Li D., Fareh S., Leung T.K., Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodelling of a different sort. Circulation 1999; 100: 87–95.
[10] Goette A., Staack T., Röcken 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: 1669–1677.
[11] Kumagai K., Nakashima H., Urata H., et al. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodelling in atrial fibrillation. J Am Coll Cardiol 2003; 41: 2197–2204.
[12] Verheule S., Wilson E., Everett T., et al. Alterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation. Circulation 2003; 107: 2615–2622.
[13] Moreno I., Caballero R., Gonzalez T., Arias C., et al. Effects of irbesartan on cloned potassium channels involved in cardiac repolarisation. J Pharmacol Exp Ther 2003; 304: 862–873.
[14] Caballero R., Delpon E., Valenzuela C., Longobardo M., et al. Direct effects of candesartan and eprosartan on human cloned potassium channels involved in cardiac repolarisation. Mol Pharmacol 2001; 59: 825–836.
[15] Van Den Berg M.P., Crijins H.J.G.M., Van Veldhuisen D.J., et al. Effects of lisinopril with heart failure and chronic atrial fibrillation. J Card Fail 1995; 1: 55–63.
[16] Madrid A.H., Bueno M.G., Rebollo J.M.G., et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation. Circulation 2002; 106: 331–336.
[17] Pederson O.D., Arndt M., Rocken C., et al. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999; 100: 2678–2681.
[18] Vermes E., Tardif J.C., Bourassa M.G., et al. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the studies of left ventricular dysfunction (SOLVD) trials. Circulation 2003; 107: 2926–2931.
[19] L'Allier P.L., Ducharme A., Keller P-F., et al. Angiotensin converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation. J Am Coll Cardiol 2004; 44: 159–164.
[20] Wachtell K., Lehto M., Hornestam B., et al. Losartan reduces the risk of new-onset atrial fibrillation in hypertensive patients with electrocardiogram left-ventricular hypertrophy: the LIFE study. Eur Heart J 2003; 24: 504 [abstract].
[21] Lamas G.A., Orav E.J., Stambler B.S., et al. Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. Pacemaker selection in the elderly investigators. N Engl J Med 1998; 338: 1097–1104.
[22] Lamas G.A., Lee K.L., Sweeney M.O., et al. Mode selection trial in sinus. Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med 2002; 346: 1854–1862.
[23] Moss A.J., Zareba W., Hall W.J., Multicenter automatic defibrillator implantation trial II investigators W.J., et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346: 877–883.
[24] Saad E.B., Marrouche N.F., Martin D.O., et al. Frequency and associations of symptomatic deterioration after dual-chamber defibrillator implantation in patients with ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2002; 90: 79–82.[CrossRef][Web of Science][Medline]
[25] Wilkoff B.L., Cook J.R., Epstein A.E., et al. Dual chamber and VVI implantable defibrillator trial investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the dual chamber and VVI implantable defibrillator (DAVID) trial. JAMA 2002; 288: 3115–3123.
[26] Madrid A.H., Peng J., Zamora J., Marin I., et al. The role of angiotensin receptor blockers and/or angiotensin converting enzyme inhibitors in the prevention of atrial fibrillation in patients with cardiovascular diseases. Pacing Clin Electrophysiol 2004; 27: 1405–1410.[CrossRef][Medline]
[27] 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.
[28] Shi Y., Li D., Tardif J.C., et al. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure. Cardiovasc Res 2002; 54: 456–461.
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