- Email: [email protected]
Natural History of Functional Tricuspid Regurgitation
JACC: CARDIOVASCULAR IMAGING
VOL.
-, NO. -, 2019
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ORIGINAL RESEARCH
Natural History of Functional Tricuspid Regurgitation Implications of Quantitative Doppler Assessment Philipp E. Bartko, MD, PHD,a Henrike Arfsten, MD,a Maria K. Frey, MD, PHD,a Gregor Heitzinger,a Noemi Pavo, MD, PHD,a Anna Cho,a Stephanie Neuhold, MD,b Timothy C. Tan, MBBS, PHD,c,d Guido Strunk, PHD,e Christian Hengstenberg, MD,a Martin Hülsmann, MD,a Georg Goliasch, MD, PHDa
ABSTRACT OBJECTIVES This study sought to define the relationship between functional tricuspid regurgitation (TR) and mortality in patients with heart failure with reduced ejection fraction (HFrEF); and to establish the prognostic value of quantitative measures of TR severity (i.e., effective regurgitant orifice area [EROA] and regurgitant volume). BACKGROUND The significance of TR in chronic heart failure is controversial. Earlier studies have shown an independent impact of TR on mortality, whereas more recent evidence suggests myocardial impairment to be the driving force of mortality rather than TR itself. Earlier studies have used qualitative measures of TR severity, hence the prognostic value of more quantitative measures of TR severity (i.e., EROA and regurgitant volumes) remains unclear. METHODS We enrolled 382 patients with HFrEF on guideline-directed medical therapy and assessed TR EROA and regurgitant volume by Doppler/2-dimensional echocardiography. All-cause mortality was defined as the primary study endpoint. RESULTS TR severity was associated with the HFrEF phenotype with more symptoms (p ¼ 0.004), higher neurohumoral activation (p < 0.001), progressive right-ventricular dilatation (p < 0.001), and impaired function (p < 0.001). Cox regression showed a strong association between quantitative measures of TR with mortality (all p < 0.001). Quantitative metrics of TR severity were consistently associated with mortality with a hazard ratio of 1.009 (95% confidence interval: 1.004 to 1.013; p < 0.001) per 0.01 cm2 increase of the EROA and of 1.013 (95% confidence interval: 1.007 to 1.020; p < 0.001) per 1-ml increase in regurgitant volume. Results remained unchanged after bootstrap- or clinical confounder-based adjustment. A spline curve pattern illustrates the association with mortality with thresholds for the EROA $0.2 cm2, and the regurgitant volume $20 ml with sustained excess mortality thereafter. CONCLUSIONS This large-scale outcome study demonstrates the prognostic value of quantitative Dopplerechocardiographic measures of TR severity in HFrEF. The thresholds for EROA and TR regurgitant volume associated with mortality in our study fall within current ranges defining nonsevere TR. This may potentially impact therapeutic decision making, particularly timing of intervention. (J Am Coll Cardiol Img 2019;-:-–-) © 2019 by the American College of Cardiology Foundation.
From the aDepartment of Internal Medicine II, Medical University of Vienna, Vienna, Austria; bDepartment of Medicine IV, KaiserFranz-Joseph-Spital, Vienna, Austria; cWestmead Hospital, Faculty of Medicine, University of Sydney, Sydney, Australia; d
Department of Cardiology, Blacktown Hospital, Blacktown, Australia; and the eFH Campus Vienna and Complexity Research,
Vienna, Austria. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 3, 2018; revised manuscript received October 19, 2018, accepted November 7, 2018.
ISSN 1936-878X/$36.00
https://doi.org/10.1016/j.jcmg.2018.11.021
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Functional Tricuspid Regurgitation
ABBREVIATIONS AND ACRONYMS CI = confidence interval
F
unctional tricuspid regurgitation (TR)
Austrian citizens (even those in foreign countries)
is a common valvular lesion and the
this allowed complete follow-up of all patients.
presence of significant TR has been
ECHOCARDIOGRAPHIC
ASSESSMENT. All
patients
associated with increased mortality (1,2).
underwent
However, the prognostic significance of TR
examination
in patients with heart failure with reduced
Echocardiography
reduced ejection fraction
ejection fraction (HFrEF) is controversial.
echocardiograms were performed using commercially
IQR = interquartile range
Earlier studies have suggested an indepen-
available equipment (Vivid7, GE Healthcare, Chicago,
dent impact of TR on mortality in patients
Illinois) by physicians and sonographers blinded to
with left ventricular systolic dysfunction,
clinical data and outcomes and interpreted by board-
B-type natriuretic peptide
where the TR is believed to cause adverse
certified physicians. Raw data with frame rates >50
NYHA = New York Heart
right-ventricular remodeling and dysfunc-
frames per second were stored digitally and images
Association
tion thus increased mortality (1–3). More
analyzed offline. Cardiac chamber sizes were assessed
PISA = proximal isovelocity
recent evidence suggests myocardial impair-
according to American Society of Echocardiography
surface area
ment to be the driving force of mortality
guideline recommendations (7). A comprehensive
RegVol = regurgitant volume
rather than TR itself, with the TR simply
assessment of the tricuspid valve and TR was
TAPSE = tricuspid annular
being a surrogate of disease severity (4).
plane systolic excursion
performed using an
Furthermore, previous studies examining
TR = functional tricuspid
approach encompassing tricuspid valve morphology,
the prognostic impact of TR have used quali-
color Doppler jet size, right atrial size, VCW, EROA,
tative measures of TR severity, hence the
and the RegVol using the proximal isovelocity surface
prognostic value of more quantitative mea-
area (PISA) method (8). Tricuspid valve morphology
sures of TR severity, such as vena contracta width
was assessed with right ventricular focused views
(VCW), effective regurgitant orifice area (EROA), and
using midsystolic frames. The proximal flow conver-
regurgitant volumes (RegVol) remains unclear. In
gence was assessed with a baseline downward shift
this study we sought to examine the prognostic
toward optimized visualization of the hemispheric
impact of TR and its severity in patients with HFrEF
shell from standard 4-chamber guided zoomed view
EROA = effective regurgitant orifice area
HFrEF = heart failure with
MR = mitral regurgitation NT-proBNP = N-terminal pro–
regurgitation
VCW = vena contracta width
a
comprehensive according
to
echocardiographic
American
guidelines
(7).
Society
of
Transthoracic
integrated, multiparametric
and the prognostic value of quantitative echocardio-
of the TR jet. For patients in atrial fibrillation, a mean
graphic measures of TR severity.
of 6 cardiac cycles was performed to account for beatto-beat variability. Mean global longitudinal strain of
METHODS
the right ventricular free wall by speckle-tracking and M-mode quantification of the tricuspid annular plane
STUDY DESIGN AND STUDY POPULATION. This was
systolic excursion (TAPSE) were also assessed using
a
noninterventional
GE EchoPac software version 201 (GE Vingmed,
study. Consecutive adult patients with HFrEF pre-
Horten, Norway). Intraobserver and interobserver
senting to the outpatient heart failure clinic of the
variability for quantitative measures of TR severity
Vienna General Hospital, a tertiary referral center,
(i.e., VCW, EROA, and RegVol) were assessed in 20
were recruited. Only patients who were euvolemic,
randomly selected patients.
clinically stable and optimized on guideline-based
STATISTICAL METHODS. Continuous data were pre-
medical therapy were recruited. HFrEF was defined
sented as median (interquartile range [IQR]) and
according to the 2016 American College of Cardiology/
compared using the Kruskal-Wallis test. Categorical
American Heart Association/Heart Failure Society
variables were compared using chi-square test. Cox
guidelines based on heart failure signs, symptoms
proportional hazards regression analysis and spline
and a left ventricular ejection fraction less than 40%
curve graphs were applied to assess the effect of
(5,6). The study protocol was approved by the Ethics
TR severity on survival. To account for potential
Committee of the Medical University of Vienna.
confounding effects, we formed a clinical confounder
CLINICAL
FOLLOW-UP.
cluster (encompassing age, sex, ischemic etiology of
Medical history, current medication, an electrocar-
heart failure, New York Heart Association [NYHA]
single-center
observational,
MEASURES
AND
diogram recording, and routine blood tests were
functional class, hypertension, diabetes, creatinine,
collected at the
All-cause
g-glutamyltransferase, left ventricular end-diastolic
mortality during 5-years follow up was defined as
volume, left ventricular ejection fraction, right
the primary endpoint. Mortality data were obtained
ventricular end-diastolic diameter, TAPSE, tricuspid
from the Austrian Death Registry. Because Austrian
valve annular diameter, tricuspid valve tenting
law requires mandatory reporting of all deaths of
area, TR maximum velocity, right-atrial volume,
time
of
enrollment.
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renin-angiotensin system antagonists, beta-blockers,
(n ¼ 44) of patients in NYHA functional class IV. With
All
respect to heart failure therapy, 93% (n ¼ 354)
continuous variables in the clusters were log-
received renin-angiotensin system antagonists, 89%
and
mineralocorticoid
antagonist
therapy).
analysis
(n ¼ 339) received beta-blockers, and 64% (n ¼ 243)
including the original and log-transformed variable
were treated with a mineralocorticoid receptor
was performed. The variable selected using this pro-
antagonist. Sixty-nine percent of patients displayed
cedure was then used for further analysis. A stepwise
greater than or equal to moderate TR. Quantitative
bootstrap resampling procedure including all afore-
assessment of TR was technically feasible in all pa-
mentioned variables was also used to identify best-
tients with more than trace TR. Thirty-one patients
fitting variables for the final multivariable Cox
with trace TR and inadequate continuous-wave
regression model. Five-hundred repeats with a p
Doppler spectrum were allocated to the low-risk
value of 0.05 for selection were performed and vari-
group. All quantitative measures of TR severity
ables selected in 70% of all repeats were included in
demonstrated good reproducibility, with an intraclass
the final cofounder model (i.e., age, g-glutamyl-
correlation
transferase, and TAPSE). All variables included in the
interobserver and intraobserver variability.
final model were not log-transformed. Additionally,
MEASURES OF FUNCTIONAL TR SEVERITY. Patients with
we assessed the predictive power of TR by a clinical
functional TR were then categorized into significant
confounder model reflecting the morphologic, func-
versus nonsignificant functional TR using thresholds
tional, and neurohumoral impairment in TR encom-
associated with increased mortality for VCW (VCW $5
passing right ventricular end-diastolic diameter,
mm), EROA (EROA $0.2 cm2 ), and RegVol (RegVol
TAPSE, N-terminal pro–B-type natriuretic peptide
of $20 ml) and the results presented in Table 1. Briefly,
transformed
and
stepwise
regression
coefficient
>0.95
when
tested
for
(NT-proBNP), and severity of mitral regurgitation
with worsening TR as reflected by increasing VCW,
(MR) (greater than moderate). Hazard ratios refer to
EROA, and RegVol, levels of NT-proBNP (p < 0.01),
a 1-SD increase in continuous variables and to an
g-glutamyltransferase (p < 0.001), NYHA functional
increase of 1 category of semiquantitative TR assess-
class (p ¼ 0.01), use of diuretics (p ¼ 0.003), and age
ment. We tested for collinearity in the multivariable
(p ¼ 0.029) also increased. Morphologically, increasing
model using the variance inflation factor. The pro-
VCW, EROA, and RegVol were associated with
portional
and
increasing right ventricular end-diastolic diameter
satisfied in all cases using Schoenfeld residuals.
(p < 0.001), increasing tricuspid valve annular diam-
Interactions between surrogates of TR severity and all
eter (p < 0.001), a more pronounced tricuspid valve
variables included in the multivariable model were
tenting area (p < 0.001), and poorer right ventricular
hazards
assumption
was
tested
tested by entering interaction terms in the Cox pro-
function evidenced by a reduction in TAPSE (p < 0.05)
portional hazards regression models. Kaplan-Meier
and right ventricular free wall strain (p < 0.05). Base-
analysis (log-rank test) was applied to assess the
line
time-dependent discriminative power of surrogates
approach is shown in Online Table 1. We noted that the
characteristics
according
to
the
integrated
of TR severity. Two-sided p values <0.05 were used
severity of TR gradually increased with NYHA func-
to indicate statistical significance. The STATA version
tional class (p ¼ 0.005) (Figure 1A) and increasing levels
11 software package (StataCorp, College Station,
of NT-proBNP (p < 0.001) (Figure 1B).
Texas) and SPSS version 24.0 (IBM Corporation, Armonk, New York) were used for all analyses.
RESULTS
QUANTITATIVE MEASURES OF FUNCTIONAL TR AND OUTCOME. During the 5-year follow-up period, 158
patients died. We observed a significant association between TR severity and mortality with a crude haz-
We enrolled 382 patients with chronic HFrEF with a
ard ratio of 1.63 (95% confidence interval [CI]: 1.35 to
median age of 68 years (IQR: 61 to 75 years). Detailed
1.97; p < 0.001). In terms of the specific measures
baseline characteristics of the study population ac-
of TR severity, we observed a hazard ratio of 1.109
cording to subsequently defined thresholds of sig-
(95% CI: 1.066 to 1.154; p < 0.001) per 1-mm increase
nificance are displayed in Table 1 and according to the
in TR VCW, 1.009 (95% CI: 1.004 to 1.013; p < 0.001)
guideline proposed integrated approach in Online
per 0.01-cm 2 increase in TR EROA, and 1.013 (95% CI:
Table 1. Seventy-eight percent (n ¼ 296) were male,
1.007 to 1.020; p < 0.001) per 1-ml increase in TR
the median NT-proBNP was 3,144 pg/ml (IQR: 1,639 to
RegVol (Table 2). Of note, there were no significant
7,620 pg/ml), and the median left ventricular ejection
interactions between the individual quantitative
fraction was 26% (IQR: 19 to 34). A total of 39%
measures of TR severity we examined and the
(n ¼ 148) were in NYHA functional class III and 12%
presence of implanted device leads (permanent
3
Bartko et al.
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Functional Tricuspid Regurgitation
T A B L E 1 Baseline Characteristics of the Study Population (n ¼ 382) According to VCW, EROA, and RegVol of TR
TR VCW <5 mm (n ¼ 296)
TR VCW $5 mm (n ¼ 86)
p Value
TR EROA <0.20 cm2 (n ¼ 301)
TR EROA $0.20 cm2 (n ¼ 81)
p Value
TR RegVol <20 ml (n ¼ 289)
TR RegVol $20 ml (n ¼ 93)
p Value
Baseline characteristics 67.4 (60.3–74.8)
71.3 (64.5–76.3)
0.016
67.8 (61.2–75)
70 (62.3–76.0)
0.38
Male
Age, yrs
223 (75)
73 (85)
0.06
224 (74)
66 (82)
0.08
217 (75)
73 (79)
0.33
Hypertension
145 (49)
46 (53)
0.63
146 (49)
42 (52)
0.54
137 (47)
51 (55)
0.25
Diabetes
81 (27)
26 (30)
0.59
79 (26)
26 (32)
0.20
73 (25)
32 (34)
0.07
Ischemic etiology of HF
59 (20)
21 (24)
0.39
60 (20)
18 (22)
0.51
56 (19)
22 (24)
0.30
Atrial fibrillation
75 (25)
46 (53)
<0.001
79 (26)
42 (52)
<0.001
74 (26)
47 (51)
<0.001
NYHA functional class
0.14
67.43 (60.4–74.6) 70.7 (63.9–76.5) 0.029
0.06
0.010
II
60 (20)
15 (17)
60 (20)
10 (12)
57 (20)
17 (18)
III
149 (50)
42 (48)
146 (49)
42 (52)
140 (48)
48 (52)
IV
29 (10)
15 (17)
31 (10)
12 (15)
28 (10)
15 (16)
1.2 (1–1.5)
1.5 (1.2–1.8)
<0.001
1.2 (1.0–1.5)
1.5 (1.1–1.8)
0.003
1.2 (1–1.5)
1.5 (1.2–1.8)
23.0 (16.5–36.0)
31.6 (22.0–43.7)
0.001
23.8 (16.5–36.2)
31.2 (21.2–44)
0.006
22.8 (16.2–36)
32 (21.7–42.9)
0.001
13.3 (12–14.3)
12.9 (11.2–14)
0.06
13.2 (12–14.2)
13.1 (11.5–14.1)
0.42
13.3 (12.1–14.2)
12.9 (11.2–14.0)
0.048 0.09
Creatinine, mg/dl Blood urea nitrogen, mg/dl Hemoglobin, mg/dl
<0.001
Aspartate transaminase, U/l
27 (21–36)
28 (22–36)
0.52
26 (21–35)
28 (23–38)
0.14
26 (21–35)
29 (23–39)
Alanine transaminase, U/l
23 (16–36)
22 (15–29)
0.26
22.5 (16–35)
21.5 (16–33)
0.54
22 (15–34)
23 (16–33)
0.83
g-glutamyltransferase, U/l
50 (29–107)
114 (62–197)
<0.001
50 (30–104.5)
118.5 (68–214)
<0.001
48 (29–99)
121 (69–214)
<0.001
NT-proBNP, pg/ml
2,728 (1,336– 6,201)
4,716 (2,385– 10,017)
<0.001
2,888 (1,307– 6,491)
4,417 (2,373– 9,394)
0.002
2,728 (1,307– 5,560)
6,132 (2,422– 9,592)
<0.001
Left ventricular end-diastolic diameter, mm
60 (55–66)
59 (54–64)
0.10
60 (55–66)
59 (53–63)
0.013
60 (55–67)
59 (53–63)
0.009
Left ventricular end-diastolic volume, ml
204 (164–262)
185 (141–232)
0.019
207 (165–264)
178 (140–224)
0.001
208 (166–270)
179 (143–224)
0.001
Echocardiographic characteristics
Left ventricular ejection fraction, %
26 (20–33)
24 (16–35)
0.39
26 (20–33)
25 (16–34)
0.66
26 (19–33)
26 (18–34)
0.64
88 (65–118.5)
116 (87–151)
<0.001
90 (67–121)
109 (85–142)
<0.001
90 (65–121)
108 (83–139)
<0.001
Right ventricular end-diastolic diameter, mm
37 (33–43)
47 (41–50)
<0.001
38 (33–44)
47 (40–50)
<0.001
37 (32–43)
46 (40–50)
<0.001
Right ventricular end-diastolic area, cm2
19.8 (16.9–24.9)
26.7 (21.5–31.2)
<0.001
20 (17–25.4)
Left atrial volume, ml
26.5 (21.4–31.3) <0.001 19.8 (16.6–25.2) 26.4 (21.5–30–9) <0.001
TAPSE, mm
18 (16–22)
16 (13–18)
0.019
18 (15–22)
16 (14–19)
<0.001
18 (15–22)
16 (14–19)
Right ventricular free wall strain, %
18 (12–22)
16 (10–18)
0.001
18 (12–22)
16 (10–18)
0.003
18 (12–22)
16 (11–19)
0.020
Right atrial volume, ml
63 (45–87)
113 (86–148)
<0.001
63 (45–89)
113 (86–150)
<0.001
63 (45–88)
112 (86–147)
<0.001
165 (56)
66 (77)
0.020
170 (57)
21 (26)
0.25
160 (55)
67 (72)
0.09
Mitral regurgitation ($moderate) TR effective regurgitant orifice area, cm2 TR regurgitant volume, ml/beat TR vena contracta width, mm
<0.001
0.06 (0.03–0.11) 0.30 (0.20–0.50) <0.001 0.06 (0.03–0.11) 0.35 (0.25–0.55) <0.001 0.06 (0.03–0.10) 0.28 (0.21–0.50) <0.001 6 (3–12) 2.51 (1.59–3.50)
34.5 (28–50)
<0.001
6 (3–11)
7.49 (6.04–8.9) <0.001 2.58 (1.61–3.61)
7.74 (5.61–9.1)
<0.001
2.48 (1.56–3.5)
7.02 (5.2–8.77) <0.001 38.85 (33–46.7) <0.001
33 (22–47)
<0.001
6 (3–12)
32.5 (25–46)
<0.001
Tricuspid annular diameter, mm
32 (26–40)
38 (32–50)
<0.001
32 (26–39.7)
39.5 (33–48.5)
<0.001
32 (26–39.29)
Tricuspid valve tenting area, mm2
1.3 (0.9–1.7)
2.2 (1.6–3.1)
<0.001
1.3 (0.9–1.7)
2.2 (1.6–3.1)
<0.001
1.3 (0.9–1.7)
2.2 (1.6–2.9)
<0.001
3 (2.7–3.4)
3.3 (2.9–3.6)
0.005
3 (2.7–3.4)
3.2 (2.8–3.5)
0.28
2.9 (2.6–3.4)
3.2 (2.9–3.6)
<0.001
Renin-angiotensin system antagonist
277 (94)
77 (90)
0.21
277 (92)
70 (86)
0.29
266 (92)
81 (87)
0.29
Beta-blockers
259 (88)
80 (93)
0.15
262 (87)
71 (88)
0.48
249 (86)
84 (90)
0.12
Mineralocorticoid antagonist
188 (64)
55 (64)
0.94
191 (64)
48 (59)
0.65
186 (64)
53 (57)
0.27
Furosemide
163 (55)
56 (65)
0.055
165 (55)
51 (63)
0.046
153 (53)
63 (68)
0.003
Amiodarone
58 (20)
24 (28)
0.09
64 (21)
17 (21)
0.88
57 (20)
24 (26)
0.18
Implanted cardioverterdefibrillator
124 (42)
41 (48)
0.34
126 (42)
35 (43)
0.10
123 (43)
38 (41)
0.88
Pacemaker
83 (14)
38 (44)
0.017
83 (28)
35 (43)
0.014
81 (28)
37 (40)
0.032
TR velocity, m/s Medication
Rhythm devices
Values are median (interquartile range) or n (%). Bold values are statistically significant. EROA ¼ effective regurgitant orifice area; HF ¼ heart failure; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; NYHA ¼ New York Heart Association; RegVol ¼ regurgitant volume; TAPSE ¼ tricuspid annular plane systolic excursion; TR ¼ functional tricuspid regurgitation; VCW ¼ vena contracta width.
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endocardial pacemakers and automatic implanted cardioverter defibrillators) or atrial fibrillation with regards to the measured outcome (all p values for interaction >0.1). These results remained essentially
F I G U R E 1 Prevalence of Functional Tricuspid Regurgitation
A 70
unchanged after adjustment using the bootstrapselected
confounder
model
and
the
P = 0.005
clinical
60
confounder model (Table 2, Online Table 2). Addi50
VCW, EROA, and RegVol with outcomes using spline analysis (Figure 2). The lower 95% CI served as the threshold for further analyses. Kaplan-Meier analysis demonstrated a significant increase in mortality in
Percentage
tionally, we also explored the association between TR
(Figure 3A), an EROA $0.20 cm
30 20
patients with a TR VCW $5 mm (p < 0.001) 2
40
(p ¼ 0.002)
10
(Figure 3B), and a RegVol $20 ml (p > 0.001) (Figure 3C).
0 NYHA I
DISCUSSION Our study is a large-scale long-term observational
80 P < 0.001 70
right ventricular systolic function, neurohumoral
60
cohort of patients with stable HFrEF. Additionally, we identified thresholds for the standard parameters used to quantify TR severity that were associated with increased mortality (i.e., VCW of $5 mm, EROA $0.2 cm2 , and RegVol of $20 ml). Of note, the cutoffs identified in our study that were predictive of mortality were all distinctly lower than current guideline cutoffs, which define severe TR. This has
Percentage
activation, and morphologic features of the tricuspid
echocardiographic measures of TR severity in a
NYHA IV
B
functional TR and mortality independent of left and
the prognostic value of the quantitative Doppler-
NYHA III
NYHA Functional Class
study that demonstrates the association between
valve complex. The results of our study also highlight
NYHA II
50 40 30 20 10 0 1st Quartile
2nd Quartile
3rd Quartile
4th Quartile
Quartiles of NT-Pro-BNP No/mild FTR
Moderate FTR
Severe FTR
clinical significance because it potentially impacts therapeutic decision making. Furthermore, the association between quantitative measures of TR severity and mortality emphasizes the potential value of
Prevalence of functional tricuspid regurgitation according to New York Heart Association functional class (A) (p ¼ 0.005) and quartiles of N-terminal pro–B-type natriuretic peptide (B) (p < 0.001). FTR ¼ functional tricuspid regurgitation; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; NYHA ¼ New York Heart Association.
routine assessment in clinical practice compared with qualitative assessments of TR severity in patients with chronic heart failure.
retrospective cohorts. Interestingly, a more recent
FUNCTIONAL TR AND MORTALITY. TR in patients
study by Neuhold et al. (4) demonstrated an inde-
with HFrEF is frequent, particularly in the advanced
pendent association of TR with survival only in the
stages. In patients with HFrEF, TR is usually left un-
subgroups of mild and moderately reduced ejection
treated in most patients because of unacceptable high
fraction but a lack of TR impact in patients with se-
perioperative mortality even in heart valve centers of
vere systolic heart failure. The authors therefore hy-
excellence (up to 10%) (9) giving rise to a clinical
pothesized that the impact of TR was inversely
management dilemma of decision for surgical inter-
dependent on HFrEF severity. Of note, only 89 pa-
vention and timing of surgery. Hung et al. (2) showed
tients in their cohort had moderate/severe TR in their
an association between TR and mortality, whereas the
subgroup analysis with severely reduced left ven-
studies by Koelling et al. (3) and Nath et al. (1) further
tricular ejection fraction. This raises the possibility
confirmed and refined the relationship in large
that the study may have been underpowered to assess
5
6
Bartko et al.
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T A B L E 2 Crude and Multivariable Cox Regression Model Assessing the Impact of Surrogates of TR Severity and Tricuspid Valve Morphology on
Long-Term Mortality (n ¼ 382) Bootstrap-Adjusted Confounder Model*
Univariable Model Crude HR (95% CI)
p Value
Clinical Confounder Model†
Adjusted HR (95% CI)
p Value
Adjusted HR (95% CI)
p Value
Surrogates of TR severity 1.63 (1.35–1.97)
<0.001
1.30 (1.06–1.60)
0.014
1.32 (0.96–1.81)
0.09
TR vena contracta width (per 1 mm)
1.109 (1.066–1.154)
<0.001
1.028 (1.013–1.044)
0.015
1.061 (1.003–1.122)
0.04
TR EROA (per 0.01 cm2)
1.009 (1.004–1.013)
<0.001
1.006 (1.001–1.011)
0.016
1.007 (1.001–1.012)
0.02
TR regurgitant volume (per 1 ml)
1.013 (1.007–1.020)
<0.001
1.007 (1.00–1.015)
0.05
1.009 (1.000–1.018)
0.04
TR semiquantitative assessment (per 1 grade)
Tricuspid valve morphology Tricuspid valve annular diameter (per 1 mm)
1.018 (1.003–1.033)
0.021
1.008 (0.993–1.024)
0.29
0.989 (0.967–1.012)
0.36
Tricuspid valve tenting area (per 1 mm2)
1.306 (1.157–1.475)
<0.001
1.142 (0.992–1.315)
0.07
1.082 (0.877–1.335)
0.46
HRs refer to an increase of regurgitant volume per 1 ml, of vena contracta width per 1 mm, of EROA per 0.01 cm2, tricuspid valve annular diameter per 1 mm, tricuspid valve tenting area per 1 mm2, and to an increase of 1 category of semiquantitative TR assessment. *Adjusted for: age, g-glutamyltransferase, and TAPSE (all variables not log-transformed). †Adjusted for: right ventricular end-diastolic diameter, TAPSE, severity of mitral regurgitation, and NT-proBNP (all variables not log-transformed). Bold values are statistically significant. CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Table 1.
for the impact of more severe TR on mortality and
TR based on current guideline cutoffs has a 1.5-times
the analysis was probably confounded by type II
increased risk of mortality. Even more striking is a
error (10).
patient with a RegVol of 20 ml (mild TR according to
QUANTITATIVE VERSUS QUALITATIVE APPROACHES TO
the current guideline cutoffs) who has a 1.5-times
ASSESSING FUNCTIONAL TR. Another potential reason
increased risk of mortality. The significance of less
for the inconsistent findings between studies may
TR is explainable by the discordance of EROA and
relate to the assessment of right ventricular systolic
RegVol in the presence of a lower driving force of the
function
that
right compared with the left heart. Tribouilloy et al.
reported an association between TR severity and
(12) examined the EROA to RegVol discordance by
mortality only assessed right ventricular systolic
comparing the difference in RegVols between TR and
and
TR
severity.
Earlier
studies
function and severity of TR qualitatively as opposed
MR lesions. More specifically, flow-reversal in MR and
to the present study, which assessed severity of TR
TR lesions with similar EROAs were compared. They
using quantitative measures. Current guidelines on
reported that there was less flow reversal in the TR
assessment of valvular regurgitation recommend
lesions compared with MR lesions. This phenomenon
an integrated approach for TR grading considering
might be attributable to the specific context of TR
structural, qualitative, semiquantitative, and quanti-
where the decreased driving force within the right
tative parameters of regurgitant severity. Especially
heart
they recognized the limited validation of quantitative
compared with MR lesions (12). Moreover, this
metrics of TR severity in patients with HFrEF (8).
discrepancy might be aggravated in the failing right
Quantitative measures of TR severity including those
heart. The spline curve analyses (Figure 2) supports
derived using the PISA technique have only been
the recommendation of an integrated approach
validated in a few comparative studies of limited size
because it demonstrates a sustained increase in
(11,12) and the prognostic value was not previously
mortality associated with a larger EROA and RegVol
results
in
lower
magnitudes
of
RegVol
demonstrated. Our data fill this gap of knowledge
(Figures 2B and 2C) but not so for VCW (Figure 2A).
by demonstrating the independent association of
This finding may also be attributable to technical
the VCW and PISA-derived EROA and RegVol with
differences because VCW is a pure geometric deter-
mortality in this high-risk cohort. The observed
minant of the regurgitant lesion, whereas the EROA
thresholds for VCW and EROA are close to the
and the RegVol is dependent on the pressure gradi-
guideline-defined range for moderate TR potentially
ents between the atrium and the ventricle and
indicating the early significance of volume load in
thereby right ventricular function. Currently there are
failing right hearts (Figures 2 and 3). Importantly, our
no data on the contributions of each of these param-
results indicate RegVol thresholds predictive of
eters to the severity of TR, which only emphasizes the
mortality that are considerably lower than proposed
importance of experienced readers to avoid mis-
guideline cutoffs. Hence, a patient with a VCW of 4
interpretations. The accuracy of measurements could
mm or an EROA of 0.3 cm 2 despite having moderate
also be further improved with 3-dimensional imaging
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Functional Tricuspid Regurgitation
techniques whereby the measurement of EROA and RegVol may be more accurate given the inherent limitations of the 2-dimensional PISA method for assessment of EROA and RegVol.
F I G U R E 2 Spline Curve Analysis of Quantitative Markers of TR Severity
A 4
THE CLINICAL IMPACT OF FUNCTIONAL TR. The
(Table 1) clearly highlight a consistent trend between severity or TR, right heart pathology, and symptoms. In our cohort, patients with trace/no TR tend to be less symptomatic clinically with less neurohumoralpathway activation (Figure 1). They do not display features of maladaptive remodeling of the tricuspid complex. Patients with moderate TR display mal-
Relative Risk of Mortality
baseline characteristics of the study population
3.5 3 2.5 2 1.5 1 0.5
adaptive remodeling of the tricuspid complex and 0
right heart (Online Table 1) as previously described
0
(13,14). The observed elevated markers of liver and renal impairment indicate an early stage of TR driven venous congestion (15). Finally, in those with severe
opathy and renal impairment suggests TR as a causative link for multiorgan involvement inducing a more complex disease course (16). POTENTIAL IMPLICATIONS FOR TRANSCATHETER TRICUSPID REPAIR. The concept of tricuspid valve
0
cially with low periprocedural mortality. It is impor-
14
15
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
3 2.5 2 1.5 1
tant to note, however, that HFrEF is a complex disease where TR influences right ventricular func-
0
may be used to determine time to intervention and a
13
C
0.5
tion and vice versa. Continuous metrics of TR severity
12
Functional Tricuspid Regurgitation – Effective Regurgitant Orifice (cm2)
Relative Risk of Mortality
to functional capacity and quality of life, and espe-
11
1
3.5
excellent feasibility, beneficiary effects with regards
10
1.5
to reduce TR. Whether this is also a reasonable
transcatheter repair (19,20). Early results show
9
2
4
currently investigating the potential role of TR
8
2.5
ures (17,18) and represents a technically possible way
increasing number of studies and registries are
7
3
insertion of a restrictive tricuspid ring is currently
treatment in HFrEF is completely unknown. An
6
0
concomitant left-sided valve disease (17,18). The
annular remodeling at the time of left-sided proced-
5
0.5
repair has been well recognized in patients with
recommended in patients with concomitant TR or
4
3.5 Relative Risk of Mortality
and g-glutamyltransferase levels. Congestive hepat-
3
4
associated with multiorgan
damage is reflected by markedly elevated creatinine
2
B
TR, pronounced right heart failure with severe systemic congestion
1
Functional Tricuspid Regurgitation - Vena Contracta Width (mm)
0
10
20
30
40
50
60
70
Functional Tricuspid Regurgitation – Regurgitant Volume (mL)
measure of interventional success. Our data favor earlier intervention because moderate regurgitant
Spline curves of relative risk of mortality according to tricuspid regurgitation severity. The
lesions are already associated with a clinically
curves show the impact of tricuspid regurgitation severity measured by vena contracta
significant impact. However, chronic heart failure is a complex, recursive disease with many factors, such as left and right ventricular function and residual
width (A), effective regurgitant orifice area (B), and regurgitant volume (C) on mortality. Dashed lines are 95% confidence intervals.
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F I G U R E 3 Kaplan-Meier Estimates of Mortality According to the Spline Curve–Defined
Thresholds of Mortality
myocardial viability potentially influencing outcomes. Specifically, whether and in which subgroups reverse remodeling and functional improvement can occur after repair of the tricuspid valve still needs to
A
1.0
be assessed by future studies. Moreover, it is still
Survival Probability
unclear if tricuspid valve repair by lower-risk transcatheter techniques at this stage would have any
0.8 Vena contracta <5 mm
benefits apart from symptomatic improvement and the benefits of transcatheter repair techniques still
0.6
need to be addressed in controlled trials. All of these Vena contracta ≥5 mm
questions can only be answered on the basis of reliable and validated metrics of TR.
0.4
STUDY 0.2
20
Patients at risk: Vena contracta <5 mm
291
229
207
174
Vena contracta ≥5 mm
91
50
40
31
B
LIMITATIONS. The
present
validation
of
quantitative TR assessment is focused only on sec-
HR 2.14 (95% CI 1.53 - 2.00); P < 0.001
0
40
ondary TR and may not be applicable to patients with
60
primary TR. The thresholds for the parameters of TR
Survival Time (Months)
severity that are predictive of increased mortality may not be applicable to patients with primary TR. However, secondary TR is far more prevalent than
1.0
primary TR in patients with chronic heart failure, Survival Probability
hence our findings are likely to be applicable to most 0.8 2
EROA <0.2 cm
patients with chronic heart failure with TR (14). The presence of permanent endocardial device leads and its impact on the accurate assessment of TR severity
0.6 2
EROA ≥0.2 cm
pose an important challenge in the quantification of TR. Despite no evidence of interaction with quanti-
0.4
tatively assessed TR we cannot rule out impact of endocardial lead presence on the accuracy of such
0.2
HR 1.74 (95% CI 1.22 - 2.49); P = 0.002
measurements.
0
20
296
226
202
173
86
48
40
32
40
60
CONCLUSIONS
Survival Time (Months)
Patients at risk: 2 EROA <0.2 cm 2
EROA ≥0.2 cm
Functional TR is independently associated with
C
mortality in HFrEF in this large-scale outcome study.
1.0
The sustained increase in mortality associated with Survival Probability
8
increases in quantitative measures of TR severity,
0.8 Regurgitant volume <20 ml
such as EROA and regurgitant volume, supports the use of such metrics in routine clinical practice.
0.6 Regurgitant volume ≥20 ml
Furthermore, thresholds identified to be associated with mortality are congruent with moderate TR as defined by current guideline recommendations. Their
0.4
prognostic value may help guide the clinical decision0.2
making process and timing of intervention. However,
HR 1.82 (95% CI 1.29 - 2.55); P = 0.001
0 Patients at risk:
20
40
the complex nature of HFrEF with competing and 60
Survival Time (Months)
Regurgitant volume <20 ml 271
218
195
169
Regurgitant volume ≥20 ml 84
56
46
36
Kaplan-Meier estimates of mortality in patients with a tricuspid regurgitation vena contracta width $5 mm (A) (p < 0.001), an effective regurgitant orifice area $0.20 cm2 (B) (p ¼ 0.002), and a regurgitant volume $20 ml (C) (p > 0.001). Hazard ratios
interacting risks between heart failure and TR and mortality
highlights
the
need
for
prospective
controlled trials.
ADDRESS
FOR
CORRESPONDENCE:
Dr.
Georg
Goliasch, Department of Internal Medicine II, Medical
are derived from a univariable Cox regression model. CI ¼ confidence interval;
University of Vienna, Waehringer Guertel 18-20,
EROA ¼ effective regurgitant orifice area; HR ¼ hazard ratio.
A-1090 Vienna, Austria. E-mail: georg.goliasch@ meduniwien.ac.at.
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PERSPECTIVES COMPETENCY IN PATIENT CARE AND
TRANSLATIONAL OUTLOOK: Use of new techniques,
PROCEDURAL SKILLS: Doppler-echocardiographic
such as transcatheter TR treatment, needs validated
quantitative assessment of the effective regurgitant
continuous metrics of lesion severity, specifically for the
orifice area and the regurgitant volume defines the in-
treatment indication and definition of interventional
dependent association of TR with mortality in patients
success. The present data define thresholds where TR is
with HFrEF and indicates thresholds predictive of mor-
associated with mortality introducing the intriguing pos-
tality for parameters used in the quantification of TR.
sibility of an early interventional approach before late heart failure stages occur.
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European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39. 8. Zoghbi WA, Adams D, Bonow RO, et al. Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr 2017;30:303–71.
3. Koelling TM, Aaronson KD, Cody RJ, Bach DS, Armstrong WF. Prognostic significance of mitral regurgitation and tricuspid regurgitation in pa-
9. Topilsky Y, Khanna AD, Oh JK, et al. Preoperative factors associated with adverse outcome after tricuspid valve replacement. Circulation 2011;123: 1929–39.
tients with left ventricular systolic dysfunction. Am Heart J 2002;144:524–9.
10. Lancellotti P, Magne J. Tricuspid valve regurgitation in patients with heart failure: does it
4. Neuhold S, Huelsmann M, Pernicka E, et al. Impact of tricuspid regurgitation on survival in
matter? Eur Heart J 2013;34:799–801.
patients with chronic heart failure: unexpected findings of a long-term observational study. Eur Heart J 2013;34:844–52. 5. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol
11. Grossmann G, Stein M, Kochs M, et al. Comparison of the proximal flow convergence method and the jet area method for the assessment of the severity of tricuspid regurgitation. Eur Heart J 1998;19:652–9. 12. Tribouilloy CM, Enriquez-Sarano M, Capps MA, Bailey KR, Tajik AJ. Contrasting effect of similar effective regurgitant orifice area in mitral and tricuspid regurgitation: a quantitative Doppler echocardiographic study. J Am Soc Echocardiogr 2002;15:958–65.
6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Car-
13. Sagie A, Schwammenthal E, Padial LR, et al. Determinants of functional tricuspid regurgitation in incomplete tricuspid valve closure: Doppler color flow study of 109 patients. J Am Coll Cardiol 1994;24:446–53.
diology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.
14. Mutlak D, Lessick J, Reisner SA, Aronson D, Dabbah S, Agmon Y. Echocardiography-based spectrum of severe tricuspid regurgitation: the
7. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by
frequency of apparently idiopathic tricuspid regurgitation. J Am Soc Echocardiogr 2007;20:405–8.
echocardiography in adults: an update from the American Society of Echocardiography and the
15. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL.
2016;68:1476–88.
Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009;53:582–8. 16. Agricola E, Marini C, Stella S, et al. Effects of functional tricuspid regurgitation on renal function and long-term prognosis in patients with heart failure. J Cardiovasc Med 2017;18:60–8. 17. Nishimura RA, Otto CM, Bonow RO, et al. 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/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252–89. 18. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63: 2438–88. 19. Hahn RT, Meduri CU, Davidson CJ, et al. Early feasibility study of a transcatheter tricuspid valve annuloplasty: SCOUT trial 30-day results. J Am Coll Cardiol 2017;69:1795–806. 20. Nickenig G, Kowalski M, Hausleiter J, et al. Transcatheter treatment of severe tricuspid regurgitation with the Edge-to-Edge MitraClip technique. Circulation 2017;135:1802–14.
KEY WORDS effective regurgitant orifice area, heart failure with reduced ejection fraction, regurgitant volume, tricuspid regurgitation, vena contracta width
A PP END IX For supplemental tables, please see the online version of this paper.
9
VOL.
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ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ORIGINAL RESEARCH
Natural History of Functional Tricuspid Regurgitation Implications of Quantitative Doppler Assessment Philipp E. Bartko, MD, PHD,a Henrike Arfsten, MD,a Maria K. Frey, MD, PHD,a Gregor Heitzinger,a Noemi Pavo, MD, PHD,a Anna Cho,a Stephanie Neuhold, MD,b Timothy C. Tan, MBBS, PHD,c,d Guido Strunk, PHD,e Christian Hengstenberg, MD,a Martin Hülsmann, MD,a Georg Goliasch, MD, PHDa
ABSTRACT OBJECTIVES This study sought to define the relationship between functional tricuspid regurgitation (TR) and mortality in patients with heart failure with reduced ejection fraction (HFrEF); and to establish the prognostic value of quantitative measures of TR severity (i.e., effective regurgitant orifice area [EROA] and regurgitant volume). BACKGROUND The significance of TR in chronic heart failure is controversial. Earlier studies have shown an independent impact of TR on mortality, whereas more recent evidence suggests myocardial impairment to be the driving force of mortality rather than TR itself. Earlier studies have used qualitative measures of TR severity, hence the prognostic value of more quantitative measures of TR severity (i.e., EROA and regurgitant volumes) remains unclear. METHODS We enrolled 382 patients with HFrEF on guideline-directed medical therapy and assessed TR EROA and regurgitant volume by Doppler/2-dimensional echocardiography. All-cause mortality was defined as the primary study endpoint. RESULTS TR severity was associated with the HFrEF phenotype with more symptoms (p ¼ 0.004), higher neurohumoral activation (p < 0.001), progressive right-ventricular dilatation (p < 0.001), and impaired function (p < 0.001). Cox regression showed a strong association between quantitative measures of TR with mortality (all p < 0.001). Quantitative metrics of TR severity were consistently associated with mortality with a hazard ratio of 1.009 (95% confidence interval: 1.004 to 1.013; p < 0.001) per 0.01 cm2 increase of the EROA and of 1.013 (95% confidence interval: 1.007 to 1.020; p < 0.001) per 1-ml increase in regurgitant volume. Results remained unchanged after bootstrap- or clinical confounder-based adjustment. A spline curve pattern illustrates the association with mortality with thresholds for the EROA $0.2 cm2, and the regurgitant volume $20 ml with sustained excess mortality thereafter. CONCLUSIONS This large-scale outcome study demonstrates the prognostic value of quantitative Dopplerechocardiographic measures of TR severity in HFrEF. The thresholds for EROA and TR regurgitant volume associated with mortality in our study fall within current ranges defining nonsevere TR. This may potentially impact therapeutic decision making, particularly timing of intervention. (J Am Coll Cardiol Img 2019;-:-–-) © 2019 by the American College of Cardiology Foundation.
From the aDepartment of Internal Medicine II, Medical University of Vienna, Vienna, Austria; bDepartment of Medicine IV, KaiserFranz-Joseph-Spital, Vienna, Austria; cWestmead Hospital, Faculty of Medicine, University of Sydney, Sydney, Australia; d
Department of Cardiology, Blacktown Hospital, Blacktown, Australia; and the eFH Campus Vienna and Complexity Research,
Vienna, Austria. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 3, 2018; revised manuscript received October 19, 2018, accepted November 7, 2018.
ISSN 1936-878X/$36.00
https://doi.org/10.1016/j.jcmg.2018.11.021
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ABBREVIATIONS AND ACRONYMS CI = confidence interval
F
unctional tricuspid regurgitation (TR)
Austrian citizens (even those in foreign countries)
is a common valvular lesion and the
this allowed complete follow-up of all patients.
presence of significant TR has been
ECHOCARDIOGRAPHIC
ASSESSMENT. All
patients
associated with increased mortality (1,2).
underwent
However, the prognostic significance of TR
examination
in patients with heart failure with reduced
Echocardiography
reduced ejection fraction
ejection fraction (HFrEF) is controversial.
echocardiograms were performed using commercially
IQR = interquartile range
Earlier studies have suggested an indepen-
available equipment (Vivid7, GE Healthcare, Chicago,
dent impact of TR on mortality in patients
Illinois) by physicians and sonographers blinded to
with left ventricular systolic dysfunction,
clinical data and outcomes and interpreted by board-
B-type natriuretic peptide
where the TR is believed to cause adverse
certified physicians. Raw data with frame rates >50
NYHA = New York Heart
right-ventricular remodeling and dysfunc-
frames per second were stored digitally and images
Association
tion thus increased mortality (1–3). More
analyzed offline. Cardiac chamber sizes were assessed
PISA = proximal isovelocity
recent evidence suggests myocardial impair-
according to American Society of Echocardiography
surface area
ment to be the driving force of mortality
guideline recommendations (7). A comprehensive
RegVol = regurgitant volume
rather than TR itself, with the TR simply
assessment of the tricuspid valve and TR was
TAPSE = tricuspid annular
being a surrogate of disease severity (4).
plane systolic excursion
performed using an
Furthermore, previous studies examining
TR = functional tricuspid
approach encompassing tricuspid valve morphology,
the prognostic impact of TR have used quali-
color Doppler jet size, right atrial size, VCW, EROA,
tative measures of TR severity, hence the
and the RegVol using the proximal isovelocity surface
prognostic value of more quantitative mea-
area (PISA) method (8). Tricuspid valve morphology
sures of TR severity, such as vena contracta width
was assessed with right ventricular focused views
(VCW), effective regurgitant orifice area (EROA), and
using midsystolic frames. The proximal flow conver-
regurgitant volumes (RegVol) remains unclear. In
gence was assessed with a baseline downward shift
this study we sought to examine the prognostic
toward optimized visualization of the hemispheric
impact of TR and its severity in patients with HFrEF
shell from standard 4-chamber guided zoomed view
EROA = effective regurgitant orifice area
HFrEF = heart failure with
MR = mitral regurgitation NT-proBNP = N-terminal pro–
regurgitation
VCW = vena contracta width
a
comprehensive according
to
echocardiographic
American
guidelines
(7).
Society
of
Transthoracic
integrated, multiparametric
and the prognostic value of quantitative echocardio-
of the TR jet. For patients in atrial fibrillation, a mean
graphic measures of TR severity.
of 6 cardiac cycles was performed to account for beatto-beat variability. Mean global longitudinal strain of
METHODS
the right ventricular free wall by speckle-tracking and M-mode quantification of the tricuspid annular plane
STUDY DESIGN AND STUDY POPULATION. This was
systolic excursion (TAPSE) were also assessed using
a
noninterventional
GE EchoPac software version 201 (GE Vingmed,
study. Consecutive adult patients with HFrEF pre-
Horten, Norway). Intraobserver and interobserver
senting to the outpatient heart failure clinic of the
variability for quantitative measures of TR severity
Vienna General Hospital, a tertiary referral center,
(i.e., VCW, EROA, and RegVol) were assessed in 20
were recruited. Only patients who were euvolemic,
randomly selected patients.
clinically stable and optimized on guideline-based
STATISTICAL METHODS. Continuous data were pre-
medical therapy were recruited. HFrEF was defined
sented as median (interquartile range [IQR]) and
according to the 2016 American College of Cardiology/
compared using the Kruskal-Wallis test. Categorical
American Heart Association/Heart Failure Society
variables were compared using chi-square test. Cox
guidelines based on heart failure signs, symptoms
proportional hazards regression analysis and spline
and a left ventricular ejection fraction less than 40%
curve graphs were applied to assess the effect of
(5,6). The study protocol was approved by the Ethics
TR severity on survival. To account for potential
Committee of the Medical University of Vienna.
confounding effects, we formed a clinical confounder
CLINICAL
FOLLOW-UP.
cluster (encompassing age, sex, ischemic etiology of
Medical history, current medication, an electrocar-
heart failure, New York Heart Association [NYHA]
single-center
observational,
MEASURES
AND
diogram recording, and routine blood tests were
functional class, hypertension, diabetes, creatinine,
collected at the
All-cause
g-glutamyltransferase, left ventricular end-diastolic
mortality during 5-years follow up was defined as
volume, left ventricular ejection fraction, right
the primary endpoint. Mortality data were obtained
ventricular end-diastolic diameter, TAPSE, tricuspid
from the Austrian Death Registry. Because Austrian
valve annular diameter, tricuspid valve tenting
law requires mandatory reporting of all deaths of
area, TR maximum velocity, right-atrial volume,
time
of
enrollment.
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renin-angiotensin system antagonists, beta-blockers,
(n ¼ 44) of patients in NYHA functional class IV. With
All
respect to heart failure therapy, 93% (n ¼ 354)
continuous variables in the clusters were log-
received renin-angiotensin system antagonists, 89%
and
mineralocorticoid
antagonist
therapy).
analysis
(n ¼ 339) received beta-blockers, and 64% (n ¼ 243)
including the original and log-transformed variable
were treated with a mineralocorticoid receptor
was performed. The variable selected using this pro-
antagonist. Sixty-nine percent of patients displayed
cedure was then used for further analysis. A stepwise
greater than or equal to moderate TR. Quantitative
bootstrap resampling procedure including all afore-
assessment of TR was technically feasible in all pa-
mentioned variables was also used to identify best-
tients with more than trace TR. Thirty-one patients
fitting variables for the final multivariable Cox
with trace TR and inadequate continuous-wave
regression model. Five-hundred repeats with a p
Doppler spectrum were allocated to the low-risk
value of 0.05 for selection were performed and vari-
group. All quantitative measures of TR severity
ables selected in 70% of all repeats were included in
demonstrated good reproducibility, with an intraclass
the final cofounder model (i.e., age, g-glutamyl-
correlation
transferase, and TAPSE). All variables included in the
interobserver and intraobserver variability.
final model were not log-transformed. Additionally,
MEASURES OF FUNCTIONAL TR SEVERITY. Patients with
we assessed the predictive power of TR by a clinical
functional TR were then categorized into significant
confounder model reflecting the morphologic, func-
versus nonsignificant functional TR using thresholds
tional, and neurohumoral impairment in TR encom-
associated with increased mortality for VCW (VCW $5
passing right ventricular end-diastolic diameter,
mm), EROA (EROA $0.2 cm2 ), and RegVol (RegVol
TAPSE, N-terminal pro–B-type natriuretic peptide
of $20 ml) and the results presented in Table 1. Briefly,
transformed
and
stepwise
regression
coefficient
>0.95
when
tested
for
(NT-proBNP), and severity of mitral regurgitation
with worsening TR as reflected by increasing VCW,
(MR) (greater than moderate). Hazard ratios refer to
EROA, and RegVol, levels of NT-proBNP (p < 0.01),
a 1-SD increase in continuous variables and to an
g-glutamyltransferase (p < 0.001), NYHA functional
increase of 1 category of semiquantitative TR assess-
class (p ¼ 0.01), use of diuretics (p ¼ 0.003), and age
ment. We tested for collinearity in the multivariable
(p ¼ 0.029) also increased. Morphologically, increasing
model using the variance inflation factor. The pro-
VCW, EROA, and RegVol were associated with
portional
and
increasing right ventricular end-diastolic diameter
satisfied in all cases using Schoenfeld residuals.
(p < 0.001), increasing tricuspid valve annular diam-
Interactions between surrogates of TR severity and all
eter (p < 0.001), a more pronounced tricuspid valve
variables included in the multivariable model were
tenting area (p < 0.001), and poorer right ventricular
hazards
assumption
was
tested
tested by entering interaction terms in the Cox pro-
function evidenced by a reduction in TAPSE (p < 0.05)
portional hazards regression models. Kaplan-Meier
and right ventricular free wall strain (p < 0.05). Base-
analysis (log-rank test) was applied to assess the
line
time-dependent discriminative power of surrogates
approach is shown in Online Table 1. We noted that the
characteristics
according
to
the
integrated
of TR severity. Two-sided p values <0.05 were used
severity of TR gradually increased with NYHA func-
to indicate statistical significance. The STATA version
tional class (p ¼ 0.005) (Figure 1A) and increasing levels
11 software package (StataCorp, College Station,
of NT-proBNP (p < 0.001) (Figure 1B).
Texas) and SPSS version 24.0 (IBM Corporation, Armonk, New York) were used for all analyses.
RESULTS
QUANTITATIVE MEASURES OF FUNCTIONAL TR AND OUTCOME. During the 5-year follow-up period, 158
patients died. We observed a significant association between TR severity and mortality with a crude haz-
We enrolled 382 patients with chronic HFrEF with a
ard ratio of 1.63 (95% confidence interval [CI]: 1.35 to
median age of 68 years (IQR: 61 to 75 years). Detailed
1.97; p < 0.001). In terms of the specific measures
baseline characteristics of the study population ac-
of TR severity, we observed a hazard ratio of 1.109
cording to subsequently defined thresholds of sig-
(95% CI: 1.066 to 1.154; p < 0.001) per 1-mm increase
nificance are displayed in Table 1 and according to the
in TR VCW, 1.009 (95% CI: 1.004 to 1.013; p < 0.001)
guideline proposed integrated approach in Online
per 0.01-cm 2 increase in TR EROA, and 1.013 (95% CI:
Table 1. Seventy-eight percent (n ¼ 296) were male,
1.007 to 1.020; p < 0.001) per 1-ml increase in TR
the median NT-proBNP was 3,144 pg/ml (IQR: 1,639 to
RegVol (Table 2). Of note, there were no significant
7,620 pg/ml), and the median left ventricular ejection
interactions between the individual quantitative
fraction was 26% (IQR: 19 to 34). A total of 39%
measures of TR severity we examined and the
(n ¼ 148) were in NYHA functional class III and 12%
presence of implanted device leads (permanent
3
Bartko et al.
4
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T A B L E 1 Baseline Characteristics of the Study Population (n ¼ 382) According to VCW, EROA, and RegVol of TR
TR VCW <5 mm (n ¼ 296)
TR VCW $5 mm (n ¼ 86)
p Value
TR EROA <0.20 cm2 (n ¼ 301)
TR EROA $0.20 cm2 (n ¼ 81)
p Value
TR RegVol <20 ml (n ¼ 289)
TR RegVol $20 ml (n ¼ 93)
p Value
Baseline characteristics 67.4 (60.3–74.8)
71.3 (64.5–76.3)
0.016
67.8 (61.2–75)
70 (62.3–76.0)
0.38
Male
Age, yrs
223 (75)
73 (85)
0.06
224 (74)
66 (82)
0.08
217 (75)
73 (79)
0.33
Hypertension
145 (49)
46 (53)
0.63
146 (49)
42 (52)
0.54
137 (47)
51 (55)
0.25
Diabetes
81 (27)
26 (30)
0.59
79 (26)
26 (32)
0.20
73 (25)
32 (34)
0.07
Ischemic etiology of HF
59 (20)
21 (24)
0.39
60 (20)
18 (22)
0.51
56 (19)
22 (24)
0.30
Atrial fibrillation
75 (25)
46 (53)
<0.001
79 (26)
42 (52)
<0.001
74 (26)
47 (51)
<0.001
NYHA functional class
0.14
67.43 (60.4–74.6) 70.7 (63.9–76.5) 0.029
0.06
0.010
II
60 (20)
15 (17)
60 (20)
10 (12)
57 (20)
17 (18)
III
149 (50)
42 (48)
146 (49)
42 (52)
140 (48)
48 (52)
IV
29 (10)
15 (17)
31 (10)
12 (15)
28 (10)
15 (16)
1.2 (1–1.5)
1.5 (1.2–1.8)
<0.001
1.2 (1.0–1.5)
1.5 (1.1–1.8)
0.003
1.2 (1–1.5)
1.5 (1.2–1.8)
23.0 (16.5–36.0)
31.6 (22.0–43.7)
0.001
23.8 (16.5–36.2)
31.2 (21.2–44)
0.006
22.8 (16.2–36)
32 (21.7–42.9)
0.001
13.3 (12–14.3)
12.9 (11.2–14)
0.06
13.2 (12–14.2)
13.1 (11.5–14.1)
0.42
13.3 (12.1–14.2)
12.9 (11.2–14.0)
0.048 0.09
Creatinine, mg/dl Blood urea nitrogen, mg/dl Hemoglobin, mg/dl
<0.001
Aspartate transaminase, U/l
27 (21–36)
28 (22–36)
0.52
26 (21–35)
28 (23–38)
0.14
26 (21–35)
29 (23–39)
Alanine transaminase, U/l
23 (16–36)
22 (15–29)
0.26
22.5 (16–35)
21.5 (16–33)
0.54
22 (15–34)
23 (16–33)
0.83
g-glutamyltransferase, U/l
50 (29–107)
114 (62–197)
<0.001
50 (30–104.5)
118.5 (68–214)
<0.001
48 (29–99)
121 (69–214)
<0.001
NT-proBNP, pg/ml
2,728 (1,336– 6,201)
4,716 (2,385– 10,017)
<0.001
2,888 (1,307– 6,491)
4,417 (2,373– 9,394)
0.002
2,728 (1,307– 5,560)
6,132 (2,422– 9,592)
<0.001
Left ventricular end-diastolic diameter, mm
60 (55–66)
59 (54–64)
0.10
60 (55–66)
59 (53–63)
0.013
60 (55–67)
59 (53–63)
0.009
Left ventricular end-diastolic volume, ml
204 (164–262)
185 (141–232)
0.019
207 (165–264)
178 (140–224)
0.001
208 (166–270)
179 (143–224)
0.001
Echocardiographic characteristics
Left ventricular ejection fraction, %
26 (20–33)
24 (16–35)
0.39
26 (20–33)
25 (16–34)
0.66
26 (19–33)
26 (18–34)
0.64
88 (65–118.5)
116 (87–151)
<0.001
90 (67–121)
109 (85–142)
<0.001
90 (65–121)
108 (83–139)
<0.001
Right ventricular end-diastolic diameter, mm
37 (33–43)
47 (41–50)
<0.001
38 (33–44)
47 (40–50)
<0.001
37 (32–43)
46 (40–50)
<0.001
Right ventricular end-diastolic area, cm2
19.8 (16.9–24.9)
26.7 (21.5–31.2)
<0.001
20 (17–25.4)
Left atrial volume, ml
26.5 (21.4–31.3) <0.001 19.8 (16.6–25.2) 26.4 (21.5–30–9) <0.001
TAPSE, mm
18 (16–22)
16 (13–18)
0.019
18 (15–22)
16 (14–19)
<0.001
18 (15–22)
16 (14–19)
Right ventricular free wall strain, %
18 (12–22)
16 (10–18)
0.001
18 (12–22)
16 (10–18)
0.003
18 (12–22)
16 (11–19)
0.020
Right atrial volume, ml
63 (45–87)
113 (86–148)
<0.001
63 (45–89)
113 (86–150)
<0.001
63 (45–88)
112 (86–147)
<0.001
165 (56)
66 (77)
0.020
170 (57)
21 (26)
0.25
160 (55)
67 (72)
0.09
Mitral regurgitation ($moderate) TR effective regurgitant orifice area, cm2 TR regurgitant volume, ml/beat TR vena contracta width, mm
<0.001
0.06 (0.03–0.11) 0.30 (0.20–0.50) <0.001 0.06 (0.03–0.11) 0.35 (0.25–0.55) <0.001 0.06 (0.03–0.10) 0.28 (0.21–0.50) <0.001 6 (3–12) 2.51 (1.59–3.50)
34.5 (28–50)
<0.001
6 (3–11)
7.49 (6.04–8.9) <0.001 2.58 (1.61–3.61)
7.74 (5.61–9.1)
<0.001
2.48 (1.56–3.5)
7.02 (5.2–8.77) <0.001 38.85 (33–46.7) <0.001
33 (22–47)
<0.001
6 (3–12)
32.5 (25–46)
<0.001
Tricuspid annular diameter, mm
32 (26–40)
38 (32–50)
<0.001
32 (26–39.7)
39.5 (33–48.5)
<0.001
32 (26–39.29)
Tricuspid valve tenting area, mm2
1.3 (0.9–1.7)
2.2 (1.6–3.1)
<0.001
1.3 (0.9–1.7)
2.2 (1.6–3.1)
<0.001
1.3 (0.9–1.7)
2.2 (1.6–2.9)
<0.001
3 (2.7–3.4)
3.3 (2.9–3.6)
0.005
3 (2.7–3.4)
3.2 (2.8–3.5)
0.28
2.9 (2.6–3.4)
3.2 (2.9–3.6)
<0.001
Renin-angiotensin system antagonist
277 (94)
77 (90)
0.21
277 (92)
70 (86)
0.29
266 (92)
81 (87)
0.29
Beta-blockers
259 (88)
80 (93)
0.15
262 (87)
71 (88)
0.48
249 (86)
84 (90)
0.12
Mineralocorticoid antagonist
188 (64)
55 (64)
0.94
191 (64)
48 (59)
0.65
186 (64)
53 (57)
0.27
Furosemide
163 (55)
56 (65)
0.055
165 (55)
51 (63)
0.046
153 (53)
63 (68)
0.003
Amiodarone
58 (20)
24 (28)
0.09
64 (21)
17 (21)
0.88
57 (20)
24 (26)
0.18
Implanted cardioverterdefibrillator
124 (42)
41 (48)
0.34
126 (42)
35 (43)
0.10
123 (43)
38 (41)
0.88
Pacemaker
83 (14)
38 (44)
0.017
83 (28)
35 (43)
0.014
81 (28)
37 (40)
0.032
TR velocity, m/s Medication
Rhythm devices
Values are median (interquartile range) or n (%). Bold values are statistically significant. EROA ¼ effective regurgitant orifice area; HF ¼ heart failure; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; NYHA ¼ New York Heart Association; RegVol ¼ regurgitant volume; TAPSE ¼ tricuspid annular plane systolic excursion; TR ¼ functional tricuspid regurgitation; VCW ¼ vena contracta width.
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Functional Tricuspid Regurgitation
endocardial pacemakers and automatic implanted cardioverter defibrillators) or atrial fibrillation with regards to the measured outcome (all p values for interaction >0.1). These results remained essentially
F I G U R E 1 Prevalence of Functional Tricuspid Regurgitation
A 70
unchanged after adjustment using the bootstrapselected
confounder
model
and
the
P = 0.005
clinical
60
confounder model (Table 2, Online Table 2). Addi50
VCW, EROA, and RegVol with outcomes using spline analysis (Figure 2). The lower 95% CI served as the threshold for further analyses. Kaplan-Meier analysis demonstrated a significant increase in mortality in
Percentage
tionally, we also explored the association between TR
(Figure 3A), an EROA $0.20 cm
30 20
patients with a TR VCW $5 mm (p < 0.001) 2
40
(p ¼ 0.002)
10
(Figure 3B), and a RegVol $20 ml (p > 0.001) (Figure 3C).
0 NYHA I
DISCUSSION Our study is a large-scale long-term observational
80 P < 0.001 70
right ventricular systolic function, neurohumoral
60
cohort of patients with stable HFrEF. Additionally, we identified thresholds for the standard parameters used to quantify TR severity that were associated with increased mortality (i.e., VCW of $5 mm, EROA $0.2 cm2 , and RegVol of $20 ml). Of note, the cutoffs identified in our study that were predictive of mortality were all distinctly lower than current guideline cutoffs, which define severe TR. This has
Percentage
activation, and morphologic features of the tricuspid
echocardiographic measures of TR severity in a
NYHA IV
B
functional TR and mortality independent of left and
the prognostic value of the quantitative Doppler-
NYHA III
NYHA Functional Class
study that demonstrates the association between
valve complex. The results of our study also highlight
NYHA II
50 40 30 20 10 0 1st Quartile
2nd Quartile
3rd Quartile
4th Quartile
Quartiles of NT-Pro-BNP No/mild FTR
Moderate FTR
Severe FTR
clinical significance because it potentially impacts therapeutic decision making. Furthermore, the association between quantitative measures of TR severity and mortality emphasizes the potential value of
Prevalence of functional tricuspid regurgitation according to New York Heart Association functional class (A) (p ¼ 0.005) and quartiles of N-terminal pro–B-type natriuretic peptide (B) (p < 0.001). FTR ¼ functional tricuspid regurgitation; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; NYHA ¼ New York Heart Association.
routine assessment in clinical practice compared with qualitative assessments of TR severity in patients with chronic heart failure.
retrospective cohorts. Interestingly, a more recent
FUNCTIONAL TR AND MORTALITY. TR in patients
study by Neuhold et al. (4) demonstrated an inde-
with HFrEF is frequent, particularly in the advanced
pendent association of TR with survival only in the
stages. In patients with HFrEF, TR is usually left un-
subgroups of mild and moderately reduced ejection
treated in most patients because of unacceptable high
fraction but a lack of TR impact in patients with se-
perioperative mortality even in heart valve centers of
vere systolic heart failure. The authors therefore hy-
excellence (up to 10%) (9) giving rise to a clinical
pothesized that the impact of TR was inversely
management dilemma of decision for surgical inter-
dependent on HFrEF severity. Of note, only 89 pa-
vention and timing of surgery. Hung et al. (2) showed
tients in their cohort had moderate/severe TR in their
an association between TR and mortality, whereas the
subgroup analysis with severely reduced left ven-
studies by Koelling et al. (3) and Nath et al. (1) further
tricular ejection fraction. This raises the possibility
confirmed and refined the relationship in large
that the study may have been underpowered to assess
5
6
Bartko et al.
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T A B L E 2 Crude and Multivariable Cox Regression Model Assessing the Impact of Surrogates of TR Severity and Tricuspid Valve Morphology on
Long-Term Mortality (n ¼ 382) Bootstrap-Adjusted Confounder Model*
Univariable Model Crude HR (95% CI)
p Value
Clinical Confounder Model†
Adjusted HR (95% CI)
p Value
Adjusted HR (95% CI)
p Value
Surrogates of TR severity 1.63 (1.35–1.97)
<0.001
1.30 (1.06–1.60)
0.014
1.32 (0.96–1.81)
0.09
TR vena contracta width (per 1 mm)
1.109 (1.066–1.154)
<0.001
1.028 (1.013–1.044)
0.015
1.061 (1.003–1.122)
0.04
TR EROA (per 0.01 cm2)
1.009 (1.004–1.013)
<0.001
1.006 (1.001–1.011)
0.016
1.007 (1.001–1.012)
0.02
TR regurgitant volume (per 1 ml)
1.013 (1.007–1.020)
<0.001
1.007 (1.00–1.015)
0.05
1.009 (1.000–1.018)
0.04
TR semiquantitative assessment (per 1 grade)
Tricuspid valve morphology Tricuspid valve annular diameter (per 1 mm)
1.018 (1.003–1.033)
0.021
1.008 (0.993–1.024)
0.29
0.989 (0.967–1.012)
0.36
Tricuspid valve tenting area (per 1 mm2)
1.306 (1.157–1.475)
<0.001
1.142 (0.992–1.315)
0.07
1.082 (0.877–1.335)
0.46
HRs refer to an increase of regurgitant volume per 1 ml, of vena contracta width per 1 mm, of EROA per 0.01 cm2, tricuspid valve annular diameter per 1 mm, tricuspid valve tenting area per 1 mm2, and to an increase of 1 category of semiquantitative TR assessment. *Adjusted for: age, g-glutamyltransferase, and TAPSE (all variables not log-transformed). †Adjusted for: right ventricular end-diastolic diameter, TAPSE, severity of mitral regurgitation, and NT-proBNP (all variables not log-transformed). Bold values are statistically significant. CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Table 1.
for the impact of more severe TR on mortality and
TR based on current guideline cutoffs has a 1.5-times
the analysis was probably confounded by type II
increased risk of mortality. Even more striking is a
error (10).
patient with a RegVol of 20 ml (mild TR according to
QUANTITATIVE VERSUS QUALITATIVE APPROACHES TO
the current guideline cutoffs) who has a 1.5-times
ASSESSING FUNCTIONAL TR. Another potential reason
increased risk of mortality. The significance of less
for the inconsistent findings between studies may
TR is explainable by the discordance of EROA and
relate to the assessment of right ventricular systolic
RegVol in the presence of a lower driving force of the
function
that
right compared with the left heart. Tribouilloy et al.
reported an association between TR severity and
(12) examined the EROA to RegVol discordance by
mortality only assessed right ventricular systolic
comparing the difference in RegVols between TR and
and
TR
severity.
Earlier
studies
function and severity of TR qualitatively as opposed
MR lesions. More specifically, flow-reversal in MR and
to the present study, which assessed severity of TR
TR lesions with similar EROAs were compared. They
using quantitative measures. Current guidelines on
reported that there was less flow reversal in the TR
assessment of valvular regurgitation recommend
lesions compared with MR lesions. This phenomenon
an integrated approach for TR grading considering
might be attributable to the specific context of TR
structural, qualitative, semiquantitative, and quanti-
where the decreased driving force within the right
tative parameters of regurgitant severity. Especially
heart
they recognized the limited validation of quantitative
compared with MR lesions (12). Moreover, this
metrics of TR severity in patients with HFrEF (8).
discrepancy might be aggravated in the failing right
Quantitative measures of TR severity including those
heart. The spline curve analyses (Figure 2) supports
derived using the PISA technique have only been
the recommendation of an integrated approach
validated in a few comparative studies of limited size
because it demonstrates a sustained increase in
(11,12) and the prognostic value was not previously
mortality associated with a larger EROA and RegVol
results
in
lower
magnitudes
of
RegVol
demonstrated. Our data fill this gap of knowledge
(Figures 2B and 2C) but not so for VCW (Figure 2A).
by demonstrating the independent association of
This finding may also be attributable to technical
the VCW and PISA-derived EROA and RegVol with
differences because VCW is a pure geometric deter-
mortality in this high-risk cohort. The observed
minant of the regurgitant lesion, whereas the EROA
thresholds for VCW and EROA are close to the
and the RegVol is dependent on the pressure gradi-
guideline-defined range for moderate TR potentially
ents between the atrium and the ventricle and
indicating the early significance of volume load in
thereby right ventricular function. Currently there are
failing right hearts (Figures 2 and 3). Importantly, our
no data on the contributions of each of these param-
results indicate RegVol thresholds predictive of
eters to the severity of TR, which only emphasizes the
mortality that are considerably lower than proposed
importance of experienced readers to avoid mis-
guideline cutoffs. Hence, a patient with a VCW of 4
interpretations. The accuracy of measurements could
mm or an EROA of 0.3 cm 2 despite having moderate
also be further improved with 3-dimensional imaging
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7
Functional Tricuspid Regurgitation
techniques whereby the measurement of EROA and RegVol may be more accurate given the inherent limitations of the 2-dimensional PISA method for assessment of EROA and RegVol.
F I G U R E 2 Spline Curve Analysis of Quantitative Markers of TR Severity
A 4
THE CLINICAL IMPACT OF FUNCTIONAL TR. The
(Table 1) clearly highlight a consistent trend between severity or TR, right heart pathology, and symptoms. In our cohort, patients with trace/no TR tend to be less symptomatic clinically with less neurohumoralpathway activation (Figure 1). They do not display features of maladaptive remodeling of the tricuspid complex. Patients with moderate TR display mal-
Relative Risk of Mortality
baseline characteristics of the study population
3.5 3 2.5 2 1.5 1 0.5
adaptive remodeling of the tricuspid complex and 0
right heart (Online Table 1) as previously described
0
(13,14). The observed elevated markers of liver and renal impairment indicate an early stage of TR driven venous congestion (15). Finally, in those with severe
opathy and renal impairment suggests TR as a causative link for multiorgan involvement inducing a more complex disease course (16). POTENTIAL IMPLICATIONS FOR TRANSCATHETER TRICUSPID REPAIR. The concept of tricuspid valve
0
cially with low periprocedural mortality. It is impor-
14
15
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
3 2.5 2 1.5 1
tant to note, however, that HFrEF is a complex disease where TR influences right ventricular func-
0
may be used to determine time to intervention and a
13
C
0.5
tion and vice versa. Continuous metrics of TR severity
12
Functional Tricuspid Regurgitation – Effective Regurgitant Orifice (cm2)
Relative Risk of Mortality
to functional capacity and quality of life, and espe-
11
1
3.5
excellent feasibility, beneficiary effects with regards
10
1.5
to reduce TR. Whether this is also a reasonable
transcatheter repair (19,20). Early results show
9
2
4
currently investigating the potential role of TR
8
2.5
ures (17,18) and represents a technically possible way
increasing number of studies and registries are
7
3
insertion of a restrictive tricuspid ring is currently
treatment in HFrEF is completely unknown. An
6
0
concomitant left-sided valve disease (17,18). The
annular remodeling at the time of left-sided proced-
5
0.5
repair has been well recognized in patients with
recommended in patients with concomitant TR or
4
3.5 Relative Risk of Mortality
and g-glutamyltransferase levels. Congestive hepat-
3
4
associated with multiorgan
damage is reflected by markedly elevated creatinine
2
B
TR, pronounced right heart failure with severe systemic congestion
1
Functional Tricuspid Regurgitation - Vena Contracta Width (mm)
0
10
20
30
40
50
60
70
Functional Tricuspid Regurgitation – Regurgitant Volume (mL)
measure of interventional success. Our data favor earlier intervention because moderate regurgitant
Spline curves of relative risk of mortality according to tricuspid regurgitation severity. The
lesions are already associated with a clinically
curves show the impact of tricuspid regurgitation severity measured by vena contracta
significant impact. However, chronic heart failure is a complex, recursive disease with many factors, such as left and right ventricular function and residual
width (A), effective regurgitant orifice area (B), and regurgitant volume (C) on mortality. Dashed lines are 95% confidence intervals.
Bartko et al.
-, NO. -, 2019
JACC: CARDIOVASCULAR IMAGING, VOL.
- 2019:-–-
Functional Tricuspid Regurgitation
F I G U R E 3 Kaplan-Meier Estimates of Mortality According to the Spline Curve–Defined
Thresholds of Mortality
myocardial viability potentially influencing outcomes. Specifically, whether and in which subgroups reverse remodeling and functional improvement can occur after repair of the tricuspid valve still needs to
A
1.0
be assessed by future studies. Moreover, it is still
Survival Probability
unclear if tricuspid valve repair by lower-risk transcatheter techniques at this stage would have any
0.8 Vena contracta <5 mm
benefits apart from symptomatic improvement and the benefits of transcatheter repair techniques still
0.6
need to be addressed in controlled trials. All of these Vena contracta ≥5 mm
questions can only be answered on the basis of reliable and validated metrics of TR.
0.4
STUDY 0.2
20
Patients at risk: Vena contracta <5 mm
291
229
207
174
Vena contracta ≥5 mm
91
50
40
31
B
LIMITATIONS. The
present
validation
of
quantitative TR assessment is focused only on sec-
HR 2.14 (95% CI 1.53 - 2.00); P < 0.001
0
40
ondary TR and may not be applicable to patients with
60
primary TR. The thresholds for the parameters of TR
Survival Time (Months)
severity that are predictive of increased mortality may not be applicable to patients with primary TR. However, secondary TR is far more prevalent than
1.0
primary TR in patients with chronic heart failure, Survival Probability
hence our findings are likely to be applicable to most 0.8 2
EROA <0.2 cm
patients with chronic heart failure with TR (14). The presence of permanent endocardial device leads and its impact on the accurate assessment of TR severity
0.6 2
EROA ≥0.2 cm
pose an important challenge in the quantification of TR. Despite no evidence of interaction with quanti-
0.4
tatively assessed TR we cannot rule out impact of endocardial lead presence on the accuracy of such
0.2
HR 1.74 (95% CI 1.22 - 2.49); P = 0.002
measurements.
0
20
296
226
202
173
86
48
40
32
40
60
CONCLUSIONS
Survival Time (Months)
Patients at risk: 2 EROA <0.2 cm 2
EROA ≥0.2 cm
Functional TR is independently associated with
C
mortality in HFrEF in this large-scale outcome study.
1.0
The sustained increase in mortality associated with Survival Probability
8
increases in quantitative measures of TR severity,
0.8 Regurgitant volume <20 ml
such as EROA and regurgitant volume, supports the use of such metrics in routine clinical practice.
0.6 Regurgitant volume ≥20 ml
Furthermore, thresholds identified to be associated with mortality are congruent with moderate TR as defined by current guideline recommendations. Their
0.4
prognostic value may help guide the clinical decision0.2
making process and timing of intervention. However,
HR 1.82 (95% CI 1.29 - 2.55); P = 0.001
0 Patients at risk:
20
40
the complex nature of HFrEF with competing and 60
Survival Time (Months)
Regurgitant volume <20 ml 271
218
195
169
Regurgitant volume ≥20 ml 84
56
46
36
Kaplan-Meier estimates of mortality in patients with a tricuspid regurgitation vena contracta width $5 mm (A) (p < 0.001), an effective regurgitant orifice area $0.20 cm2 (B) (p ¼ 0.002), and a regurgitant volume $20 ml (C) (p > 0.001). Hazard ratios
interacting risks between heart failure and TR and mortality
highlights
the
need
for
prospective
controlled trials.
ADDRESS
FOR
CORRESPONDENCE:
Dr.
Georg
Goliasch, Department of Internal Medicine II, Medical
are derived from a univariable Cox regression model. CI ¼ confidence interval;
University of Vienna, Waehringer Guertel 18-20,
EROA ¼ effective regurgitant orifice area; HR ¼ hazard ratio.
A-1090 Vienna, Austria. E-mail: georg.goliasch@ meduniwien.ac.at.
JACC: CARDIOVASCULAR IMAGING, VOL.
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Bartko et al.
- 2019:-–-
Functional Tricuspid Regurgitation
PERSPECTIVES COMPETENCY IN PATIENT CARE AND
TRANSLATIONAL OUTLOOK: Use of new techniques,
PROCEDURAL SKILLS: Doppler-echocardiographic
such as transcatheter TR treatment, needs validated
quantitative assessment of the effective regurgitant
continuous metrics of lesion severity, specifically for the
orifice area and the regurgitant volume defines the in-
treatment indication and definition of interventional
dependent association of TR with mortality in patients
success. The present data define thresholds where TR is
with HFrEF and indicates thresholds predictive of mor-
associated with mortality introducing the intriguing pos-
tality for parameters used in the quantification of TR.
sibility of an early interventional approach before late heart failure stages occur.
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KEY WORDS effective regurgitant orifice area, heart failure with reduced ejection fraction, regurgitant volume, tricuspid regurgitation, vena contracta width
A PP END IX For supplemental tables, please see the online version of this paper.
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