ARTICLE IN PRESS
Determinants of Exercise-Induced Mitral Regurgitation
Using Three-Dimensional Transesophageal
Echocardiography Combined With Isometric Handgrip
Exercise
Yu Harada, MD, Hiroto Utsunomiya, MD, PhD*, Hitoshi Susawa, MD, Kosuke Takahari, MD,
Hajime Takemoto, MD, Yusuke Ueda, MD, Kanako Izumi, MD, Kiho Itakura, MD,
Takayuki Hidaka, MD, PhD, and Yukiko Nakano, MD, PhD
Using three-dimensional (3D) transesophageal echocardiography (TEE) and isometrichandgrip exercise (IHE), we investigated the determinants of exercise-induced mitral
regurgitation (MR) according to MR etiologies. Seventy-six patients with more than moderate MR, 40 patients with functional MR (FMR) and 36 patients with degenerative MR(DMR), underwent 3D TEE combined with IHE. Mitral valve (MV) geometry and 3D
vena contracta area (3D VCA) were simultaneously evaluated at baseline and during IHE.
With regard to exercise-induced MR, D3D VCA was calculated as the difference between
3D VCA at baseline and 3D VCA during IHE. IHE caused different changes in MV geometry between etiologies and led to exacerbation of 3D VCA at baseline. Larger D3D VCA
was observed in the FMR group compared with the DMR group (15.9 § 10.3 mm2 versus
7.3 § 4.2 mm2; p < 0.0001). In multivariate analyses, tenting height and 3D VCA wereselected as independent factors associated with D3D VCA in the FMR group (p = 0.0135
and p = 0.0201, respectively), while flail width was selected as an independent factor associated with D3D VCA in the DMR group (p = 0.0066). In conclusion, IHE alters mitral valve
geometry and causes exacerbation of MR regardless of MR etiology and the determinantsof exercise-induced MR differed between MR etiologies. © 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/) (Am J Cardiol 2021;00:1−8)

Dynamic changes in mitral regurgitation (MR) during
exercise are well-known as exercise-induced MR. Whenthe exacerbation is severe, it is considered a prognosticatorin heart failure (HF) patients.1,2 Exercise-stress echocardiography is an essential tool for diagnosis of exerciseinduced MR. However, in previous studies, characterizations of the mechanisms for exercise-induced MR were
hampered by several limitations of 2-dimensional (2D)
transthoracic echocardiography (TTE) based quantitative
assessment of mitral valve (MV) and MR.1−3 In contrast,with the development of 3-dimensional (3D) echocardiography and dedicated software analysis over the past decade,3D transesophageal echocardiography (TEE) allows accurate measurement of the MV geometry and MR severity.4,5Furthermore, isometric handgrip exercise (IHE) has long
been reported as a useful method to differentiate patientswith risk for HF among patient populations.6 In contrast to
Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. Manuscript received December 22, 2020; revised manuscript received and accepted
April 13, 2021.
Sources of Funding: This work was partially supported by MSD Life Science Foundation, Public Interest Incorporated Foundation. This work wasalso supported by Takeda Science Foundation.
Disclosures: All authors have reported they have no relationships relevant to the contents of this paper to disclose.
*Corresponding author: Tel: (81) 82 257 5540; fax: (81) 82 257 1569.
E-mail address: hutsu@hiroshima-u.ac.jp (H. Utsunomiya).

dynamic load-testing (e.g., cycle exercise), it can be performed even during TEE. In this study, using 3D TEE combined with IHE, we sought to evaluate the changes in MV
geometry and MR severity during exercise and to investigate the determinants of exercise-induced MR in functional
MR (FMR) compared with degenerative MR (DMR).
Methods
We prospectively enrolled symptomatic patients withmoderate or greater MR at baseline who underwent 3D
TEE at Hiroshima University Hospital between May 2017
and July 2019. The patient population was divided into an
FMR group and a DMR group based on pathogenic stratification by 2D TTE. The etiology of MR was defined as
FMR if resulting from regional myocardial dysfunction or
global remodeling of the LV in the presence of an anatomically normal valve apparatus, or as DMR if resulting fromstructural defects of the MV due to leaflet prolapse or flail.
Patients with other degenerative alterations including rheumatic or sclerotic changes, or definite diagnosis of infective
endocarditis were excluded. Patients with MV stenosis orprevious valve surgery were also excluded. Informed consent was obtained from all participants and the study protocol was approved by our institutional ethics committee.
A comprehensive 2D TTE study was performed by experienced sonographers using a commercially available ultrasound system (EPIQ7 with S5-1 probe; Philips, Andover,

0002-9149/© 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
https://doi.org/10.1016/j.amjcard.2021.04.018

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The American Journal of Cardiology (www.ajconline.org)

MA). All measurements and recordings were performed
according to the American Society of Echocardiography
recommendations.7 LV end-diastolic volume, LV end-systolic volume, LV ejection fraction, and left atrial (LA) volume were calculated by the modified Simpson method
using apical 2- and 4-chamber views.8 Systolic pulmonary
artery pressure (SPAP) was calculated according to guidelines and right atrial pressure was estimated from the inferior vena cava diameter and respiratory changes.9 Severityof MR was graded comprehensively by an integrative
approach using semiquantitative parameters and at least
one quantitative parameter, including proximal isovelocity
surface area-derived effective regurgitant orifice area, vena
contracta width, regurgitant volume, and presence of systolic flow reversal in pulmonary veins according to the recommendations of the European Society of Cardiology andAmerican Society of Echocardiography using three MR
grades: mild, moderate, and severe.10,11 Regurgitant volume was calculated by the proximal isovelocity surface
area method. Regurgitant fraction was determined by the
regurgitant volume, while LV stroke volume was calculated
as the difference between LV end-diastolic volume and LV
end-systolic volume. In patients with atrial fibrillation, theparameters were calculated as means of 3 to 5 measurements.
3D TEE was performed using an EPIQ7 ultrasound system equipped with a matrix-array transducer that could display both 2D and 3D images (X7-2t or X8-2t Live 3D TEEtransducer; Philips). All patients were administered an
intravenous injection of diazepam and pentazocine for sedation during the 3D TEE examination. Volume datasets wereobtained in the live 3D zoom mode (median frame rate: 17Hz) or 6-beat full volume mode (median frame rate: 69 Hz)
focusing on the MV. In addition, color Doppler live 3Dzoom or 6-beat full volume datasets were acquired at thenarrowest possible depth under breath-hold to obtain ahigher volume rate (median frame rate: 35 Hz). In patientswith atrial fibrillation or inability to hold their breath, thelive 3D zoom mode with 1-beat volume acquisition waschosen. The live 3D zoom or full volume datasets were digitally stored for off-line analysis and imported into a QLAB
workstation (version 10.7; Philips).
Just before the 3D TEE examination, maximal voluntary
contraction (MVC) was measured in all patients using thehandgrip diameter. During 3D TEE, all patients wereadministered sedative drugs intermittently according totheir level of sedation. After 3D volume data acquisition atbaseline for offline analysis, drug administration was
stopped to control patient awakening. In the final TEE
examination, patients used their dominant hand to perform
3 minutes of IHE at 30% MVC in a left lateral decubitus
position. Systolic blood pressure (BP), diastolic BP, andheart rate were measured using an automated brachial arteryBP cuff (BMS-1763; Nihon Kohden, Tokyo, Japan).
Finally, hemodynamic status and 3D volume data focusedon the MV were carefully recorded for the final minute of
IHE.
All 3D volume datasets were analyzed offline using the
QLAB mitral valve navigation (MVN) and 3D quantification (3DQ) software package (Philips). Regarding the timing for assessment of 3D MV geometry and 3D VCA, theoccurrence of the peak velocity in the corresponding continuous wave Doppler signals was used for orientation. In all
FMR patients, the mid-systolic frame was selected, while in
17 DMR patients (38%), the mid-to-late systolic frame wasselected. The QLAB MVN software semi-automaticallytracked the landmarks in a specified frame to create a 3D
mitral model. After approval of the tracking, the software
provided several 3D measurements of the MV geometry:anterolateral-posteromedial (AL-PM) diameter, anteriorposterior (A-P) diameter, annular area, annular height, tenting height, tenting volume, prolapse height, and prolapse
volume (Figure 1 A−H).4 Furthermore, in all DMR
patients, a cross-sectional plane through the MV leaflets
was selected and the maximum flail gap and width were
measured with movement of the 2D planes in the 3D spaceat the same frame (Figure 1 I and J). All measurements
were acquired at baseline and during IHE with specified
timing of the systolic phase.
By quantitative analysis of 3D color Doppler data,
the 3D VCA was derived through three multiplanarreconstruction planes in a specified frame. After the two
orthogonal long-axis planes were aligned parallel withthe direction of the proximal MR jet, the short-axis
plane was aligned perpendicular to the narrowest neckof the MR jet just above the left atrial side of the flow
convergence zone. The resultant short-axis image of the
MR jet was manually traced to obtain the 3D VCA.5
The three multiplanar reconstruction planes of the regurgitant jet, 3D color MV image, and measured 3D VCA
in each FMR and DMR patient are shown in Figure 2.
3D VCA was measured at baseline and during IHE in
all patients. D3D VCA was defined as the change in 3D
VCA during exercise and calculated by the difference
between 3D VCA at baseline and 3D VCA during IHE.
Statistical analyses were performed with JMP ver. 14.0
software (SAS Institute Inc., Cary, NC). Continuous variables were expressed as median (25th and 75th percentiles)
or mean § standard deviation (SD). Groups comparisonswere performed by Student’s t-test. A paired t-test was used
to compare hemodynamic status and MV geometry at restand during IHE. Comparisons of the effects of IHE on MV
geometry between the groups were carried out by two-way
ANOVA for repeated measures. Correlations between peakVo2 and D3D VCA in the FMR and DMR groups wereassessed by Pearson correlation coefficients and linear
regression analysis. Multivariate stepwise linear regression
analysis was performed to identify contributing factors
related to D3D VCA in the FMR and DMR groups, and significant variables in the univariate analyses were enteredinto the models. The following potential univariate predictors at baseline were initially considered for the analysis:
systolic BP, diastolic BP, heart rate, AL-PM diameter, A-P
diameter, annular area, annular height, tenting height, tenting volume, prolapse height, prolapse volume, flail gap, flailwidth, and baseline 3D VCA. For reproducibility, 3D TEEmeasurements, as described by absolute differences with
SDs and intraclass correlations, were analyzed in a randomly selected sample of 40 datasets in MR patients (20FMR patients and 20 DMR patients). The selected datasets
were evaluated at 1 month after the initial measurement by
the first author for intra observer variability and by a second

ARTICLE IN PRESS
Valvular Heart Disease/Determinants of Exercise-Induced MR

3

Figure 1. 3D parameters of MV geometry. (A−H) After approval of the tracking, the MVN software semi-automatically creates a 3D mitral model and provides 3D parameters of the MV. (I, J) In patients with degenerative MR, flail gap (I) and flail width (J) are searched and measured at their maximum length
in a cross-sectional plane through the MV leaflets. 3D = three-dimensional; MV = mitral valve; MR = mitral regurgitation; MV = mitral valve.

observer for interobserver variability. Two-sided values ofp < 0.05 were considered statistically significant.
Results
A total of 76 patients were enrolled in the study. The
FMR group consisted of 40 patients comprising 17 dilated
cardiomyopathy, 10 ischemic cardiomyopathy, and 13 atrial
MR, while the DMR group consisted of 36 patients comprising 21 leaflet prolapse and 15 leaflet flail. The clinicaland TTE parameters in the two MR groups are summarizedin Table 1. In the 2D TTE parameters, the FMR group had
significantly larger LV end-diastolic volume, LV end-systolic volume, and lower LV ejection fraction (all p < 0.001)
with larger LA volume. As for MR severity, both regurgitant volume and fraction were similar in the two groups(Table 1).
The hemodynamic status and 3D parameters of MV
geometry in the two MR groups at baseline and during IHE
are summarized in Table 2. In the baseline 3D parametersof MV geometry, AL-PM diameter, A-P diameter, annulararea, and annular height also showed no significant

Figure 2. . Examples of 3D VCA quantitative analysis in functional MR and degenerative MR. Using acquired 3D color Doppler MV data, the QLAB 3DQ
software can display three orthogonal planes of the regurgitant jet and a 3D MV image. After the two orthogonal long-axis planes are set with the directionof the regurgitant jet, 3D VCA is obtained by the short-axis plane at the narrowest neck region of the regurgitant jet (white circles). VCA = vena contracta
area. Other abbreviations as Figure 1.

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4The American Journal of Cardiology (www.ajconline.org)

Table 1
Clinical and echocardiographic characteristics
Variable

Functional
MR (n = 40)

Degenerative
MR (n = 36)p

Age (years)
71 (61−77)
68 (60−74)
0.96
Men
25 (63%)22 (61%)0.90
1.61 (1.46−1.72) 1.59 (1.43−1.77)
0.63
Body surface area (m2)
Atrial fibrillation
13 (33%)
3 (8%)
0.02
Hypertension
29 (73%)18 (50%)
0.04
Left ventricular end140 (105−201) 111 (81−136)< 0.001
diastolic volume (mL)
Left ventricular end89 (56−134)
39 (31−46)< 0.001
systolic volume (mL)
Left ventricular ejection
36 (28−48)
66 (62−69)< 0.001
fraction (%)
Left atrial volume (mL)
100 (76−132)
85 (64−110)
0.046
Systolic pulmonary artery
36 (29−49)
34 (27−40)
0.40
pressure (mm Hg)
Severe mitral regurgitation
23 (58%)27 (75%)
0.11
Regurgitant volume (mL)
44 (32−56)
61 (44−75)
0.22
Regurgitant fraction (%)
47 (42−64)
51 (44−57)
0.81
Data are shown as median (interquartile range) or n (%).

differences. The FMR group had higher tenting height andlarger tenting volume than the DMR group (both p <0.0001). In contrast, the DMR group had higher prolapse
height and larger prolapse volume than the FMR group(both p < 0.0001). IHE elevated the baseline systolic BP,
diastolic BP, and heart rate in both MR groups (all p <0.001). The changes in systolic BP and heart rate did not
differ significantly between the two groups, whereas thechanges in diastolic BP were larger in the DMR group compared with the FMR group (Table 2). In the FMR group,
significant augmentations in tenting height and tenting volume were observed during IHE (both p < 0.001). Meanwhile, in the DMR group, significant reductions in annularheight and tenting volume were observed during IHE (bothp < 0.02). Furthermore, significant augmentations in prolapse height, prolapse volume, flail gap, and flail width
were observed in the DMR group (Table 2).
Representative 3D color Doppler images of the MV and
MR at baseline and during IHE in both MR groups areshown in the upper panels in Figure 3A and 3B. Different
mitral models in each phase analyzed by the MVN softwareare shown in the lower panels of Figure 3A and 3B.
Figure 4 shows the changes in 3D VCA caused by IHE.
In our study, baseline 3D VCA in the FMR group was
smaller than that in the DMR group (36.7 § 17.5 mm2 vs46.4 § 19.0 mm2; p = 0.022). IHE caused significant exacerbations of baseline 3D VCA in both MR groups (FMR:
36.7 § 17.5 mm2 to 52.6 § 24.0 mm2; DMR: 46.4 § 19.0mm2 to 53.8 § 21.1 mm2; both p < 0.0001). Despite thepresence of smaller 3D VCA at baseline, the FMR group
had larger D3D VCA than the DMR group (15.9 § 10.3mm2 vs 7.3 § 4.2 mm2; p < 0.0001).
As shown in Table 3, univariable analyses revealed that
tenting height, tenting volume, and baseline 3D VCA weresignificantly correlated with D3D VCA in the FMR group.
Meanwhile, AL-PM diameter, prolapse height, prolapse
volume, flail gap, flail width, and baseline 3D VCA weresignificantly correlated with D3D VCA in the DMR group.
When these univariable determinants were entered into themultivariable stepwise linear regression analysis, tenting
height (p = 0.014) and baseline 3D VCA (p = 0.02) wereselected as independent predictors of D3D VCA in the
FMR group, whereas only flail width (p = 0.007) was
selected as an independent predictor of D3D VCA in the
DMR group.
The intra observer and interobserver variabilities of the
3D TEE datasets were 1.9 § 1.4 and 2.4 § 1.9 mm for 3D
measurements of MV geometry and 2.5 § 1.7 and 3.2 §2.4 mm2 for 3D VCA, respectively. The intraclass

Table 2
Impacts of isometric handgrip exercise on hemodynamic status and 3D mitral valve geometry
Variable

Hemodynamic status
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
Heart rate (bpm)
3D mitral valve geometry
AL-PM diameter (mm)A-P diameter (mm)Annular area (100 mm2)
Annular height (mm)Tenting height (mm)Tenting volume (mL)
Prolapse height (mm)
Prolapse volume (mL)
Flail gap (mm)
Flail width (mm)Functional MR (n = 40)

Degenerative MR (n = 36)

p (time- group interaction)

Baseline

HandgripBaseline

Handgrip122 § 2874 § 1877 § 17138 § 32*
83 § 18*84 § 16*131 § 1978 § 1272 § 12149 § 19*94 § 13*,y80 § 12*

0.51
0.01
0.73

39.6 § 5.8
31.9 § 5.2
10.5 § 3.1
4.3 § 1.3
8.8 § 2.6
3.8 § 1.7
0.3 § 0.7
0.0 § 0.0
N/A
N/A

39.6 § 5.9
31.7 § 5.2
10.3 § 3.1
4.1 § 1.3
9.3 § 2.6*
4.1 § 1.8*
0.2 § 0.7
0.0 § 0.0
N/A
N/A

39.2 § 4.2
31.4 § 4.2
10.2 § 2.3
3.8 § 1.1
6.0 § 1.9y
1.5 § 0.9y
3.9 § 2.1y
0.5 § 0.5y
3.7 § 1.5
11.2 § 3.1

39.5 § 4.4
31.8 § 4.1
10.3 § 2.4
3.4 § 0.7*,y5.8 § 1.9y
1.4 § 0.9*,y4.6 § 2.2*
0.6 § 0.7*
4.0 § 1.9*
11.6 § 3.2*

0.23
0.14
0.08
0.36
< 0.001< 0.001< 0.001< 0.001
N/A
N/A

Data are shown as mean § SD.
* p < 0.05 versus baseline.
yp < 0.05 versus functional MR.
AL-PM, anterolateral-posteromedial; A-P, antero-posterior.

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Valvular Heart Disease/Determinants of Exercise-Induced MR

5

Figure 3. . Representative cases of IHE-stress 3D TEE. (Upper) 3D color MV images at baseline and during IHE in both MR groups (left, functional MR;
right, degenerative MR). (Lower) 3D MV geometry analyzed by the MVN software at baseline and during IHE in both MR groups (left, functional MR; right,
degenerative MR). Note that exacerbation of the MR jet and the changes in MV geometry occur concomitantly during IHE. IHE = isometric handgrip exercise. Other abbreviations as Figure 1.

correlations (95% confidence intervals) were 0.94 (0.92−0.96) and 0.93 (0.91−0.95) for 3D measurements of MV
geometry and 0.92 (0.90−0.95) and 0.90 (0.86−0.93) for
3D VCA, respectively.
Discussion
To date, several studies using 2D TTE with cycle
exercise have shown that exercise-induced MR was
associated with acute pulmonary edema, exercise intolerance, and poor prognosis regardless of the MR
etiology.1,3,12,13 Indeed, exercise-stress echocardiography

has proven to be a strong prognostic indicator inpatients with unexplained dyspnea and may be usefulfor classification of heart failure with preserved LV
ejection fraction.14,15 Thus, the current guidelines of theAmerican Society of Echocardiography and European
Association of Echocardiography recommend 2D TTEwith cycle ergometer exercise for general diastolic stresstesting.16,17 However, compared with TEE, it is wellknown that TTE has several clinical limitations to its
application from the perspective of imaging quality. For
example, obesity, poor acoustic window limited byrespiratory excursion, and motion artifacts impair the

Figure 4. Changes in 3D VCA during IHE in the two MR groups. IHE significantly increases baseline 3D VCA in both MR groups (circles, functional MR;
triangles, degenerative MR), but larger D3D VCA is observed in the functional MR group compared with the degenerative MR group (p < 0.0001). * p <0.0001 versus baseline, yp = 0.022 versus functional MR, zp = 0.82 versus functional MR. IHE = isometric handgrip exercise. Other abbreviations as Figures
1 and 2.

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The American Journal of Cardiology (www.ajconline.org)

Table 3
Correlations and associations of baseline hemodynamic status and 3D mitral valve geometry with D3D vena contracta area during isometric handgrip
exercise
Functional MR

Tenting height
Tenting volume (per 0.1 mL)
Baseline 3D vena contracta area

UnivariablepBb

95% CI

p

VIF

0.47
0.28
0.45

0.002
0.079
0.003

1.456

0.366

0.318-2.593

.014

1.098

0.202

0.343

0.034-0.371

.02

1.098

Degenerative MR

AL-PM diameter
Prolapse height
Prolapse volume (per 0.1 mL)
Flail gap
Flail width
Baseline 3D vena contracta area

Multivariabler

Univariable

Multivariable

r

p

0.29
0.36
0.34
0.39
0.44
0.41

0.088
0.029
0.044
0.020
0.007
0.013

B

b

95% CI

p

VIF

0.611

0.445

0.182-1.039

.007

1.000

b, standardized regression coefficient; CI, confidence interval; VIF, variance inflation factor.

measurement accuracy for MV geometry and quantitative MR.18,19 Furthermore, these limitations are known
to be exacerbated by cycle exercise, even at low intensity. In contrast, 3D TEE combined with IHE makes it
possible to obtain accurate parameters of MV geometry
and 3D VCA without such limitations. The present study
substantiates the hypotheses suggested by several priorstudies, highlighting the putative value of 3D echocardiography-based evaluation of the mechanisms of exercise-induced MR. The main findings in the present
cohort of symptomatic patients with moderate or greater
MR were: (1) IHE alters MV geometry and causes
exacerbation of 3D VCA regardless of MR etiology; and(2) the factors associated with D3D VCA differ between
FMR and DMR.
With regard to changes in MV geometry during IHE, thepresent study showed that IHE in the FMR group significantly increased tenting height and volume with no annularparametrical changes. Overt heart failure symptoms frequently occur in FMR because of LV dysfunction andremodeling. It has been presumed that exercise-induced
MR in FMR is caused by increased tethering force in theMV, which is affected by various components during exercise, including LV geometry (size and sphericity), dys-synchrony, and induced myocardial ischemia. 20,21 Althoughchanges in LV geometry were not evaluated in this study,
we believe that increased LV afterload during IHE altered
LV geometry and then increased the tethering force in the
MV. Meanwhile, the MV geometry response during IHE in
the DMR group was entirely different, comprisingdecreases in annular height, tenting height, and tenting volume, and increases in prolapse height, prolapse volume,
flail gap, and flail width. No significant changes in AL-PM
diameter, A-P diameter, and annular area were observed
during IHE in the DMR group, similar to the FMR group.
In DMR, therefore, the increase in LV afterload during IHE
may contribute to compression of the MV toward the left
atrium, followed by augmentation of the extent of leaflet
prolapse. The newly advocated exercise test, IHE-stress 3D
TEE, demonstrated these MV geometrical changes andtheir association with increases in 3D VCA, suggesting

different mechanisms for exercise-induced MR according
to its etiology.
In this study, tenting height and baseline 3D VCA wereselected as multivariable determinants of exercise-induced
MR in patients with FMR, whereas only flail width wasselected in patients with DMR. Therefore, even if nonsevere MR is observed on resting echocardiography,
patients with clinically significant MR who have effort dyspnea in daily life or are hospitalized for worsening heart
failure should be suspicious for MR exacerbation upon
exercise, especially among FMR patients with large tenting
height and baseline 3D VCA and DMR patients with large
flail width. Furthermore, transient increases in MR during
exercise may accelerate progression of LV remodeling and/or valvular degeneration, which can trigger further deformation of the MV with greater extents of leaflet tethering
and/or prolapse. Our findings establish the determinants ofexercise-induced MR differed between MR etiologies, andhighlight the importance for simultaneous assessment of
MR severity and MV geometry during exercise in heart failure patients with moderate or greater MR.
There were some limitations in this study. This was asingle-center study. Because of the small number ofpatients in the study population, the strength of the imaging
variables for incremental addition to determine exerciseinduced MR is uncertain. Further validation in a larger multicenter study is required to confirm our findings. Second,the changes in the LV and atrial geometry, which may help
differentiate atrial from ventricular FMR and the IHEinduced pathophysiology of atrial vs ventricular FMR, were
not evaluated in this study. Finally, we selected patientswith MR based on the presence of leaflet prolapse or flailleaflet as DMR. Therefore, our findings cannot be applied
to patients with other degenerative alterations, such as rheumatic or sclerotic changes, infective endocarditis.
Authors’ Statement
List of all Authors: Yu Harada, Hiroto Utsunomiya,
Hitoshi Susawa, Kosuke Takahari, Hajime Takemoto,
Yusuke Ueda, Kanako Izumi, Kiho Itakura, Takayuki

ARTICLE IN PRESS
Valvular Heart Disease/Determinants of Exercise-Induced MR

Hidaka, Yukiko Nakano. Corresponding Author: Hiroto
Utsunomiya
The corresponding author is responsible for ensuringthat the descriptions are accurate and agreed by all
authors. The roles of all authors in this manuscript islisted as follows:
1 Yu Harada: Visualization, Investigation, and Writing −original draft preparation.
2 Hiroto Utsunomiya: Conceptualization, Methodology,
Funding acquisition, and Writing − review & editing.
3 Hitoshi Susawa: Investigation.
4 Kosuke Takahari: Validation.
5 Hajime Takemoto: Investigation.
6 Yusuke Ueda: Investigation.
7 Kanako Izumi: Investigation.
8 Kiho Itakura: Formal Analysis.
9 Takayuki Hidaka: Project administration.
10 Yukiko Nakano: Project administration and Supervision.

Conflict of Interest Statement
This statement is to certify that all authors have seen andapproved the manuscript being submitted, have contributed
significantly to the work, attest to the validity and legitimacy of the data and its interpretation, and agree to its submission to The American Journal of Cardiology.
We attest that the article is the Authors’ original work,
has not received prior publication and is not under consideration for publication elsewhere.
On behalf of all Co-Authors, the corresponding Author
shall bear full responsibility for the submission. Anychanges to the list of authors, including changes in order,
additions or removals will require the submission of a new
author agreement form approved and signed by all the original and added submitting authors.
All authors are requested to disclose any actual or potential conflict of interest including any financial, personal orother relationships with other people or organizations
within three years of beginning the submitted work that
could inappropriately influence, or be perceived to influence, their work. If there are no conflicts of interest, the
COI should read: “The authors report no relationships that
could be construed as a conflict of interest”.
Acknowledgments
We would like to thank Hiroshi Ofuji and Takayuki
Hataoka from Philips Electronics Japan for their technicalassistance. We also thank Alison Sherwin, PhD, from
Edanz Group (https://en-author-services.edanzgroup.com/)for editing a draft of this manuscript.
1. Lancellotti P, Troisfontaines P, Toussaint A, Pierard LA. Prognostic
importance of exercise-induced changes in mitral regurgitation inpatients with chronic ischemic left ventricular dysfunction. Circulation 2003;108:1713–1717.
2. Lancellotti P, Gerard PL, Pierard LA. Long-term outcome of patientswith heart failure and dynamic functional mitral regurgitation. Eur
Heart J 2005;26:1528–1532.

7

3. Magne J, Lancellotti P, Pierard LA. Exercise-induced changes indegenerative mitral regurgitation. J Am Coll Cardiol 2010;56:300–309.
4. Lee APW, Hsiung MC, Salgo IS, Fang F, Xie JM, Zhang YC, Lin QS,
Looi JL, Wan S, Wong RHL, Underwood MJ, Sun JP, Yin WH, Wei
J, Tsai SK, Yu CM. Quantitative analysis of mitral valve morphology
in mitral valve prolapse with real-time 3-dimensional echocardiography: Importance of annular saddle shape in the pathogenesis of mitral
regurgitation. Circulation 2013;127:832–841.
5. Thavendiranathan P, Phelan D, Collier P, Thomas JD, Flamm SD,
Marwick TH. Quantitative assessment of mitral regurgitation. JACC
Cardiovasc Imaging 2012;5:1161–1175.
6. Samuel TJ, Beaudry R, Haykowsky MJ, Sarma S, Nelson MD. Diastolic stress testing: similarities and differences between isometrichandgrip and cycle echocardiography. J Appl Physiol 2018;125:529–
535.
7. Kehl DW, Rader F, Siegel RJ. Echocardiographic features and clinicaloutcomes of flail mitral leaflet without severe mitral regurgitation. J
Am Soc Echocardiogr 2017;30:1162–1168.
8. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L,
Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P,
Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang
W, Voigt JU. Recommendations for cardiac chamber quantification byechocardiography in adults: An update from the American society of
echocardiography and the European association of cardiovascularimaging. Eur Heart J Cardiovasc Imaging 2015;16:233–271.
9. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the
echocardiographic assessment of the right heart in adults:a report fromthe American Society of Echocardiography. J Am Soc Echocardiogr
2010;23:685–713.
10. Lancellotti P, Tribouilloy C, Hagendorff A, Popescu BA, Edvardsen
T, Pierard LA, Badano L, Zamorano JL. Recommendations for the
echocardiographic assessment of native valvular regurgitation: an
executive summary from the European Association of Cardiovascular
Imaging. Eur Hear J - Cardiovasc Imaging 2013;14:611–644.
11. Zoghbi WA, Adams D, Bonow RO, Enriquez-Sarano M, Foster E,
Grayburn PA, Hahn RT, Han Y, Hung J, Lang RM, Little SH, ShahDJ, Shernan S, Thavendiranathan P, Thomas JD, Weissman NJ. Recommendations for noninvasive evaluation of native valvular regurgitation. J Am Soc Echocardiogr 2017:1–69.
12. Pierard LA, Lancellotti P. The role of Ischemic mitral regurgitation in
the pathogenesis of acute pulmonary edema. N Engl J Med
2004;351:1627–1634.
13. Utsunomiya H, Hidaka T, Susawa H, Izumi K, Harada Y, Kinoshita
M, Itakura K, Masada K, Kihara Y. Exercise-stress echocardiography
and effort intolerance in asymptomatic/minimally symptomaticpatients with degenerative mitral regurgitation combined invasive−noninvasive hemodynamic monitoring. Circ Cardiovasc Imaging
2018;11:1–13.
14. AlJaroudi W, Alraies MC, Halley C, Rodriguez L, Grimm RA,
Thomas JD, Jaber WA. Impact of progression of diastolic dysfunction
on mortality in patients with normal ejection fraction. Circulation
2012;125:782–788.
15. Obokata M, Kane GC, Reddy YN V, Olson TP, Melenovsky V, Borlaug BA. Role of diastolic stress testing in the evaluation for heart failure with preserved ejection fraction. Circulation 2017;135:825–838.
16. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Qui~nones MA.
Doppler tissue imaging: a noninvasive technique for evaluation of left
ventricular Relaxation and Estimation of Filling Pressures. J Am Coll
Cardiol 1997;30:1527–1533.
17. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, Dokainish H,
Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Alexandru Popescu B, Waggoner AD.
Recommendations for the evaluation of left ventricular diastolic
function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Hear J − Cardiovasc Imaging
2016;17:1321–1360.
18. Haykowsky MJ, Brubaker PH, Morgan TM, Kritchevsky S, Eggebeen
J, Kitzman DW. Impaired aerobic capacity and physical functional
performance in older heart failure patients with preserved ejection
fraction: Role of lean body mass. J Gerontol - Ser A Biol Sci Med Sci
2013;68:968–975.

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8The American Journal of Cardiology (www.ajconline.org)

19. Upadhya B, Haykowsky MJ, Eggebeen J, Kitzman DW. Exercise
intolerance in heart failure with preserved ejection fraction: More thana heart problem. J Geriatr Cardiol 2015;12:294–304.
20. Bertrand PB, Schwammenthal E, Levine RA, Vandervoort PM. Exercise dynamics in secondary mitral regurgitation. Circulation
2017;135:297–314.

21. Goliasch G, Bartko PE, Pavo N, Neuhold S, Wurm R, Mascherbauer J,
Lang IM, Strunk G, H€ulsmann M. Refining the prognostic impact offunctional mitral regurgitation in chronic heart failure. Eur Heart J
2018;39:39–46.