Extramitral Valvular Cardiac Involvement in PatientsaDepartme
den, The Neth
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dTurku Heart C
Turku, Finlan
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(http://creative
https://doi.org/With Significant Secondary Mitral RegurgitationGurpreet K. Singh, MDa, Farnaz Namazi, MDa, Kensuke Hirasawa, MD, PhDa,
Pieter van der Bijl, MD, PhDa, Aniek L. van Wijngaarden, MDa, N. Mai Vo, MDa,
Gregg W. Stone, MDb,c, Nina Ajmone Marsan, MD, PhDa, Victoria Delgado, MD, PhDa, and
Jeroen J. Bax, MD, PhDa,d,*nt o
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10.Patients with secondary mitral regurgitation (SMR) often have extramitral valve cardiac
involvement, which can influence the prognosis. SMR can be defined according to groups
of extramitral valve cardiac involvement. The prognostic implications of such groups in
patients with moderate and severe SMR (significant SMR) are unknown. A total of 325
patients with significant SMR were classified according to the extent of cardiac involvement
on echocardiography: left ventricular involvement (group 1), left atrial involvement (group
2), tricuspid valve and pulmonary artery vasculature involvement (group 3), or right ven-
tricular involvement (group 4). The primary end point was all-cause mortality. The preva-
lence of each cardiac involvement group was 17% in group 1, 12% in group 2, 23% in
group 3%, and 48% in group 4. Group 3 and group 4 were independently associated with
all-cause mortality (hazard ratio 1.794, 95% confidence interval 1.067 to 3.015, p = 0.027
and hazard ratio 1.857, 95% confidence interval 1.145 to 3.012, p = 0.012, respectively). In
conclusion, progressive extramitral valve cardiac involvement (group 3 and group 4) was
independently associated with all-cause mortality in patients with significant SMR. ©
2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC
BY license (http://creativecommons.org/licenses/by/4.0/) (Am J Cardiol 2022;162:143−149)f Cardiology, Leiden University Medical Center, Lei-
nds; bThe Zena and Michael A. Wiener Cardiovascular
hool of Medicine at Mount Sinai, New York, New York;
lar Research Foundation, New York, New York; and
ter, University of Turku and Turku University Hospital,
anuscript received May 27, 2021; revised manuscript
ted September 17, 2021.
or disclosure information.
g author: Tel: +3175262020; fax: +31715266809.
s: j.j.bax@lumc.nl (J.J. Bax).
www.ajconline.orgThe Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license
mons.org/licenses/by/4.0/)
1016/j.amjcard.2021.09.022Guideline-directed medical therapy for heart failure
(including cardiac resynchronization therapy [CRT]) has
been demonstrated to reverse left ventricular (LV) remodel-
ing and reduce secondary mitral regurgitation (SMR) in
selected patients.1,2 However, patients who remain with mod-
erate-to-severe or severe SMR despite guideline-directed
medical therapy exhibit high morbidity and mortality.3 The
high operative risk and relatively high SMR recurrence rate
may explain the low referral rate for mitral valve interven-
tion.4−6 More recently, transcatheter mitral valve repair with
MitraClip (Abbott, Abbott Park, Illinois) was demonstrated
to improve the prognosis of selected patients with heart fail-
ure and SMR with symptoms refractory to medical therapy.7
The echocardiographic criteria that indicate the need for
mitral valve intervention comprise measures of SMR sever-
ity, LV ejection fraction (LVEF), and LV volumes.7−9 How-
ever, the spectrum of cardiac abnormalities that accompany
SMR and that influence patient outcomes is broader. Cardiac
classification algorithms have been applied to severe aortic
stenosis and have shown that extra-aortic valve, cardiac
involvement provides incremental prognostic value over
measures of aortic stenosis severity.10 Accordingly, thepresent study proposes an algorithm to divide patients with
SMR into groups based on their extramitral valve, cardiac
involvement and evaluated its prognostic implications.
Methods
Patients with moderate and severe SMR (significant
SMR) and reduced LVEF <50% were identified between
1999 and 2018 from ongoing registries of patients with
SMR at the Leiden University Medical Center (The Nether-
lands) and are included in this analysis. Patients were clas-
sified into 4 groups of cardiac involvement, based on the
presence of extramitral valvular cardiac involvement
derived from the first echocardiogram performed with
patients in a hemodynamic stable condition showing signifi-
cant SMR (Figure 1): group 1: LV involvement (LV end-
diastolic diameter ≥57 mm and/or LVEF <50%); group 2:
left atrial (LA) involvement (LA volume index >34 ml/m2
and/or history of atrial fibrillation); group 3: tricuspid valve
or pulmonary artery vasculature involvement (systolic pul-
monary artery pressure [SPAP] ≥40 mm Hg and/or signifi-
cant tricuspid regurgitation [TR]); group 4: right ventricular
(RV) involvement (tricuspid annular plane systolic excur-
sion [TAPSE] ≤17 mm). Importantly, patients were classi-
fied according to the highest cardiac involvement group;
thus, for example, if patients had LVEF <50% and TAPSE
≤17 mm, they were included in group 4.
Patients with previous mitral valve intervention (surgical
mitral valve repair, mitral valve replacement, or transcath-
eter edge-to-edge mitral valve repair) or incomplete echo-
cardiographic data to determine the extramitral valvular
cardiac involvement were excluded. Clinical and demo-
graphic data were collected using the departmental patient
Figure 1. Groups of cardiac involvement in patients with significant sec-
ondary mitral regurgitation. LA= left atrial; LAVI = left atrial volume
index; LV = left ventricular; LVEDD= left ventricular end diastolic diam-
eter; LVEF= left ventricular ejection fraction; RV= right ventricular;
SPAP= systolic pulmonary arterial pressure; TAPSE = tricuspid annular
plane systolic excursion; TR= tricuspid regurgitation.
Figure 2. Distribution of the total population according to different groups
of cardiac involvement. LA = left atrial; LV = left ventricular; RV = right
ventricular; TV = tricuspid valve.
144 The American Journal of Cardiology (www.ajconline.org)information system. For retrospective analysis of clinically
acquired data which were anonymously handled, the insti-
tutional review board waived the need for patient written
informed consent.
Transthoracic echocardiography was performed with the
patients at rest, lying in the left lateral decubitus position, using
commercially available ultrasound systems (GE Vingmed
Ultrasound, General Electric, Milwaukee, Wisconsin)
equipped with 3.5MHz orM5S transducers. Two-dimensional
and Doppler data were acquired from parasternal, apical, and
subcostal views. LV end-diastolic diameter was measured on
the parasternal long-axis view.11 The apical 2- and 4-chamber
views were used to measure the LV end-diastolic and end-sys-
tolic volumes, and LVEF was calculated according to
Simpson’s biplane method.11 LA volumes were measured at
the end of ventricular systole on the 2- and 4-chamber apical
views, using the biplane method of disks, and indexed for
body surface area (LA volume index).11 Stroke volume was
calculated with the following equation: Stroke volume = LV
outflow tract velocity time integral £ cross-sectional area of
the LV outflow tract.12 The severity of mitral regurgitation
was assessed according to current recommendations, using
qualitative, semiquantitative, and quantitative data. If measur-
able, quantitative measurements were conducted according to
the proximal isovelocity surface area method, for which the
effective regurgitant orifice area was measured and regurgitant
volume was calculated by multiplying effective regurgitant
orifice area by the mitral valve velocity time integral.12,13 The
severity of TR was semiquantitatively assessed using vena
contracta width: mild <0.3 cm, moderate 0.3 to 0.69 cm, and
severe ≥0.7 cm.12,13 Significant TR was defined as moderateor severe TR. RV systolic function was assessed using the
TAPSE measured on the focused 4-chamber apical view and
M-mode.11,14 To estimate the SPAP the RV pressure was cal-
culated from the peak velocity of the TR jet, according to the
simplified Bernoulli’s equation, to which the right atrial pres-
sure was identified by the inspiratory collapse and diameter of
the inferior vena cava were added.11,14
Patients were followed up for the occurrence of mitral
valve intervention (i.e., surgical mitral valve repair,
mitral valve replacement, and percutaneous edge-to-edge
mitral valve repair) and all-cause mortality. The primary
outcome was all-cause mortality. Mortality data were col-
lected from the departmental patient information system,
which is linked to the governmental death registry database.
In addition, to evaluate the heart failure treatment in this
population, the occurrence of CRT was investigated.
Continuous data are presented as mean § SD when nor-
mally distributed or as median and interquartile range when
non-normally distributed. Categorical data are presented as
frequencies and percentages. Comparison of continuous data,
when normally distributed, was performed using the one-way
analysis of variance analysis with Bonferroni’s post hoc anal-
ysis or, when non-normally distributed, with the Kruskal-
Wallis test. Categorical data were compared using the chi-
square test. Kaplan-Meier analysis was used to estimate the
event-free survival rates of patients in the various groups dur-
ing follow-up. The event-free survival rates were compared
using the log-rank test. Univariable Cox proportional hazards
analysis was performed to evaluate the association between
the extramitral valvular cardiac involvement groups and other
clinical and echocardiographic variables with all-cause mor-
tality. Mitral valve intervention was also included as a time-
dependent variable in this analysis. The hazard ratio and 95%
confidence interval were reported. In the univariable analysis,
clinically relevant variables were selected and included in the
multivariable Cox proportional hazards model. A two-sided p
<0.05 was considered statistically significant. Statistical anal-
yses were performed using IBM SPSS Statistics for Win-
dows, Version 25.0. (Armonk, New York: IBM Corp.)Results
A total of 325 patients (mean age 69 § 10 years, 66%
male) with severely reduced LVEF (mean 29 § 9%) were
included. The distribution of patients across the different
groups of cardiac involvement is presented in Figure 2. The
Table 1
Clinical characteristics according to cardiac involvement
Variable Total
population
(n=325)
Group 1 LV
involvement
(n=54)
Group 2
LA involvement
(n=40)
Group 3 TV or pulmonary
artery vasculature
involvement (n=76)
Group 4 RV
involvement
(n=155)
p-value
Male 213 (66%) 32 (59%) 25 (63%) 48 (63%) 108 (70%) 0.480
Age (years) 69 § 10 62 § 12 67 § 12 66 § 10 68 § 9* 0.001
Body surface area (m2) 1.9 § 0.21 1.9 § 0.21 1.9 § 0.23 1.9 § 0.21 1.9 § 0.20 0.987
Creatinine (mmol/L) 101 (81-136) 90 (75-117) 103 (75-132) 98 (87-133) 109 (85-153)* 0.009
NYHA ≥ II 306 (94%) 51 (94%) 38 (95%) 71 (93%) 146 (94%) 0.987
Atrial fibrillation 172 (53%) 0 (0%) 23 (58%) 40 (53%) 109 (70%) <0.001
CRT 33 (10%) 3 (6%) 5 (13%) 5 (7%) 20 (13%) 0.279
Diabetes mellitus 69 (21%) 9 (17%) 7 (18%) 15 (20%) 38 (25%) 0.550
Hypertension 132 (41%) 22 (41%) 18 (45%) 28 (37%) 64 (41%) 0.850
COPD 38 (12%) 4 (7%) 3 (8%) 10 (13%) 21 (14%) 0.509
Beta-blocker 236 (73%) 41 (76%) 28 (70%) 54 (71%) 113 (73%) 0.911
ACE or ARB 263 (81%) 46 (85%) 34 (85%) 64 (84%) 119 (77%) 0.344
Diuretics 278 (86%) 42 (78%) 29 (73%) 66 (87%) 141 (91%) 0.008
Values are mean § SD, median [IQR], or n (%).
* p<0.05 versus stage 1.
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchroni-
zation therapy; LA = left atrial; LV = left ventricular; NYHA = New York Heart Association; RV = right ventricular; TV = tricuspid valve.
Valvular Heart Disease/Cardiac Involvement in Secondary Mitral Regurgitation 145clinical and echocardiographic characteristics of the overall
population and for each cardiac involvement group are
listed in Tables 1 and 2, respectively. Patients in group 4
(RV involvement) were older and had worse kidney func-
tion compared with group 1 (LV involvement). During a
median follow-up of 67 months (interquartile range: 27 to
121 months), 192 patients died (59%), 148 patients (46%)Table 2
Echocardiographic characteristics according to cardiac involvement
Variable Total
population
(n=325)
Group 1
LV involvement
(n=54)
G
LA i
LV end-diastolic diameter (mm) 67 § 10 67 § 9 7
LV end-diastolic volume (ml) 196 (144-250) 209 (172-255) 200
LV end-systolic volume (ml) 142 (97-184) 155 (110-188) 135
Stroke volume (ml) 43 § 13 46 § 12 4
LV ejection fraction (%) 29 § 9 28 § 9
Left atrial volume index (ml/m2) 38 (29-49) 25 (19-30) 40
SPAP (mmHg) 43 § 13 28 § 7
TAPSE (mm) 18 (13-20) 20 (19-22) 19
EROA (mm2) 20 (14-29) 16 (12-20) 19
Regurgitant volume (ml) 31 § 15 28 § 15 3
Mitral regurgitation
Moderate 52 (16%) 15 (28%) 6
Moderate-severe 129 (40%) 28 (52%) 2
Severe 144 (44%) 11 (20%) 1
Tricuspid regurgitation
Moderate 74 (23%) 0 (0%)
Severe 23 (7%) 0 (0%)
Values are mean § SD, median [IQR], or n (%). Missing: EROA 91/325; left
volume 34/325; tricuspid regurgitation 4/325.
* p<0.05 versus stage 1.
y p<0.05 versus stage 2.
z p<0.05 versus stage 3.
EROA = effective regurgitant orifice area; LA = left atrial; LV = left vent
SPAP = systolic pulmonary artery pressure; TAPSE = tricuspid annular plane systunderwent mitral valve intervention and 258 patients (79%)
received CRT (Table 3). The Kaplan-Meier analysis for all-
cause mortality in the total population is shown in Figure 3.
Patients in group 1 had better survival as compared with the
patients in groups 3 and 4. The 1- and 8-year mortality rates
for patients in group 1 were 6% and 33% respectively,
which is lower than the mortality rates of patients in groupsroup 2
nvolvement
(n=40)
Group 3 TV or pulmonary
artery vasculature
involvement (n=76)
Group 4
RV involvement
(n=155)
p-value
0 § 11 67 § 11 65 § 9 0.073
(129-268) 193 (144-248) 185 (139-240) 0.304
(88-186) 138 (97-181) 136 (93-186) 0.468
7 § 12 43 § 11 40 § 14*,y 0.005
30 § 9 30 § 9 28 § 9 0.452
(34-52)* 38 (35-49)* 44 (36-56)* <0.001
32 § 6 49 § 12*,y 49 § 12*,y <0.001
(18-21) 20 (18-23) 13 (11-15)*,y,z <0.001
(11-24) 20 (15-30)* 20 (15-30)* 0.006
1 § 13 33 § 16 31 § 15 0.405
0.002
(15%) 9 (12%) 22 (14%)
0 (50%) 27 (36%) 54 (35%)
4 (35%) 40 (53%) 79 (51%)
<0.001
0 (0%) 18 (25%) 56 (37%)
0 (0%) 6 (8%) 17 (11%)
atrial volume index 2/325; regurgitant volume 92/325; SPAP 5/325; stroke
ricular; RV = right ventricular; SMR = secondary mitral regurgitation;
olic excursion; TV = tricuspid valve.
Table 3
Clinical outcomes during follow-up
Variable Total
population
(n=325)
Group 1
LV involvement
(n=54)
Group 2
LA involvement
(n=40)
Group 3 TV or pulmonary
artery vasculature
involvement (n=76)
Group 4 RV
involvement
(n=155)
p-value
CRT at baseline + follow-up 258 (79%) 47 (87%) 29 (73%) 60 (79%) 122 (79%) 0.370
MV intervention at follow-up 0.168
Transcatheter edge-to-edge repair 51 (16%) 3 (6%) 7 (18%) 9 (12%) 32 (21%)
MV repair 95 (29%) 13 (24%) 13 (33%) 27 (36%) 42 (27%)
MV replacement 2 (1%) - - 1 (1%) 1 (1%)
Concomitant TVP 71 (22%) 8 (15%) 7 (18%) 19 (25%) 37 (24%) 0.420
Concomitant AVR 2 (1%) 1 (2%) - 1 (1%) - 0.367
Concomitant CABG 29 (9%) 5 (9%) 2 (5%) 10 (13%) 12 (8%) 0.439
Values are n (%). CRT at baseline is included in this follow-up table.
AVR = aortic valve replacement; CABG = coronary artery bypass graft; CRT = cardiac resynchronization therapy; LA = left atrial; LV = left ventricular;
MV = mitral valve; RV = right ventricular; TV = tricuspid; TVP = tricuspid valvuloplasty.
Figure 3. Kaplan-Meier curve analysis for all-cause mortality for the over-
all population according to the groups of cardiac involvement. Group
1 = Left ventricular involvement; Group 2 = Left atrial involvement;
Group 3 = Tricuspid valve or pulmonary artery vasculature involvement;
Group 4 = Right ventricular involvement.
146 The American Journal of Cardiology (www.ajconline.org)3 and 4, which were 12% and 17% at 1-year and 53%, and
57% at 8 years of follow-up, respectively.
The univariable and multivariable Cox regression analy-
sis evaluating the association between the groups of extra-
mitral valvular cardiac involvement and all-cause mortality
in the total population are listed in Table 4. In the univari-
able analysis, group 3 and group 4 were significantly associ-
ated with all-cause mortality. After correcting for age, male
gender, kidney function, and chronic obstructive pulmonary
disease, groups 3 and 4 remained independently associated
with worse survival.
The univariable and multivariable Cox regression analy-
sis evaluating the association between the groups of extra-
mitral valvular cardiac involvement and all-cause mortality
in the total population, while adding mitral valve interven-
tion as a time-dependent variable, are listed in Table 5.
After correcting in the multivariable analysis, for age, male
gender, kidney function, chronic obstructive pulmonary dis-
ease, and mitral valve intervention (as a time-dependentvariable), groups 3 and 4 remained independently associ-
ated with worse survival.Discussion
This study showed that progressive extramitral valvular
cardiac involvement is independently associated with all-
cause mortality, a finding mainly driven by group 3 (tricus-
pid valve or pulmonary artery vasculature involvement)
and group 4 (RV involvement).
SMR is characterized by LV remodeling and dysfunction
that leads to leaflet malcoaptation with the mitral valve leaf-
lets being structurally normal.15 If left untreated, progres-
sion of LV dysfunction and mitral regurgitation can cause
volume and pressure overload which can lead to further LV
and LA dilation. Chronically elevated LA pressures can
cause sustained pulmonary hypertension that can ultimately
result in TR with RV dilation and dysfunction.16,17 The
prevalence of extramitral valvular cardiac involvement in
patients with SMR has previously been reported.7,18−23
Atrial fibrillation has been reported in 34% of patients with
severe SMR22 and 55% in moderate-to-severe and severe
SMR.7 TR has been observed in 30% of the patients who
underwent mitral valve repair.21 The prevalence of pulmo-
nary hypertension in patients with SMR and LV systolic
dysfunction is approximately 40%.20 Another study
reported an SPAP of ≥40 mm Hg in 58% of the patients
with severe SMR.19 RV dysfunction is present in 42% to
83% of patients with at least moderate SMR.18,23 This study
provides further insights regarding the prevalence of vari-
ous aspects of extravalvular cardiac involvement and classi-
fied them. Group 4, characterized by RV involvement, was
the most prevalent (48%) indicating that our patient popula-
tion is representative of a cohort with advanced heart
disease.
Several studies have shown an association between the
various groups of extravalvular cardiac involvement and
outcomes in patients with SMR. LV dysfunction24,25 and
LA dilation26,27 have been independently associated with
an increased risk for mortality. In a large cohort of 1,256
patients with heart failure (73% with SMR), LV systolic
dysfunction was independently associated with all-cause
mortality.25 Rossi et al27 reported an independent relation
Table 4
Univariable and multivariable Cox proportional hazard analysis in the total population
Univariable Analysis Multivariable Analysis
HR (95% CI) p-value HR (95% CI) p-value
Age (years) 1.032 (1.017-1.048) <0.001 1.025 (1.009-1.041) 0.002
Men 1.622 (1.184-2.224) 0.003 1.220 (0.878-1.694) 0.236
Creatinine (mmol/L) 1.007 (1.005-1.009) <0.001 1.005 (1.003-1.008) <0.001
Atrial fibrillation 1.268 (0.952-1.687) 0.104
COPD 2.005 (1.367-2.939) <0.001 1.434 (0.968-2.123) 0.072
MV intervention at follow-up 1.166 (0.875-1.555) 0.295
LV ejection fraction (%) 0.981 (0.965-0.997) 0.018
LA volume index (ml/m2) 1.011 (1.004-1.017) 0.002
SPAP (mmHg) 1.026 (1.015-1.036) <0.001
Significant TR 1.412 (1.042-1.913) 0.026
TAPSE (mm) 0.957 (0.929-0.987) 0.005
SMR moderate (reference) <0.001
SMR moderate-severe 2.951 (1.766-4.933)
SMR severe 3.516 (2.111-5.857)
Group 1 (reference)
Group 2 1.386 (0.751-2.560) 0.296 1.114 (0.600-2.070) 0.732
Group 3 2.165 (1.294-3.622) 0.003 1.794 (1.067-3.015) 0.027
Group 4 2.562 (1.598-4.107) <0.001 1.857 (1.145-3.012) 0.012
COPD = chronic obstructive pulmonary disease; LA = left atrial; LV = left ventricular; MV = mitral valve; SMR = secondary mitral regurgitation;
SPAP = systolic pulmonary artery pressure; TAPSE = tricuspid annular plane systolic excursion; TR = tricuspid regurgitation. Group 1 = LV involvement;
Group 2 = LA involvement; Group 3 = Tricuspid valve or pulmonary artery vasculature involvement; Group 4 = Right ventricular involvement.
Table 5
Univariable and multivariable Cox proportional hazard analysis in the total population with mitral valve intervention as a time-dependent variable
Univariable Analysis Multivariable Analysis
HR (95% CI) p-value HR (95% CI) p-value
Age (years) 1.032 (1.017-1.048) <0.001 1.025 (1.009-1.042) 0.002
Men 1.622 (1.184-2.224) 0.003 1.307 (0.936-1.824) 0.116
Creatinine (mmol/L) 1.007 (1.005-1.009) <0.001 1.005 (1.003-1.008) <0.001
COPD 2.005 (1.367-2.939) <0.001 1.342 (0.902-1.997) 0.146
MV intervention at follow-up* 1.489 (1.118-1.984) 0.006 1.383 (1.027-1.862) 0.033
Group 1 (reference)
Group 2 1.386 (0.751-2.560) 0.296 1.074 (0.578-1.997) 0.821
Group 3 2.165 (1.294-3.622) 0.003 1.700 (1.009-2.865) 0.046
Group 4 2.562 (1.598-4.107) <0.001 1.760 (1.082-2.862) 0.023
*Mitral valve intervention as a time-dependent variable.
COPD = chronic obstructive pulmonary disease; MV = mitral valve. Group 1 = Left ventricular involvement; Group 2 = Left atrial involvement; Group 3 =
Tricuspid valve or pulmonary artery vasculature involvement; Group 4 = Right ventricular involvement.
Valvular Heart Disease/Cardiac Involvement in Secondary Mitral Regurgitation 147between LA size and mortality in patients with heart failure,
while Palmiero et al26 confirmed that LA function is a pow-
erful predictor of clinical outcomes in patients with heart
failure and SMR. However, these studies did not group the
patients according to the extent of cardiac involvement. In
the present study, LV dysfunction and LA dilation were not
associated with all-cause mortality when the extravalvular
cardiac involvement groups were taken into consideration.
This finding suggests that the more advanced groups have a
stronger association with the outcome than LVEF and LA
dilation considered individually. Other studies have also
shown that pulmonary hypertension,19,20,28,29 significant
TR30, and RV dysfunction18,23 are associated with an
increased risk for mortality in patients with SMR. In a
cohort of 692 patients with LV systolic dysfunction and
SMR, the presence of pulmonary hypertension was inde-
pendently associated with an increased risk of mortality.29
Dini et al18 reported that in patients with chronic heart fail-
ure and moderate-to-severe SMR, RV function (assessed byTAPSE) was a major determinant of clinical outcomes. In
our study group, 3 (tricuspid valve or pulmonary artery vas-
culature involvement) and group 4 (RV involvement) were
the strongest predictors for all-cause mortality. Interest-
ingly, mitral valve intervention was also independently
associated with all-cause mortality when taking into
account as a time-dependent variable. This could be
explained by the fact that in our study, patients in the
advanced groups more often received mitral valve interven-
tion. Future studies are needed to investigate if these
advanced groups benefit and show any cardiac improve-
ment (allowing reclassification to a lower group) after
mitral valve intervention.
The present study has limitations related to its retrospec-
tive design. The majority of the patients were included in
group 4, suggesting that our population represents a cohort
with advanced heart disease. For the evaluation of RV dys-
function, only TAPSE was used. A combination of other
RV function parameters may have provided stronger
148 The American Journal of Cardiology (www.ajconline.org)prognostic information. Moreover, the specific cause of
death was unknown in this study.
In conclusion, extramitral valvular cardiac involvement,
beyond LV dysfunction, was present in most patients with
significant SMR. Group 3 (tricuspid valve or pulmonary
artery vasculature involvement) and group 4 (RV involve-
ment) were the strongest predictors for all-cause mortality.Disclosures
The Department of Cardiology of the Leiden University
Medical Center received research grants from Abbott Vas-
cular, Bayer, Bioventrix, Biotronik, Boston Scientific,
Edwards Lifesciences, GE Healthcare, and Medtronic. Vic-
toria Delgado received speaker fees from Abbott Vascular,
Edward Lifesciences, GE Healthcare, Merck Sharp &
Dohme, and Medtronic. Nina Ajmone Marsan received
speakers fees from Abbott Vascular and GE Healthcare.
Jeroen J Bax received speaker fees from Abbott Vascular.
The remaining authors have no conflicts of interest to
declare.
1. Nasser R, Van Assche L, Vorlat A, Vermeulen T, Van Craenenbroeck
E, Conraads V, Van der Meiren V, Shivalkar B, Van Herck P, Claeys
MJ. Evolution of functional mitral regurgitation and prognosis in med-
ically managed heart failure patients with reduced ejection fraction.
JACC Heart Fail 2017;5:652–659.
2. St John Sutton MG, Plappert T, Abraham WT, Smith AL, DeLurgio
DB, Leon AR, Loh E, Kocovic DZ, Fisher WG, Ellestad M, Messen-
ger J, Kruger K, Hilpisch KE, Hill MR. Multicenter InSync Random-
ized Clinical Evaluation (MIRACLE) Study Group. Effect of cardiac
resynchronization therapy on left ventricular size and function in
chronic heart failure. Circulation 2003;107:1985–1990.
3. Agricola E, Ielasi A, Oppizzi M, Faggiano P, Ferri L, Calabrese A,
Vizzardi E, Alfieri O, Margonato A. Long-term prognosis of medically
treated patients with functional mitral regurgitation and left ventricular
dysfunction. Eur J Heart Fail 2009;11:581–587.
4. Goldstein D, Moskowitz AJ, Gelijns AC, Ailawadi G, Parides MK,
Perrault LP, Hung JW, Voisine P, Dagenais F, Gillinov AM, Thourani
V, Argenziano M, Gammie JS, Mack M, Demers P, Atluri P, Rose
EA, O’Sullivan K, Williams DL, Bagiella E, Michler RE, Weisel RD,
Miller MA, Geller NL, Taddei-Peters WC, Smith PK, Moquete E,
Overbey JR, Kron IL, O'Gara PT, Acker MA, CTSN. Two-year out-
comes of surgical treatment of severe ischemic mitral regurgitation. N
Engl J Med 2016;374:344–353.
5. Lorusso R, Gelsomino S, Vizzardi E, D’Aloia A, De Cicco G, Luc
a F,
Parise O, Gensini GF, Stef
ano P, Livi U, Vendramin I, Pacini D, Di
Bartolomeo R, Miceli A, Varone E, Glauber M, Parolari A, Giuseppe
Arlati F, Alamanni F, Serraino F, Renzulli A, Messina A, Troise G,
Mariscalco G, Cottini M, Beghi C, Nicolini F, Gherli T, Borghetti V,
Pardini A, Caimmi PP, Micalizzi E, Fino C, Ferrazzi P, Di Mauro M,
Calafiore AM, ISTIMIR Investigators. Mitral valve repair or replace-
ment for ischemic mitral regurgitation? The Italian study on the treat-
ment of ischemic mitral regurgitation (ISTIMIR). J Thorac
Cardiovasc Surg 2013;145:128–138.
6. Petrus AHJ, Dekkers OM, Tops LF, Timmer E, Klautz RJM, Braun J.
Impact of recurrent mitral regurgitation after mitral valve repair for
functional mitral regurgitation: long-term analysis of competing out-
comes. Eur Heart J 2019;40:2206–2214.
7. Stone GW, Lindenfeld J, Abraham WT, Kar S, Lim DS, Mishell JM,
Whisenant B, Grayburn PA, Rinaldi M, Kapadia SR, Rajagopal V,
Sarembock IJ, Brieke A, Marx SO, Cohen DJ, Weissman NJ, Mack
MJ, COAPT Investigators. Transcatheter mitral-valve repair in
patients with heart failure. N Engl J Med 2018;379:2307–2318.
8. Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung
B, Lancellotti P, Lansac E, Rodriguez Mu~noz D, Rosenhek R, Sj€ogren
J, Tornos Mas P, Vahanian A, Walther T, Wendler O, Windecker S,
Zamorano JL, ESC Scientific Document Group. 2017 ESC/EACTSguidelines for the management of valvular heart disease. Eur Heart J
2017;38:2739–2791.
9. Nishimura RA, Otto CM, Bonow RO, Carabello BA, 3rd Erwin JP,
Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O'Gara PT, Rigolin VH,
Sundt TM 3rd, Thompson A. 2017 aha/acc focused update of the
2014 aha/acc guideline for the management of patients with valvular
heart disease: a report of the American College of Cardiology/Ameri-
can Heart Association task force on clinical practice guidelines. J Am
Coll Cardiol 2017;70:252–289.
10. Genereux P, Pibarot P, Redfors B, Mack MJ, Makkar RR, Jaber WA,
Svensson LG, Kapadia S, Tuzcu EM, Thourani VH, Babaliaros V,
Herrmann HC, Szeto WY, Cohen DJ, Lindman BR, McAndrew T,
Alu MC, Douglas PS, Hahn RT, Kodali SK, Smith CR, Miller DC,
Webb JG, Leon MB. Staging classification of aortic stenosis based on
the extent of cardiac damage. Eur Heart J 2017;38:3351–3358.
11. 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 by
echocardiography in adults: an update from the American Society of
Echocardiography and the European Association of Cardiovascular
Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–270.
12. Zoghbi WA, Adams D, Bonow RO, Enriquez-Sarano M, Foster E,
Grayburn PA, Hahn RT, Han Y, Hung J, Lang RM, Little SH, Shah
DJ, Shernan S, Thavendiranathan P, Thomas JD, Weissman NJ. Rec-
ommendations for noninvasive evaluation of native valvular regurgita-
tion: a report from the American Society of Echocardiography
developed in collaboration with the society for cardiovascular mag-
netic resonance. J Am Soc Echocardiogr 2017;30:303–371.
13. Lancellotti P, Tribouilloy C, Hagendorff A, Popescu BA, Edvard-
sen T, Pierard LA, Badano L, Zamorano JL, Scientific Document
Committee of the European Association of Cardiovascular. Rec-
ommendations for the echocardiographic assessment of native val-
vular regurgitation: an executive summary from the European
Association of Cardiovascular Imaging. Eur Heart J Cardiovasc
Imaging 2013;14:611–644.
14. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chan-
drasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the
echocardiographic assessment of the right heart in adults: a report
from the American Society of Echocardiography endorsed by the
European Association of Echocardiography, a registered branch of the
European Society of Cardiology, and the Canadian Society of Echo-
cardiography. J Am Soc Echocardiogr 2010;23:685–788.
15. Asgar AW, Mack MJ, Stone GW. Secondary mitral regurgitation in
heart failure: pathophysiology, prognosis, and therapeutic considera-
tions [published correction appears in J Am Coll Cardiol
2015;65:2265]. J Am Coll Cardiol 2015;65:1231–1248.
16. Patel H, Desai M, Tuzcu EM, Griffin B, Kapadia S. Pulmonary
hypertension in mitral regurgitation. J Am Heart Assoc 2014;3:
e000748.
17. Sanz J, Sanchez-Quintana D, Bossone E, Bogaard HJ, Naeije R. Anat-
omy, function, and dysfunction of the right ventricle: JACC state-of-
the-art review. J Am Coll Cardiol 2019;73:1463–1482.
18. Dini FL, Conti U, Fontanive P, Andreini D, Banti S, Braccini L, De
Tommasi SM. Right ventricular dysfunction is a major predictor of
outcome in patients with moderate to severe mitral regurgitation and
left ventricular dysfunction. Am Heart J 2007;154:172–179.
19. Kainuma S, Taniguchi K, Toda K, Funatsu T, Kondoh H, Nishino M,
Daimon T, Sawa Y. Pulmonary hypertension predicts adverse cardiac
events after restrictive mitral annuloplasty for severe functional mitral
regurgitation. J Thorac Cardiovasc Surg 2011;142(4):783–792.
20. Magne J, Pibarot P, SenGupta PP, Donal E, Rosenhek R, Lancellotti P.
Pulmonary hypertension in valvular disease: a comprehensive review
on pathophysiology to therapy from the HAVEC group. JACC Cardio-
vasc Imaging 2015;8:83–99.
21. Matsunaga A, Duran CM. Progression of tricuspid regurgitation after
repaired functional ischemic mitral regurgitation. Circulation
2005;112(suppl):I453–I457.
22. Obadia JF, Messika-Zeitoun D, Leurent G, Iung B, Bonnet G, Piriou
N, Lef
evre T, Piot C, Rouleau F, Carrie D, Nejjari M, Ohlmann P,
Leclercq F, Saint Etienne C, Teiger E, Leroux L, Karam N, Michel N,
Gilard M, Donal E, Trochu JN, Cormier B, Armoiry X, Boutitie F,
Maucort-Boulch D, Barnel C, Samson G, Guerin P, Vahanian A,
Mewton N, MITRA-FR Investigators. Percutaneous repair or medical
Valvular Heart Disease/Cardiac Involvement in Secondary Mitral Regurgitation 149treatment for secondary mitral regurgitation. N Engl J Med
2018;379:2297–2306.
23. Yalonetsky S, Eden H, Lessick J, Kapeliovich M, Dragu R, Mutlak D,
Carasso S, Reisner S, Agmon Y, Hammerman H, Aronson D. Impact
of functional mitral regurgitation on right ventricular function and out-
come in patients with right ventricular infarction. Am J Cardiol
2014;114:36–41.
24. Bursi F, Barbieri A, Grigioni F, Reggianini L, Zanasi V, Leuzzi C,
Ricci C, Piovaccari G, Branzi A, Modena MG. Prognostic implications
of functional mitral regurgitation according to the severity of the
underlying chronic heart failure: a long-term outcome study. Eur J
Heart Fail 2010;12:382–388.
25. Rossi A, Dini FL, Faggiano P, Agricola E, Cicoira M, Frattini S, Sim-
ioniuc A, Gullace M, Ghio S, Enriquez-Sarano M, Temporelli PL.
Independent prognostic value of functional mitral regurgitation in
patients with heart failure. A quantitative analysis of 1256 patients
with ischaemic and non-ischaemic dilated cardiomyopathy. Heart
2011;97:1675–1680.
26. Palmiero G, Melillo E, Ferro A, Carlomagno G, Sordelli C, Ascione R,
Monda V, Severino S, Ascione L, Caso P. Significant functional mitral
regurgitation affects left atrial function in heart failure patients:haemodynamic correlations and prognostic implications. Eur Heart J
Cardiovasc Imaging 2019;20(9):1012–1019.
27. Rossi A, Temporelli PL, Quintana M, Dini FL, Ghio S, Hillis GS,
Klein AL, Marsan NA, Prior DL, Yu CM, Poppe KK, Doughty RN,
Whalley GA, MeRGE Heart Failure Collaborators. Independent rela-
tionship of left atrial size and mortality in patients with heart failure:
an individual patient meta-analysis of longitudinal data (merge heart
failure). Eur J Heart Fail 2009;11:929–936.
28. Ghoreishi M, Evans CF, DeFilippi CR, Hobbs G, Young CA, Griffith
BP, Gammie JS. Pulmonary hypertension adversely affects short- and
long-term survival after mitral valve operation for mitral regurgitation:
implications for timing of surgery. J Thorac Cardiovasc Surg
2011;142:1439–1452.
29. Miller WL, Mahoney DW, Enriquez-Sarano M. Quantitative doppler-
echocardiographic imaging and clinical outcomes with left ventricular
systolic dysfunction: independent effect of pulmonary hypertension.
Circ Cardiovasc Imaging 2014;7:330–336.
30. Gyoten T, Messroghli D, Schenk S, Rochor K, Grimmig O, Just S,
Fritzsche D. Impact of preinterventional tricuspid regurgitation on out-
come of MitraClip therapy in patients with severely reduced ejection
fraction. Open Heart 2020;7:e001203.