Left Atrial Phasic Function and Its Association With Atrial Fibrillation in Patients After Transcatheter Aortic Valve Implantation

Accepted Manuscript Left Atrial Phasic Function and its Association with Atrial Fibrillation in Patients after Transcatheter Aortic Valve Implantation Frédéric Poulin, MD, MSc, Paaladinesh Thavendiranathan, MD, MSc, Shemy Carasso, MD, Harry Rakowski, MD, Eric M. Horlick, MDCM, Mark D. Osten, MD, Robert J. Cusimano, MD, Anna Woo, MD, SM PII:

S0828-282X(17)30187-3

DOI:

10.1016/j.cjca.2017.04.005

Reference:

CJCA 2418

To appear in:

Canadian Journal of Cardiology

Received Date: 3 February 2017 Revised Date:

1 April 2017

Accepted Date: 16 April 2017

Please cite this article as: Poulin F, Thavendiranathan P, Carasso S, Rakowski H, Horlick EM, Osten MD, Cusimano RJ, Woo A, Left Atrial Phasic Function and its Association with Atrial Fibrillation in Patients after Transcatheter Aortic Valve Implantation, Canadian Journal of Cardiology (2017), doi: 10.1016/j.cjca.2017.04.005. 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 1 Left Atrial Phasic Function and its Association with Atrial Fibrillation in Patients after

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Transcatheter Aortic Valve Implantation

Frédéric Poulin, MD, MSca; Paaladinesh Thavendiranathan, MD, MSca; Shemy Carasso, MDa; Harry Rakowski, MDa; Eric M. Horlick, MDCMa; Mark D. Osten, MDa; Robert J. Cusimano,

Peter Munk Cardiac Center, Toronto General Hospital, University of Toronto, Toronto, Canada.

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a

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MDa; Anna Woo, MD, SMa

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Short title: Left Atrial Recovery after TAVI

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None

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Financial support

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Correspondence: Dr. Frédéric Poulin, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON, Canada, M5G 2C4; Tel.: 416-340-5270; Fax: 416-340-3959; e-mail: [email protected]

ACCEPTED MANUSCRIPT 2 Brief summary We aimed to assess the impact of TAVI on the recovery of LA phasic function (reservoir, conduit, contraction) and to assess the relationship between LA function and new-onset atrial

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fibrillation (NAF) after TAVI. Prior to TAVI (n=52), the 3 emptying fractions and all speckletracking echocardiography parameters of LA function were reduced. Intrinsic LA compliance and contractile properties improved at midterm follow-up. Pre-procedural LA early diastolic

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strain rate was associated with the development of NAF following TAVI.

ACCEPTED MANUSCRIPT 3 Abstract Background: Left atrial (LA) size is a marker of prognosis in severe aortic stenosis (AS). The aims of this retrospective study were to assess the impact of transcatheter aortic valve

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implantation (TAVI) on the recovery of LA phasic function and to assess the relationship between LA function and new-onset atrial fibrillation (NAF) after TAVI.

Methods: In this retrospective cohort study, LA function was measured using biplane volumes

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and 2D speckle tracking echocardiography (STE) in 52 patients (median age, 81 years) with severe AS prior to TAVI and at midterm follow-up. Twenty healthy subjects ≥75 years were

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used as controls.

Results: Prior to TAVI, the 3 phasic volumetric emptying fractions and all STE-derived parameters of LA function were significantly reduced. At 5 ± 3 months post TAVI, there was an improvement in LA reservoir and contractile function. However, LA phasic volumes and

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emptying fractions showed minimal changes. Fourteen patients had NAF in the early postprocedural period after TAVI. These patients experienced longer hospitalization (11 days vs 6 days; P=.002). By bivariable logistic regression analysis, the use of a transapical approach and

after TAVI.

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the LA early diastolic strain rate pre-TAVI were significantly associated with NAF immediately

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Conclusions: Severe AS is associated with LA dysfunction. Intrinsic LA compliance and LA contractile properties by STE improved at midterm follow-up after TAVI.

Pre-procedural LA

early diastolic strain rate may predict the development of NAF following TAVI pending confirmation by larger prospective evaluations.

ACCEPTED MANUSCRIPT 4 Introduction In patients with severe aortic stenosis (AS), left atrial (LA) enlargement and dysfunction are associated with the evolution of symptoms, the recurrence of heart failure after aortic valve

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replacement,(1) the development of early postoperative atrial fibrillation (AF)(2), and

mortality.(3) Transcatheter aortic valve implantation (TAVI) is now considered the treatment of choice for patients with severe AS at high risk for open-heart surgery.(4) However, post-

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procedural new-onset atrial fibrillation (NAF) occurs commonly (up to 32% of patients)(5) and increases the risk of thromboembolic complications (6) and the length of hospitalization.(5)

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Since there are no good predictors of the patients who are at increased risk for developing NAF, a better understanding of LA size and function in elderly patients with AS and the changes that occur following TAVI may provide methods to better identify and risk stratify patients with severe AS.

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Speckle-tracking echocardiography (STE) is a sensitive tool allowing quantification and detection of subtle alterations in the three LA phasic functions: reservoir, conduit and contractile.(7) Previous work in patients with AS using STE have demonstrated that all strain-

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derived parameters of LA function are reduced.(8) We therefore sought to determine the impact of TAVI on changes in LA size and phasic

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function by using comprehensive quantification of LA volumes and 2D speckle-tracking imaging, respectively, before and after TAVI in patients with severe AS. Our secondary objective was to assess the echocardiographic (echo) determinants of NAF and its influence on post-procedural length of stay and the recovery of LA function at midterm follow-up.

Methods

ACCEPTED MANUSCRIPT 5 Study design Study Population This retrospective study consisted of patients undergoing TAVI for symptomatic severe AS at a

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single center (Toronto General Hospital, University of Toronto). Patients were included if

transthoracic echocardiograms obtained before and at medium-term follow-up (between 2 to 12 months) were available for review. Exclusion criteria were: (1) the presence of AF during the

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echo study (since atrial mechanics cannot be adequately assessed) or (2) inadequate endocardial definition of the LA walls, resulting in poor speckle-tracking. The control group consisted of 20

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patients ≥ 75 years with no significant underlying heart disease (based on clinical and echo assessments). The study protocol was approved by the local institutional Ethics Committee.

Transcatheter Aortic Valve Implantation

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Eligibility criteria for the TAVI were the presence of symptomatic severe native or prosthetic valve stenosis with an aortic valve area ≤ 1.0 cm2 and/or mean systolic aortic gradient >40 mmHg. In the setting of LV systolic dysfunction and low-gradient AS, the severity of AS was

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confirmed by low-dose dobutamine echocardiography. All patients were considered to be at high risk for death with conventional surgical aortic valve replacement as determined by a

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multidisciplinary team.

Clinical data

Demographic characteristics, comorbidities, previous cardiac procedures, and functional status were prospectively collected. Post-procedural length of stay was defined as the number of days spent in the hospital from the date of the procedure. New-onset AF was defined as any episode

ACCEPTED MANUSCRIPT 6 of AF during the hospitalization following the TAVI that lasts longer than 30 seconds in a patient with no prior history of AF.(9)

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Echocardiography

Transthoracic echo and Doppler studies were performed before TAVI and at midterm follow-up in accordance with the American Society of Echocardiography and VARC-2 guidelines.(9, 10)

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Aortic valve area was calculated using the continuity equation. Peak and mean systolic

digitally stored for offline analyses.

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transaortic gradients were calculated using the simplified Bernoulli equation. All images were

Left atrial myocardial mechanics and volumetric phasic functions

Quantitative assessment of LA mechanics by STE was performed during sinus rhythm before

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and after TAVI using Vector Velocity Imaging version 3 (Siemens Medical Solutions USA, Mountain View, CA) by a single operator who was blinded to clinical data. Apical four- and two-chamber views were used to obtain longitudinal strain and strain rate (SR), averaging 6 LA

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segments. Peak negative strain and SR during late diastole (pump), total strain and peak positive SR during ventricular systole (reservoir), and peak positive strain and negative SR during early

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diastole (conduit) were derived from the time-strain and SR curves, taking the electrocardiographic P-wave as the reference point (Figure 1). The maximal, minimal and preatrial contraction LA volumes were measured (Simpson method of disks) and the three phasic emptying fractions quantified (Supplemental Table S1).

Intraobserver and interobserver variability

ACCEPTED MANUSCRIPT 7 Ten randomly selected studies were reanalyzed by the same observer several months after the initial analysis. A second experienced observer, blinded to previously obtained data, analyzed the

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same patients and the exact same loops for the assessment of interobserver variability.

Statistical Analyses

Categorical variables are expressed as frequencies and percentages. Continuous variables are

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summarized as mean ± standard deviation or median (interquartile range (IQR)), depending on the normality of distribution. Echo parameters before and after TAVI were compared using

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McNemar’s test for categorical variables and the paired t-test or Wilcoxon signed-rank test for continuous variables, as appropriate. Comparisons between the sinus rhythm and the NAF groups were analysed using Pearson’s chi-square tests for categorical variables and Student’s unpaired t-test or Wilcoxon signed-rank test for continuous data. Comparisons of the change in

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echo parameters after TAVI between patients in the two groups (sinus rhythm versus NAF) were performed using analysis of covariance. Univariable and multivariable logistic regression models were used to identify factors associated with post-TAVI NAF. The multivariable model

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was built by selecting the only variable that was significant on the univariable screen and including a second variable (the TAVI approach) that has been previously shown to be

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associated with the development of NAF.(5) Receiver operating characteristic (ROC) curve analysis was performed to assess the discriminatory power of the LA early diastolic SR for the occurrence of NAF. Intraobserver and interobserver variability was assessed by the intraclass correlation coefficient and the coefficient of variation. A level of significance of .05 was set for all analyses. All statistical analyses were conducted using SPSS, version 20 (SPSS Inc., Chicago IL).

ACCEPTED MANUSCRIPT 8 Results Study Population

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Among the 124 patients who underwent TAVI for severe AS from 2007 to 2012, and who had available pre-procedural and midterm follow-up transthoracic echocardiograms, 52 were eligible for this study. The excluded individuals consisted of 23 patients due to the presence of AF at the time of the echo study (before TAVI in 21 patients and at mid-term follow-up in 2 patients) and

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49 patients because of poor endocardial tracking (caused mainly by insufficient endocardial

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definition). Ten patients were excluded for the second purpose of predicting NAF since they were known with pre-existent AF. The median age was 81 years (interquartile range, 77-86) and 54% were men. (Table 1) The median logistic European System for Cardiac Operative Risk Evaluation score was 14.4% [10.0-22.6]. The control group consisted of 20 elderly subjects (median age 79 years, interquartile range, 78-81; 45% male, hypertension in 70%) with no echo

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evidence of significant ventricular dysfunction or hemodynamically significant valvular lesions. There was no statistically significant difference between the 52 study patients and the 72 excluded patients with regards to age, gender, history of pre-TAVI AF, LA size, LVEF, and the

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severity of AS (Supplementary Table S2). Excluded patients had higher logistic EuroSCORE.

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Transcatheter Aortic Valve Implantation Transapical and transfemoral approaches were employed in 32 (62%) and 18 (35%) cases, respectively. The direct transaortic approach was required in two patients. Edwards SAPIEN valves were implanted in 43 patients (83%) and Medtronic Corevalve in 9 patients (17%).

Pre- and post-TAVI valvular and ventricular parameters

ACCEPTED MANUSCRIPT 9 Follow-up transthoracic echocardiograms performed 5 ± 3 months post-TAVI after the procedure with no significant difference between the sinus rhythm and NAF groups (5.8±3.9 vs 5.5±3.0 months, P=0.80). An increase in the aortic valve area (from 0.7 ± 0.2 to 1.6 ± 0.3 cm2

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[P<.001]), accompanied by a significant decrease in the mean trans-aortic pressure gradient (from 50 ± 17 to 11 ± 4 mmHg [P<.001]) were demonstrated (Table 2). In parallel, a significant regression in LV mass (from 132 ± 41 to 118 ± 32 g/m2, P=.003) was observed. Before TAVI,

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the mean LVEF was 58 ± 11% and 4 patients had LVEF ≤35%. There was only a small

proportion of the cohort (12%) that had at least moderate mitral regurgitation. After TAVI, there

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was no significant change in LV volumes, LVEF, E/E’ ratio, and proportion of patients with significant mitral regurgitation (Table 2). No or trivial, mild, moderate, and severe post-TAVI AR were found in 20 (39%), 22 (42%), 8 (15%), and 2 patients (4%), respectively.

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Left atrial volume and function

In the cohort, severe AS was associated with severe dilatation of the LA cavity (maximal LA volume 51 ± 18 mL/m2). Compared to the age-balanced control group, patients had significantly

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larger LA minimal volume (25 ± 12 vs 16 ± 8 mL/m2; P=.003), pre-A volume (37 ± 14 vs 28 ± 10 mL/m2; P=.01) and a trend towards larger maximal LA volume (51 ± 18 vs 43 ± 13 mL/m2;

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P=.07) (Table 3). All 3 phasic volumetric emptying fractions (total, passive, and active emptying fractions) and all STE-derived parameters of LA function were significantly reduced in patients with severe AS when compared with the control subjects (Table 3).

At midterm follow-up, LA phasic volumes and emptying fractions showed no significant changes (Table 3). However, the analysis of LA myocardial mechanics by STE revealed an improvement in LA reservoir function (positive SR from 0.89 ± 0.31 to 1.12 ± 0.41 s-1; P=.001)

ACCEPTED MANUSCRIPT 10 and a trend towards an improvement in LA contractile function (negative strain from -9.9 ± 4.5 to -11.7 ± 5.5%; P=.05) (Table 3).

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New-Onset atrial fibrillation after TAVI

Among the forty-two patients without a previous history of AF, 14 (33%) developed NAF after TAVI. These episodes of NAF were successfully treated with amiodarone in 7 patients,

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electrical cardioversion in 2 patients, and they terminated spontaneously in 5 patients. The

occurrence of NAF in the early post-procedural period was associated with a significantly longer

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post-procedural hospital length of stay (11 days (IQR 8-16 days) vs 6 days (IQR 5-10 days); post-TAVI NAF vs post-TAVI sinus rhythm, P=.002).

Age, gender, EuroSCORE, baseline aortic valve area, mean transaortic gradient and grade of

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mitral regurgitation were not associated with the occurrence of NAF (Table 4). Patients with NAF were more likely to have a history of hypertension (100% in NAF vs 64% in sinus rhythm; P=.009). NAF occurred in 17% of patients treated by the transfemoral and 40% of patients

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treated by the transapical or direct transaortic approaches (P=.15). The proportion of moderate or severe post-TAVI AR was not significantly more common in patients who developed NAF

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(36%) versus those who maintained sinus rhythm (17%) (P=.12).

As shown in Table 5, pre-TAVI LA volumes and emptying fractions were not significantly different in the sinus rhythm vs the patients with NAF. However, in comparing LA strain values prior to TAVI, patients with NAF had significantly lower absolute pre-TAVI LA early diastolic SR (-0.39 ± 0.21 vs. -0.56 ± 0.21 s-1; NAF vs sinus rhythm, respectively, P=.01), suggesting better pre-procedural LA conduit function (in the early diastolic phase) in patients who remained

ACCEPTED MANUSCRIPT 11 in sinus rhythm (versus those who developed NAF) following TAVI. In addition, there was a trend towards lower total strain and positive strain in patients with NAF by STE. The only significant factor associated with NAF by univariable logistic regression was LA early diastolic

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negative SR. (Supplementary Table S3) By bivariable logistic regression analysis including LA early diastolic SR and the type of TAVI approach (transfemoral vs. non-transfemoral), both variables remain associated with NAF (LA early diastolic SR (Odds Ratio (OR) 1.8 per absolute

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0.10 s-1 reduction; P= .008 and transapical or direct transaortic approach (OR 8.2; P=.03)). The optimal cutoff point for LA early diastolic SR was -0.44 s-1 with 64% sensitivity and 68%

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specificity (area under the curve, 0.72; confidence interval 0.55-0.88; P=.02) (Figure 2). In the presence of a history of hypertension, a non-transfemoral approach, and an absolute baseline LA early diastolic SR lower than -0.44s-1, the risk of developing NAF is estimated at 78%.

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At midterm echo follow-up, all 14 patients who experienced an episode of early NAF remained in sinus rhythm. Patients with early postoperative NAF had significantly larger post-TAVI minimal LA volume (29 ± 14 vs 21 ± 8mL/m2), worse LA total emptying fraction (45 ± 15 vs 55

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± 11%), and worse active emptying fraction (28 ± 15 vs 37 ± 12%) when compared to the patients who remained in sinus rhythm after TAVI. Furthermore, patients in the NAF group had

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worse post-TAVI peak negative strain and late diastolic SR (reflecting contractile and conduit function respectively) compared to those who were in sinus rhythm following TAVI, after adjusting for pre-TAVI values (Table 5).

Intraobserver and interobserver variability Analysis of intra- and interobserver variability demonstrated very good agreement between observations (Supplementary Table S4).

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Discussion Our results demonstrate that patients with severe AS referred for TAVI have severe LA

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dilatation and dysfunction. Left atrial reservoir and contractile function assessed by STE improved at midterm follow-up after TAVI. However, LA size and function based on

volumetric measurements remained largely unchanged. Left atrial early diastolic SR was

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associated with early post TAVI NAF. New-onset AF was associated with a significantly

increased length of hospitalization, nearly doubling in the subgroup that developed new post-

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TAVI NAF. At mid-term follow-up, by both volumetric and STE methods performed in sinus rhythm, LA contractile function following TAVI was significantly better in the patients who remained in sinus rhythm when compared with the patients who developed early transient post-

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procedural NAF.

Left atrial myocardial mechanics in AS and post-TAVI In response to a chronically elevated afterload, the LA enlarges progressively, which contributes

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to maintain the stroke volume of the LA through the recruitment of Starling forces.(8) Progressive AS eventually leads to LA failure with decrease in all three strain-derived phasic

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functions (8), which was also shown here. In other mid-term post-TAVI studies assessing LA remodeling, reservoir (11-13) and conduit (13) functions improved while contractile function either improved (12) or remained unchanged (13). In our cohort, STE demonstrated some amelioration in both LA compliance and contractility, which might contribute to restoring stroke volume and functional capacity after the TAVI. The fact that changes in LA function were best appreciated by measures of LA deformation (i.e. STE) rather than volumetric methods, also documented by Spethmann et al. (13), demonstrates the better sensitivity of STE-based methods.

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Importantly, we observed enhanced LA function despite the absence of meaningful changes in parameters of diastolic function or surrogates of LV filling pressures (E/E’ ratio). The LA does

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not only respond to elevated filling pressure and high afterload. Indeed, longstanding pressure overload induces changes in LA myocardial architecture (interstitial fibrosis).(8) Left atrial longitudinal strain impairment was recently shown to correlate closely with the extent of biopsy-

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proven LA fibrosis.(14) We hypothesize that the improvement in strain measures in our patients following TAVI may imply attenuated progression of fibrosis or the consequence of better

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ventricular hemodynamics. In addition, the effect of residual insults on the LA (such as systemic hypertension, concomitant mitral valve disease, and diastolic dysfunction) and the relatively short follow-up may explain the modest and incomplete recovery in LA function.

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New-onset atrial fibrillation

NAF after TAVI is a common complication and is associated with higher rates of cerebrovascular events.(5) The high incidence rate of NAF in our study (33%) and the

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associated prolonged hospital stay corroborate previous findings.(5) However, these rates are higher than the incidence rate of 10-15% also reported previously and may reflect the higher

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utilization of transapical approach in our local practice.(6) Camelli et al. found that LA strain (reservoir) was the strongest predictor of NAF after surgical AVR.(2) There are limited data on the specific risk factors predisposing to NAF in TAVI.(5) LA size was not independently associated with the development of NAF in our study. Instead, we found that LA early diastolic SR, a marker of conduit function, was associated with NAF. This is an important finding as previous studies on TAVI patients had not assessed the impact of LA function on clinical events. The LA conduit phase is modulated by LA compliance, LV relaxation, and early diastolic

ACCEPTED MANUSCRIPT 14 pressures. Therefore, the association of LA early diastolic SR with NAF is not unexpected. The use of a non-transfemoral approach was also independently associated with NAF. Although this parameter was not significant on our univariable screen, it was found to be significant when

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adjusted for LA early diastolic negative SR. This is consistent with prior findings of association between the TAVI approach and development of NAF. (5) Whether such a prediction model for NAF will lead to strategies to pretreat high risk patients for development of NAF with

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antiarrhythmic drugs will need to be determined prospectively.

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The occurrence of NAF early post-TAVI was associated with worse LA remodeling at midterm follow-up, affecting the more intrinsic functions, the reservoir and the pump. We hypothesize that the NAF subgroup reflects patients with a more diseased LA, with a decreased ability to normalize LA functional parameters. Although these patients were in sinus rhythm at the time of

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the midterm echo study, we cannot exclude that patients with early post-TAVI NAF may have experienced ongoing clinically silent episodes of paroxysmal atrial fibrillation, which may have

Limitations

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caused ongoing mechanical stunning and adverse LA remodeling.

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We excluded a significant proportion of patients due to inherent technical limitations associated with retrospective LA deformation analysis and due to the need to analyze echocardiographic parameters with patients in sinus rhythm. Selection bias is unlikely, however, because the excluded patients did not differ from the study population. Second, our midterm follow-up may have been insufficient to demonstrate the complete extent of LA remodeling (especially the LA volumes) in an elderly cohort of mainly octogenarians. Third, since the study patients consisted of elderly individuals, and since the majority of these patients had their primary Cardiology

ACCEPTED MANUSCRIPT 15 follow-up at other centers, we were unable to systematically perform serial Holter monitors to assess for the presence of paroxysmal episodes of atrial fibrillation during the follow-up period. Finally, the number of events in our study was small and these findings are hypothesis-

prospective cohort is needed.

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Conclusions

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generating. Independent validation of the diagnostic value of LA early diastolic SR in a larger

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In patients with severe AS, sensitive markers of intrinsic LA dysfunction measured by STE improved at midterm follow-up after TAVI. However, LA functional recovery was limited in the presence of post-procedural NAF. Patients with post procedure NAF had a significantly longer length of stay when compared to those without NAF. Pre-procedural LA early diastolic

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evaluations.

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strain rate may predict NAF following TAVI pending confirmation by larger prospective

ACCEPTED MANUSCRIPT 16 Acknowledgements

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None.

Funding None.

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Disclosures

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Dr Horlick serves as a consultant for Edwards LifeSciences and Medtronic.

ACCEPTED MANUSCRIPT 17 REFERENCES

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1. Dahl JS, Videbaek L, Poulsen MK, Pellikka PA, Veien K, Andersen LI, et al. Noninvasive assessment of filling pressure and left atrial pressure overload in severe aortic valve stenosis: relation to ventricular remodeling and clinical outcome after aortic valve replacement. J Thorac Cardiovasc Surg. 2011;142(3):e77-83. 2. Cameli M, Lisi M, Reccia R, Bennati E, Malandrino A, Solari M, et al. Pre-operative left atrial strain predicts post-operative atrial fibrillation in patients undergoing aortic valve replacement for aortic stenosis. Int J Cardiovasc Imaging. 2014;30(2):279-86. 3. Beach JM, Mihaljevic T, Rajeswaran J, Marwick T, Edwards ST, Nowicki ER, et al. Ventricular hypertrophy and left atrial dilatation persist and are associated with reduced survival after valve replacement for aortic stenosis. J Thorac Cardiovasc Surg. 2014;147(1):362-9 e8. 4. Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, et al. Twoyear outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med. 2012;366(18):1686-95. 5. Amat-Santos IJ, Rodes-Cabau J, Urena M, DeLarochelliere R, Doyle D, Bagur R, et al. Incidence, predictive factors, and prognostic value of new-onset atrial fibrillation following transcatheter aortic valve implantation. J Am Coll Cardiol. 2012;59(2):178-88. 6. Mok M, Urena M, Nombela-Franco L, Ribeiro HB, Allende R, Delarochelliere R, et al. Clinical and prognostic implications of existing and new-onset atrial fibrillation in patients undergoing transcatheter aortic valve implantation. J Thromb Thrombolysis. 2013;35(4):450-5. 7. Mor-Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. Eur J Echocardiogr. 2011;12(3):167-205. 8. O'Connor K, Magne J, Rosca M, Pierard LA, Lancellotti P. Left atrial function and remodelling in aortic stenosis. Eur J Echocardiogr. 2011;12(4):299-305. 9. Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Thorac Cardiovasc Surg. 2013;145(1):6-23. 10. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16(3):233-70. 11. D'Andrea A, Padalino R, Cocchia R, Di Palma E, Riegler L, Scarafile R, et al. Effects of transcatheter aortic valve implantation on left ventricular and left atrial morphology and function. Echocardiography. 2015;32(6):928-36. 12. D'Ascenzi F, Cameli M, Henein M, Iadanza A, Reccia R, Lisi M, et al. Left atrial remodelling in patients undergoing transcatheter aortic valve implantation: a speckle-tracking prospective, longitudinal study. Int J Cardiovasc Imaging. 2013;29(8):1717-24. 13. Spethmann S, Baldenhofer G, Dreger H, Stuer K, Sanad W, Saghabalyan D, et al. Recovery of left ventricular and left atrial mechanics in various entities of aortic stenosis 12 months after TAVI. Eur Heart J Cardiovasc Imaging. 2014;15(4):389-98. 14. Cameli M, Lisi M, Righini FM, Massoni A, Natali BM, Focardi M, et al. Usefulness of atrial deformation analysis to predict left atrial fibrosis and endocardial thickness in patients

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undergoing mitral valve operations for severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol. 2013;111(4):595-601.

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Table 1 Baseline Characteristics All Patients Clinical characteristic

Age (y)

81 [77-86]

Male

28 (54) 2

22 ± 6

NYHA class III or IV

43 (83)

History of atrial fibrillation

10 (19)

History of smoking

23 (44)

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Hypertension

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BMI (kg/m )

39 (75)

Dyslipidemia

37 (71)

Diabetes mellitus

12 (23)

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Previous myocardial infarction

10 (19) 6 (12)

Cerebral vascular disease

5 (10)

Previous PCI

16 (31)

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Peripheral vascular disease

Previous CABG

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Previous aortic valve replacement

16 (31) 3 (6)

Chronic lung disease

5 (10)

Renal insufficiency (GFR≤50mL/min)

19 (37)

Logistic EuroSCORE (%)

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(n=52)

14.4 [10.0-22.6]

BMI, Body-mass index; NYHA, New York Heart Association; PCI, percutaneous coronary artery intervention; CABG, coronary artery bypass graft surgery; GFR, glomerular filtration rate. Data are expressed as median (range), number (percentage), or mean ± SD.

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Baseline

Follow-up

Echocardiographic parameter

(n=52)

(n=52)

2

0.70 ± 0.18

1.60 ± 0.30

50 ± 17

11 ± 4

Aortic valve area (cm )

2

58 ± 25

LV systolic volume/BSA (mL/m )

26 ± 16

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Aortic mean gradient (mmHg)

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Table 2 Echocardiographic parameters before and after TAVI

Left ventricular mass index (g/m ) Stroke volume (mL/beat)

2

2

LVEF (%)

Mitral A velocity (m/s) E/A ratio

Lateral E’ (cm/s) E/E’ ratio

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Deceleration time (ms)

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Mitral regurgitation (moderate or greater) RVSP (mm Hg)

<.001 .53

26 ± 16

.77

132 ± 41

118 ± 32

.003

57 ± 23

60 ± 17

.25

58 ± 11

60 ± 12

.20

0.86 ± 0.27

0.95 ± 0.29

.03

0.95 ± 0.28

0.99 ± 0.28

.31

1.1 ± 0.7

1.1 ± 0.7

.84

272 ± 61

247 ± 50

.04

7.8 ± 3.1

8.6 ± 3.0

.27

11.8 ± 5.4

11.9 ± 5.8

.92

6 (12)

3 (6)

.25

41 ± 11

42 ± 12

.74

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Mitral E velocity (m/s)

<.001

60 ± 20

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LV diastolic volume/BSA (mL/m )

P-value

LV, Left ventricular; BSA, body surface area; LVEF, left ventricular ejection fraction; RVSP, right ventricular systolic pressure.

Data are expressed as mean ± SD.

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Table 3 Left atrial volumes and phasic function before and after TAVI

Pre-TAVI

(n=20)

(n=52)

43 ± 13 16 ± 8 28 ± 10

51 ± 18 25 ± 12* 37 ± 14*

64 ± 11

52 ± 13*

VOLUMETRIC METHOD

P-value†

50 ± 16 24 ± 12 36 ± 15

.51 .49 .70

53 ± 13

.57

34 ± 10

28 ± 11*

29 ± 11

.75

46 ± 11

33 ± 15*

35 ± 15

.53

33.5 ± 11.8 1.42 ± 0.44

21.0 ± 7.4* 0.89 ± 0.31*

22.5 ± 7.6 1.12 ± 0.41

.28 .001

18.6 ± 7.7 -1.00 ± 0.44

11.1 ± 7.0* -0.51 ± 0.22*

10.8 ± 4.7 -0.55 ± 0.23

.61 .32

-15.0 ± 5.5 -1.51 ± 0.61

-9.9 ± 4.5* -0.93 ± 0.47*

-11.7 ± 5.5 -1.04± 0.58

.05 .27

EP

TE D

LA reservoir function Strain total (%) -1 SR positive (s ) LA conduit function Strain positive (%) -1 SR early diastolic negative (s ) LA contractile function Strain negative (%) -1 SR late diastolic negative (s )

M AN U

SPECKLE-TRACKING ECHO METHOD

(n=52)

SC

2

LA volumes/BSA (mL/m ) V max V min V preA LA reservoir function Total emptying fraction (%) LA conduit function Passive emptying fraction (%) LA contractile function Active emptying fraction (%)

Post-TAVI

RI PT

Controls

*p < 0.05 : AS patients pre-TAVI versus controls.

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† Pre versus post TAVI.

BSA, Body-surface area; V max, maximal LA volume; V min, minimal LA volume; V preA, LA volume before the electrocardiographic P-wave; SR, strain rate Data are expressed as mean ± SD.

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Table 4 Comparison of baseline characteristics according to the occurrence of postprocedural new AF New AF

(n=28)

(n=14)

P-value

83 [77-87]

.30

16 (57) 23 ± 7

7 (50) 19 ± 3

.66 .06

NYHA class III or IV

24 (86)

11 (79)

.56

History of AF Hypertension

0 (0) 18 (64)

0 (0) 14 (100)

.009

Previous myocardial infarction

4 (14)

3 (21)

.43

Previous PCI Previous CABG

8 (29) 12 (43)

7 (50) 2 (14)

.17 .06

Mitral regurgitation (moderate or greater) Chronic lung disease Logistic EuroSCORE (%) 2

Aortic valve area (cm ) Aortic mean gradient (mmHg) 2

LV diastolic volume/BSA (mL/m ) 2

3 (12)

1 (7)

.56

2 (7)

2 (14)

.41

14.0 [10.4-25.2]

14.6 [5.9-19.2]

.47

0.71 ± 0.21

0.70 ± 0.10

.82

51 ± 17

47 ± 19

.47

62 ± 19

49 ± 20

.05

21 ± 15

.14

Left ventricular mass index (g/m2)

138 ± 44

116 ± 33

.10

LVEF (%)

55 ± 13

58 ± 9

.43

Mitral E velocity (m/s) Mitral A velocity (m/s)

0.88 ± 30

0.85 ± 0.23

.83

0.89 ± 0.24

1.05 ± 0.37

.13

1.1 ± 0.7

1.0 ± 0.7

.56

Deceleration time (ms) Lateral E’ (cm/s)

273 ± 64 7.8 ± 3.1

267 ± 59 8.4 ± 2.5

.80 .62

E/E’ ratio

12.6 ± 5.1

10.5 ± 3.4

.25

39 ± 13

43 ± 8

.31

AC C

RVSP (mm Hg)

EP

E/A ratio

29 ± 14

TE D

LV systolic volume/BSA (mL/m )

SC

80 [76-84]

Male 2 BMI (kg/m )

M AN U

Age (y)

Sinus rhythm

RI PT

Baseline Characteristics

AF, Atrial fibrillation BMI, body-mass index; NYHA, New York Heart Association; PCI, percutaneous coronary artery intervention; CABG, coronary artery bypass graft surgery, LV, Left ventricular, LVEF, left ventricular ejection fraction, RVSP, right ventricular systolic pressure. Data are expressed as median (range), number (percentage), or mean ± SD.

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23

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24 Table 5 LA remodeling after TAVI according to the occurrence of post-procedural NAF New AF (n=14)

Pre-TAVI

Post-TAVI

P-value*

Pre-TAVI

47 ± 12 23 ± 9 34 ± 10

47 ± 13 21 ± 8 34 ± 11

.99 .43 .98

52 ± 20 27 ± 16 38 ± 17

52 ± 13

55 ± 11

28 ± 13

29 ± 11

33 ± 13

37 ± 12

22.4 ± 8.7 0.93 ± 0.36

22.5 ± 7.2 1.13 ± 0.38

VOLUMETRIC METHOD

EP

12.2 ± 8.4 -0.56 ± 0.21

9.9 ± 4.3 -0.56 ± 0.27

AC C

LA reservoir function Strain total (%) -1 SR positive (s ) LA conduit function Strain positive (%) -1 SR early diastolic negative (s ) LA contractile function Strain negative (%) -1 SR late diastolic negative (s )

-10.2 ± 4.8 -0.97 ± 0.51

-12.6 ± 4.8 -1.10± 0.51

P-value*

P-value§

51 ± 15 29 ± 14 39 ± 15

.83 .55 .75

.62 .05 .31

M AN U .26

52 ± 14

45 ± 15

.06

.01

.82

29 ± 10

25 ± 8

.20

.27

.21

33 ± 15

28 ± 15

.20

.03

.95 .008

18.1 ± 4.8 0.80 ± 0.18

19.9 ± 5.9 0.94 ± 0.34

.19 .09

.45 .31

.17 .98

7.9 ± 4.1 -0.39 ± 0.21†

11.4 ± 4.6 -0.52 ± 0.17

.008 .02

.15 .67

.06 .15

-10.1 ± 3.6 -0.93 ± 0.35

-8.5 ± 4.5 -0.78 ± 0.39

.18 .24

.01 .03

TE D

SPECKLE-TRACKING ECHO METHOD

Post-TAVI

SC

2

LA volumes/BSA (mL/m ) V max V min V preA LA reservoir function Total emptying fraction (%) LA conduit function Passive emptying fraction (%) LA contractile function Active emptying fraction (%)

RI PT

Sinus rhythm (n=28)

* Pre versus post TAVI † Comparison of baseline values in no NAF vs. NAF groups; p<0.05 § Comparisons of the change in echo parameters after TAVI between patients with no NAF vs NAF were performed using Analysis of Covariance (ANCOVA) with the absolute difference from baseline as the outcome and preprocedural values as the covariate. BSA, Body surface area; NAF, new-onset atrial fibrillation; V max, maximal LA volume; V min, minimal LA volume; V preA, LA volume before the electrocardiographic P-wave; SR, strain rate.

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25

AC C

EP

TE D

M AN U

SC

RI PT

Data are expressed as mean ± SD.

ACCEPTED MANUSCRIPT 26 Figure legends Figure 1 Left atrial (LA) strain (Panel A) and strain rate (Panel B) average curves illustrating phasic function in a patient with severe AS. Peak negative strain (Ԑ) and peak negative strain rate

RI PT

during late diastole reflect LA contractile function, total strain and peak positive strain rate during ventricular systole reflect the LA reservoir function, and peak positive strain and peak negative

are gated on the electrocardiographic P-wave.

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(Ԑ), Peak negative strain.

SC

strain rate during early diastole reflect the LA conduit function. Time-strain and strain rate curves

Figure 2 Receiver operating characteristic (ROC) analysis displaying the association between LA early diastolic strain rate and new-onset atrial fibrillation following transcatheter aortic valve

AC C

EP

TE D

implantation.

AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

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SC

RI PT

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