Clinical Context and Mechanism of Functional Tricuspid

Clinical Context and Mechanism of Functional Tricuspid
Regurgitation in Patients With and Without
Pulmonary Hypertension
Yan Topilsky, MD; Amber Khanna; MD; Thierry Le Tourneau; MD; Soon Park; MD; Hector Michelena; MD;
Rakesh Suri; MD, DPhil; Douglas W. Mahoney; MS; Maurice Enriquez-Sarano, MD
Downloaded from http://circimaging.ahajournals.org/ by guest on November 1, 2016
Background—Functional tricuspid regurgitation (FTR) with structurally normal valve is of poorly defined mechanisms.
Prevalence and clinical context of idiopathic FTR (Id-FTR) (without overt TR cause) are unknown.
Methods and Results—To investigate prevalence, clinical context, and mechanisms specific to FTR types, Id-FTR versus
pulmonary hypertension-related (PHTN-FTR, systolic pulmonary pressure ⱖ50 mm Hg), we analyzed 1161 patients
with prospectively quantified TR. Id-FTR (prevalence 12%) was associated with aging and atrial fibrillation. For
mechanistic purposes, we measured valvular and right ventricular (RV) remodeling in 141 Id-FTR matched to 140
PHTN-FTR and to 99 controls with trivial TR for age, sex, atrial fibrillation, and ejection fraction. PHTN-FTR and
Id-FTR were also matched for TR effective-regurgitant-orifice (ERO). Id-FTR valvular alterations (versus controls)
were largest annular area (3.53⫾0.6 versus 2.74⫾0.4 cm2, P⬍0.0001) and lowest valvular/annular coverage ratio
(1.06⫾0.1 versus 1.45⫾0.2, P⬍0.0001) but normal valve tenting height. PHTN-FTR had mild annular enlargement but
excessive valve tenting height (0.8⫾0.3 versus 0.35⫾0.1 cm, P⬍0.0001). Valvular changes were linked to specific RV
changes, largest basal dilatation, and normal length (RV conical deformation) in Id-FTR versus longest RV with
elliptical/spherical deformation in PHTN-FTR. With increasing FTR severity (ERO ⱖ40 mm2), changes specific to each
FTR type were accentuated, and RV function (index of myocardial performance) was consistently reduced.
Conclusions—Id-FTR is frequent, linked to aging and atrial fibrillation, can be severe, and is of unique mechanism. In
Id-FTR, excess annular and RV-basal enlargement exhausts valvular/annular coverage reserve, and RV conical
deformation does not cause notable valvular tenting. Conversely, PHTN-FTR is determined by valvular tethering with
tenting linked to RV elongation and elliptical/spherical deformation. These specific FTR-mechanisms may be important
in considering surgical correction in FTR. (Circ Cardiovasc Imaging. 2012;5:314-323.)
Key Words: tricuspid regurgitation 䡲 echocardiography 䡲 pulmonary hypertension 䡲 atrial fibrillation
T
ricuspid regurgitation (TR) can be caused by organic
valve diseases but often occurs on structurally normal
tricuspid valves, called functional TR (FTR).1 Because of a
long-recognized relationship between FTR and left-sided
cardiac2,3 or pulmonary1,4 diseases, the link FTR excessive
afterload of pulmonary hypertension (PHTN) is construed as
core FTR mechanism and is the main focus of guidelines for
valve diseases5; however, FTR remains a frustrating condition, poorly understood.6 Epidemiological studies uncovered
TR with high prevalence, even without PHTN,7 and, conversely, severe PHTN does not necessarily cause notable
FTR.8 Accruing reports noted FTR with normal pulmonary
pressure9 and without overt cause, despite comprehensive
workup,10 referred as idiopathic FTR (Id-FTR).9,11–14 Id-FTR
prevalence, clinical context, and mechanisms are unknown,
underscoring the general need for better FTR mechanism
understanding.1 Previous studies implicated various candidate
FTR mechanisms, annular3,15,16 or valvular,16,17 but uncertainty persists on processes yielding FTR, particularly when
severe.1 This issue is clinically important because severe
TR may portend poor prognosis,18,19 and its treatment with
valve repair is mired by frustrating failures,17,20 –24 poorly
understood.24,25
Clinical Perspective on p 323
In defining FTR mechanism, previous studies were hindered by heterogeneity of causes and patient characteristics
when all TR types are amalgamated.26 Paucity of comprehensive quantitative assessment of right ventricular (RV) characteristics, valvular alterations, and TR severity (particularly,
with physiological measures such as ERO) also prevent
examination of quantitative links between FTR degree and
Received July 10, 2011; accepted March 5, 2012.
From the Division of Cardiovascular Diseases and Internal Medicine (Y.T., A.K., T.L.T., H.M., M.E.-S.), Health-Science Research (D.W.M.), and
Cardiovascular Surgery (S.P., R.S.), Mayo College of Medicine, Rochester, Minnesota.
Correspondence to Maurice Enriquez-Sarano, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St SW.,
Rochester, MN 55905. E-mail Sarano.maurice@mayo.edu
© 2012 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
314
DOI: 10.1161/CIRCIMAGING.111.967919
Topilsky et al
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valvular-ventricular complex alterations; however, these hindrances can now be addressed, starting with careful selection
of FTR types examined. Recent advances in noninvasive
Doppler echocardiography allow consistent measurement of
regurgitant volume (RVol) and ERO,27–29 providing important insights into TR pathophysiology.27,30 Quantification of
valvular-ventricular complex deformation, which provided
crucial information in functional mitral regurgitation,31 can
also be obtained in FTR simultaneously to TR quantitation.26
Thus, to gain mechanistic insights specific to each FTR type,
we analyzed our prospectively quantified TR population in
whom comprehensive imaging of RV, right atrial (RA), and
tricuspid valvular complex had also been performed. We
examined prevalence and characteristics of FTR types and
then matched these FTR types to analyze mechanistic features. We hypothesized that mechanisms linking valvular
alterations and RV remodeling to FTR quantified degree are
different in patients with id-FTR versus those with TR related
to PHTN (PHTN-FTR).
Methods
Design
The study was designed with 2 aims. First, among patients enrolled
in prospective TR quantitation, we assessed Id-FTR prevalence and
clinical context with etiologic stratification of all patients, emphasizing those classified as Id-FTR, and ascertaining absence of any
known TR cause. Second, for FTR mechanism, Id-FTR, PHTN-FTR
groups, and the control-group with physiological-trivial TR, strictly
matched for baseline characteristics, were compared for detailed
valvular-ventricular characteristics. Computer-generated frequency
matching involved dynamic bins of potential controls and produced
groups (not pairs) similar to the Id-FTR group for the predefined
baseline characteristics (see below) from the 336 available of
PHTN-FTR, with prospectively quantified TR. Frequency matching
to Id-FTR was also applied for normal controls, with measurable TR
velocity examined during the same period. This matching process
allowed quantitative direct comparison of RV, RA, and valvularventricular complex differences.
Eligibility
For defining prevalence and context of Id-FTR, we analyzed all
patients without pericardial or endocardial disease in whom prospective TR quantitation was performed between 1995 and 2005.
For defining specific mechanisms of Id-FTR (versus PHTN-FTR),
eligibility criteria were (1) presence of FTR characterized by
structurally normal tricuspid leaflets (no organic valve disease); (2)
measurable systolic pulmonary artery pressure (SPAP), based on
clearly defined TR signal by continuous-wave Doppler and inferior
vena cava size and respiratory variation; (3) absence of overt left
ventricular systolic dysfunction (ejection fraction ⱖ50% in all
patients); (4) absence of pacemaker or defibrillator wire across
tricuspid valve; (5) absence of congenital, pericardial, endocardial,
or other valve disease; (6) TR holosystolic and prospectively
quantified; and (7) high-quality imaging allowing quantitation of
RV, RA, and tricuspid valvular complex. Age, sex, symptoms, and
atrial fibrillation (AFib) were not exclusion criteria. There were 141
patients labeled Id-FTR with no detectable TR cause (even after
echocardiographic review) and without likely pulmonary hypertension by current guidelines (SPAP ⬍50mm Hg).4 We frequency
matched these patients with Id-FTR for age, sex, ejection fraction,
AFib, and TR-ERO to 140 patients with FTR similarly quantified
and likely pulmonary hypertension (SPAP ⱖ50 mm Hg),4 computerselected from all those with PHTN-FTR (n⫽336). Patients with
Id-FTR were also matched for age, sex, AFib, and ejection fraction
to controls (99 patients), with normal Doppler echocardiography and
TR trivial (jet ⬍1.0 cm2; ERO, 0) but with peak velocity clearly
Mechanisms of Functional TR
315
measurable to calculate SPAP and exclude likely pulmonary hypertension (SPAP ⬍50 mm Hg). Thus, all 380 patients in this mechanistic analysis had ejection fraction ⱖ50%, structurally normal
tricuspid valve, and FTR by Doppler echocardiography. The study
was powered (80%, 0.05) to detect at least 30% difference in
tricuspid annulus diameter and tenting height between patients with
and without PHTN.
Doppler Echocardiography
Comprehensive Doppler echocardiography was performed in patients instructed to breathe normally. All TR, RV, and RA measurements were averages of inspiratory and expiratory measurements30
ⱖ5 cardiac cycles.
Hemodynamic Assessment
SPAP was estimated using continuous-wave Doppler and inferior
vena cava diameter and respiratory variation. Forward stroke volume, cardiac output, and index were calculated using pulsed
Doppler.
Valvular-Ventricular Complex Assessment
Valvular-ventricular complex assessment used current recommendations.32,33 From 4-chamber views encompassing the entire RV, end-systolic and end-diastolic RV areas, length, and midventricular and basal
diameters were measured. RV shape ratios, basal to midventricle
diameter and RV sphericity index (mid-diameter⫻length)/ (basal diameter), were calculated in systole (after tricuspid closure).26 RV free-wall
thickness and outflow tract diameter were measured.32,34 RV function
was evaluated by RV end-systolic area, fractional area change (fractional shortening [FS]) and index of myocardial performance (RIMP).35
Tricuspid annulus systolic and diastolic diameters (% contraction
calculated)33,34 and systolic valve tenting height and area were measured.17 Tricuspid leaflets length (septal⫹anterior leaflets) was measured and ratio to systolic annulus diameter calculated to assess valvular
coverage of annulus in systole. RA end-systolic area and length allowed
RA volume calculation using area-length formula. Cavity areas and
diameters were normalized to body surface area.
TR Assessment
TR assessment used color-flow imaging and quantitative measures.27–29
TR color-jet area was planimetered and ratio to RA area was calculated.
TR quantitation used proximal flow convergence (PISA) as validated27–29 (Figure 1). Corrections for leaflets-angle and TR velocity27–29
allowed calculation of regurgitant flow, ERO area (regurgitant flow/
velocity), and RVol. TR duration was measured directly using Doppler
signal.
Statistical Analysis
Results were expressed as mean⫾ SD or percentages. Group
comparisons used the ANOVA and Tuckey-Kramer test for posthoc
multiple comparisons. Associations between morphology and FTR
severity were analyzed univariably by classifying patients as
trivial-TR (ERO, 0), mild-moderate TR (ERO, 1 to 39 mm2), and
severe TR (ERO ⱖ40 mm2).27 Intragroup (Id-FTR or PHTN-FTR)
univariable associations with ERO were analyzed, including
controls-TTR patients and testing for trends. Multivariable analyses
used logistic regression models with ERO ⱖ40 mm2 as dependent
variables, including interaction terms for FTR types and analyses
within FTR type. RV characteristic association with ⬎median
tenting height (0.6 cm) and ⬎median valvular/annular ratio (1.1)
used similar sequence. All multivariable models were adjusted for
age, sex, and AFib. Interobserver and intraobserver variability, in 11
random patients with blinded measurements, used paired t test,
Bland-Altman plotting, and concordance coefficient of correlation.
P⬍0.05 was considered significant. Analyses were performed with
SAS version 9.2 and JMP 9 (SAS Institute Inc).
Results
Burden and Clinical Context of Id-FTR
The 1161 patients examined prospectively and quantitatively
for TR were classified etiologically in sequential manner.
316
Circ Cardiovasc Imaging
May 2012
A
B
RV
RV
T
T
RA
RA
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C
D
Figure 1. Examples of valvular alterations in Functional Tricuspid Regurgitation. Figures 1A and 1B show the tricuspid valve deformation with annular dimensions marked by the white line and valvular tenting (T). Figures 1C and 1D show the large proximal flow convergence for the same patients appearing in yellow after down-shift of color baseline. Figures 1A and 1C correspond to idiopathic functional tricuspid regurgitation; Figures 1B and 1D correspond to functional tricuspid regurgitation with pulmonary hypertension. RV
indicates right ventricle; RA, right atrium.
Traditional causes included 4 groups, congenital TR (any
congenital heart disease resulting in TR, including atrial
septal defect), organic or pacemaker/defibrillator-associated
TR (TR without congenital disease associated with structural tricuspid disease or a lead penetrating the tricuspid
orifice), TR with left-sided valvular disease more than moderate, and TR with left ventricular systolic dysfunction
(ejection fraction ⬍50%). Remaining patients had FTRclassified PHTN-linked with SPAP ⱖ50mm Hg or Id-FTR
with SPAP ⬍50mm Hg. Prevalence of TR etiologies was TR
associated with congenital diseases, 8.9%; organic/pacemaker TR, 11.9%; TR of left valvular disease, 25.9%; and TR
of left ventricular systolic dysfunction, 12.2%. Thus, traditional causes of TR (congenital, organic, left valvular, and left
ventricular dysfunction) represented 58.9% of patients.
PHTN-FTR involved 28.9% and Id-FTR, 12.2%. TR causes
were similarly distributed in our community (Olmsted
County, Minn) or distantly referred (P⫽0.35).
Clinical context, comparing Id-FTR versus PHTN-FTR
versus traditional TR causes, showed Id-FTR associated with
older age (71.5⫾13.8 versus 67.4⫾16.5 versus 61.6⫾20.8
years respectively; P⬍0.0001-all comparisons), female sex
(69.5% versus 71.0% and 54.7% respectively; P⬍0.0001)
and AFib at diagnosis (51.0% versus 19.1% versus 11.5%;
P⬍0.0001). AFib prevalence was higher in Id-FTR whether
TR was severe (ERO ⱖ40 mm2, 57.3% versus 23.0% versus
14.8%; P⬍0.0001) or less severe (ERO ⬍40 mm2, 38.4%
versus 16.0% versus 7.2%; P⬍0.0001). Thus, Id-FTR links to
aging, and AFib underscores the importance of appropriate
matching versus PHTN-FTR for TR mechanistic analysis.
Mechanistic Matched Analysis:
Baseline Characteristics
The mechanistic analysis included 380 patients with FTR,
ranging from trivial to severe (Table 1). Comparison between
groups verified that matching was successful. By design,
SPAP was higher in PHTN group but SPAP and TR velocity
were similar (Table 2) in Id-FTR and controls-TTR. Although
not part of matching, blood pressure, heart rate, or cardiac
index displayed no difference between groups. Thus, matching achieved groups similar in many aspects and with specific
crucial differences: Id-FTR and PHTN-FTR had similar ERO
(P⫽0.34) and differed essentially by likely PHTN. Id-FTR
and control-TTR had identical AFib prevalence and differed
essentially by FTR degree. Observer variability was low for
all measurements (all P⬎0.23) with all CCC ⱖ0.70.
Contrasting TR Characteristics by FTR Types
TR and associated RV and RA characteristics are listed in
Table 2. By design, ERO matched between Id-FTR and
PHTN-FTR and was assigned null value in controls-TTR
(ERO, 0); however, RVol was higher in PHTN-FTR versus
Topilsky et al
Mechanisms of Functional TR
317
Table 1. Baseline Characteristics of Patients Overall and Stratified by Functional Tricuspid
Regurgitation Type
Groups Characteristics
All Patients
Controls-TTR (N⫽99)
Id-FTR (N⫽141)
Age, y
PHTN-FTR (N⫽140)
71.2⫾14.0
72.2⫾12.3
71.4⫾13.9
AFib, (%)
46.1
49.5
51.0
39.3
0.1
Sex, (% males)
31.3
32.3
31.2
30.7
0.96
EF, %
SBP, mm Hg
70.4⫾15.3
P Value
0.62
63.5⫾6.0
64.1⫾5.7
63.1⫾6.4
63.3⫾5.8
0.48
126.2⫾21.6
126.3⫾21.8
128.5⫾20.0
124.2⫾19.9
0.2
72.7⫾16.0
73.9⫾16.3
71.4⫾17.2
73.3⫾14.2
0.43
2.8⫾1.3
2.9⫾0.7
3.0⫾1.9
0.17
49.5⫾21.7
32.5⫾6.5
HR
CI L 䡠 min⫺1 䡠 m2
SPAP, mm Hg
2.7⫾0.62.
39.6⫾6.9
71.5⫾20.6*†‡
⬍0.0001
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TTR indicates trivial (physiological) tricuspid regurgitation; Id-FTR, idiopathic functional TR; PHTN-FTR, functional TR due to
pulmonary hypertension; AFib, atrial fibrillation; EF, ejection fraction; SBP, systolic blood pressure; HR, heart rate; CI, cardiac index;
SPAP, systolic pulmonary artery pressure.
*P⬍0.05 vs Controls TTR.
†P⬍0.001 vs Controls-TTR ⫹ P⬍0.05 vs Id-FTR.
‡P⬍0.001 vs Id-FTR.
Id-FTR, owing to larger driving force (pressure) and
TR duration. Higher TR flow and velocity in PHTNFTR resulted in larger jet and jet/RA ratio than in
Id-FTR. Volume overload yielded larger diastolic RV
size in Id-FTR versus controls-TTR and even larger in
PHTN-FTR.
Table 2. Characteristics of Tricuspid Regurgitation and Right
Ventricle Stratified by Functional Tricuspid Regurgitation Type
Etiologic Groups of Functional
TR (FTR)
TR
Characteristics
N
TR Velocity, m/s
TR Duration,
msec
Controls-TTR
Id-FTR
PHTN-FTR
99
141
140
2.54⫾0.3
2.68⫾0.3
397.2⫾55.8 407.6⫾50.8
3.73⫾0.6†§
422.0⫾50.2*
P Value
Between
Groups
⬍0.0001
0.001
⬍0.0001
TR ERO, mm2
0
47⫾33†
TR RVol. mL/beat
0
37.0⫾19.5†
TR jet area, cm2
⬍1.0
8.4⫾4.6†
13.9⫾6.8†§
⬍0.0001
TR jet/RA area
ratio, %
⬍5.0
41⫾19†
47⫾18†§
⬍0.0001
RV-EDA index,
cm2/m2
12.2⫾2.6
15.4⫾4,5†
16.8⫾6.2†‡
⬍0.0001
RV-ESA index,
cm2/m2
6.9⫾1.6
9.6⫾3.4†
9.8⫾5.1†
⬍0.0001
44⫾20†
51.3⫾25.5†§ ⬍0.0001
RV-AFS, %
41.9⫾10.6
37.5⫾10.9*
42.1⫾12.5⫹
0.001
RIMP ratio
0.31⫾0.16
0.42⫾0.18†
0.47⫾0.27†
⬍0.0001
RA volume index,
mL/m2
26.2⫾8.8
46.7⫾23.8†
50.3⫾27.2†
⬍0.0001
TT indicates trivial tricuspid regurgitation; Id-FTR, idiopathic functional
tricuspid regurgitation; PHTN-FTR, pulmonary hypertension-related functional
tricuspid regurgitation; ERO, effective regurgitant orifice; RVol, regurgitant
volume; RA, right atrium; RV, right ventricle; RV-EDA, right ventricular end
diastolic area (4-chamber view); RV-ESA, right ventricular end systolic area
(4-chamber view); RV-AFS, right ventricle area fractional shortening; RIMP,
right index of myocardial performance.
*P⬍0.05 vs Controls TTR.
†P⬍0.001 vs Controls-TTR.
‡P⬍0.05 vs Id-FTR.
§P⬍0.001 vs Id-FTR.
Variables measuring RV function showed complex
changes. In Id-FTR, RV end-systolic enlargement was concordant with decreased FS and increased RIMP versus
controls-TTR, despite similar SPAP, demonstrating serious
RV function alterations. Conversely, in PHTN-FTR, variables measuring RV function are discordant, with RV FS
similar to controls-TTR but with higher RV end-systolic size
and RIMP, emphasizing incipient RV dysfunction. Larger
RA in Id-FTR and PHTN-FTR versus controls-TTR demonstrates RA distention linked to FTR beyond the similarly
prevalent AFib. FTR types were stratified according to FTR
severity (ERO ⱖ40mm2)27 in Table 3. With severe FTR, RV
enlarged in both groups, but RV FS declined in Id-FTR
versus maintained in PHTN-FTR (P⫽0.0002), although similarly increased RV end-systolic size and RIMP suggest
similar RV function alterations. Thus, serious RV and RA
consequences are markedly influenced by FTR type (PHTNFTR versus Id-FTR).
Contrasting Alterations of Valvular-Ventricular
Complex by FTR Types
Valvular alterations by FTR types are shown in Figure 2,
overall and stratified by ERO (⬍40 or ⱖ40mm2) in Table 3.
Tricuspid annulus systolic dimension (Figure 2A) is increased in both FTR types versus controls-TTR but larger
in Id-FTR versus PHTN-FTR even after stratification by
ERO (Table 3). Conversely, leaflet-length is similar in
controls-TTR, Id-FTR, and PHTN-FTR (2.11⫾0.34 versus
2.06⫾0.30 versus 2.12⫾0.31 cm/m2, P⫽0.26). Thus, systolic annulus coverage by leaflets (Figure 2C) is highest in
controls and lowest in Id-FTR even after stratification by
ERO (Table 3). Ventricular displacement of leaflets (tenting height, Figure 2B) is not exaggerated versus controlsTTR in Id-FTR but is markedly exaggerated in PHTN-FTR
even after stratification by ERO (Table 3). Thus, more
severe PHTN-FTR is characterized by more tenting height,
in contrast to Id-FTR. Conversely, increased tenting area
reflects both larger annulus and tenting height and thereby
is not discriminant.
318
Circ Cardiovasc Imaging
Table 3.
May 2012
RV, RA Dimensions, and Valvular Alterations, Stratified by TR Severity and Functional Regurgitation Type
Control-TTR
(N⫽99)
ERO ⬍40mm2
Id-FTR
(N⫽78)
ERO ⱖ40mm2
Id-FTR
(N⫽63)
P Value
for trend
ERO ⬍40mm2
PHTN-FTR
(N⫽74)
ERO ⱖ40mm2
PHTN- FTR
(N⫽66)
P Value
for trend
P Value
PHT-FTR
vs Id-FTR*
53⫾18
⬍0.0001
38⫾12
67⫾28
⬍0.0001
⬍0.0001
RVol, mL
0
25⫾8
2
RV-EDA index cm /m
12.1⫾2.6
13.9⫾3.3
17.2⫾5.1
⬍0.0001
15.3⫾4.0
18.5⫾7.6
⬍0.0001
0.11
RV-ESA index cm2/m2
6.9⫾1.6
8.5⫾2.4
10.9⫾4.0
⬍0.0001
8.9⫾3.3
10.7⫾6.4
⬍0.0001
0.8
RIMP ratio
0.31⫾0.16
0.41⫾0.17
0.44⫾0.19
0.0003
0.43⫾0.18
0.51⫾0.33
⬍0.0001
0.11
RV-AFS, %
41.9⫾10.6
38.5⫾11.1
36.2⫾10.7
0.002
41.8⫾11.6
42.3⫾13.4
0.79
2
0.0002
RA volume index, cm /m
26.2⫾8.8
38.1⫾17.9
57.5⫾25.8
⬍0.0001
47.3⫾29.5
53.6⫾24.2
⬍0.0001
Tenting area, cm2
0.48⫾0.18
0.73⫾0.6
0.87⫾0.47
⬍0.0001
1.14⫾0.52
1.38⫾0.84
⬍0.0001
⬍0.0001
Tenting height, cm
3
2
0.6
0.42⫾0.44
0.41⫾0.4
0.25
0.7⫾0.23
0.89⫾0.32
⬍0.0001
⬍0.0001
3.3⫾0.5
4.2⫾0.7
4.7⫾0.7
⬍0.0001
3.6⫾0.6
3.9⫾0.7
⬍0.0001
⬍0.0001
Ann-4C systolic diameter, cm
2.74⫾0.36
3.4⫾0.6
3.74⫾0.6
⬍0.0001
3.2⫾0.56
3.4⫾0.6
⬍0.0001
0.0002
Ann-4C systolic contraction, %
15.8⫾8.9
18.4⫾11.5
19.6⫾9.6
0.18
11.2⫾12.1
12.3⫾11.1
0.24
0.002
2.1⫾0.3
2.1⫾0.3
2.0⫾0.3
0.09
2.1⫾0.3
2.1⫾0.3
0.52
0.04
1.45⫾0.2
1.11⫾0.11
1.00⫾0.09
⬍0.0001
1.26⫾0.21
1.20⫾0.17
⬍0.0001
⬍0.0001
⬍0.0001
Leaflet length index, cm/m2
Leaflet/annular ratio
RV basal diameter index cm/m
1.7⫾0.20
2.4⫾0.3
2.6⫾0.5
⬍0.0001
1.9⫾0.3
2.1⫾0.3
⬍0.0001
RV mid cavitary index cm/m2
1.8⫾0.3
2.2⫾0.3
2.5⫾0.5
⬍0.0001
2.2⫾0.4
2.5⫾0.7
⬍0.0001
RV length index cm/m2
4.1⫾0.5
4.1⫾0.5
4.4⫾0.6
0.01
4.4⫾0.5
4.8⫾0.7
⬍0.0001
1.8⫾0.3
2.1⫾0.3
2.2⫾0.4
⬍0.0001
2.1⫾0.3
2.2⫾0.4
⬍0.0001
2
RVO, diameter index cm/m2
2
RV wall thickness index mm/m
Basal/ Mid cavitary ratio
RV sphericity index†
0.6
⬍0.0001
0.5
3.1⫾0.6
3.3⫾0.7
3.4⫾0.8
0.09
4.7⫾0.9
5.2⫾1.2
⬍0.0001
⬍0.0001
0.97⫾0.1
1.07⫾0.12
1.07⫾0.12
⬍0.0001
0.87⫾0.13
0.86⫾0.16
⬍0.0001
⬍0.0001
8.1⫾1.2
6.9⫾1.1
7.6⫾1.3
0.05
9.9⫾2.1
10.9⫾3.9
⬍0.0001
⬍0.0001
RV indicates right ventricle; RA, right atrium; TR, tricuspid regurgitation; TTR indicates trivial tricuspid regurgitation; Id-FTR, idiopathic functional tricuspid regurgitation; PHTN-FTR,
pulmonary hypertension-related functional tricuspid regurgitation; Ann-4C, tricuspid annulus in 4-chamber view; ERO, effective regurgitant orifice; RV-EDA, right ventricular end diastolic
area; RV-ESA, right ventricular end systolic areas (4-chamber view); RV-AFS, right ventricle area fractional shortening; RIMP, right index of myocardial performance.
*P value for difference in trend between PHT-FTR and Id-FTR.
†RV mid diameter and length product divided by basal diameter.
In multivariable analysis (entire population), adjusting for
age, sex, and AFib, tenting height (P⬍0.0001) and leaflet/
annulus ratio (P⫽0.0002) were independently associated with
ERO ⱖ40 mm2 (AUC, 0.79); however, there was significant
Annulus Diameter
interaction between ERO determinants and FTR type
(P⬍0.0001). Indeed, the only independent ERO valvulardeterminants are lower leaflet/annular ratio in Id-FTR
(P⬍0.0001; AUC, 0.90) and higher tenting height in PHTN-
Leaflet/
Annulus Ratio
Tenting Height
1.45±0.2
A
B
5
**
4
**‡
C
1.23±0.2
1.5
1.5
3.53±0.6 **‡
3.3±0.6
**
1.06±0.1
**‡
0.8±0.3
2.74±0.4
1.0
1.0
3
cm
0.42±0.4
cm
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0.35⫾0.1
Ann-4C diastolic diameter, cm
2
0.35±0.1
0.5
0.5
1
0.0
0.0
0
Controls-
TTR
Id- PHTNFTR FTR
Controls-
TTR
*P<0.05 vs. TTR, ** P<0.001 vs. TTR
IdFTR
PHTN
-FTR
Controls-
TTR
Id- PHTNFTR
FTR
+ P<0.05 vs. Id-FTR, ‡ P<0.001 vs. Id-FT
Figure 2. Valvular alterations in patients
with Functional Tricuspid Regurgitation
(FTR) according to FTR type, idiopathic
(Id-FTR) versus related to pulmonary
hypertension (PHTN-FTR). The variables
represented are tricuspid annular diameter (2A), tricuspid valve tenting height
(2B) and the ratio of tricuspid leaflet
length to annular diameter (2C). Id-FTR
displays marked annular dilatation, low
tenting height, and low leaflet tissue
coverage of the enlarged annulus. Conversely, PHTN-FTR displays less annular
enlargement but more tenting, resulting
in similarly poor coaptation.
Topilsky et al
A
Mechanisms of Functional TR
319
B
Figure 3. Right ventricular and atrial
alterations in 2 patients with functional
tricuspid regurgitation. LV indicates left
ventricle; LA, left atrium; RV, right ventricle; and RA, right atrium. Figure 3A corresponds to a patient with idiopathic tricuspid regurgitation and Figure 3B
corresponds to a patient with tricuspid
regurgitation with pulmonary hypertension. Note the considerable dilatation of
RV and RA in both cases but with
marked differences in RV shape and
length between the 2 patients.
RV
LV
RV
LV
LA
RA
LA
RA
RV Basal
Width Index
A
B
**
2.5±0.4
3
1.7±0.2
RV Mid-Cavitary
Width Index
**
2.36±0.6
3
**‡
**
2.35±0.4
versus controls-TTR but was markedly increased in
PHTN-FTR (Figure 4C), particularly severe PHTN-FTR
(Table 3). Mid-RV diameters are similarly increased in
Id-FTR and PHTN-FTR, but basal-RV diameters are considerably increased in Id-FTR and only slightly in PHTNFTR (Figure 4B and 4A). Thus, ratio of RV basal diameter
to length (Figure 4E) and ratio of RV basal to midventric-
RV Length
RV Wall
RV WidthIndex
Thickness Index Length ratio
**‡
C 4.1±0.5
4.2±0.6
5
D
4.6±0.6
1.8±0.3
2.0±0.3
E
1.0
12
10
4
**
0.59±0.08
2
1
**‡
mm
1
8
3
cm
cm
2
cm
Downloaded from http://circimaging.ahajournals.org/ by guest on November 1, 2016
FTR (P⬍0.0001; AUC, 0.86). In 11 patients with Id-FTR
who underwent tricuspid valve surgery (4 replacements, 7
repairs), direct valve inspection showed in all marked annular
dilatation with normal valve tissue gross appearance.
RV morphology (Figure 3 and 4 and Table 3) was
different between FTR types. Although RV was enlarged
in both FTR types, RV length was not increased in Id-FTR
0.42±0.06
3.4±0.8
6
‡
0.44±0.07
4.9±1.1
0.5
2
4
1
0
0
TTR
Id- PHTNFTR FTR
TTR
Id- PHTNFTR FTR
3.1±0.6
2
0
0
TTR
*P<0.05 vs. TTR, ** P<0.001 vs. TTR
Id- PHTNFTR FTR
0
TTR
Id- PHTNFTR FTR
TTR
Id- PHTNFTR FTR
+ P<0.05 vs. Id-FTR, ‡ P<0.001 vs. Id-FT
Figure 4. Right Ventricular (RV) alterations according to Functional Tricuspid Regurgitation (FTR) type, idiopathic (Id-FTR) versus related
to pulmonary hypertension (PHTN-FTR). The variables are RV basal width (diameter), indexed to body surface area (4A), RV midcavitary
width index (4B), RV length index (4C), RV wall thickness (4D), and RV ratio of basal width to length (4E). Id-FTR and PHTN-FTR present different form of RV remodeling: In Id-FTR marked RV, basal widening, with little lengthening and no wall thickening; in PHTN-FTR
less RV, basal widening, more lengthening, and wall-thickening. Thus, RV shape, measured by basal-width/length ratio is different in
Id-FTR versus PHTN-FTR.
320
Circ Cardiovasc Imaging
May 2012
E
E
E
D
D
D
C
C
G
C
Downloaded from http://circimaging.ahajournals.org/ by guest on November 1, 2016
A
B
A
B
B
A
F
F
F
Controls
Id-FTR
PHTN-FTR
Figure 5. Schematic representation of right ventricular (RV) and right atrial (RA) remodeling and valvular deformation comparing
matched normal controls to idiopathic FTR (Id-FTR) versus related to pulmonary hypertension (PHTN-FTR). In Id-FTR and PHTN-FTR,
for similar effective regurgitant orifice, similar systolic RV and RA enlargement versus controls is noted; however, in Id-FTR, there is
marked tricuspid annular and RV basal widening, with normal tricuspid leaflet length, resulting in reduced annular coverage in systole.
Limited RV lengthening or RV walls centrifugal displacement (conical-shaped RV) does not cause leaflet tethering and tenting. In PHTNFTR, there is less annular enlargement and better leaflet coverage, but RV lengthening and eccentricity (elliptical-shaped RV) yields tricuspid leaflets tethering and tenting, with ultimate coaptation loss identical in Id-FTR and PHTN-FTR.
ular diameter (Table 3) are highest in Id-FTR, consistent
with RV conical deformation (versus controls). Conversely, lowest ratio of RV basal to midventricular diameter and highest sphericity index in PHTN-FTR are consistent with RV elliptical/spherical deformation (versus
controls). RV shape and size changes in PHTN-FTR and
Id-FTR versus controls are schematically presented in
Figure 5. RV changes independently determine valvular
changes in multivariable analysis. In PHTN-FTR, higher
RV sphericity (P⬍0.0001) and RIMP (P⫽0.007) are
independently associated with tenting height ⱖ0.6 cm
(AUC, 0.88) and higher RVol (both P⬍0.001). Conversely, in Id-FTR, higher RV basal/length ratio is the only
RV characteristic independently linked to leaflet/annular
ratio ⬍1.1 (P⬍0.0001; AUC, 0.88). RV wall thickness was
highest in PHTN-FTR (Figure 4D), as expected.
Discussion
The present series of consecutively and prospectively
quantified TR shows that Id-FTR represents about 12% of
patients with TR. Irrespective of classification chosen to
assess TR-etiology, Id-FTR is without any known cause
but shows a strong link to aging and AFib. Mechanistic
analysis based on comprehensive quantitation of TR, RV,
RA, and valvular-ventricular complex and matching of
baseline characteristics between FTR types provides important insights into FTR mechanisms and pathophysiology. FTR with or without PHTN can be severe and lead to
untoward consequences, with RV dilatation and increased
end-systolic RV size and RIMP, suggesting universally
reduced RV function with increasing FTR severity. FTR
mechanisms are different in Id-FTR and PHTN-FTR despite similar ERO (valve lesion) with specific valvularventricular complex alterations. Id-FTR main valvular
mechanism is exhaustion of annular coverage reserve by
tricuspid leaflets owing to marked annular enlargement,
but valvular tenting plays no or minimal role. PHTN-FTR
main mechanism is valvular tethering with tenting above
the annular level, reducing coaptation, but annular enlargement is modest. These contrasting valvular mechanisms
determining directly FTR severity are associated with
specific RV remodeling patterns. In PHTN-FTR, the RV is
not only larger but also longer with more elliptical/
spherical deformation, and more RV deformation is linked
to higher valve tenting and, thereby, larger ERO. Conversely, in Id-FTR, RV shows conical deformation without
Topilsky et al
elongation and with larger RV base. Wider RV base and
annulus are linked to lower valvular-annular coverage and
larger ERO. Thus, FTR is not uniform, and the TR, RV,
and valvular-ventricular complex characteristics are specific to each FTR type. Thus, in clinical practice, TR
severity and characteristics should be fully described and
integrated into clinical decision-making regarding FTR
treatment.
Importance of Functional Tricuspid Regurgitation
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Management of severe tricuspid regurgitation (TR) is complex and mired by frustration.23,36 Doppler echocardiography
often shows a structurally normal tricuspid valve associated
with TR.7 Clinical significance and management of TR
remain uncertain,5 but recent series suggest that TR37 and,
particularly FTR, seriously impact outcome,2,18,19 a concept
vetted by recent reviews.24,38 FTR importance is supported by
Id-FTR notable prevalence, 12% of this quantified population
(after extensive verification that other TR causes were not
ignored), which is not a referral artifact. Id-FTR links to
aging, and AFib9 –14 suggests a growing burden, which,
combined with PHTN-FTR frequency, warrants precisely
delineating FTR mechanisms1,6 to ultimately improve FTR
treatment.22 Relatively small series, lack of quantitative
assessment, and multiplicity of “causes” hindered mechanistic analyses.16,17,26,39 To address this vexing issue, we took
advantage of prospective efforts at quantifying TR, strictly
defined patients’ subsets, and carefully matched FTR types.
Valvular Mechanism of Functional
Tricuspid Regurgitation
FTR was considered as 1 entity,1,16 with annular dilatation as
core mechanism,9,11 and a possible, but uncertain, contributing role of leaflet-tethering.16,17,40 RV remodeling contribution to FTR development is also controversial.6,8,16,38 Our
study shows that valvular determinants of FTR lesion severity
(ERO) are specific to each FTR type. In Id-FTR, exhaustion
of the valvular coverage reserve of the excessively dilated
annulus mainly determines TR severity. Considerable annular
dilatation is required for incomplete tricuspid coaptation15
because substantial redundancy of leaflet tissue prevents TR3
in normal tricuspid valves (ratio leaflets/annular length, 1.45).
With severe Id-FTR (ERO ⱖ0.4 cm2), leaflet coverage
declined markedly, with decreasing coaptation not owing to
retracted leaflets, as available valvular tissue was similar in
all subsets. The Id-FTR entity is not well-known, not only
mechanistically but also clinically, and awareness of its
existence was raised by few seminal reports.9,11,12,14 Although
our data highlight Id-FTR exhaustion of valvular reserve in
covering the enlarged tricuspid annulus, the cause of annular
enlargement remains uncertain. AFib association suggests
links to atrial enlargement,11 but Id-FTR also occurs in sinus
rhythm, and its link to aging may reflect annular degeneration. Among 11 Id-FTR patients who underwent TR surgery, 3 underwent RA and atrioventricular groove biopsy,
showing interstitial fibrosis with mild myocyte hypertrophy. These nonspecific observations incite further tissue
analysis of tricuspid annulus to uncover biological mechanisms of Id-FTR.
Mechanisms of Functional TR
321
Conversely, in PHTN-FTR, annular dilatation, although
present, is less impressive, and tricuspid annulus coverage is
closer to normal. Thus, another factor causing TR is required
to explain the ERO similar to Id-FTR. In PHTN-FTR, leaflet
deformation with increased tenting height40 and intraventricular leaflets’ displacement, preventing appropriate coaptation,39 is the main determinant of ERO. Thus, our quantitative
data show that Id-FTR and PHTN-FTR result from 2 distinct
mechanisms, exhaustion of leaflet coverage reserve in IdFTR, and leaflet deformation with tenting in PHTN-FTR.
Right Ventricular Alterations in Functional
Tricuspid Regurgitation
RV remodeling occurs in both FTR types, with RV dilatation
associated to volume overload versus controls-TTR; however, despite similar regurgitant lesion (ERO) by design,
patients with PHTN-FTR versus Id-FTR incur larger RVol,
owing to inherent hemodynamic differences (greater TR
duration and driving force) and larger RV diastolic volume.
This difference in RV volume overload affects RV function
assessment. In Id-FTR, there is concordant alteration of RV
function indices, with increasing TR severity. In PHTN-FTR,
with large volume overload, RV FS remains high, and RV
dysfunction may be undetected by casual examination.41
Furthermore, RV remodeling is radically different in Id-FTR
and PHTN-FTR, despite similar ERO with valvular-ventricular complex alterations specific of each FTR type.
In Id-FTR, RV displays conical deformation, with concordant RV basal and annular enlargement,15 although RV
length is not affected. This type of RV remodeling cannot
cause apical or lateral displacement of tricuspid papillary
muscles, and we found no evidence of valvular tethering.
Consequently, valve tenting height is not different from
controls, and larger tenting area is purely linked to annular
enlargement.
Conversely, in PHTN-FTR, RV basal and tricuspid annular
dilatations, although present, were unrelated to FTR severity,
and RV was elongated with spherical/elliptical deformation.20,26 These RV changes, specific of PHTN-FTR, tend to
eccentrically displace the tricuspid papillary muscles, laterally and apically and in view of chordal inextensibility, are
logically linked to tricuspid leaflet tethering and apical
tenting.20 Thus, despite substantial leaflet availability for
annulus coverage, systolic valve deformation, with tenting of
PHTN, reduces tricuspid coaptation, yielding similar ERO in
PHTN-FTR and Id-FTR. Therefore, in each FTR type,
concordant ventricular-valvular complex alterations explain
very different FTR-mechanisms in Id-FTR versus
PHTN-FTR.
Study Limitations
TR-cause classification may be disputed, but Id-FTR has no
overt cause, irrespective of classifications. Id-FTR may be
doubted, but in those who underwent tricuspid surgery,
absence of known TR cause and marked annular dilatation
were confirmed by direct visualization. Matching by ERO,
warranted to compare Id-FTR and PHTN-FTR, differing
mechanisms, leading to similar lesion severity implies larger
RVol and RV volumes in PHTN-FTR, owing to afterload
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May 2012
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differences. Future studies should analyze whether RVolmatching is associated with differing RV size, shape, and
function.
Echo-Doppler methods may be criticized. The PISA
method to quantify TR has not been used as widely as for
other regurgitations28 but has been validated29 and confirmed
by our institution and others.27 Assessing RV remodeling is
complex but was based on current guidelines.32,33 SPAP
determination using TR signal may be criticized but allows to
reliably classify patients with and without likely PHTN42 and
is the basis of clinical guidelines.4 If Id-FTR focused only on
unlikely PHTN (SPAP ⱕ36 mm Hg),4 FTR severity determinants remained unchanged (Leaflet/Annular ratio determines
ERO, P⬍0.0001; AUC, 0.96; RV basal/length ratio strongly
associated to Leaflet/Annular ratio, P⬍0.0001; AUC, 0.87).
Thus, exact boundaries of Id-FTR definition do not affect
mechanistic analysis results.
6.
7.
8.
9.
10.
11.
12.
Conclusions
Our quantitative study shows that FTR is frequent and that
id-FTR represents a notable proportion, may be severe, and is
strongly associated to aging and Afib. Comprehensive quantitation also shows that FTR is a complex entity with
contrasting mechanisms, depending on FTR type. Id-FTR is
related to tricuspid annular dilatation, with exhaustion of
leaflet annular coverage reserve and with little or no role for
leaflet tenting in the loss of coaptation, leading to severe TR.
In Id-FTR, RV basal dilatation without elongation results in
RV conical deformation. Conversely, PHTN-FTR is predominantly due to valve deformation with tenting and only
modest annular enlargement. Valvular tenting and leaflet
tethering are linked to RV elongation and elliptical/spherical
deformation. Hence, RV remodeling and functional response
to volume/pressure overload are complex and differ widely,
depending on FTR type. These mechanistic insights provide
important clues on FTR development and on potential approaches to surgical correction.
13.
14.
15.
16.
17.
18.
19.
Disclosures
Dr Enriquez-Sarano discloses a research grant funding from Abbott
Laboratories. No other disclosure was reported.
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CLINICAL PERSPECTIVE
Tricuspid regurgitation is frequent but not well-understood. Most often, it occurs despite structurally normal leaflets and
is termed functional tricuspid regurgitation (FTR). This study evaluated the clinical context and mechanisms of FTR in
patients in whom we performed quantification of tricuspid regurgitation, valvular deformation, and ventricular remodeling.
We compared 2 FTR types that were caused by pulmonary hypertension versus FTR without overt cause (id-FTR). We
matched groups for important characteristics at diagnosis (particularly the regurgitant orifice) and also included, as
controls, patients of the same age with trivial TR. The results show that id-FTR occurs in older patients mostly with Afib.
This observation is important because our study shows the mechanism of idiopathic FTR to be isolated enlargement of the
tricuspid annulus, a known consequence of Afib, resulting in insufficient annulus coverage by the leaflets. This annular
enlargement is associated with a conical deformation of the RV, which does not cause leaflet deformation. Conversely, with
pulmonary hypertension, the RV is elongated and spherically deformed, leading to leaflet traction exerted by the papillary
muscles, as well as deformation and tenting of leaflets, which cannot cover the annulus, despite its modest dilatation. Thus,
the mechanism of FTR is not uniform. Our results enhance the understanding of the context and mechanisms for FTR and
may help inform improved treatment strategies.
Clinical Context and Mechanism of Functional Tricuspid Regurgitation in Patients With
and Without Pulmonary Hypertension
Yan Topilsky, Amber Khanna, Thierry Le Tourneau, Soon Park, Hector Michelena, Rakesh
Suri, Douglas W. Mahoney and Maurice Enriquez-Sarano
Downloaded from http://circimaging.ahajournals.org/ by guest on November 1, 2016
Circ Cardiovasc Imaging. 2012;5:314-323; originally published online March 23, 2012;
doi: 10.1161/CIRCIMAGING.111.967919
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