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  <front>
    <journal-meta>
      <journal-id journal-id-type="publisher-id">ijcs</journal-id>
      <journal-title-group>
        <journal-title>International Journal of Cardiovascular Sciences</journal-title>
        <abbrev-journal-title abbrev-type="publisher">Int. J. Cardiovasc. Sci.</abbrev-journal-title>
      </journal-title-group>
      <issn pub-type="ppub">2359-4802</issn>
      <issn pub-type="epub">2359-5647</issn>
      <publisher>
        <publisher-name>Sociedade Brasileira de Cardiologia</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v3">86JhDpjKtPph6p4cPH6s3bw</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v2">S2359-56472018000600569</article-id>
      <article-id pub-id-type="publisher-id" specific-use="previous-pid">S2359-56472018005012101</article-id>
      <article-id pub-id-type="doi">10.5935/2359-4802.20180075</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>ORIGINAL ARTICLES</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Does Percutaneous Left Atrial Appendage Closure Affect Left Atrial Performance?</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Madeira</surname>
            <given-names>Marta</given-names>
          </name>
          <xref ref-type="fn" rid="fn1">*</xref>
          <xref ref-type="aff" rid="aff1">1</xref>
          <xref ref-type="aff" rid="aff2">2</xref>
          <xref ref-type="corresp" rid="c1"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Teixeira</surname>
            <given-names>Rog&#233;rio</given-names>
          </name>
          <xref ref-type="fn" rid="fn1">*</xref>
          <xref ref-type="aff" rid="aff1">1</xref>
          <xref ref-type="aff" rid="aff2">2</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Reis</surname>
            <given-names>Liliana</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Dinis</surname>
            <given-names>Paulo</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Paiva</surname>
            <given-names>Lu&#237;s</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
          <xref ref-type="aff" rid="aff2">2</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Botelho</surname>
            <given-names>Ana</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Costa</surname>
            <given-names>Marco</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Gon&#231;alves</surname>
            <given-names>Lino</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">1</xref>
          <xref ref-type="aff" rid="aff2">2</xref>
        </contrib>
      </contrib-group>
      <aff id="aff1">
        <label>1</label>
        <institution content-type="orgname">Centro Hospitalar e Universit&#225;rio de Coimbra</institution>
        <institution content-type="orgdiv1">Hospital Geral</institution>
        <institution content-type="orgdiv2">Servi&#231;o de Cardiolog&#237;a</institution>
        <addr-line>
          <city>Coimbra</city>
        </addr-line>
        <country country="PT">Portugal</country>
        <institution content-type="original">Servi&#231;o de Cardiolog&#237;a, Centro Hospitalar e Universit&#225;rio de Coimbra - Hospital Geral, Coimbra - Portugal</institution>
      </aff>
      <aff id="aff2">
        <label>2</label>
        <institution content-type="orgname">Universidade de Coimbra</institution>
        <institution content-type="orgdiv1">Faculdade de Medicina</institution>
        <addr-line>
          <city>Coimbra</city>
        </addr-line>
        <country country="PT">Portugal</country>
        <institution content-type="original">Faculdade de Medicina da Universidade de Coimbra, Coimbra - Portugal</institution>
      </aff>
      <author-notes>
        <corresp id="c1"><bold>Mailing Address:: Marta Madeira</bold>, Servi&#231;o de Cardiologia, Centro Hospitalar e Universit&#225;rio de Coimbra - Quinta dos Vales, S. Martinho do Bispo. Postal Code: 3045-043, Coimbra - Portugal E-mail: <email>marta.jesus.madeira@gmail.com</email>
				</corresp>
        <fn fn-type="con" id="fn1">
          <label>*</label>
          <p>Both authors contributed equally to the paper</p>
        </fn>
      </author-notes>
      <pub-date pub-type="epub">
        <day>01</day>
        <month>11</month>
        <year>2018</year>
      </pub-date>
      <pub-date pub-type="collection">
        <season>Nov-Dec</season>
        <year>2018</year>
      </pub-date>
      <volume>31</volume>
      <issue>6</issue>
      <fpage>569</fpage>
      <lpage>577</lpage>
      <history>
        <date date-type="received">
          <day>09</day>
          <month>09</month>
          <year>2017</year>
        </date>
        <date date-type="rev-recd">
          <day>11</day>
          <month>04</month>
          <year>2018</year>
        </date>
        <date date-type="accepted">
          <day>02</day>
          <month>07</month>
          <year>2018</year>
        </date>
      </history>
      <permissions>
        <license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/" xml:lang="en">
          <license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
        </license>
      </permissions>
      <abstract>
        <title>Abstract</title>
        <sec>
          <title>Background:</title>
          <p>Percutaneous left atrial appendage (LAA) occlusion may be an alternative therapy for atrial fibrillation (AF) patients with contraindication for anti-coagulation therapy. However, the influence of LAA occlusion on left atrial (LA) performance has not been studied.</p>
        </sec>
        <sec>
          <title>Objective:</title>
          <p>Our aim was to evaluate the influence of percutaneous LAA occlusion device on LA function by transthoracic echocardiography plus speckle-tracking echocardiography (STE).</p>
        </sec>
        <sec>
          <title>Methods:</title>
          <p>We included 16 patients undergoing percutaneous LAA closure with adequate echocardiographic window for the study of LA mechanics. Transthoracic echocardiography was performed before and after the procedure. LA volumes were calculated using the biplane method, and LA mechanics were assessed using STE. The analysis focused on the LA reservoir phase strain and strain rate.</p>
        </sec>
        <sec>
          <title>Results:</title>
          <p>Seventy-five percent of patients had permanent atrial fibrillation. Embolic and bleeding risk scores used were CHA<sub>2</sub>DS<sub>2</sub>-VASc [median of 4-5] and HAS-BLED [median of 2-3]. Major bleeding (62%) was the most common indication for the procedure. Percutaneous LAA closure was performed successfully in all patients, without major complications. No differences were found in maximum LA volume (44 &#177; 11 vs. 46 &#177; 13 mL/m<sup>2</sup>; p = 0.54), minimum LA volume (32 &#177; 8 vs. 37 &#177; 14 mL/m<sup>2</sup>; p = 0.09) or LA emptying fraction (26 &#177; 17 vs. 21 &#177; 14%; p = 0.33) before and after the procedure. Similarly, no differences were noted in left atrial strain (13.7 &#177; 11.1 vs. 13.0 &#177; 8.8%; p = 0.63) or strain rate (1.06 &#177; 0.26 vs. 1.13 &#177; 0.34 s<sup>-1</sup>; p = 0.38) in the reservoir phase.</p>
        </sec>
        <sec>
          <title>Conclusions:</title>
          <p>Our data suggest that percutaneous LAA closure does not affect LA reservoir function.</p>
        </sec>
      </abstract>
      <kwd-group xml:lang="en">
        <title>Keywords:</title>
        <kwd>Atrial Fibrillation</kwd>
        <kwd>Atrial Appendage</kwd>
        <kwd>Heart Atria</kwd>
        <kwd>Echocardiography, Transthoracic</kwd>
      </kwd-group>
    </article-meta>
  </front>
  <body>
    <sec sec-type="intro">
      <title>Introduction</title>
      <p>Atrial fibrillation is the most common sustained cardiac arrhythmia,<xref ref-type="bibr" rid="B1">1</xref> with a current estimated prevalence of 1.5% to 2%.<xref ref-type="bibr" rid="B2">2</xref> It is considered a major cause of systemic embolism, increasing the risk for ischemic stroke by 5 times.<xref ref-type="bibr" rid="B2">2</xref><sup>,</sup><xref ref-type="bibr" rid="B3">3</xref> Oral anticoagulation has been shown to effectively reduce the risk for stroke in patients with atrial fibrillation and is one of the cornerstones of management.<xref ref-type="bibr" rid="B2">2</xref> 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.<xref ref-type="bibr" rid="B3">3</xref> Several studies have shown that, in patients with nonvalvular atrial fibrillation, 90% of thrombus formation occurs in the left atrial appendage (LAA).<xref ref-type="bibr" rid="B4">4</xref><sup>,</sup><xref ref-type="bibr" rid="B5">5</xref> Therefore, 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.<xref ref-type="bibr" rid="B6">6</xref> Recently, the non-inferiority of LAA exclusion over warfarin for stroke prevention was demonstrated in patients with nonvalvular atrial fibrillation.<xref ref-type="bibr" rid="B7">7</xref>
			</p>
      <p>It 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.<xref ref-type="bibr" rid="B8">8</xref> The 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.<xref ref-type="bibr" rid="B9">9</xref> Surgical 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.<xref ref-type="bibr" rid="B10">10</xref> However, 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.</p>
      <p>Two-dimensional speckle-tracking echocardiography (2D-STE) is a recently developed, angle-independent, semiautomated technique used to evaluate the myocardium.<xref ref-type="bibr" rid="B11">11</xref> It 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.<xref ref-type="bibr" rid="B11">11</xref> In 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.<xref ref-type="bibr" rid="B12">12</xref> Measurements of left atrial strain (&#400;R) and strain rate (SR<sub>R</sub>) during the reservoir phase can be used to describe atrial function physiology and are sensitive to detect early functional remodeling before anatomical changes occur.<xref ref-type="bibr" rid="B12">12</xref><sup>,</sup><xref ref-type="bibr" rid="B13">13</xref>
			</p>
      <p>We 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.</p>
    </sec>
    <sec sec-type="methods">
      <title>Methods</title>
      <sec>
        <title>Patients</title>
        <p>Twenty-five patients with non-valvular atrial fibrillation and a high risk for stroke with a CHA<sub>2</sub>DS<sub>2</sub>-VASc Score of &#8805; 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.</p>
        <p>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.</p>
        <p>Clinical data included past medical history, current medication, the CHA<sub>2</sub>DS<sub>2</sub>-VASc and HAS-BLED scores, and diagnostic evaluation by routine laboratory testing, electrocardiography, and echocardiography.</p>
        <p>Sixteen patients with good echocardiographic window for assessment of the left atrial mechanics were included in our study.</p>
        <p>The study was approved by the ethics committee of our institution.</p>
      </sec>
      <sec>
        <title>Echocardiographic evaluation</title>
        <p>Echocardiography was performed on the day before and 3 months after percutaneous closure of the LAA.</p>
        <p>Echocardiographic examinations were performed using an ultrasound system (Vivid 7, General Electric<sup>&#174;</sup>, Horten, Norway) and tissue harmonic imaging at 1.7/3.4 MHz. A complete echocardiographic study was performed using standard views according to current guidelines.<xref ref-type="bibr" rid="B14">14</xref> Three 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.</p>
        <p>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.<xref ref-type="bibr" rid="B15">15</xref> Minimum left atrial volume was measured at left ventricular end-diastolic 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.<xref ref-type="bibr" rid="B15">15</xref>
				</p>
        <p>The 2D-STE method was used to calculate regional and global longitudinal &#400;R and SR<sub>R</sub> (<xref ref-type="fig" rid="f1">Figure 1</xref>). 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<sup>&#174;</sup>, 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 &#400;R and strain rate for each of the twelve segments and the average global strain. Peak &#400;R were expressed in percentages and SR<sub>R</sub> in s<sup>-1</sup>. 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 &#400;R.<xref ref-type="bibr" rid="B16">16</xref> Therefore, we also performed a comparison between left atrial lateral wall strain and SR<sub>R</sub> 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.</p>
        <p>
          <fig id="f1">
            <label>Figure 1</label>
            <caption>
              <title>Global left atrial strain during reservoir phase (&#400;R) 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.</title>
            </caption>
            <graphic xlink:href="2359-5647-ijcs-31-06-0569-80075-gf01.jpg"/></fig>
        </p>
      </sec>
      <sec>
        <title>LAA closure procedure</title>
        <p>LAA closure device was implanted in the catheterization laboratory. The device used was an Amplatzer<sup>&#174;</sup> (St. Jude Medical, St. Paul, Minnesota, USA) and was delivered through an appropriate sheath depending on the size of the selected occluder through a puncture in the femoral vein. Deployment and position of the device were controlled by fluoroscopy, and by periprocedural transesophageal or intracardiac echocardiography. LAA was reached through a transseptal puncture. Decision on device size was made upon anatomical morphology, and measurements in echocardiography and fluoroscopy. Oral anticoagulation, if present, was discontinued 48 hours prior to the procedure. During procedure, heparin was administered with an activated clotting time of 250s. Dual antiplatelet therapy with aspirin 100 mg and clopidogrel 75 mg was recommended for 1 month, followed by long-term antiplatelet therapy with aspirin 100 mg daily. No oral anticoagulation was recommended after device implantation.</p>
      </sec>
      <sec>
        <title>Statistical analysis</title>
        <p>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 &#400;R and follow-up time; and when patients were separated by group (no change and decrease of &#400;R and SR<sub>R</sub>), 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.</p>
        <p>Statistical analysis was carried out with SPSS<sup>&#174;</sup>15 and GraphPad Prism<sup>&#174;</sup> 6.05. A two-tailed p value &lt; 0.05 was considered statistically significant.</p>
      </sec>
    </sec>
    <sec sec-type="results">
      <title>Results</title>
      <sec>
        <title>Population characteristics</title>
        <p>Mean age of our sample was 71 &#177; 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<sub>2</sub>DS<sub>2</sub>-VASc score of 5 [4-5] and HAS-BLED score of 3 [2-3].</p>
        <p>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 &#177; 2 mm), without any major complications during or after the procedure.</p>
        <p>Characteristics of the study population are summarized in <xref ref-type="table" rid="t1">Table 1</xref>.</p>
        <table-wrap id="t1">
          <label>Table 1</label>
          <caption>
            <title>General characteristics of the study group (n = 16)</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup>
              <col width="50%"/>
              <col width="50%"/>
            </colgroup>
            <tbody>
              <tr>
                <td align="left">Age, years</td>
                <td align="center">71 &#177; 9</td>
              </tr>
              <tr>
                <td align="left">Male sex</td>
                <td align="center">10/16 (63%)</td>
              </tr>
              <tr>
                <td align="left">Atrial fibrillation</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Permanent</td>
                <td align="center">12/16 (75%)</td>
              </tr>
              <tr>
                <td align="left">Persistent</td>
                <td align="center">1/16 (6%)</td>
              </tr>
              <tr>
                <td align="left">Paroxysmal</td>
                <td align="center">3/16 (19%)</td>
              </tr>
              <tr>
                <td align="left">CHA2DS2-VASc score</td>
                <td align="center">5 [4 - 5]</td>
              </tr>
              <tr>
                <td align="left">HAS-BLED score</td>
                <td align="center">3 [2 - 3]</td>
              </tr>
              <tr>
                <td align="left">Indication for LAA closure</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Major bleeding</td>
                <td align="center">10/16 (63%)</td>
              </tr>
              <tr>
                <td align="left">Labile INR</td>
                <td align="center">3/16 (19%)</td>
              </tr>
              <tr>
                <td align="left">Embolic event despite anticoagulation</td>
                <td align="center">2/16 (13%)</td>
              </tr>
              <tr>
                <td align="left">Poor compliance with anticoagulation</td>
                <td align="center">1/16 (6%)</td>
              </tr>
              <tr>
                <td align="left">Cardiac plug device size, mm</td>
                <td align="center">24 &#177; 2</td>
              </tr>
              <tr>
                <td align="left">Left ventricular ejection fraction</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">Normal range</td>
                <td align="center">13/16 (81%)</td>
              </tr>
              <tr>
                <td align="left">Mildly abnormal</td>
                <td align="center">3/16 (19%)</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN1">
              <p>LAA: left atrial appendage; INR: international normalized ratio. Data expressed as mean and standard deviation, percentage or median and interquartile range.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
      </sec>
      <sec>
        <title>LA volume and emptying fraction</title>
        <p>Maximum and minimum values of left atrial volume and the left atrial emptying fraction before and after the procedure are represented in <xref ref-type="fig" rid="f2">Fig. 2</xref> and <xref ref-type="fig" rid="f3">Fig. 3</xref>, respectively. No differences were found in maximum left atrial volume (44 &#177; 11 vs. 46 &#177; 13 mL/m<sup>2</sup>; p = 0.54), minimum left atrial volume (32 &#177; 8 vs. 37 &#177; 14 mL/m<sup>2</sup>; p = 0.09), or the left atrial emptying fraction (26 &#177; 17% vs. 21 &#177; 14%; p = 0.33) after the intervention compared with the baseline values.</p>
        <p>
          <fig id="f2">
            <label>Figure 2</label>
            <caption>
              <title>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.</title>
            </caption>
            <graphic xlink:href="2359-5647-ijcs-31-06-0569-80075-gf02.jpg"/></fig>
        </p>
        <p>
          <fig id="f3">
            <label>Figure 3</label>
            <caption>
              <title>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.</title>
            </caption>
            <graphic xlink:href="2359-5647-ijcs-31-06-0569-80075-gf03.jpg"/></fig>
        </p>
      </sec>
      <sec>
        <title>Left atrium reservoir &#400;R and SR<sub>R</sub></title>
        <p>Global and regional peak &#400;R and SR<sub>R</sub> of the 12 segments before and months after percutaneous closure of the LAA are listed in <xref ref-type="table" rid="t2">Table 2</xref>. Similar values of &#400;R (10.1 [8.1-14.7] vs. 12.7 [5.4-16.5]%; p = 0.81) and SR<sub>R</sub> (1.06 &#177; 0.26 vs. 1.13 &#177; 0.34 s<sup>-1</sup>; p = 0.38) were observed before and after the procedure (<xref ref-type="fig" rid="f4">Figure 4</xref>).</p>
        <table-wrap id="t2">
          <label>Table 2</label>
          <caption>
            <title>Global and regional peak left atrial strain (&#400;R) and strain rate (SR<sub>R</sub>) during reservoir phase of the 12 segments before and after percutaneous closure of the left atrial appendage (LAA)</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup>
              <col width="25%"/>
              <col width="25%"/>
              <col width="25%"/>
              <col width="25%"/>
            </colgroup>
            <thead>
              <tr>
                <th align="left" style="background-color:#C5C6C8">
								</th>
                <th align="center" style="background-color:#C5C6C8">Basal</th>
                <th align="center" style="background-color:#C5C6C8">After LAA occlusion</th>
                <th align="center" style="background-color:#C5C6C8">p</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td align="left">Global &#400;R, %</td>
                <td align="center">10.1 [8.1 - 14.7]</td>
                <td align="center">12.7 [5.4 - 16.5]</td>
                <td align="center">0.81</td>
              </tr>
              <tr>
                <td align="left">Lateral basal &#400;R, %</td>
                <td align="center">18.6 [10.5 - 28.8]</td>
                <td align="center">17.6 [11.0 - 22.3]</td>
                <td align="center">0.49</td>
              </tr>
              <tr>
                <td align="left">Lateral mid &#400;R, %</td>
                <td align="center">10.1 [6.0 - 18.8]</td>
                <td align="center">9.0 [4.4 - 16.4]</td>
                <td align="center">0.40</td>
              </tr>
              <tr>
                <td align="left">Lateral apical &#400;R, %</td>
                <td align="center">7.1 [3.9 - 13.6]</td>
                <td align="center">5.9 [2.0 - 15.7]</td>
                <td align="center">0.84</td>
              </tr>
              <tr>
                <td align="left">Septal apical &#400;R, %</td>
                <td align="center">9.1 [4.9 - 18.4]</td>
                <td align="center">8.5 [3.9 - 16.8]</td>
                <td align="center">0.38</td>
              </tr>
              <tr>
                <td align="left">Septal mid &#400;R, %</td>
                <td align="center">12.0 [8.1 - 17.5]</td>
                <td align="center">9.8 [3.2 - 22.5]</td>
                <td align="center">0.86</td>
              </tr>
              <tr>
                <td align="left">Septal basal &#400;R, %</td>
                <td align="center">13.2 [5.2 - 21.8]</td>
                <td align="center">12.2 [2.7 - 23.6]</td>
                <td align="center">0.84</td>
              </tr>
              <tr>
                <td align="left">Global SRR, s<sup>-1</sup></td>
                <td align="center">1.06 &#177; 0.26</td>
                <td align="center">1.13 &#177; 0.34</td>
                <td align="center">0.38</td>
              </tr>
              <tr>
                <td align="left">Lateral basal SRR, s<sup>-1</sup></td>
                <td align="center">1.14 &#177; 0.49</td>
                <td align="center">1.20 &#177; 0.62</td>
                <td align="center">0.60</td>
              </tr>
              <tr>
                <td align="left">Lateral mid SRR, s<sup>-1</sup></td>
                <td align="center">1.04 &#177; 0.42</td>
                <td align="center">1.10 &#177; 0.56</td>
                <td align="center">0.61</td>
              </tr>
              <tr>
                <td align="left">Lateral apical SRR, s<sup>-1</sup></td>
                <td align="center">1.18 &#177; 0.50</td>
                <td align="center">1.05 &#177; 0.48</td>
                <td align="center">0.41</td>
              </tr>
              <tr>
                <td align="left">Septal apical SRR, s<sup>-1</sup></td>
                <td align="center">1.00 &#177; 0.54</td>
                <td align="center">1.10 &#177; 0.45</td>
                <td align="center">0.50</td>
              </tr>
              <tr>
                <td align="left">Septal mid SRR, s<sup>-1</sup></td>
                <td align="center">0.94 &#177; 0.45</td>
                <td align="center">1.01 &#177; 0.29</td>
                <td align="center">0.45</td>
              </tr>
              <tr>
                <td align="left">Septal basal SRR, s<sup>-1</sup></td>
                <td align="center">1.39 &#177; 0.53</td>
                <td align="center">1.35 &#177; 0.62</td>
                <td align="center">0.86</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN2">
              <p>&#400;R: left atrial strain during the reservoir phase; LAA: left atrial appendage; SR<sub>R</sub>: left atrial strain rate in the reservoir phase. &#400;R values compared by the Mann-Whitney test and SR<sub>R</sub> values by the t-test.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <p>
          <fig id="f4">
            <label>Figure 4</label>
            <caption>
              <title>Global left atrial strain (&#400;R) and strain rate during reservoir phase (SRR) 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.</title>
            </caption>
            <graphic xlink:href="2359-5647-ijcs-31-06-0569-80075-gf04.jpg"/></fig>
        </p>
        <p>Assessment of left atrial lateral wall revealed similar &#400;R (11.0 [6.5-19.8]% vs. 8.2 [2.7-15.9]%; p = 0.60) and SR<sub>R</sub> (1.01 [0.78-1.54] vs. 1.02 [0.85-1.56] s<sup>-1</sup>; p = 0.75) before and after the procedure.</p>
        <p>In 44% of patients, there was a decrease in &#400;R. There were no differences regarding patient age, baseline left atrial volume, left atrial emptying fraction, &#400;R, SR<sub>R</sub>, CHA<sub>2</sub>DS<sub>2</sub>-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 &#400;R values (<xref ref-type="table" rid="t3">Table 3</xref>).</p>
        <table-wrap id="t3">
          <label>Table 3</label>
          <caption>
            <title>Patients with reduction in left atrial mechanics in the reservoir phase</title>
          </caption>
          <table frame="hsides" rules="groups">
            <colgroup>
              <col width="25%"/>
              <col width="25%"/>
              <col width="25%"/>
              <col width="25%"/>
            </colgroup>
            <thead>
              <tr>
                <th align="left" style="background-color:#C5C6C8">
								</th>
                <th align="left" colspan="2" style="background-color:#C5C6C8;border-bottom-width:thin;border-bottom-style:solid">Reduction in left atrial mechanics in the reservoir phase</th>
                <th align="center" rowspan="3" style="background-color:#C5C6C8">p</th>
              </tr>
              <tr>
                <th align="left" style="background-color:#C5C6C8">
								</th>
                <th align="center" style="background-color:#C5C6C8">Yes (7/16 -</th>
                <th align="center" style="background-color:#C5C6C8">No (9/16 -</th>
              </tr>
              <tr>
                <th align="left" style="background-color:#C5C6C8">
								</th>
                <th align="center" style="background-color:#C5C6C8">44%)</th>
                <th align="center" style="background-color:#C5C6C8">56%)</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td align="left">Age, years</td>
                <td align="center">67 [66 - 73]</td>
                <td align="center">77 [69 - 81]</td>
                <td align="center">0.09</td>
              </tr>
              <tr>
                <td align="left">Permanent atrial</td>
                <td align="center">
								</td>
                <td align="center">
								</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">fibrillation</td>
                <td align="center">4/7 (57%)</td>
                <td align="center">8/9 (89%)</td>
                <td align="center">0.26</td>
              </tr>
              <tr>
                <td align="left">CHA<sub>2</sub>DS<sub>2</sub>-VASc</td>
                <td align="center">5 [3 - 5]</td>
                <td align="center">5 [4 - 6]</td>
                <td align="center">0.35</td>
              </tr>
              <tr>
                <td align="left">HAS-BLED score</td>
                <td align="center">3 [2 - 4]</td>
                <td align="center">3 [2 - 3]</td>
                <td align="center">0.92</td>
              </tr>
              <tr>
                <td align="left">Cardiac plug device size, mm</td>
                <td align="center">24 [22 - 25]</td>
                <td align="center">24 [21 - 25]</td>
                <td align="center">0.83</td>
              </tr>
              <tr>
                <td align="left">Baseline mildly abnormal LVEF</td>
                <td align="center">0/0</td>
                <td align="center">3/9 (33%)</td>
                <td align="center">0.09</td>
              </tr>
              <tr>
                <td align="left">Baseline left atrium</td>
                <td align="center">
								</td>
                <td align="center">
								</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">volume, mL</td>
                <td align="center">41 [33 - 45]</td>
                <td align="center">46 [40 - 62]</td>
                <td align="center">0.27</td>
              </tr>
              <tr>
                <td align="left">Baseline left atrium</td>
                <td align="center">
								</td>
                <td align="center">
								</td>
                <td align="center">
								</td>
              </tr>
              <tr>
                <td align="left">emptying fraction, %</td>
                <td align="center">25 [13 - 49]</td>
                <td align="center">18 [15 - 39]</td>
                <td align="center">0.43</td>
              </tr>
              <tr>
                <td align="left">Baseline global &#400;R, %</td>
                <td align="center">14.4 [8.7 - 26.4]</td>
                <td align="center">9.2 [5.6 - 14.0]</td>
                <td align="center">0.14</td>
              </tr>
              <tr>
                <td align="left">Baseline global SR<sub>R</sub>, s<sup>-1</sup></td>
                <td align="center">1.1 [0.9 - 1.2]</td>
                <td align="center">1.0 [0.8 - 1.1]</td>
                <td align="center">0.25</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN3">
              <p>LVEF: left ventricle ejection fraction; &#400;R: left atrium strain during the reservoir phase; SR<sub>R</sub>: left atrium strain rate reservoir phase.</p>
              <p>Comparison of variables was performed with a Mann-Whitney test and SR<sub>R</sub> values by the t-test. Data expressed as mean and standard deviation or median and interquartile range.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
      </sec>
    </sec>
    <sec sec-type="discussion">
      <title>Discussion</title>
      <p>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.</p>
      <p>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.<xref ref-type="bibr" rid="B12">12</xref> 2D-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.<xref ref-type="bibr" rid="B17">17</xref> Considering the limitations of the classical indices of left atrial function, assessment of &#400;R by 2D-STE may represent a relatively rapid and easy-to-perform 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.<xref ref-type="bibr" rid="B18">18</xref> Furthermore, recent studies have shown that 2D-STE is feasible and reproducible.<xref ref-type="bibr" rid="B18">18</xref><sup>-</sup><xref ref-type="bibr" rid="B20">20</xref> It has been suggested that &#400;R 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.<xref ref-type="bibr" rid="B18">18</xref><sup>,</sup><xref ref-type="bibr" rid="B19">19</xref> It has also been demonstrated that the left atrial reservoir &#400;R is associated with fibrosis and can thus represent left atrial stiffness.<xref ref-type="bibr" rid="B21">21</xref>
			</p>
      <p>Contrary 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.<xref ref-type="bibr" rid="B22">22</xref><sup>,</sup><xref ref-type="bibr" rid="B23">23</xref> Furthermore, the highest density of atrial natriuretic-peptide 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.<xref ref-type="bibr" rid="B24">24</xref> Hondo et al.,<xref ref-type="bibr" rid="B23">23</xref> 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.,<xref ref-type="bibr" rid="B25">25</xref> 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.</p>
      <p>In a study conducted by Kamohara et al.,<xref ref-type="bibr" rid="B26">26</xref> 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.,<xref ref-type="bibr" rid="B27">27</xref> 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.,<xref ref-type="bibr" rid="B28">28</xref> 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 follow-up. 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 &#400;R and SR<sub>R</sub> after the procedure.</p>
      <p>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.,<xref ref-type="bibr" rid="B29">29</xref> 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 was expressed by increased left atrial volumes and decreased left atrial emptying fractions,<xref ref-type="bibr" rid="B15">15</xref> &#400;R, and SR<sub>R</sub>.<xref ref-type="bibr" rid="B12">12</xref> Furthermore, Sasaki et al.,<xref ref-type="bibr" rid="B30">30</xref> demonstrated that left atrial peak systolic &#400;R 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.,<xref ref-type="bibr" rid="B29">29</xref> suggest that the exclusion of the LAA does not seem to have a further impact on compromised left atrial physiology.</p>
      <p>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).<xref ref-type="bibr" rid="B31">31</xref> Despite 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.</p>
      <p>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 &#400;R values, consistent with the results of the studies mentioned above.</p>
      <sec>
        <title>Limitations</title>
        <p>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.</p>
        <p>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.</p>
      </sec>
    </sec>
    <sec sec-type="conclusions">
      <title>Conclusion</title>
      <p>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.</p>
    </sec>
  </body>
  <back>
    <ref-list>
      <title>References</title>
      <ref id="B1">
        <label>1</label>
        <mixed-citation>1 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke. 1991;22(8):983-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Wolf</surname>
              <given-names>PA</given-names>
            </name>
            <name>
              <surname>Abbott</surname>
              <given-names>RD</given-names>
            </name>
            <name>
              <surname>Kannel</surname>
              <given-names>WB</given-names>
            </name>
          </person-group>
          <article-title>Atrial fibrillation as an independent risk factor for stroke: the Framingham study</article-title>
          <source>Stroke</source>
          <year>1991</year>
          <volume>22</volume>
          <issue>8</issue>
          <fpage>983</fpage>
          <lpage>988</lpage>
        </element-citation>
      </ref>
      <ref id="B2">
        <label>2</label>
        <mixed-citation>2 Kirchhof P, Benussi B, Kotecha D, Ahlsson A, Atar D, Casadei B, et al; ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893-2962.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kirchhof</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Benussi</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Kotecha</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Ahlsson</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Atar</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Casadei</surname>
              <given-names>B</given-names>
            </name>
            <etal/>
            <collab>ESC Scientific Document Group</collab>
          </person-group>
          <article-title>2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS</article-title>
          <source>Eur Heart J</source>
          <year>2016</year>
          <volume>37</volume>
          <issue>38</issue>
          <fpage>2893</fpage>
          <lpage>2962</lpage>
        </element-citation>
      </ref>
      <ref id="B3">
        <label>3</label>
        <mixed-citation>3 Saw J, Lempereur M. Percutaneous left atrial appendage closure: procedural techniques and outcomes. JACC Cardiovasc Interv. 2014;7(11):1205-20.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Saw</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Lempereur</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title>Percutaneous left atrial appendage closure: procedural techniques and outcomes</article-title>
          <source>JACC Cardiovasc Interv</source>
          <year>2014</year>
          <volume>7</volume>
          <issue>11</issue>
          <fpage>1205</fpage>
          <lpage>1220</lpage>
        </element-citation>
      </ref>
      <ref id="B4">
        <label>4</label>
        <mixed-citation>4 Onalan O, Crystal E. Left atrial appendage exclusion for stroke prevention in patients with nonrheumatic atrial fibrillation. Stroke. 2007;38(2 Suppl):624-30.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Onalan</surname>
              <given-names>O</given-names>
            </name>
            <name>
              <surname>Crystal</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title>Left atrial appendage exclusion for stroke prevention in patients with nonrheumatic atrial fibrillation</article-title>
          <source>Stroke</source>
          <year>2007</year>
          <volume>38</volume>
          <issue>2</issue>
          <supplement>Suppl</supplement>
          <fpage>624</fpage>
          <lpage>630</lpage>
        </element-citation>
      </ref>
      <ref id="B5">
        <label>5</label>
        <mixed-citation>5 Beigel R, Wunderlich NC, Ho SY, Arsanjani R, Siegel RJ. The left atrial appendage: anatomy, function, and noninvasive evaluation. JACC Cardiovasc Imaging. 2014;7(12):1251-65.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Beigel</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Wunderlich</surname>
              <given-names>NC</given-names>
            </name>
            <name>
              <surname>Ho</surname>
              <given-names>SY</given-names>
            </name>
            <name>
              <surname>Arsanjani</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Siegel</surname>
              <given-names>RJ</given-names>
            </name>
          </person-group>
          <article-title>The left atrial appendage: anatomy, function, and noninvasive evaluation</article-title>
          <source>JACC Cardiovasc Imaging</source>
          <year>2014</year>
          <volume>7</volume>
          <issue>12</issue>
          <fpage>1251</fpage>
          <lpage>1265</lpage>
        </element-citation>
      </ref>
      <ref id="B6">
        <label>6</label>
        <mixed-citation>6 Seeger J, Bothner C, Dahme T, Gonska B, Scharnbeck D, Markovic S, et al. Efficacy and safety of percutaneous left atrial appendage closure to prevent thromboembolic events in atrial fibrillation patients with high stroke and bleeding risk. Clin Res Cardiol. 2016;105(3):225-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Seeger</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Bothner</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Dahme</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Gonska</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Scharnbeck</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Markovic</surname>
              <given-names>S</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Efficacy and safety of percutaneous left atrial appendage closure to prevent thromboembolic events in atrial fibrillation patients with high stroke and bleeding risk</article-title>
          <source>Clin Res Cardiol</source>
          <year>2016</year>
          <volume>105</volume>
          <issue>3</issue>
          <fpage>225</fpage>
          <lpage>229</lpage>
        </element-citation>
      </ref>
      <ref id="B7">
        <label>7</label>
        <mixed-citation>7 Holmes DR Jr, Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol. 2014;64(1):1-12. Erratum in: J Am Coll Cardiol. 2014;64(11):1186</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Holmes</surname>
              <given-names>DR</given-names>
              <suffix>Jr</suffix>
            </name>
            <name>
              <surname>Kar</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Price</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Whisenant</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Sievert</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Doshi</surname>
              <given-names>SK</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2014</year>
          <volume>64</volume>
          <issue>1</issue>
          <fpage>1</fpage>
          <lpage>12</lpage>
          <comment>Erratum in: J Am Coll Cardiol. 2014;64(11):1186</comment>
        </element-citation>
      </ref>
      <ref id="B8">
        <label>8</label>
        <mixed-citation>8 St&#246;llberger C, Schneider B, Finsterer J. Elimination of the left atrial appendage to prevent stroke or embolism? Anatomic, physiologic, and pathophysiologic considerations. Chest. 2003;124(6):2356-62.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>St&#246;llberger</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Schneider</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Finsterer</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Elimination of the left atrial appendage to prevent stroke or embolism? Anatomic, physiologic, and pathophysiologic considerations</article-title>
          <source>Chest</source>
          <year>2003</year>
          <volume>124</volume>
          <issue>6</issue>
          <fpage>2356</fpage>
          <lpage>2362</lpage>
        </element-citation>
      </ref>
      <ref id="B9">
        <label>9</label>
        <mixed-citation>9 Hondo T, Okamoto M, Yamane T, Kawagoe T, Karakawa S, Yamagata T, et al. The role of the left atrial appendage. A volume loading study in open-chest dogs. Jpn Heart J. 1995;36(2):225-34.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hondo</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Okamoto</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Yamane</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Kawagoe</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Karakawa</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Yamagata</surname>
              <given-names>T</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>The role of the left atrial appendage. A volume loading study in open-chest dogs</article-title>
          <source>Jpn Heart J</source>
          <year>1995</year>
          <volume>36</volume>
          <issue>2</issue>
          <fpage>225</fpage>
          <lpage>234</lpage>
        </element-citation>
      </ref>
      <ref id="B10">
        <label>10</label>
        <mixed-citation>10 Bansal M, Kasliwal R. Echocardiography for left atrial appendage structure and function. Indian Heart J. 2012;64(5):469-75.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Bansal</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Kasliwal</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
          <article-title>Echocardiography for left atrial appendage structure and function</article-title>
          <source>Indian Heart J</source>
          <year>2012</year>
          <volume>64</volume>
          <issue>5</issue>
          <fpage>469</fpage>
          <lpage>475</lpage>
        </element-citation>
      </ref>
      <ref id="B11">
        <label>11</label>
        <mixed-citation>11 Mor-Avi V, Lang R, Badano L, 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. J Am Soc Echocardiogr. 2011;24(3):277-313.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Mor-Avi</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Lang</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Badano</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Belohlavek</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Cardim</surname>
              <given-names>NM</given-names>
            </name>
            <name>
              <surname>Derumeaux</surname>
              <given-names>G</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>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</article-title>
          <source>J Am Soc Echocardiogr</source>
          <year>2011</year>
          <volume>24</volume>
          <issue>3</issue>
          <fpage>277</fpage>
          <lpage>313</lpage>
        </element-citation>
      </ref>
      <ref id="B12">
        <label>12</label>
        <mixed-citation>12 Vieira MJ, Teixeira R, Gon&#231;alves L, Gersh BJ. Left Atrial Mechanics: Echocardiographic Assessment and Clinical Implications. J Am Soc Echocardiogr. 2014;27(5):463-78.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Vieira</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Teixeira</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Gon&#231;alves</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Gersh</surname>
              <given-names>BJ</given-names>
            </name>
          </person-group>
          <article-title>Left Atrial Mechanics: Echocardiographic Assessment and Clinical Implications</article-title>
          <source>J Am Soc Echocardiogr</source>
          <year>2014</year>
          <volume>27</volume>
          <issue>5</issue>
          <fpage>463</fpage>
          <lpage>478</lpage>
        </element-citation>
      </ref>
      <ref id="B13">
        <label>13</label>
        <mixed-citation>13 Goette A, Kalman JM, Aguinaga L, Akar J, Cabrera JA, Chen SA, et al. EHRA/HRS/APHRS/SOLAECE expert consensus on Atrial cardiomyopathies: definition, characterization, and clinical implication. Europace. 2016;18(10):1455-1490.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Goette</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Kalman</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Aguinaga</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Akar</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Cabrera</surname>
              <given-names>JA</given-names>
            </name>
            <name>
              <surname>Chen</surname>
              <given-names>SA</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>EHRA/HRS/APHRS/SOLAECE expert consensus on Atrial cardiomyopathies: definition, characterization, and clinical implication</article-title>
          <source>Europace</source>
          <year>2016</year>
          <volume>18</volume>
          <issue>10</issue>
          <fpage>1455</fpage>
          <lpage>1490</lpage>
        </element-citation>
      </ref>
      <ref id="B14">
        <label>14</label>
        <mixed-citation>14 Evangelista A, Flachskampf F, Lancellotti P, Badano L, Aguilar R, Monaghan M, et al; European Association of Echocardiography. European Association of Echocardiography recommendations for standardization of performance, digital storage and reporting of echocardiographic studies. Eur J Echocardiogr. 2008;9(4):438-48.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Evangelista</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Flachskampf</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Lancellotti</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Badano</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Aguilar</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Monaghan</surname>
              <given-names>M</given-names>
            </name>
            <etal/>
            <collab>European Association of Echocardiography</collab>
          </person-group>
          <article-title>European Association of Echocardiography recommendations for standardization of performance, digital storage and reporting of echocardiographic studies</article-title>
          <source>Eur J Echocardiogr</source>
          <year>2008</year>
          <volume>9</volume>
          <issue>4</issue>
          <fpage>438</fpage>
          <lpage>448</lpage>
        </element-citation>
      </ref>
      <ref id="B15">
        <label>15</label>
        <mixed-citation>15 Lang R, Badano L, 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. J Am Soc Echocardiogr. 2015;28(1):1-39.e14.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Lang</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Badano</surname>
              <given-names>L</given-names>
            </name>
            <name>
              <surname>Mor-Avi</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Afilalo</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Armstrong</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Ernande</surname>
              <given-names>L</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging</article-title>
          <source>J Am Soc Echocardiogr</source>
          <year>2015</year>
          <volume>28</volume>
          <issue>1</issue>
          <fpage>1</fpage>
          <lpage>39.e14</lpage>
        </element-citation>
      </ref>
      <ref id="B16">
        <label>16</label>
        <mixed-citation>16 Donal E, Lip GY, Galderisi M, Goette A, Shah D, Marwan M, et al. EACVI/ EHRA Expert Consensus Document on the role of multimodality imaging for the evaluation of patients with atrial fibrillation. Eur Heart J Cardiovasc Imaging. 2016;17(4):355-83.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Donal</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Lip</surname>
              <given-names>GY</given-names>
            </name>
            <name>
              <surname>Galderisi</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Goette</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Shah</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Marwan</surname>
              <given-names>M</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>EACVI/ EHRA Expert Consensus Document on the role of multimodality imaging for the evaluation of patients with atrial fibrillation</article-title>
          <source>Eur Heart J Cardiovasc Imaging</source>
          <year>2016</year>
          <volume>17</volume>
          <issue>4</issue>
          <fpage>355</fpage>
          <lpage>383</lpage>
        </element-citation>
      </ref>
      <ref id="B17">
        <label>17</label>
        <mixed-citation>17 Leitman M, Lysyansky P, Sidenko S, Shir V, Peleg E, Binenbaum M, et al. Two-dimensional strain - a novel software for real-time quantitative echocardiographic assessment of myocardial function. J Am Soc Echocardiogr. 2004;17(10):1021-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Leitman</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Lysyansky</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Sidenko</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Shir</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Peleg</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Binenbaum</surname>
              <given-names>M</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Two-dimensional strain - a novel software for real-time quantitative echocardiographic assessment of myocardial function</article-title>
          <source>J Am Soc Echocardiogr</source>
          <year>2004</year>
          <volume>17</volume>
          <issue>10</issue>
          <fpage>1021</fpage>
          <lpage>1029</lpage>
        </element-citation>
      </ref>
      <ref id="B18">
        <label>18</label>
        <mixed-citation>18 Cameli M, Caputo M, Mondillo S, Ballo P, Palmerini E, Lisi M, et al. Feasibility and reference values of left atrial longitudinal strain imaging by two-dimensional speckle tracking. Cardiovasc Ultrasound. 2009 Feb 8;7:6.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Cameli</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Caputo</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Mondillo</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Ballo</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Palmerini</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Lisi</surname>
              <given-names>M</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Feasibility and reference values of left atrial longitudinal strain imaging by two-dimensional speckle tracking</article-title>
          <source>Cardiovasc Ultrasound</source>
          <day>09</day>
          <month>02</month>
          <year>2009</year>
          <volume>7</volume>
          <fpage>6</fpage>
          <lpage>6</lpage>
        </element-citation>
      </ref>
      <ref id="B19">
        <label>19</label>
        <mixed-citation>19 Vianna-Pinton R, Moreno CA, Baxter CM, Lee KS, Tsang TS, Appleton CP. Two-dimensional speckle-tracking echocardiography of the left atrium: feasibility and regional contraction and relaxation differences in normal subjects. J Am Soc Echocardiogr. 2008;22(3):299-305.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Vianna-Pinton</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Moreno</surname>
              <given-names>CA</given-names>
            </name>
            <name>
              <surname>Baxter</surname>
              <given-names>CM</given-names>
            </name>
            <name>
              <surname>Lee</surname>
              <given-names>KS</given-names>
            </name>
            <name>
              <surname>Tsang</surname>
              <given-names>TS</given-names>
            </name>
            <name>
              <surname>Appleton</surname>
              <given-names>CP</given-names>
            </name>
          </person-group>
          <article-title>Two-dimensional speckle-tracking echocardiography of the left atrium: feasibility and regional contraction and relaxation differences in normal subjects</article-title>
          <source>J Am Soc Echocardiogr</source>
          <year>2008</year>
          <volume>22</volume>
          <issue>3</issue>
          <fpage>299</fpage>
          <lpage>305</lpage>
        </element-citation>
      </ref>
      <ref id="B20">
        <label>20</label>
        <mixed-citation>20 Kim D, Lee K, Lee S, Jeong SY, Lee YS, Choi YJ, et al. Feasibility of two-dimensional global longitudinal strain and strain rate imaging for the assessment of left atrial function: a study in subjects with a low probability of cardiovascular disease and normal exercise capacity. Echocardiography. 2009;26(10):1179-87.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kim</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Lee</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Lee</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Jeong</surname>
              <given-names>SY</given-names>
            </name>
            <name>
              <surname>Lee</surname>
              <given-names>YS</given-names>
            </name>
            <name>
              <surname>Choi</surname>
              <given-names>YJ</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Feasibility of two-dimensional global longitudinal strain and strain rate imaging for the assessment of left atrial function: a study in subjects with a low probability of cardiovascular disease and normal exercise capacity</article-title>
          <source>Echocardiography</source>
          <year>2009</year>
          <volume>26</volume>
          <issue>10</issue>
          <fpage>1179</fpage>
          <lpage>1187</lpage>
        </element-citation>
      </ref>
      <ref id="B21">
        <label>21</label>
        <mixed-citation>21 Gottdiener J, Kitzman D, Aurigemma G, Arnold AM, Manolio TA. Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons &gt; or =65 years of age (the Cardiovascular Health Study). Am J Cardiol. 2006;97(1):83-9.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Gottdiener</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Kitzman</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Aurigemma</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Arnold</surname>
              <given-names>AM</given-names>
            </name>
            <name>
              <surname>Manolio</surname>
              <given-names>TA</given-names>
            </name>
          </person-group>
          <article-title>Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons &gt; or =65 years of age (the Cardiovascular Health Study)</article-title>
          <source>Am J Cardiol</source>
          <year>2006</year>
          <volume>97</volume>
          <issue>1</issue>
          <fpage>83</fpage>
          <lpage>89</lpage>
        </element-citation>
      </ref>
      <ref id="B22">
        <label>22</label>
        <mixed-citation>22 Syed F, Desimone C, Friedman PA, Asirvatham SJ. Left atrial appendage exclusion for atrial fibrillation. Cardiol Clin. 2014;32(4):601-25.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Syed</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Desimone</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Friedman</surname>
              <given-names>PA</given-names>
            </name>
            <name>
              <surname>Asirvatham</surname>
              <given-names>SJ</given-names>
            </name>
          </person-group>
          <article-title>Left atrial appendage exclusion for atrial fibrillation</article-title>
          <source>Cardiol Clin</source>
          <year>2014</year>
          <volume>32</volume>
          <issue>4</issue>
          <fpage>601</fpage>
          <lpage>625</lpage>
        </element-citation>
      </ref>
      <ref id="B23">
        <label>23</label>
        <mixed-citation>23 Hondo T, Okamoto M, Yamane T, Kawagoe T, Karakawa S, Yamagata T, et al. The role of the left atrial appendage: a volume loading study in open-chest dogs. Jpn Heart J. 1995;36(2):225-34.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hondo</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Okamoto</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Yamane</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Kawagoe</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Karakawa</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Yamagata</surname>
              <given-names>T</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>The role of the left atrial appendage: a volume loading study in open-chest dogs</article-title>
          <source>Jpn Heart J</source>
          <year>1995</year>
          <volume>36</volume>
          <issue>2</issue>
          <fpage>225</fpage>
          <lpage>234</lpage>
        </element-citation>
      </ref>
      <ref id="B24">
        <label>24</label>
        <mixed-citation>24 Tabata T, Oki T, Yamada H, Abe M, Onose Y, Thomas JD. Relationship between left atrial appendage function and plasma concentration of atrial natriuretic peptide. Eur J Echocardiogr. 2000;1(2):130-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Tabata</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Oki</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Yamada</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Abe</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Onose</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Thomas</surname>
              <given-names>JD</given-names>
            </name>
          </person-group>
          <article-title>Relationship between left atrial appendage function and plasma concentration of atrial natriuretic peptide</article-title>
          <source>Eur J Echocardiogr</source>
          <year>2000</year>
          <volume>1</volume>
          <issue>2</issue>
          <fpage>130</fpage>
          <lpage>137</lpage>
        </element-citation>
      </ref>
      <ref id="B25">
        <label>25</label>
        <mixed-citation>25 Davis CA 3rd, Rembert JC, Greenfield JC Jr. Compliance of left atrium with and without left atrium appendage. Am J Physiol. 1990;259(4 Pt 2):H1006-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Davis</surname>
              <given-names>CA 3rd</given-names>
            </name>
            <name>
              <surname>Rembert</surname>
              <given-names>JC</given-names>
            </name>
            <name>
              <surname>Greenfield</surname>
              <given-names>JC</given-names>
              <suffix>Jr</suffix>
            </name>
          </person-group>
          <article-title>Compliance of left atrium with and without left atrium appendage</article-title>
          <source>Am J Physiol</source>
          <year>1990</year>
          <volume>259</volume>
          <issue>4</issue>
          <issue-part>Pt 2</issue-part>
          <fpage>H1006</fpage>
          <lpage>H1008</lpage>
        </element-citation>
      </ref>
      <ref id="B26">
        <label>26</label>
        <mixed-citation>26 Kamohara K, Popovic Z, Daimon M, Martin M, Ootaki Y, Akiyama M, et al. Impact of left atrial appendage exclusion on left atrial function. J Thorac Cardiovasc Surg. 2007;133(1):174-81.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Kamohara</surname>
              <given-names>K</given-names>
            </name>
            <name>
              <surname>Popovic</surname>
              <given-names>Z</given-names>
            </name>
            <name>
              <surname>Daimon</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Martin</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Ootaki</surname>
              <given-names>Y</given-names>
            </name>
            <name>
              <surname>Akiyama</surname>
              <given-names>M</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Impact of left atrial appendage exclusion on left atrial function</article-title>
          <source>J Thorac Cardiovasc Surg</source>
          <year>2007</year>
          <volume>133</volume>
          <issue>1</issue>
          <fpage>174</fpage>
          <lpage>181</lpage>
        </element-citation>
      </ref>
      <ref id="B27">
        <label>27</label>
        <mixed-citation>27 Tabata T, Oki T, Yamada H, Iuchi A, Ito S, Hori T, et al. Role of Left Atrial Appendage in Left Atrial Reservoir Function as Evaluated by Left Atrial Appendage Clamping. Am J Cardiol. 1998;81(3):327-32.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Tabata</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Oki</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Yamada</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Iuchi</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Ito</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Hori</surname>
              <given-names>T</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Role of Left Atrial Appendage in Left Atrial Reservoir Function as Evaluated by Left Atrial Appendage Clamping</article-title>
          <source>Am J Cardiol</source>
          <year>1998</year>
          <volume>81</volume>
          <issue>3</issue>
          <fpage>327</fpage>
          <lpage>332</lpage>
        </element-citation>
      </ref>
      <ref id="B28">
        <label>28</label>
        <mixed-citation>28 Johansson B, Bech-Hanssen O, Berglin E, Blomstr&#246;m P, Holmgren A, Jensen SM, et al. Atrial function after left atrial epicardial cryoablation for atrial fibrillation in patients undergoing mitral valve surgery. J Interv Card Electrophysiol. 2012;33(1):85-91.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Johansson</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Bech-Hanssen</surname>
              <given-names>O</given-names>
            </name>
            <name>
              <surname>Berglin</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Blomstr&#246;m</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Holmgren</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Jensen</surname>
              <given-names>SM</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Atrial function after left atrial epicardial cryoablation for atrial fibrillation in patients undergoing mitral valve surgery</article-title>
          <source>J Interv Card Electrophysiol</source>
          <year>2012</year>
          <volume>33</volume>
          <issue>1</issue>
          <fpage>85</fpage>
          <lpage>91</lpage>
        </element-citation>
      </ref>
      <ref id="B29">
        <label>29</label>
        <mixed-citation>29 Hanna I, Kolm P, Martin R, Reisman M, Gray W, Block PC. Left Atrial Structure and Function After Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO): six-month echocardiographic follow-up. J Am Coll Cardiol. 2004;43(10):1868-72.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Hanna</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Kolm</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Martin</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Reisman</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Gray</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Block</surname>
              <given-names>PC</given-names>
            </name>
          </person-group>
          <article-title>Left Atrial Structure and Function After Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO): six-month echocardiographic follow-up</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2004</year>
          <volume>43</volume>
          <issue>10</issue>
          <fpage>1868</fpage>
          <lpage>1872</lpage>
        </element-citation>
      </ref>
      <ref id="B30">
        <label>30</label>
        <mixed-citation>30 Sasaki S, Watanabe T, Tamura H, Nishiyama S, Wanezaki M, Sato C, et al. Left atrial strain as evaluated by two-dimensional speckle tracking predicts left atrial appendage dysfunction in patients with acute ischemic stroke. BBA Clin. 2014 Sep 28;2:40-7.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Sasaki</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Watanabe</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Tamura</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Nishiyama</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Wanezaki</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Sato</surname>
              <given-names>C</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Left atrial strain as evaluated by two-dimensional speckle tracking predicts left atrial appendage dysfunction in patients with acute ischemic stroke</article-title>
          <source>BBA Clin</source>
          <day>28</day>
          <month>09</month>
          <year>2014</year>
          <volume>2</volume>
          <fpage>40</fpage>
          <lpage>47</lpage>
        </element-citation>
      </ref>
      <ref id="B31">
        <label>31</label>
        <mixed-citation>31 Coisne A, Pilato R, Brigadeau F, Klug D, Marquie C, Souissi Z, et al. Percutaneous left atrial appendage closure improves left atrial mechanical function through Frank-Starling mechanism. Heart Rhythm. 2017;14(5):710-6.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Coisne</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Pilato</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Brigadeau</surname>
              <given-names>F</given-names>
            </name>
            <name>
              <surname>Klug</surname>
              <given-names>D</given-names>
            </name>
            <name>
              <surname>Marquie</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Souissi</surname>
              <given-names>Z</given-names>
            </name>
            <etal/>
          </person-group>
          <article-title>Percutaneous left atrial appendage closure improves left atrial mechanical function through Frank-Starling mechanism</article-title>
          <source>Heart Rhythm</source>
          <year>2017</year>
          <volume>14</volume>
          <issue>5</issue>
          <fpage>710</fpage>
          <lpage>716</lpage>
        </element-citation>
      </ref>
    </ref-list>
  </back>
</article>
