Author + information
- Received November 9, 2009
- Revision received May 17, 2010
- Accepted May 17, 2010
- Published online January 18, 2011.
- Laurens F. Tops, MD, PhD,
- Victoria Delgado, MD, PhD,
- Matteo Bertini, MD,
- Nina Ajmone Marsan, MD,
- Dennis W. Den Uijl, MD,
- Serge A.I.P. Trines, MD, PhD,
- Katja Zeppenfeld, MD, PhD,
- Eduard Holman, MD, PhD,
- Martin J. Schalij, MD, PhD and
- Jeroen J. Bax, MD, PhD⁎ ()
- ↵⁎Reprints requests and correspondence
: Dr. Jeroen J. Bax, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
Objectives The purpose of this study was to assess left atrial (LA) strain during long-term follow-up after catheter ablation for atrial fibrillation and to find predictors for LA reverse remodeling.
Background The association between LA reverse remodeling and improvement in LA strain after catheter ablation has not been investigated thus far.
Methods In 148 patients undergoing catheter ablation for atrial fibrillation, LA volumes and LA strain were assessed with echocardiography at baseline and after a mean of 13.2 ± 6.7 months of follow-up. The study population was divided according to LA reverse remodeling at follow-up: responders were defined as patients who exhibited 15% or more reduction in maximum LA volume at long-term follow-up. Left atrial systolic (LAs) strain was assessed with tissue Doppler imaging.
Results At follow-up, 93 patients (63%) were classified as responders, whereas 55 patients (37%) were nonresponders. At baseline, LAs strain was significantly higher in the responders as compared with the nonresponders (19 ± 8% vs. 14 ± 6%; p = 0.001). Among the responders, a significant increase in LAs strain was noted from baseline to follow-up (from 19 ± 8% to 22 ± 9%; p < 0.05), whereas no change was noted among the nonresponders. LAs strain at baseline was an independent predictor of LA reverse remodeling (odds ratio: 1.813; 95% confidence interval: 1.102 to 2.982; p = 0.019).
Conclusions In the present study, 63% of the patients exhibited LA reverse remodeling after catheter ablation for atrial fibrillation, with a concomitant improvement in LA strain. LA strain at baseline was an independent predictor of LA reverse remodeling.
Left atrial (LA) enlargement is associated with cardiac morbidity and is a robust predictor of cardiovascular outcome (1,2). The relationship between LA enlargement and atrial fibrillation (AF) has been well recognized. However, it still remains controversial whether LA enlargement causes AF (3), or vice versa (4).
Reversal of LA enlargement, or reverse remodeling, has been demonstrated with drug therapy and after restoration of sinus rhythm with cardioversion (5). In addition, it has been shown that LA reverse remodeling may occur after successful catheter ablation for AF (6).
At the same time, LA function may improve after restoration of sinus rhythm with catheter ablation (7). Using tissue Doppler imaging, it has been demonstrated that LA strain may improve at 3 months after successful catheter ablation for AF (8). However, it is unclear whether these changes in LA strain remain during long-term follow-up. More important, the association between LA reverse remodeling and the improvement in LA strain has not been investigated thus far. Accordingly, the purpose of the present study was to evaluate reverse remodeling and LA strain during long-term follow-up after catheter ablation for AF. In addition, predictors for LA reverse remodeling were studied.
Study population and study protocol
The study population comprised 148 patients from an ongoing clinical registry (6) with symptomatic drug-refractory AF, who were referred for radiofrequency catheter ablation. Before the ablation procedure and after 12 months of follow-up, an extensive echocardiographic evaluation was performed to assess LA strain. In a subgroup of patients with an available echocardiogram during sinus rhythm both at baseline and at follow-up (n = 122), LA late diastolic strain (representing LA active contraction) and left ventricular (LV) systolic strain were assessed. At long-term follow-up, the study population was divided according to reverse remodeling of the LA after the catheter ablation procedure.
Catheter ablation procedure
The protocol of the catheter ablation procedure has been described in more detail elsewhere (9). In brief, electrical isolation of all pulmonary veins from the LA was attempted using an electroanatomic mapping system with an image integration module (CARTO and CartoMerge, Biosense Webster, Diamond Bar, California). Endocardial mapping and ablation was performed with a 4-mm quadripolar mapping and ablation catheter, with an open loop irrigated tip (7-F Thermocool, Biosense Webster). A 6-F diagnostic catheter placed in the right atrium served as a temporal reference. Radiofrequency current was applied outside the ostia of all pulmonary veins using the following settings: irrigation rate, 20 ml/min; maximum temperature, 50°C; and maximum radiofrequency energy, 30 W. At each point, a radiofrequency current was applied until a voltage of <0.1 mV was achieved, with a maximum of 60 s per point. The procedure was considered successful when pulmonary vein isolation was confirmed by recording the entrance block during sinus rhythm or pacing in the coronary sinus. All patients received heparin intravenously (activated clotting time, >300 s) to avoid thromboembolic complications.
After the catheter ablation procedure, all patients were evaluated at the outpatient clinic on a regular basis. All medication, including antiarrhythmic drugs, was continued in all patients during the first 3 months of follow-up. Afterward, antiarrhythmic drugs were discontinued at the discretion of the physician. A surface electrocardiogram was acquired at every follow-up visit, and 24-h Holter monitoring was performed at 3- to 6-month intervals. Maintenance of sinus rhythm during follow-up was defined as the absence of symptomatic recurrences lasting more than 3 min and/or the absence of AF episodes lasting more than 30 s detected with 24-h Holter monitoring or surface electrocardiography, after a blanking period of 1 month (10).
Two-dimensional echocardiography was performed within 2 days before the ablation procedure and at 12 months of follow-up. Two-dimensional images were recorded with the patient in the left lateral decubitus position using a commercially available system (Vivid 7, General Electric-Vingmed, Milwaukee, Wisconsin). Images were acquired using a 3.5-MHz transducer at a depth of 16 cm in the parasternal and apical views (standard long-axis and 2- and 4-chamber images). Standard 2-dimensional images and color Doppler data were saved in cine loop format. All analyses were performed offline using commercial software (Echopac 7.0.0, General Electric-Vingmed).
LV end-diastolic and end-systolic volumes were assessed from the apical 2- and 4-chamber images and were indexed to body surface area; LV ejection fraction was calculated using the biplane Simpson's rule (11). LV diastolic function was evaluated using the following Doppler measurements: ratio of early to late diastolic filling velocities and deceleration time of the E-wave (12). In addition, LV systolic strain and strain rate were assessed using color-coded tissue Doppler imaging in a subgroup of patients, as previously described (13).
LA Volumes and Ejection Fraction
LA volumes were measured on apical 2- and 4-chamber views. Maximum left atrial volume (LAmax) was defined as the largest LA volume just before mitral valve opening; minimum LA volume (LAmin) was defined as the smallest possible LA volume in ventricular diastole. All LA volumes were indexed to body surface area, as recommended (14). LA total emptying fraction (LAEF) was derived from LA volumes: LAEF = ([LAmax − LAmin]/LAmax) × 100.
Definition of LA Reverse Remodeling
To study the determinants of reverse remodeling of the LA after catheter ablation, the study population was divided into 2 groups according to the extent of decrease in LAmax during follow-up (15). Responders were defined as patients who exhibited 15% or more reduction in LAmax at long-term follow-up. The nonresponders were patients who demonstrated a decrease in LAmax of <15%, or an increase in LAmax during follow-up.
LA Strain Analysis
LA deformation properties were studied using color-coded tissue Doppler imaging by offline analysis of standard apical 2- and 4-chamber images of 3 consecutive heart beats. Frame rates were at least 115 frames/s, and the sector width was adjusted to allow the highest possible frame rate.
A sample volume (6 × 4 mm) was placed at the basal to mid parts of the LA septum and lateral wall (4-chamber view) and the LA anterior and inferior wall (2-chamber view). If necessary, Gaussian 60 smoothing was applied to create clear strain curves, as previously described (16). From the reconstructed strain curves, myocardial LA longitudinal lengthening or left atrial systolic (LAs) strain, representing LA expansion function, was identified as the peak positive strain value during LV systole. In a subgroup of patients with an available echocardiogram during sinus rhythm both at baseline and at follow-up (n = 122), myocardial LA shortening, or left atrial late diastolic (LAa) strain, representing LA active contraction, was identified as the peak negative strain value during LV diastole occurring after the P-wave on the electrocardiogram. The different cardiac phases of systole and the early and late diastole were defined with the use of the transmitral Doppler profile of the aortic and the mitral valve.
Peak LAs strain and LAa strain were assessed for the 4 regions (septal, lateral, anterior, inferior) and were averaged to acquire global LAs strain and LAa strain values. Similarly, the LAs strain rate and LAa strain rate, representing the speed at which LA deformation occurs, were assessed in the 4 regions and averaged (Fig. 1).
All continuous variables had normal distribution (as evaluated by Kolmogorov-Smirnov tests). Summary statistics for these variables therefore are presented as mean ± SD. Categorical data are summarized as frequencies and percentages.
Differences in clinical and echocardiographic variables between the responders and the nonresponders were evaluated using unpaired Student t tests (continuous variables), chi-square tests (dichotomous variables), or Fisher exact tests (dichotomous variables, with small frequencies), as appropriate. Differences in continuous variables between baseline and follow-up were evaluated using paired Student t tests.
Intraobserver and interobserver reproducibility for the assessment of LA strain and LA strain rate were determined by Bland-Altman analysis. Intraobserver reproducibility was determined by repeating the strain and strain rate measurements at 2 different time points by 1 experienced reader (L.F.T.) in 15 randomly selected patients. A second experienced reader (N.A.M.) performed the strain analysis in the same 15 patients, providing the interobserver reproducibility data. The mean bias with limits of agreement (2 SD) from Bland-Altman analysis is reported.
To explore potential predictors of response, univariate analysis of baseline clinical and echocardiographic characteristics was performed first. Odds ratios were calculated with 95% confidence intervals as an estimate of the risk associated with each variable. LAmax, LAs strain, and LAs strain rate were introduced in the model as increments of multiples of the standard deviation. Independent predictors of LA reverse remodeling were obtained by performing a multivariate logistic regression analysis based on enter model. Those variables with p < 0.1 at the univariate analysis were included. Statistical analyses were performed using SPSS software (version 15.0, SPSS, Inc., Chicago, Illinois). All statistical tests were 2-sided, and a p value <0.05 was considered significant.
A total of 148 patients were treated with radiofrequency catheter ablation. Baseline characteristics of the total study population are summarized in Table 1. AF was paroxysmal in 112 patients (76%) and persistent in 36 patients (24%). Mean duration of follow-up was 13.2 ± 6.7 months. During follow-up, 99 patients (67%) remained in sinus rhythm, whereas 49 patients (33%) had recurrence of AF. None of the patients underwent a repeat procedure during follow-up.
LA volumes and strain analysis
In the overall study population, LAmax decreased significantly from baseline to follow-up (from 30 ± 7 ml/m2 to 25 ± 7 ml/m2, p < 0.001). In parallel, LAmin decreased from 18 ± 6 ml/m2 to 15 ± 7 ml/m2 (p < 0.001). Finally, there was a modest but statistically significant improvement in LAEF from baseline to follow-up in the overall study population (from 41 ± 13% to 45 ± 14%, p = 0.002).
LA strain and strain rate measurements were feasible in 2078 of 2160 attempted segments (96%). In 15 randomly selected patients, reproducibility data for LA strain and LA strain rate measurements was assessed. Both interobserver and intraobserver agreement for the assessment of LA strain and LA strain rate were good. The results of the Bland-Altman analysis are presented in Figure 2.
In the overall study population, LA deformation properties showed a significant improvement during follow-up. LAs strain increased from 17 ± 7% to 19 ± 9% (p = 0.001), and LAs strain rate increased from 1.1 ± 0.4 1/s to 1.2 ± 0.5 1/s (p = 0.001). Similarly, LAa strain improved from −4 ± 3% to −6 ± 6% (p = 0.03), and LAa strain rate improved from −1.4 ± 0.7 1/s to −1.6 ± 0.7 1/s (p = 0.03).
LA reverse remodeling
Based on the cutoff value (≥ 15% decrease in LAmax), 93 patients (63%) were classified as responders, whereas 55 patients (37%) were nonresponders. Baseline characteristics of the 2 groups are listed in Table 1. The proportion of patients with paroxysmal AF was significantly higher among the responders compared with the nonresponders (82% vs. 65%, p = 0.03).
Responders Versus Nonresponders
Mean follow-up duration was comparable in the 2 groups (responders 12.7 ± 5.2 months vs. nonresponders 13.8 ± 8.6 months, p= 0 .3). Importantly, 69% (n = 38) of the nonresponders experienced recurrence of AF, as compared with 12% (n = 11) of the responders (p < 0.001). At follow-up, 34 responders (37%) and 17 nonresponders (31%) were not receiving any antiarrhythmic agents (p = 0.6). Most of the patients were receiving either beta-blockers or class IC antiarrhythmic agents. There were no differences between the 2 groups regarding the use of beta-blockers (27% vs. 22%, respectively, p = 0.6) and class IC antiarrhythmic agents (32% vs. 31%, p = 1.0) at follow-up.
Left ventricular systolic strain improved significantly in the responders during follow-up (from −20 ± 5% to −22 ± 4%, p < 0.05), whereas it decreased in the nonresponders (from −20 ± 5% to −18 ± 5%, p < 0.05). Similarly, an improvement in LV systolic strain rate was noted in the responders, and an impairment was noted in the nonresponders (Table 2).
LA Volume and Strain Analysis
By definition, LAmax decreased significantly in the responders (from 31 ± 7 ml/m2 to 22 ± 6 ml/m2, p < 0.001), whereas a small increase was observed in the nonresponders (from 29 ± 5 ml/m2 to 31 ± 6 ml/m2, p = 0.002). LAmin was comparable in the 2 groups at baseline. However, a significant decrease was observed in the responders during follow-up, resulting in a significant difference between the 2 groups at follow-up (Table 2). Finally, LAEF increased significantly in the responders, whereas no change was noted in the nonresponders (Table 2).
LA deformation properties demonstrated different trends during follow-up according to the presence of LA reverse remodeling. LAs strain was significantly higher at baseline in the responders, as compared with the nonresponders (Table 2). In addition, a significant increase in LAs strain was noted in the responders, whereas no change was observed in the nonresponders (Fig. 3). Similarly, LAs strain rate at baseline was significantly higher in the responders, as compared with the nonresponders (Table 2). During follow-up, LAs strain rate increased significantly in the responders, whereas no change was observed in the nonresponders (Table 2). Similar trends were noted for LAa strain and LAa strain rate. Whereas LAa strain and strain rate improved significantly in the responders, LAa strain remained similar and LAa strain rate decreased in the nonresponders (Table 2, Fig. 3).
Prediction of LA reverse remodeling
Univariate and multivariate logistic regression analysis was performed to determine the predictors of LA reverse remodeling. The results of the logistic regression analysis are shown in Table 3. At multivariate analysis, independent predictors of LA reverse remodeling after catheter ablation were LAs strain at baseline (odds ratio: 1.813; 95% confidence interval: 1.102 to 2.982, p = 0.019) and LAmax (odds ratio: 1.785; 95% confidence interval: 1.137 to 2.804, p = 0.012).
In the present study, LA reverse remodeling and LA strain were studied in 148 patients undergoing catheter ablation for AF. In 93 patients (63%), LA reverse remodeling was noted at long-term follow-up. In these patients, LA systolic and late diastolic strain and strain rate increased significantly from baseline to follow-up. In patients without LA reverse remodeling, no significant changes in LA strain and strain rate were noted. Importantly, LAs strain and LAmax at baseline were both independent predictors of LA reverse remodeling.
LA reverse remodeling
LA remodeling includes structural, electrical, metabolic, and neurohumoral changes and may occur in response to several pathologic processes. Atrial dilatation is an important aspect of LA structural remodeling (1). Recently, it has been suggested that the extent of LA structural remodeling may play an important role in the success of AF ablation (17). Interestingly, several studies have demonstrated that this atrial enlargement is, at least partially, reversible (18,19). Although the exact underlying pathophysiology of LA reverse remodeling remains unclear, it has been suggested that reversal of LA dilatation may have prognostic implications and may reduce the risk of AF (5). Therefore, LA reverse remodeling may become a surrogate marker of success after AF ablation. Typically, maintenance of sinus rhythm during follow-up is used to define successful catheter ablation (10). However, asymptomatic AF recurrence may result in overestimation of success. Importantly, in the present study, there is an overlap between responders and patients who maintained sinus rhythm (82 of 93 responders) and nonresponders and patients with recurrence of AF (38 of 55 nonresponders). Therefore, LA reverse remodeling may be a more robust marker for successful AF ablation that can be quantified easily. However, the ablation lesions themselves may result in a decrease in LA size as well (20), limiting the use of LA reverse remodeling as a marker of success.
In the present study, predictors for LA reverse remodeling also were studied. Although the proportion of patients with paroxysmal and persistent AF was different among the responders and the nonresponders, the type of AF was not predictive for LA reverse remodeling at multivariate analysis. This indicates that the type of AF is not an independent determinant of LA structural changes that deteriorate LA myocardial deformation and reduce the ability of the LA to reverse remodel. Interestingly, at multivariate analysis, both LA systolic strain and LAmax were predictors of LA reverse remodeling during follow-up. LA systolic strain and LAmax may provide complementary information on structural changes (LA remodeling) in AF patients. In fact, LAmax at baseline is closely related to reversal of LA dilatation. However, LA systolic strain may be a more sensitive parameter of changes in LA wall structure by providing information on mechanical properties and functions of the LA myocardium. In patients with AF, a severe impairment of LA systolic strain may reflect a reduced LA compliance and a more advanced remodeling of the LA that may not be reversed after catheter ablation.
LA strain analysis
Recent studies have demonstrated the feasibility of strain analysis to assess segmental LA function (21). In the present study, tissue Doppler imaging was used to assess LA peak systolic and late diastolic strain, which represent LA reservoir function and LA booster pump function, respectively (22). At baseline, LA strain was impaired as compared with previously reported values for healthy controls (23,24). LA reservoir function is determined mainly by LV systolic function and LA wall stiffness (25). In patients with AF and preserved LV ejection fraction, subtle changes in LV and LA myocardium already may be present (26,27). Indeed, myocardial deformation imaging techniques may reveal these subtle changes. Impaired LAs strain and strain rate indicate reduced compliance of the LA and indirectly may reflect high fibrosis content. These functional changes therefore may reflect structural changes that may determine the ability of the LA to reverse remodel after catheter ablation for AF.
Interestingly, an improvement in LA strain was observed in patients with LA reverse remodeling during follow-up. Several other studies have demonstrated improvements in LA strain in response to therapy (28,29). Schneider et al. (8) noted a significant increase in LA systolic strain in patients who maintained sinus rhythm after catheter ablation, whereas it remained unchanged in patients with recurrence of AF. In addition, it was demonstrated that LA systolic strain and strain rate may predict the maintenance of sinus rhythm during 3 months of follow-up (8).
In the present study, similar improvements in LA strain and strain rate were observed in 148 patients after long-term follow-up. In addition, it was demonstrated that LA systolic strain at baseline is an independent predictor for LA reverse remodeling during follow-up. Previously, it was demonstrated that LA systolic strain may predict the maintenance of sinus rhythm after cardioversion (26). Although the exact mechanism remains to be elucidated, it may well be that the degree of impairment in atrial compliance (represented by LA systolic strain) plays an important role in the ability to reverse LA enlargement and to maintain sinus rhythm during follow-up.
Interestingly, the improvements in LA strain and strain rate in the responders were accompanied by improvements in LV systolic strain. Restoration of sinus rhythm with catheter ablation may result in an improved LA function and subsequently more efficient LV filling pattern and LV mechanics (7,30). Simultaneously, the improvement in LV systolic function and diastolic filling pattern resulting from heart rhythm normalization may result in an improved LA function, and therefore may be a determinant of LA reverse remodeling. Additional studies are warranted to elucidate whether the improvement in LV mechanics precedes the improvement in LA function or vice versa.
In the present study, 63% of the patients exhibited LA reverse remodeling after catheter ablation for AF. In these responders, LA strain and strain rate increased significantly from baseline to follow-up. In contrast, no changes in LA strain and strain rate were noted in the nonresponders. Besides LAmax, LA systolic strain at baseline was an independent predictor of LA reverse remodeling.
Drs. Delgado and Marsan are financially supported by the Research Fellowship of the European Society of Cardiology. Dr. Delgado has received speaker honoraria and consulting fees from St. Jude Medical. Dr. Zeppenfeld has received consulting fees from St. Jude Medical. Dr. Schalij has received grants from Biotronik, Medtronic, and Boston Scientific Corporation. Dr. Bax has received grants from Biotronik, Medtronic, Boston Scientific Corporation, Bristol-Myers Squibb Medical Imaging, St. Jude Medical, GE Healthcare, and Edwards Lifesciences. All other authors have reported that they have no relationships to disclose. Drs. Tops and Delgado contributed equally to this work. Tom Marwick, MBBS, PhD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- atrial fibrillation
- left atrium/atrial
- left atrial late diastolic
- left atrial total emptying fraction
- maximum left atrial volume
- minimum left atrial volume
- left atrial systolic
- left ventricle/ventricular
- Received November 9, 2009.
- Revision received May 17, 2010.
- Accepted May 17, 2010.
- American College of Cardiology Foundation
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