JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 24, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.09.062
Right Ventricular Dysfunction,
But Not Tricuspid Regurgitation,
Is Associated With Outcome Late
After Left Heart Valve Procedure
Andreas A. Kammerlander, MD,* Beatrice A. Marzluf, MD, MSC,y Alexandra Graf, PHD,z Alina Bachmann, MD,*
Alfred Kocher, MD,x Diana Bonderman, MD,* Julia Mascherbauer, MD*
ABSTRACT
BACKGROUND Significant tricuspid regurgitation (TR) late after left heart valve procedure is frequent and associated
with increased morbidity. Surgical correction carries a significant mortality risk, whereas the impact of TR on survival
in these patients is unclear.
OBJECTIVES This study sought to assess the impact of significant TR late after left heart valve procedure.
METHODS A total of 539 consecutive patients with previous left heart valve procedure (time interval from valve
procedure to enrollment 50 30 months) were prospectively followed for 53 15 months.
RESULTS Significant TR (defined as moderate or greater severity by echocardiography) was present in 91 (17%) patients
(65% female). Patients with TR presented with more symptoms (New York Heart Association functional class $II 55% vs.
31%), lower glomerular filtration rates (61 19 ml/min vs. 68 18 ml/min), and a higher likelihood of atrial fibrillation
(41% vs. 20%), all statistically significant. Right ventricular (RV) systolic function was worse in patients with significant
TR (RV fractional area change 43 11% vs. 47 9%, p < 0.001). A total of 117 (22%) patients died during follow-up.
By Kaplan-Meier analysis, overall survival was significantly worse in patients with significant TR (log-rank p < 0.001).
However, by multivariable Cox analysis, only RV fractional area change, age, left atrial size, diabetes, and previous
coronary artery bypass graft procedure were significantly associated with mortality, but not tricuspid regurgitation.
CONCLUSIONS RV dysfunction, but not significant TR, is independently associated with survival late after left heart
valve procedure. (J Am Coll Cardiol 2014;64:2633–42) © 2014 by the American College of Cardiology Foundation.
A
lthough significant tricuspid regurgitation
left-sided myocardial disease (2,3,5), but also accom-
(TR) is a common finding (1), data about its
panies advanced mitral and aortic valve disease (7–9).
prognostic relevance remain sparse (2–5).
According to current recommendations, patients
Mostly “functional” in nature, TR is the consequence
with primary TR without severe RV dysfunction
of geometric alterations caused by right ventricular
could benefit from surgical correction at the time
(RV) dilation, distortion of the subvalvular apparatus,
of left heart valve procedure if TR is severe or the
tricuspid annular dilation, or a combination of these
tricuspid annulus is dilated (10,11). In addition,
factors (6). Significant (moderate and severe) func-
tricuspid procedure might be considered in patients
tional TR frequently occurs in combination with
with previous left heart valve intervention and
From the *Department of Cardiology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria; yDepartment of
Thoracic Surgery, Otto Wagner Hospital, Vienna, Austria; zDepartment of Medical Statistics, Medical University of Vienna, Vienna
General Hospital, Vienna, Austria; and the xDepartment of Cardiothoracic Surgery, Medical University of Vienna, Vienna General
Hospital, Vienna, Austria. This study received support from the Austrian Society of Cardiology (to Dr. Mascherbauer), the
Österreichischer Herzfonds (to Dr. Mascherbauer), and the Austrian fellowship grant KLI 245 (to Dr. Mascherbauer). The authors
have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
You can also listen to this issue’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
Manuscript received June 19, 2014; revised manuscript received August 14, 2014, accepted September 8, 2014.
2634
Kammerlander et al.
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:2633–42
RV Dysfunction and Outcomes in Left Heart Valve Procedure
ABBREVIATIONS
(recurrent) significant TR (10,11). This setting,
tricuspid repair during follow-up were not excluded.
AND ACRONYMS
however, frequently poses a challenge for the
According to the study design (noninterventional,
treating physician because the surgical risk in
purely observational), written informed consent
these patients may be substantial, but the
was not demanded. The ethics committee of the
prognostic impact of TR is not well defined.
Medical University of Vienna approved the study
Discrepant morbidity and mortality rates
protocol.
AF = atrial fibrillation
CABG = coronary artery
bypass graft
CMR = cardiac magnetic
resonance imaging
GFR = glomerular
have been reported (12–15). Table 1 summa-
CLINICAL DATA. Baseline assessment at study entry
rizes the small number of previous studies on
(as detailed in the preceding text) included medical
filtration rate
the impact of TR late after left heart valve
history, assessment of current medication, phys-
HF = heart failure
procedure. In addition, no data are available
ical examination, electrocardiogram, blood tests, and
LV = left ventricle/ventricular
regarding the beneficial effect of isolated
a transthoracic echocardiogram.
RV = right ventricle/ventricular
TR = tricuspid regurgitation
TV = tricuspid valve
redo tricuspid valve (TV) procedure in these
patients, whereas the procedure carries a
significant operative risk, with 30-day mor-
The following data were collected:
Age, sex, body mass index, and body surface area
using the Mosteller formula (18)
tality rates between 15% (16) and 19% (17).
Type and number of previous cardiac procedures
SEE PAGE 2643
Additive EuroSCORE (19)
To clarify the impact of significant TR late after left
heart valve procedure on outcome, we performed the
New York Heart Association functional class
Presence of comorbidities: coronary artery disease
present prospective long-term observational study.
(coronary artery stenosis of >50% lumen loss or
METHODS
artery bypass grafting (CABG), chronic obstructive
fractional flow reserve <0.8), previous coronary
pulmonary disease (long-term use of bronchodila-
STUDY POPULATION. Between January 2007 and
tors or use of steroids for lung disease), arterial hy-
December 2008, 571 consecutive patients with pre-
pertension (blood pressure $140/90 mm Hg at
vious left heart valve procedure presented to our
repeated measurements; or use of antihypertensive
outpatient heart valve clinic and agreed to partici-
agents), atrial fibrillation (AF) (present on the elec-
pate in the present observational study. The left
trocardiogram at index examination or verified
heart valve procedure had to have occurred at
episode of AF within the last 6 months), hypercho-
least 6 months before inclusion. Thirty-two patients
lesterolemia (total serum cholesterol $240 mg/dl or
with significant TR were excluded from further
cholesterol-lowering medication), diabetes (fasting
analysis because of a pacemaker or an implantable
blood glucose level >126 mg/dl or use of antidiabetic
cardioverter-defibrillator
medication), estimated glomerular filtration rate
(potentially
causing
or
aggravating TR). Hence, 539 patients were eligible for
(GFR) using the simplified Modification of Diet in
statistical analysis. From study entry, all data were
Renal Disease formula (20)
collected prospectively. Patients who underwent
Pacemaker/implantable cardioverter-defibrillator
T A B L E 1 Summary of Studies With Data on Prognostic Value of Significant TR After Left-Sided Procedure
Surgery (%)
N
AV
MV
AVþMV
þTV
Significant TR Late After Surgery
Kwak et al., 2008 (14)
335
22
52
26
4.5
27%; follow-up 139 25 months
Retrospective study
Poorer event-free survival in patients with
TR by Kaplan-Meier analysis, apparent
only after 10 years of follow-up
No multivariable analysis
Song et al., 2009 (12)
638
34
51
15
—
8%; follow-up 101 24 months
Retrospective study
Poorer survival in patients with TR
by Kaplan-Meier analysis
No multivariable analysis
Garcia Fuster et al.,
2011 (13)
801
—
100
—
—
9%; follow-up ranging from
16–192 months
Retrospective study
No impact of significant TR on overall survival
No multivariable analysis
Firs Author, Year (Ref. #)
Values are n, %, or mean SD.
AV ¼ aortic valve; MV ¼ mitral valve; TR ¼ tricuspid regurgitation; þTV ¼ additional tricuspid valve.
Comment
Kammerlander et al.
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:2633–42
ECHOCARDIOGRAPHIC DATA. All transthoracic echo-
cardiography studies were performed by board-
T A B L E 2 Echocardiographic Parameters Used for Grading TR Severity
Moderate
Severe
Tricuspid valve
Normal
Mild
Normal or abnormal
Abnormal/flail leaflet/poor
coaptation
Right ventricular/right
atrial/IVC size
Normal*
Normal or dilated
Dilated
certified physicians, using high-end scanners such
as the GE Vivid 5 and Vivid 7 (GE Healthcare, Wauwatosa, Wisconsin). The evaluation included M-mode
echocardiography, 2-dimensional echocardiography,
and conventional and color Doppler ultrasonography
VC width, mm
Not defined
Not defined, but <7
>7
according to current recommendations (21–23). Left
PISA radius, mm
#5
6–9
>9
Hepatic vein flow
Systolic dominance
Systolic blunting
Systolic reversal
ventricular (LV) ejection fraction was assessed with
the biplane Simpson’s method. RV function was
assessed by the percent RV fractional area change,
areaend-systolic areaÞ
defined as ðend-diastolic
100, accordend-diastolic area
ing to recent recommendations (24). In addition,
tricuspid
annular
2635
RV Dysfunction and Outcomes in Left Heart Valve Procedure
plane
systolic
excursion
*Unless there are other reasons for right ventricular or right atrial enlargement (e.g., pulmonary hypertension,
pulmonary valve disease). Adapted with permission from Lancellotti et al. (21).
IVC ¼ inferior vena cava; PISA ¼ proximal isovelocity surface area; VC ¼ vena contracta; TR ¼ tricuspid
regurgitation.
was
measured.
TR was quantified by an integrated approach
(Table 2). Echocardiographic parameters used for
grading included TV morphology; RV, right atrial,
and inferior vena cava size; vena contracta width;
proximal flow convergence radius; and hepatic
function, kidney function, and systolic pulmonary
artery pressure. Statistical analyses were performed
using SPSS Statistics version 18 (IBM, Armonk,
New York) and SAS release 9.2 (SAS Institute, Cary,
North Carolina).
venous flow pattern (21,23,25–27). Moderate and
severe TR were considered “significant” TR and
were compared with no and mild TR. The gradua-
T A B L E 3 Baseline Patient Characteristics
tion into nonsignificant TR and significant TR was
chosen to account for inaccuracies as a result of
the semiquantitative assessment of TR by echocardiography
and
has
previously been
deemed
Age at index date, yrs
Additive EuroSCORE
reasonable (5,28).
STATISTICAL ANALYSIS. Continuous data are ex-
pressed as mean SD or as median with corre-
Chi-square
tests
8.99 2.33
9.0 (7.0–11.0)
8.81 2.26
9.0 (7.0–10.0)
9.84 2.48
10.0 (8.0–12.0)
p Value*
0.096
<0.001
48
65
0.004
1.83 0.24
1.83 (1.67–1.97)
0.017
BMI, kg/m2
26.9 4.5
26.2 (23.8–29.3)
26.9 4.5
26.3 (23.8–29.3)
26.6 4.9
25.9 (23.8–29.0)
0.464
Total number of previous
valve procedures
and Fisher exact tests were used for categorical
CAD
variables. Kaplan-Meier estimates were used to
Previous myocardial
infarction
calculate 1-, 2-, 3-, 4-, and 5-year survival rates.
70.2 13.2
75.0 (63.0–79.0)
1.89 0.22
1.88 (1.73–2.05)
$2
test.
68.8 11.6
69.0 (62.0–78.0)
51
1
sum
69.0 11.9
69.0 (62.0–78.0)
1.88 0.22
1.87 (1.72–2.03)
the
rank
Significant TR
(n ¼ 91, 17%)
BSA, m2
Differences between 2 groups were analyzed using
Wilcoxon
Nonsignificant TR
(n ¼ 448, 83%)
Female
sponding interquartile range. Categorical variables
are presented in percent and/or total numbers.
All Patients
(N ¼ 539)
0.019
92
93
8
7
86
14
28
28
26
0.766
7
8
6
0.519
Previous CABG
15
14
18
0.420
Differences between survival curves were ana-
Atrial fibrillation
24
20
41
<0.001
lyzed using a log-rank test. Differences in these
Hypertension
61
59
70
0.051
and all other tests were considered significant at
Diabetes
15
14
20
0.164
p # 0.05.
Hypercholesterolemia
45
47
36
0.069
A multivariable Cox regression was performed to
identify parameters associated with overall mortality.
All baseline variables (Table 3) and echocardiographic
measurements (Table 4) were assessed. Variables
COPD
9
8
13
0.122
34
31
55
<0.001
Leg edema
11
9
21
0.003
Jugular vein distension
8
5
20
<0.001
NYHA $2
GFR, ml/min
with a significant univariate influence (p < 0.05 in
the univariate Cox regression model) were included
in the multiple regression analysis with backward
selection.
In a previous work (5), a strong interaction of
TR and LV systolic function was found. Therefore,
data were also tested for significant interactions with
TR, particularly with respect to LV and RV systolic
ICD/PM
66.3 18.1
64.7 (55.4–79.0)
5
67.5 17.7
65.5 (56.3–79.5)
60.8 18.8
58.5 (45.5–76.4)
0.002
6
0
0.014
Values are mean SD, median (interquartile range), or %. *p values for continuous data derive from the
Wilcoxon rank sum test, and the chi-square test was used for categorical data. Values in bold indicate significant
p values.
BMI ¼ body mass index; BSA ¼ body surface area; CABG ¼ coronary artery bypass grafting; CAD ¼ coronary
artery disease; COPD ¼ chronic obstructive pulmonary disease; GFR ¼ glomerular filtration rate; ICD ¼
implantable cardioverter-defibrillator; NYHA ¼ New York Heart Association functional class; PM ¼ pacemaker;
TR ¼ tricuspid regurgitation.
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Kammerlander et al.
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:2633–42
RV Dysfunction and Outcomes in Left Heart Valve Procedure
In patients with previous aortic valve replacement,
T A B L E 4 Echocardiographic Data
significant TR appeared in 14%.
All Patients
(N ¼ 539)
Nonsignificant TR
(n ¼ 448, 83%)
Significant TR
(n ¼ 91, 17%)
LVEDD, mm
46.6 5.9
46.0 (43.0–50.0)
46.5 5.6
46.0 (43.0–49.0)
47.0 6.9
46.0 (43.0–50.0)
0.569
LVEDD/BSA, mm/m2
25.0 3.4
24.7 (22.8–27.0)
24.8 3.2
24.5 (22.7–26.8)
26.0 4.0
25.9 (23.2–28.4)
0.008
RVEDD, mm
33.7 5.3
34.0 (30.0–37.0)
33.1 4.7
33.0 (30.0–36.0)
36.8 6.4
37.0 (32.8–41.3)
<0.001
RVEDD/BSA, mm/m2
18.1 3.2
17.8 (16.1–20.0)
17.7 2.9
17.6 (15.9–19.3)
20.3 3.6
20.2 (18.0–22.3)
<0.001
(p ¼ 0.019).
LA, mm
59.1 9.3
58.0 (53.0–64.0)
57.7 7.8
57.0 (53.0–63.0)
66.0 12.7
64.0 (58.0–73.0)
<0.001
TR patients presented with larger left (p ¼ 0.008) and
LA/BSA, mm/m2
31.9 6.0
30.9 (28.0–34.6)
30.9 5.0
30.1 (27.6–33.5)
36.5 7.9
34.6 (32.2–40.9)
<0.001
RA, mm
57.0 8.9
55.0 (51.0–61.0)
55.6 7.3
55.0 (51.0–60.0)
63.8 12.3
60.0 (56.0–71.0)
<0.001
30.7 5.6
30.0 (26.6–33.5)
29.8 4.8
29.2 (26.3–32.7)
35.2 7.1
33.7 (30.8–39.0)
<0.001
57.4 7.6
59.0 (52.0–63.0)
57.6 7.5
59.0 (52.0–63.0)
56.3 8.2
56.0 (52.0–63.0)
0.202
RA/BSA, mm/m
2
LVEF, %
p Value*
Table 3 shows baseline patient characteristics
according to TR severity. Patients with significant
TR were more often female (p ¼ 0.004), had lower
GFR (p ¼ 0.002), more often presented with AF
(p < 0.001), and were more symptomatic (p < 0.001).
They also had more previous valve (redo) procedures
Table 4 displays echocardiographic data at baseline.
right (p < 0.001) ventricles, larger left (p < 0.001) and
right (p < 0.001) atria, and worse RV systolic function
(p < 0.001).
O u t c o m e a n a l y s i s . Patients were followed for 53 15 months, and all completed follow-up. A total of 117
(22%) patients died during follow-up. Causes of death
are given in Table 5. Cardiovascular death was the
LVEF <50%
12
11
15
0.285
TAPSE, mm
16.3 4.8
16.0 (13.0–19.0)
16.6 4.6
16.0 (13.0–19.0)
15.5 5.3
15.0 (11.0–19.3)
0.205
leading cause of mortality and was more frequent
RV FAC, %
46.2 9.9
46.0 (41.0–53.0)
47.1 9.4
48.0 (41.0–54.0)
42.5 10.9
42.0 (32.0–51.0)
<0.001
2 patients had TV repair procedure during follow-up:
2.87 0.42
2.8 (2.6–3.1)
2.78 0.35
2.7 (2.5–3.0)
3.23 0.49
3.2 (2.9–3.5)
<0.001
40.3 11.5
38.0 (32.0–46.0)
37.4 8.8
36.0 (31.5–41.0)
51.6 13.8
51.0 (41.0–60.5)
<0.001
6
4
19
<0.001
MR
4
2
15
81% in patients without significant TR (log-rank test,
AS
0.4
0.4
0
p < 0.001) (Figure 2).
Peak TR velocity, m/s
sPAP, mm Hg
Significant valve
lesion other
than TR
among patients with significant TR (p ¼ 0.045). Only
1 died perioperatively, but the other survived and
remained in the analysis.
By Kaplan-Meier analysis, overall survival was
significantly worse in patients with significant TR,
with 1-, 3-, and 5-year survival rates of 92%, 81%,
and 64%, respectively, compared with 96%, 89%, and
AR
1.7
1.1
4.4
MS
0.4
0.2
0.2
Per the results of the univariable and multivariable Cox regression analyses (Table 6), significant
Values are mean SD, median (interquartile range), or %. *p values for continuous data derive from the Wilcoxon
rank sum test, and the chi-square test was used for categorical data. Values in bold indicate significant p values.
AR ¼ aortic regurgitation; AS ¼ aortic stenosis; FAC ¼ fractional area change; LA ¼ left atrial longitudinal
diameter, apical 4-chamber view; LVEDD ¼ left ventricular end-diastolic diameter, apical 4-chamber view; MR ¼
mitral regurgitation; MS ¼ mitral stenosis; RA ¼ right atrial longitudinal diameter, apical 4-chamber view;
RVEDD ¼ right ventricular end-diastolic diameter, apical 4-chamber view; sPAP ¼ systolic pulmonary artery
pressure; TAPSE ¼ tricuspid annular plane systolic excursion; other abbreviations as in Tables 2 and 3.
TR (p < 0.001), age (p < 0.001), GFR (p < 0.001),
coronary artery disease (p ¼ 0.001), previous CABG
(p < 0.001), New York Heart Association functional
class $2 (p ¼ 0.001), chronic obstructive pulmonary
disease (p ¼ 0.030), diabetes (p ¼ 0.002), left and
right atrial and RV size indexed to body surface
area (all p < 0.001), peak TR velocity (p < 0.001),
and RV systolic function (p < 0.001) were signifi-
RESULTS
cantly associated with survival in the univariable
analysis.
CLINICAL AND SURGICAL DATA. Figure 1 depicts
By multivariable analysis, however, only age, left
patient baseline characteristics according to type of
atrial size, RV systolic function, diabetes, and previ-
valve procedure. The mean period from left heart
ous CABG, but not TR, remained significantly associ-
valve procedure to enrollment was 50 30 months.
ated with outcome.
The majority of patients underwent previous aortic
We also tested our data for potential interactions,
valve replacement (65%). The remaining patients had
particularly with respect to LV and RV systolic func-
previous isolated mitral valve procedure (19%), com-
tion, kidney function, and peak TR velocity. No sig-
bined aortic and mitral valve procedure (10%), or
nificant interactions were detected.
previous TV surgery in addition to any other valve
(6%). Significant TR most frequently occurred in pa-
DISCUSSION
tients with previous surgery of the TV (34%), followed
by previous combined aortic and mitral valve proce-
The present prospective, long-term, observational
dure (25%) and mitral valve procedure alone (17%).
study of 571 patients examined the impact of
Kammerlander et al.
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:2633–42
2637
RV Dysfunction and Outcomes in Left Heart Valve Procedure
F I G U R E 1 Patient Baseline Characteristics According to Type of Valve Surgery
571 patients
after left-sided valve procedure
32 patients with significant TR and
PM / ICD excluded
539 patients
50±30 months after left-sided valve procedure
Type of previous cardiac procedure
AVR
65%
MV-procedure
19%
AVR + MV-procedure TV + any left-sided procedure
10%
6%
TR grade at
index date
86%
14%
83%
17%
Non-significant TR
75%
66%
34%
25%
Significant TR
Follow-up: 53±15 months
A total of 571 patients were included in the study, of whom 65% underwent AVR, 19% MV procedure, 10% combined AVR and MV procedure,
and 6% TV procedure combined with any left-sided procedure. Pie graphs indicate the percent of significant and nonsignificant TR in the
respective groups. Patients were followed for 53 15 months. AVR ¼ aortic valve replacement; ICD ¼ implantable cardioverter-defibrillator;
MV ¼ mitral valve; PM ¼ pacemaker; TV ¼ tricuspid valve; TR ¼ tricuspid regurgitation.
significant TR late after left heart valve procedure. Our
801 patients with late significant TR after left heart
data show that RV dysfunction, but not TR, is inde-
valve procedure, but no significant increase in mor-
pendently associated with outcome in this setting.
tality. Kwak et al. (14) retrospectively evaluated
Reoccurrence or new development of signifi-
335 patients after left heart valve procedure. The
cant TR late after left heart valve procedure is
endpoint, defined as cardiovascular death and redo
found frequently and varies between 9% and 49%
(13–15,29,30). These patients represent a challenging
population because they often experience severe
T A B L E 5 Causes of Death
symptoms, conservative treatment options are lim-
All Patients
(N ¼ 117)
Nonsignificant TR
(n ¼ 84)
Significant TR
(n ¼ 33)
Diseases of the circulatory
system (cardiac death)
68 (58.1)
44 (52.4)
24 (72.7)
0.045
Neoplasms
0.020
ited, and redo surgery carries a high risk (10,16,17).
Significant TR has been identified as a predictor
of mortality in patients undergoing routine echocar-
p Value
23 (19.7)
21 (25.0)
2 (6.1)
Diseases of the respiratory system
9 (7.7)
7 (8.3)
2 (6.1)
1.000*
Endocrine, nutritional and
metabolic diseases
5 (4.3)
5 (6.0)
0 (0)
0.320*
after left heart valve procedure, the evidence with
Injury, poisoning, and certain other
consequences of external causes
4 (3.4)
3 (3.6)
1 (3.0)
1.000*
respect to the impact of TR on outcome remains
Diseases of the digestive system
3 (2.6)
1 (1.2)
2 (6.1)
0.191*
limited. Song et al. (12) retrospectively investigated
Diseases of the genitourinary system
2 (1.7)
1 (1.2)
1 (3.0)
0.486*
more than 600 patients after left heart valve proce-
Symptoms, signs, and abnormal
clinical and laboratory findings,
not elsewhere classified
3 (2.6)
2 (2.4)
1 (3.0)
1.000*
diography (4), heart failure (HF) patients (2,3,5) and
patients with mitral valve disease (31–33).
However, for patients presenting with TR late
dure. Late significant TR was associated with worse
outcome, defined as a combination of cardiovascular
death, need for redo surgery, and hospital admission
due to congestive HF. Conversely, Garcia Fuster et al.
(13) reported higher frequencies of chronic HF in
Values are n (%). *p values derived from the Fisher exact test; all other p values derived from the chi-square test.
Values in bold indicate significant p values.
TR ¼ tricuspid regurgitation.
2638
Kammerlander et al.
JACC VOL. 64, NO. 24, 2014
RV Dysfunction and Outcomes in Left Heart Valve Procedure
CENT RAL I LLU ST RATI ON
DECEMBER 23, 2014:2633–42
Pathogenetic Processes Underlying TR in Patients With Previous Left Heart Valve Procedure
Kammerlander, A.A. et al. J Am Coll Cardiol. 2014; 64(24):2633–42.
Continued on the next page
Kammerlander et al.
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:2633–42
surgery, was more frequently reached by patients with
significant TR, but only after 10 years of follow-up.
2639
RV Dysfunction and Outcomes in Left Heart Valve Procedure
F I G U R E 2 Kaplan-Meier Estimate for Overall Survival
It must be emphasized that all these studies
were retrospectively designed and lack assessment of
100
RV function as well as multivariable regression
no/mild TR
analyses.
80
Therefore, the present large prospective study
moderate TR
though significant TR was strongly associated with
mortality by univariable Cox and Kaplan-Meier analysis (Figure 2, Table 6), only RV function, but not
TR, remained associated with outcome in the multivariable model (Table 6).
Survival (%)
adds important information. Our data show that al60
severe TR
40
Recently, Gulati and coworkers (34) reported on
the important prognostic value of RV function by
20
cardiac magnetic resonance imaging (CMR) in patients with dilated cardiomyopathy. RV ejection
fraction of #45% was shown to be significantly associated with adverse outcome. The present data underline the similar importance of RV function for
0
0
12
24
prognosis in patients presenting late after left heart
valve procedure. Although assessment of RV function
by echocardiography is challenging, an integrated
approach including assessment of RV size, comprehensive visual assessment of contractility, and tricuspid annular plane systolic excursion allows the
distinction between normal and abnormal RV function with good accuracy (24).
The development or progression of “functional”
TR late after left heart valve procedure follows as a
consequence of geometric alterations of the RV. It
has recently been shown in aortic stenosis patients
that after aortic valve replacement, LV hypertrophy
36
48
60
Time (Months)
Year
1
Death (n)
Number at Risk
Survival (%)
Failure (%)
18
430
96
4
Death (n)
Number at Risk
Survival (%)
Failure (%)
5
63
93
7
Death (n)
Number at Risk
Survival (%)
Failure (%)
2
21
91
9
2
3
No/mild TR (n=448)
29
50
419
398
94
89
6
11
Moderate TR (n=68)
8
14
60
54
88
79
12
21
Severe TR (n=23)
3
3
20
20
87
87
13
13
4
5
69
379
85
15
84
364
81
19
20
48
71
29
24
44
65
35
7
16
70
30
9
14
61
39
decreases, but the degree of diffuse interstitial
myocardial fibrosis remains unchanged (35). Diffuse
Numbers at the bottom indicate the number of patients at risk and the number of events
myocardial fibrosis has been linked with diastolic
at each follow-up year. A significant difference in survival was found between patients
dysfunction and elevated LV end-diastolic pressures, promoting post-capillary pulmonary hyper-
with no/mild TR and moderate TR (log-rank p ¼ 0.001) as well as severe TR (log-rank
p ¼ 0.013). Survival between patients with moderate and severe TR was not different
(log-rank p ¼ 0.762). TR ¼ tricuspid regurgitation.
tension (36). The elevation of pulmonary pressure
induces RV pressure overload, RV dilation, distortion of the tricuspid valvular apparatus, and finally,
CENTRAL ILLUSTRATION
(A) Left heart valve disease causes a rise in left atrial (LA) pressure and in pulmonary arterial wedge pressure, dilating the left atrium. (B) Over
time, LA pressure and pulmonary arterial wedge pressure increase further. Pulmonary vascular compliance declines, adding to the increasing
resistance against the right ventricle (RV). RV end-diastolic pressure rises, leading to right atrial (RA) dilation. Two additional mechanisms may
aggravate RV pressure overload: 1) diffuse fibrosis/extracellular matrix expansion of the left ventricular myocardium (particularly in patients
with aortic stenosis), leading to a further increase in left ventricular end-diastolic and, consequently, LA pressure; and 2) remodeling of the
pulmonary vascular bed. (C) The RV fails to compensate for pressure overload and dilates. Tricuspid annular dilation and distortion of the
subvalvular apparatus lead to increasing tricuspid regurgitation (TR) and subsequent further RA dilation. (D) In many patients, surgical
correction of the left-sided valve lesion does not result in complete regression of the described changes. Postcapillary pulmonary hypertension
persists and may lead to increasing RV size, worsening RV function, and, consequently, increasing TR. The degree of pathological changes
depends on the severity of left heart valve disease and the timing of surgery. LV ¼ left ventricle.
2640
Kammerlander et al.
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:2633–42
RV Dysfunction and Outcomes in Left Heart Valve Procedure
T A B L E 6 Univariable and Multivariable Cox Regression Analysis for All-Cause Mortality
Univariable Cox Regression Analysis
Multivariable Cox Regression Analysis
Variable
Hazard Ratio (95% CI)
p Value*
Variable
Hazard Ratio (95% CI)
p Value*
Age
1.082 (1.060–1.105)
<0.001
Age
1.053 (1.022–1.085)
0.001
GFR
0.976 (0.966–0.986)
<0.001
LA/BSA
1.044 (1.012–1.077)
CAD
1.844 (1.272–2.673)
0.001
RV FAC
0.945 (0.922–0.968)
CABG
2.187 (1.437–3.328)
<0.001
CABG
2.469 (1.356–4.496)
0.003
NYHA $2
1.813 (1.257–2.673)
0.001
Diabetes
2.018 (1.084–3.756)
0.027
0.030
COPD
1.793 (1.058–3.039)
Diabetes
1.958 (1.281–2.995)
0.002
Significant TR
2.143 (1.432–3.206)
<0.001
LA/BSA
1.062 (1.043–1.081)
<0.001
RA/BSA
1.067 (1.042–1.093)
<0.001
RVEDD/BSA
1.088 (1.038–1.140)
<0.001
Peak TR velocity
3.437 (2.349–5.030)
<0.001
RV FAC
0.931 (0.910–0.952)
<0.001
0.007
<0.001
*p values derive from univariable (left columns) and multivariable (right columns) Cox regression using a backward selection. Values in bold indicate significant p values.
CI ¼ confidence interval; other abbreviations as in Tables 2, 3, and 4.
significant TR. The assumption that TR late after left
STUDY LIMITATIONS. We collected the presented
heart valve procedure develops secondary to post-
data in a single-center setting; therefore, a center-
capillary pulmonary hypertension is supported by
specific bias cannot be excluded. However, the major
more prominent left atrial dilation in patients with
advantages of limiting data collection to a single cen-
severe TR, and also higher estimated pulmonary
ter are: 1) inclusion of a homogenous patient popula-
artery pressures by echocardiography (Table 4). The
tion; 2) adherence to a constant clinical routine;
Central Illustration displays the pathogenetic pro-
3) constant quality of echocardiographic work-up; and
cesses underlying TR late after left heart valve
4) constant follow-up.
procedure.
Pulmonary hypertension as a result of left heart
Renal impairment is a common finding in patients
with severe TR and RV dysfunction. The majority of
disease (Dana Point 2) can cause significant TR,
our
but correcting TR may not be sufficient to modify
(GFR ¼ 66.3 18.1 ml/min) (Table 3). However, in
patients
presented
with
renal
dysfunction
the outcome of these patients. Because of this, RV
only 1.9% of patients was GFR <30 ml/min. Thus, our
function seems to be a more important predictor of
data are not necessarily transposable to patients with
outcome. However, from the pathophysiological
severe renal failure. The present study is also limited
point of view, a double load on the RV (pressure plus
by the lack of data on rehospitalization for HF. LV
volume related to the presence of TR) will produce
volumes and conduction abnormalities were not
consequences. The presence of significant TR leads
evaluated.
to more dilation and more RV systolic dysfunction,
Accurate determination of RV dysfunction in the
and through this, to worse outcome. However, when
presence of significant TR is difficult because RV
we excluded patients with dilated right heart cham-
unloading as a result of TR may be misleading, on top
bers from the multivariable Cox regression analysis,
of technical limitations of 2-dimensional echocardi-
similar results were obtained.
ography used to assess the RV. CMR is currently the
The guidelines on the management of valvular
gold standard for the assessment of RV function.
heart disease currently recommend surgical correc-
Unfortunately, systematic CMR data are not available
tion of severe primary TR and of significant TR at the
for the present population.
time of left heart valve procedure (10). In patients
As impairment of RV function in our patients
who present with TR after previous left heart valve
seems to be linked with elevated pulmonary artery
procedure, the guidelines propose a Class IIa, Level of
pressures, caused by high LV filling pressures,
Evidence: C recommendation for surgical correction.
invasive hemodynamic data would be of great
The present data challenge this recommendation
interest. Unfortunately, systematic right heart cath-
because they imply that TR in these patients is a
eterization was not performed; thus, hemodynamic
result of elevated pulmonary pressures, which cannot
data are only available in a small proportion of our
be modified by TV procedure.
patients.
Kammerlander et al.
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:2633–42
RV Dysfunction and Outcomes in Left Heart Valve Procedure
CONCLUSIONS
PERSPECTIVES
Significant TR late after left heart valve procedure
is frequent but, in contrast to RV dysfunction, age,
left atrial size, diabetes, and previous CABG, not
independently associated with survival.
In light of these results, isolated surgical correction
of significant TR late after left heart valve procedure
may not be beneficial. Further studies are needed to
define specific groups of patients who would clearly
benefit from such a procedure.
Mascherbauer,
Department
gitation frequently develops late after left heart valve surgery.
However, in contrast to right ventricular dysfunction, age, left
atrial size, diabetes, and previous coronary artery bypass procedure, it is not independently associated with reduced survival.
COMPETENCY IN PATIENT CARE: Isolated surgical correction of significant tricuspid regurgitation may not be beneficial
late after left heart valve procedure.
REPRINT REQUESTS AND CORRESPONDENCE : Dr.
Julia
COMPETENCY IN MEDICAL KNOWLEDGE: Tricuspid regur-
of
Cardiology,
Medical University of Vienna, University Hospital,
TRANSLATIONAL OUTLOOK: Further studies are needed to
define specific groups of patients who would benefit from isolated
repair of tricuspid regurgitation late after left heart valve procedure.
Waehringer Guertel 18–20, A-1090 Vienna, Austria.
E-mail: [email protected].
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