Does Percutaneous Left Atrial Appendage Closure Affect Left Atrial Performance ?

Mailing Address:: Marta Madeira Serviço de Cardiologia, Centro Hospitalar e Universitário de Coimbra Quinta dos Vales, S. Martinho do Bispo. Postal Code: 3045-043, Coimbra Portugal E-mail: marta.jesus.madeira@gmail.com Does Percutaneous Left Atrial Appendage Closure Affect Left Atrial Performance? Marta Madeira,*1,2 Rogério Teixeira,*1,2 Liliana Reis,1 Paulo Dinis,1 Luís Paiva,1,2 Ana Botelho,1 Marco Costa,1 Lino Gonçalves1,2 Serviço de Cardiologia, Centro Hospitalar e Universitário de Coimbra Hospital Geral,1 Coimbra Portugal Faculdade de Medicina da Universidade de Coimbra,2 Coimbra Portugal * Both authors contributed equally to the paper


Introduction
Atrial fibrillation is the most common sustained cardiac arrhythmia, 1 with a current estimated prevalence of 1.5% to 2%. 2 It is considered a major cause of systemic embolism, increasing the risk for ischemic stroke by 5 times. 2,3Oral anticoagulation has been shown to effectively reduce the risk for stroke in patients with atrial fibrillation and is one of the cornerstones of management. 2 However, a significant proportion (30% -50%) of eligible patients do not receive oral anticoagulation due to the presence of absolute contraindications or a perceived high risk of bleeding. 3Several studies have shown that, in patients with nonvalvular atrial fibrillation, 90% of thrombus formation occurs in the left atrial appendage (LAA). 4,5herefore, devices for LAA closure have been developed as an alternative to oral anticoagulation in patients at high risk for stroke with contraindications to anticoagulation therapy. 6Recently, the non-inferiority of LAA exclusion over warfarin for stroke prevention was demonstrated in patients with nonvalvular atrial fibrillation. 7 was previously believed that the LAA was a vestigial structure with no meaningful function.LAA is now thought to play an important role in normal cardiac hemodynamics. 8The appendage is more compliant than the left atrium, acting as a reservoir to attenuate the rise in intra-atrial pressure in response to various hemodynamic factors. 9Surgical clamping or removal of the LAA has been shown to cause an immediate increase in left atrial pressure, left atrial size, and pulmonary-and mitral-inflow velocities. 10However, both the relative contribution of appendage distensibility to the passive elastic-chamber properties of the left atrium and the physiological and hemodynamic importance of the LAA are currently uncertain.Furthermore, the influence of the LAA occlusion device on left atrial performance has not yet been defined.Two-dimensional speckle-tracking echocardiography (2D-STE) is a recently developed, angle-independent, semiautomated technique used to evaluate the myocardium. 11It uses standard B-mode images to track blocks of speckles from frame to frame, and measures myocardial lengthening and shortening relative to the baseline -the Lagrangian method.2D-STE provides local myocardial information from which displacement, velocity, strain, and strain rate can be derived, allowing an accurate assessment of longitudinal, radial, and circumferential myocardial mechanics. 11In recent years, left atrial mechanics have been used as a surrogate for left atrial performance, which is influenced by the left atrial wall properties, left atrial volume, and left atrial pressure, and also by the left ventricular longitudinal systolic function. 12Measurements of left atrial strain (ƐR) and strain rate (SR R ) during the reservoir phase can be used to describe atrial function physiology and are sensitive to detect early functional remodeling before anatomical changes occur. 12,13 hypothesized that left atrial function, assessed by echocardiographic parameters and 2D-STE, would decrease after percutaneous LAA closure.Therefore, our aim was to evaluate the influence of the LAA closure device on left atrial physiology.

Patients
Twenty-five patients with non-valvular atrial fibrillation and a high risk for stroke with a CHA 2 DS 2 -VASc Score of ≥ 1 admitted to our centre for percutaneous LAA closure between August of 2010 and August of 2015 were enrolled in this retrospective study.Nine patients were excluded due to lack of adequate echocardiographic evaluation before or after the procedure or poor echocardiographic window for the evaluation of left atrial mechanics.
Referral indications for percutaneous LAA closure were contra-indication for long-term oral anticoagulation, bleeding events during oral anticoagulation, labile international normalized ratio (INR) or embolic events despite proper anticoagulation.
Clinical data included past medical history, current medication, the CHA 2 DS 2 -VASc and HAS-BLED scores, and diagnostic evaluation by routine laboratory testing, electrocardiography, and echocardiography.
Sixteen patients with good echocardiographic window for assessment of the left atrial mechanics were included in our study.
The study was approved by the ethics committee of our institution.

Echocardiographic evaluation
Echocardiography was performed on the day before and 3 months after percutaneous closure of the LAA.Echocardiographic examinations were performed using an ultrasound system (Vivid 7, General Electric ® , Horten, Norway) and tissue harmonic imaging at 1.7/3.4MHz.A complete echocardiographic study was performed using standard views according to current guidelines. 14Three consecutive heart cycles were acquired for quantification of the left atrial size and 2D-STE analysis for sinus rhythm patients, and five consecutive heart cycles were obtained for atrial fibrillation patients.
Left atrial volume was assessed by the biplane method of disks from the apical 4-and 2-chamber views and the measurements were indexed to the body surface area according to established recommendations. 15Minimum left atrial volume was measured at left ventricular enddiastolic volume, and maximum left atrial volume at end-systole.Left atrial emptying fraction was calculated as (maximum left atrial volume -maximum left atrial volume)/ maximum left atrial volume. 15e 2D-STE method was used to calculate regional and global longitudinal ƐR and SR R (Figure 1).A minimum frame rate of 60 frames/sec was required for a reliable operation of the program.The recordings were processed using an acoustic-tracking dedicated software (EchoPAQ 9.0, GE Healthcare ® , Horten, Norway), which allowed for an off-line semi-automated analysis of speckle-based strain.Left atrial endocardial surface was manually traced in end-systole in both four-and two-chamber views by a point-and-click approach.An epicardial surface tracing was then automatically generated by the system, generating the region of interest (ROI).For definition of the ROI at the discontinuity of the left atrial wall (corresponding to pulmonary veins and left atrial appendage), the limit of left atrial endocardial and epicardial surfaces at the junction of these structures was extrapolated.After manual adjustment of ROI width and shape to ensure optimal tracking, the software divided the ROI into six segments (basal, middle and apical segments of the atrial septum and lateral wall), and the tracking quality of each segment was automatically scored as either acceptable or non-acceptable, with possible further manual correction.Segments from which good quality images could not be obtained were rejected by the software and excluded from the analysis.In subjects with good quality images, a total of twelve segments were analyzed.The software displayed peak longitudinal ƐR and strain rate for each of the twelve segments and the average global strain.Peak ƐR were expressed in percentages and SR R in s -1 .Since left atrial wall strain is reliably imaged and is not constrained by other cardiac chambers, recent consensus of imaging for evaluation of atrial fibrillation patients recommend the evaluation of this parameter rather than global ƐR. 16herefore, we also performed a comparison between left atrial lateral wall strain and SR R at baseline and after device implantation.Since we included patients with atrial fibrillation and sinus rhythm, we used the first left ventricular systolic frame as the frame of interest -QRS timed analysis.

LAA closure procedure
LAA closure device was implanted in the catheterization laboratory.The device used was an Amplatzer ® (St.Jude Medical, St. Paul, Minnesota, USA) and was delivered

Statistical analysis
The Kolmogorov-Smirnov test was used to evaluate the distribution of the continuous variables.In the overall sample, all variables were normally distributed, except for ƐR and follow-up time; and when patients were separated by group (no change and decrease of ƐR and SR R ), the variables were not normally distributed.According to distribution normality, continuous data were presented as mean and standard deviation or as median and interquartile range.Quantitative variables with normal distribution were compared by the t-test and quantitative variables without normal distribution by the Mann-Whitney test.Qualitative variables were compared using the chi-square test.Differences between baseline and post-implantation of the LAA occlusion device were analysed by the paired sample t-test.
Statistical analysis was carried out with SPSS ® 15 and GraphPad Prism ® 6.05.A two-tailed p value < 0.05 was considered statistically significant.

Population characteristics
Mean age of our sample was 71 ± 9 years, with male predominance (63%).Seventy-five percent of patients had permanent atrial fibrillation.There was no history of percutaneous atrial fibrillation ablation attempt or surgical Maze procedure.Our population had a high embolic and bleeding risk, expressed by a median CHA 2 DS 2 -VASc score of 5 [4-5] and HAS-BLED score of 3 [2-3].
Major bleeding (62%) was the most common indication for the procedure, followed by labile INR (19%), embolic events despite anticoagulation (13%), and poor compliance with anticoagulation medication (6%).Percutaneous LAA closure was performed successfully in all patients using the cardiac plug device (size, 24 ± 2 mm), without any major complications during or after the procedure.
Characteristics of the study population are summarized in Table 1.

LA volume and emptying fraction
Maximum and minimum values of left atrial volume and the left atrial emptying fraction before and after the procedure are represented in Fig. 2 and Fig. 3, respectively.No differences were found in maximum left atrial volume (44 ± 11 vs. 46 ± 13 mL/m 2 ; p = 0.54), minimum left atrial volume (32 ± 8 vs. 37 ± 14 mL/m 2 ; p = 0.09), or the left atrial emptying fraction (26 ± 17%  Left atrium reservoir ƐR and SR R Global and regional peak ƐR and SR R of the 12 segments before and months after percutaneous closure of the LAA are listed in Table 2. Similar values of ƐR (10.1 [8.1-14.7] vs. 12.7 [5.4-16.5]%;p = 0.81) and SR R (1.06 ± 0.26 vs. 1.13 ± 0.34 s -1 ; p = 0.38) were observed before and after the procedure (Figure 4).
In 44% of patients, there was a decrease in ƐR.There were no differences regarding patient age, baseline left atrial volume, left atrial emptying fraction, ƐR, SR R , CHA 2 DS 2 -VASc or HAS-BLED scores, cardiac-plug device size, or incidence of cardiovascular adverse events during follow-up between patients with decreased and unaltered postoperative ƐR values (Table 3).

Discussion
Our investigation demonstrates that changes in left atrial fraction volume are minimal after LAA percutaneous closure, and mechanics of the left atrial reservoir phase assessed by 2D-STE are not significantly different before and after the procedure.
Structural and functional remodelling of the left atrium has been proposed as a surrogate for diastolic dysfunction and a predictor of cardiovascular outcomes such as new-onset atrial fibrillation, stroke, heart failure, mortality after myocardial infarction, severity of diastolic dysfunction, and cardiovascular death. 122D-STE is a novel method for quantitative real-time assessment of regional myocardial deformation.The technology tracks acoustic speckles or kernels rather than using Doppler myocardial velocities. 17Considering the limitations of the classical indices of left atrial function, assessment of ƐR by 2D-STE may represent a relatively rapid and easy-toperform technique for assessing left atrial function, due to its semiautomated nature and off-line processing.In fact, in contrast to Doppler-derived parameters, 2D-STE has the advantage of being angle-independent, and less affected by reverberation, side lobe and drop-out artefacts. 189][20] It has been suggested that ƐR allows an excellent assessment of the atrial deformation profile during an entire cardiac cycle, closely following left atrial physiology, and can be used to evaluate dynamic left atrial function. 18,19It has also been demonstrated that the left atrial reservoir ƐR is associated with fibrosis and can thus represent left atrial stiffness. 21ntrary to earlier belief, LAA is now thought to play an important role in normal cardiac hemodynamics, acting as an adaptive chamber in conditions of volume overload to attenuate the rise in intra-atrial pressure. 22,23urthermore, the highest density of atrial natriureticpeptide granules of the heart is found in LLA, and the release of atrial natriuretic peptide with consequent diuresis is an important compensatory mechanism involved in the maintenance of normal fluid homeostasis. 24ondo et al., 23 in a study performed in 10 open-chest dogs, reported that the LAA is more compliant than the left atrial main chamber.They also found a higher dimensional increase in the LAA than the left atrial main chamber during left atrial volume overload.Davis et al., 25 reported, in a study using 6 isolated canine left atria, that the LAA may enable the entire left atrium to better adapt reservoir function to physiologic conditions by protecting the pulmonary capillary system from encountering a rise in pressure.
In a study conducted by Kamohara et al., 26 to investigate the short-term and midterm effects of LAA exclusion on left atrial function, involving 19 dogs with 90 days of follow-up, the authors showed no significant difference in the transmitral flow tissue Doppler imaging measurements, left atrial pressure, left ventricular volume, or stroke volume.Tabata et al., 27 evaluated the role of LAA in left atrial reservoir function by assessing changes in left atrial flow dynamics after LAA clamping during cardiac surgery.The subjects of the study were 8 patients who had undergone coronary artery bypass grafting and 7 who had undergone valvular surgery for mitral regurgitation; all patients were in sinus rhythm.They demonstrated that, in both groups, mean left atrial pressure and maximum left atrial dimension significantly increased during LAA clamping.The authors concluded that the LAA is more compliant than the left atrial main chamber and plays an important role in left atrial reservoir function.Johansson et al., 28 explored the effects on atrial and ventricular function of restoring sinus rhythm after epicardial cryoablation and closure of the LAA in 65 patients with mitral valve disease and atrial fibrillation.In patients who were in sinus rhythm, peak velocity during atrial contraction and the reservoir function were lower in patients that underwent LAA closure than in the control group at 6 months of followup.In summary, it seems that in patients who are in sinus rhythm, LAA occlusion might negatively influence left atrial reservoir function.In fact, our patients in sinus rhythm had a decrease in ƐR and SR R after the procedure.
However, in patients with atrial fibrillation, closure of the LAA does not seem to have an impact on left atrial reservoir function.Hanna et al., 29  was expressed by increased left atrial volumes and decreased left atrial emptying fractions, 15 ƐR, and SR R . 12urthermore, Sasaki et al., 30 demonstrated that left atrial peak systolic ƐR is independently associated with LAA dysfunction in patients with atrial fibrillation.Hence, in our population of patients with left atrial chamber dysfunction at baseline, a reduced LAA function might also be present.Our results, along with those of Hanna et al., 29 suggest that the exclusion of the LAA does not seem to have a further impact on compromised left atrial physiology.
Nevertheless, a recent study with 33 patients (20 patients with atrial fibrillation) demonstrated that LAA closure was associated with an improvement in left atrial mechanical function in a 45-day follow-up, and these changes appeared to be related to changes in loading conditions (Frank-Starling effect). 31Despite favourable short-term outcomes, the long-term effects of an increase in left atrial volume might lead to deleterious effects, mainly in patients with sinus rhythm.We must also highlight that although there was an increase in peak atrial longitudinal strain at discharge compared to baseline, peak atrial longitudinal strain tended to be lower 45 days as compared with discharge (p = 0.08).Therefore, with a longer follow-up, peak atrial longitudinal strain might return to baseline levels as observed in our study.
Most previous studies were performed in patients with sinus rhythm and evaluated left atrial function immediately after LAA closure; the long-term hemodynamic effects of this procedure in patients who are in sinus rhythm are currently not known.Although we did not find any statistically significant difference between patients with decreased and with similar left atrial reservoir function after the procedure, the former group might have better left atrial function at baseline since a lower number of patients had lower left atrial volumes, higher left atrial emptying fractions, and higher ƐR values, consistent with the results of the studies mentioned above.

Limitations
Our study has several limitations.First, this was a single-center study with a relatively small sample size.However, there is a paucity of data regarding the effects of percutaneous LAA closure on left atrial function in the literature.Second, the retrospective nature of the study limited the evaluation of additional clinical and analytical parameters.Third, although we analyzed the impact of LAA percutaneous closure on left atrial mechanics, the design of our study made the assessment of clinical outcomes impossible.Finally, most of our patients had atrial fibrillation and left atrial dysfunction at baseline.It would therefore be important to study the influence of LAA percutaneous closure on left atrial function in patients who are in sinus rhythm with normal or slightly altered left atrial function.
Further studies including large populations of patients in sinus rhythm and in atrial fibrillation are needed to provide definitive evidence of the impact of LAA occlusion not only on left atrial physiology at long term, assessed by 2D-STE, but also on clinical outcomes.

Conclusion
We have demonstrated that in patients with atrial fibrillation and contraindication to oral anticoagulation, percutaneous LAA closure does not have a negative effect on left atrial reservoir function in patients with permanent atrial fibrillation.Further studies with a larger population of patients are warranted to confirm this finding.

Figure 1 -
Figure 1 -Global left atrial strain during reservoir phase (ƐR) before and after percutaneous closure of the left atrial appendage (LAA).Differences between baseline and post-LAA occlusion device implantation data were analysed by paired sample t-test.

Figure 2 -
Figure 2 -Maximum and minimum volume of the left atrium before and after percutaneous closure of the left atrial appendage (LAA).Differences between baseline and post-LAA occlusion device implantation data were analysed by paired sample t-test.

Figure 3 -
Figure 3 -Left atrial emptying fraction before and after percutaneous closure of the left atrial appendage (LAA).Differences between baseline and post-LAA occlusion device implantation data were analysed by paired sample t-test.

Figure 4 -
Figure 4 -Global left atrial strain (ƐR) and strain rate during reservoir phase (SR R ) before and after percutaneous closure of the left atrial appendage.Differences between baseline and post-LAA occlusion device implantation data were analysed by paired sample t-test.
conducted a study designed to evaluate the effects of percutaneous LAA transcatheter occlusion on anatomic and hemodynamic properties of the mitral valve and left upper pulmonary vein in 10 patients with atrial fibrillation.At 6 months of follow-up, left superior pulmonary vein diameter, peak systolic and diastolic flow velocities, left atrial size, severity of mitral regurgitation, and mitral valve peak E-wave velocity showed no significant change from baseline.In our sample, patients at baseline had decreased left atrial reservoir function, which References Madeira et al.Atrial appendage closure and atrial performance Int J Cardiovasc Sci.2018; [online].aheadprint, PP.0-0 Original Article

Table 1 -General characteristics of the study group (n = 16)
LAA: left atrial appendage; INR: international normalized ratio.Data expressed as mean and standard deviation, percentage or median and interquartile range.

Table 2 -Global and regional peak left atrial strain (ƐR) and strain rate (SR R ) during reservoir phase of the 12 segments before and after percutaneous closure of the left atrial appendage (LAA)
ƐR: left atrial strain during the reservoir phase; LAA: left atrial appendage; SR R : left atrial strain rate in the reservoir phase.ƐR values compared by the Mann-Whitney test and SR R values by the t-test.

Table 3 -Patients with reduction in left atrial mechanics in the reservoir phase Reduction in left atrial mechanics in the reservoir
LVEF: left ventricle ejection fraction; ƐR: left atrium strain during the reservoir phase; SR R : left atrium strain rate reservoir phase.Comparison of variables was performed with a Mann-Whitney test and SR R values by the t-test.Data expressed as mean and standard deviation or median and interquartile range.