Determinants of Exercise: Induced Mitral Regurgitation Using Three-Dimensional Transesophageal Echocardiography Combined With Isometric Handgrip Exercise

概要

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 isometric
handgrip 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 were
selected 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 determinants
of 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. When
the exacerbation is severe, it is considered a prognosticator
in 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.4,5
Furthermore, isometric handgrip exercise (IHE) has long
been reported as a useful method to differentiate patients
with 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 was
also 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 with
moderate 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 from
structural 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 or
previous 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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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 Severity
of 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 and
American 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, the
parameters 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 TEE
transducer; Philips). All patients were administered an
intravenous injection of diazepam and pentazocine for sedation during the 3D TEE examination. Volume datasets were
obtained in the live 3D zoom mode (median frame rate: 17
Hz) or 6-beat full volume mode (median frame rate: 69 Hz)
focusing on the MV. In addition, color Doppler live 3D
zoom or 6-beat full volume datasets were acquired at the
narrowest possible depth under breath-hold to obtain a
higher volume rate (median frame rate: 35 Hz). In patients
with atrial fibrillation or inability to hold their breath, the
live 3D zoom mode with 1-beat volume acquisition was
chosen. 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 the
handgrip diameter. During 3D TEE, all patients were
administered sedative drugs intermittently according to
their level of sedation. After 3D volume data acquisition at
baseline 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, and
heart rate were measured using an automated brachial artery
BP cuff (BMS-1763; Nihon Kohden, Tokyo, Japan).
Finally, hemodynamic status and 3D volume data focused
on 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, the

occurrence 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 was
selected. The QLAB MVN software semi-automatically
tracked 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 space
at 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 multiplanar
reconstruction planes in a specified frame. After the two
orthogonal long-axis planes were aligned parallel with
the direction of the proximal MR jet, the short-axis
plane was aligned perpendicular to the narrowest neck
of the MR jet just above the left atrial side of the flow
convergence zone. ...

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