novel mechanistic insights into atrial functional mitral

Circulation Journal Vol.80, October 2016

2240 MACHINO-OHTSUKA T et al.Circulation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

clipping for MR.11–13 To decide the most effective therapeutic strategy for the MV, understanding the precise mechanism of the atrial functional MR is essential. The utility of 3D trans-esophageal echocardiography (TEE) for evaluating the detailed pathogenesis of MR has been widely accepted.14,15 Accord-ingly, the present study aimed to investigate the characteristics of the MV structure and dynamics through 3D-TEE in patients with atrial functional MR and lone persistent AF.

Editorial p 2098

MethodsStudy ProtocolThe subjects were enrolled into the present study as illustrated in Figure 1. Definitions of atrial functional MR were as fol-lows: MR that occurs with LA enlargement, and is not caused

he long burden of persistent atrial fibrillation (AF) leads to progression of left atrial (LA) remodeling.1,2 A severely enlarged LA sometimes causes significant

functional mitral regurgitation (MR), though there is no evi-dence of left ventricular (LV) remodeling or organic changes of the mitral valve (MV). Such MR seen in patients with AF was recently termed “atrial functional MR”.3–5 The interfer-ence of the coaptation of the leaflets because of mitral annular (MA) dilatation has been postulated as the main worsening factor of atrial MR.4,6,7 However, this postulation has been controversial8 and the 3-dimensional (3D) investigation of the mechanism of atrial functional MR is still limited.5 In patients with lone AF, significant MR may not be so rare4,9 and has been an important therapeutic target3,7 because of the associa-tion with a poor prognosis.10 Recent development of medical devices has provided various treatment options ranging from surgical MV repair to catheter-based annuloplasty or leaflet

T

Received May 6, 2016; revised manuscript received July 7, 2016; accepted July 18, 2016; released online August 17, 2016 Time for primary review: 11 days

Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, JapanMailing address: Yoshihiro Seo, MD, PhD, Cardiovascular Division, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba

305-8575, Japan. E-mail: [email protected] doi: 10.1253/circj.CJ-16-0435All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Novel Mechanistic Insights Into Atrial Functional Mitral Regurgitation

– 3-Dimensional Echocardiographic Study –Tomoko Machino-Ohtsuka, MD, PhD; Yoshihiro Seo, MD, PhD; Tomoko Ishizu, MD, PhD;

Kimi Sato, MD; Akinori Sugano, MD; Masayoshi Yamamoto, MD, PhD; Yoshie Hamada-Harimura, MD; Kazutaka Aonuma, MD, PhD

Background: Left atrial remodeling caused by persistent atrial fibrillation (AF) causes atrial functional mitral regur-gitation (MR), even though left ventricular (LV) remodeling and organic changes of the mitral leaflets are lacking. The detailed mechanism of atrial functional MR has not been fully investigated.

Methods and Results: Of 1,167 patients with AF who underwent 3D transesophageal echocardiography, 75 patients were retrospectively selected who developed no, mild, or moderate-to-severe atrial functional MR (n=25 in each group) despite an LV ejection fraction ≥50% and LV volumes within the normal range. Mitral valve morphology and dynamics were analyzed. Patients with moderate-to-severe MR had a larger mitral annulus (MA) area, smaller MA area fraction, and greater nonplanarity angle and tethering angle of the posterior mitral leaflet (PML) compared with other groups (all P<0.001). In the multiple regression analysis, the MA area, MA area fraction, nonplanarity angle, and PML angle were independent determinants of the effective regurgitant orifice area of MR after adjusting for LV parameters (adjusted R2=0.725, P<0.001). The PML angle and MA area had a higher standardized regression coefficient (β=0.403, P<0.001, β=0.404, P<0.001, respectively) than the other variables.

Conclusions: Functional atrial MR in persistent AF is caused by not only MA dilatation, but also by multiple factors including the MA contractile dysfunction, disruption of the annular saddle shape, and atriogenic PML tethering. (Circ J 2016; 80: 2240 – 2248)

Key Words: Atrial fibrillation; Left atrium; Mitral regurgitation; Three-dimensional transesophageal echocardiography

ORIGINAL ARTICLEValvular Heart Disease


22413D Analysis of Atrial Functional MR

eter was determined based on the American Society of Echo-cardiography recommendations.17,18 The LV volumes and LVEF were calculated by a modified Simpson’s method. The LA volume was defined as the largest LA volume just before the MV opening. It was measured from the apical view with the biplane method of disks and indexed to the body surface area. The right atrial (RA) area was measured on a still image of the apical 4-chamber view at mid-systole. The peak veloc-ity of the early (E) transmitral flow was recorded from the long-axis view by pulsed Doppler echocardiography. Tissue Doppler imaging was used to measure the early peak diastolic velocity (E’) at the mitral annular septal and lateral corners. The E/E’ ratio was calculated as E divided by the average of the 2 E’ velocities. We averaged 3 consecutive beats in SR and 5 consecutive beats in AF to obtain these measurements.

Color-flow Doppler images of the MR and tricuspid regur-gitation (TR) jets were acquired at a Nyquist limit of 50–60 cm/s. Quantification of the MR was performed as recommended by the American Society of Echocardiography using an integrated method, including measurement of the vena contracta width, effective regurgitant orifice area (EROA), and the area ratio of the MR jet to LA in mid-systole.19 The vena contracta width was measured from a magnified parasternal long-axis view. The EROA was calculating using the proximal isovelocity surface area method from apical views. The area ratio of the MR jet to LA was averaged from the apical 4- and 2-chamber views. Moderate-to-severe MR was defined by the presence of at least 2 of 3 color Doppler criteria categorizing the MR severity (ratio of the MR jet area to the LA area ≥20%, vena contracta width ≥3 mm, EROA ≥0.3 cm).19 Mild MR was defined by the presence of at least 2 of 3 criteria (ratio of the MR jet area to the LA area <20%, vena contracta width <3 mm, EROA <0.3 cm).19 Trace MR was classified as no MR. The ratio of the maximal TR jet area on color-flow mapping

by degenerative changes of the MV, LV remodeling or LV systolic dysfunction (as defined in the following text). We retrospectively screened 1,167 patients with persistent AF out of 2,595 patients who underwent transthoracic echocardiogra-phy (TTE) and TEE on the same day with a clinical indication between January 2012 and June 2015. Exclusion criteria were (1) absence of LA remodeling, defined16 as LA volume index (LAVI) ≤34 ml/m2 (n=3); (2) any regional wall motion abnor-malities, systolic LV dysfunction and enlargement of the LV, defined either as an LV ejection fraction (EF) <50% or LV end-diastolic volume (LVEDV) >74 ml/m2 for males and 61 ml/m2 for females16 (n=95); (3) structural mitral leaflet abnormality, such as leaflet prolapse or rheumatic disease (n=27); (4) mitral annulus (MA) calcification (n=78); (5) pre-vious MV surgery (n=1); (6) moderate or greater aortic valve disease (n=16); (7) congenital heart disease (n=2); (8) hyper-trophic cardiomyopathy (n=1); and (9) inadequate image qual-ity (n=37). Of the remaining cohort (n=907), 25 patients were diagnosed as moderate-to-severe functional atrial MR. To compare the MV morphology among the patients with differ-ent MR severities, we enrolled sex-, age-, and body surface area-matched patients with no MR (n=25) and mild atrial MR (n=25) from the remaining cohort. In addition, we included 25 control subjects who underwent TEE because of a clinical indication, but were revealed to not have cardiac disease. The clinical characteristics were also recorded as defined by the consultant cardiologist. Ethical approval of the present study was obtained from the local review committee, and all patients gave written informed consent.

Conventional TTE ExaminationThe 2D images were recorded with an iE33 ultrasound system equipped with an S5-1 phased array transducer (Philips Medical Systems, Andover, MA, USA). Each echocardiographic param-

Figure 1. Flowchart of the study of atrial functional MR. A total of 100 patients, including 75 with persistent atrial fibrillation (AF) and 25 controls, were enrolled. BSA, body surface area; LV, left ventricular; MR, mitral regurgitation; MV, mitral valve; TEE, trans-esophageal echocardiography.


2242 MACHINO-OHTSUKA T et al.

for a statistical analysis per frame and per percentage of the cardiac cycle. Using this software, we automatically quanti-fied the following measurements: MA anterior-posterior diam-eter, MA anterolateral-posteromedial diameter, sphericity index, as the ratio between anterior-posterior and anterolateral-pos-teromedial diameters, MA circumference, 2D (projected) MA area, nonplanarity angle (NPA) of the annulus, quantification of the “saddle shape” of the annulus, MV tenting volume, and anterior mitral leaflet (AML) and posterior mitral leaflet (PML) areas. The ratio of the PML area to the AML area was calcu-lated. The sum of both leaflet closure areas, defined as the total closure area and the ratio of the total leaflet closure area to the annulus area, was calculated. The systolic annulus area frac-tion was defined as (MA area late systole–MA area early systole)/MA area late systole×100%) as previously described.5 Because the measurement of the leaflet tethering angles is not supported by eSie Valves, we determined them in the mid-systole frame using the 3D quantification of QLAB (Philips Ultrasound) as described previously (Figure 2).24

Statistical AnalysisData are summarized as the mean ± standard deviation for continuous variables. Categorical variables are presented as percentages. The intergroup comparisons of the baseline char-acteristics, measurements of the echocardiography at specific time points in the cardiac cycle, and intragroup comparisons of the MA area and NPA during the cardiac cycle used 1-way ANOVA with post-hoc Tukey test. The linear association between the continuous variables was made using Pearson’s correlation coefficient. Regression analysis was used to evalu-ate the association between the MV measurements and EROA. A multivariate linear regression was further performed among

to RA area was measured on the apical 4-chamber view, as previously described.20

3D TEE ExaminationAfter an oral viscous and spray lidocaine gargle and swallow for local pharyngeal and esophageal anesthesia, all patients received intravenous sedation. TEE was performed using the iE33 ultrasound system equipped with an X7-2t TEE ultra-sound probe providing a range frequency of 2.0–7.0 MHz and both 2D and 3D matrix arrays (Philips Medical Systems). In the 25 control subjects, the 3D images were recorded with R-wave gating over 4 beats. In the 75 patients with AF, a 3D live zoom mode of an index beat, which was the beat after the nearly equal preceding and pre-preceding intervals, was used for each measurement as previously described.21 To increase the temporal resolution, care was taken to minimize the sector width and length, and the 3D images were recorded at a frame rate of at least 9 frames/s.

Dynamic MV Geometric AnalysisThe 3D datasets were analyzed using the 3D, knowledge-based, eSie Valves valve-modeling software, (Siemens Medical Solutions, Mountain View, CA, USA). The feasibility and methodology of the dynamic geometric analysis has been established previously.22,23 Briefly, after importing the data into the software, the end-systolic and end-diastolic frames were decided by visual identification. Next, the MV annulus and leaflets were automatically detected over each frame to con-struct a detailed morphology of the MV. After manual correc-tion of all alignments of the MV in each frame by the observer, the 3D MV model and quantified MV morphological measure-ments were displayed (Figure 2). Measured data were exported

Figure 2. Example of the modeling and quantification of the mitral valve structure. (A) The mitral annulus and leaflets of imported 3D transesophageal echocardiography data are automatically detected and their tracing is manually corrected in differently ori-ented planes. (B) 4D visualization and quantified measurements of the mitral valve (MV) morphology for the entire cardiac cycle. (C) Automatic calculation of the angles between the plane of the annulus and anterior (white arrow) and posterior (red arrow) mitral leaflets in a 3D MV reconstruction.



ResultsBaseline Characteristics and TTE FindingsThe general characteristics of the studied patients are sum-marized in Table 1. The patients with moderate-to-severe atrial MR had longer AF duration compared with the lesser MR groups. Regression analysis revealed significant correla-tion between AF duration and EROA (r=0.645, P<0.001). The TTE measurements and their correlations with EROA are shown in Table 2. Notably, the LAVI displayed the strongest correlation with EROA. There was also significant correlation

the variables with P values of <0.10 by a univariate correlation analysis to identify the independent determinants of EROA. To evaluate the correlation between the other variables, we performed a collinearity analysis before the multivariate anal-ysis. To avoid any problems caused by the collinearity, only the annulus area was entered into the multivariate models instead of the measurements of the annulus diameter and leaf-let area. The reproducibility was tested in 15 randomly selected patients. A value of P<0.05 was considered to be statistically significant. All statistical analyses were performed using SPSS statistics 22 software (SPSS Inc, Chicago, IL, USA).

Table 1. Baseline Characteristics of Subjects in a Study of Atrial Functional MR

Control (n=25)

Patients with AF (n=75)

P value*No MR (n=25)

Mild MR (n=25)

Moderate-to- severe MR

(n=25)

Age, years 66±8 66±9 66±9 66±9 0.866

Female sex 8 (32%) 8 (32%) 8 (32%) 8 (32%) 1.000

Body surface area, m2 　 1.69±0.19† 1.68±0.18 1.68±0.18 1.68±0.18 0.775

Duration of AF, years – 　　　3±3† 　　　4±5† 13±10 <0.001　Hypertension 12 (48%) 10 (40%) 10 (40%) 12 (48%) 0.885

Diabetes 3 (12%) 2 (8%) 2 (8%) 2 (8%) 0.947

History of stroke 2 (8%) 3 (12%) 2 (8%) 4 (15%) 0.771

Status during echocardiography

Systolic arterial pressure, mmHg 128±14 124±19 120±14 122±12 0.123

Diastolic arterial pressure, mmHg 72±11 73±15 71±12 71±13 0.916

Heart rate, beats/min 65±11 65±13 67±14 71±9 0.320

Results are shown as the mean ± SD or as the number (percentage in the same group). *Statistical difference (1-way ANOVA) among the groups. †P<0.01 vs. patients with moderate-to-severe MR (post-hoc test). AF, atrial fibrillation; MR, mitral regurgitation.

Table 2. Measurements on Transthoracic Echocardiography of Subjects in a Study of Atrial Functional MR

Control (n=25)


P value*

Correlation with EROA

No MR (n=25)

Mild MR (n=25)

Moderate-to-severe MR

(n=25)r P value

LVEF 65±7　　　　　 62±9　 61±7　　　 61±9 　0.240 −0.185　　　0.057

LV end-diastolic diameter, mm/m2 27±2　　　　　 28±3　 29±4　　　 29±3 　0.072 0.184 　0.058

LV end-systolic diameter, mm/m2 17±3　　　　　 19±3† 19±3†　　　　19±3† 　0.009 0.163 　0.095

LV end-diastolic volume, ml/m2 53±15　　　　53±13　 53±10　 54±10 　0.064 0.098 　0.322

LV end-systolic volume, ml/m2 19±8　　　　　 20±7　 21±6　　　 21±7 　0.698 0.172 　0.079

LA diameter, mm/m2 21±4‡　　　 23±2‡ 27±5‡　　　 35±8 <0.001 0.693 <0.001

LA volume, ml/m2 28±7‡　　　 37±11‡ 51±16‡ 128±105 <0.001 0.760 <0.001

Mitral inflow E wave, cm/s 67±20‡ 68±19‡ 75±25‡ 113±32 <0.001 0.668 <0.001

E’, cm/s 8.6±2.8‡ 8.5±2.6‡ 9.3±3.8　 10.9±5.0 0.01 0.301 　0.003

E/E’ ratio 8.1±2.9‡ 　　8.3±2.3　 8.4±2.8　 10.5±4.2 0.03 0.241 　0.016

MR severity

Ratio of the MR jet area to the LA area, % – – 18±7　　　 48±11 <0.001 0.856 <0.001

Vena contracta width, mm – – 2.2±0.6　 3.8±1.4 <0.001 0.847 <0.001

EROA, cm2 – – 0.06±0.04　 0.41±0.14 <0.001 – –

TR severity

TR jet area, cm2/m2 0.4±0.4‡ 0.9±1.6‡ 1.2±0.7‡ 4.1±2.2 <0.001 0.678 <0.001

RA area, cm2/m2 7.9±2.2‡ 8.3±1.9‡ 8.5±2.2‡ 16.2±7.1 <0.001 0.686 <0.001

Ratio of the TR jet area to the RA area, % 4.8±5.0‡ 10.9±6.7‡ 12.2±16.3‡ 24.7±9.5 <0.001 0.495 <0.001

Results are shown as the mean ± SD. *Statistical difference among the 4 groups by a 1-way ANOVA or unpaired t-test between 2 groups. †P<0.05 vs. control; ‡P<0.05 vs. patients with moderate-to-severe MR. EF, ejection fraction; EROA, effective regurgitant orifice area; LA, left atrial; LV, left ventricular; RA, right atrium; TR, tricuspid regurgitation. Other abbreviations as in Table 1.



Table 3. Comparison of the 3D Mitral Valvular Geometry of the Controls and Patients With AF in a Study of Atrial Functional MR

Control (n=25)


P value*

Correlation with EROA

No MR (n=25)

Mild MR (n=25)

Moderate-to-severe MR

(n=25)r P value

Mitral annulus

Anteroposterior diameter, cm 2.99±0.37† 3.11±0.34† 3.31±0.40† 3.74±0.66 <0.001 0.559 <0.001

Anterolateral-posteromedial diameter, cm 3.37±0.44† 3.44±0.37† 3.71±0.39‡ 4.08±0.62 <0.001 0.551 <0.001

Sphericity index 0.89±0.06 0.90±0.07　 0.90±0.11　 0.92±0.09 　0.792 0.076 　0.445

Circumference, cm 10.45±1.22† 10.69±1.01† 11.68±1.22‡ 12.79±1.87 <0.001 0.564 <0.001

Annulus area, cm2 7.76±1.56† 8.59±1.65† 9.71±1.94† 12.34±3.18 <0.001 0.640 <0.001

Systolic annulus area fraction, % 22.35±1.04† 15.57±7.52† 11.04±7.52‡ 6.87±4.49 <0.001 −0.413　 <0.001

Nonplanarity angle, ° 151±7†　　　 151±8†　　　 152±11† 162±7　　 <0.001 0.529 <0.001

Mitral leaflets

AML angle, ° 18±5　 19±10‡ 18±5　 15±3 　0.012 −0.257　　0.006

PML angle, ° 29±11† 30±9† 31±8† 52±14 <0.001 0.639 <0.001

AML area, cm2 4.62±0.85† 5.49±0.99† 6.07±1.42† 7.92±2.71 　0.001 0.516 <0.001

PML area, cm2 3.99±1.09†,§ 4.68±1.10　　　5.34±1.34　 5.11±1.08 　0.001 0.197 　0.049

PML to AML area ratio 0.86±0.22† 0.85±0.17‡ 0.88±0.23† 0.65±0.17 <0.001 −0.382　 <0.001

Total leaflet closure area, cm2 9.65±1.64† 10.17±1.85† 11.42±2.21‡ 13.06±3.45 <0.001 0.314 　0.003

Leaflet closure area to annulus area ratio 1.17±0.14‡ 1.15±0.09‡ 1.15±0.06‡ 1.05±0.10 　0.018 −0.379　 <0.001

Tenting volume, ml 1.46±0.62 1.54±0.74　　　2.12±1.08　 1.72±0.86 　0.316 0.049 　0.620

Results are shown as the mean ± SD. *Statistical difference among the 4 groups. All measurements except the systolic annulus area fraction were the values measured during mid-systole. †P<0.01, ‡P<0.05 vs. patients with moderate-to-severe MR; §P<0.01 vs. patients with mild MR. AML, anterior mitral leaflet; NPA, nonplanarity angle; PML, posterior mitral leaflet. Other abbreviations as in Table 1.

Figure 3. Differences in the mitral valve (MV) morphology between mild and severe atrial functional mitral regurgitation (MR) in patients with persistent atrial fibrillation (AF). (A) Example of mild atrial MR. No tethering and normal coaptation of the leaflets are seen on 2D echocardiography (2DE). The 4D MV model shows a normal saddle-shaped annulus and preserved mitral annulus (MA) contraction during systole. (B) Example of severe atrial functional MR caused by AF lasting for 15 years. On 2DE, a huge left atrium (LA) causes mounting of the posterior MA on the bended posterior inlet of the left ventricle and results in posterior mitral leaflet (PML) dominant tethering (yellow arrow). The 4D MV model also reveals annular flattening, PML tethering displayed as blue, and a reduction of the free margin of the PML (red arrows). Please note the different Y-axis scales of the measurements of the annulus area. AML, anterior mitral leaflet; ED, end-diastole; ES, end-systole; LAVI, left atrial volume index.



MR. MA area, PML angle, MA area, NPA, and the area ratio of PML to AML significantly correlated with EROA. These parameters also correlated with LAVI (r=0.639, P<0.001, r=0.545, P<0.001, r=0.385, P<0.001, and r=0.301, P=0.002, respectively). Figure 3 demonstrates the 3D-TEE findings of representative cases. In a patient with severe atrial MR, a huge LA causes the mounting of the posterior MA to the bended posterior inlet of the LV. Consequently, PML dominant teth-ering and restriction of PML margin occurred. Also, the patient with severe atrial MR demonstrated notable alterations of the annulus such as dilatation and flattening in comparison with patients showing mild atrial MR. The 4D analysis of MA dynamics showed that the extremely dilated annulus in the patient with severe atrial MR scarcely changed its area during the cardiac cycle and annulus contraction shown as systolic MA area fraction reduced compared with mild atrial MR.

between the LAVI and duration of AF (P=0.590, P<0.001). LV size and EF were within the normal ranges and there were no correlations with LV parameters and EROA. The RA area, TR jet area and the ratio of the TR area to the RA area were greater in the moderate-to-severe MR group than in other groups. The mitral E velocity, MA E’ velocity and the E/E’ ratio tended to be higher in parallel with deterioration of MR.

MV Parameters of 3D-TEEMV parameters measured by 3D-TEE were summarized in Table 3. The MA had a trend towards being larger and flatter and having worse contraction in the moderate-to-severe atrial MR group compared with either the patients with lesser MR or controls. Associated with MR deterioration, the PML teth-ering angle became greater; however, the AML angle did not. Although the AML enlarged when the MA dilated, the PML failed to increase its area sufficiently. As a result, the area ratio of PML to AML decreased in parallel with progression of

Figure 4. Differences in the 3D mitral annulus (MA) dynamics among the patients with atrial fibrillation (AF) and the controls. Measurements of MA area (A) and nonplanarity angle (B) in each phase of the cardiac cycle in patients with AF classified accord-ing to mitral regurgitation (MR) severity and control subjects. Intergroup comparisons at each time point revealed the moderate-to-severe atrial MR group showed the greatest values in both measurements (P<0.01 for both). Intragroup comparisons revealed that control subjects show a change in annulus morphology during the cardiac cycle (P<0.05 for both), whereas patients with AF show inadequate mitral annular contraction and saddle deepening in early systole. *P<0.01 compared with the other 3 groups at specific time points in the cardiac cycle (post-hoc test); †P<0.05 compared with values in other cardiac phases in the control group (post-hoc test).

Table 4. Multivariate Regression Analysis of the Determinants Associated With EROA

Variables

Model using the MV variables

(adjusted R2=0.726)

Model adjusted for the LA volume

(adjusted R2=0.736)

Model adjusted for the LV variables

(adjusted R2=0.725)

β P value β P value β P value

Annulus area, cm2 　0.363 <0.001　　0.279 0.001 　0.404 <0.001　Annulus area fraction, % −0.161 0.007 −0.151 0.009 −0.173 0.005

Nonplanarity angle, ° 　0.177 0.008 　0.179 0.005 　0.183 0.006

AML angle, ° −0.144 0.042 −0.112 0.041 −0.107 0.063

PML angle, ° 　0.351 <0.001　　0.324 <0.001　　0.403 <0.001　PML to AML area ratio −0.143 0.016 −0.109 0.067 −0.139 0.021

Leaflet closure area to annulus area ratio −0.020 0.738 −0.014 0.813 −0.018 0.722

LA volume index, ml/m2 – – 　0.247 0.002 – –

LV end-diastolic volume, ml/m2 – – – – 　0.011 0.850

LVEF, % – – – – −0.077 0.219

Systolic arterial pressure, mmHg 　0.068 0.220 　0.054 0.318 　0.063 0.255

β, standardized regression coefficient. Other abbreviations as in Tables 1–3.



larger and the area ratio of the PML to the AML became smaller according to worsening MR. This finding may be sup-ported by the recently proposed concept of “atriogenic PML tethering”.27 The extremely stretched LA posterior wall leads to inward bending of the posterobasal wall of the LV.28 The ventricular surface of the PML becomes pressed against the crest of the LV inlet, and the free margin of the PML available for coaptation decreases. Also, traction of the LA wall causes posterior annulus displacement onto the crest of the LV inlet, because the MA is histologically embedded in the LA wall.27 These morphological changes of the annulus augment the PML restriction via a mechanism in which LV remodeling does not contribute to it.27 Atriogenic PML tethering is practi-cally observed in patients who undergo an MV repair for atrial functional MR;3 however, to the best of our knowledge, we have provided, for the first time with statistical significance, evidence of the importance of atriogenic PML tethering asso-ciated with aggravation of the functional atrial MR. The tent-ing volume has been considered a measure of the degree of leaflet tethering below the annular plane in functional MR related to LV remodeling.29 However, we found no correlation between the tenting volume and EROA in the present study, which may be explained by both the asymmetric pattern of the leaflet tethering and the flattened annulus.30

Other coexisting annular factors, such as the systolic cir-cumferential contraction supporting effective leaflet coapta-tion and nonplanar geometry attenuating the leaflet stress, are also important for preventing regurgitation in a coordinated manner.26 The present study also revealed that annulus flatten-ing and contractile dysfunction progressed in parallel with severe enlargement of the LA and MA and they significantly exerted an influence on the worsening of atrial MR.

Regarding the other TTE findings, the RA and TR jet areas were greater in the moderate-to-severe MR group in compari-son with the other groups. Long-standing AF can cause sig-nificant dilatation of not only the LA but also the RA, leading to mitral and tricuspid annular dilatation and causing valvular regurgitation.20 Dilatation and overload of the right-sided heart may interfere with the MA structure and dynamics; however, further research is required to confirm that. In the present study, E velocity, E’ velocity and E/E’ ratio tended to be higher in parallel with deterioration of MR. Interpretation of E’ and E/E’ ratio as markers of diastolic dysfunction has a limitation, especially in patients with MR. It has been reported that LV filling pressures were not predictable by the E/E’ ratio in sub-jects with MR and preserved LV function,31 because E/E’ is generally increased in such patients caused by increased flow across the regurgitant valve. Also, patients with chronic MR have preserved LV relaxation and decreased LV stiffness to compensate for the volume overload.32 These previous find-ings may be consistent with the findings of the present study. LA remodeling and AF are surrogate markers of LV diastolic dysfunction. Therefore, patients in the present study might have had LV diastolic dysfunction to some extent; however, gradu-ally developing moderate-to-severe MR might cause compen-satory preservation of LV relaxation as previously reported.32

Clinical ImplicationsAtrial functional MR has been considered to be simply caused by annulus dilatation in previous studies based on conven-tional 2D echocardiography.4,6,7 However, the 3D analysis of the comprehensive MV structure and dynamics in the present study allowed us to clarify more complicated characteristics of atrial MR. Epidemiological data have revealed that the worldwide prevalence and incidence of AF have been progres-

Comparisons of Annular DynamicsDifferences of MA dynamics during end-diastole to end-sys-tole in each group are shown in Figure 4. MA area and NPA were larger at all individual time points in patients with mod-erate-to-severe MR than in others. In the control subjects, MA area reduced consistent with annular contraction and NPA- representing saddle-shape deepened markedly in early systole.

Determinants of Severity of Atrial Functional MRThe independent determinants of EROA were analyzed using multiple linear regression analysis (Table 4). MA area, annu-lus area fraction, NPA, and PML tethering angle were identi-fied as having a primary independent contribution after adjusting for LVEDV and systolic arterial pressure. Also, these variables were significant predictors after adjusting for LAVI. It is note-worthy that the PML tethering angle and MA area achieved higher standardized regression coefficients compared with the other variables.

Reproducibility of the MV ParametersIntraobserver correlation coefficients and mean absolute per-centage errors for MA area, MA area fraction, NPA and PML angle were 0.98 and 6.2±5.0%, 0.91 and 5.9±4.2%, 0.95 and 3.2±2.0%, and 0.92 and 5.1±3.7%, respectively. Interobserver correlation coefficients and mean absolute percentage errors for the same parameters were 0.93 and 6.5±6.7%, 0.89 and 9.9±6.8%, 0.93 and 4.2±3.4%, and 0.91 and 9.5±4.5%, respec-tively.

DiscussionThis study demonstrated that: (1) long-lasting AF causes LA remodeling that leads to morphological and functional changes in the MA and leaflets; (2) atrial functional MR has multiple deterioration factors including MA dilatation, a flattened annular saddle shape, annulus contractile dysfunction, and PML dominant tethering; and (3) the PML tethering angle is the most influential, independent factor for determining the EROA, along with annulus dilatation.

For a long time, whether MA dilatation alone is sufficient for the development of functional atrial MR has been contro-versial because there have been discrepant findings.3,5–8,20 Our findings provide novel evidence regarding this issue. Patients with AF had a trend of MA enlargement compared with the control subjects; however, that did not always lead to signifi-cant MR, which may be partly explained by compensatory enlargement of the leaflets, so-called mitral adaptation. Mitral adaptation has been observed in patients with LV remodeling and MA dilatation in ischemic or dilated cardiomyopathy.25 Although whether MA remodeling caused by AF-induced LA dilatation is also capable of such compensation has not been clarified thus far,26 our results showed that the mitral leaflets demonstrated the capacity of adaptation by compensatory enlargement to some extent in response to mechanical stretch from MA dilatation caused by the LA remodeling. However, the leaflets were unable to cover the extremely enlarged MA completely, as seen in the decrease of the leaflet closure area to annulus area ratio in the patients with moderate-to-severe MR. Thus, if MA dilates beyond the limits of leaflet adapta-tion, sufficient leaflet coaptation is impaired and atrial MR may occur.

Further, the most significant point we proved is that PML tethering unrelated to LV remodeling is seen in an enlarged LA and independently determines the severity of the atrial MR. Our results showed that the PML tethering angle became



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sively increasing based on global aging.33 In this social trend, the clinical significance of atrial functional MR may further increase in the future. Our results provided the following clinical suggestions. Considering extreme LA dilatation is the primary cause of atrial MR, therapeutic strategies to prevent or reverse the LA remodeling caused by AF should be empha-sized, as previously reported.4 Further, PML tethering inde-pendently aggravated the atrial functional MR, along with the annulus area, and therefore, a therapeutic approach for both the annulus and leaflets, such as simultaneous annuloplasty and chordal reconstruction, may be important options for cor-rection of atrial functional MR.

Study LimitationsFirstly, this was a retrospective, single-center study and the number of enrolled patients was relatively limited. Therefore, we could not separately analyze patients with moderate and severe atrial MR in interclass comparisons. However, we confirmed the main findings with our multivariate analysis that can continuously evaluate the effect of each variable on EROA. Also, the definition of moderate-to-severe MR has been commonly adopted in previous studies that investigated the prognosis of primary or secondary MR.34,35 Hence, we believe integrated analysis of moderate and severe MR can fit clinical practice. Secondly, patients with moderate-to-severe atrial MR had a slightly larger LVEDV than the other groups. However, these measurements were within the normal range16,36 and multivariate analysis revealed that PML tethering and MA dilatation were independent determinants of ERO even after adjusting for the LVEDV and LVEF. Therefore, these MV morphological changes are unrelated to LV remodeling and independently contribute to the development of atrial func-tional MR. Thirdly, the 3D data sets were acquired in a zoom mode in the patients who continued an AF rhythm during echocardiography. That might have affected the measurements of the annular dynamics because of lower frame rates. How-ever, the 3D image analysis was in line with the methodology of a previous study that investigated the MV dynamics in atrial functional MR.5 Finally, there were differences in the MA measurements during the cardiac cycle between the con-trol subjects and patients with AF; however, an AF rhythm itself might have an effect on the dynamics of the MA.37 Fur-ther investigation with a larger number of subjects using the latest 3D-TEE machines that are able to obtain 3D images with a higher frame rate during a single cardiac beat are desir-able to confirm the results of the present study.

ConclusionsAtrial functional MR caused by LA remodeling by long-standing persistent AF consisted of multiple alterations in the static morphology and dynamics of the MV. In particular, atriogenic PML tethering was the most influential deteriora-tion factor in atrial functional MR, along with MA dilatation.

AcknowledgmentsThe authors thank Dr Tran S. Toan of the Department of Cardiology, Cho Ray Hospital, for his assistance with the data preparation.

DisclosuresNone.

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novel mechanistic insights into atrial functional mitral

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