Europace Advance Access originally published online on July 28, 2008
Europace 2008 10(10):1138-1144; doi:10.1093/europace/eun195
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Atrial fibrillation
Fibrillatory rate response to candesartan in persistent atrial fibrillation
1 Department of Cardiology, Lund University, Lund, Sweden; 2 Department of Electrophysiology, Heart Center Leipzig, Leipzig, Germany; 3 Department of Internal Medicine, Asker and Baerum Hospital, Rud, Norway; 4 Department of Electroscience, Lund University, Lund, Sweden
Manuscript submitted 5 May 2008. Accepted after revision 9 July 2008.
* Corresponding author. Tel: +46 46 17 10 00; fax: +46 46 15 78 57. E-mail address: andreas.bollmann{at}kard.lu.se
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Abstract |
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Introduction: Angiotensin-receptor blockers may exert favourable anti-arrhythmic effects in atrial fibrillation (AF), but their mechanisms are not fully understood. In this study, we tested the hypotheses that (i) candesartan reduces atrial fibrillatory rate and (ii) fibrillatory rate and its response to candesartan are related with the outcome of cardioversion. For this purpose, a post hoc subanalysis of the randomized, placebo-controlled CAPRAF (Candesartan in the Prevention of Relapsing Atrial Fibrillation) trial was performed.
Methods and results: Patients with AF undergoing electrical cardioversion were randomized to receive candesartan 8 mg once daily (n = 58) or matching placebo (n = 66) and no additional class I or III anti-arrhythmic drugs. Fibrillatory rate was determined from ECG lead V1 at baseline and at the day of cardioversion using spatiotemporal QRST cancellation and time–frequency analysis. The median time on treatment was 29 days. Candesartan reduced fibrillatory rate [399 ± 48 vs. 388 ± 49 fibrillations/min (fpm), P = 0.04], but not placebo (402 ± 58 vs. 402 ± 61 fpm, P = 0.986). Candesartan effects were only observed if the baseline fibrillatory rate was high [>420 fpm: 445 ± 21 vs. 415 ± 49 fpm, P = 0.006 vs. intermediate (360–420 fpm): 397 ± 19 vs. 391 ± 37 fpm, P = 0.351 vs. low (<360 fpm): 326 ± 26 vs. 338 ± 29 fpm, P = 0.179]. Cardioversion success was 100% in patients with an on-treatment rate <360 fpm vs. 83% in patients with higher rates (P = 0.02). Risk for AF recurrence was similar in patients with low (64%), intermediate (75%), or high on-treatment rates (63%, P = 0.446) and was also independent of candesartan effects on the fibrillatory rate.
Conclusion: In patients with persistent AF, candesartan decreases the fibrillatory rate, but this effect is restricted to patients with high baseline fibrillatory rates and is not associated with improved cardioversion outcome. Fibrillatory rates <360 fpm are associated with successful cardioversion, but not with AF recurrence.
Key Words: Atrial fibrillation, ECG, Remodelling, Angiotensin-receptor blockade, Cardioversion
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Introduction |
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There is growing evidence that blockade of the renin–angiotensin–aldosterone system, e.g. by angiotensin-converting enzyme-inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs), has anti-arrhythmic effects on atrial fibrillation (AF). On the one hand, there are some studies that have shown a significant reduction in the AF incidence in patients treated with ACEIs or ARBs for heart failure or post-myocardial infarction.1
,2 On the other hand, limited data suggest that AF recurrences following cardioversion can also be reduced by these treatment modalities. However, AF relapses could only be reduced when ACEI or ARB treatment was combined with anti-arrhythmic drugs,3,4 whereas in a more recent investigation5 in which patients were not treated with additional class I or III anti-arrhythmic drugs, ARB administration had no effect on AF recidivism after cardioversion. Mechanisms linked to favourable clinical effects have been mainly derived from animal studies and include aspects of both structural and electrical remodelling.6,7 Interestingly, ARB treatment also has direct electrophysiological effects, particularly it prolongs action potential duration and atrial refractoriness,8,9 whereas in an acute study in humans, angiotensin infusion had no measurable effects on atrial electrophysiology.10
Atrial refractoriness, in turn, is closely correlated with atrial fibrillatory rate.11 In order to non-invasively assess atrial fibrillatory rate in humans, time–frequency analysis of the surface ECG has been developed, validated, and applied in different AF populations.12 Several studies have shown that spontaneous fibrillatory rate changes as well as those induced by autonomic manoeuvres or anti-arrhythmic drugs may be monitored using this technique. In particular, class III anti-arrhythmic drugs have consistently found to induce a fibrillatory rate decrease, which can be attributed to the prolongation of atrial refractoriness.13 Moreover, the fibrillatory rate was able to predict AF recurrence following cardioversion.14–16
The conflicting results regarding AF recurrences following cardioversion after ARB treatment,3–5 together with the not-fully understood anti-arrhythmic effects of ARB in AF, motivated the current study. We tested the hypotheses that (i) candesartan prolongs atrial refractoriness expressed by a fibrillatory rate reduction and (2) fibrillatory rate and its response to candesartan are related with the outcome of cardioversion. In addition, clinical and echocardiographic variables associated with fibrillatory rate were analysed. For this purpose, a post hoc subanalysis of the randomized, placebo-controlled CAPRAF (Candesartan in the Prevention of Relapsing Atrial Fibrillation) trial5 was performed.
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Methods |
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Patient population and study design
This study is a post hoc subset analysis of the CAPRAF study, which has been presented in detail elsewhere.5
Briefly, 171 patients undergoing planned electrical cardioversion for persistent AF were randomized to receive candesartan 8 mg once daily (n = 86) or matching placebo (n = 85) in a double-blind fashion. Patients aged 
18 years were eligible if they had electrocardiographically documented AF of >48 h duration and were candidates for electrical cardioversion. Exclusion criteria were hypersensitivity or contraindication to any ARB or any ACEI, current treatment with an ARB, ACEI, and class I or III anti-arrhythmic drugs, significant renal artery stenosis, serum creatinine >225 µmol/L, serum potassium >5.5 mmol/L, serum sodium <128 mmol/L, severe hepatic dysfunction, life-limiting disease, or substance abuse, which may affect study participation, previous cardioversion for AF within the last month, thyrotoxicosis, systolic blood pressure <100 mmHg, hypertension requiring intensified treatment prior to cardioversion, pregnancy, or lactation. Treatment was given for 3–6 weeks before cardioversion, depending on the time required on warfarin treatment to maintain an international normalized ratio >2.0 for a minimum of 3 weeks.
Electrical cardioversion was performed under propofol anaesthesia. A maximum of four direct current R-wave synchronized monophasic discharges were given in the following sequence: 200, 360, and 360 J in the antero-lateral electrode position and then 360 J in the antero-posterior electrode position, until sinus rhythm was restored. During the course of the study, the protocol was changed, allowing biphasic discharges to be used because of a higher success rate. A maximum of four biphasic shocks were given in the following sequence: 150, 270, and 270 J in the antero-lateral electrode position and then 270 J in the antero-posterior electrode position, until sinus rhythm was restored. Cardioversion was deemed successful if sinus rhythm was established and maintained for at least one beat.
Successfully cardioverted patients received candesartan 16 mg od or matching placebo from the day after cardioversion for the remaining 6 months of follow-up period, or until relapse of AF was documented. Patients did not receive additional class I or III anti-arrhythmic drugs or ACEI. Patients were seen for ECG 1 week, 6 weeks, 3 and 6 months after cardioversion, or at any time if they had symptoms indicating AF recurrence.
All patients provided written, informed consent in accordance with the revised Declaration of Helsinki before enrolment. The study was approved by the Regional Ethics Committee and the Norwegian Medicines Agency and registered at the website clinicaltrials.gov (NCT00130975 [ClinicalTrials.gov] ).
As presented in detail,5 candesartan treatment had no effect on the AF recurrence rate.
ECG acquisition and time–frequency analysis
Digital ECG recordings were available for the time–frequency analysis both at baseline and at the day of cardioversion in 124 patients (58 in the candesartan group and 66 in the placebo group), which are included in this study (Figure 1). Patient characteristics of the subgroups are representative of the main CAPRAF population.
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ECG recordings (500 Hz, 12 bit, 0.05–300 Hz) were downloaded from the CAPRAF ECG database (GE/Marquette MAC 5000, Milwaukee, WI, USA). Surface ECG lead V1 was processed using analysis techniques, which have been described in detail before.17
Briefly, after high-pass filtering to remove baseline wander, atrial fibrillatory activity was extracted using spatiotemporal QRST cancellation (Figure 2, top panel).18 As the dominant frequency component of interest is within the 4–9 Hz range, the resulting fibrillatory baseline signal was downsampled to 50 Hz and subjected to spectral analysis.
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One spectral estimate of the atrial signal was obtained every second from overlapping 2.5 s windows by short-term Fourier transform (segment-wise fast Fourier transform). Thus, this instantaneous signal was represented in a spectral profile (Figure 2, bottom left) that was also used for quality control excluding non-reliable signal intervals. Subsequently, the frequency of the atrial signal was trended as a function of time (Figure 2, bottom right).19
Frequencies were converted to fibrillatory rates with its unit fibrillations/min (fpm; rate=frequencyx60). Mean fibrillatory rate (in fpm) defined as the average of fibrillatory rate estimates over the 10 s ECG segment was determined.
Statistical analysis
Continuous variables are presented as mean ± 1 SD or as median, whereas categorical variables are presented as frequencies (%).
The possible relation between continuous clinical variables and fibrillatory rate as well as fibrillatory rate changes was analysed using bivariate correlations (Pearson). Student's t-test for unpaired data or Mann–Whitney U-test was used to compare fibrillatory rates among categorical clinical variables. Multivariate analysis that included variables with a P-value less than 0.1 found in the univariate analysis was used to identify independent predictors for (i) fibrillatory rate and (ii) fibrillatory rate changes. Student's t-test for paired data or Wilcoxon rank test was used to compare fibrillatory rates at baseline and at the day of cardioversion. In addition, analysis of variance with repeated measures was performed to detect the possible influence of candesartan treatment on fibrillatory rates.
Patients (i) with successful cardioversion were compared with those with unsuccessful cardioversion and (ii) who remained in sinus rhythm with those with AF recurrence. For the latter analysis, patients with unsuccessful cardioversion were excluded. For those comparisons, continuous variables were examined for statistical significance by a Student's t-test or Mann–Whitney U test, whereas categorical data were compared by the 
2 test or Fisher's exact test where appropriate. Kaplan–Meier curves for AF-free survival were generated for different fibrillatory rate ranges and compared using the log-rank test.
A two-tailed P-value of less than 0.05 was considered significant.
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Patients' characteristics and relation with fibrillatory rate
Patients' characteristics are shown in Table 1. The duration of AF before randomization was unknown in 75 patients (60%) and known in 49 patients (24 in the candesartan group and 25 in the placebo group; median 11 and 12 weeks, respectively). No differences between the randomized groups were evident at baseline.
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There was a weak negative correlation between fibrillatory rates at baseline and age (r = –0.292, P = 0.001) and left atrial diameter (r = –0.200, P = 0.027). The presence of coronary heart disease had no significant impact on baseline fibrillatory rates, whereas hypertensive patients tended to have lower fibrillatory rates (386 ± 51 vs. 407 ± 53 fpm, P = 0.052). Female gender was associated with lower fibrillatory rates (373 ± 49 vs. 411 ± 52 fpm, P < 0.001). Patients who took verapamil also had lower fibrillatory rates than those who did not (384 ± 50 vs. 410 ± 53 fpm, P = 0.008), whereas treatment with beta-blockers or digitoxin had no impact on fibrillatory rate.
In a multivariate linear regression model, age (B = –1.24, P = 0.004), gender (B = 30.2, P = 0.005), left atrial diameter (B = –1.75, P = 0.028), and use of verapamil (B = –24.1, P = 0.013) were independently related to the fibrillatory rate.
Treatment effects on fibrillatory rate
The median time on treatment with candesartan or placebo from baseline to cardioversion was 29 days in both groups. Baseline fibrillatory rates were similar in the candesartan and placebo groups. Candesartan reduced fibrillatory rate (399 ± 48 vs. 388 ± 49 fpm, P = 0.04), but not placebo (402 ± 58 vs. 402 ± 61 fpm, P = 0.986; Figure 3).
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In the univariate and multivariate analyses, the baseline fibrillatory rate was the only predictor of fibrillatory rate changes (B = –0.251, P < 0.001).
Fibrillatory rate changes with candesartan were restricted to patients with a high fibrillatory rate (>420 fpm) at baseline. In this subgroup, candesartan reduced fibrillatory rates from 445 ± 21 to 415 ± 49 fpm (P = 0.006). In contrast, in patients with an intermediate (360–420 fpm) or low (<360 fpm) fibrillatory rate at baseline, the fibrillatory rate was unchanged after candesartan (397 ± 19 vs. 391 ± 37 fpm, P = 0.351 and 326 ± 26 vs. 338 ± 29 fpm, P = 0.179, respectively).
On-treatment fibrillatory rates were lower with candesartan when compared with placebo (415 ± 49 vs. 454 ± 53 fpm, P = 0.014) in patients with high but similar in patients with intermediate (391 ± 37 vs. 386 ± 31 fpm, P = 0.562) and low baseline rates (338 ± 29 vs. 350 ± 42 fpm, P = 0.412; Figure 4).
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Fibrillatory rate and outcome of cardioversion
Cardioversion was successful in 107 patients (69 with monophasic and 38 with biphasic shocks) and unsuccessful in 16 patients (all monophasic shocks and one patient refused cardioversion). Fibrillatory rates tended to be lower (392 ± 56 vs. 421 ± 53 fpm, P = 0.051) in patients with successful cardioversion when compared with patients in whom cardioversion was unsuccessful. Cardioversion success was 100% in patients with a fibrillatory rate <360 fpm as opposed to 83% in patients with higher fibrillatory rates (P = 0.02; Figure 5). The proportion of biphasic shocks was similar in patients with fibrillatory rates <360 fpm and in those with higher rates (28.6 vs. 31.6%).
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The Kaplan–Meier curve and log-rank analysis of AF-free survival after cardioversion showed no significant relationship between fibrillatory rates on the day of cardioversion and risk of AF relapse (Figure 6).
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There was no effect of candesartan-induced fibrillatory rate reduction on cardioversion outcome.
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Main findings
This study is, to the best of our knowledge, the first to non-invasively analyse ARB effects on fibrillatory rate in persistent AF, thereby elucidating possible in vivo anti-arrhythmic effects. Several clinical determinants of baseline fibrillatory rate such as age, gender, left atrial diameter, and use of verapamil could be identified. Overall, the fibrillatory rate was slightly reduced by candesartan. The analysis of rate changes according to baseline fibrillatory rate, the strongest predictor of fibrillatory rate response, revealed, however, differential drug effects. Although there was a substantial rate decrease in patients with the highest baseline rates, candesartan had no significant effects if low or intermediate baseline rates were present. In turn, the observed rate reduction had no effect on cardioversion outcome, although lower on-treatment fibrillatory rates were associated with higher cardioversion success but not with AF recurrence.
Determinants of fibrillatory rate
It is a common observation that in AF, fibrillatory waves of the ECG vary among patients with respect to waveform and repetition rate. In this analysis, we thought to elucidate possible clinical variables associated with this variation, whereas in other studies, the influence of gene variants is being explored.20
In a multivariate linear regression model, advancing age, female gender, left atrial size, and use of verapamil were independently related with lower fibrillatory rates in our population.
First, an inverse correlation between fibrillatory rate and patients' age has already been reported in different AF populations.21–23 This finding can be explained by longer refractory periods and slower conduction—both resulting in slower fibrillatory rates—which are present in ageing atria.24
Secondly, lower fibrillatory rates in women compared with men have previously been found in univariate, but not in multivariate analysis, in one study of 125 patients with persistent AF.22 This finding may be explained by hormonal effects on atrial electrophysiology. In an experimental study,25 estradiol—similar to verapamil (discussed subsequently)—prevented pacing-induced shortening of atrial refractoriness, which in turn is associated with lower fibrillatory rates during AF.
Thirdly, at a first glance, the inverse correlation between left atrial diameter and fibrillatory rate is surprising. It may be speculated, however, that in patients with small atria, the electrical remodelling process is the dominating mechanism, whereas in patients with larger atria, a structural remodelling component is more pronounced. In fact, experimental studies suggest shorter refractoriness in the former and longer refractoriness in the latter AF model,26 which is consistent with our findings.
Fourth, the observation of lower rates in verapamil-treated patients has been reported in previous studies.27,28 In one cross-sectional investigation, a lower fibrillatory rate has been found in patients taking long-term oral verapamil when compared with those without this drug.28 Accordingly, a significant reduction in the fibrillatory rate (maximum after 5 days with steady state thereafter) has been observed in a longitudinal study of 10 patients with persistent AF after oral verapamil administration.27
Fibrillatory rate response to candesartan
Overall, a small but significant rate reduction with candesartan was observed, whereas fibrillatory rate remained stable in the placebo arm.
A stable fibrillatory rate in persistent AF in the placebo group with a median AF duration of 12 weeks indicates a fully developed electrical remodelling process within week(s) after AF onset, which is in agreement with experimental observations.29 Similarly, no fibrillatory rate difference between patients with short (<30 days) compared with patients with longer AF duration has been reported before.16
Of special importance is the differential rate behaviour stratified by the baseline fibrillatory rate. Interestingly, the observed fibrillatory rate reduction with candesartan can mainly be attributed to its effects in the group of patients with higher (>420 fpm) baseline fibrillatory rates. On the one hand, ARB treatment influences the structural substrate for AF by reducing the amount of interstitial fibrosis.30 On the other hand, angiotensin via angiotensin-1 receptor stimulation has electrophysiological effects in the atria through potentiation of the slowly activating component of the delayed rectifier K+ current (IKs). This leads to the shortening of the action potential duration and refractoriness, but can be reversed by ARB treatment (valsartan).9 Interestingly, ARB treatment has previously been found to prolong action potential duration and produce block of potassium currents that is frequency-dependent.8 This observation may explain our findings that the fibrillatory rate reduction with candesartan was only observed in patients with high baseline fibrillatory rates (short refractoriness).
In contrast, our finding of unchanged fibrillatory rates after candesartan in patients with lower baseline fibrillatory rates is in agreement with a previous study on the acute effects of angiotensin on atrial electrophysiology.10 In this study of 12 patients with supraventricular tachycardias but not AF and consequently normal atrial refractoriness, acute angiotensin infusion did not alter atrial refractoriness or conduction. On the basis of this study and our observation, it can be speculated that angiotensin and its blockade are not implicated in electrical remodelling, especially if the atrial refractoriness is normal or only slightly shortened (as in our patients with lower fibrillatory rates).
Outcome of cardioversion
Cardioversion was successful in all of our patients with a fibrillatory rate below 360 fpm, but in only 83% in patients with higher rates. This observation is in agreement with the previous studies showing an association between the atrial defibrillation threshold and the degree of electrical remodelling. In studies in humans, the minimal energy requirement for external31 and internal14 cardioversion was moderately correlated with baseline fibrillatory rate. This finding is also supported by one experimental study32 that revealed shock efficacy to be dependent on AF organization as quantified from electrograms (organization index).
Atrial premature beats with short coupling intervals have been shown to promote early AF reinitiation following cardioversion.33,34 Atrial fibrillation reinduction by an atrial premature beat relies on the fact that a relatively short atrial wavelength (conduction velocity x refractory period) must be present.35 As fibrillatory rate is an indirect measure of atrial refractoriness,11 it may consequently be a marker for AF susceptibility after cardioversion. However, in contrast to previous studies,14–16 no relation between fibrillatory rate as well as candesartan-induced rate changes and AF recurrence was found in this study. On the one hand, this indicates that factors beyond electrical remodelling expressed as fibrillatory rate are more important for AF recurrence, particularly for late AF relapses when electrical remodelling is reversed but structural remodelling is still present.36 On the other hand, study differences between this and previous cardioversion studies need to be emphasized. Although the vast majority of patients studied earlier14,15 received additional class I or III anti-arrhythmic drugs, this was not the case in this population. In a more recent study16 in which only 
10% of the patients received class III anti-arrhythmic drugs, the most prominent predictive effect of fibrillatory rate was found in patients with short AF duration (<30 days). This subgroup could, however, not be studied here, i.e. the pre-cardioversion treatment period was already 29 days.
Study limitations
In addition to the limitations discussed already with the CAPRAF study,5 such as patient number, characteristics, and, in particular, the unknown AF duration in 60%, the following specific issues of this substudy need to be addressed.
First, this study was limited by testing one drug dosage before cardioversion, and the time of its administration was restricted to ~4 weeks. Whether other (higher) dosages and longer treatment periods affect fibrillatory rate differently remains to be determined. Moreover, whether there is an ARB class effect or whether ACEIs exhibit similar effects on fibrillatory rate is unknown.
Secondly, although care was taken to acquire subsequent ECG recordings under comparable conditions, factors such as the anticipation of the cardioversion may affect atrial electrophysiology through changes in autonomic tone and may consequently be associated with spontaneous fibrillatory rate variability.
Thirdly, ECG analysis was restricted to one parameter of the electrical remodelling process, i.e. fibrillatory rate as a marker of atrial refractoriness and post-cardioversion P waves as a marker of atrial conduction are currently being evaluated. Similarly, markers of structural remodelling such as metalloproteinases as well as markers of haemostasis are under investigation.
Fourth, all unsuccessful cardioversions occurred with the application of monophasic shocks. Consequently, the finding on the relation between fibrillatory rate and cardioversion outcome is restricted to this subgroup.
Finally, a follow-up strategy with more frequent, sequential (Holter) ECG monitoring would have been preferable. However, missed asymptomatic AF episodes would have been present equally in all fibrillatory rate subgroups and should consequently have no effect on the relation between fibrillatory rate and AF recurrence.
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Conclusions |
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In patients with persistent AF, candesartan decreases fibrillatory rate, but this effect is restricted to patients with high baseline fibrillatory rates and is not associated with improved cardioversion outcome. Fibrillatory rates <360 fpm are associated with successful cardioversion, but not with AF recurrence.
Conflict of interest: none declared.
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This study has been performed in and supported in part by the NordForsk network ‘Electrocardiology in Atrial Fibrillation’. The CAPRAF main study was sponsored by the Regional Health Corporation of Eastern Norway and the Medical Research Foundation, Asker&Baerum Hospital, Norway. AstraZeneca, Molndal, Sweden provided the study medication, and AstraZeneca, Oslo, Norway supported the study with a grant to cover for laboratory analyses. D.H. and M.S. are supported by the Volkswagen Foundation, Germany.
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[1] Anand K, Mooss AN, Hee TT, Mohiuddin SM. Meta-analysis: inhibition of renin–angiotensin system prevents new-onset atrial fibrillation. Am Heart J (2006) 152:217–22.[CrossRef][Web of Science][Medline]
[2] Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol (2005) 45:1832–9.
[3] Ueng KC, Tsai TP, Yu WC, Tsai CF, Lin MC, Chan KC, et al. Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation. Results of a prospective and controlled study. Eur Heart J (2003) 24:2090–8.
[4] Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation (2002) 106:331–6.
[5] Tveit A, Grundvold I, Olufsen M, Seljeflot I, Abdelnoor M, Arnesen H, et al. Candesartan in the prevention of relapsing atrial fibrillation. Int J Cardiol (2007) 120:85–91.[CrossRef][Web of Science][Medline]
[6] Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, 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) 104:2608–14.
[7] Shi Y, Li D, Tardif JC, Nattel S. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure. Cardiovasc Res (2002) 54:456–61.
[8] Caballero R, Delpon E, Valenzuela C, Longobardo M, Gonzalez T, Tamargo J. Direct effects of candesartan and eprosartan on human cloned potassium channels involved in cardiac repolarization. Mol Pharmacol (2001) 59:825–36.
[9] Zankov DP, Omatsu-Kanbe M, Isono T, Toyoda F, Ding WG, Matsuura H, et al. Angiotensin II potentiates the slow component of delayed rectifier K+ current via the AT1 receptor in guinea pig atrial myocytes. Circulation (2006) 113:1278–86.
[10] Kistler PM, Davidson NC, Sanders P, Fynn SP, Stevenson IH, Spence SJ, et al. Absence of acute effects of angiotensin II on atrial electrophysiology in humans. J Am Coll Cardiol (2005) 45:154–6.
[11] Capucci A, Biffi M, Boriani G, Ravelli F, Nollo G, Sabbatani P, et al. Dynamic electrophysiological behavior of human atria during paroxysmal atrial fibrillation. Circulation (1995) 92:1193–202.
[12] Husser D, Stridh M, Cannom DS, Bhandari AK, Girsky MJ, Kang S, et al. Validation and clinical application of time–frequency analysis of atrial fibrillation electrocardiograms. J Cardiovasc Electrophysiol (2007) 18:41–6.[CrossRef][Web of Science][Medline]
[13] Bollmann A, Husser D, Mainardi L, Lombardi F, Langley P, Murray A, et al. Analysis of surface electrocardiograms in atrial fibrillation: techniques, research, and clinical applications. Europace (2006) 8:911–26.
[14] Bollmann A, Mende M, Neugebauer A, Pfeiffer D. Atrial fibrillatory frequency predicts atrial defibrillation threshold and early arrhythmia recurrence in patients undergoing internal cardioversion of persistent atrial fibrillation. Pacing Clin Electrophysiol (2002) 25:1179–84.[CrossRef][Medline]
[15] Bollmann A, Husser D, Steinert R, Stridh M, Sörnmo L, Olsson SB, et al. Echo- and electrocardiographic predictors for atrial fibrillation recurrence following cardioversion. J Cardiovasc Electrophysiol (2003) 14:S162–5.[CrossRef][Web of Science][Medline]
[16] Holmqvist F, Stridh M, Waktare JE, Sörnmo L, Olsson SB, Meurling CJ. Atrial fibrillatory rate and sinus rhythm maintenance in patients undergoing cardioversion of persistent atrial fibrillation. Eur Heart J (2006) 27:2201–7.
[17] Stridh M, Sörnmo L, Meurling CJ, Olsson SB. Characterization of atrial fibrillation using the surface ECG: time-dependent spectral properties. IEEE Trans Biomed Eng (2001) 48:19–27.[CrossRef][Web of Science][Medline]
[18] Stridh M, Sörnmo L. Spatiotemporal QRST cancellation techniques for analysis of atrial fibrillation. IEEE Trans Biomed Eng (2001) 48:105–11.[CrossRef][Web of Science][Medline]
[19] Stridh M, Bollmann A, Olsson SB, Sörnmo L. Time–frequency analysis of atrial tachyarrhythmias: detection and feature extraction. IEEE Eng Med Biol Mag (2006) 25:31–9.[CrossRef][Web of Science][Medline]
[20] Bollmann A, Husser D, Stridh M, Sörnmo L, Hindricks G, Roden DM, et al. A genotype dependent intermediate ECG phenotype in patients with persistent lone atrial fibrillation (abstract). Circulation (2007) 116:II:477.
[21] Xi Q, Sahakian AV, Frohlich TG, Ng J, Swiryn S. Relationship between pattern of occurrence of atrial fibrillation and surface electrocardiographic fibrillatory wave characteristics. Heart Rhythm (2004) 1:656–63.[CrossRef][Web of Science][Medline]
[22] Bollmann A, Husser D, Stridh M, Holmqvist F, Roijer A, Meurling CJ, et al. Atrial fibrillatory rate and risk of left atrial thrombus in atrial fibrillation. Europace (2007) 9:621–6.
[23] Husser D, Cannom DS, Bhandari AK, Stridh M, Sörnmo L, Olsson SB, et al. Electrocardiographic characteristics of fibrillatory waves in new-onset atrial fibrillation. Europace (2007) 9:638–42.
[24] Sakabe K, Fukuda N, Soeki T, Shinohara H, Tamura Y, Wakatsuki T, et al. Relation of age and sex to atrial electrophysiological properties in patients with no history of atrial fibrillation. Pacing Clin Electrophysiol (2003) 26:1238–44.[CrossRef][Medline]
[25] Chen YJ, Lee SH, Hsieh MH, Hsiao CJ, Yu WC, Chiou CW, et al. Effects of 17beta-estradiol on tachycardia-induced changes of atrial refractoriness and cisapride-induced ventricular arrhythmia. J Cardiovasc Electrophysiol (1999) 10:587–98.[Web of Science][Medline]
[26] Shinagawa K, Li D, Leung TK, Nattel S. Consequences of atrial tachycardia-induced remodeling depend on the preexisting atrial substrate. Circulation (2002) 105:251–7.
[27] Meurling CJ, Ingemansson MP, Roijer A, Carlson J, Lindholm CJ, Smideberg B, et al. Attenuation of electrical remodelling in chronic atrial fibrillation following oral treatment with verapamil. Europace (1999) 1:234–41.
[28] Bollmann A, Sonne K, Esperer HD, Toepffer I, Klein HU. Patients with persistent atrial fibrillation taking oral verapamil exhibit a lower atrial frequency on the ECG. Ann Noninvasive Electrocardiol (2002) 7:92–7.[CrossRef][Web of Science][Medline]
[29] Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation (1995) 92:1954–68.
[30] Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Seiko K. Effect of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol (2003) 41:2197–204.
[31] Tai CT, Chen SA, Liu AS, Yu WC, Ding YA, Chang MS, et al. Spectral analysis of chronic atrial fibrillation and its relation to minimal defibrillation energy. Pacing Clin Electrophysiol (2002) 25:1747–51.[CrossRef][Medline]
[32] Everett TH IV, Moorman JR, Kok LC, Akar JG, Haines DE. Assessment of global atrial fibrillation organization to optimize timing of atrial defibrillation. Circulation (2001) 103:2857–61.
[33] Sra J, Biehl M, Blanck Z, Dhala A, Jazayeri MR, Deshpande S, et al. Spontaneous reinitiation of atrial fibrillation following transvenous atrial defibrillation. Pacing Clin Electrophysiol (1998) 21:1105–10.[CrossRef][Medline]
[34] Timmermans C, Rodriguez LM, Smeets JL, Wellens HJ. Immediate reinitiation of atrial fibrillation following internal atrial defibrillation. J Cardiovasc Electrophysiol (1998) 9:122–8.[Web of Science][Medline]
[35] Smeets JL, Allessie MA, Lammers WJ, Bonke FI, Hollen J. The wavelength of the cardiac impulse and reentrant arrhythmias in isolated rabbit atrium. The role of heart rate, autonomic transmitters, temperature, and potassium. Circ Res (1986) 58:96–108.
[36] Everett TH IV, Li H, Mangrum JM, McRury ID, Mitchell MA, Redick JA, et al. Electrical, morphological, and ultrastructural remodeling and reverse remodeling in a canine model of chronic atrial fibrillation. Circulation (2000) 102:1454–60.
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