Accepted Manuscript Effect of Left Ventricular Diastolic Dysfunction on Outcomes of Atrial Fibrillation Ablation Prabhat Kumar , MBBS Ankit Patel , MD J. Paul Mounsey , BMBCh PhD Eugene H. Chung , MD Jennifer D. Schwartz , MD Irion W. Pursell , RN Anil K. Gehi , MD PII:
S0002-9149(14)01120-5
DOI:
10.1016/j.amjcard.2014.05.012
Reference:
AJC 20466
To appear in:
The American Journal of Cardiology
Received Date: 27 March 2014 Revised Date:
6 May 2014
Accepted Date: 6 May 2014
Please cite this article as: Kumar P, Patel A, Mounsey JP, Chung EH, Schwartz JD, Pursell IW, Gehi AK, Effect of Left Ventricular Diastolic Dysfunction on Outcomes of Atrial Fibrillation Ablation, The American Journal of Cardiology (2014), doi: 10.1016/j.amjcard.2014.05.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Effect of Left Ventricular Diastolic Dysfunction on Outcomes of Atrial Fibrillation Ablation
Jennifer D Schwartz MD, Irion W Pursell RN, Anil K. Gehi MD.
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Prabhat Kumar MBBS, Ankit Patel MD, J Paul Mounsey BMBCh PhD, Eugene H Chung MD,
Department of Medicine, Division of Cardiovascular Medicine, University of North Carolina,
Address of Correspondence Anil K Gehi MD FHRS Assistant Professor of Medicine
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Running title: AF ablation and LV diastolic dysfunction
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Chapel Hill, NC, USA
Heart and Vascular 160 Dental Circle, CB 7075 Chapel Hill, NC 27599
Fax: 919-966-4366
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Tel: 919-966-4743
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University of North Carolina at Chapel Hill
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Email: [email protected] Disclosures:
Prabhat Kumar: none; Ankit Patel: none; J Paul Mounsey: paid speaker and consultant to Boston Scientific and St Jude Medical; Eugene H Chung: none; Jennifer D Schwartz: none; Irion W Pursell: none; Anil K Gehi: none.
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Abstract Left ventricular diastolic dysfunction (LVDD) is an important pathogenic factor for atrial fibrillation (AF). There is a little data on the effect of LVDD on recurrence of AF after
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catheter ablation. A cohort of 124 patients (59.9±11.7 years, 73.9% male and 55% with paroxysmal AF) with recalcitrant AF and normal LV systolic function (LVEF≥50%)
undergoing ablation was studied. Each patient underwent trans-thoracic echocardiography
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and LVDD was meticulously graded using rhythm-independent (AF or sinus rhythm) transmitral and tissue Doppler parameters. Patients underwent catheter ablation of AF using a
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step-wise protocol. All patients were followed at 3, 6, and 12 months with recurrent AF (>30 sec) captured by EKG and/or 7-day monitor. Kaplan-Meier survival analysis and Cox proportional hazards model were used. There was no LVDD in 72 (58%) of patients, while 33 (26.6%), 10 (8.1%), and 9 (7.3%) of patients had grade 1, 2, or 3 LVDD respectively. AF recurred in 49 (39.5%) of patients with median time to recurrence of 248 days. Patients
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with higher grade of LVDD were increasingly more likely to have recurrence (37.5% for no LVDD, 30.3%, 60% and 66.7% for grades 1,2 and 3 LVDD respectively). Significant LVDD (grade2/3) was an independent predictor of recurrence (HR 2.6, p=0.009) after adjusting
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for persistent (vs. paroxysmal) AF and LA volume. In conclusion, patients with more severe LVDD have a higher risk of AF recurrence after catheter ablation. These patients may derive
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less benefit from ablation or may require a more extensive ablation approach.
Key words: Atrial fibrillation, Catheter ablation, Left ventricular diastolic dysfunction, Left atrial volume.
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Introduction Catheter ablation of atrial fibrillation (AF), a common management strategy in symptomatic AF patients resistant to antiarrhythmic medications, is often associated with
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recurrence of both AF and atrial flutter. Left atrial remodeling is one of the most important factors to predict the recurrence of AF after catheter ablation. 1 There is paucity of data evaluating the effect of left ventricular diastolic dysfunction (LVDD) on the outcome of
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catheter ablation for AF. Few studies evaluating the effect of LVDD on the outcome of
catheter ablation have been performed and are limited by inadequate, non-uniform or
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nondiscriminatory evaluation of LVDD2-6 and have failed to discriminate between the effect of structural atrial remodeling and LVDD. 2 Our study systematically evaluates the effect of LVDD on AF recurrence in patients undergoing catheter ablation. Methods
Consecutive patients who underwent catheter ablation were enrolled in a data
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registry in order to evaluate outcomes of ablation. For this study, patients with normal LV systolic function who had available predictor data and adequate follow-up were included in this retrospective analysis. The Institutional Review Board approved the study and all the
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participating patients gave a written informed consent for review of data for the purpose of research. Patients were otherwise treated according to standard of care. Patients with 2+ or
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more mitral regurgitation, mitral stenosis, significant mitral annular calcification, a mitral ring or a mitral valve prosthesis, which can affect the tissue-doppler evaluation of LVDD, were excluded from the study. A comprehensive clinical history and physical examination was performed on all the patients at the time of enrollment. All patients underwent a detailed transthoracic echocardiography and laboratory evaluation at the baseline.
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All patients underwent evaluation of LV systolic function; LA and LV chamber sizes and volumes; LV wall thickness and LV diastolic function with mitral inflow Doppler and tissue Doppler. LV volumes were assessed by Simpson’s method with measurements made
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in 4-chamber and 2-chamber views and LV ejection fraction was calculated. LV mass was
calculated from the LV chamber volumes and LV wall thickness measured at end-diastole. Left atrial chamber dimensions and volumes were measured in 2-chamber and 4-chamber
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views using Simpson’s and area-length methods. Left ventricular diastolic dysfunction was assessed and graded according to American Society of Echocardiography recommendations
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using parameters unaffected by patient’s rhythm (sinus rhythm or AF). 7 Left atrial volumes were not used in grading patient’s left ventricular diastolic dysfunction as they were used as independent parameter for assessing the risk of recurrent AF. LVDD was graded 0-3 as described below:
Grade 0: Early diastolic velocity of the septal mitral annulus by tissue Doppler (e’) >= 8
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cm/sec.
Grade 1: e’ < 8 cm/sec and deceleration time (DT) from maximum early ventricular filling velocity to baseline > 200 ms
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Grade 2: e’ < 8 cm/sec and DT 160-200 ms Grade 3: e’ < 8 cm/sec and DT < 160 ms
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All echocardiographic measurements were assessed by two expert echocardiographers (P.K. and A.P.) who were blinded to patient outcomes data. The physicians performing catheter ablation were blinded to the LVDD data on the patients. Catheter ablation was performed on all patients at the University of North Carolina
Hospitals Electrophysiology laboratory. Details of the ablation procedure have been previously published. 8 In brief, left atrial access was achieved by double trans-septal puncture. Antral isolation was performed using an irrigated ablation catheter (Chili II,
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Boston Scientific) guided by a lasso catheter and impedance-based mapping system (Ensite/NaVX, St Jude Medical). In those with persistent AF, following antral isolation, catheter ablation of AF was
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performed using a step-wise protocol including complex fractionated atrial electrograms
ablation and linear ablation. Linear ablation lesions included a roofline connecting the right and left superior pulmonary veins, a mitral isthmus line connecting the left inferior
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pulmonary vein to the mitral annulus and lower posterior left atrial line to isolate the
coronary sinus. If the rhythm organized to an atrial flutter or atrial tachycardia, this was
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mapped and ablated. Patients were cardioverted with ibutilide and/or direct current cardioversion if they were still in AF after completion of the ablation protocol. Cavotricuspid isthmus ablation was performed in all patients with documented atrial flutter, and in all patients with persistent AF. For ablation with closed irrigation catheter power of 25-40 W was used with a target catheter-tip temperature of 41°C. Power was reduced to
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25-30 W while ablating on the posterior wall and esophageal temperature monitoring was used to reduce the chance of esophageal injury. Patients were followed at 6 weeks, 3, 6 and 12 months following the ablation
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procedure. At each follow up a clinical interview, full clinical examination and electrocardiography were performed. Patients with implanted pacemaker or implantable
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cardioverter-defibrillator had interrogation of their device to look for any evidence of AF at each of their visits. Long term cardiac monitoring was used at 3 and 12 months to assess for asymptomatic atrial fibrillation. Recurrence was defined as >30 seconds of documented AF or atrial flutter/atrial tachycardia occurring after a blanking period of three months after ablation. Characteristics of the cohort were analyzed using measures of central tendency. Descriptive characterization of continuous variables was calculated as mean and standard
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deviation and frequencies were calculated for categorical variables. Arrhythmia-free survival curves were charted by Kaplan–Meier analysis first for all patients in the cohort. Multivariable Cox proportional hazards models were used including the pre-specified
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covariates: AF pattern (persistent vs. paroxysmal) and left atrial volume. Using the log-rank test, AF recurrence was compared in patients with paroxysmal or persistent AF, with and without diastolic dysfunction. Kaplan-Meier analysis was used to draw arrhythmia free
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survival curves in all the patients and in patients with various grades of LVDD. All analyses were performed using statistical software STATA version 11.0 (College Station, TX).
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Results
The study population (Table 1) consisted of 124 patients with atrial fibrillation undergoing a first catheter ablation for atrial fibrillation. Mean age of the cohort was 59.9±11.7 years and 74% were male. Atrial fibrillation was persistent in 45% of the patients and the duration of AF prior to catheter ablation procedure was 62.8±77.0 months. Risk
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factors of atrial fibrillation have been summarized in table 1. Mean CHADS2 score was 1.0 in these patients. Almost 60% of the patients were on beta-blockers and the majority of patients were on antiplatelets or anticoagulant (Table 1). All patients had failed a trial of
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antiarrhythmic drug therapy prior to ablation. A majority (63%) of the patients were on antiarrhythmic medications beyond three months after catheter ablation.
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LVDD was present in 52 (42%) of the patients. LVDD was present in 45% of the patient who had recurrent AF and in 40% of the patients who did not have recurrent AF after catheter ablation. Analyzing the patients having recurrent AF by grade of LVDD showed increasing fraction of patients with higher grade, with 37.5%, 30.3%, 60% and 66.7% of patients with no LVDD, grade 1, 2 and 3 LVDD respectively having recurrent AF (figure 1). There was a clear step-up in recurrence rate with more than grade 1 LVDD. Left atrial diameter of the patients was 43±7 mm and left atrial volume was 80±34 ml. Left atrial
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diameter and left atrial volume were not significantly different in patients with and without AF recurrence (LA diameter: 44±7 mm vs. 43±8 mm, p=0.16; LA volume: 81±32 ml vs. 79±37 ml, p=0.66). LV systolic function and LV end diastolic dimensions were 62±9% and
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49±6 mm with no significant difference between patients who had recurrence of AF compared to the patients without recurrence (Table 2).
During the mean follow up of 354 days, recurrent AF was seen in 49 (39.5%) of the
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patients. Median time to recurrence was 248 days. Univariate Cox proportionate hazard
analysis demonstrated persistent AF and LVDD grade 2 or 3 as significant predictors of AF
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recurrence. No other patient characteristics including age, gender, duration of AF, comorbidities, medications or CHADS2 score were predictors of AF recurrence on univariate analysis (Table 1).
In multivariate analysis (Table 3) including LVDD, AF pattern, and LA volume, both AF pattern and significant LVDD remained significant determinants of AF recurrence.
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Patients with persistent AF were over 2 times more likely to have AF recurrence [HR 2.01 (1.11-3.65) p = 0.022; figure 1]. Presence of LVDD grade 2 or 3 increased the risk to recurrence of AF by more than two and a half times compared to no LVDD or grade 1 LVDD
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Discussion
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[HR 2.58 (1.27-5.25); p = 0.009; figure 2].
We studied the effect of LVDD on recurrence of AF after catheter ablation procedure.
Our study demonstrates that severe LVDD of grade 2 or 3 is associated with an increased likelihood of AF recurrence in patients undergoing AF ablation. The presence of significant LVDD was associated with more than 2.5 times the risk of AF recurrence after adjusting for potential confounders including type of AF (persistent vs. paroxysmal), and LA volume. In addition, consistent with prior studies, we found that patients with persistent AF were at
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higher risk of recurrent AF than patients with paroxysmal AF. It is important to note that the parameters to assess LVDD in all these patients were uniform and did not include rhythm dependent parameters like A wave on trans-mitral Doppler and a’ on tissue Doppler.
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LA volume was excluded from the assessment of LVDD as it was considered as an independent predictor of AF recurrence.
LVDD has been recognized to be an important predictor of clinical progression of
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AF.9 It has been found to be an important determinant of recurrent AF after cardioversion, postoperative AF after cardiac surgery, and new AF in patients with acute myocardial
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infarction. 10-12 Its proarrhythmic effect is likely secondary to electrical and anatomical remodeling due to elevated filling pressure in the LA. LVDD imparts its effects through increased LA preload, afterload and wall stress and leads to fibrosis and dilatation of LA. 13 In addition to structural remodeling of the LA, electrical remodeling at the cellular level triggered by increased preload, afterload and wall stress are mechanistically important. 14-17
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Remodeling of the LA including dilatation and fibrosis exclusive of LVDD is an important factor predisposing to incident AF. 18 Moreover, anatomic remodeling of the LA may be an effect of AF and not only a cause. For these reasons, it is important to consider LA dilatation
from LVDD.
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as an independent parameter while assessing the factors determining recurrent AF separate
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Previous studies have found that LVDD predicts recurrent AF in patients undergoing ablation for atrial fibrillation by catheter-based procedure and with open surgery. 2-6 However, our study differs from them on two basic methodological points. First, we used uniform criteria irrespective of rhythm to assess LVDD. Second, we did not include LA volume in assessment of LVDD recognizing that although LA dilatation is an effect of LVDD, this may be an independent predictor of AF recurrence. The largest study by Cha et al2 demonstrating that LVDD was associated with more frequent recurrence of AF after
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catheter ablation, did not use a uniform grading of LVDD for sinus rhythm and AF and also used LA volume in the grading, which precludes adjustment for contribution of atrial dilatation on AF recurrence. Nonetheless, this is the only study with comprehensive
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evaluation of LVDD and its effect on recurrent AF after catheter ablation. Other prior studies assessing the effect of LVDD on recurrent AF after catheter ablation were limited by short follow up of three months and use of single parameter assessment of LVDD. One much
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smaller study also demonstrated the effect of LVDD on surgical ablation of atrial fibrillation in patients undergoing coronary artery bypass grafting. 4 Appropriate, uniform, and
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comprehensive evaluation of LVDD in our study allowed overcoming some of the limitations mentioned above including elimination of confounding effects of LA volume parameters. In addition, our study population did not include patients with significant mitral regurgitation, significant mitral stenosis, significant mitral annular calcification, a mitral ring or a mitral valve prosthesis, which can affect the tissue-doppler evaluation of LVDD.
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The role of LVDD as a risk for AF occurrence was studied most extensively in the large Cardiovascular Health Study, which interestingly showed independent roles of LA dilatation and LVDD in incident AF. 9 It is important to note from this study that both LVDD
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and LA dilatation are independent predictors of incident AF in these patients when analysis to segregate their role was performed. Our study indicates a more important role of LVDD
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in recurrent AF, as the risk of AF is almost unchanged after adjusting for the covariates in the Cox models.
Our study highlights the high rate of recurrent AF in patients with severe LVDD
(grade 2 or 3). A very high recurrence rate of AF in patients with severe LVDD undergoing catheter ablation is concerning and suggests the need for additional intervention in these patients, which may include more extensive ablation, antiarrhythmic therapy and more aggressive medical therapy of conditions causing severe LVDD.
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There are certain limitations with respect to design and analysis of this study. Patients underwent stepwise ablation and hence all patients did not have a standard set of ablation lesions. However, ablation protocol was not modified by knowledge of extent of
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LVDD so should not affect the overall results. Similarly, use of antiarrhythmic medications was not uniform and was done as per treating physician’s judgment. Patients in our study were mostly male and had a relatively low CHADS2 score, suggestive of a relatively
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healthier population compared to many other AF ablation series. This likely explains the
low predominance of patients with significant LVDD. As such, results from our study may
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not be generalizable to other patient populations. Although cardiac monitors were used as appropriate, symptoms were taken into consideration to assess for recurrent AF by EKG and/or monitor. It is likely that patients with more severe LVDD will have worse symptoms;
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hence recurrent AF in them is more likely to come to notice.
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after transcatheter ablation?: a meta-analysis. Int J Cardiol 2012;167:1984-1989.
2. Cha YM, Wokhlu A, Asirvatham SJ, Shen WK, Friedman PA, Munger TM, Oh JK, Monahan KH, Haroldson JM, Hodge DO, Herges RM, Hammill SC, Packer DL. Success of ablation for
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3. Ejima K, Shoda M, Arai K, Suzuki A, Yagishita D, Yagishita Y, Yashiro B, Sato T, Manaka T, Ashihara K, Hagiwara N. Impact of diastolic dysfunction on the outcome of catheter ablation in patients with atrial fibrillation. Int J Cardiol 2011;164:88-93.
4. Houltz B, Johansson B, Berglin E, Karlsson T, Edvardsson N, Wandt B. Left ventricular diastolic function and right atrial size are important rhythm outcome predictors after
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intraoperative ablation for atrial fibrillation. Echocardiography 2010;27:961-968. 5. Hu YF, Hsu TL, Yu WC, Huang SH, Tsao HM, Tai CT, Lin YJ, Chang SL, Lo LW, Tuan TC, Chang CJ, Tsai WC, Lee PC, Tang WH, Chen SA. The impact of diastolic dysfunction on the
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6. Li C, Ding X, Zhang J, Zhou C, Chen Y, Rao L. Does the E/e' index predict the maintenance of sinus rhythm after catheter ablation of atrial fibrillation? Echocardiography 2010;27:630636.
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8. Golden K, Mounsey JP, Chung E, Roomiani P, Morse MA, Patel A, Gehi A. Atrial fibrillation ablation using a closed irrigation radiofrequency ablation catheter. Pacing Clin Electrophysiol 2012;35:506-516.
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10. Caputo M, Urselli R, Capati E, Navarri R, Sinesi L, Furiozzi F, Ballo P, Palazzuoli A, Favilli R, Mondillo S. Usefulness of left ventricular diastolic dysfunction assessed by pulsed tissue
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Doppler imaging as a predictor of atrial fibrillation recurrence after successful electrical cardioversion. Am J Cardiol 2011;108:698-704.
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Cardiol 2011;58:953-961.
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13. Rosenberg MA, Manning WJ. Diastolic dysfunction and risk of atrial fibrillation: a mechanistic appraisal. Circulation 2012;126:2353-2362. 14. Calkins H, el-Atassi R, Leon A, Kalbfleisch S, Borganelli M, Langberg J, Morady F. Effect of the atrioventricular relationship on atrial refractoriness in humans. Pacing Clin Electrophysiol 1992;15:771-778.
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2002;40:1636-1644.
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diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol
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Figure Legends Figure 1 Bar chart showing percentage of patients having recurrent AF graded by LVDD.
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Figure 2
Kaplan-Meier survival curve showing more recurrent AF in patients with history of
persistent AF. Red line represents persistent AF while the blue line represents paroxysmal
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AF. Figure 3
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Kaplan-Meier survival curve showing recurrent AF in patients with no or grade 1 LVDD compared to patients with more significant grade 2 or 3 LVDD. Red line represents grade 2
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or 3 LVDD while the blue line represents less severe or no LVDD.
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Table 1: Patient characteristics, stratified by recurrence of atrial fibrillation Recurrence after ablation
Overall (N=124)
Variables
Yes (N=49)
Age (years)
59.9±11.7
61.7±10.7
Men
74%
76%
BMI (Kg/m2)
32.0±7.5
32.7±8.0
AF duration (months)
62.8±77.0
63.7±73.6
Persistent AF
45%
59%
Hypertension
57%
58%
Diabetes mellitus
22%
Coronary artery disease Heart failure
P*
No (N= 75) 0.41
73%
0.83
31.5±7.1
0.50
62.2±79.4
0.96
36%
0.009
57%
0.92
22%
22%
0.94
18%
11%
23%
0.09
12%
11%
13%
0.87
7.0%
4.4%
8.6%
0.56
60%
55%
63%
0.39
22%
20%
23%
0.88
Ace-Inhibitor / Angiotensin receptor 42%
45%
40%
0.66
Statin
37%
39%
0.31
58%
59%
58%
0.67
59%
61%
58%
0.88
18%
18%
18%
0.38
1.0±1.0
1.0±1.0
1.0±1.0
0.84
66.9%
82.6%
63.4%
0.02
Medications Beta-blocker Calcium-channel blocker
Warfarin Dabigatran CHADS2
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AAD beyond 3 months
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38%
Aspirin
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Tobacco use
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58.7±12.3
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*p-value for univariable predictor using Cox proportional hazard analysis AAD: Antiarrhythmic drugs
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Table 2: Echocardiographic characteristics, stratified by recurrence of atrial fibrillation
Variable
Overall (N=124)
LV ejection fraction (%)
p*
Recurrence after ablation No (N= 75) 63±10
0.61
LV end diastolic diameter
49±6
48±6
49±7
0.32
LV mass (g)
204±63
204±54
204±69
LA diameter (mm)
43±7
44±7
43±8
LA area (cm2)
22±6
23±6
21±6
LA volume (ml)
80±34
81±32
79±37
0
72
27
45
1
33
10
23
2
10
3
9
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Diastolic grade
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62±9
Yes (N=49) 60±9
0.99
0.16
0.22
0.66
Ref 0.33
6
4
0.04
6
3
0.11
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*p-value for univariable predictor using Cox proportional hazard analysis. Numbers for various grades of LVDD in the bottom four rows are absolute number of patients. LA: left atrial LV: left ventricular
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Table 3: Multivariable analysis of determinants of recurrent atrial fibrillation p value
0.009
Hazard ratio (adjusted)* 2.01 (1.11-3.65)
Diastolic dysfunction grade 2 or 3
2.53 (1.30-4.93)
0.006
2.57 (1.27-5.25)
0.009
Left atrial volume
1.01 (0.99-1.01)
0.66
1.00 (0.99-1.01)
0.803
0.022
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p value
Persistent Atrial fibrillation
Hazard ratio (unadjusted) 1.71 (1.22-3.83)
Variable
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*Adjusted for LVDD, AF pattern, antiarrhythmic drug use, AF duration and left atrial volume.
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S0002-9149(14)01120-5
DOI:
10.1016/j.amjcard.2014.05.012
Reference:
AJC 20466
To appear in:
The American Journal of Cardiology
Received Date: 27 March 2014 Revised Date:
6 May 2014
Accepted Date: 6 May 2014
Please cite this article as: Kumar P, Patel A, Mounsey JP, Chung EH, Schwartz JD, Pursell IW, Gehi AK, Effect of Left Ventricular Diastolic Dysfunction on Outcomes of Atrial Fibrillation Ablation, The American Journal of Cardiology (2014), doi: 10.1016/j.amjcard.2014.05.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Effect of Left Ventricular Diastolic Dysfunction on Outcomes of Atrial Fibrillation Ablation
Jennifer D Schwartz MD, Irion W Pursell RN, Anil K. Gehi MD.
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Prabhat Kumar MBBS, Ankit Patel MD, J Paul Mounsey BMBCh PhD, Eugene H Chung MD,
Department of Medicine, Division of Cardiovascular Medicine, University of North Carolina,
Address of Correspondence Anil K Gehi MD FHRS Assistant Professor of Medicine
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Running title: AF ablation and LV diastolic dysfunction
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Chapel Hill, NC, USA
Heart and Vascular 160 Dental Circle, CB 7075 Chapel Hill, NC 27599
Fax: 919-966-4366
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Tel: 919-966-4743
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University of North Carolina at Chapel Hill
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Email: [email protected] Disclosures:
Prabhat Kumar: none; Ankit Patel: none; J Paul Mounsey: paid speaker and consultant to Boston Scientific and St Jude Medical; Eugene H Chung: none; Jennifer D Schwartz: none; Irion W Pursell: none; Anil K Gehi: none.
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Abstract Left ventricular diastolic dysfunction (LVDD) is an important pathogenic factor for atrial fibrillation (AF). There is a little data on the effect of LVDD on recurrence of AF after
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catheter ablation. A cohort of 124 patients (59.9±11.7 years, 73.9% male and 55% with paroxysmal AF) with recalcitrant AF and normal LV systolic function (LVEF≥50%)
undergoing ablation was studied. Each patient underwent trans-thoracic echocardiography
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and LVDD was meticulously graded using rhythm-independent (AF or sinus rhythm) transmitral and tissue Doppler parameters. Patients underwent catheter ablation of AF using a
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step-wise protocol. All patients were followed at 3, 6, and 12 months with recurrent AF (>30 sec) captured by EKG and/or 7-day monitor. Kaplan-Meier survival analysis and Cox proportional hazards model were used. There was no LVDD in 72 (58%) of patients, while 33 (26.6%), 10 (8.1%), and 9 (7.3%) of patients had grade 1, 2, or 3 LVDD respectively. AF recurred in 49 (39.5%) of patients with median time to recurrence of 248 days. Patients
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with higher grade of LVDD were increasingly more likely to have recurrence (37.5% for no LVDD, 30.3%, 60% and 66.7% for grades 1,2 and 3 LVDD respectively). Significant LVDD (grade2/3) was an independent predictor of recurrence (HR 2.6, p=0.009) after adjusting
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for persistent (vs. paroxysmal) AF and LA volume. In conclusion, patients with more severe LVDD have a higher risk of AF recurrence after catheter ablation. These patients may derive
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less benefit from ablation or may require a more extensive ablation approach.
Key words: Atrial fibrillation, Catheter ablation, Left ventricular diastolic dysfunction, Left atrial volume.
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Introduction Catheter ablation of atrial fibrillation (AF), a common management strategy in symptomatic AF patients resistant to antiarrhythmic medications, is often associated with
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recurrence of both AF and atrial flutter. Left atrial remodeling is one of the most important factors to predict the recurrence of AF after catheter ablation. 1 There is paucity of data evaluating the effect of left ventricular diastolic dysfunction (LVDD) on the outcome of
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catheter ablation for AF. Few studies evaluating the effect of LVDD on the outcome of
catheter ablation have been performed and are limited by inadequate, non-uniform or
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nondiscriminatory evaluation of LVDD2-6 and have failed to discriminate between the effect of structural atrial remodeling and LVDD. 2 Our study systematically evaluates the effect of LVDD on AF recurrence in patients undergoing catheter ablation. Methods
Consecutive patients who underwent catheter ablation were enrolled in a data
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registry in order to evaluate outcomes of ablation. For this study, patients with normal LV systolic function who had available predictor data and adequate follow-up were included in this retrospective analysis. The Institutional Review Board approved the study and all the
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participating patients gave a written informed consent for review of data for the purpose of research. Patients were otherwise treated according to standard of care. Patients with 2+ or
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more mitral regurgitation, mitral stenosis, significant mitral annular calcification, a mitral ring or a mitral valve prosthesis, which can affect the tissue-doppler evaluation of LVDD, were excluded from the study. A comprehensive clinical history and physical examination was performed on all the patients at the time of enrollment. All patients underwent a detailed transthoracic echocardiography and laboratory evaluation at the baseline.
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All patients underwent evaluation of LV systolic function; LA and LV chamber sizes and volumes; LV wall thickness and LV diastolic function with mitral inflow Doppler and tissue Doppler. LV volumes were assessed by Simpson’s method with measurements made
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in 4-chamber and 2-chamber views and LV ejection fraction was calculated. LV mass was
calculated from the LV chamber volumes and LV wall thickness measured at end-diastole. Left atrial chamber dimensions and volumes were measured in 2-chamber and 4-chamber
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views using Simpson’s and area-length methods. Left ventricular diastolic dysfunction was assessed and graded according to American Society of Echocardiography recommendations
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using parameters unaffected by patient’s rhythm (sinus rhythm or AF). 7 Left atrial volumes were not used in grading patient’s left ventricular diastolic dysfunction as they were used as independent parameter for assessing the risk of recurrent AF. LVDD was graded 0-3 as described below:
Grade 0: Early diastolic velocity of the septal mitral annulus by tissue Doppler (e’) >= 8
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cm/sec.
Grade 1: e’ < 8 cm/sec and deceleration time (DT) from maximum early ventricular filling velocity to baseline > 200 ms
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Grade 2: e’ < 8 cm/sec and DT 160-200 ms Grade 3: e’ < 8 cm/sec and DT < 160 ms
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All echocardiographic measurements were assessed by two expert echocardiographers (P.K. and A.P.) who were blinded to patient outcomes data. The physicians performing catheter ablation were blinded to the LVDD data on the patients. Catheter ablation was performed on all patients at the University of North Carolina
Hospitals Electrophysiology laboratory. Details of the ablation procedure have been previously published. 8 In brief, left atrial access was achieved by double trans-septal puncture. Antral isolation was performed using an irrigated ablation catheter (Chili II,
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Boston Scientific) guided by a lasso catheter and impedance-based mapping system (Ensite/NaVX, St Jude Medical). In those with persistent AF, following antral isolation, catheter ablation of AF was
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performed using a step-wise protocol including complex fractionated atrial electrograms
ablation and linear ablation. Linear ablation lesions included a roofline connecting the right and left superior pulmonary veins, a mitral isthmus line connecting the left inferior
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pulmonary vein to the mitral annulus and lower posterior left atrial line to isolate the
coronary sinus. If the rhythm organized to an atrial flutter or atrial tachycardia, this was
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mapped and ablated. Patients were cardioverted with ibutilide and/or direct current cardioversion if they were still in AF after completion of the ablation protocol. Cavotricuspid isthmus ablation was performed in all patients with documented atrial flutter, and in all patients with persistent AF. For ablation with closed irrigation catheter power of 25-40 W was used with a target catheter-tip temperature of 41°C. Power was reduced to
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25-30 W while ablating on the posterior wall and esophageal temperature monitoring was used to reduce the chance of esophageal injury. Patients were followed at 6 weeks, 3, 6 and 12 months following the ablation
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procedure. At each follow up a clinical interview, full clinical examination and electrocardiography were performed. Patients with implanted pacemaker or implantable
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cardioverter-defibrillator had interrogation of their device to look for any evidence of AF at each of their visits. Long term cardiac monitoring was used at 3 and 12 months to assess for asymptomatic atrial fibrillation. Recurrence was defined as >30 seconds of documented AF or atrial flutter/atrial tachycardia occurring after a blanking period of three months after ablation. Characteristics of the cohort were analyzed using measures of central tendency. Descriptive characterization of continuous variables was calculated as mean and standard
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deviation and frequencies were calculated for categorical variables. Arrhythmia-free survival curves were charted by Kaplan–Meier analysis first for all patients in the cohort. Multivariable Cox proportional hazards models were used including the pre-specified
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covariates: AF pattern (persistent vs. paroxysmal) and left atrial volume. Using the log-rank test, AF recurrence was compared in patients with paroxysmal or persistent AF, with and without diastolic dysfunction. Kaplan-Meier analysis was used to draw arrhythmia free
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survival curves in all the patients and in patients with various grades of LVDD. All analyses were performed using statistical software STATA version 11.0 (College Station, TX).
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Results
The study population (Table 1) consisted of 124 patients with atrial fibrillation undergoing a first catheter ablation for atrial fibrillation. Mean age of the cohort was 59.9±11.7 years and 74% were male. Atrial fibrillation was persistent in 45% of the patients and the duration of AF prior to catheter ablation procedure was 62.8±77.0 months. Risk
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factors of atrial fibrillation have been summarized in table 1. Mean CHADS2 score was 1.0 in these patients. Almost 60% of the patients were on beta-blockers and the majority of patients were on antiplatelets or anticoagulant (Table 1). All patients had failed a trial of
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antiarrhythmic drug therapy prior to ablation. A majority (63%) of the patients were on antiarrhythmic medications beyond three months after catheter ablation.
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LVDD was present in 52 (42%) of the patients. LVDD was present in 45% of the patient who had recurrent AF and in 40% of the patients who did not have recurrent AF after catheter ablation. Analyzing the patients having recurrent AF by grade of LVDD showed increasing fraction of patients with higher grade, with 37.5%, 30.3%, 60% and 66.7% of patients with no LVDD, grade 1, 2 and 3 LVDD respectively having recurrent AF (figure 1). There was a clear step-up in recurrence rate with more than grade 1 LVDD. Left atrial diameter of the patients was 43±7 mm and left atrial volume was 80±34 ml. Left atrial
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diameter and left atrial volume were not significantly different in patients with and without AF recurrence (LA diameter: 44±7 mm vs. 43±8 mm, p=0.16; LA volume: 81±32 ml vs. 79±37 ml, p=0.66). LV systolic function and LV end diastolic dimensions were 62±9% and
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49±6 mm with no significant difference between patients who had recurrence of AF compared to the patients without recurrence (Table 2).
During the mean follow up of 354 days, recurrent AF was seen in 49 (39.5%) of the
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patients. Median time to recurrence was 248 days. Univariate Cox proportionate hazard
analysis demonstrated persistent AF and LVDD grade 2 or 3 as significant predictors of AF
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recurrence. No other patient characteristics including age, gender, duration of AF, comorbidities, medications or CHADS2 score were predictors of AF recurrence on univariate analysis (Table 1).
In multivariate analysis (Table 3) including LVDD, AF pattern, and LA volume, both AF pattern and significant LVDD remained significant determinants of AF recurrence.
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Patients with persistent AF were over 2 times more likely to have AF recurrence [HR 2.01 (1.11-3.65) p = 0.022; figure 1]. Presence of LVDD grade 2 or 3 increased the risk to recurrence of AF by more than two and a half times compared to no LVDD or grade 1 LVDD
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Discussion
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[HR 2.58 (1.27-5.25); p = 0.009; figure 2].
We studied the effect of LVDD on recurrence of AF after catheter ablation procedure.
Our study demonstrates that severe LVDD of grade 2 or 3 is associated with an increased likelihood of AF recurrence in patients undergoing AF ablation. The presence of significant LVDD was associated with more than 2.5 times the risk of AF recurrence after adjusting for potential confounders including type of AF (persistent vs. paroxysmal), and LA volume. In addition, consistent with prior studies, we found that patients with persistent AF were at
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higher risk of recurrent AF than patients with paroxysmal AF. It is important to note that the parameters to assess LVDD in all these patients were uniform and did not include rhythm dependent parameters like A wave on trans-mitral Doppler and a’ on tissue Doppler.
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LA volume was excluded from the assessment of LVDD as it was considered as an independent predictor of AF recurrence.
LVDD has been recognized to be an important predictor of clinical progression of
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AF.9 It has been found to be an important determinant of recurrent AF after cardioversion, postoperative AF after cardiac surgery, and new AF in patients with acute myocardial
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infarction. 10-12 Its proarrhythmic effect is likely secondary to electrical and anatomical remodeling due to elevated filling pressure in the LA. LVDD imparts its effects through increased LA preload, afterload and wall stress and leads to fibrosis and dilatation of LA. 13 In addition to structural remodeling of the LA, electrical remodeling at the cellular level triggered by increased preload, afterload and wall stress are mechanistically important. 14-17
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Remodeling of the LA including dilatation and fibrosis exclusive of LVDD is an important factor predisposing to incident AF. 18 Moreover, anatomic remodeling of the LA may be an effect of AF and not only a cause. For these reasons, it is important to consider LA dilatation
from LVDD.
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as an independent parameter while assessing the factors determining recurrent AF separate
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Previous studies have found that LVDD predicts recurrent AF in patients undergoing ablation for atrial fibrillation by catheter-based procedure and with open surgery. 2-6 However, our study differs from them on two basic methodological points. First, we used uniform criteria irrespective of rhythm to assess LVDD. Second, we did not include LA volume in assessment of LVDD recognizing that although LA dilatation is an effect of LVDD, this may be an independent predictor of AF recurrence. The largest study by Cha et al2 demonstrating that LVDD was associated with more frequent recurrence of AF after
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catheter ablation, did not use a uniform grading of LVDD for sinus rhythm and AF and also used LA volume in the grading, which precludes adjustment for contribution of atrial dilatation on AF recurrence. Nonetheless, this is the only study with comprehensive
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evaluation of LVDD and its effect on recurrent AF after catheter ablation. Other prior studies assessing the effect of LVDD on recurrent AF after catheter ablation were limited by short follow up of three months and use of single parameter assessment of LVDD. One much
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smaller study also demonstrated the effect of LVDD on surgical ablation of atrial fibrillation in patients undergoing coronary artery bypass grafting. 4 Appropriate, uniform, and
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comprehensive evaluation of LVDD in our study allowed overcoming some of the limitations mentioned above including elimination of confounding effects of LA volume parameters. In addition, our study population did not include patients with significant mitral regurgitation, significant mitral stenosis, significant mitral annular calcification, a mitral ring or a mitral valve prosthesis, which can affect the tissue-doppler evaluation of LVDD.
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The role of LVDD as a risk for AF occurrence was studied most extensively in the large Cardiovascular Health Study, which interestingly showed independent roles of LA dilatation and LVDD in incident AF. 9 It is important to note from this study that both LVDD
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and LA dilatation are independent predictors of incident AF in these patients when analysis to segregate their role was performed. Our study indicates a more important role of LVDD
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in recurrent AF, as the risk of AF is almost unchanged after adjusting for the covariates in the Cox models.
Our study highlights the high rate of recurrent AF in patients with severe LVDD
(grade 2 or 3). A very high recurrence rate of AF in patients with severe LVDD undergoing catheter ablation is concerning and suggests the need for additional intervention in these patients, which may include more extensive ablation, antiarrhythmic therapy and more aggressive medical therapy of conditions causing severe LVDD.
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There are certain limitations with respect to design and analysis of this study. Patients underwent stepwise ablation and hence all patients did not have a standard set of ablation lesions. However, ablation protocol was not modified by knowledge of extent of
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LVDD so should not affect the overall results. Similarly, use of antiarrhythmic medications was not uniform and was done as per treating physician’s judgment. Patients in our study were mostly male and had a relatively low CHADS2 score, suggestive of a relatively
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healthier population compared to many other AF ablation series. This likely explains the
low predominance of patients with significant LVDD. As such, results from our study may
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not be generalizable to other patient populations. Although cardiac monitors were used as appropriate, symptoms were taken into consideration to assess for recurrent AF by EKG and/or monitor. It is likely that patients with more severe LVDD will have worse symptoms;
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hence recurrent AF in them is more likely to come to notice.
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1. D'Ascenzo F, Corleto A, Biondi-Zoccai G, Anselmino M, Ferraris F, di Biase L, Natale A, Hunter RJ, Schilling RJ, Miyazaki S, Tada H, Aonuma K, Yenn-Jiang L, Tao H, Ma C, Packer D, Hammill S, Gaita F. Which are the most reliable predictors of recurrence of atrial fibrillation
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after transcatheter ablation?: a meta-analysis. Int J Cardiol 2012;167:1984-1989.
2. Cha YM, Wokhlu A, Asirvatham SJ, Shen WK, Friedman PA, Munger TM, Oh JK, Monahan KH, Haroldson JM, Hodge DO, Herges RM, Hammill SC, Packer DL. Success of ablation for
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atrial fibrillation in isolated left ventricular diastolic dysfunction: a comparison to systolic dysfunction and normal ventricular function. Circ Arrhythm Electrophysiol 2011;4:724-732.
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3. Ejima K, Shoda M, Arai K, Suzuki A, Yagishita D, Yagishita Y, Yashiro B, Sato T, Manaka T, Ashihara K, Hagiwara N. Impact of diastolic dysfunction on the outcome of catheter ablation in patients with atrial fibrillation. Int J Cardiol 2011;164:88-93.
4. Houltz B, Johansson B, Berglin E, Karlsson T, Edvardsson N, Wandt B. Left ventricular diastolic function and right atrial size are important rhythm outcome predictors after
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intraoperative ablation for atrial fibrillation. Echocardiography 2010;27:961-968. 5. Hu YF, Hsu TL, Yu WC, Huang SH, Tsao HM, Tai CT, Lin YJ, Chang SL, Lo LW, Tuan TC, Chang CJ, Tsai WC, Lee PC, Tang WH, Chen SA. The impact of diastolic dysfunction on the
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atrial substrate properties and outcome of catheter ablation in patients with paroxysmal atrial fibrillation. Circ J 2010;74:2074-2078.
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6. Li C, Ding X, Zhang J, Zhou C, Chen Y, Rao L. Does the E/e' index predict the maintenance of sinus rhythm after catheter ablation of atrial fibrillation? Echocardiography 2010;27:630636.
7. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelisa A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;10:165-193.
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8. Golden K, Mounsey JP, Chung E, Roomiani P, Morse MA, Patel A, Gehi A. Atrial fibrillation ablation using a closed irrigation radiofrequency ablation catheter. Pacing Clin Electrophysiol 2012;35:506-516.
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9. Rosenberg MA, Gottdiener JS, Heckbert SR, Mukamal KJ. Echocardiographic diastolic parameters and risk of atrial fibrillation: the Cardiovascular Health Study. Eur Heart J 2012;33:904-912.
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10. Caputo M, Urselli R, Capati E, Navarri R, Sinesi L, Furiozzi F, Ballo P, Palazzuoli A, Favilli R, Mondillo S. Usefulness of left ventricular diastolic dysfunction assessed by pulsed tissue
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Doppler imaging as a predictor of atrial fibrillation recurrence after successful electrical cardioversion. Am J Cardiol 2011;108:698-704.
11. Melduni RM, Suri RM, Seward JB, Bailey KR, Ammash NM, Oh JK, Schaff HV, Gersh BJ. Diastolic dysfunction in patients undergoing cardiac surgery: a pathophysiological mechanism underlying the initiation of new-onset post-operative atrial fibrillation. J Am Coll
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Cardiol 2011;58:953-961.
12. Jons C, Joergensen RM, Hassager C, Gang UJ, Dixen U, Johannesen A, Olsen NT, Hansen TF, Messier M, Huikuri HV, Thomsen PE. Diastolic dysfunction predicts new-onset atrial
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fibrillation and cardiovascular events in patients with acute myocardial infarction and depressed left ventricular systolic function: a CARISMA substudy. Eur J Echocardiogr
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2010;11:602-607.
13. Rosenberg MA, Manning WJ. Diastolic dysfunction and risk of atrial fibrillation: a mechanistic appraisal. Circulation 2012;126:2353-2362. 14. Calkins H, el-Atassi R, Leon A, Kalbfleisch S, Borganelli M, Langberg J, Morady F. Effect of the atrioventricular relationship on atrial refractoriness in humans. Pacing Clin Electrophysiol 1992;15:771-778.
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15. Efremidis M, Sideris A, Prappa E, Filippatos G, Athanasias D, Kardara D, Sioras I, Kardaras F. Effect of atrial pressure increase on effective refractory period and vulnerability to atrial fibrillation in patients with lone atrial fibrillation. J Interv Card Electrophysiol
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1999;3:307-310.
16. Nattel S, Maguy A, Le Bouter S, Yeh YH. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 2007;87:425-
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456.
17. Tsai CT, Chiang FT, Tseng CD, Yu CC, Wang YC, Lai LP, Hwang JJ, Lin JL. Mechanical
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stretch of atrial myocyte monolayer decreases sarcoplasmic reticulum calcium adenosine triphosphatase expression and increases susceptibility to repolarization alternans. J Am Coll Cardiol 2011;58:2106-2115.
18. Tsang TS, Gersh BJ, Appleton CP, Tajik AJ, Barnes ME, Bailey KR, Oh JK, Leibson C, Montgomery SC, Seward JB. Left ventricular diastolic dysfunction as a predictor of the first
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2002;40:1636-1644.
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diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol
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Figure Legends Figure 1 Bar chart showing percentage of patients having recurrent AF graded by LVDD.
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Figure 2
Kaplan-Meier survival curve showing more recurrent AF in patients with history of
persistent AF. Red line represents persistent AF while the blue line represents paroxysmal
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AF. Figure 3
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Kaplan-Meier survival curve showing recurrent AF in patients with no or grade 1 LVDD compared to patients with more significant grade 2 or 3 LVDD. Red line represents grade 2
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or 3 LVDD while the blue line represents less severe or no LVDD.
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Table 1: Patient characteristics, stratified by recurrence of atrial fibrillation Recurrence after ablation
Overall (N=124)
Variables
Yes (N=49)
Age (years)
59.9±11.7
61.7±10.7
Men
74%
76%
BMI (Kg/m2)
32.0±7.5
32.7±8.0
AF duration (months)
62.8±77.0
63.7±73.6
Persistent AF
45%
59%
Hypertension
57%
58%
Diabetes mellitus
22%
Coronary artery disease Heart failure
P*
No (N= 75) 0.41
73%
0.83
31.5±7.1
0.50
62.2±79.4
0.96
36%
0.009
57%
0.92
22%
22%
0.94
18%
11%
23%
0.09
12%
11%
13%
0.87
7.0%
4.4%
8.6%
0.56
60%
55%
63%
0.39
22%
20%
23%
0.88
Ace-Inhibitor / Angiotensin receptor 42%
45%
40%
0.66
Statin
37%
39%
0.31
58%
59%
58%
0.67
59%
61%
58%
0.88
18%
18%
18%
0.38
1.0±1.0
1.0±1.0
1.0±1.0
0.84
66.9%
82.6%
63.4%
0.02
Medications Beta-blocker Calcium-channel blocker
Warfarin Dabigatran CHADS2
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AAD beyond 3 months
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38%
Aspirin
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Tobacco use
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58.7±12.3
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*p-value for univariable predictor using Cox proportional hazard analysis AAD: Antiarrhythmic drugs
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Table 2: Echocardiographic characteristics, stratified by recurrence of atrial fibrillation
Variable
Overall (N=124)
LV ejection fraction (%)
p*
Recurrence after ablation No (N= 75) 63±10
0.61
LV end diastolic diameter
49±6
48±6
49±7
0.32
LV mass (g)
204±63
204±54
204±69
LA diameter (mm)
43±7
44±7
43±8
LA area (cm2)
22±6
23±6
21±6
LA volume (ml)
80±34
81±32
79±37
0
72
27
45
1
33
10
23
2
10
3
9
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Diastolic grade
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62±9
Yes (N=49) 60±9
0.99
0.16
0.22
0.66
Ref 0.33
6
4
0.04
6
3
0.11
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*p-value for univariable predictor using Cox proportional hazard analysis. Numbers for various grades of LVDD in the bottom four rows are absolute number of patients. LA: left atrial LV: left ventricular
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Table 3: Multivariable analysis of determinants of recurrent atrial fibrillation p value
0.009
Hazard ratio (adjusted)* 2.01 (1.11-3.65)
Diastolic dysfunction grade 2 or 3
2.53 (1.30-4.93)
0.006
2.57 (1.27-5.25)
0.009
Left atrial volume
1.01 (0.99-1.01)
0.66
1.00 (0.99-1.01)
0.803
0.022
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p value
Persistent Atrial fibrillation
Hazard ratio (unadjusted) 1.71 (1.22-3.83)
Variable
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*Adjusted for LVDD, AF pattern, antiarrhythmic drug use, AF duration and left atrial volume.
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