Methods

We enrolled consecutive patients aged ≥18 years symptomatic paroxysmal AF and low CHADS ₂ scores (≤1) treated for maintenance of sinus rhythm with catheter ablation therapy according to the diagnostic and therapeutic criteria of the guidelines on AF of the Heart Rhythm Society. In addition, these patients should not have evidence of structural heart disease, determined by conventional echocardiographic methods as (1) left ventricular (LV) dysfunction (LV ejection fraction [LVEF] <55% by Simpson’s method), (2) cardiomyopathy, and (3) valvular heart disease (defined as mild, moderate, or severe mitral or aortic stenosis and moderate or severe mitral, tricuspid, or aortic regurgitation according to the diagnostic criteria of the guidelines on valvular heart disease of the American College of Cardiology). We included consecutive patients admitted to the Department of Cardiology (Campus Virchow-Klinikum) of Charité University Hospital for first catheter-based ablation therapy for symptomatic paroxysmal AF with no response to antiarrhythmic drugs from November 2009 until November 2011. The institutional review board approved this research project, and informed consent was obtained from all subjects.

The selection of exclusion criteria in this study was based on the guidelines on AF of the Heart Rhythm Society. In this regard, to avoid secondary causes of AF, patients with active coronary artery disease were excluded from this study (i.e., patients with unstable angina or non–ST-segment elevation myocardial infarction without revascularization or with revascularization within the past 30 days, patients with ST-segment elevation acute myocardial infarction within the past 30 days, subjects waiting for coronary artery bypass graft or within 90 days postoperatively, subjects with chronic stable angina, and patients with evidence of myocardial ischemia assessed by stress echocardiography). In addition, with the purpose of excluding other possible secondary causes of AF, patients with the following characteristics were excluded from this study: (1) severe pulmonary disease, defined as pulmonary pathology with supplemental oxygen requirement, (2) severe kidney disease, defined as estimated glomerular filtration rate <30 ml/min/1.73 m ² for ≥3 months, history of renal transplantation, or severe acute renal failure with dialysis requirement, (3) severe chronic liver disease or history of liver transplantation, (4) congenital heart disease, (5) pericardial disease characterized by pericardial effusion (echo-free space in end-diastole ≥5mm) or constrictive pericarditis, (6) cardiomyopathy, (7) valvular heart disease, defined as mild, moderate, or severe mitral or aortic stenosis and moderate or severe mitral, tricuspid, or aortic regurgitation (according to the diagnostic criteria of the American College of Cardiology) , and (8) hyper- or hypothyroidism. Furthermore, to avoid underestimations of the atrial or ventricular myocardial measurements, patients with valvular heart surgery, mitral annular calcification (≥5 mm), cardiac pacing, and poor 2-dimensional quality in ≥1 myocardial segment of the left ventricle or the left atrium (not suitable for analysis by 2-dimensional speckle-tracking echocardiography in apical 4-chamber, 2-chamber, and long-axis views) were also excluded from this study. Moreover, to avoid mistakes and underestimations of the atrial and ventricular myocardial measurements, patients with atrial or ventricular arrhythmias at the time of the echocardiographic analyses were also excluded.

All patients were examined at rest in the left lateral decubitus position using a Vivid 7 ultrasound system (GE Vingmed Ultrasound AS, Horten, Norway), followed by off-line analysis using an EchoPAC version 110.1.0 workstation (GE Vingmed Ultrasound AS; i.e., measurements by 2-dimensional speckle-tracking echocardiography). The echocardiographic measurements and analyses were performed by experienced echocardiographers blinded to each other’s results during the hospitalization of the patients for catheter ablation therapy (i.e., after the catheter ablation procedure and before hospital discharge). LV diameters, LV volumes, LV mass, and grading of LV hypertrophy, the LVEF (Simpson’s method), and LA volumes and enlargement (i.e., maximal LA volume index [LAVI] >28 ml/m ² ) were assessed as recommended by the American Society of Echocardiography. All echocardiographic measurements using speckle-tracking (mean frame rate 67.8 ± 8.2 frames/s), Doppler, and conventional 2-dimensional echocardiography were calculated as the average of 3 measurements at conditions of respiratory (<20 breaths/min), hemodynamic (systolic blood pressure 90 to 180 mm Hg), and electrical (heart rate 60 to 99 beats/min and sinus rhythm) stability.

Analyses of global LV systolic and diastolic myocardial function using 2-dimensional speckle-tracking echocardiography were performed off-line and blinded to the clinical characteristics of the patients. Measurements of LV longitudinal systolic strain and LV longitudinal early diastolic strain rate (SRe) were performed at the basal, mid, and apical levels in the apical 4-chamber, 2-chamber, and long-axis views (i.e., 18 segments of the left ventricle). The average values of LV longitudinal peak negative systolic strain (during LV systole) and LV longitudinal peak positive early diastolic SRe (during LV diastole) from 18 LV segments are referred to as LV global longitudinal systolic strain (LV strain) and LV global longitudinal SRe, respectively. On the basis of previously validated studies we defined LV myocardial systolic and diastolic dysfunction as LV strain >−16% and LV SRe <0.95 s ⁻¹ , respectively.

Analyses of global LA systolic and diastolic myocardial function were performed off-line and blinded to the clinical characteristics of the patients using 2-dimensional speckle-tracking echocardiography ( Figure 1 ). Measurements of LA strain (a parameter of the myocardial diastolic function of the left atrium) were performed at each LA myocardial segment of the apical 4-chamber and 2-chamber views. The average value of LA peak positive strain (LA strain) during LV systole from all LA segments was determined as the myocardial diastolic function of the left atrium. In addition, we determined the myocardial systolic function of the left atrium, which was assessed as the average value of LA peak negative strain rate (SRa) during LV late diastole or atrial contraction from all segments of the left atrium analyzed in the apical 4-chamber and 2-chamber views. Furthermore, volumetric echocardiographic assessments of LA systolic function were also obtained. In this regard, using conventional LA measurements, we assessed the LA ejection fraction (LAEF) and the LA active emptying fraction, which were calculated as follows : LAEF = [(maximal LA volume − minimal LA volume)/maximal LA volume] × 100; LA active emptying fraction = [(LA volume at the onset of the P wave on the electrocardiogram − minimal LA volume)/LA volume at the onset of the P-wave on the electrocardiogram] × 100. The LAEF and LA active emptying fraction were derived in the apical 4- and 2-chamber views using 2-dimensional (Simpson’s method) echocardiography.

Example showing the assessment of global LA myocardial diastolic and systolic function, measured by LA strain and LA SRa, respectively. The dotted white curve indicates the average of the myocardial function of all LA segments.

To compare the rates and absolute values of an alteration of myocardial function of the left atrium between patients with paroxysmal AF and asymptomatic patients without histories of AF, we additionally included a control group (i.e., asymptomatic subjects without histories of AF of similar ages, gender, and LVEFs as the group with AF). A total of 84 asymptomatic subjects without histories of AF were included (mean age 63.5 ± 5.1 years, 28.6% women, mean LVEF 62.1 ± 6.4%). Clinical characteristics and conventional echocardiographic assessments of this cohort of control subjects are listed in more detail on-line in Supplemental Table 1 . Furthermore, we also included a group of healthy subjects with the aim of determining the 0.5th percentile of systolic and diastolic myocardial function of the LA in this population, which was utilized to define a systolic and diastolic myocardial dysfunction of the left atrium (i.e., values <0.5th percentile from healthy subjects). Healthy subjects were defined as all those with normal echocardiographic findings according to the diagnostic criteria of the American Society of Echocardiography and the American College of Cardiology and without histories or presence of ≥1 of the following findings: cardiovascular disease; pathology with known cardiovascular involvement; kidney, liver, or lung disease; and medications with known cardiovascular effects. A total of 118 healthy subjects (age range 18 to 68 years, 61% women, mean LVEF 62.5 ± 5.5%) were included, and the mean values of LA myocardial systolic and diastolic function in this group were as follows: LA SRa −2.46 ± 0.71 s ⁻¹ , LAEF 72.3 ± 9.6%, LA active emptying fraction 56.3 ± 11.0%, and LA strain 44.91 ± 12.44%. In this regard, we defined LA systolic and diastolic myocardial dysfunction as LA SRa >−0.85 s ⁻¹ and LA strain <18.8%, respectively, and LA volumetric systolic dysfunction as LAEF <40% or LA active emptying fraction <28%. Clinical characteristics and conventional echocardiographic assessments of this cohort of healthy subjects are listed in more detail on-line in Supplemental Table 2 .

One irrigated-tip ablation catheter (IBI Therapy CoolPath Duo, St. Jude Medical, St. Paul, Minnesota; or NAVISTAR THERMOCOOL, Biosense Webster, Diamond Bar, California) and a circular mapping catheter (IBI Inquiry Optima, St. Jude Medical; or Lasso, Biosense Webster) were positioned in the left atrium after double transseptal puncture under fluoroscopic guidance. The geometry of the left atrium was reconstructed using a 3-dimensional mapping system (Ensite NavX, St. Jude Medical; or CARTO, Biosense Webster). Circumferential pulmonary vein isolation was carried out with the irrigated-tip catheter (irrigation flow 20 ml/min) and a Stockert 70 RF Generator (Biosense Webster) with a maximal power of 35 W and a maximal temperature of 43°C. Finally, the complete isolation of pulmonary veins was verified by the circular catheter. Besides pulmonary vein isolation, no additional ablation lesions (i.e., LA linear lesion, ablation of regions with complex fractionated electrograms, or ablation of extrapulmonary vein foci) were placed. Antiarrhythmic drugs were suspended after the blanking period of the first 3 months subsequent to the procedure.

The primary end point of the present study was the recurrence of AF, atrial flutter, or atrial tachycardia outside of the blanking period of the first 3 months subsequent to the ablation procedure. The key end point for this analysis was the rate of AF, atrial flutter, or atrial tachycardia after hospital discharge for catheter ablation therapy (analyzing only the first recurrence of AF, atrial flutter, or atrial tachycardia after the ablation, without taking into account early recurrences corresponding to the blanking period). Patients were followed in our outpatient clinic at 3, 6, and 12 months and yearly afterward. Moreover, at these visits, we verified the maintenance of sinus rhythm using Holter monitoring. In addition, all patients were instructed to contact our department or the referring cardiologist of our institution in case of symptoms suggestive of arrhythmia recurrence with the purpose of obtaining an electrocardiogram during these episodes to confirm or exclude recurrence of atrial arrhythmias.

Continuous data are presented as mean ± SD and dichotomous data as percentages. Differences in continuous variables between groups (comparisons of 2 groups) were assessed using Student’s t tests. Categorical variables were compared using chi-square tests and Fisher’s exact tests as appropriate. Comparisons among ≥3 groups were assessed using 1-way analysis of variance. To analyze the interrelations of LA myocardial function with different clinical and echocardiographic variables, we performed a simple regression analysis. Moreover, to analyze the predictors of systolic and diastolic LA myocardial dysfunction, we performed a logistic regression analysis. In addition, the selection of independent variables associated with LA myocardial dysfunction was completed using a forward stepwise multivariate analysis. We implemented receiver-operating characteristic curves to evaluate the association of LA systolic and diastolic myocardial function with the primary end point. An optimal cut-off value was chosen as one with maximal sensitivity and specificity using the Youden index (sensitivity + specificity − 1). In addition, we tested the relation of those cut-off points of LA systolic and diastolic myocardial function to determine the primary outcome. In this regard, a logistic regression analysis was performed. Odds ratios with corresponding 95% confidence intervals were then calculated. Finally, the selection of independent variables for the prediction of the primary outcome was performed using a forward stepwise multivariate analysis. Differences were considered statistically significant at p <0.05. All statistical analyses were performed with StatView version 5.0 (SAS Institute Inc., Cary, North Carolina) and SPSS Statistics version 19.0 (IBM, Armonk, New York). Additionally, to determine the reproducibility of LA myocardial measurements using speckle-tracking echocardiography, we analyzed intra- and interobserver variability in 20 randomly selected patients using Bland-Altman analysis, which was not of clinical significance (intra- and interobserver variability, respectively, as mean absolute differences: LA strain 0.34 ± 0.42% and 0.42 ± 0.44%, LA SRa −0.08 ± 0.12 s ⁻¹ and −0.07 ± 0.10 s ⁻¹ ).

Results

A total of 124 patients with paroxysmal AF met the eligibility criteria during the inclusion period. However, 40 patients could not be enrolled, because of poor 2-dimensional quality in ≥1 segment of the left ventricle or the left atrium not suitable for analysis by 2-dimensional speckle-tracking echocardiography (n = 12) or because of high CHADS ₂ scores (≥2) (n = 28). Thus, 84 patients with paroxysmal AF and low CHADS ₂ scores (≤1) treated with catheter ablation therapy were finally included and followed up during a period of 19.2 ± 5.4 months. Baseline clinical and myocardial characteristics of these patients are listed in Table 1 . All patients had follow-up of ≥1 year. The primary end point occurred in 19 patients (i.e., 19 recurrences of AF after catheter ablation therapy). The average time to the primary end point was 8.1 months (57.9% between the 3rd and 6th months, 31.6% between the 7th and 12th months, and 10.5% after 1 year of catheter ablation therapy). The characteristics of the recurrence of AF were as follows: symptomatic 100%, paroxysmal 73.6%, and persistent 26.4%. No patient experienced sudden death, ventricular tachycardia, or acute coronary syndromes during the follow-up period.

Patients with paroxysmal AF and low CHADS ₂ scores (≤1) had significantly more impaired systolic and diastolic LA myocardial function than asymptomatic control patients without histories of AF (all p values <0.0001; Figure 2 ). In relation to these findings, the rates of systolic and diastolic LA myocardial dysfunction were considerably elevated in patients with paroxysmal AF and low CHADS ₂ scores (33.3% and 39.3%, respectively), whereas in control subjects, the rates of systolic and diastolic LA dysfunction were only 2.4% and 3.6%, respectively (all p values <0.0001; Figure 2 ). In contrast, using conventional echocardiographic analyses such as LAVI, although the differences were statistically significant, we did not find important differences between patients with paroxysmal AF and control subjects ( Figure 3 ). In line with these findings, importantly, we detected using speckle-tracking echocardiography a high percentage of systolic and diastolic LA myocardial alterations in patients with paroxysmal AF in whom the conventional LA volumetric measurements were normal ( Figure 4 ). Concerning the possible factors that could be associated with systolic and diastolic LA myocardial dysfunction in patients with paroxysmal AF, we found that LV myocardial systolic dysfunction (i.e., LV strain >−16%) was the principal factor associated with systolic and diastolic LA myocardial dysfunction (see on-line Supplemental Tables 2 and 3) . In contrast, when we focused the analyses on LV systolic and diastolic myocardial function using speckle-tracking echocardiography, we did not find important differences between patients with paroxysmal AF and control subjects without histories of AF. In this regard, the rates of LV myocardial systolic and diastolic dysfunction evaluated by speckle-tracking echocardiography in patients with paroxysmal AF were 19.0% and 14.3% and in control subjects 26.2% and 36.9%, respectively (p = 0.2712 and 0.0007).

Patients with paroxysmal AF and low CHADS ₂ scores (≤1) have significantly impaired LA systolic and diastolic myocardial function compared to asymptomatic control subjects without histories of AF (mean ± SD values for each group are shown in the boxes). In the box plots, the central line represents the median, the length of the box represents the interquartile range (25th to 75th percentile), and the bars indicate the 10th and 90th percentiles (top). In addition, patients with paroxysmal AF had high rates of systolic and diastolic LA myocardial dysfunction.

Analysis of LA volumetric function in patients with paroxysmal AF with low CHADS ₂ scores (≤1) and in asymptomatic control subjects without histories of AF.

In patients with histories of paroxysmal AF, although conventional and volumetric echocardiographic methods indicate that the left atrium is normal (i.e., LAVI ≤28 ml/m ² [n = 48] or LAEF ≥40% [n = 75]), new and more sensitive myocardial analyses such as speckle-tracking echocardiography reveal systolic and diastolic LA myocardial dysfunction in these patients.

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