Left Atrial Deformation Analysis in Patients with Corrected Tetralogy of Fallot by 3D Speckle-Tracking Echocardiography (from the MAGYAR-Path Study)

Background Three-dimensional (3D) echocardiography coupled with speckle-tracking echocardiographic (STE) capability is a novel methodology which has been demontrated to be useful for the assessment of left atrial (LA) volumes and functional properties. There is increased scientific interest on myocardial deformation analysis in adult patients with corrected tetralogy of Fallot (cTOF). Objectives To compare LA volumes, volume-based functional properties and strain parameters between cTOF patients and age- and gender-matched healthy controls. Methods The study population consisted of 19 consecutive adult patients with cTOF in sinus rhythm nursing at the University of Szeged, Hungary (mean age: 37.9 ± 11.3 years, 8 men, who had repair at the age of 4.1 ± 2.5 years). They all had undergone standard transthoracic two-dimensional Doppler echocardiographic study extended with 3DSTE. Their results were compared to 23 age- and gender-matched healthy controls (mean age: 39.2 ± 10.6 years, 14 men). Results Increased LA volumes and reduced LA emptying fractions respecting cardiac cycle could be demonstrated in cTOF patients compared to controls. LA stroke volumes featuring all LA functions showed no differences between the 2 groups examined. LA global and mean segmental uni- and multidirectional peak strains featuring LA reservoir function were found to be diminished in adult patients with cTOF as compared to controls. Similarly to peak strains reduced global and mean segmental LA strains at atrial contraction characterizing atrial booster pump function could be demonstrated in cTOF patients as compared to controls. Conclusions Significant deterioration of all LA functions could be demonstrated in adult patients with cTOF late after repair.

Recently, alterations in right (RV) 3,4 and left ventricular (LV) 4 and right atrial (RA) 5 functional properties could be demonstrated by 3DSTE.However, quantitative left atrial (LA) deformation assessment has never been performed in cTOF patients.Therefore, the present study aimed to detect changes in LA volumes, volumebased functional properties and strain parameters in cTOF patients as compared to age-and gender-matched healthy controls.

Patient population
Since 1961, more than 2,700 congenital heart disease patients have been treated and/or operated on at the Department of Pediatrics, Department of Heart Surgery, and 2nd Department of Medicine and Cardiology Center at the University of Szeged.

Introduction
Nowadays the angle-independent speckle-tracking echocardiography-derived (STE) myocardial deformation analysis is one of the main focus of cardiac ultrasound technology. 1 Threedimensional (3D) echocardiography coupled with STE capability is a novel methodology which has been demonstrated to be useful for the assessment of volumes and functional properties of cardiac chambers. 23DSTE allows complex assessment of atrial and ventricular morphology and function including volumetric and strain measurements from the same acquired 3D dataset.
][5] healthy control subjects without risk factors or known disorders in different age groups were examined by 3DSTE to assess the normal values of 3DSTE-derived parameters.From this pool 20 age-and gender-matched healthy subjects (mean age: 39.2 ± 10.6 years, 14 men) were selected who served as a control group in this particular study.All cTOF patients and controls were examined by two-dimensional (2D) Doppler, tissue Doppler echocardiography (TDI) and 3DSTE.The present study is a part of MAGYAR-Path Study (Motion Analysis of the heart and Great vessels bY three-dimensionAl speckle-tRacking echocardiography in Pathological cases) which has been organized at our department to examine diagnostic and prognostic significance of 3DSTE-derived variables.The institutional human research committee approved the study which complied with the 1975 Declaration of Helsinki.Informed consent was obtained from all cTOF patients and control subjects.

Two-dimensional Doppler and tissue Doppler echocardiography
All M-mode (MME), 2D Doppler and TDI studies were performed in the left lateral decubitus position with a commercially available Toshiba Artida TM echocardiography equipment (Toshiba Medical Systems, Tokyo, Japan) using a PST-30SBP phased-array transducer in all patients.LV dimensions were assessed by MME using the Teichholz method. 7alvular regurgitations were confirmed by colour Doppler echocardiography-derived visual grading.Following Doppler assessment of E/A, the ratio of transmitral E velocity to early diastolic mitral annular velocity (E/E') was measured by TDI.

Three-dimensional speckle-tracking echocardiography
All 3D echocardiographic data acquisitions were performed using a 1-4 MHz PST-25SX matrix phased-array transducer (Toshiba Medical Systems, Tokyo, Japan). 2 During a single breathhold full volume 3D datasets were created from the apical view from 6 wedge-shaped subvolumes using 6-beat electrocardiographically gated acquisitions.LA was quantified by the 3D Wall Motion Tracking software version 2.7 (Toshiba Medical Systems, Tokyo, Japan). 8Each 3D dataset was displayed in a five plane-view, namely apical two-(AP2CH) and fourchamber (AP4CH) views and three short-axis views at different levels of the LA.After positioning the main axis line through the center of the LA cavity the reader traced LA endocardial border in both orthogonal long-axis views.Firstly, the edge of the septal side of the mitral valve ring was traced, then markers were set in a counterclockwise rotation around the LA to the edge of the lateral side of the mitral valve ring.Subsequently, 3D wall motion tracking was then automatically performed through the entire cardiac cycle.

3DSTE for left atrial volumetric measurements
][10][11][12] End-systolic LA volume [largest LA volume before mitral valve opening (V max )], enddiastolic LA volume [smallest LA volume before mitral valve closure (V min )] and diastolic LA volume before atrial contraction [at time of P wave on ECG (V preA )] could be measured using the LA 3D cast, from which the following functional properties were calculated: Reservoir function: -Total Atrial Stroke Volume (TASV): V max −V min .

3DSTE for left atrial strain measurements
1][12][13][14] Not only global and mean segmental peak strains featuring LA reservoir function were measured for each patient, but strains at atrial contraction, characteristics of LA active contraction, were also evaluated (Figure 1).

Stastical analysis
Continuous data are presented as mean values ± standard deviation, while categorical data are summarized as a count and percentage.For comparing variables, the Student's t-test, chisquare analysis, and Fisher's exact test were used.All statistical tests were two-tailed and statistical significance was defined with a probability value less than 0.05.Recently, intra-and interobserver agreements for LA volumes and functional properties were performed in papers originating from MAGYAR-Healthy and MAGYAR-Path Studies. 8,11Data were analysed using Medcalc software (MedCalc, Mariakerke, Belgium).

Clinical data
Risk factors, medications applied and 2D echocardiographic data are presented in Table 1.Significant (>grade 2) mitral and tricuspid regurgitations could be detected in 2 (11%) and 8 (42%) cTOF patients.None of the healthy controls had significant regurgitations.The TAPSE and RV-FAC values of cTOF patients proved to be 18.2 ± 4.6 mm and 34.2 ± 3.9%, respectively.

3DSTE-derived LA volumes and volume-based functional properties
Increased LA volumes and reduced LA emptying fractions respecting cardiac cycle could be demonstrated in cTOF patients compared to controls.LA stroke volumes featuring all LA functions showed no differences between the groups examined (Table 2).

3DSTE-derived LA peak strain parameters
LA global and mean segmental uni-and multidirectional peak strains featuring LA reservoir function were found to be diminished in adult patients with cTOF as compared to controls (Table 3).

3DSTE-derived LA strain parameters at atrial contraction
Similarly to peak strains reduced global and mean segmental LA strains at atrial contraction characterizing atrial booster pump function could be demonstrated in cTOF patients as compared to controls (Table 3).

Discussion
][10][11][12][13][14] The study reported here is the first to analyse 3DSTE-derived LA deformation in adult patients with cTOF.Increased LA volumes and diminished LA emptying fractions and strains could be demonstrated in this detailed analysis.Results suggest significant deterioration of all LA functions (reservoir, conduit and booster pump) in adult patients with cTOF late after repair.4][5] In a recent study RV free wall strain and strain rate were found to be decreased in adults late after TOF repair, especially at the apical segment suggesting that apical function is most affected in these RVs. 4 Regarding the LV, septal strain was decreased indicating that RV dysfunction adversely affects LV function, probably by mechanical coupling of the ventricles.In another study, the majority of adults with cTOF showed a reduced LV twist. 22Strikingly, one-quarter of these patients had an abnormal apical rotation which has been found to be associated with decreased systolic LV and RV function.These findings suggested that abnormal apical rotation could be a new objective diagnostic criterion for detection of ventricular dysfunction in cTOF.
The complexity of RA dysfunction could also be demonstrated by 3DSTE in cTOF patients. 5Comparing this with the present study, both RA and LA volumes seemed to be increased in adult patients with cTOF.Moreover, large similarity of RA and LA deformation could also be demonstrated: while RA/LA emptying fractions were found to be decreased, RA/LA stroke volumes remained unchanged.All the peak LA strains and LA strains at atrial contraction were found to be reduced and this reduction was more pronounced in cTOF as compared to the values related to RA. Therefore it seems that the LA is very important.From other studies also the LA proved to be important. 23veral factors may play a role in the altered atrial function in cTOF, such as the interaction between both atria, the presence of mitral/tricuspid regurgitation, arrhythmias and changes in both ventricular features as demonstrated before.Further studies are warranted to understand the real pathophysiologic background of these findings.

Limitation
The present study covered only a relatively small number of patients from a single center by a single observer (DP).Therefore, future multicenter studies with larger patient populations are necessary.Another limitation of image acquisition for 3DSTE is the relatively slow volume rate.During creating 3D model of the LA, septum was considered as a part of the LA similarly to other studies evaluating RA. 5 Finally, LA appendage and pulmonary veins were excluded which could theoretically affect results.During the present study, LV, RV and RA functional characterization was not aimed to be performed.

Conclusions
Significant deterioration of all LA functions could be demonstrated in adult patients with cTOF late after repair.

Figure 1 -
Figure 1 -Images from three-dimensional (3D) full-volume dataset showing left atrium (LA) in a patient with corrected tetralogy of Fallot is presented: (A) apical fourchamber view, (B) apical two-chamber view, (C3) short-axis view at basal, (C5) mid-and (C7) superior left atrial level.A 3D cast (D), volumetric data (E), time -global volume and time -segmental strain curves (F) of the LA are also presented.Dashed curve (F) represents LA volume changes during cardiac cycle with maximum (V max ), minimum (V min ) LA volumes and LA volume at atrial contraction (V preA ).White arrow represents peak strain, while dashed arrow represents strain at atrial contraction (F).LA: left atrium; LV: left ventricle.

Table 1 -Demographic and clinical data of patients with tetralogy of Fallot and that of controls
ACE: angiotensin-converting enzyme; LA: left atrial; LV: left ventricular; cTOF: corrected tetralogy of Fallot.