ORIGINAL ARTICLE

European Journal of Cardio-Thoracic Surgery 46 (2014) 720–728 doi:10.1093/ejcts/ezt656 Advance Access publication 11 February 2014

Quantification of the functional consequences of atrial fibrillation and surgical ablation on the left atrium using cardiac magnetic resonance imaging Jason O. Robertson, Anson M. Lee, Rochus K. Voeller, Marci S. Damiano, Richard B. Schuessler and Ralph J. Damiano* Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, Barnes-Jewish Hospital, St Louis, MO, USA * Corresponding author. Division of Cardiothoracic Surgery, Washington University School of Medicine, Barnes-Jewish Hospital, Campus Box 8234, 660 S. Euclid Ave, St Louis, MO 63110, USA. Tel: +1-314-3627327; fax: +1-314-7470917; e-mail: [email protected] (R.J. Damiano). Received 2 September 2013; received in revised form 6 December 2013; accepted 20 December 2013

Abstract OBJECTIVES: The effect of atrial fibrillation (AF) on left atrial (LA) function has not been well defined and has been largely based on limited echocardiographic evaluation. This study examined the effect of AF and a subsequent Cox-Maze IV (CMIV) procedure on atrial function. METHODS: Cardiac magnetic resonance imaging (cMRI) was performed in 20 healthy volunteers, 8 patients with paroxysmal atrial fibrillation (PAF) and 7 patients with persistent or long-standing persistent atrial fibrillation (LSP AF). Six of the PAF patients underwent surgical ablation with the CMIV procedure and 5 underwent both pre- and postoperative cMRIs. The persistent or LSP AF patients underwent only postoperative cMRIs because all scans were performed with patients in normal sinus rhythm. Volume–time curves throughout the cardiac cycle and regional wall shortening were evaluated using the cine images and compared across groups. RESULTS: Compared with normal volunteers, patients with PAF had significantly decreased reservoir contribution to left ventricular (LV) filling (P = 0.0010), an increased conduit function contribution (P = 0.04) and preserved booster pump function (P = 0.14). Following the CMIV procedure, significant reductions were noted with respect to reservoir and booster pump function, with corresponding increases in conduit function. These differences were more drastic in patients with persistent/LSP AF. Regional wall motion was significantly reduced by PAF in all wall segments (P < 0.05), but was not further reduced by the CMIV. Despite changes in LA function, LV function was preserved following surgery. CONCLUSIONS: PAF significantly altered LA function and has a detrimental effect on regional wall motion. Surgical intervention further altered LA function, but the reasons for this are likely multifactorial and not entirely related to the lesion set itself. Keywords: Atrial fibrillation • Magnetic resonance imaging • Atrial function

INTRODUCTION Atrial fibrillation (AF) is known to interfere with the normal mechanical functioning of the atrium, and its effects on cardiac function may persist even when patients are in sinus rhythm. Studies have shown that dilatation of the atrium occurs early in AF and is related to cardiovascular morbidity and mortality [1]. Contractile and structural remodelling also occur in AF, leading to significant fibrosis, hypertrophy and myolysis; reduced left atrial (LA) contractility and impaired transport function [2]. Relatively few studies have formally examined the effect of AF on atrial function. Several reports have shown a decreased left atrial ejection fraction in patients with AF [3]. The Cox-Maze procedure was introduced to restore normal sinus rhythm in patients with AF and has become the surgical gold standard in its treatment. Previous studies examining the effect of the Cox-Maze procedure on atrial function were based on echocardiography and were limited to demonstrating atrial

function as evidenced by the presence or absence of an A-wave on echocardiography [4, 5]. There have been no studies to assess the effects of the Cox-Maze IV (CMIV) procedure on either global or regional left atrial function in patients in a more comprehensive manner. The evaluation of atrial function has attracted much less attention than that of ventricular function, and published studies on normal and pathological atrial function are limited. Atrial function is conceptually more complex and has been more challenging to quantify than ventricular function. It is now well established that the LA converts the continuous pulmonary venous return into intermittent, high inflow into the left ventricular (LV) during mitral valve opening with three distinct functional components: reservoir, conduit and booster pump function [6, 7]. During ventricular systole, the LA serves as a ‘reservoir’ and undergoes passive expansion that is driven by the apical descent of the mitral annulus, resulting in the generation of the pulmonary venous Doppler S-wave. Reservoir function is affected by LA compliance

© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

J.O. Robertson et al. / European Journal of Cardio-Thoracic Surgery

METHODS Patient populations and data collection This study enrolled 20 healthy control subjects and 15 patients with AF. All patients with paroxysmal atrial fibrillation (PAF) were enrolled prospectively, and those with persistent or long-standing persistent (LSP) AF were enrolled either prospectively or retrospectively. Eight patients had paroxysmal AF and 7 patients had persistent or LSP AF. cMRI scans were obtained in all normal patients, preoperatively in all PAF patients and postoperatively in the 6 PAF patients who went on to receive a CMIV operation, which was performed as previously described [12]. Patients with persistent AF were only scanned postoperatively from a lone CMIV because, by definition, they were in AF preoperatively, precluding our ability to obtain a scan that would be comparable with the postoperative one obtained while in NSR. Significant structural or functional disease and any contraindication to MRI (e.g. non-compatible biometallic implants and claustrophobia) excluded patients from enrolment. This study was approved by the Washington University Institutional Review Board.

Imaging technique Subjects were scanned using a clinical 1.5-T Cardiovascular MRI system (Acheiva 1.5 T, Release 2.5.3, Philips Healthcare Systems; Best, Netherlands). Anatomical and functional cine images of the heart were acquired using a designated cardiac phase array coil and a retrospectively gated, breath-held, balanced turbo field echo method with parallel imaging that was adopted from the approach previously described by Bowman and Kovacs [9]. Survey images and standard planes were obtained for the horizontal long-axis (HLA), short-axis and LV outflow tract (LVOT) views. High-resolution cine loops of the HLA and LVOT views were then obtained while subjects held their breath (average of 10–15 s breath-holds, depending on the heart rate). Retrospective gating, a technique that does not require a pause at end diastole for prospective R-wave detection, allowed imaging of the entire R–R interval of the cardiac cycle. The HLA view was used to scan short-axis cine stack images perpendicular to the HLA axis. Approximately 20 short-axis stacks were generated 8 mm apart with zero gap, spanning from the LV apex through the superior-posterior wall of the LA. Short-axis cine image stacks were obtained during breath-holds, and cine loops were obtained for each slice for a full cardiac cycle. Each short-axis cine loop was divided into 30 cardiac phases. The repetition time, echo time and flip angles were 3.0 ms, 1.5 ms and 60°, respectively. In-plane resolution was 1.41 mm obtained with a field of view of 32 cm and a matrix size of 192 × 256 interpolated to 256 × 256. Total scanning time was
45 min. Heart rate was recorded during the entire examination and the R–R interval was synchronized accordingly during image acquisition. The scans were analysed using the ViewForum software (Philips Healthcare Systems), Merge eFilm (Merge Healthcare, Inc., Milwaukee, WI, USA) and Scion Image (Scion, Frederick, MD, USA).

Assessment of global left atrial function Global LA functional analysis was performed by computing the volume changes in the LA and LV throughout the full cardiac cycle. Volume–time relationships of the LA and LV were derived using the short-axis stacks. The endocardial contours of the LA and LV in each short-axis image slice at each phase of the cardiac cycle were manually traced (Supplementary Fig. S1) to calculate the cross-sectional area in pixels, which was then converted to square centimetre. Using the slice thickness of 0.8 cm, the segmental volumes were calculated in millilitre for each short-axis stack. Simpson’s rule was applied to derive the total LA and LV volumes at each phase of the cardiac cycle by summing the segmental volumes of the respective heart chambers using the following equation: ! n X Chamber volume ¼ Ai d ð1Þ i¼1

where n represents the number of short-axis image slices spanning the LA or LV, Ai is the area of the endocardial contour from the image slice at the ith level and d is the slice thickness. This process of determining total volumes at each phase of the cardiac cycle was semi-automated for patients analysed using the ViewForum software. Papillary muscles and the pulmonary veins were excluded from the tracings. The LVOT and left atrial appendage (LAA) (in preoperative and normal patients) were

ADULT CARDIAC

and relaxation, and it is an important determinant of cardiac output (CO) [8]. As the mitral valve opens following completion of ventricular ejection, the LA functions as a ‘conduit’ for the passage of blood that flows directly from the pulmonary veins into the LV. Although there is inflow from the pulmonary veins into the LA during early diastole (represented by the Doppler D-wave), LA volume is actually decreasing during this time as evidenced by the Doppler E-wave [9]. This occurs because LA reservoir and conduit volumes enter the LV simultaneously during early diastole. The rate of LV relaxation is an important determinant of LA conduit function because of the suction effect generated by the ventricle [10]. The last phase is characterized by active LA contraction and constitutes the ‘booster pump’ function of the LA, which serves as an additional determinant of ventricular end-diastolic volume. The relative importance of this active emptying (as opposed to passive emptying) increases with normal aging and in patients with diseased ventricles [11]. This active ejection, often known as the ‘atrial kick’, corresponds to the transmitral Doppler echocardiographic A-wave and is always accompanied by a slight amount of reverse flow into the pulmonary veins (represented by the pulmonary venous Doppler A-wave). The purpose of this study was to (i) non-invasively perform a comprehensive quantification of global and regional LA function in normal individuals and patients with AF, (ii) determine the effect of AF on LA function and (iii) determine the effect of surgical intervention with a CMIV on LA function. To achieve this, we employed cardiac magnetic resonance imaging (cMRI) both to assess global atrial function and to characterize regional function of the LA by quantifying segmental wall motion using a novel approach. MRI is an excellent tool for studying cardiac physiology because of its non-invasive nature, its high-resolution image quality and its ability to record cardiac motion with distinct contrast between the myocardium and the blood. It has a major advantage over echocardiography in that its threedimensional data format allows accurate measurement of cardiac chamber volumes in any plane through the heart during the entire cardiac cycle without requiring geometric assumptions and estimations.

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identified and included in the volumetry. All volume calculations were performed by two authors (Jason O. Robertson and Rochus K. Voeller). User-dependent variability in this method has been previously studied using 10 randomly selected short-axis images of the LV and LA and has been found to be negligible [9]. A typical cMRI LA volume–time curve with the corresponding electrocardiogram (ECG) tracing of a normal subject is illustrated in Fig. 1. As the LV enters its systolic phase after the QRS complex, the LA begins to passively fill with pulmonary venous return from Point A, the minimal LA volume (LAmin) at ventricular end diastole. Approximately halfway through the cardiac cycle, the LA reaches its maximal volume at ventricular end systole (LAmax, Point B) and the LA begins to passively empty its contents into the LV via the mitral valve opening. Point C refers to the mid-diastolic relative minimal volume (LArel min) at the end of passive LA emptying. Point D is the relative maximal volume (LArel max) immediately prior to atrial systole. A normal LV volume–time curve is also plotted in Fig. 1, where Point E represents the LV end-diastolic volume (LVEDV) and Point F represents the LV end-systolic volume (LVESV). LV stroke volume (LVSV) equals LVEDV − LVESV. Using the parameters extrapolated from the LA and LV volume– time curves, the global function of the LA was calculated in terms of LA booster pump volume (LABPV), LA reservoir volume (LARV) and LA conduit volume (LACV) contribution to LV filling. LARV was defined as LAmax − LArel min (B–C). The LABPV was defined as LArel max − LAmin (D–A). LACV could not be determined from the LA volume–time curve alone, and had to be calculated using the following equation: LVSV ¼ LABPV þ LARV þ LACV

ð2Þ

The LVSV must equal total inflow from the LA, so the LACV may be derived following the calculation of the LVSV, LABPV and LARV from the LV and LA volume–time curves, respectively. In order to further quantify left atrial reservoir, conduit and booster pump function, several additional measurements were also computed, as previously reported by Järvinen et al. [13] and Spencer et al. [11] using the following equations: Cyclic LA volume change ðLACC Þ ¼ LAmax  LAmin

Normalization for body surface area (BSA) was performed for LACC, but since the remaining indices of LA function are expressed as percentages, adjustment for BSA was typically not required.

Assessment of regional left atrial wall motion Regional LA function was assessed in all subjects by visualizing segmental wall motion using cine MRIs. The LA wall was divided into four segments: anterior, posterior, medial and lateral. The percent shortening of each of the LA wall segments was estimated by calculating the difference in the distance between the superior aspect of the LA (defined as the fixed reference point) and the corresponding position on the mitral annulus during atrial end systole and end diastole (Fig. 2). As shown in Supplementary Fig. S2, the HLA cine MRIs were used to visualize and measure the medial and lateral LA wall segmental motion, and the LVOT view was used to measure the anterior and posterior LA wall. This method of quantifying LA regional function was based on the observation that the superior, mediastinal aspect of the LA adjacent to the right pulmonary veins remains stationary during the cardiac cycle. The simplified mechanical motion of the LA is that of a piston; the mitral annulus acts as a piston moving superiorly and inferiorly during the cardiac cycle. Under normal conditions, the LA wall glides smoothly against the pericardium during this piston-like motion of the mitral annulus (Fig. 2).

Statistical analysis Continuous and categorical variables are expressed as mean ± SD and as number and percentage, respectively, unless otherwise specified. Comparisons were performed using a two-tailed, Student’s t-test for normally distributed, continuous variables and

ð3Þ

LA percent total emptying ðLAPTE Þ ¼ ðLAmax  LAmin Þ/LAmax  100

ð4Þ

LA expansion index ðLAEI Þ ¼ ðLAmax  LAmin Þ/LAmin  100 ð5Þ LA passive emptying percentage of total emptying ðLAPE Þ ¼ ðLAmax  LArel max Þ/ðLAmax  LAmin Þ  100

ð6Þ

LA passive emptying index ðLAPEI Þ ¼ ðLAmax  LArel max Þ/LAmax  100

ð7Þ

LA active emptying percentage of total emptying ðLAAE Þ ¼ ðLArel max  LAmin Þ/ðLAmax  LAmin Þ  100

ð8Þ

LA active emptying index ðLAAEI Þ ¼ ðLArel max  LAmin Þ/LArel max  100

ð9Þ

LA active ejection fraction ðLAEF Þ ¼ ðLArel max  LAmin Þ/LAmax  100

ð10Þ

Figure 1: LA- and LV-volume vs time curves. From the LV curve, stroke volume (E–F) and LVEF can be calculated. See text for details on LA curve points A through D. A: LA minimal volume, LAmin; B: LA maximal volume, LAmax; C: LA relative minimal volume, LArel min; D: LA relative maximal volume, LArel max.

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Fisher’s exact test for categorical variables. A Mann–Whitney U-test was used for non-parametric data. Matched data were analysed using a paired t-test following the demonstration of normality using the method of Kolmogorov and Smirnov. Multiple groups were compared using a one-way analysis of variance (ANOVA). A P-value of