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Effects of Sinus Rhythm Maintenance on Left Heart Function After Electrical Cardioversion of Atrial Fibrillation: Implications for Tachycardia-Induced Cardiomyopathy
Canadian Journal of Cardiology 31 (2015) 36e43
Clinical Research
Effects of Sinus Rhythm Maintenance on Left Heart Function After Electrical Cardioversion of Atrial Fibrillation: Implications for Tachycardia-Induced Cardiomyopathy Andreas J. Zimmermann, MD,a,* Matthias Bossard, MD,a,b,* Stefanie Aeschbacher, MSc,a Tobias Schoen, MD,a Gian Voellmin, MSc,a Yves Suter, MD,b Anouk Lehmann, BSc,a Thomas Hochgruber, MD,a Katrin Pumpol, MD,a Christian Sticherling, MD,b Michael Kühne, MD,b David Conen, MD, MPH,a and Beat A. Kaufmann, MDb a
Department of Medicine, University Hospital Basel, Basel, Switzerland b
Cardiology Division, University Hospital Basel, Basel, Switzerland
ABSTRACT
RESUM E
Background: The role of tachycardia-induced cardiomyopathy vs tachycardia-related short diastolic filling period and reduced atrial contraction in decline of left ventricular ejection fraction (LVEF) in atrial fibrillation (AF) is uncertain. We aimed to characterize left heart changes over time in patients with AF who undergo electrical cardioversion (ECV). Methods: Consecutive AF patients who were to undergo ECV were enrolled. Patients with unstable or acute heart failure, severe valvular diseases, recent open-heart surgery, major disorders, or an unsuccessful ECV were excluded. Transthoracic echocardiography, including 3-dimensional left atrial and ventricular volume acquisitions, was performed 1-2 hours before and after ECV, and 4-6 weeks later. Results: In 73 patients (77% male, 66 11 years), ECV resulted in an immediate increase in LVEF (from 43 [interquartile range (IQR),
Introduction : Le rôle de la cardiomyopathie induite par tachycardie riode diastolique de remplissage lie e à la par rapport à la courte pe duction de la contraction auriculaire entraînant une tachycardie et la re jection ventriculaire gauche (FEVG) lors de diminution de la fraction d’e fibrillation auriculaire (FA) est mis en doute. Nous avions pour but de riser les changements du cœur gauche au fil du temps chez les caracte lectrique patients souffrant de FA qui subissent une cardioversion e (CVE). thodes : Les patients conse cutifs souffrant de FA qui devaient subir Me te inscrits. Les patients souffrant d’une insuffisance la CVE ont e instable ou d’une insuffisance cardiaque aiguë, de valvulopathies cemment subi une chirurgie à cœur ouvert, souffrant graves, ayant re te exclus. de troubles majeurs ou ayant subi sans succès la CVE ont e chocardiographie transthoracique, y compris les acquisitions en 3D L’e
Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting approximately 1%-2% of the general population, and epidemiologic data indicate that this figure will likely increase in the coming decades.1-4 Patients with AF experience increased rates of death, stroke, reduced exercise capacity, and are more likely to be hospitalized or suffer from heart failure than similar patients without AF.2,3,5-7 AF can be a consequence of heart failure with increased left atrial pressure.3 However, AF with poorly controlled ventricular rate can
itself also be the cause of heart failure with decreased left ventricular (LV) ejection fraction (LVEF), an entity also referred to as tachycardia-induced cardiomyopathy (TIC).8-11 TIC can be caused by a variety of tachyarrhythmias, but most commonly is a consequence of AF.6,8-11 TIC can lead to a clinical picture of heart failure, and is considered reversible on resolution of the tachycardia.8,9,11 The incidence of TIC is not well characterized, but it is estimated that approximately 50% of patients in AF have some impairment of LV systolic function.6,9 Shortened diastolic filling period, lack of active atrial contraction, and structural changes in the LV myocardium are all believed to contribute to reduced systolic function in AF with poor control of ventricular rate.5,12-17 Animal models of rapid pacing-induced cardiomyopathy have revealed ultrastructural changes in cardiomyocytes including depletion of myocyte energy stores, abnormal calcium handling, and mitochondrial defects as potential causes of cardiomyopathy.6,8-10,18-20 Also, noncritical ischemia with
Received for publication June 17, 2014. Accepted October 22, 2014. *These authors contributed equally to this work. Corresponding author: Dr Beat A. Kaufmann, Cardiology Division, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Tel.: þ41-61-265-52-14; fax: þ41-61-265-45-98. E-mail: [email protected] See page 42 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2014.10.032 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Zimmermann et al. Cardiac Changes After Electrical Cardioversion in AF
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33-50%] to 48 [IQR, 40-53%]; P < 0.0001). Four to 6 weeks after ECV, ejection fraction increased further in patients who remained in sinus rhythm (SR) (n ¼ 55) to 55 (IQR, 44-62)%; P < 0.001. In patients with AF relapse, LVEF returned to values comparable to pre-ECV (n ¼ 18) (44 [IQR, 32-51]%; P ¼ 0.03). The atrial emptying fraction did not significantly change immediately after ECV (n ¼ 69; from 20 [IQR, 1325]% to 20 [IQR, 15-28]%; P ¼ 0.14). Only patients who remained in SR showed an increase in atrial emptying fraction after 4-6 weeks (n ¼ 51; to 37 [IQR, 26-48]%; P < 0.0001 vs post-ECV). Conclusions: Immediate improvement in LVEF after ECV explains approximately 50% of total LVEF increase over time. However, in SR, LVEF, and atrial function continuously increase over 4-6 weeks after ECV. This might be attributable to recovery of tachycardia-induced cardiomyopathy.
te re alise e 1 à 2 des volumes auriculaire et ventriculaire gauches, a e heures avant et après la CVE, et de 4 à 6 semaines plus tard. sultats : Chez 73 patients (77 % de sexe masculin, de 66 11 Re une augmentation imme diate de la FEVG ans), la CVE a entraîne (de 43 [intervalle interquartile (IIQ), 33-50 %] à 48 [IIQ, 40-53 %]; P < 0,0001). Quatre (4) à 6 semaines après la CVE, la fraction jection a augmente davantage chez les patients qui sont reste s en d’e rythme sinusal (RS; n ¼ 55) à 55 (IIQ, 44-62)%; P < 0,001. Chez les patients ayant subi une rechute de la FA, la FEVG est revenue à des rieures à la CVE (n ¼ 18; 44 [IIQ, valeurs comparables aux valeurs ante 32-51]%; P ¼ 0,03). La fraction de vidange de l’oreillette n’a presque imme diatement après la CVE (n ¼ 69; de 20 [IIQ, 13-25]% pas change s en RS à 20 [IIQ, 15-28]%; P ¼ 0,14). Seuls les patients qui sont reste une augmentation de la fraction de vidange de l’oreillette ont montre après 4 à 6 semaines (n ¼ 51; à 37 [IIQ, 26-48]%; P < 0,0001 vs après la CVE). lioration imme diate de la FEVG après la CVE Conclusions : L’ame explique approximativement 50 % de l’augmentation totale de la FEVG au fil du temps. Cependant, en RS, la FEVG et la fonction auriculaire augmentent continuellement au cours des 4 à 6 semaines qui suivent rison de la cardiomyopathie la CVE. Ceci serait attribuable à la gue induite par tachycardie.
underlying abnormal subendocardial to subepicardial blood flow ratios possibly contribute to TIC.21,22 In addition, changes of the extracellular matrix with reduced collagen support of adjoining myocytes has been reported.18 Although the changes that occur in TIC have been mainly described in animal models, the relative contribution of AF-related TIC vs rapid heart rate-related short diastolic filling period, and reduced atrial contraction to impaired LVEF in patients is not well characterized. The aim of this study was therefore to (1) characterize the changes over time in LVEF, LV volumes, and left atrial function and volumes; and (2) to relate these changes to changes in heart rate in a well-defined cohort of patients with AF who undergo cardioversion.
cardioversion (Internationalized Normal Value [INR] value < 2 at admission and/or a history of insufficient anticoagulation), or left atrial thrombi were excluded using a transesophageal echocardiogram. ECV was performed according to institutional guidelines. Transthoracic echocardiograms were performed immediately before and within 1-2 hours after ECV, and 4-6 weeks later. At follow-up, heart rhythm and rate was reassessed using 12-lead and HolterECGs. Patients with relapse of AF after primarily successful ECV remained in the study. If ECV was unsuccessful, patients were excluded. Patients were also excluded from the analysis if 1 of the echocardiograms was incomplete, incompatible, or missing. Echocardiographic image acquisition and quantification
Methods Study population Consecutive, patients with persistent AF, defined as a nonself terminating episode lasting > 7 days3 who were scheduled to undergo electrical cardioversion (ECV) were prospectively enrolled. Patients had to be older than 18 years and persistent AF had to be confirmed using Holter-electrocardiogram (ECG). Exclusion criteria were unstable and acute heart failure, untreated severe valvular disease, limiting active or chronic major diseases, and a history of open heart surgery within 3 months before enrollment. Study protocol Informed consent was obtained from all patients. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee. Persistence and heart rate (HR) of AF was assessed using 12lead and Holter-ECGs. All patients had to have appropriate oral anticoagulation for at least 3 weeks before and 4 weeks after ECV. In patients with insufficient anticoagulation before
Echocardiograms were performed with an iE33 (Philips Medical Systems, Andover, MA) equipped with a X3-1 or X5-1 transducer by 3 experienced cardiologists (B.A.K., A.K.-S., and F.-P.S.). Two-dimensional cine loops of the parasternal long and short axis, and of the apical 2-, 3-, and 4-chamber views were obtained in each patient. For real-time 3-dimensional echocardiography (RT3DE) imaging, full volume loops were collected during breath hold with gated acquisition and with sector size and depth optimized to obtain the highest possible frame rate. Gain settings were adjusted to allow for additional adjustment during postprocessing. For the assessment of the left ventricle, trigger delay was set to 0 ms. For the assessment of the left atrium (LA), the image view was modified if necessary to obtain optimal delineation of the left atrial structures, and the trigger delay was set to 300 ms for coverage of the entire ventricular diastole. Thus, at least 2 RT3DE data sets were gathered per patient and transferred to a workstation for offline analysis with dedicated 3-dimensional quantification software packages (LVand 4D-LA-analysis; TomTec-Imaging Systems, Unterschleissheim Munich, Germany).23,24
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For 3-D assessment of the left ventricle and LA, the analyzer specified mitral valve closure and opening to manually define end-diastole and end-systole. For RT3DE analysis of the left ventricle, initial contours of the left ventricle at enddiastole and end-systole were defined for the apical 4chamber, 2-chamber, and long-axis views. The software tool, using a fully automated border detection technique, then formed 3-dimensional models of the left ventricle. The calculated endocardial contours were displayed on multiple long- and short-axis cine images for manual adjustment. For ventricular contouring, the papillary muscles of the left ventricle were enclosed in the endocardial tracking. The software then calculated LV end-diastolic and end-systolic volumes (LVEDV and LVESV, respectively, [mL]), LV stroke volume (SV; mL), and LVEF.24 For RT3DE analysis of the LA, initial contours of the LA at end-diastole and end-systole were manually defined for the apical 4-chamber, 2-chamber, and long-axis views excluding the left atrial appendage and pulmonary veins.23,24 The software then generated a 3-dimensional polyhedral model of the LA using automated border detection. Similar to LV quantification, the endocardial contours were displayed for manual adjustment.23,24 The software then calculated the maximal (VMax [mL]) and minimal (mL) left atrial volumes and left atrial SV (mL) and total left atrial emptying fraction (aEF [%], defined as aEF ¼ [VMaxminimal volume]/VMax 100).23,24 Two physicians (A.J.Z. and M.B.) performed the measurements. Analysis was performed blinded for patient identity and study point in time, although blinding regarding cardiac rhythm was not possible. Interobserver agreement was assessed using repeated LVEF, LVEDV, and VMax measurements from 10 randomly selected subjects 12 months after the first analysis; mean differences were 6 3%, 4 3 mL, and 9 7 mL for the LVEF, LVEDV, and VMax, respectively. Statistical analysis Baseline characteristics were grouped according to the presence or absence of AF at follow-up. Normally distributed variables were compared using paired Student t test, otherwise Wilcoxon rank sum test was used. Categorical variables were compared using c2 or Fisher exact tests, as appropriate. Linear regression models were fitted for each pair of points in time. The response variable (difference of EF between 2 points of time) was modelled by a single explanatory variable (difference of HR between the same 2 points of time). For the explanatory variable, point estimates, 95% confidence intervals, and P values for the Wald significance tests were calculated. In addition, the variance of the change in EF explained by the change in HR was calculated and given as a proportion of the total variance (coefficient of determination, R2), for which point estimates and 95% confidence intervals were calculated. Continuous data are expressed as mean SD or median (interquartile range; IQR), and categorical data as frequency or percentage. A P value < 0.05 was prespecified to indicate statistical significance. All analyses were performed using SAS version 9.3 (SAS Institute Inc, Cary, NC) and R Core Team (R Foundation for Statistical Computing, Vienna, Austria; http://r-project.org).
Canadian Journal of Cardiology Volume 31 2015
Results Baseline characteristics of the study cohort From March 2010 to April 2013, 108 consecutive patients with persistent AF were enrolled. Excluded were 10 patients with unsuccessful cardioversion, 21 patients who had incomplete or incompatible echocardiographic data sets, 3 patients who underwent pacemaker implantation during follow-up; and 1 patient with a newly diagnosed severe hypertrophic obstructive cardiomyopathy. Thus, the final analysis included 73 patients. Of these, 55 patients (76%) were still in sinus rhythm (SR) at follow-up, and 18 patients experienced a relapse of AF at follow-up. The baseline characteristics, stratified according to the presence or absence of SR at follow-up, are displayed in Supplemental Table S1. In the entire study population, the mean age was 66 11 years and 77% were male. Median (IQR) duration of the persistent AF episodes were 18 (13-25) and 16 (11-23) weeks among patients with SR and AF at follow-up, respectively (P ¼ 0.45). Among 13 patients, duration of the AF episodes were longer than 12 months or the beginning was not assessable. At study entry, the overall median time (IQR) > 120 beats per minute (bpm) was 300 (30-600) minutes among all included individuals. Before the ECV, we found no significant difference between the SR and AF group (300 [40-670] and 220 [25-555] minutes, respectively; P ¼ 0.51). In a comparison of the 2 subgroups, no significant differences were observed in the prevalence of arterial hypertension, coronary artery disease, stroke, diabetes, or heart failure. Cardiac medication between the 2 groups did not differ. The median dose of the b-blocker equivalent metoprolol was 100 (IQR, 50-200) mg and 42% of patients were receiving class III antiarrhythmic agents (amiodarone or dronaderone). Regarding echocardiographic parameters, patients with a relapse of AF showed a trend to an increased relative wall thickness at baseline, but did not differ regarding baseline LV mass, LVEF, or indexed left atrial volume. At study entry, median (IQR) brain natriuretic peptide levels were 256 (141-406) ng/L and 215 (155-398) ng/L in individuals with SR and in AF, respectively (P ¼ 1.00). Compared with patients who reverted to AF at follow-up, those who remained in SR at follow-up had a significant decrease in mean (IQR) brain natriuretic peptide levels; 137 (82-275) ng/L vs 221 (145-300) ng/L, respectively (P < 0.0001). The median systolic blood pressure (IQR) did not significantly differ between the SR and the AF cohort at study entry (135 [125-147] and 131 [123-140] mm Hg, respectively; P ¼ 0.58), nor did it differ at follow-up (137 [125150] and 137 [125-148] mm Hg, respectively; P ¼ 0.79). In addition, there were no relevant changes in systolic blood pressure within the SR and AF group (P ¼ 0.15 and P ¼ 0.42, respectively). Changes in HR during follow-up A successful ECV resulted in an immediate decrease in HR (from 84 bpm [IQR, 76-97] to 60 bpm [IQR 55-66]; P < 0.0001; Table 1). Patients who remained in SR had a further significant decrease in HR at follow-up (55 [IQR, 51-60] bpm; P ¼ 0.0004). In patients with AF relapse at followup, HR significantly increased again (87 [IQR, 75-96] bpm;
Zimmermann et al. Cardiac Changes After Electrical Cardioversion in AF
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Table 1. Characterization of cardiac volumes and ejection fraction before and after ECV and at follow-up stratified according to rhythm (all patients, n ¼ 73) P Before ECV Heart rate, bpm* SR group 84 (75-99) AF group 80 (77-94) Difference, P 0.83 Left ventricular function and volumesy LVEF, % SR group 43 (31-50) AF group 45 (34-50) Difference, P 0.47 LVSV, mL SR group 36 (46-28) AF group 38 (27-43) Difference, P 0.76 LVESV, mL SR group 52 (33-75) AF group 49 (39-62) Difference, P 0.78 LVEDV, mL SR group 91 (62-121) AF group 84 (73-98) Difference, P 0.90 Left atrial function and volumesz aEF, % SR group 18 (13-24) AF group 22 (9-31) Difference, P 0.38 VMin, mL SR group 68 (60-85) AF group 79 (51-91) Difference, P 0.86 VMax, mL SR group 90 (77-103) AF group 97 (71-116) Difference, P 0.44 LASV, mL SR group 16 (13-21) AF group 15 (10-25) Difference, P 0.75
After ECV
At Follow-Up
Before vs After ECV
After ECV vs Follow-Up
59 (55-64) 61 (54-68) 0.59
55 (51-60) 87 (75-96) < 0.0001
< 0.0001 < 0.0001
0.0004 0.008
48 (38-53) 49 (43-55) 0.54
55 (44-62) 44 (32-51) 0.0006
< 0.0001 0.11
< 0.0001 0.03
48 (39-56) 52 (43-54) 0.70
54 (45-64) 38 (28-50) 0.0002
< 0.0001 0.003
0.0002 0.003
50 (38-68) 49 (38-57) 0.50
42 (33-62) 49 (43-58) 0.15
0.80 0.77
0.005 0.44
95 (76-125) 103 (84-109) 0.78
99 (78-134) 86 (74-103) 0.07
0.0002 0.004
0.78 0.08
20 (15-30) 19 (11-28) 0.68
37 (26-48) 16 (9-27) < 0.0001
0.05 0.83
< 0.0001 0.27
63 (50-85) 66 (55-104) 0.27
48 (40-63) 74 (58-104) 0.002
0.15 1.00
< 0.0001 0.70
86 (64-102) 86 (76-126) 0.17
73 (64-104) 90 (73-120) 0.13
0.54 0.64
0.89 0.50
16 (12-23) 16 (13-20) 0.81
29 (21-38) 15 (9-23) 0.0004
0.32 0.87
< 0.0001 0.35
Data are presented as median (interquartile range). P values were based on Mann-Whitney U test for independent variables and Wilcoxon rank sum test for dependent data. aEF, atrial emptying fraction; AF, atrial fibrillation; bpm, beats per minute; ECV, electrical cardioversion; LASV, left atrial stroke volume; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end systolic volume; LVSV, left ventricular stroke volume; SR, sinus rhythm; Vmax, maximum left atrial volume; Vmin, minimal left atrial volume. * This represents the median heart rate during the duration of the echocardiogram acquisition. y These 2 groups of patients in SR and AF represented 55 and 18 patients, respectively. z These 2 groups of patients in SR and AF represented 51 and 18 patients, respectively.
P ¼ 0.008). At follow-up, Holter-ECG assessment revealed a significant difference between the SR and AF group (0 [0-15] and 210 [25-480] in minutes > 120 bpm, respectively; P < 0.0001). Changes in LV volumes and ejection fraction Development of the LVEF according to the absence or presence of AF at follow-up is displayed in Table 1 and Figure 1. A successful ECV resulted in an immediate significant increase in LVEF and SV. Patients with SR at follow-up experienced a further significant increase in LVEF and SV. The immediate increase in LVEF in patients with SR at follow-up amounted to 41% of the total recovery of LVEF over 4-6 weeks, whereas the increase thereafter accounted for 59% of the total recovery in LV function. In these patients, the immediate increase in LVEF and SV was accompanied by
a significant increase in LVEDV, whereas a modest decrease in LVESV did not reach statistical significance. To the contrary, in the same patients, the further increase in LVEF up to 4-6 weeks depended mainly on a significant decrease in LVESV, whereas a modest further increase in LVEDV was not statistically significant (Table 1). Correlation of changes in LVEF to changes in HR during follow-up Changes in HR immediately before and after ECV showed a significant correlation to changes in LVEF and variability of the changes in HR accounted for about one-third of the variability of the changes in LVEF, in patients who remained in SR and in those who relapsed to AF during follow-up (R2 ¼ 0.369; 95% confidence interval, 0.210-0.519; Table 2 and Fig. 2). During further follow-up, changes in HR
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Figure 1. Evolution in left ventricular ejection fraction (LVEF) from points in time of before to after treatment and after treatment to follow-up among patients with sinus rhythm and atrial fibrillation at the follow-up examination. ECV, electrical cardioversion.
accounted for only a very small part of the improvement in LVEF in patients who remained in SR (Fig. 1). In contrast, among those with an AF relapse at follow-up, the variability in HR explained approximately one-third of the variance of the LVEF (Table 2).
Changes in left atrial volumes and function ECV did not lead to immediate changes in left atrial volumes or left atrial functional parameters (Table 1). However, in patients who remained in SR during follow-up, return of mechanical atrial function led to a significant increase in aEF and left atrial SV. Meanwhile, the maximal atrial volume did not substantially change (Table 1).
Discussion Shortening of diastolic filling time, loss of atrial mechanical activity, and increased HR are all thought to contribute to reduced LVEF in patients with AF with insufficiently controlled ventricular rate. In this study we show that ECV results in an immediate improvement in LVEF, and that further improvement ensues over a period of 4-6 weeks in patients who remain in SR. About one-third of this immediate improvement was related to the reduction in HR and accompanied by a significant increase in LVEDV (Tables 1 and 2). Interestingly, this relationship was observed despite the fact that HR was well controlled in this sample. Further improvement shows a much weaker relation to changes in HR and is accompanied by a significant decrease in LVESV and improvement in left atrial function.
Figure 2. Variance in left ventricular ejection fraction (EF) related to change in heart rate (HR) from points in time of (A) before to after treatment and (B) after treatment to follow-up among patients with sinus rhythm at the follow-up examination. R2 is the proportion of variance in left ventricular EF change explained by HR. The vertical lines indicate the lengths of the residuals and the sloped line resembles the models fitted to the subgroup of patients without atrial fibrillation relapse. bpm, beats per minute; CI, confidence interval.
Zimmermann et al. Cardiac Changes After Electrical Cardioversion in AF
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Table 2. Results of the linear models for change in LVEF with the single predictor, “change in HR” at different points in time (n ¼ 73) Sinus rhythm group R * (n ¼ 55) AF relapse group R2 (n ¼ 18) 2
From Before ECV to Follow-Up
From Before ECV to Early After ECV
From Early After ECV to Follow-Up
0.299 (0.137-0.447) 0.083 (0.207 to 0.280)
0.296 (0.095-0.485) 0.335 (0.073 to 0.702)
0.036 (0.099 to 0.131) 0.280 (0.067 to 0.597)
Data are presented as R2 (95% confidence interval). AF, atrial fibrillation; ECV, electrical cardioversion; HR, heart rate; LVEF, left ventricular ejection fraction. * R2 is the proportion of variance in LVEF change explained by HR.
Early LV changes after ECV Our data indicate that early changes in LV function after ECV are based predominantly on a regularization and reduction in HR and thus an increased LV filling time. Increased beat-to-beat variability in cycle length has a negative effect on LV performance independent of HR.15 Additionally, increased cycle lengths after ECV contribute to increased LV performance via the Frank Starling mechanism.25 Although changes in LVEF after ECV have been examined in a number of studies, with the exception of 1 study, early changes have not been measured.13,14,26 Raymond et al. used M-mode imaging in 15 patients to assess LV function before and 2-16 hours after ECV, and reported an increase in SV and EF caused by a combination of increasing end-diastolic volume and declining end-systolic volume.5 In our larger sample and using RT3DE, the increase in LVEF after ECV was based on increases in end-diastolic volume only. This discrepancy might be explained by the earlier point in time after ECV (< 2 h) at which LV function and volumes were assessed in our study, and in fact our data are more likely to reflect the pure effect of rate reduction and regularization early after ECV. Late LV and left atrial changes after ECV TIC is caused by ultrastructural changes at a cellular level affecting myocyte function and extracellular matrix architecture.6,8-10,18-20,27 In animal models with termination of rapid pacing, improvement in LV function is accompanied by a partial reversion of these ultrastructural changes.8,9,27 In our study, the short-term improvement related to changes in HR was followed by a further improvement in patients remaining in SR. This further improvement of LVEF by an absolute 7 percentage points was not explained by changes in HR. Unlike short-term changes in LV function, the improvement in LV function at 4-6 weeks went along with a significant reduction in LVESV, and LVEDV remained unchanged. These changes argue for an improvement in myocardial contractility, which might be explained by a reversal of myocyte and extracellular changes occurring in TIC. Although our findings of a continued improvement of LV function at 4-6 weeks parallel findings of other studies,5,12-14,16,26,28,29 early assessment of LV function in a well defined time window after ECV allowed us to much better discern changes related to reversal of TIC thereafter, which were responsible for half of the total improvement in LVEF in our study. It should be noted that the continued improvement in LVEF that we saw over 4-6 weeks occurred despite the fact that the HR in our population was already well controlled before ECV. Thus, our data also indicate that AF can lead to impaired LV function even in the absence of tachycardia defined according to clinical criteria.
There is an apparent discrepancy between the improvement that we found in LVEF after cardioversion to SR, and the inability to demonstrate clinical benefits of restoration of SR in large clinical trials, like Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), in which the patient population was similar to ours.4,30 However, it should be kept in mind, that in clinical trials approximately 60% of patients assigned to a rhythm control strategy are in SR at 60 months, and in addition, subgroup analyses of patients who maintain long-term rhythm control treatment demonstrate a better outcome vs those assigned to a rate control strategy.4,30 Whereas left atrial mechanical function did not improve immediately after ECV, recovery of left atrial mechanical function was evident at 4-6 weeks with a significant increase in total aEF that was associated with a decrease in the minimal atrial volume and might have contributed to improvement in LV function. Up to 4-6 weeks, maximal atrial volume tended to decrease in patients who remained in SR, however, this decrease was not statistically significant. Thus, after 4-6 weeks, recovery of mechanical atrial function did occur, whereas this time frame might have been too short to detect reverse remodelling of the LA.31,32 Our cohort is representative and comparable to other study cohorts that undergo ECV.33 There are limitations to our study that deserve mentioning. The cohort’s separation into SR and AF is a posttreatment variable. Hence, one cannot draw a directionality or causality of the effect. Additionally, our results apply only to patients with persistent AF, and generalizability to other patient groups remains uncertain. Duration of persistent AF is a predictor of success of ECV and maintenance of SR after cardioversion. The reported persistent AF episodes are approximations in some patients, because they could not recall the exact episode start. Echocardiographic measurements were performed using RT3DE in AF before ECV; although well validated in patients with SR, this technique is not extensively validated for assessment of cardiac function and structure during AF. However, given the superior reproducibility of RT3DE over time as opposed to conventional 2-dimensional methods, we chose to use RT3DE imaging data sets for all points in time.34,35 Because echo reviewers were aware of the patient’s rhythm, blinding of imaging data sets was not possible with regard to pre- and post-ECV. It should also be kept in mind that rather than myocardial contractility, we measured LVEF, which is not only influenced by contractility, but also by other factors such as, for example pre- and afterload. Thus, the modest further slowing of HR in patients remaining in SR from after ECV to follow-up could contribute to the increase in LVEF due to increased preload. However, whereas we found a correlation of changes in HR with changes in LVEF from pre-ECV to postECV, such a correlation was not present for changes that occurred between post-ECV and follow-up, which is indirect
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evidence for a contribution of recovery of myocyte function to the improvement in LVEF. Last, we only assessed cardiac function at 3 time points; obviously, a closer echocardiographic and electrocardiographic follow-up would add further aspects regarding the course of myocardial recovery after ECV.
7. Suman-Horduna I, Roy D, Frasure-Smith N, et al. Quality of life and functional capacity in patients with atrial fibrillation and congestive heart failure. J Am Coll Cardiol 2013;61:455-60.
Conclusions In patients with persistent AF who undergo ECV, LVEF rapidly improves after the procedure. This immediate change in LVEF explains approximately 50% of total LVEF improvement over time, and is strongly associated with changes in HR. It is found even among individuals with normofrequent AF. Over the next 4-6 weeks, further improvement in LVEF occurs, which, however, correlates only weakly with changes in HR. There might be factors other than the HR involved in improvement in LVEF and thus reversal of AF-related TIC.
9. Umana E, Solares CA, Alpert MA. Tachycardia-induced cardiomyopathy. Am J Med 2003;114:51-5.
Acknowledgements The authors acknowledge the support of Drs Arnheid Kessel-Schaefer (A.K.-S.) and Frank-Peter Stephan (F.-P.S.) in acquisition of several echocardiograms.
8. Shinbane JS, Wood MA, Jensen DN, et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol 1997;29:709-15.
10. Nerheim P, Birger-Botkin S, Piracha L, Olshansky B. Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachycardia. Circulation 2004;110:247-52. 11. Calvo N, Bisbal F, Guiu E, et al. Impact of atrial fibrillation-induced tachycardiomyopathy in patients undergoing pulmonary vein isolation. Int J Cardiol 2013;168:4093-7. 12. Welikovitch L, Lafreniere G, Burggraf GW, Sanfilippo AJ. Change in atrial volume following restoration of sinus rhythm in patients with atrial fibrillation: a prospective echocardiographic study. Can J Cardiol 1994;10:993-6. 13. Xiong C, Sonnhag C, Nylander E, Wranne B. Atrial and ventricular function after cardioversion of atrial fibrillation. Br Heart J 1995;74: 254-60. 14. Upshaw CB Jr. Hemodynamic changes after cardioversion of chronic atrial fibrillation. Arch Intern Med 1997;157:1070-6.
Funding Sources This study was supported by a grant of the Mach Gaensslen Foundation (to David Conen). David Conen and Beat A. Kaufmann have received grants from the Swiss National Science Foundation (PP00P3_133681, 3232B0_141603, and 310030_149718, respectively). Disclosures The authors have no conflicts of interest to disclose. References 1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370-5. 2. Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. JAMA 2011;305:2080-7. 3. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (Compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS Recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:1935-44. 4. Ionescu-Ittu R, Abrahamowicz M, Jackevicius CA, et al. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch Intern Med 2012;172: 997-1004.
15. Clark DM, Plumb VJ, Epstein AE, Kay GN. Hemodynamic effects of an irregular sequence of ventricular cycle lengths during atrial fibrillation. J Am Coll Cardiol 1997;30:1039-45. 16. Viswanathan K, Daniak SM, Salomone K, et al. Effect of cardioversion of atrial fibrillation on improvement in left ventricular performance. Am J Cardiol 2001;88:439-41. 17. Therkelsen SK, Groenning BA, Svendsen JH, Jensen GB. Atrial and ventricular volume and function evaluated by magnetic resonance imaging in patients with persistent atrial fibrillation before and after cardioversion. Am J Cardiol 2006;97:1213-9. 18. Spinale FG, Tomita M, Zellner JL, et al. Collagen remodeling and changes in LV function during development and recovery from supraventricular tachycardia. Am J Physiol 1991;261:H308-18. 19. Perreault CL, Shannon RP, Komamura K, Vatner SF, Morgan JP. Abnormalities in intracellular calcium regulation and contractile function in myocardium from dogs with pacing-induced heart failure. J Clin Invest 1992;89:932-8. 20. Yamamoto K, Burnett JC Jr, Meyer LM, et al. Ventricular remodeling during development and recovery from modified tachycardia-induced cardiomyopathy model. Am J Physiol 1996;271:R1529-34. 21. Spinale FG, Tanaka R, Crawford FA, Zile MR. Changes in myocardial blood flow during development of and recovery from tachycardiainduced cardiomyopathy. Circulation 1992;85:717-29. 22. Shannon RP, Komamura K, Shen YT, Bishop SP, Vatner SF. Impaired regional subendocardial coronary flow reserve in conscious dogs with pacing-induced heart failure. Am J Physiol 1993;265:H801-9.
5. Raymond RJ, Lee AJ, Messineo FC, Manning WJ, Silverman DI. Cardiac performance early after cardioversion from atrial fibrillation. Am Heart J 1998;136:435-42.
23. Rohner A, Brinkert M, Kawel N, et al. Functional assessment of the left atrium by real-time three-dimensional echocardiography using a novel dedicated analysis tool: initial validation studies in comparison with computed tomography. Eur J Echocardiogr 2011;12:497-505.
6. Deedwania PC, Lardizabal JA. Atrial fibrillation in heart failure: a comprehensive review. Am J Med 2010;123:198-204.
24. Buechel RR, Sommer G, Leibundgut G, et al. Assessment of left atrial functional parameters using a novel dedicated analysis tool for real-time
Zimmermann et al. Cardiac Changes After Electrical Cardioversion in AF three-dimensional echocardiography: validation in comparison to magnetic resonance imaging. Int J Cardiovasc Imaging 2013;29:601-8. 25. Gosselink AT, Blanksma PK, Crijns HJ, et al. Left ventricular beat-tobeat performance in atrial fibrillation: contribution of Frank-Starling mechanism after short rather than long RR intervals. J Am Coll Cardiol 1995;26:1516-21.
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31. Mattioli AV, Bonatti S, Bonetti L, Mattioli G. Left atrial size after cardioversion for atrial fibrillation: effect of external direct current shock. J Am Soc Echocardiogr 2003;16:271-6. 32. Khan IA. Atrial stunning: basics and clinical considerations. Int J Cardiol 2003;92:113-28.
26. Wozakowska-Kaplon B, Opolski G. Effects of sinus rhythm restoration in patients with persistent atrial fibrillation: a clinical, echocardiographic and hormonal study. Int J Cardiol 2004;96:171-6.
33. Flaker G, Lopes RD, Al-Khatib SM, et al. Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol 2014;63:1082-7.
27. Spinale FG, Zellner JL, Tomita M, Crawford FA, Zile MR. Relation between ventricular and myocyte remodeling with the development and regression of supraventricular tachycardia-induced cardiomyopathy. Circ Res 1991;69:1058-67.
34. Mor-Avi V, Sugeng L, Lang RM. Real-time 3-dimensional echocardiography: an integral component of the routine echocardiographic examination in adult patients? Circulation 2009;119:314-29.
28. Emilsson K, Wandt B. The relation between ejection fraction and mitral annulus motion before and after direct-current electrical cardioversion. Clin Physiol 2000;20:218-24. 29. Nishino M, Hoshida S, Tanouchi J, et al. Time to recover from atrial hormonal, mechanical, and electrical dysfunction after successful electrical cardioversion of persistent atrial fibrillation. Am J Cardiol 2000;85: 1451-4. 30. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation 2004;109:1509-13.
35. Thavendiranathan P, Liu S, Verhaert D, et al. Feasibility, accuracy, and reproducibility of real-time full-volume 3D transthoracic echocardiography to measure LV volumes and systolic function: a fully automated endocardial contouring algorithm in sinus rhythm and atrial fibrillation. JACC Cardiovasc Imaging 2012;5:239-51.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2014.10.032.
Clinical Research
Effects of Sinus Rhythm Maintenance on Left Heart Function After Electrical Cardioversion of Atrial Fibrillation: Implications for Tachycardia-Induced Cardiomyopathy Andreas J. Zimmermann, MD,a,* Matthias Bossard, MD,a,b,* Stefanie Aeschbacher, MSc,a Tobias Schoen, MD,a Gian Voellmin, MSc,a Yves Suter, MD,b Anouk Lehmann, BSc,a Thomas Hochgruber, MD,a Katrin Pumpol, MD,a Christian Sticherling, MD,b Michael Kühne, MD,b David Conen, MD, MPH,a and Beat A. Kaufmann, MDb a
Department of Medicine, University Hospital Basel, Basel, Switzerland b
Cardiology Division, University Hospital Basel, Basel, Switzerland
ABSTRACT
RESUM E
Background: The role of tachycardia-induced cardiomyopathy vs tachycardia-related short diastolic filling period and reduced atrial contraction in decline of left ventricular ejection fraction (LVEF) in atrial fibrillation (AF) is uncertain. We aimed to characterize left heart changes over time in patients with AF who undergo electrical cardioversion (ECV). Methods: Consecutive AF patients who were to undergo ECV were enrolled. Patients with unstable or acute heart failure, severe valvular diseases, recent open-heart surgery, major disorders, or an unsuccessful ECV were excluded. Transthoracic echocardiography, including 3-dimensional left atrial and ventricular volume acquisitions, was performed 1-2 hours before and after ECV, and 4-6 weeks later. Results: In 73 patients (77% male, 66 11 years), ECV resulted in an immediate increase in LVEF (from 43 [interquartile range (IQR),
Introduction : Le rôle de la cardiomyopathie induite par tachycardie riode diastolique de remplissage lie e à la par rapport à la courte pe duction de la contraction auriculaire entraînant une tachycardie et la re jection ventriculaire gauche (FEVG) lors de diminution de la fraction d’e fibrillation auriculaire (FA) est mis en doute. Nous avions pour but de riser les changements du cœur gauche au fil du temps chez les caracte lectrique patients souffrant de FA qui subissent une cardioversion e (CVE). thodes : Les patients conse cutifs souffrant de FA qui devaient subir Me te inscrits. Les patients souffrant d’une insuffisance la CVE ont e instable ou d’une insuffisance cardiaque aiguë, de valvulopathies cemment subi une chirurgie à cœur ouvert, souffrant graves, ayant re te exclus. de troubles majeurs ou ayant subi sans succès la CVE ont e chocardiographie transthoracique, y compris les acquisitions en 3D L’e
Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting approximately 1%-2% of the general population, and epidemiologic data indicate that this figure will likely increase in the coming decades.1-4 Patients with AF experience increased rates of death, stroke, reduced exercise capacity, and are more likely to be hospitalized or suffer from heart failure than similar patients without AF.2,3,5-7 AF can be a consequence of heart failure with increased left atrial pressure.3 However, AF with poorly controlled ventricular rate can
itself also be the cause of heart failure with decreased left ventricular (LV) ejection fraction (LVEF), an entity also referred to as tachycardia-induced cardiomyopathy (TIC).8-11 TIC can be caused by a variety of tachyarrhythmias, but most commonly is a consequence of AF.6,8-11 TIC can lead to a clinical picture of heart failure, and is considered reversible on resolution of the tachycardia.8,9,11 The incidence of TIC is not well characterized, but it is estimated that approximately 50% of patients in AF have some impairment of LV systolic function.6,9 Shortened diastolic filling period, lack of active atrial contraction, and structural changes in the LV myocardium are all believed to contribute to reduced systolic function in AF with poor control of ventricular rate.5,12-17 Animal models of rapid pacing-induced cardiomyopathy have revealed ultrastructural changes in cardiomyocytes including depletion of myocyte energy stores, abnormal calcium handling, and mitochondrial defects as potential causes of cardiomyopathy.6,8-10,18-20 Also, noncritical ischemia with
Received for publication June 17, 2014. Accepted October 22, 2014. *These authors contributed equally to this work. Corresponding author: Dr Beat A. Kaufmann, Cardiology Division, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Tel.: þ41-61-265-52-14; fax: þ41-61-265-45-98. E-mail: [email protected] See page 42 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2014.10.032 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Zimmermann et al. Cardiac Changes After Electrical Cardioversion in AF
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33-50%] to 48 [IQR, 40-53%]; P < 0.0001). Four to 6 weeks after ECV, ejection fraction increased further in patients who remained in sinus rhythm (SR) (n ¼ 55) to 55 (IQR, 44-62)%; P < 0.001. In patients with AF relapse, LVEF returned to values comparable to pre-ECV (n ¼ 18) (44 [IQR, 32-51]%; P ¼ 0.03). The atrial emptying fraction did not significantly change immediately after ECV (n ¼ 69; from 20 [IQR, 1325]% to 20 [IQR, 15-28]%; P ¼ 0.14). Only patients who remained in SR showed an increase in atrial emptying fraction after 4-6 weeks (n ¼ 51; to 37 [IQR, 26-48]%; P < 0.0001 vs post-ECV). Conclusions: Immediate improvement in LVEF after ECV explains approximately 50% of total LVEF increase over time. However, in SR, LVEF, and atrial function continuously increase over 4-6 weeks after ECV. This might be attributable to recovery of tachycardia-induced cardiomyopathy.
te re alise e 1 à 2 des volumes auriculaire et ventriculaire gauches, a e heures avant et après la CVE, et de 4 à 6 semaines plus tard. sultats : Chez 73 patients (77 % de sexe masculin, de 66 11 Re une augmentation imme diate de la FEVG ans), la CVE a entraîne (de 43 [intervalle interquartile (IIQ), 33-50 %] à 48 [IIQ, 40-53 %]; P < 0,0001). Quatre (4) à 6 semaines après la CVE, la fraction jection a augmente davantage chez les patients qui sont reste s en d’e rythme sinusal (RS; n ¼ 55) à 55 (IIQ, 44-62)%; P < 0,001. Chez les patients ayant subi une rechute de la FA, la FEVG est revenue à des rieures à la CVE (n ¼ 18; 44 [IIQ, valeurs comparables aux valeurs ante 32-51]%; P ¼ 0,03). La fraction de vidange de l’oreillette n’a presque imme diatement après la CVE (n ¼ 69; de 20 [IIQ, 13-25]% pas change s en RS à 20 [IIQ, 15-28]%; P ¼ 0,14). Seuls les patients qui sont reste une augmentation de la fraction de vidange de l’oreillette ont montre après 4 à 6 semaines (n ¼ 51; à 37 [IIQ, 26-48]%; P < 0,0001 vs après la CVE). lioration imme diate de la FEVG après la CVE Conclusions : L’ame explique approximativement 50 % de l’augmentation totale de la FEVG au fil du temps. Cependant, en RS, la FEVG et la fonction auriculaire augmentent continuellement au cours des 4 à 6 semaines qui suivent rison de la cardiomyopathie la CVE. Ceci serait attribuable à la gue induite par tachycardie.
underlying abnormal subendocardial to subepicardial blood flow ratios possibly contribute to TIC.21,22 In addition, changes of the extracellular matrix with reduced collagen support of adjoining myocytes has been reported.18 Although the changes that occur in TIC have been mainly described in animal models, the relative contribution of AF-related TIC vs rapid heart rate-related short diastolic filling period, and reduced atrial contraction to impaired LVEF in patients is not well characterized. The aim of this study was therefore to (1) characterize the changes over time in LVEF, LV volumes, and left atrial function and volumes; and (2) to relate these changes to changes in heart rate in a well-defined cohort of patients with AF who undergo cardioversion.
cardioversion (Internationalized Normal Value [INR] value < 2 at admission and/or a history of insufficient anticoagulation), or left atrial thrombi were excluded using a transesophageal echocardiogram. ECV was performed according to institutional guidelines. Transthoracic echocardiograms were performed immediately before and within 1-2 hours after ECV, and 4-6 weeks later. At follow-up, heart rhythm and rate was reassessed using 12-lead and HolterECGs. Patients with relapse of AF after primarily successful ECV remained in the study. If ECV was unsuccessful, patients were excluded. Patients were also excluded from the analysis if 1 of the echocardiograms was incomplete, incompatible, or missing. Echocardiographic image acquisition and quantification
Methods Study population Consecutive, patients with persistent AF, defined as a nonself terminating episode lasting > 7 days3 who were scheduled to undergo electrical cardioversion (ECV) were prospectively enrolled. Patients had to be older than 18 years and persistent AF had to be confirmed using Holter-electrocardiogram (ECG). Exclusion criteria were unstable and acute heart failure, untreated severe valvular disease, limiting active or chronic major diseases, and a history of open heart surgery within 3 months before enrollment. Study protocol Informed consent was obtained from all patients. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee. Persistence and heart rate (HR) of AF was assessed using 12lead and Holter-ECGs. All patients had to have appropriate oral anticoagulation for at least 3 weeks before and 4 weeks after ECV. In patients with insufficient anticoagulation before
Echocardiograms were performed with an iE33 (Philips Medical Systems, Andover, MA) equipped with a X3-1 or X5-1 transducer by 3 experienced cardiologists (B.A.K., A.K.-S., and F.-P.S.). Two-dimensional cine loops of the parasternal long and short axis, and of the apical 2-, 3-, and 4-chamber views were obtained in each patient. For real-time 3-dimensional echocardiography (RT3DE) imaging, full volume loops were collected during breath hold with gated acquisition and with sector size and depth optimized to obtain the highest possible frame rate. Gain settings were adjusted to allow for additional adjustment during postprocessing. For the assessment of the left ventricle, trigger delay was set to 0 ms. For the assessment of the left atrium (LA), the image view was modified if necessary to obtain optimal delineation of the left atrial structures, and the trigger delay was set to 300 ms for coverage of the entire ventricular diastole. Thus, at least 2 RT3DE data sets were gathered per patient and transferred to a workstation for offline analysis with dedicated 3-dimensional quantification software packages (LVand 4D-LA-analysis; TomTec-Imaging Systems, Unterschleissheim Munich, Germany).23,24
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For 3-D assessment of the left ventricle and LA, the analyzer specified mitral valve closure and opening to manually define end-diastole and end-systole. For RT3DE analysis of the left ventricle, initial contours of the left ventricle at enddiastole and end-systole were defined for the apical 4chamber, 2-chamber, and long-axis views. The software tool, using a fully automated border detection technique, then formed 3-dimensional models of the left ventricle. The calculated endocardial contours were displayed on multiple long- and short-axis cine images for manual adjustment. For ventricular contouring, the papillary muscles of the left ventricle were enclosed in the endocardial tracking. The software then calculated LV end-diastolic and end-systolic volumes (LVEDV and LVESV, respectively, [mL]), LV stroke volume (SV; mL), and LVEF.24 For RT3DE analysis of the LA, initial contours of the LA at end-diastole and end-systole were manually defined for the apical 4-chamber, 2-chamber, and long-axis views excluding the left atrial appendage and pulmonary veins.23,24 The software then generated a 3-dimensional polyhedral model of the LA using automated border detection. Similar to LV quantification, the endocardial contours were displayed for manual adjustment.23,24 The software then calculated the maximal (VMax [mL]) and minimal (mL) left atrial volumes and left atrial SV (mL) and total left atrial emptying fraction (aEF [%], defined as aEF ¼ [VMaxminimal volume]/VMax 100).23,24 Two physicians (A.J.Z. and M.B.) performed the measurements. Analysis was performed blinded for patient identity and study point in time, although blinding regarding cardiac rhythm was not possible. Interobserver agreement was assessed using repeated LVEF, LVEDV, and VMax measurements from 10 randomly selected subjects 12 months after the first analysis; mean differences were 6 3%, 4 3 mL, and 9 7 mL for the LVEF, LVEDV, and VMax, respectively. Statistical analysis Baseline characteristics were grouped according to the presence or absence of AF at follow-up. Normally distributed variables were compared using paired Student t test, otherwise Wilcoxon rank sum test was used. Categorical variables were compared using c2 or Fisher exact tests, as appropriate. Linear regression models were fitted for each pair of points in time. The response variable (difference of EF between 2 points of time) was modelled by a single explanatory variable (difference of HR between the same 2 points of time). For the explanatory variable, point estimates, 95% confidence intervals, and P values for the Wald significance tests were calculated. In addition, the variance of the change in EF explained by the change in HR was calculated and given as a proportion of the total variance (coefficient of determination, R2), for which point estimates and 95% confidence intervals were calculated. Continuous data are expressed as mean SD or median (interquartile range; IQR), and categorical data as frequency or percentage. A P value < 0.05 was prespecified to indicate statistical significance. All analyses were performed using SAS version 9.3 (SAS Institute Inc, Cary, NC) and R Core Team (R Foundation for Statistical Computing, Vienna, Austria; http://r-project.org).
Canadian Journal of Cardiology Volume 31 2015
Results Baseline characteristics of the study cohort From March 2010 to April 2013, 108 consecutive patients with persistent AF were enrolled. Excluded were 10 patients with unsuccessful cardioversion, 21 patients who had incomplete or incompatible echocardiographic data sets, 3 patients who underwent pacemaker implantation during follow-up; and 1 patient with a newly diagnosed severe hypertrophic obstructive cardiomyopathy. Thus, the final analysis included 73 patients. Of these, 55 patients (76%) were still in sinus rhythm (SR) at follow-up, and 18 patients experienced a relapse of AF at follow-up. The baseline characteristics, stratified according to the presence or absence of SR at follow-up, are displayed in Supplemental Table S1. In the entire study population, the mean age was 66 11 years and 77% were male. Median (IQR) duration of the persistent AF episodes were 18 (13-25) and 16 (11-23) weeks among patients with SR and AF at follow-up, respectively (P ¼ 0.45). Among 13 patients, duration of the AF episodes were longer than 12 months or the beginning was not assessable. At study entry, the overall median time (IQR) > 120 beats per minute (bpm) was 300 (30-600) minutes among all included individuals. Before the ECV, we found no significant difference between the SR and AF group (300 [40-670] and 220 [25-555] minutes, respectively; P ¼ 0.51). In a comparison of the 2 subgroups, no significant differences were observed in the prevalence of arterial hypertension, coronary artery disease, stroke, diabetes, or heart failure. Cardiac medication between the 2 groups did not differ. The median dose of the b-blocker equivalent metoprolol was 100 (IQR, 50-200) mg and 42% of patients were receiving class III antiarrhythmic agents (amiodarone or dronaderone). Regarding echocardiographic parameters, patients with a relapse of AF showed a trend to an increased relative wall thickness at baseline, but did not differ regarding baseline LV mass, LVEF, or indexed left atrial volume. At study entry, median (IQR) brain natriuretic peptide levels were 256 (141-406) ng/L and 215 (155-398) ng/L in individuals with SR and in AF, respectively (P ¼ 1.00). Compared with patients who reverted to AF at follow-up, those who remained in SR at follow-up had a significant decrease in mean (IQR) brain natriuretic peptide levels; 137 (82-275) ng/L vs 221 (145-300) ng/L, respectively (P < 0.0001). The median systolic blood pressure (IQR) did not significantly differ between the SR and the AF cohort at study entry (135 [125-147] and 131 [123-140] mm Hg, respectively; P ¼ 0.58), nor did it differ at follow-up (137 [125150] and 137 [125-148] mm Hg, respectively; P ¼ 0.79). In addition, there were no relevant changes in systolic blood pressure within the SR and AF group (P ¼ 0.15 and P ¼ 0.42, respectively). Changes in HR during follow-up A successful ECV resulted in an immediate decrease in HR (from 84 bpm [IQR, 76-97] to 60 bpm [IQR 55-66]; P < 0.0001; Table 1). Patients who remained in SR had a further significant decrease in HR at follow-up (55 [IQR, 51-60] bpm; P ¼ 0.0004). In patients with AF relapse at followup, HR significantly increased again (87 [IQR, 75-96] bpm;
Zimmermann et al. Cardiac Changes After Electrical Cardioversion in AF
39
Table 1. Characterization of cardiac volumes and ejection fraction before and after ECV and at follow-up stratified according to rhythm (all patients, n ¼ 73) P Before ECV Heart rate, bpm* SR group 84 (75-99) AF group 80 (77-94) Difference, P 0.83 Left ventricular function and volumesy LVEF, % SR group 43 (31-50) AF group 45 (34-50) Difference, P 0.47 LVSV, mL SR group 36 (46-28) AF group 38 (27-43) Difference, P 0.76 LVESV, mL SR group 52 (33-75) AF group 49 (39-62) Difference, P 0.78 LVEDV, mL SR group 91 (62-121) AF group 84 (73-98) Difference, P 0.90 Left atrial function and volumesz aEF, % SR group 18 (13-24) AF group 22 (9-31) Difference, P 0.38 VMin, mL SR group 68 (60-85) AF group 79 (51-91) Difference, P 0.86 VMax, mL SR group 90 (77-103) AF group 97 (71-116) Difference, P 0.44 LASV, mL SR group 16 (13-21) AF group 15 (10-25) Difference, P 0.75
After ECV
At Follow-Up
Before vs After ECV
After ECV vs Follow-Up
59 (55-64) 61 (54-68) 0.59
55 (51-60) 87 (75-96) < 0.0001
< 0.0001 < 0.0001
0.0004 0.008
48 (38-53) 49 (43-55) 0.54
55 (44-62) 44 (32-51) 0.0006
< 0.0001 0.11
< 0.0001 0.03
48 (39-56) 52 (43-54) 0.70
54 (45-64) 38 (28-50) 0.0002
< 0.0001 0.003
0.0002 0.003
50 (38-68) 49 (38-57) 0.50
42 (33-62) 49 (43-58) 0.15
0.80 0.77
0.005 0.44
95 (76-125) 103 (84-109) 0.78
99 (78-134) 86 (74-103) 0.07
0.0002 0.004
0.78 0.08
20 (15-30) 19 (11-28) 0.68
37 (26-48) 16 (9-27) < 0.0001
0.05 0.83
< 0.0001 0.27
63 (50-85) 66 (55-104) 0.27
48 (40-63) 74 (58-104) 0.002
0.15 1.00
< 0.0001 0.70
86 (64-102) 86 (76-126) 0.17
73 (64-104) 90 (73-120) 0.13
0.54 0.64
0.89 0.50
16 (12-23) 16 (13-20) 0.81
29 (21-38) 15 (9-23) 0.0004
0.32 0.87
< 0.0001 0.35
Data are presented as median (interquartile range). P values were based on Mann-Whitney U test for independent variables and Wilcoxon rank sum test for dependent data. aEF, atrial emptying fraction; AF, atrial fibrillation; bpm, beats per minute; ECV, electrical cardioversion; LASV, left atrial stroke volume; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end systolic volume; LVSV, left ventricular stroke volume; SR, sinus rhythm; Vmax, maximum left atrial volume; Vmin, minimal left atrial volume. * This represents the median heart rate during the duration of the echocardiogram acquisition. y These 2 groups of patients in SR and AF represented 55 and 18 patients, respectively. z These 2 groups of patients in SR and AF represented 51 and 18 patients, respectively.
P ¼ 0.008). At follow-up, Holter-ECG assessment revealed a significant difference between the SR and AF group (0 [0-15] and 210 [25-480] in minutes > 120 bpm, respectively; P < 0.0001). Changes in LV volumes and ejection fraction Development of the LVEF according to the absence or presence of AF at follow-up is displayed in Table 1 and Figure 1. A successful ECV resulted in an immediate significant increase in LVEF and SV. Patients with SR at follow-up experienced a further significant increase in LVEF and SV. The immediate increase in LVEF in patients with SR at follow-up amounted to 41% of the total recovery of LVEF over 4-6 weeks, whereas the increase thereafter accounted for 59% of the total recovery in LV function. In these patients, the immediate increase in LVEF and SV was accompanied by
a significant increase in LVEDV, whereas a modest decrease in LVESV did not reach statistical significance. To the contrary, in the same patients, the further increase in LVEF up to 4-6 weeks depended mainly on a significant decrease in LVESV, whereas a modest further increase in LVEDV was not statistically significant (Table 1). Correlation of changes in LVEF to changes in HR during follow-up Changes in HR immediately before and after ECV showed a significant correlation to changes in LVEF and variability of the changes in HR accounted for about one-third of the variability of the changes in LVEF, in patients who remained in SR and in those who relapsed to AF during follow-up (R2 ¼ 0.369; 95% confidence interval, 0.210-0.519; Table 2 and Fig. 2). During further follow-up, changes in HR
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Canadian Journal of Cardiology Volume 31 2015
Figure 1. Evolution in left ventricular ejection fraction (LVEF) from points in time of before to after treatment and after treatment to follow-up among patients with sinus rhythm and atrial fibrillation at the follow-up examination. ECV, electrical cardioversion.
accounted for only a very small part of the improvement in LVEF in patients who remained in SR (Fig. 1). In contrast, among those with an AF relapse at follow-up, the variability in HR explained approximately one-third of the variance of the LVEF (Table 2).
Changes in left atrial volumes and function ECV did not lead to immediate changes in left atrial volumes or left atrial functional parameters (Table 1). However, in patients who remained in SR during follow-up, return of mechanical atrial function led to a significant increase in aEF and left atrial SV. Meanwhile, the maximal atrial volume did not substantially change (Table 1).
Discussion Shortening of diastolic filling time, loss of atrial mechanical activity, and increased HR are all thought to contribute to reduced LVEF in patients with AF with insufficiently controlled ventricular rate. In this study we show that ECV results in an immediate improvement in LVEF, and that further improvement ensues over a period of 4-6 weeks in patients who remain in SR. About one-third of this immediate improvement was related to the reduction in HR and accompanied by a significant increase in LVEDV (Tables 1 and 2). Interestingly, this relationship was observed despite the fact that HR was well controlled in this sample. Further improvement shows a much weaker relation to changes in HR and is accompanied by a significant decrease in LVESV and improvement in left atrial function.
Figure 2. Variance in left ventricular ejection fraction (EF) related to change in heart rate (HR) from points in time of (A) before to after treatment and (B) after treatment to follow-up among patients with sinus rhythm at the follow-up examination. R2 is the proportion of variance in left ventricular EF change explained by HR. The vertical lines indicate the lengths of the residuals and the sloped line resembles the models fitted to the subgroup of patients without atrial fibrillation relapse. bpm, beats per minute; CI, confidence interval.
Zimmermann et al. Cardiac Changes After Electrical Cardioversion in AF
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Table 2. Results of the linear models for change in LVEF with the single predictor, “change in HR” at different points in time (n ¼ 73) Sinus rhythm group R * (n ¼ 55) AF relapse group R2 (n ¼ 18) 2
From Before ECV to Follow-Up
From Before ECV to Early After ECV
From Early After ECV to Follow-Up
0.299 (0.137-0.447) 0.083 (0.207 to 0.280)
0.296 (0.095-0.485) 0.335 (0.073 to 0.702)
0.036 (0.099 to 0.131) 0.280 (0.067 to 0.597)
Data are presented as R2 (95% confidence interval). AF, atrial fibrillation; ECV, electrical cardioversion; HR, heart rate; LVEF, left ventricular ejection fraction. * R2 is the proportion of variance in LVEF change explained by HR.
Early LV changes after ECV Our data indicate that early changes in LV function after ECV are based predominantly on a regularization and reduction in HR and thus an increased LV filling time. Increased beat-to-beat variability in cycle length has a negative effect on LV performance independent of HR.15 Additionally, increased cycle lengths after ECV contribute to increased LV performance via the Frank Starling mechanism.25 Although changes in LVEF after ECV have been examined in a number of studies, with the exception of 1 study, early changes have not been measured.13,14,26 Raymond et al. used M-mode imaging in 15 patients to assess LV function before and 2-16 hours after ECV, and reported an increase in SV and EF caused by a combination of increasing end-diastolic volume and declining end-systolic volume.5 In our larger sample and using RT3DE, the increase in LVEF after ECV was based on increases in end-diastolic volume only. This discrepancy might be explained by the earlier point in time after ECV (< 2 h) at which LV function and volumes were assessed in our study, and in fact our data are more likely to reflect the pure effect of rate reduction and regularization early after ECV. Late LV and left atrial changes after ECV TIC is caused by ultrastructural changes at a cellular level affecting myocyte function and extracellular matrix architecture.6,8-10,18-20,27 In animal models with termination of rapid pacing, improvement in LV function is accompanied by a partial reversion of these ultrastructural changes.8,9,27 In our study, the short-term improvement related to changes in HR was followed by a further improvement in patients remaining in SR. This further improvement of LVEF by an absolute 7 percentage points was not explained by changes in HR. Unlike short-term changes in LV function, the improvement in LV function at 4-6 weeks went along with a significant reduction in LVESV, and LVEDV remained unchanged. These changes argue for an improvement in myocardial contractility, which might be explained by a reversal of myocyte and extracellular changes occurring in TIC. Although our findings of a continued improvement of LV function at 4-6 weeks parallel findings of other studies,5,12-14,16,26,28,29 early assessment of LV function in a well defined time window after ECV allowed us to much better discern changes related to reversal of TIC thereafter, which were responsible for half of the total improvement in LVEF in our study. It should be noted that the continued improvement in LVEF that we saw over 4-6 weeks occurred despite the fact that the HR in our population was already well controlled before ECV. Thus, our data also indicate that AF can lead to impaired LV function even in the absence of tachycardia defined according to clinical criteria.
There is an apparent discrepancy between the improvement that we found in LVEF after cardioversion to SR, and the inability to demonstrate clinical benefits of restoration of SR in large clinical trials, like Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), in which the patient population was similar to ours.4,30 However, it should be kept in mind, that in clinical trials approximately 60% of patients assigned to a rhythm control strategy are in SR at 60 months, and in addition, subgroup analyses of patients who maintain long-term rhythm control treatment demonstrate a better outcome vs those assigned to a rate control strategy.4,30 Whereas left atrial mechanical function did not improve immediately after ECV, recovery of left atrial mechanical function was evident at 4-6 weeks with a significant increase in total aEF that was associated with a decrease in the minimal atrial volume and might have contributed to improvement in LV function. Up to 4-6 weeks, maximal atrial volume tended to decrease in patients who remained in SR, however, this decrease was not statistically significant. Thus, after 4-6 weeks, recovery of mechanical atrial function did occur, whereas this time frame might have been too short to detect reverse remodelling of the LA.31,32 Our cohort is representative and comparable to other study cohorts that undergo ECV.33 There are limitations to our study that deserve mentioning. The cohort’s separation into SR and AF is a posttreatment variable. Hence, one cannot draw a directionality or causality of the effect. Additionally, our results apply only to patients with persistent AF, and generalizability to other patient groups remains uncertain. Duration of persistent AF is a predictor of success of ECV and maintenance of SR after cardioversion. The reported persistent AF episodes are approximations in some patients, because they could not recall the exact episode start. Echocardiographic measurements were performed using RT3DE in AF before ECV; although well validated in patients with SR, this technique is not extensively validated for assessment of cardiac function and structure during AF. However, given the superior reproducibility of RT3DE over time as opposed to conventional 2-dimensional methods, we chose to use RT3DE imaging data sets for all points in time.34,35 Because echo reviewers were aware of the patient’s rhythm, blinding of imaging data sets was not possible with regard to pre- and post-ECV. It should also be kept in mind that rather than myocardial contractility, we measured LVEF, which is not only influenced by contractility, but also by other factors such as, for example pre- and afterload. Thus, the modest further slowing of HR in patients remaining in SR from after ECV to follow-up could contribute to the increase in LVEF due to increased preload. However, whereas we found a correlation of changes in HR with changes in LVEF from pre-ECV to postECV, such a correlation was not present for changes that occurred between post-ECV and follow-up, which is indirect
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Canadian Journal of Cardiology Volume 31 2015
evidence for a contribution of recovery of myocyte function to the improvement in LVEF. Last, we only assessed cardiac function at 3 time points; obviously, a closer echocardiographic and electrocardiographic follow-up would add further aspects regarding the course of myocardial recovery after ECV.
7. Suman-Horduna I, Roy D, Frasure-Smith N, et al. Quality of life and functional capacity in patients with atrial fibrillation and congestive heart failure. J Am Coll Cardiol 2013;61:455-60.
Conclusions In patients with persistent AF who undergo ECV, LVEF rapidly improves after the procedure. This immediate change in LVEF explains approximately 50% of total LVEF improvement over time, and is strongly associated with changes in HR. It is found even among individuals with normofrequent AF. Over the next 4-6 weeks, further improvement in LVEF occurs, which, however, correlates only weakly with changes in HR. There might be factors other than the HR involved in improvement in LVEF and thus reversal of AF-related TIC.
9. Umana E, Solares CA, Alpert MA. Tachycardia-induced cardiomyopathy. Am J Med 2003;114:51-5.
Acknowledgements The authors acknowledge the support of Drs Arnheid Kessel-Schaefer (A.K.-S.) and Frank-Peter Stephan (F.-P.S.) in acquisition of several echocardiograms.
8. Shinbane JS, Wood MA, Jensen DN, et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol 1997;29:709-15.
10. Nerheim P, Birger-Botkin S, Piracha L, Olshansky B. Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachycardia. Circulation 2004;110:247-52. 11. Calvo N, Bisbal F, Guiu E, et al. Impact of atrial fibrillation-induced tachycardiomyopathy in patients undergoing pulmonary vein isolation. Int J Cardiol 2013;168:4093-7. 12. Welikovitch L, Lafreniere G, Burggraf GW, Sanfilippo AJ. Change in atrial volume following restoration of sinus rhythm in patients with atrial fibrillation: a prospective echocardiographic study. Can J Cardiol 1994;10:993-6. 13. Xiong C, Sonnhag C, Nylander E, Wranne B. Atrial and ventricular function after cardioversion of atrial fibrillation. Br Heart J 1995;74: 254-60. 14. Upshaw CB Jr. Hemodynamic changes after cardioversion of chronic atrial fibrillation. Arch Intern Med 1997;157:1070-6.
Funding Sources This study was supported by a grant of the Mach Gaensslen Foundation (to David Conen). David Conen and Beat A. Kaufmann have received grants from the Swiss National Science Foundation (PP00P3_133681, 3232B0_141603, and 310030_149718, respectively). Disclosures The authors have no conflicts of interest to disclose. References 1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370-5. 2. Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. JAMA 2011;305:2080-7. 3. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (Compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS Recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:1935-44. 4. Ionescu-Ittu R, Abrahamowicz M, Jackevicius CA, et al. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch Intern Med 2012;172: 997-1004.
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Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2014.10.032.