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

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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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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

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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.

Bartko et al.

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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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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.

9