Pretreatment with ACE inhibitors improves acute outcome of electrical cardioversion in patients with persistent atrial fibrillation

  • Trudeke Van Noord1Email author,

    Affiliated with

    • Harry JGM Crijns2,

      Affiliated with

      • Maarten P van den Berg1,

        Affiliated with

        • Dirk J Van Veldhuisen1 and

          Affiliated with

          • Isabelle C Van Gelder1

            Affiliated with

            BMC Cardiovascular Disorders20055:3

            DOI: 10.1186/1471-2261-5-3

            Received: 13 April 2004

            Accepted: 24 January 2005

            Published: 24 January 2005

            Abstract

            Background

            Persistent atrial fibrillation (AF) is difficult to treat. In the absence of class I or III antiarrhythmic drugs sinus rhythm is maintained in only 30% of patients during the first year after electrical cardioversion (ECV). One of the remodeling processes induced by AF is fibrosis, which relates to inducibility and maintenance of AF. The renin-angiotensin system may play a important role in this. The aim of this study was to investigate the role of angiotensin-converting enzyme (ACE) inhibitor use on efficacy of ECV, and occurrence of subacute recurrences.

            Methods

            One hundred-seven consecutive patients with persistent AF underwent ECV. In twenty-eight (26%) patients ACE inhibitors had been started before initiation of the present episode of AF ('pre-treated' patients).

            Results

            ECV was successful in 96% of patients who were on ACE inhibitors before start of the present episode of AF compared to 80% of the patients not pre-treated (p = 0.04). After 1 month of follow-up 49% of the pre-treated patients and 50% of those not pre-treated with ACE inhibition were still in sinus rhythm (p=ns). Multivariate analysis showed that pre-treatment with ACE inhibitors and a smaller left atrial size were independent predictors of successful ECV (OR = 5.8, C.I. 1.3–26.1, and OR = 5.6, C.I. 1.2–25.3, respectively).

            Conclusions

            Pre-treatment with ACE inhibitors may improve acute success of ECV but does not prevend AF recurrences.

            Background

            Persistent atrial fibrillation (AF) is difficult to treat. In the absence of class I or III antiarrhythmic drugs sinus rhythm is maintained in only 30–50% of patients during the first year after Direct Current electrical cardioversion (ECV)[1, 2]. Furthermore, even following an aggressive approach with repeated ECVs and use of prophylactic drugs, arrhythmia-free outcome is still poor: only 39% of patients maintain sinus rhythm during two years of follow-up[1, 2]. Notwithstanding the recent results of AFFIRM and RACE showing no beneficial effect of rhythm control over rate control a rhythm control strategy may be indicated in severely symptomatic patients and those with a tachycardiomyopathy[3]. In recent years research has focused on the atrial remodeling processes that are induced by AF itself and that trigger the arrhythmia to become sustained: "AF begets AF"[4]. One of the remodeling processes induced by AF is fibrosis. Fibrosis causes dispersion of conduction, which, in its turn is related to inducibility of AF[5]. The renin-angiotensin system seems to play an important role in the development of fibrosis in heart failure. It was shown that pre-treatment with enalapril may attenuate atrial fibrosis and conduction abnormalities in a canine model of heart failure, and the occurrence of AF in patients with left ventricular dysfunction [57]. A recent experimental study showed that angiotensin II blockers may prevent electrical remodeling when started before start of AF[8].

            In the present study we report on the effects of ACE inhibition on the outcome of ECV and the prevention of early recurrences after ECV of persistent AF.

            Methods

            One hundred-seven consecutive patients with persistent AF, defined as the presence of AF for at least 24 hours were included in this study[9]. ECV was performed according to a previously described step up protocol[10]. Successful ECV was defined as the presence of sinus rhythm for at least 4 hours after ECV. No difference was made between unsuccessful ECV due to shock failure or due to an immediate recurrence of AF (within 2 minutes after successful ECV). ACE pre-treatment was defined as use of ACE inhibitors before onset of the current AF episode. Most patients on ACE inhibitors used these drugs for hypertension or congestive heart failure. To make sure that all patients were not completely remodeled at the very moment of start of the current episode of AF (and thereby verifying the fact that they were treated with ACE inhibitors before the process of electrical remodeling started), only patients with at least 1 month sinus rhythm before the current episode of AF were included in this study. Duration of AF was determined as precisely as possible by previous electrocardiograms, 24-hours Holter registrations, and by the patient's history. None of the patients were on class I or III antiarrhythmic drugs neither at the moment of ECV nor during follow-up.

            Statistical analysis

            Quantitative variables were compared between groups using a two-tailed t-test for normally distributed variables or a Wilcoxon two-sample test for skewed distributed variables. For qualitative variables (categorical or ordered), group differences were evaluated using a Fisher's exact test or a Chi-square test. Accordingly, baseline characteristics are given in mean ± SD, median and range (min-max) or percentages.

            To determine the predictive factors for successful ECV, an univariate logistic regression analysis was performed using the relevant baseline predictors. Variables with a p-value < 0.20 were selected for the multiple logistic regression analysis to derive a model with statistically significant predictors, by using a backward selection method. All p-values are two-sided and a p-value of < 0.05 was considered statistically significant. SAS version 6.12 (Cary, NC) was used for all statistical evaluations.

            Results

            Baseline characteristics are listed in table 1. Twenty-eight patients (26%) were treated with ACE inhibitors before start of the current episode of AF (pre-treated patients). In the latter group, ECV was successful in 96% while in the group of patients not pre-treated with ACE inhibitors before start of the current AF episode only 80% had a successful ECV (p = 0.04).
            Table 1

            Baseline characteristics

             

            All

            Successful ECV

            Unsuccessful ECV

            P

             

            N = 107

            N = 90

            N = 17

             

            Duration in days, median (range)

                

            current episode

            115(71–175)

            113 (61–175)

            126 (81–189)

            ns

            total AF duration

            144 (95–232)

            142 (86–213)

            160 (102–340)

            Ns

            Number of previous ECVs, N(range)

            1 (0–5)

            1 (0–5)

            1(0–3)

            Ns

            Underlying heart disease * (%)

                

            Left ventricular dysfunction

            21%

            25%

            0%

            0.02

            Hypertension

            30%

            32%

            17%

            ns

            Valve disease

            19%

            19%

            22%

            ns

            Coronary artery disease

            22%

            21%

            28%

            ns

            Lone AF

            16%

            16%

            15%

            ns

            Echocardiography (mm ± SD)

                

            LA parasternal long axis

            47 ± 8

            47 ± 9

            47 ± 8

            ns

            LA 4 chamber view long axis

            67 ± 9

            67 ± 10

            67 ± 6

            ns

            LA 4 chamber view short axis

            46 ± 8

            46 ± 9

            43 ± 5

            ns

            RA 4 chamber view long axis

            62 ± 8

            62 ± 8

            63 ± 7

            ns

            LVEDD

            50 ± 8

            50 ± 8

            50 ± 7

            ns

            LVESD

            35 ± 10

            35 ± 10

            33 ± 9

            ns

            Medication

                

            Beta blocker

            49%

            50%

            48%

            ns

            Calcium channel blocker

            36%

            36%

            37%

            ns

            Digoxin

            47%

            46%

            49%

            ns

            ACE pretreatment

            26%

            30%

            6%

            0.04

            Diuretics

            31%

            31%

            29%

            ns

            Angiotensin receptor blocker

            1%

            1%

            0%

            ns

            * more then 1 entity per patient

            AF = atrial fibrillation, ECV = electrical cardioversion, LA = left atrium, RA = right atrium, LVEDD = left ventricular end diastolic diameter, LVESD = left ventricular end systolic diameter

            In general, patients treated with ACE inhibitors before start of the current episode of AF had more evidence for heart disease than those who were not pre-treated. Prevalence of hypertension (46% versus 24%, respectively, p = 0.03), and left ventricular dysfunction (40% versus 14%, respectively, p = 0.01) was significantly higher in the pre-treated group in comparison to those who were not pre-treated with ACE inhibitors. (Table 2) Furthermore, there was a trend towards a higher prevalence of coronary artery disease in the pre-treated group compared to the not pre-treated group (36% versus 18%, respectively p = 0.07).
            Table 2

            Baseline characteristics divided in ACE pre-treatment and no ACE pre-treatment.

             

            No ACE pre-treatment

            ACE-pre-treatment

            P

             

            N = 79

            N = 28

             

            Duration in days, median (range)

               

            current episode

            121 (74–178)

            96 (59–135)

            ns

            total AF duration

            161 (105–247)

            117 (63–160)

            ns

            Number of previous ECVs, N(range)

            1 (0–5)

            1(0–3)

            ns

            Underlying heart disease * (%)

               

            Left ventricular dysfunction

            14%

            40%

            0.01

            Hypertension

            24%

            46%

            0.03

            Valve disease

            19%

            21%

            ns

            Coronary artery disease

            18%

            36%

            0.07

            Lone AF

            17%

            14%

            ns

            Echocardiography (mm ± SD)

               

            LA parasternal long axis

            46 ± 7

            50 ± 10

            0.03

            LA 4 chamber view long axis

            66 ± 9

            67 ± 12

            ns

            LA 4 chamber view short axis

            45 ± 8

            49 ± 10

            ns

            RA 4 chamber view long axis

            61 ± 8

            64 ± 7

            ns

            LVEDD

            49 ± 7

            54 ± 8

            0.01

            LVESD

            34 ± 9

            38 ± 12

            ns

            Medication

               

            Beta blocker

            51%

            47%

            ns

            Calcium channel blocker

            35%

            39%

            ns

            Digoxin

            45%

            51%

            ns

            Diuretics

            29%

            34%

            ns

            Angiotensin receptor blocker

            1%

            0%

            ns

            * more then 1 entity per patient

            AF = atrial fibrillation, ECV = electrical cardioversion, LA = left atrium, RA = right atrium, LVEDD = left ventricular end diastolic diameter, LVESD = left ventricular end systolic diameter

            An additional 21 patients received ACE inhibitors after start of the current episode of AF because of either insufficiently treated hypertension or left ventricular dysfunction newly documented with echocardiography. Success of ECV in these patients was comparable to patients who were not treated with ACE inhibitors at all (80% and 82%, respectively). Use of beta adrenergic receptor blockers, calcium channel blockers or digoxin, started before the present episode of AF or not, did not influence success of ECV.

            After 1 month of follow-up 49% of the pre-treated patients compared to 50% of those who were not pre-treated with ACE inhibition were still in sinus rhythm (Table 3, Figure 1).
            Table 3

             

             

            All

            No ACE-pretreatment

            ACE-pretreatment

            P

            Successful ECV (%)

            84%

            80%

            96%

            0.04

            SR at 1 month follow-up (%)

            50%

            50%

            49%

            ns

            ECV = electrical cardioversion, SR = sinus rhythm

            http://static-content.springer.com/image/art%3A10.1186%2F1471-2261-5-3/MediaObjects/12872_2004_Article_60_Fig1_HTML.jpg
            Figure 1

            Effect of pretreatment with ACE-inhibitors before start of AF.

            Multivariate analysis showed that pre-treatment with ACE inhibitors and a smaller left atrial size were independent predictors of successful ECV (OR = 5.8, C.I. 1.3–26.1 and OR = 5.6, C.I. 1.2–25.3, respectively).

            Discussion

            Main results

            This post-hoc retrospective analysis shows that use of ACE inhibitors before the onset of AF enhances acute ECV outcome but it does not improve maintenance of sinus rhythm. Furthermore, when ACE inhibitiors are instituted later, i.e. after the start of AF, it does no longer improve success of ECV.

            Effect of ACE-inhibition on structural remodeling

            ACE inhibitors reduce the incidence of AF in patients with left ventricular dysfunction[7, 6]. This may be related to the protective effects of ACE inhibitors, which help to maintain atrial integrity and attenuate fibrosis[5]. In the present study pre-treatment with an oweveHowACE inhibitor (i.e. use of ACE inhibitors before onset of the arrhythmia) improved acute outcome of ECV. In view of the above this suggests that ACE inhibitors may prevent or diminish AF induced structural remodeling. These clinical findings are compatible with experimental findings showing that ACE-inhibition could attenuate heart failure induced atrial functional remodeling and fibrosis in dogs[11]. In atrial tissue from AF patients an ACE-dependent increase of activated extracellular signal-regulated kinase (Erk) type 1 and 2 was found, which may contribute to the development of atrial fibrosis during AF[12].

            Effect of ACE-inhibition on electrical remodeling

            In 1995 it was shown that AF induces several electrophysiological changes, called electrical remodeling[4]. Experimental data show that ACE inhibition prevents short-term (< 2 hours) tachycardia-induced atrial electrical remodeling[8, 13]. However, enalapril could not attenuate or prevent the long-term (7 days) effects of tachycardia on remodeling[8]. Several studies have investigated the role of calcium channel blockers on electrical remodeling. In these studies it was also shown that although there was a short-term prevention of electrical remodeling, calcium channel blockers did not have a long-term protective effect on electrical remodeling [1416].

            Effect on AF recurrences

            Madrid et al. investigated the role of the angiotensin II type 1 receptor antagonist irbesartan in amiodarone treated patients[17]. Persistent AF patients were randomized to either treatment with amiodarone alone or treatment with amiodarone in combination with irbesartan. Drug treatment was started at least 3 weeks before cardioversion but after the start of AF. No differences were found in electrical cardioversion outcome between the two treatment groups which is in contrast to the present study. This may relate to the fact that all patients were in AF at the very moment of start of irbesartan. Two months after cardioversion it appeared that patients treated with irbesartan and amiodarone had a significantly lower AF recurrence rate compared to amiodarone alone treated patients, 15% versus 37%, respectively (p = 0.007). This difference was maintained during a median follow-up of 254 days. According to their figure 2, the benefit of irbesartan (in combination with amiodarone) was mainly achieved by reduction of recurrences after the first two weeks after cardioversion. An earlier study on the role of ACE inhibitors in patients with heart failure and AF showed a trend towards more patients maintaining sinus rhythm after ECV when instituted on lisinopril in comparison to patients not treated with lisinopril[18]. In the present study no difference in recurrence rate could be found between patients with and without ACE-pretreatment.

            Limitations of the study

            This was a non-randomized and post-hoc analysis. This implies that all findings can only be used to generate hypotheses. However, this is the first clinical study showing that ACE-inhibition initiated before start of AF enhances direct ECV outcome.

            Only a very small amount of patients was on angiotensin receptor blockers. Whether the effect of pretreatment with angiotensin receptor blockers on cardioversion outcome would be the same as the effect of pretreatment with ACE inhibitors could not be investigated in this study. However, in this context the results of the study of Madrid et al. are encouraging [17].

            Conclusions

            Pretreatment with ACE-inhibitors significantly improves acute outcome of ECV when initiated before the onset of AF but it does not lead to better maintenance of sinus rhythm. When ACE inhibitiors are, however, instituted later, i.e. after the start of AF, it does no longer improve success of ECV.

            Declarations

            Authors’ Affiliations

            (1)
            Department of Cardiology, Thoraxcenter, University Hospital Groningen
            (2)
            Department of Cardiology, University Hospital Maastricht

            References

            1. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD: A comparison of rate control and rhythm control in patients with atrial fibrillation. [http://​PM:​12466506]N Engl J Med 2002, 347:1825–1833.View ArticlePubMed
            2. van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ: A Comparison of Rate Control and Rhythm Control in Patients with Recurrent Persistent Atrial Fibrillation. N Engl J Med 2002, 347:1834–1840.View ArticlePubMed
            3. Crijns HJ, van den Berg MP, van Gelder IC, van Veldhuisen DJ: Management of atrial fibrillation in the setting of heart failure. Eur Heart J 1997, 18 Suppl C:C45–C49.PubMed
            4. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA: Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995, 92:1954–1968.PubMed
            5. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S: 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.View ArticlePubMed
            6. Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M, Guerra PG, Ducharme A: 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, 107:1291–1296.View ArticlePubMed
            7. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C: Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999, 100:376–380.PubMed
            8. Nakashima H, Kumagai K, Urata H, Gondo N, Ideishi M, Arakawa K: Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation 2000, 101:2612–2617.PubMed
            9. Gallagher MM, Camm J: Classification of atrial fibrillation. Am J Cardiol 1998, 82:18N–28N.View ArticlePubMed
            10. van Gelder IC, Crijns HJGM, Lie KI: Characteristics of patients with chronic atrial fibrillation and the prediction of successful DC electrical cardioversion. Atrial fibrillation: a treatable disease? (Edited by: Kingma JH, van Hemel NM and Lie KI). Kluwer Academic Publishers 1992, 67–86.
            11. Shi Y, Ducharme A, Li D, Gaspo R, Nattel S, Tardif JC: Remodeling of atrial dimensions and emptying function in canine models of atrial fibrillation. Cardiovasc Res 2001, 52:217–225.View ArticlePubMed
            12. Goette A, Staack T, Rocken C, Arndt M, Geller JC, Huth C, Ansorge S, Klein HU, Lendeckel U: 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.View ArticlePubMed
            13. Shinagawa K, Mitamura H, Ogawa S, Nattel S: Effects of inhibiting Na(+)/H(+)-exchange or angiotensin converting enzyme on atrial tachycardia-induced remodeling. Cardiovasc Res 2002, 54:438–446.View ArticlePubMed
            14. Lee SH, Yu WC, Cheng JJ, Hung CR, Ding YA, Chang MS, Chen SA: Effect of verapamil on long-term tachycardia-induced atrial electrical remodeling. Circulation 2000, 101:200–206.PubMed
            15. Tieleman RG, De Langen C, van Gelder IC, de Kam PJ, Grandjean J, Bel KJ, Wijffels MC, Allessie MA, Crijns HJ: Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997, 95:1945–1953.PubMed
            16. Benardeau A, Fareh S, Nattel S: Effects of verapamil on atrial fibrillation and its electrophysiological determinants in dogs. Cardiovasc Res 2001, 50:85–96.View ArticlePubMed
            17. Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C: Use of irbesartan to maintain sinus rhythm in patients with long- lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002, 106:331–336.View ArticlePubMed
            18. van den Berg MP, Crijns HJGM, van Veldhuisen DJ, Griep N, de Kam PJ, Lie KI: Effects of lisinopril in patients with heart failure and chronic atrial fibrillation. J Card Fail 1995, 1:355–363.View ArticlePubMed
            19. Pre-publication history

              1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1471-2261/​5/​3/​prepub

            Copyright

            © Van Noord et al. 2005

            This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.