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Posterior left atrial isolation for atrial fibrillation in left ventricular diastolic impairment is associated with better arrhythmia free survival
Posterior left atrial isolation for atrial fibrillation in left ventricular diastolic impairment is associated with better arrhythmia free survival Chrishan Nalliah, Toon Wei Lim, Abhishek Bhaskaran, Eddy Kizana, Pramesh Kovoor, Liza Thomas, David L. Ross, Stuart P. Thomas PII: DOI: Reference:
S0167-5273(15)00095-9 doi: 10.1016/j.ijcard.2015.01.068 IJCA 19629
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
26 September 2014 22 December 2014 26 January 2015
Please cite this article as: Nalliah Chrishan, Lim Toon Wei, Bhaskaran Abhishek, Kizana Eddy, Kovoor Pramesh, Thomas Liza, Ross David L., Thomas Stuart P., Posterior left atrial isolation for atrial fibrillation in left ventricular diastolic impairment is associated with better arrhythmia free survival, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.01.068
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ACCEPTED MANUSCRIPT POSTERIOR LEFT ATRIAL ISOLATION FOR ATRIAL FIBRILLATION IN LEFT VENTRICULAR DIASTOLIC IMPAIRMENT IS ASSOCIATED WITH BETTER ARRHYTHMIA FREE SURVIVAL.
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Short title: Nalliah et al. Posterior left atrial isolation in left ventricular diastolic impairment. Chrishan NALLIAH BSc, MBBS1, Toon Wei LIM MBBS, FRACP, PhD1,2, Abhishek
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BHASKARAN MBBS, MRCP, FRACP1, Eddy KIZANA MBBS, FRACP, PhD1, Pramesh KOVOOR MBBS, FRACP, PhD1, Liza THOMAS MBBS, FRACP, PhD3, David L ROSS MBBS, FRACP, FACC1, Stuart P THOMAS BMed, FRACP, PhD, FHRS1
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Word Count: 4374
Department of Cardiology, Westmead Hospital, Sydney, Australia Department, National University Hospital, Singapore 3 Department of Cardiology, Liverpool Hospital, Sydney, Australia 1
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2 Cardiac
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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
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Address for Correspondence: Dr Stuart Thomas, Westmead Hospital, Department of Cardiology, Hawkesbury Road, Westmead, NSW, 2145. Telephone: 61 2 9845 5555 Fax: 61 2 9845 8323 Email: [email protected] Acknowledgement of grant support: This work was supported by a project grant from the National Health and Medical Research Council of Australia (ID Nos: 512223). TWL was supported by an Australian Postgraduate Award. Conflict of interests: The authors report no relationships that could be construed as a conflict of interest.
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ACCEPTED MANUSCRIPT Abstract:
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Background: Patients with left ventricular diastolic impairment (LVDI) have higher rates of arrhythmia recurrence following atrial fibrillation (AF) ablation.
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Past studies have implicated the posterior left atrium (LA) in atrial arrhythmia maintenance in conditions that cause LVDI. We prospectively compared posterior LA isolation (PLAI) with wide antral isolation (WAI) in patients with
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LVDI having AF ablation.
Methods: We conducted a sub-study of a previously published large randomized
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control study that compared PLAI with WAI. Two hundred and twenty consecutive consenting patients referred for catheter ablation of AF (paroxysmal
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135, persistent 48, long standing persistent 37) were recruited (female 43, mean
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age 59±10 years). Transthoracic echocardiography identified 50 (23%) patients with LVDI and preserved left ventricular systolic function (ejection
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fraction≥50%). Cox regression analysis was utilized to identify independent predictors of atrial arrhythmia after ablation.
Results: Patients were followed for median 4.6 (inter quartile range 4.0-5.5) years. Patients with LVDI having PLAI had better arrhythmia free survival than patients randomized to conventional ablation (Log rank P=0.028). The only independent predictor of recurrence utilizing Cox regression analysis was ablation strategy (2.3 [1.15-4.74], P=0.026).
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ACCEPTED MANUSCRIPT Conclusion: Posterior isolation of the LA results in superior atrial arrhythmia free survival in patients with LVDI. Further investigation is required to
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determine potential mechanisms.
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Clinical Trial Registration: http://www.anzctr.org.au;ACTRN12606000467538
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LVDI=Left ventricular diastolic impairment PVI=pulmonary vein isolation AF=atrial fibrillation EF=ejection fraction BMI=body mass index MIL=mitral isthmus line OAT=organized atrial tachycardia LA=left atrium PLAI=posterior left atrial isolation WAI-wide antral isolation PLA=posterior left atrium CFAE=complex fractionated atrial electrogram DT= deceleration time
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Abbreviations:
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ACCEPTED MANUSCRIPT Introduction:
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Patients with left ventricular diastolic impairment (LVDI) have more severe atrial fibrillation (AF) symptoms.1 Some studies suggest that successful ablation
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of AF reverses LVDI.2
Reant et al demonstrated reversal of left ventricular diastolic impairment
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following ablation of isolated paroxysmal and permanent AF.2 A further study by
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Cha et al showed improved diastolic function by at least 1 grade following ablation. Despite the potential benefit of successful AF ablation in LVDI, freedom
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from arrhythmia was reduced compared with patients with normal diastolic
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function utilizing a conventional ablation approach.3
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Effective ablation strategies for AF in patients with LVDI have scarcely been explored. We have previously reported better freedom from AF following
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posterior left atrial isolation (PLAI) strategy compared with a wide antral isolation (WAI).4
Previous animal and human studies have identified the posterior left atrium as a potential arrhythmic culprit in atrial stretch. It can harbor regions of fractionation5, 6, conduction delay7 and block8 that may contribute to arrhythmogenesis. We prospectively compared the efficacy of PLAI with WAI in patients with LVDI.
Methods:
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This is a sub-study of patients with LVDI from a large randomized controlled
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study of patients having PLAI versus WAI for AF.4 The study was approved by the Sydney West Area Health Service Human Research Ethics Committee and
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conforms with the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was obtained from each patient.
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Catheter ablation:
Patients were randomized to one of four ablation groups in a 2x2 factorial
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design: posterior left atrial isolation (PLAI) versus wide antral isolation (WAI)
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and mitral isthmus line (MIL) versus no mitral isthmus line (no MIL).
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Prior to AF ablation cardiac CT was performed on all patients to characterize and define atrial anatomy. An eletroanatomic map of the atria was generated during
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the procedure, using a three dimensional non-fluoroscopic mapping system (CARTO-XP, Biosense Webster or Ensite NavX, St Jude Medical). A trans esophageal echocardiogram was performed before the procedure to exclude left atrial thrombus and to visualize the inter-atrial septum.
These lesion sets have been described in detail previously (see Fig 1).4 In brief, PLAI involved a single ring of lesions enclosing all pulmonary veins and posterior LA. WAI consisted of application of two separate rings that each independently electrically isolated the left and right pulmonary vein pairs respectively. A line of lesions on the LA roof linking the superior portion of both rings was made in the
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ACCEPTED MANUSCRIPT WAI group. The MI line was performed by a line of lesions connecting the ring segment adjacent to the left inferior pulmonary vein to the mitral annulus.
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Conduction block was confirmed by standard pacing maneuvers during sinus rhythm. In addition to PLAI or WAI, areas of complex fractionated atrial
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electrograms (CFAE) outside the isolated area were targeted for further ablation in cases of persistent or long standing persistent AF, where AF did not terminate
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after pulmonary vein isolation.9
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Post procedure care:
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Patients were commenced on Enoxaparin post procedure and on Warfarin the day after the procedure. Enoxaparin was ceased after 10 days or when the
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patients INR exceeded 2.0. Anticoagulation was not ceased during follow up.
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Antiarrhythmic drugs were not routinely given to patients.
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Echocardiogram:
All patients underwent a comprehensive transthoracic echocardiogram preprocedurally. Left ventricular volumes and left ventricular ejection fractions (EF) were calculated using Simpson’s biplane method utilizing images obtained in the apical four and two chamber views and indexed to the patient’s body surface area. Biplane left atrial (LA) volume was also measured and indexed to BSA. To avoid the confounding effect of impaired systolic function, patients with EF<50% were excluded from the study. Left ventricular diastolic function was evaluated
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ACCEPTED MANUSCRIPT using standard American Society of Echocardiography criteria.10 LVDI was graded as follows: 1 (mild LVDI, E/A<0.8, deceleration time (DT)>200ms,
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average E/e’≤8), 2 (moderate LVDI, E/A 0.8-1.5, DT 160-200ms, average E/e’ 9-
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12) and 3 (severe LVDI, E/A≥2, DT<160ms, average E/e’≥13).
Follow up:
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The primary endpoint was freedom from all atrial tachyarrhythmia. Following
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ablation, patients entered a 3 month blanking period. Atrial tachyarrhythmia recurrence was defined according to Heart Rhythm Society/European Heart
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Rhythm Association/European Cardiac Arrhythmia Society consensus statement on catheter and surgical ablation of AF, as electrocardiographic (EKG)
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documented AF or organized atrial tachycardia (OAT) > than 30 seconds
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duration.11 All patients were clinically followed at the outpatient clinic 3, 6, 9 and 12 months after the procedure. Patients were then followed at 6 monthly
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intervals for the following 2 years. Seven day Holter monitoring was performed in patients without documented recurrence at 6, 12 and 36 months post procedure.
Repeat procedures:
Patients with AF or OAT recurrence were offered a repeat procedure. In patients that were randomized to PLAI, line gaps were identified and ablated, resulting in re-isolation of the pulmonary veins. However, patients initially randomized to WAI underwent floor-line ablation in addition to ablation of line gaps. Inducible
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ACCEPTED MANUSCRIPT atrial tachycardias were mapped and ablated in all patients. Thus, the posterior
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left atrium was electrically isolated in all patients that had second procedures.
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Statistical analysis:
Continuous data are expressed as mean±SD or as numbers and percentages as appropriate, and categorical variables are expressed as median [interquartile
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range]. The distributions of continuous variables between groups were
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compared using Student two tailed t-tests or Kruskal-Wallis tests as appropriate. Chi-squared or Fisher’s exact tests were used to test for association between
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categorical variables. Candidate variables for inclusion in multivariable models (logistic and Cox) were those significant at the P≤0.1 level on univariate analysis.
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Multiple logistic regression analysis with backward stepwise variable selection
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was used to identify independent predictors of diastolic impairment. Kaplan Meier curves were used to illustrate the distribution of the time to recurrence by
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group. Multiple Cox proportional hazards models were used to identify independent predictors of arrhythmia recurrence and to quantify the extent of association. Hazard ratios with associated 95% confidence intervals (CI) are reported. For all statistical tests, a 2-tailed P value≤0.05 was considered significant. Analyses were performed using SPSS version 21 (SPSS Inc, Chicago, Illinois). All figures were generated using SPSS version 21.
Results:
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ACCEPTED MANUSCRIPT Two hundred and twenty consecutive highly symptomatic patients with AF were prospectively recruited (female 43, mean age 59±10 years), with mean AF
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duration of 8±7years (paroxysmal 135, persistent 48, long standing persistent 37) in the original study. Twenty two patients with impaired systolic function
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(EF<50%), were excluded from the study. Of the remaining 198 patients, fifty (23%) patients had LVDI with preserved LV function (EF≥50%).
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Baseline characteristics of patients with and without LVDI are presented in Table
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1. Patients with LVDI were older, had a higher BMI and were more likely to have long standing persistent AF. There was a trend toward higher CHADS2 scores in
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patients with LVDI but this failed to reach significance. Independent predictors of LVDI using linear regression analysis were age (HR 1.09 per year [CI: 1.03-
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1.16], P=0.002), BMI (1.18 per unit kg/m2 [1.08-1.31], P=0.001), LA volume (1.16
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per mm3 [1.10-1.22], P<0.001) and long standing persistent AF (2.64 compared
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with paroxysmal/persistent AF [1.06-6.61], P=0.038) (Table 2).
Clinical characteristics of patients with LVDI having PLAI (n=20) and WAI (n=30) were similar. (Table 3) MIL ablation (PLAI 13 versus WAI 18, P=0.72) and CFAE ablation (PLAI 6 versus WAI 7, P=0.74) was also similar in the two groups. Medication use following AF ablation was similar between the two groups.
Patients were followed for a minimum of 3.2 years, with median follow up of 4.6 (interquartile range: 4-5.5) years. PLAI resulted in superior freedom from atrial tachyarrhythmia compared with WAI in patients with LVDI (PLAI 8 (40%) versus WAI 22 (73%), P=0.02, Fig 2). MIL ablation did not impact on atrial
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ACCEPTED MANUSCRIPT tachyarrhythmia recurrence (MIL 19 (61%) versus no MIL 11 (58%), P=0.76, Fig 3). Only first procedure results are relevant to this study, because the posterior
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left atrium was electrically isolated in all patients that had repeat procedures.
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The only independent predictor of recurrence in patients with LVDI utilizing Cox regression analysis after adjusting for baseline characteristics was ablation strategy (2.53 compared with PLAI, [1.12-5.69], P=0.025). Long standing
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persistent AF was not a univariable predictor of recurrence despite numerically
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higher numbers in the WAI group (0.75 compared with paroxysmal/persistent AF, [0.22-2.56], P=0.65). Markers of severity of left ventricular diastolic
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impairment (deceleration time, mitral annular velocity and grade of diastolic
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impairment) did not predict arrhythmia recurrence.
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Freedom from atrial tachyarrhythmia was similar in patients with and without LVDI (LVDI 30 (60%) versus normal LV diastolic function 82 (55%) P=0.57).
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Ablation strategy did not significantly impact on recurrence in patients with normal diastolic function (PLAI 44 (55%) versus WAI 38 (56%), P=0.60).
Discussion:
This is the first study to demonstrate superior efficacy with a specific ablation strategy in patients with left ventricular diastolic impairment but preserved left ventricular systolic function in preventing recurrences of atrial arrhythmias. PLAI was superior to the WAI strategy for AF in patients with isolated left ventricular diastolic impairment over a long duration of follow up. This was
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ACCEPTED MANUSCRIPT confirmed on multivariate analysis where the ablation strategy was the only independent predictor of arrhythmia recurrence in patients with LVDI. Our
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results suggest that evaluation of left ventricular diastolic function is important for patients referred for AF ablation because patients with LVDI might have
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better outcomes with PLAI.
We observed that patients with LVDI were older, had higher BMI’s, had larger
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atria and were more likely to have long standing persistent AF. These findings
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populations already described.
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are consistent with previous studies1, 12-14, and imply that our cohort is similar to
Previous studies have demonstrated cardiac remodeling, reversal of diastolic
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dysfunction and improved quality of life following successful ablation for AF.2, 3
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There are few studies evaluating the efficacy of different ablation strategies for AF in patients with impaired diastolic function. In a study by Cha et al,
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arrhythmic recurrences were higher among patients with LVDI after circumferential ablation outside the pulmonary vein ostia. 3 In the present study, PLAI substantially decreased the recurrence rate among patients with LVDI up to 3 years after the index procedure, rendering the efficacy of AF ablation equivalent to groups with normal diastolic function.
Jais et al observed higher left ventricular end diastolic pressures in lone AF compared with patients with accessory pathways,15 implying that left atrial stretch and enlargement may lead to AF in patients with LVDI. Fractionation,
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ACCEPTED MANUSCRIPT scar, slowed effective refractory periods and conduction block characterize the
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electroanatomical changes observed with atrial stretch. 16-18
The posterior LA has been implicated in the AF substrate in atrial stretch. Non-
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contact mapping demonstrated a vertical line of functional block on the PLA. This corresponded with an abrupt change in subendocardial fiber orientation in post mortem hearts that acted as a wave break with daughter wavelet or macro re-
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entrant circuit formation,7 and is more prominent in patients with left atrial
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dilatation.5 Roberts-Thompson et al performed epicardial mapping of the posterior LA during cardiac surgery and observed extensive regions of slowed
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conduction, CFAE’s and constant lines of delay that predisposed to circuitous wave front propagation in patients with left atrial enlargement, mitral
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regurgitation or AF.6 In a heart failure ovine model, regions of fibrosis around
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pulmonary vein ostia anchored reentrant circuits and impaired wave
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propagation.19
This raises two potential explanations for our results. Firstly, electrical isolation of the posterior wall may directly neutralize the electrical substrate driving AF. Alternatively, successful ablation may result in improved left ventricular diastolic function leading to decreased atrial stretch and electro-anatomical remodeling. However, in the absence of long term data assessing left ventricular diastolic function, it is difficult to draw conclusions regarding the mechanism for our observations. Echocardiographic assessment of left ventricular diastolic function following ablation is inaccurate because of atrial remodeling following radiofrequency injury.20 Furthermore, assessment following the index procedure
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ACCEPTED MANUSCRIPT is difficult because of extensive ablation of CFAE in persistent AF and repeated
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procedures after arrhythmia recurrence.
We have previously shown that PLAI in a large cohort of 220 patients resulted in
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fewer AF recurrences without affecting OAT recurrence.4 A recent meta-analysis observed that wide area pulmonary vein isolation is more favorable in paroxysmal and persistent AF.21 Substrate dependent factors extraneous to the
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pulmonary veins have been implicated in permanent AF.22 PLAI may electrically
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isolate and thus neutralize such extraneous triggers/substrate.
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Clinical Implications:
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Data describing different ablation strategies in patients with LVDI is scarce. PLAI
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appears a useful ablation strategy in patients with diastolic impairment that results in ablation efficacy comparable to patients with normal left ventricular
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diastolic function. This result may implicate the posterior LA as a potential arrhythmic culprit in LVDI.
Limitations:
The main limitation of this study is that patient numbers are small making it unwise to draw definitive conclusions. However, it raises interesting hypotheses implicating the posterior left atrium in diastolic impairment and AF. Larger trials are needed to validate this result.
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ACCEPTED MANUSCRIPT Secondly, there is no direct data localizing arrhythmic substrate to the posterior LA. Thus, we can only postulate a mechanistic link between our results and the
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potential AF substrate. However, past studies have suggested that the posterior LA contributes to the mileu predisposing to AF. Future studies that investigate
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this link should incorporate evaluation of arrhythmic substrate on the posterior wall.
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Finally, there were numerically (but not statistically) more cases of long standing
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persistent AF in the WAI compared with the PLAI group. Although AF type was not predictive of recurrence following Cox regression analysis, it is difficult to
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completely exclude its effect on recurrence in a small study. Larger studies are required to explore the impact of AF type on this lesion set. However, this study
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Conclusion:
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generates compelling hypotheses that warrant further exploration.
PLAI results in better arrhythmia free survival in patients with isolated LVDI. This result is consistent with previous data implicating the posterior left atria in arrhythmogenesis. More studies investigating PLAI in LVDI are required.
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ACCEPTED MANUSCRIPT References.
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10.
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Kosiuk J, Van Belle Y, Bode K, Kornej J, Arya A, Rolf S, Husser D, Hindricks G, Bollmann A. Left ventricular diastolic dysfunction in atrial fibrillation: Predictors and relation with symptom severity. J Cardiovasc Electrophysiol. 2012;23:1073-1077 Reant P, Lafitte S, Jais P, Serri K, Weerasooriya R, Hocini M, Pillois X, Clementy J, Haissaguerre M, Roudaut R. Reverse remodeling of the left cardiac chambers after catheter ablation after 1 year in a series of patients with isolated atrial fibrillation. Circulation. 2005;112:2896-2903 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 atrial fibrillation in isolated left ventricular diastolic dysfunction: A comparison to systolic dysfunction and normal ventricular function. Circ Arrhythm Electrophysiol. 2011;4:724-732 Lim TW, Koay CH, See VA, McCall R, Chik W, Zecchin R, Byth K, Seow SC, Thomas L, Ross DL, Thomas SP. Single-ring posterior left atrial (box) isolation results in a different mode of recurrence compared with wide antral pulmonary vein isolation on long-term follow-up: Longer atrial fibrillation-free survival time but similar survival time free of any atrial arrhythmia. Circ Arrhythm Electrophysiol. 2012;5:968-977 Roberts-Thomson KC, Stevenson IH, Kistler PM, Haqqani HM, Goldblatt JC, Sanders P, Kalman JM. Anatomically determined functional conduction delay in the posterior left atrium relationship to structural heart disease. J Am Coll Cardiol. 2008;51:856-862 Roberts-Thomson KC, Stevenson I, Kistler PM, Haqqani HM, Spence SJ, Goldblatt JC, Sanders P, Kalman JM. The role of chronic atrial stretch and atrial fibrillation on posterior left atrial wall conduction. Heart Rhythm. 2009;6:1109-1117 Markides V, Schilling RJ, Ho SY, Chow AW, Davies DW, Peters NS. Characterization of left atrial activation in the intact human heart. Circulation. 2003;107:733-739 Kalifa J, Tanaka K, Zaitsev AV, Warren M, Vaidyanathan R, Auerbach D, Pandit S, Vikstrom KL, Ploutz-Snyder R, Talkachou A, Atienza F, Guiraudon G, Jalife J, Berenfeld O. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation. 2006;113:626633 Li WJ, Bai YY, Zhang HY, Tang RB, Miao CL, Sang CH, Yin XD, Dong JZ, Ma CS. Additional ablation of complex fractionated atrial electrograms after pulmonary vein isolation in patients with atrial fibrillation: A metaanalysis. Circ Arrhythm Electrophysiol. 2011;4:143-148 Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2009;22:107-133
NU
1.
16
ACCEPTED MANUSCRIPT Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, Damiano RJ, Jr., Davies DW, DiMarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haines DE, Haissaguerre M, Hindricks G, Iesaka Y, Jackman W, Jalife J, Jais P, Kalman J, Keane D, Kim YH, Kirchhof P, Klein G, Kottkamp H, Kumagai K, Lindsay BD, Mansour M, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Nakagawa H, Natale A, Nattel S, Packer DL, Pappone C, Prystowsky E, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM, Wilber D. 2012 hrs/ehra/ecas expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm. 2012;9:632-696 e621 Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Risks for atrial fibrillation and congestive heart failure in patients >/=65 years of age with abnormal left ventricular diastolic relaxation. The American journal of cardiology. 2004;93:54-58 Wang TJ, Parise H, Levy D, D'Agostino RB, Sr., Wolf PA, Vasan RS, Benjamin EJ. Obesity and the risk of new-onset atrial fibrillation. JAMA : the journal of the American Medical Association. 2004;292:2471-2477 Tedrow UB, Conen D, Ridker PM, Cook NR, Koplan BA, Manson JE, Buring JE, Albert CM. The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation the whs (women's health study). J Am Coll Cardiol. 2010;55:2319-2327 Jais P, Peng JT, Shah DC, Garrigue S, Hocini M, Yamane T, Haissaguerre M, Barold SS, Roudaut R, Clementy J. Left ventricular diastolic dysfunction in patients with so-called lone atrial fibrillation. J Cardiovasc Electrophysiol. 2000;11:623-625 Roberts-Thomson KC, John B, Worthley SG, Brooks AG, Stiles MK, Lau DH, Kuklik P, Shipp NJ, Kalman JM, Sanders P. Left atrial remodeling in patients with atrial septal defects. Heart Rhythm. 2009;6:1000-1006 John B, Stiles MK, Kuklik P, Brooks AG, Chandy ST, Kalman JM, Sanders P. Reverse remodeling of the atria after treatment of chronic stretch in humans: Implications for the atrial fibrillation substrate. J Am Coll Cardiol. 2010;55:1217-1226 Sparks PB, Mond HG, Vohra JK, Jayaprakash S, Kalman JM. Electrical remodeling of the atria following loss of atrioventricular synchrony: A long-term study in humans. Circulation. 1999;100:1894-1900 Tanaka K, Zlochiver S, Vikstrom KL, Yamazaki M, Moreno J, Klos M, Zaitsev AV, Vaidyanathan R, Auerbach DS, Landas S, Guiraudon G, Jalife J, Berenfeld O, Kalifa J. Spatial distribution of fibrosis governs fibrillation wave dynamics in the posterior left atrium during heart failure. Circulation research. 2007;101:839-847 Wylie JV, Jr., Peters DC, Essebag V, Manning WJ, Josephson ME, Hauser TH. Left atrial function and scar after catheter ablation of atrial fibrillation. Heart Rhythm. 2008;5:656-662 Parkash R, Tang AS, Sapp JL, Wells G. Approach to the catheter ablation technique of paroxysmal and persistent atrial fibrillation: A meta-analysis of the randomized controlled trials. J Cardiovasc Electrophysiol. 2011;22:729-738
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18. 19.
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Lin WS, Tai CT, Hsieh MH, Tsai CF, Lin YK, Tsao HM, Huang JL, Yu WC, Yang SP, Ding YA, Chang MS, Chen SA. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation. 2003;107:3176-3183
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ACCEPTED MANUSCRIPT Table 1 Baseline characteristics.
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Diastolic impairment n=50 62±8 11 (22)
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102 (69) 33 (22) 13 (9) 71 [33, 131] 0 [0,1] 3±1 80/68 (54/46) 71 (48) 28±4 59 (40) 59 (40) 12 (8) 0.7±0.15 0.11±0.03 7±2 208±58 31±9 58±5
26 (52) 9 (18) 15 (30) 64 [32, 123] 1 [0,1] 3±2 20/30 (40/60) 31 (62) 31±5 26 (52) 26 (52) 5 (10) 0.86±0.18 0.07±0.02 13±4 193±51 44±10 57±6
P Value 0.001 0.56 0.001 0.35 0.08 0.12 0.11 0.10 0.015 0.13 0.13 0.68 <0.001 <0.001 <0.001 0.095 <0.001 0.37
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Age, years Females, n (%) AF Type, n (%) Paroxysmal Persistent Long standing persistent Months of AF, median [IQR] CHADS2 Score, median [IQR] AAD’s failed PLAI/WAI (%) MI line, n (%) BMI, kg/m2 Hypertension, n (%) Hyperlipidemia, n (%) Diabetes, n (%) E (m/s) e’ (m/s) E/e’ Deceleration Time (ms) LA Volume (cm3) EF, %
Normal diastolic function n=148 58±11 27 (18)
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Table 1. Baseline characteristics. AAD anti-arrhythmic drugs, BMI body mass index, CHADS2=congestive heart failure, hypertension, age>65 and stroke/TIA, EF ejection fraction, IQR inter-quartile range, LA left atrium, MI mitral isthmus, PLAI posterior left atrial isolation, WAI wide antral isolation.
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ACCEPTED MANUSCRIPT Table 2 Predictors of diastolic impairment before the ablation procedure.
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Univariable predictors of Multivariable predictors of diastolic impairment diastolic impairment HR (95% CI) P Value HR (95% CI) P Value 1.05 [1.01-1.08]
0.009
1.07 [1.02-1.13]
0.005
BMI (per kg/m2)
1.09 [1.02-1.16]
0.018
1.12 [1.03-1.21]
0.007
Long standing persistent AF
4.45 [1.94-10.21]
<0.001
2.64 [1.06-6.61]
0.038
LA Volume (per mm3)
1.16 [1.10-1.22]
<0.001
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Age (per year)
<0.001
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1.15 [1.10-1.20]
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Table 2. Univariable and multivariable predictors of diastolic impairment. AF atrial fibrillation, BMI body mass index, CI confidence interval, HR hazard ratio, LA left atrium.
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ACCEPTED MANUSCRIPT Table 3 Baseline characteristics of patients with impaired diastolic function.
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12 (60) 5 (25) 3 (15) 30±4 14 (56) 1.2±0.9 53±9 44±8 13 (65) 6 (30)
14 (47) 5 (17) 11 (36) 31±6 18 (53) 1.0±0.8 53±10 43±12 18 (60) 7 (23)
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WAI n=30 62±7 9 (27)
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Age, yrs Females n, % AF Type n, % Paroxysmal Persistent Long standing persistent BMI, kg/m2 Hypertension n, % CHADS2 score EF, % LA Volume (mm3) MI line n, % CFAE ablation n, % CFAE sites: LA roof Atrial septum Pulmonary veins Coronary sinus Other Diastolic grade, median [IQR]
PLAI n=20 63±8 2 (10)
1 (5) 1 (5) 1 (5) 1 (5) 5 (25) 2 [2,2]
5 (17) 5 (17) 0 (0) 3 (10) 6 (21) 2 [2,3]
P value 0.76 0.16 0.40 0.60 1.00 0.24 0.93 0.74 0.72 0.74
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Table 3. Baseline characteristics of patients with impaired diastolic function having PLAI versus conventional ablation. LA left atrium, PLAI posterior left atrial isolation, WAI wide antral isolation. CHADS2=congestive heart failure, hypertension, age>65, stroke/TIA. IQR, inter-quartile range.
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Fig 1. Panel A. WAI surrounding the left and right sided pulmonary veins (PV) (posterior view) with a roofline joining the superior left and right rings. Panel B. WAI in left lateral view. Panel C. A single ring of ablation lesions encircling the 4 PV’s isolating the posterior left atria (PLAI). Panel D. Mitral isthmus line connecting mitral annulus to the ring as it passes close to the left inferior PV. (Image from Circulation: arrhythmia and electrophysiology 2012; 5:968) PLAI posterior left atrial isolation, WAI wide antral isolation.
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Fig 2. Freedom from atrial tachyarrhythmia in patients with impaired diastolic function having PLAI versus conventional ablation. Censored events are indicated by a cross. Number of patients at risk are displayed at 6 monthly intervals. PLAI posterior left atrial isolation, WAI wide antral isolation.
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Fig 3. Patients with impaired diastolic function stratified based on MI line. Number of patients at risk are displayed at 6 monthly intervals. Censored events are indicated by a cross. MI mitral isthmus.
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S0167-5273(15)00095-9 doi: 10.1016/j.ijcard.2015.01.068 IJCA 19629
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
26 September 2014 22 December 2014 26 January 2015
Please cite this article as: Nalliah Chrishan, Lim Toon Wei, Bhaskaran Abhishek, Kizana Eddy, Kovoor Pramesh, Thomas Liza, Ross David L., Thomas Stuart P., Posterior left atrial isolation for atrial fibrillation in left ventricular diastolic impairment is associated with better arrhythmia free survival, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.01.068
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 POSTERIOR LEFT ATRIAL ISOLATION FOR ATRIAL FIBRILLATION IN LEFT VENTRICULAR DIASTOLIC IMPAIRMENT IS ASSOCIATED WITH BETTER ARRHYTHMIA FREE SURVIVAL.
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Short title: Nalliah et al. Posterior left atrial isolation in left ventricular diastolic impairment. Chrishan NALLIAH BSc, MBBS1, Toon Wei LIM MBBS, FRACP, PhD1,2, Abhishek
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BHASKARAN MBBS, MRCP, FRACP1, Eddy KIZANA MBBS, FRACP, PhD1, Pramesh KOVOOR MBBS, FRACP, PhD1, Liza THOMAS MBBS, FRACP, PhD3, David L ROSS MBBS, FRACP, FACC1, Stuart P THOMAS BMed, FRACP, PhD, FHRS1
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Word Count: 4374
Department of Cardiology, Westmead Hospital, Sydney, Australia Department, National University Hospital, Singapore 3 Department of Cardiology, Liverpool Hospital, Sydney, Australia 1
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2 Cardiac
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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
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Address for Correspondence: Dr Stuart Thomas, Westmead Hospital, Department of Cardiology, Hawkesbury Road, Westmead, NSW, 2145. Telephone: 61 2 9845 5555 Fax: 61 2 9845 8323 Email: [email protected] Acknowledgement of grant support: This work was supported by a project grant from the National Health and Medical Research Council of Australia (ID Nos: 512223). TWL was supported by an Australian Postgraduate Award. Conflict of interests: The authors report no relationships that could be construed as a conflict of interest.
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ACCEPTED MANUSCRIPT Abstract:
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Background: Patients with left ventricular diastolic impairment (LVDI) have higher rates of arrhythmia recurrence following atrial fibrillation (AF) ablation.
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Past studies have implicated the posterior left atrium (LA) in atrial arrhythmia maintenance in conditions that cause LVDI. We prospectively compared posterior LA isolation (PLAI) with wide antral isolation (WAI) in patients with
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LVDI having AF ablation.
Methods: We conducted a sub-study of a previously published large randomized
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control study that compared PLAI with WAI. Two hundred and twenty consecutive consenting patients referred for catheter ablation of AF (paroxysmal
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135, persistent 48, long standing persistent 37) were recruited (female 43, mean
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age 59±10 years). Transthoracic echocardiography identified 50 (23%) patients with LVDI and preserved left ventricular systolic function (ejection
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fraction≥50%). Cox regression analysis was utilized to identify independent predictors of atrial arrhythmia after ablation.
Results: Patients were followed for median 4.6 (inter quartile range 4.0-5.5) years. Patients with LVDI having PLAI had better arrhythmia free survival than patients randomized to conventional ablation (Log rank P=0.028). The only independent predictor of recurrence utilizing Cox regression analysis was ablation strategy (2.3 [1.15-4.74], P=0.026).
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ACCEPTED MANUSCRIPT Conclusion: Posterior isolation of the LA results in superior atrial arrhythmia free survival in patients with LVDI. Further investigation is required to
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determine potential mechanisms.
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Clinical Trial Registration: http://www.anzctr.org.au;ACTRN12606000467538
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LVDI=Left ventricular diastolic impairment PVI=pulmonary vein isolation AF=atrial fibrillation EF=ejection fraction BMI=body mass index MIL=mitral isthmus line OAT=organized atrial tachycardia LA=left atrium PLAI=posterior left atrial isolation WAI-wide antral isolation PLA=posterior left atrium CFAE=complex fractionated atrial electrogram DT= deceleration time
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Abbreviations:
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ACCEPTED MANUSCRIPT Introduction:
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Patients with left ventricular diastolic impairment (LVDI) have more severe atrial fibrillation (AF) symptoms.1 Some studies suggest that successful ablation
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of AF reverses LVDI.2
Reant et al demonstrated reversal of left ventricular diastolic impairment
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following ablation of isolated paroxysmal and permanent AF.2 A further study by
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Cha et al showed improved diastolic function by at least 1 grade following ablation. Despite the potential benefit of successful AF ablation in LVDI, freedom
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from arrhythmia was reduced compared with patients with normal diastolic
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function utilizing a conventional ablation approach.3
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Effective ablation strategies for AF in patients with LVDI have scarcely been explored. We have previously reported better freedom from AF following
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posterior left atrial isolation (PLAI) strategy compared with a wide antral isolation (WAI).4
Previous animal and human studies have identified the posterior left atrium as a potential arrhythmic culprit in atrial stretch. It can harbor regions of fractionation5, 6, conduction delay7 and block8 that may contribute to arrhythmogenesis. We prospectively compared the efficacy of PLAI with WAI in patients with LVDI.
Methods:
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This is a sub-study of patients with LVDI from a large randomized controlled
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study of patients having PLAI versus WAI for AF.4 The study was approved by the Sydney West Area Health Service Human Research Ethics Committee and
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conforms with the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was obtained from each patient.
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Catheter ablation:
Patients were randomized to one of four ablation groups in a 2x2 factorial
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design: posterior left atrial isolation (PLAI) versus wide antral isolation (WAI)
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and mitral isthmus line (MIL) versus no mitral isthmus line (no MIL).
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Prior to AF ablation cardiac CT was performed on all patients to characterize and define atrial anatomy. An eletroanatomic map of the atria was generated during
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the procedure, using a three dimensional non-fluoroscopic mapping system (CARTO-XP, Biosense Webster or Ensite NavX, St Jude Medical). A trans esophageal echocardiogram was performed before the procedure to exclude left atrial thrombus and to visualize the inter-atrial septum.
These lesion sets have been described in detail previously (see Fig 1).4 In brief, PLAI involved a single ring of lesions enclosing all pulmonary veins and posterior LA. WAI consisted of application of two separate rings that each independently electrically isolated the left and right pulmonary vein pairs respectively. A line of lesions on the LA roof linking the superior portion of both rings was made in the
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ACCEPTED MANUSCRIPT WAI group. The MI line was performed by a line of lesions connecting the ring segment adjacent to the left inferior pulmonary vein to the mitral annulus.
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Conduction block was confirmed by standard pacing maneuvers during sinus rhythm. In addition to PLAI or WAI, areas of complex fractionated atrial
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electrograms (CFAE) outside the isolated area were targeted for further ablation in cases of persistent or long standing persistent AF, where AF did not terminate
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after pulmonary vein isolation.9
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Post procedure care:
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Patients were commenced on Enoxaparin post procedure and on Warfarin the day after the procedure. Enoxaparin was ceased after 10 days or when the
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patients INR exceeded 2.0. Anticoagulation was not ceased during follow up.
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Antiarrhythmic drugs were not routinely given to patients.
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Echocardiogram:
All patients underwent a comprehensive transthoracic echocardiogram preprocedurally. Left ventricular volumes and left ventricular ejection fractions (EF) were calculated using Simpson’s biplane method utilizing images obtained in the apical four and two chamber views and indexed to the patient’s body surface area. Biplane left atrial (LA) volume was also measured and indexed to BSA. To avoid the confounding effect of impaired systolic function, patients with EF<50% were excluded from the study. Left ventricular diastolic function was evaluated
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ACCEPTED MANUSCRIPT using standard American Society of Echocardiography criteria.10 LVDI was graded as follows: 1 (mild LVDI, E/A<0.8, deceleration time (DT)>200ms,
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average E/e’≤8), 2 (moderate LVDI, E/A 0.8-1.5, DT 160-200ms, average E/e’ 9-
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12) and 3 (severe LVDI, E/A≥2, DT<160ms, average E/e’≥13).
Follow up:
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The primary endpoint was freedom from all atrial tachyarrhythmia. Following
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ablation, patients entered a 3 month blanking period. Atrial tachyarrhythmia recurrence was defined according to Heart Rhythm Society/European Heart
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Rhythm Association/European Cardiac Arrhythmia Society consensus statement on catheter and surgical ablation of AF, as electrocardiographic (EKG)
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documented AF or organized atrial tachycardia (OAT) > than 30 seconds
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duration.11 All patients were clinically followed at the outpatient clinic 3, 6, 9 and 12 months after the procedure. Patients were then followed at 6 monthly
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intervals for the following 2 years. Seven day Holter monitoring was performed in patients without documented recurrence at 6, 12 and 36 months post procedure.
Repeat procedures:
Patients with AF or OAT recurrence were offered a repeat procedure. In patients that were randomized to PLAI, line gaps were identified and ablated, resulting in re-isolation of the pulmonary veins. However, patients initially randomized to WAI underwent floor-line ablation in addition to ablation of line gaps. Inducible
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ACCEPTED MANUSCRIPT atrial tachycardias were mapped and ablated in all patients. Thus, the posterior
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left atrium was electrically isolated in all patients that had second procedures.
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Statistical analysis:
Continuous data are expressed as mean±SD or as numbers and percentages as appropriate, and categorical variables are expressed as median [interquartile
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range]. The distributions of continuous variables between groups were
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compared using Student two tailed t-tests or Kruskal-Wallis tests as appropriate. Chi-squared or Fisher’s exact tests were used to test for association between
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categorical variables. Candidate variables for inclusion in multivariable models (logistic and Cox) were those significant at the P≤0.1 level on univariate analysis.
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Multiple logistic regression analysis with backward stepwise variable selection
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was used to identify independent predictors of diastolic impairment. Kaplan Meier curves were used to illustrate the distribution of the time to recurrence by
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group. Multiple Cox proportional hazards models were used to identify independent predictors of arrhythmia recurrence and to quantify the extent of association. Hazard ratios with associated 95% confidence intervals (CI) are reported. For all statistical tests, a 2-tailed P value≤0.05 was considered significant. Analyses were performed using SPSS version 21 (SPSS Inc, Chicago, Illinois). All figures were generated using SPSS version 21.
Results:
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ACCEPTED MANUSCRIPT Two hundred and twenty consecutive highly symptomatic patients with AF were prospectively recruited (female 43, mean age 59±10 years), with mean AF
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duration of 8±7years (paroxysmal 135, persistent 48, long standing persistent 37) in the original study. Twenty two patients with impaired systolic function
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(EF<50%), were excluded from the study. Of the remaining 198 patients, fifty (23%) patients had LVDI with preserved LV function (EF≥50%).
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Baseline characteristics of patients with and without LVDI are presented in Table
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1. Patients with LVDI were older, had a higher BMI and were more likely to have long standing persistent AF. There was a trend toward higher CHADS2 scores in
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patients with LVDI but this failed to reach significance. Independent predictors of LVDI using linear regression analysis were age (HR 1.09 per year [CI: 1.03-
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1.16], P=0.002), BMI (1.18 per unit kg/m2 [1.08-1.31], P=0.001), LA volume (1.16
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per mm3 [1.10-1.22], P<0.001) and long standing persistent AF (2.64 compared
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with paroxysmal/persistent AF [1.06-6.61], P=0.038) (Table 2).
Clinical characteristics of patients with LVDI having PLAI (n=20) and WAI (n=30) were similar. (Table 3) MIL ablation (PLAI 13 versus WAI 18, P=0.72) and CFAE ablation (PLAI 6 versus WAI 7, P=0.74) was also similar in the two groups. Medication use following AF ablation was similar between the two groups.
Patients were followed for a minimum of 3.2 years, with median follow up of 4.6 (interquartile range: 4-5.5) years. PLAI resulted in superior freedom from atrial tachyarrhythmia compared with WAI in patients with LVDI (PLAI 8 (40%) versus WAI 22 (73%), P=0.02, Fig 2). MIL ablation did not impact on atrial
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ACCEPTED MANUSCRIPT tachyarrhythmia recurrence (MIL 19 (61%) versus no MIL 11 (58%), P=0.76, Fig 3). Only first procedure results are relevant to this study, because the posterior
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left atrium was electrically isolated in all patients that had repeat procedures.
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The only independent predictor of recurrence in patients with LVDI utilizing Cox regression analysis after adjusting for baseline characteristics was ablation strategy (2.53 compared with PLAI, [1.12-5.69], P=0.025). Long standing
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persistent AF was not a univariable predictor of recurrence despite numerically
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higher numbers in the WAI group (0.75 compared with paroxysmal/persistent AF, [0.22-2.56], P=0.65). Markers of severity of left ventricular diastolic
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impairment (deceleration time, mitral annular velocity and grade of diastolic
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impairment) did not predict arrhythmia recurrence.
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Freedom from atrial tachyarrhythmia was similar in patients with and without LVDI (LVDI 30 (60%) versus normal LV diastolic function 82 (55%) P=0.57).
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Ablation strategy did not significantly impact on recurrence in patients with normal diastolic function (PLAI 44 (55%) versus WAI 38 (56%), P=0.60).
Discussion:
This is the first study to demonstrate superior efficacy with a specific ablation strategy in patients with left ventricular diastolic impairment but preserved left ventricular systolic function in preventing recurrences of atrial arrhythmias. PLAI was superior to the WAI strategy for AF in patients with isolated left ventricular diastolic impairment over a long duration of follow up. This was
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ACCEPTED MANUSCRIPT confirmed on multivariate analysis where the ablation strategy was the only independent predictor of arrhythmia recurrence in patients with LVDI. Our
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results suggest that evaluation of left ventricular diastolic function is important for patients referred for AF ablation because patients with LVDI might have
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better outcomes with PLAI.
We observed that patients with LVDI were older, had higher BMI’s, had larger
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atria and were more likely to have long standing persistent AF. These findings
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populations already described.
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are consistent with previous studies1, 12-14, and imply that our cohort is similar to
Previous studies have demonstrated cardiac remodeling, reversal of diastolic
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dysfunction and improved quality of life following successful ablation for AF.2, 3
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There are few studies evaluating the efficacy of different ablation strategies for AF in patients with impaired diastolic function. In a study by Cha et al,
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arrhythmic recurrences were higher among patients with LVDI after circumferential ablation outside the pulmonary vein ostia. 3 In the present study, PLAI substantially decreased the recurrence rate among patients with LVDI up to 3 years after the index procedure, rendering the efficacy of AF ablation equivalent to groups with normal diastolic function.
Jais et al observed higher left ventricular end diastolic pressures in lone AF compared with patients with accessory pathways,15 implying that left atrial stretch and enlargement may lead to AF in patients with LVDI. Fractionation,
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ACCEPTED MANUSCRIPT scar, slowed effective refractory periods and conduction block characterize the
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electroanatomical changes observed with atrial stretch. 16-18
The posterior LA has been implicated in the AF substrate in atrial stretch. Non-
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contact mapping demonstrated a vertical line of functional block on the PLA. This corresponded with an abrupt change in subendocardial fiber orientation in post mortem hearts that acted as a wave break with daughter wavelet or macro re-
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entrant circuit formation,7 and is more prominent in patients with left atrial
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dilatation.5 Roberts-Thompson et al performed epicardial mapping of the posterior LA during cardiac surgery and observed extensive regions of slowed
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conduction, CFAE’s and constant lines of delay that predisposed to circuitous wave front propagation in patients with left atrial enlargement, mitral
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regurgitation or AF.6 In a heart failure ovine model, regions of fibrosis around
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pulmonary vein ostia anchored reentrant circuits and impaired wave
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propagation.19
This raises two potential explanations for our results. Firstly, electrical isolation of the posterior wall may directly neutralize the electrical substrate driving AF. Alternatively, successful ablation may result in improved left ventricular diastolic function leading to decreased atrial stretch and electro-anatomical remodeling. However, in the absence of long term data assessing left ventricular diastolic function, it is difficult to draw conclusions regarding the mechanism for our observations. Echocardiographic assessment of left ventricular diastolic function following ablation is inaccurate because of atrial remodeling following radiofrequency injury.20 Furthermore, assessment following the index procedure
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ACCEPTED MANUSCRIPT is difficult because of extensive ablation of CFAE in persistent AF and repeated
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procedures after arrhythmia recurrence.
We have previously shown that PLAI in a large cohort of 220 patients resulted in
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fewer AF recurrences without affecting OAT recurrence.4 A recent meta-analysis observed that wide area pulmonary vein isolation is more favorable in paroxysmal and persistent AF.21 Substrate dependent factors extraneous to the
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pulmonary veins have been implicated in permanent AF.22 PLAI may electrically
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isolate and thus neutralize such extraneous triggers/substrate.
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Clinical Implications:
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Data describing different ablation strategies in patients with LVDI is scarce. PLAI
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appears a useful ablation strategy in patients with diastolic impairment that results in ablation efficacy comparable to patients with normal left ventricular
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diastolic function. This result may implicate the posterior LA as a potential arrhythmic culprit in LVDI.
Limitations:
The main limitation of this study is that patient numbers are small making it unwise to draw definitive conclusions. However, it raises interesting hypotheses implicating the posterior left atrium in diastolic impairment and AF. Larger trials are needed to validate this result.
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ACCEPTED MANUSCRIPT Secondly, there is no direct data localizing arrhythmic substrate to the posterior LA. Thus, we can only postulate a mechanistic link between our results and the
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potential AF substrate. However, past studies have suggested that the posterior LA contributes to the mileu predisposing to AF. Future studies that investigate
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this link should incorporate evaluation of arrhythmic substrate on the posterior wall.
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Finally, there were numerically (but not statistically) more cases of long standing
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persistent AF in the WAI compared with the PLAI group. Although AF type was not predictive of recurrence following Cox regression analysis, it is difficult to
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completely exclude its effect on recurrence in a small study. Larger studies are required to explore the impact of AF type on this lesion set. However, this study
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Conclusion:
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generates compelling hypotheses that warrant further exploration.
PLAI results in better arrhythmia free survival in patients with isolated LVDI. This result is consistent with previous data implicating the posterior left atria in arrhythmogenesis. More studies investigating PLAI in LVDI are required.
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Kosiuk J, Van Belle Y, Bode K, Kornej J, Arya A, Rolf S, Husser D, Hindricks G, Bollmann A. Left ventricular diastolic dysfunction in atrial fibrillation: Predictors and relation with symptom severity. J Cardiovasc Electrophysiol. 2012;23:1073-1077 Reant P, Lafitte S, Jais P, Serri K, Weerasooriya R, Hocini M, Pillois X, Clementy J, Haissaguerre M, Roudaut R. Reverse remodeling of the left cardiac chambers after catheter ablation after 1 year in a series of patients with isolated atrial fibrillation. Circulation. 2005;112:2896-2903 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 atrial fibrillation in isolated left ventricular diastolic dysfunction: A comparison to systolic dysfunction and normal ventricular function. Circ Arrhythm Electrophysiol. 2011;4:724-732 Lim TW, Koay CH, See VA, McCall R, Chik W, Zecchin R, Byth K, Seow SC, Thomas L, Ross DL, Thomas SP. Single-ring posterior left atrial (box) isolation results in a different mode of recurrence compared with wide antral pulmonary vein isolation on long-term follow-up: Longer atrial fibrillation-free survival time but similar survival time free of any atrial arrhythmia. Circ Arrhythm Electrophysiol. 2012;5:968-977 Roberts-Thomson KC, Stevenson IH, Kistler PM, Haqqani HM, Goldblatt JC, Sanders P, Kalman JM. Anatomically determined functional conduction delay in the posterior left atrium relationship to structural heart disease. J Am Coll Cardiol. 2008;51:856-862 Roberts-Thomson KC, Stevenson I, Kistler PM, Haqqani HM, Spence SJ, Goldblatt JC, Sanders P, Kalman JM. The role of chronic atrial stretch and atrial fibrillation on posterior left atrial wall conduction. Heart Rhythm. 2009;6:1109-1117 Markides V, Schilling RJ, Ho SY, Chow AW, Davies DW, Peters NS. Characterization of left atrial activation in the intact human heart. Circulation. 2003;107:733-739 Kalifa J, Tanaka K, Zaitsev AV, Warren M, Vaidyanathan R, Auerbach D, Pandit S, Vikstrom KL, Ploutz-Snyder R, Talkachou A, Atienza F, Guiraudon G, Jalife J, Berenfeld O. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation. 2006;113:626633 Li WJ, Bai YY, Zhang HY, Tang RB, Miao CL, Sang CH, Yin XD, Dong JZ, Ma CS. Additional ablation of complex fractionated atrial electrograms after pulmonary vein isolation in patients with atrial fibrillation: A metaanalysis. Circ Arrhythm Electrophysiol. 2011;4:143-148 Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2009;22:107-133
NU
1.
16
ACCEPTED MANUSCRIPT Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, Damiano RJ, Jr., Davies DW, DiMarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haines DE, Haissaguerre M, Hindricks G, Iesaka Y, Jackman W, Jalife J, Jais P, Kalman J, Keane D, Kim YH, Kirchhof P, Klein G, Kottkamp H, Kumagai K, Lindsay BD, Mansour M, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Nakagawa H, Natale A, Nattel S, Packer DL, Pappone C, Prystowsky E, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM, Wilber D. 2012 hrs/ehra/ecas expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm. 2012;9:632-696 e621 Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Risks for atrial fibrillation and congestive heart failure in patients >/=65 years of age with abnormal left ventricular diastolic relaxation. The American journal of cardiology. 2004;93:54-58 Wang TJ, Parise H, Levy D, D'Agostino RB, Sr., Wolf PA, Vasan RS, Benjamin EJ. Obesity and the risk of new-onset atrial fibrillation. JAMA : the journal of the American Medical Association. 2004;292:2471-2477 Tedrow UB, Conen D, Ridker PM, Cook NR, Koplan BA, Manson JE, Buring JE, Albert CM. The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation the whs (women's health study). J Am Coll Cardiol. 2010;55:2319-2327 Jais P, Peng JT, Shah DC, Garrigue S, Hocini M, Yamane T, Haissaguerre M, Barold SS, Roudaut R, Clementy J. Left ventricular diastolic dysfunction in patients with so-called lone atrial fibrillation. J Cardiovasc Electrophysiol. 2000;11:623-625 Roberts-Thomson KC, John B, Worthley SG, Brooks AG, Stiles MK, Lau DH, Kuklik P, Shipp NJ, Kalman JM, Sanders P. Left atrial remodeling in patients with atrial septal defects. Heart Rhythm. 2009;6:1000-1006 John B, Stiles MK, Kuklik P, Brooks AG, Chandy ST, Kalman JM, Sanders P. Reverse remodeling of the atria after treatment of chronic stretch in humans: Implications for the atrial fibrillation substrate. J Am Coll Cardiol. 2010;55:1217-1226 Sparks PB, Mond HG, Vohra JK, Jayaprakash S, Kalman JM. Electrical remodeling of the atria following loss of atrioventricular synchrony: A long-term study in humans. Circulation. 1999;100:1894-1900 Tanaka K, Zlochiver S, Vikstrom KL, Yamazaki M, Moreno J, Klos M, Zaitsev AV, Vaidyanathan R, Auerbach DS, Landas S, Guiraudon G, Jalife J, Berenfeld O, Kalifa J. Spatial distribution of fibrosis governs fibrillation wave dynamics in the posterior left atrium during heart failure. Circulation research. 2007;101:839-847 Wylie JV, Jr., Peters DC, Essebag V, Manning WJ, Josephson ME, Hauser TH. Left atrial function and scar after catheter ablation of atrial fibrillation. Heart Rhythm. 2008;5:656-662 Parkash R, Tang AS, Sapp JL, Wells G. Approach to the catheter ablation technique of paroxysmal and persistent atrial fibrillation: A meta-analysis of the randomized controlled trials. J Cardiovasc Electrophysiol. 2011;22:729-738
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Lin WS, Tai CT, Hsieh MH, Tsai CF, Lin YK, Tsao HM, Huang JL, Yu WC, Yang SP, Ding YA, Chang MS, Chen SA. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation. 2003;107:3176-3183
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ACCEPTED MANUSCRIPT Table 1 Baseline characteristics.
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Diastolic impairment n=50 62±8 11 (22)
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102 (69) 33 (22) 13 (9) 71 [33, 131] 0 [0,1] 3±1 80/68 (54/46) 71 (48) 28±4 59 (40) 59 (40) 12 (8) 0.7±0.15 0.11±0.03 7±2 208±58 31±9 58±5
26 (52) 9 (18) 15 (30) 64 [32, 123] 1 [0,1] 3±2 20/30 (40/60) 31 (62) 31±5 26 (52) 26 (52) 5 (10) 0.86±0.18 0.07±0.02 13±4 193±51 44±10 57±6
P Value 0.001 0.56 0.001 0.35 0.08 0.12 0.11 0.10 0.015 0.13 0.13 0.68 <0.001 <0.001 <0.001 0.095 <0.001 0.37
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PT
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Age, years Females, n (%) AF Type, n (%) Paroxysmal Persistent Long standing persistent Months of AF, median [IQR] CHADS2 Score, median [IQR] AAD’s failed PLAI/WAI (%) MI line, n (%) BMI, kg/m2 Hypertension, n (%) Hyperlipidemia, n (%) Diabetes, n (%) E (m/s) e’ (m/s) E/e’ Deceleration Time (ms) LA Volume (cm3) EF, %
Normal diastolic function n=148 58±11 27 (18)
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Table 1. Baseline characteristics. AAD anti-arrhythmic drugs, BMI body mass index, CHADS2=congestive heart failure, hypertension, age>65 and stroke/TIA, EF ejection fraction, IQR inter-quartile range, LA left atrium, MI mitral isthmus, PLAI posterior left atrial isolation, WAI wide antral isolation.
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ACCEPTED MANUSCRIPT Table 2 Predictors of diastolic impairment before the ablation procedure.
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Univariable predictors of Multivariable predictors of diastolic impairment diastolic impairment HR (95% CI) P Value HR (95% CI) P Value 1.05 [1.01-1.08]
0.009
1.07 [1.02-1.13]
0.005
BMI (per kg/m2)
1.09 [1.02-1.16]
0.018
1.12 [1.03-1.21]
0.007
Long standing persistent AF
4.45 [1.94-10.21]
<0.001
2.64 [1.06-6.61]
0.038
LA Volume (per mm3)
1.16 [1.10-1.22]
<0.001
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Age (per year)
<0.001
NU
1.15 [1.10-1.20]
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Table 2. Univariable and multivariable predictors of diastolic impairment. AF atrial fibrillation, BMI body mass index, CI confidence interval, HR hazard ratio, LA left atrium.
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ACCEPTED MANUSCRIPT Table 3 Baseline characteristics of patients with impaired diastolic function.
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12 (60) 5 (25) 3 (15) 30±4 14 (56) 1.2±0.9 53±9 44±8 13 (65) 6 (30)
14 (47) 5 (17) 11 (36) 31±6 18 (53) 1.0±0.8 53±10 43±12 18 (60) 7 (23)
NU
SC RI
PT
WAI n=30 62±7 9 (27)
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Age, yrs Females n, % AF Type n, % Paroxysmal Persistent Long standing persistent BMI, kg/m2 Hypertension n, % CHADS2 score EF, % LA Volume (mm3) MI line n, % CFAE ablation n, % CFAE sites: LA roof Atrial septum Pulmonary veins Coronary sinus Other Diastolic grade, median [IQR]
PLAI n=20 63±8 2 (10)
1 (5) 1 (5) 1 (5) 1 (5) 5 (25) 2 [2,2]
5 (17) 5 (17) 0 (0) 3 (10) 6 (21) 2 [2,3]
P value 0.76 0.16 0.40 0.60 1.00 0.24 0.93 0.74 0.72 0.74
0.15
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Table 3. Baseline characteristics of patients with impaired diastolic function having PLAI versus conventional ablation. LA left atrium, PLAI posterior left atrial isolation, WAI wide antral isolation. CHADS2=congestive heart failure, hypertension, age>65, stroke/TIA. IQR, inter-quartile range.
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ACCEPTED MANUSCRIPT Figure abbreviations
SC RI
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Fig 1. Panel A. WAI surrounding the left and right sided pulmonary veins (PV) (posterior view) with a roofline joining the superior left and right rings. Panel B. WAI in left lateral view. Panel C. A single ring of ablation lesions encircling the 4 PV’s isolating the posterior left atria (PLAI). Panel D. Mitral isthmus line connecting mitral annulus to the ring as it passes close to the left inferior PV. (Image from Circulation: arrhythmia and electrophysiology 2012; 5:968) PLAI posterior left atrial isolation, WAI wide antral isolation.
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Fig 2. Freedom from atrial tachyarrhythmia in patients with impaired diastolic function having PLAI versus conventional ablation. Censored events are indicated by a cross. Number of patients at risk are displayed at 6 monthly intervals. PLAI posterior left atrial isolation, WAI wide antral isolation.
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Fig 3. Patients with impaired diastolic function stratified based on MI line. Number of patients at risk are displayed at 6 monthly intervals. Censored events are indicated by a cross. MI mitral isthmus.
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AC CE
PT ED
MA
NU
SC RI
Figure 1.
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0
PLAI WAI
20 30
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Years
CE
PT
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MA
NU
SC RI
PT
Figure 2.
0.5
1.0
1.5
2.0
2.5
3.0
17 19
15 16
14 13
14 12
14 11
14 10
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MIL No MIL
31 19
0.5
1.0
1.5
2.0
2.5
3.0
21 15
19 12
16 11
15 11
14 11
12 11
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Years
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Figure 3.
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