European Journal of Heart Failure (2021) REVIEW

doi:10.1002/ejhf.2398

Challenges and future perspectives of

transcatheter tricuspid valve interventions:
adopt old strategies or adapt to new
opportunities?
Giulio Russo1,2*, Maurizio Taramasso3, Daniela Pedicino1,2, Marco Gennari4,
Mara Gavazzoni5, Alberto Pozzoli6, Denisa Muraru5, Luigi P. Badano5,
Marco Metra7, and Francesco Maisano8
1 Fondazione Policlinico Universitario A. Gemelli, IRCSS, Rome, Italy; 2 Università Cattolica del Sacro Cuore, Rome, Italy; 3 HerzZentrum Hirslanden, Zurich, Switzerland; 4 IRCCS
Centro Cardiologico Monzino, Milan, Italy; 5 IRCCS, Instituto Auxologico Italiano, S. Luca Hospital, University of Milano-Bicocca, Milan, Italy; 6 Heart Surgery Unit, Cardiocentro
Ticino, Lugano, Switzerland; 7 Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy;
and 8 University Hospital San Raffaele, Milan, Italy
Received 17 July 2021; revised 2 December 2021; accepted 4 December 2021

Tricuspid regurgitation (TR) is a highly prevalent valvular heart disease and is associated with an increased risk of cardiovascular events
and death at long-term follow-up. Functional TR accounts for over 90% of TR and is mainly due to annular or right ventricular dilatation.
Most often, TR is observed in patients with left-sided valvular heart disease (with or without previous surgical correction) and pulmonary
hypertension. Isolated TR is less frequent, though burdened by high surgical mortality. This, together with an incomplete understanding of
the disease, has brought to a significant undertreatment in spite of the growing evidence of the impact of severe TR on mortality. Moreover,
uncertainties about the appropriate timing for intervention and the predictors of procedural success have contributed to limit TR treatment.
Transcatheter tricuspid valve replacement or repair interventions represent novel and less invasive alternatives to surgery and have shown
early promising results. The purpose of this review is to provide a complete and updated overview of TR pathology with a special focus on
current percutaneous treatment options, future challenges and directions.
..........................................................................................................
Keywords Tricuspid regurgitation • Valvular heart disease • Tricuspid valve repair • Tricuspid valve
replacement • Structural heart disease interventions • transcatheter tricuspid valve interventions
.....................................

several transcatheter technologies have been developed to treat

Introduction inoperable and high-risk patients, and early feasibility results are
Tricuspid valve (TV) disease has been neglected (the ‘forgotten promising, albeit many challenges still remain. The aim of this
valve’) for a long time and, in most cases, it has been considered as review is to provide an updated overview of current evidence on
a secondary issue compared to left-sided heart disease. In addition, percutaneous treatment of TR and available transcatheter devices
the impact of TV pathologies on survival remains to be clearly with a glimpse to future perspectives for TR therapies.
defined and its incidence has been underestimated. Conversely,
recent data demonstrated that tricuspid regurgitation (TR) is as
prevalent as aortic stenosis and affects long-term outcomes, if left
Epidemiology
untreated. Surgical treatment represents the mainstay and is mainly The Framingham Heart Study reported an overall prevalence
performed during left-sided heart valve interventions. Isolated TV of moderate-to-severe TR of 0.8%.3 More recently, an analysis
surgery is burdened by high mortality rates.1,2 In this perspective, conducted on more than 20 000 patients found that about 5% of

*Corresponding author. Institute of Cardiology, Fondazione Policlinico Universitario A. Gemelli, IRCSS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 1, 00168 Rome,
Italy. Email: giuliorusso.md@gmail.com

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2 G. Russo et al.

patients had at least moderate TR and that the total prevalence implantation or TAVI is an independent predictor of mortality and,

..................................................................................
of moderate-to-severe TR was 0.6%, very close to severe aortic consequently, should not be considered as an innocent bystander.10
stenosis.4 Moreover, given that TR was found to correlate with age,
being far more frequent in people aged >65 years, its prevalence is
expected to increase in the near future.4 Epidemiological data also Aetiology
show the independent prognostic impact of TR. A recent analysis
As for mitral regurgitation, TR is divided into primary/organic and
of almost half-million patients with heart failure in the United States
secondary/functional11 (Figure 1). Primary or organic TR is uncom-
showed a progressive increase in mortality in mild, moderate and
mon and involves congenital heart diseases (e.g., Ebstein’s anomaly)
severe TR, with adjusted mortality hazard ratios for the new cases
and acquired diseases such as trauma, carcinoid syndrome,
of 1.48 (95% confidence interval [CI] 1.44–1.52), 1.92 (95% CI
endomyocardial fibrosis, rheumatic disease and endocarditis.
1.86–1.99) and 2.44 (95% CI 2.32–2.57), respectively.5 In another
Intracardiac device lead-induced TR is often considered part of this
series of 33 305 patients from Tel Aviv, 1-year mortality rates were
category, though it might represent an independent subcategory.
7.7% for patients with no/trivial TR, 16.8% for patients with mild Functional or secondary TR (FTR) is by far the most common
TR, 29.5% for patients with moderate TR, and 45.6% for patients cause of TR, accounting for over 90% of cases of TR.12 It results
with severe TR (p < 0.001).6 from negative right ventricular (RV) remodelling affecting the
The reported concomitant severe TR among patients undergo- tricuspid annulus and leaflet coaptation. The most common cause
ing transcatheter aortic valve implantation (TAVI) varies according is left-sided heart disease, followed by pulmonary hypertension
to baseline operative risk, ranging from 1.7% in low-risk pro- (PH). In such cases, FTR can occur in the context of aortic or
files to 15.2% in high-risk patients. The effect of TAVI on TR is mitral valve (MV) disease, or it can be observed late after treat-
highly heterogeneous, though in more than half of the cases the ment of primary left-sided heart valve disease. As TR progresses,
TR degree remained unchanged at 30-day follow-up.7,8 Similarly, the TV annulus dilates in the anterolateral direction of the RV
in 146 patients with functional mitral regurgitation undergo- free wall and becomes more planar while leaflet tethering due to
ing MitraClip implantation, almost one third had concomitant papillary muscle displacement impairs leaflet coaptation. The area
moderate-to-severe TR and although TR degree improved at of malcoaptation is usually located centrally or extends from the
30-day follow-up, residual moderate-to-severe TR persisted anteroseptal commissure towards the posteroseptal one.
after MitraClip therapy in 26.6% of patients.9 Overall, concomi- Finally, an emerging and frequent cause of FTR is the so-called
tant moderate-to-severe TR in patients undergoing MitraClip ‘atrial’ TR due to persistent atrial fibrillation: in these cases, TV

Figure 1 Aetiology of tricuspid regurgitation. ARVD, arrhythmogenic right ventricular dysplasia; LV, left ventricular; RV, right ventricular; TV,
tricuspid valve.

© 2021 European Society of Cardiology

Tricuspid regurgitation and transcatheter therapies 3

Table 1 Current recommendation for tricuspid regurgitation management according to ACC/AHA and ESC/EACTS
guidelines17,18

Class of recommendation
and level of evidence
.....................................
ACC/AHA ESC/EACTS
(2020) (2021)
...........................................................................................................................................
Primary TR
Severe TR in patients undergoing left-sided valve surgery I-B I-C
Patients with signs and symptoms of right-sided HF and severe TR IIa-B I-C
Asymptomatic or minimally symptomatic patients with severe TR and RV dilatation IIb-C IIa-C
Patients with moderate TR undergoing left-sided valve surgery – IIa-C

Secondary TR
Severe TR in patients undergoing left-sided valve surgery I-B I-B
Mild or moderate functional TR at the time of left-sided valve surgery with TA dilatation (>40 mm or IIa-B IIa-B
>21 mm/m2 by 2D echocardiography)
Mild, moderate, or greater functional TR at the time of left-sided valve surgery with prior signs and IIa-B –
symptoms of right HF
Patients with severe TR (w/w previous left-sided surgery) who are symptomatic or have progressive IIb-B IIa-B
RV dilatation, in the absence of severe RV or LV dysfunction and severe pulmonary vascular
disease/hypertension
Patients with signs and symptoms of right-sided HF and severe isolated TR attributable to annular IIa-B –
dilatation (in the absence of pulmonary hypertension or left-sided disease) who are poorly
responsive to medical therapy
Transcatheter treatment of symptomatic severe TR may be considered in inoperable patients at a – IIb-C
Heart Valve Centre with expertise in the treatment of tricuspid valve disease

2D, two-dimensional; HF, heart failure; LV, left ventricular; RV, right ventricular; TA, tricuspid annulus; TR, tricuspid regurgitation.

annular remodelling results from primary atrial dilatation rather or history of right heart failure. In general, surgeons should always
.............................................................................

than ventricular remodelling.13–15 consider TR correction in the context of left-sided interventions

as reoperation is associated with higher mortality rates, and the
addition of TV repair does not increase the risk at the time of
Treatment indications the index procedure. Indeed, FTR after previous left-sided heart
valve surgery represents more than 10% of all isolated TR and
Over the last years, an increasing attention has been paid to is burdened by high morbidity and mortality, probably due to
the TV, for both atrial TR or in the context of left-sided valve advanced age and presence of RV failure and comorbidities.1,26
interventions.1,16 In this setting, guidelines suggest to intervene only if no severe
According to current guidelines, the presence and severity of RV failure or severe PH are present. However, careful patient
symptoms as well as RV geometry and function should guide treat- selection represents a key aspect for safe and successful TR
ment of patients with isolated primary TR (Table 1).17–19 The correction.
intervention can be performed through a right minithoracotomy Of note, the latest European guidelines have introduced for
or median sternotomy approach, with repair being preferred over the first time transcatheter TV interventions (TTVI) as a possible
replacement. However, regardless of the technique used, perioper- therapy for secondary TR in inoperable patients to be performed
ative mortality is high (4%–17%), likely due to late referral, multiple in experienced Heart Valve Centres.18
comorbidities and the lack of a dedicated operative risk score for
TV treatment which could properly stratify surgical risk.20–23
Functional TR correction in the context of left-sided heart The lesson learnt from surgical
valve surgery is fairly more common, especially in patients with
severe TR, as isolated correction of left-sided valve disease is
techniques
unlikely to significantly improve TR. In less than severe TR, current As a consequence of surgical limitations and operative mortality,
surgical practice is less univocal due to the lack of strong evidence transcatheter TV treatments have grown and, over the last years,
and controversial data on perioperative mortality and long-term have gained increasing attention. In most cases, surgical experience
survival.24,25 As for mild or moderate TR, current guidelines represented the basis to conceive and build percutaneous devices
recommend concomitant TV repair in case of annular dilatation and techniques to address TR.

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4 G. Russo et al.

Surgical annuloplasty is the mainstay of FTR as it improves leaflet view (corresponding to the intercommissural view of the MV)

........................................................................................................................................................................
coaptation and restores annular geometry. It can be performed might be used. Issues to address TTVI are displayed in Figure 2 and
either by suture techniques or prosthetic ring placement. Suture Table 2.
annuloplasty is mainly based on the techniques described by Kay
and De Vega.27,28 The former consists of bicuspidalization of the
TV through plication of the posterior leaflet, but it does not Computed tomography
address the tendency of the anterior annulus to dilate and creates Although direct quantification of TR is not feasible with CT,
a hypofunctional posterior leaflet. The latter is based on suturing it has become a complementary tool for the pre-procedural
the annulus surrounding the anterior and posterior leaflets, but planning of several devices thanks to its excellent spatial resolution.
this technique is limited by suture dehiscence due to the frequent Currently, the anatomic regurgitant orifice area during systole and
presence of friable tissue. Ring annuloplasty permanently fixes the quantification of tricuspid annular area during diastole represent
annulus by stitching a rigid or semi-rigid prosthetic ring. Current two surrogates for TR assessment. CT plays a central role for
data support the use of ring annuloplasty due to the lower TV replacement and annuloplasty procedures providing detailed
rate of recurrent severe TR at 5 years as compared to suture information on TV anatomy, TV surrounding structures (e.g., right
annuloplasty.29–31 In addition, multiple risk factors for reduced coronary artery), right chambers, inferior (IVC) and superior vena
durability have been identified, including advanced leaflet tethering, cava (SVC) (Figure 2).
chronic atrial fibrillation, use of flexible rings, PH, large annular
diameter, and presence of pacemaker leads.
Cardiac magnetic resonance
Cardiac magnetic resonance represents an excellent imaging tech-
Imaging techniques nique for valvular regurgitation and it is the gold standard for the
for transcatheter tricuspid valve assessment of ventricular volumes and ejection fraction. However,
interventions its role in the TR work-up is still limited as TR severity classi-
fication by CMR has not been validated due to the lack of ade-
Although echocardiography represents the first-line technique, quate reference standards. For this reason, its role in the setting
several limitations exist and a multimodality approach with cardiac of TR needs to be defined yet. Moreover, the exam might be
magnetic resonance (CMR) and computed tomography (CT) might limited by other factors: CMR usually requires longer time, mea-
be helpful to better characterize and understand TV disease.32 surements might be affected by irregular heart rhythms, it might
be incompatible with some intracardiac devices and patients might
Echocardiography suffer from claustrophobia. One interesting point is the very recent
four-dimensional flow imaging software that allows assessment of
Echocardiography (transthoracic [TTE] and transoesophageal cardiac fluid dynamics.
[TEE]) represents the essential imaging technique both in the
pre-procedural and intra-procedural assessment of patients
with TR. In particular, in the pre-procedural evaluation, TTE
is fundamental to define the TR mechanism and grade as well
Right heart catheterization
as to assess TV anatomy and the right chamber function. The The combination of PH and TR is often present and their coexis-
role of three-dimensional (3D) echocardiography in addition to tence affects prognosis and operative risk.36,37 However, the role
two-dimensional (2D) echocardiography is becoming of utmost of right heart catheterization (RHC) in the pre-procedural assess-
importance as it provides detailed information on the TV and ment of TR is not well defined and patients with PH have often
TV annular anatomy, TR mechanism, right atrial (RA) and RV been excluded from the studies. Current European guidelines men-
function and volumes as well as the surrounding structures.33 In tion the importance of RHC in the setting of severe TR to assess
this perspective, an accurate assessment of TV anatomy is key as it PH as Doppler gradient may underestimate measurements, while
might affect technical success and outcome in patients undergoing American guidelines suggest RHC only in case of inadequate TTE
transcatheter edge-to-edge repair (TEER).34 or discrepancy with clinical presentation.15,16
Qualitative and quantitative criteria for the definition of TR Pulmonary hypertension is often assessed only by echocardiog-
severity are described in the latest European guidelines while a raphy, though recent data have shown that the diagnostic sensitivity
new 5-grade classification for TR has recently been proposed.16,35 of echocardiography to detect PH is only 55% and those patients
RV function assessment in the context of severe TR remains chal- with discordant results from invasive and echocardiographic assess-
lenging as no parameter is accurate being closely dependent on ment have the worst outcomes, possibly due to a more severe
loading conditions. In this perspective, 3D measurements might TR and to a suboptimal procedural success.38 Such data suggest
play a role in RV function assessment. Alongside TTE, TEE is funda- that echocardiography alone might be insufficient to detect PH
mental, especially for leaflet device procedures: beside anatomical during pre-procedural screening and that PH itself (defined as
criteria, an unsuitable TEE window might be a limitation for the systolic pulmonary artery pressure >50 mmHg) does not neces-
TV clipping procedure. The transgastric view is the key projection sarily preclude TTVI. In this regard, some authors recommend
for clipping, though also the deep oesophageal RV inflow/outflow to systematically perform RHC and to assess mean pulmonary

© 2021 European Society of Cardiology

Tricuspid regurgitation and transcatheter therapies 5

Figure 2 Treatment algorithm for percutaneous approach to tricuspid regurgitation. A/P, anterior-posterior; CT, computed tomography; IJV,
internal jugular vein; IVC, inferior vena cava; LH, left heart; mPAP, mean pulmonary artery pressure; RCA, right coronary artery; RHC, right
heart catheterization; RV, right ventricular; RVOT, right ventricular outflow tract; SL, septal-lateral; sPAP, systolic pulmonary artery pressure;
SVC, superior vena cava; TA, tricuspid annulus; TR, tricuspid regurgitation; TEE, transoesophageal echocardiography; TEER, transcatheter
edge-to-edge repair; TPG, transpulmonary gradient; TTE, transthoracic echocardiography; TTVI, transcatheter tricuspid valve intervention;
TV, tricuspid valve.

artery pressure (mPAP), pulmonary vascular resistance (PVR) and

.......................................................................

Table 2 Issues to be considered in the choice between

right ventriculo–arterial coupling.39 Moreover, RHC provides addi-
TriClip and Cardioband
tional information as compared to echocardiography; in particular,
transpulmonary gradient (TPG), pulmonary wedge pressure and
TriClip Cardioband
................................................................ PVR were found to be important predictors of survival in the set-
Ideal patient characteristics ting of TEER with the worst outcomes observed in the pre-capillary
Anteroseptal TR jet Central TR jet PH group (high mPAP and high TPG).40
Normal appearing leaflets TA dilatation (pure FTR) In conclusion, although more data are needed, current evidence
Coaptation gap <3–4 mm Non-severe leaflet tethering suggest that RHC should always be performed before TTVI to
(TH <0.76 cm) better characterize TR and to define its prognosis.
Good TEE windows Distance to RCA >2 mm
No PM/ICD lead Good TEE windows
No PM/ICD lead Transcatheter tricuspid valve
Advantages
Large experience with Directly addresses TR
interventions
clipping technology in MV mechanism (annular dilatation) Several percutaneous devices have been conceived and the first
Higher operators’ confidence More durable results (surgical that obtained the CE mark was the one reproducing a ring
with the device experience) annuloplasty technique (Cardioband). Currently, four devices
Disadvantages
have received the CE mark, i.e. TriClip, PASCAL, TricValve and
Targets only leaflet Complex and time consuming
Cardioband. They address different mechanisms underlying TR,
Highly operator-dependent
but at present TEER and annuloplasty with Cardioband have the
FTR, functional tricuspid regurgitation; ICD, implantable cardioverter- largest experience for TV interventions (Table 2). In the following
defibrillator; MV, mitral valve; PM, pacemaker; RCA, right coronary artery; TA, paragraphs, the most important available devices and scientific
tricuspid annulus; TEE, transoesophageal echocardiography; TH, tenting height;
TR, tricuspid regurgitation. data are presented, grouping the devices according to their main
mechanism of action (Figure 3 and Table 3).41–46

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6 G. Russo et al.

Figure 3 Available devices for transcatheter tricuspid valve interventions.

Table 3 Current available devices and study outcomes

Coaptation Annuloplasty Replacement

................................................................... .........................................
MitraClip TriClip Pascal Cardioband Heterotopic Orthotopic
(n = 249) (n = 85) (n = 63) (n = 30) (n = 25) (n = 30)
...............................................................................................................................................................
Mechanism Edge-to-edge Edge-to-edge clipping Edge-to-edge clipping Direct annuloplasty Valve replacement in Valve
clipping with spacer by cinchable ring IVC ± SVC replacement
and anchors position in TV position
Study Mehr et al.41 TRILUMINATE42 (and CLASP43 (and Eleid M, TRI-REPAIR44 Lauten et al.45 Hahn et al.46
Von Bardeleben RS, unpublished data)
unpublished data)
Baseline characteristics
FTR, % 90 84 92 100 96 –
EROA, cm2 0.70 0.65 0.71 0.78 – 0.75
VC, mm 10 17 15 12.3 – 13.7
RVFAC, % – 36 – 35.8 – –
TAPSE, mm 16 14 15 14.0 16.5 14.0
Gap width, mm 5 – – / – –
Outcome
Technical/procedural 77 91 98 100 96 87
success
Longest follow-up 290 days 2 years 6 months 2 years 12 30 days
Mortality 20 19 3 26 63 12.5
TR ≤moderate 72 62 77 72 / 95

EROA, effective regurgitant orifice area; FTR, functional tricuspid regurgitation; IVC, inferior vena cava; RVFAC, right ventricular fractional area change; RVSP, right ventricular systolic pressure; SVC,
superior vena cava; TAPSE, tricuspid annular plane systolic excursion; TV, tricuspid valve; VC, vena contracta.

Coaptation and leaflet devices and high-volume Heart Valve Centres. More recently, the TriClip
.................

(Abbott Vascular) system has been tested and gained the CE mark.
TriClip
It consists of two parts: a clip delivery system and a steerable
The initial experience with TV clipping was gained with the Mitr- guiding catheter. Its technology is similar to that of MitraClip,
aClip (Abbott Vascular, Santa Clara, CA, USA) device adapted though some changes have been applied in order to facilitate
to the TV and, consequently, performed only in experienced manoeuvrability and tracking towards the TV and its navigation

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Tricuspid regurgitation and transcatheter therapies 7

between the TV leaflets. It is introduced via the femoral vein Early results on seven patients showed that Mistral is safe,

........................................................................................................................................................................
under general anaesthesia. The intervention is guided by 2D, 3D reduces TR and improves RV function and exercise capacity.48 So
TTE and TEE and by fluoroscopy. Recently, the newest TriClip G4 far, no chordae injury has been observed but experience is still
system received the CE mark as well, with four different implant limited and further data are needed.
sizes (NT and XT, both with standard and wide configuration) and
independent leaflet grasping features.
The early results of TEER therapies with both MitraClip and Annuloplasty devices
TriClip are promising (Table 3). Ring annuloplasty
According to the TriValve registry including 249 patients treated Cardioband
with the MitraClip device, the procedural success is 77%, with The Cardioband system (Edwards Lifesciences) is a transfemoral,
durable TR improvement in more than two thirds of patients incomplete ring that closely reproduces surgical annuloplasty. It
and a mortality rate of 20% at 1-year follow-up.41 The TRILUMI- is implanted on the atrial side of the tricuspid annulus from
NATE trial, based on the novel TriClip technology, showed even commissure to commissure through multiple metal repositionable
more encouraging results: TR grade improvement to moderate and retrievable anchors fixing the device to the tissue. It is available
or less was observed in 71% and 60% of patients at 1-year42 and in six lengths to cover a wide range of annulus circumference sizes.
2-year follow-up (Von Bardeleben RS, unpublished data), respec- In tricuspid position, due to the enlarged annulus, usually almost
tively. Alongside this, functional status and quality of life improved only the longest size is implanted. The company is working on even
significantly with 19% all-cause mortality at 2-year follow-up. Fur- longer sizes specific for the tricuspid position.
ther data on larger populations and longer follow-up will help to Two-year data from the single-arm, multicentre, prospective
better define the best candidates and predictors of long-term pro- TRI-REPAIR study have recently been published.44 Technical suc-
cedural success. cess was achieved in all the 30 patients enrolled and one in-hospital
death was recorded. Patients enrolled had severe heart failure at
baseline with 83% in New York Heart Association class III–IV.
Pascal
They had, however, a relatively favourable outcome with an over-
The Pascal TV repair system (Edwards Lifesciences, Irvine, CA, all mortality of 26.7% at 2-year follow-up. Echocardiographic,
USA) is a 22 Fr system that combines the advantages of leaflet functional and symptom improvements were recorded over a
clasping to the physical properties of a spacer to overcome some 2-year observation period, though torrential TR persisted in 9%
limitations observed with these devices in cases of large coaptation of patients. Such data were confirmed also in the early feasibility
gaps and to further reduce the total regurgitant area. In addition, a study where device success achieved 93% with 100% survival at
configuration without central spacer is also available (Pascal ACE) 30-day follow-up.49
improving ease of subvalvular navigation thanks to is narrower
profile. Other ring annuloplasty technologies
Initial experience was limited to compassionate use in 28 The Percutaneous Annuloplasty System (Cardiac Implants LLC,
high-risk patients.47 Procedural success was 86% with a mortal- Tarrytown, NY, USA) represents a fully percutaneous circumfer-
ity rate of 7% at 30-day follow-up and an acceptable safety profile. ential annuloplasty system. It is implanted through the right jugular
More recently, data from the CLASP TR early feasibility study on vein and consists of a flexible ring with a built-in adjusting cord and
63 patients were published43 and presented at last EuroPCR 2021 10 barbed 7.5-mm stakes.
(Eleid M, unpublished data). Procedural success was 98% (at least The first-in-human procedure was successful with a significant
1-grade reduction of TR and no major adverse events at 30 days) and sustained TR grade improvement over 1-year follow-up.50
while all-cause mortality was 3% at 6-month follow-up and 89%
achieved at least 1 grade TR reduction (Table 3). Of note, device
implantation was unsuccessful in five cases due to either complex Suture annuloplasty
anatomy or poor quality echocardiographic imaging. The CLASP II Currently, few technologies are under development and have
trial is currently randomizing 825 patients with severe TR to either active programmes: the Minimally Invasive Annuloplasty (MIA)
Pascal treatment or optimal medical therapy (NCT04097145). The technology (Micro Interventional Devices, Newton, PA, USA)
device obtained CE mark in 2020. is a sutureless annuloplasty system consisting of compliant,
self-tensioning low-mass anchors and a thermoplastic elastomer
(MyoLast) deployed in the tricuspid annulus. The feasibility and
Mistral safety study (STTAR trial, not registered) is underway to assess
The Mistral technology (Mitralix, Yokneam, Israel) is a spiral-shaped this novel technology among 40 patients with FTR.
single nitinol wire approximating the leaflet chordae by grasp- Additionally, another technique based on the surgical Hetzer’s
ing and enclosing the TV chordae tendinae. In this way, it cre- double-orifice technique has been developed (Pledget-Assisted
ates a ‘bouquet’ of chordae tendinae improving leaflet coap- Suture Tricuspid Annuloplasty, PASTA): the septolateral apposition
tation and modifying RV geometry. Of note, it does not pre- is achieved through the implantation of two pledgeted sutures at
clude other percutaneous repair options (e.g., leaflet clipping, the septal and anterior tricuspid annulus and then through the
annuloplasty). suture tightening.

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8 G. Russo et al.

Tricuspid valve replacement and graspers located in the proximal and distal part of the stent.

........................................................................................................................................................................
A minimally invasive right thoracotomy is required for transatrial
Heterotopic (caval valve implantation) implantation. Alternatively, the transjugular route has been tested
using 80 cm long flexible and steerable catheter with a 45 Fr
Heterotopic TV implantation is an alternative approach to ortho-
hydrophilic introducer sheath.
topic implantation with the objective to improve symptoms by pro-
So far, the valve has been implanted in 30 patients, with a tech-
tecting the venous system from elevated RA pressure and systolic
nical success of 87%. The most commonly used access site was the
caval backflow in severe TR, without any correction of TV dis-
transatrial approach. In-hospital mortality was 10%, increasing to
ease. The caval valve implantation (CAVI) experience started with
13% at 30-day follow-up. Procedural complications included mal-
balloon-expandable valves (Edwards Sapien XT/3) and the positive
positioning requiring surgical conversion, pacemaker implantation
initial results led to two dedicated types of self-expanding valves
due conduction abnormalities, and RV perforation.46
for CAVI: TricValve (P&F Products Features Vertriebs, Weßling,
The Evoque system (Edwards Lifesciences) has been tested in
Germany) and Tricento (NVT, Hechingen, Germany).45 TricValve
56 patients with a procedural success of 94% (Kodali S, unpub-
consists of two self-expanding bioprostheses made of bovine
lished data). All patients achieved at least 1 grade TR reduction
pericardium leaflets on a nitinol stent, whereas Tricento is a
and 98% achieved reduction in TR to none/trace or mild at 30 days.
custom-made self-expanding valved stent bioprosthesis (porcine
All-cause mortality at 30-day follow-up was 3.8% and a significant
pericardium) spanning from IVC to SVC. TricValve is available in
improvement in clinical and functional status was also observed.
two sizes for both SVC and IVC with maximum treatment range
Currently, a prospective randomized trial comparing TV replace-
of 34 mm for SVC and 35 mm for IVC. Patients screening requires
ment with Evoque to optimal medical therapy is enrolling patients
CT scan with particular attention to IVC and SVC distance and
(TRISCEND II, NCT04482062).
diameters, distance from hepatic veins to IVC, position of coro-
Early experience with the Intrepid technology (Medtronic, Min-
nary sinus and the azygos vein. In selected cases, TricValve allows
neapolis, MN, USA) in three compassionate cases has also been
only one prosthesis implantation (usually IVC) whereas Tricento
presented and a Medtronic early feasibility study is ongoing to eval-
may adapt to different anatomies being custom-made.
uate the Transfemoral Intrepid System in patients with severe TR
From a technical perspective, the large and variable diameters
(Bapat V, unpublished data).
of the IVC and SVC and the length of the landing zone between
the hepatic veins and inferior cavo–RA junction are the major
challenges. Other emerging replacement
The first-in-human experience was reported in 2018 and technologies
included 25 patients treated with 31 balloon-expandable or
There are currently some new technologies in the pre-clinical
self-expandable valves in the caval position.44 Patients received
evaluation phase. The LuX-Valve (Jenscare Biotechnology, Ningbo,
a single inferior (n = 19) or bicaval (n = 6) valve implantation,
China) is a self-expanding prosthesis made of bovine pericardial
with 92% procedural success, immediate caval backflow reduction
tissue onto a nitinol stent frame, implanted through the transatrial
and significant functional improvement at 10 months. Device
approach. Currently, first-in-man results in 12 patients receiving
embolization occurred in two patients at 30 days, and 30-day and
LuxValve for compassionate use have been described.51
1-year mortality was 12% and 63%, respectively. TricValve has
Another promising and innovative technology is represented by
recently received the CE mark.
the TriSol Valve (TriSol Medical Ltd., Inc., Yokneam, Israel). The
Some issues about CAVI need to addressed: (i) long-term
valve apparatus consists of a single bovine pericardial piece attached
tolerability and durability, especially regarding the risk for RV
to the nitinol frame and anchoring to the annulus through multiple
function deterioration by increased preload in patients with prior
arms. It is made of two leaflets closing in a dome-shaped structure
depressed RV function; and (ii) RA ventricularization: as the right
with the aim of avoiding sudden RV afterload increase.
atrium becomes part of the right ventricle, RA pressure is expected
Finally, the CardioValve technology (Valtech Cardio Ltd, Or
to increase. However, in most patients undergoing CAVI the right
Yehuda, Israel) after MV implantation has now been described also
atrium is already severely dilated and, consequently, less prone to
in tricuspid position.52
further dilatation. More data are needed to better describe RA
pressure behaviour in the early and late phases after CAVI and to
establish whether this may have a clinical impact. Valve-in-valve and valve-in-ring
Redo surgery in patients with prior TV replacement has a higher
risk as compared to the index procedure with an in-hospital mor-
Orthotopic tality of more than 13%.53 As for the mitral position, transcatheter
The first successful cases of orthotopic transcatheter TV replace- TV implantation of a TAVI prosthesis represents a possible ther-
ment were reported with the NaviGate device (NaviGate Cardiac apeutic option for patients with recurrent TV disease following
Structures, Inc., Lake Forest, CA, USA). It is a biological trileaflet a surgical implant. Percutaneous valve-in-valve and valve-in-ring
valved stent made of nitinol alloy and equine pericardium. Cur- implantation in tricuspid position has been described in several case
rently, four sizes are available to cover tricuspid annular diameters reports, either for a degenerated tricuspid bioprosthesis or for ring
from 36 to 52 mm. The anchoring system is based on winglets annuloplasty failure, and mid-term outcomes (median follow-up

© 2021 European Society of Cardiology

Tricuspid regurgitation and transcatheter therapies 9

time of 13 months) have shown positive results with only 3% mor-

........................................................................................................................................................................
Table 4 Outcome predictors of the edge-to-edge
tality at 30-day follow-up.54–57
repair for tricuspid regurgitation
The first implants were done mainly via a transatrial or tran-
sjugular access. More recently, the transfemoral route has been
Predictors of successful repair
described and, in cases of a narrow caval-to-annulus angle, a Jet location: central/anteroseptal
contralateral snare has been successfully used to simplify the Coaptation gap ≤6.4 mm (MitraClip NT mostly)
implant procedure, by improving co-axiality.58 The most used types Coaptation gap ≤8.0 mm (MitraClip XTR)
of implanted valves are the Melody valve (Medtronic) and the EROA ≤0.7 cm2
Edwards SAPIEN valve (Edwards Lifesciences), according to sur- Tenting area ≤3.2 cm2
gical valve/ring sizes.59–61 The implantation technique has been Baseline TR severity
described in detail elsewhere.62 Predictors of mortality
Surgical rings in tricuspid position usually have an open con- Procedural failure
figuration and a non-circular, non-planar shape. Consequently, as Absence of sinus rhythm
Kidney dysfunction
compared to MV-in-ring, TV-in-ring presents some specific difficul-
Predictors of mortality: invasive haemodynamic
ties: although the ring has the advantage of providing the landmarks
mPAP ≥30 mmHg
and anchoring for a percutaneous valve implantation, it also creates sPAP ≥50 mmHg
a non-circular landing zone with the inability to seal completely the TPG ≥17 mmHg
open segment with the implanted valve. Unlike the mitral position, Pulmonary vascular resistance
however, the risk of RV outflow obstruction is absent, and resid- RV stroke work
ual perivalvular leak and risk of embolization are less common as a
EROA, effective regurgitant orifice area; mPAP, mean pulmonary artery pressure;
result of the low-pressure RV system.63
sPAP, systolic pulmonary artery pressure; RV, right ventricular; TPG, transpul-
In general, an accurate pre-procedural planning is key for proce- monary gradient; TR, tricuspid regurgitation.
dural success and, consequently, a multimodality imaging approach
based on CT, 3D TEE and fluoroscopy is highly advisable.
Although further data with longer follow-up are required, cur- among experts (level of evidence C).18,19 It is worth noting that
rent evidence shows that both TV-in-valve and valve-in-ring are current guidelines are mainly based on surgical outcomes, and
safe, feasible and effective. Therapeutic advances with more con- refer to the risk/benefit assessment of high-risk procedures. Being
formable or repositionable valves and additional sealing capacity are transcatheter procedures at lower risk, a change in the current
required to reduce regurgitation after transcatheter valve-in-ring decision-making tree might be warranted. However, in general,
implantation. transcatheter procedures cannot provide the same efficacy as
surgery. The evidence in this field is growing. Available data pro-
vided some predictors of both procedural success and survival in
Too early, too late: the ‘right’ patients undergoing TEER (Table 4). Recently, it has been demon-
timing for intervention in the era strated that the absence of central/anteroseptal TR jet location,
larger coaptation gap, larger tricuspid tenting area and larger
of catheter-based interventions effective regurgitant orifice area (EROA) predict procedural failure
As for MV disease, timing of intervention is crucial also for the and, in turn, affect survival.29 Cut-off values for coaptation gap may
TV. However, the detection of the ideal window to treat TR is vary according to clip type (NTR or XTR) while the specific cut-off
even more complex than MV interventions. First, TR is often value for EROA predicting procedural failure was reported to be
asymptomatic or poorly symptomatic and patients might come 70 mm2 , which is between massive and torrential TR, according to
to attention in a later stage of the disease. Second, the lack of the new proposed scheme.32,67 This suggests that in most cases,
solid data for TR correction in the surgical field and the limited treated patients belong to the more than severe TR category, when
knowledge of TV disease lead Heart Teams to underestimate the probably it is too late to improve survival significantly. Indeed,
prognostic relevance of TR and very often to procrastinate and recent data show that baseline torrential and massive TR is less
withdraw the intervention because deemed either too early or likely to improve to moderate or less TR at 1-year follow-up.39
too late. In this regard, three premises should be considered: (i) Of note, tricuspid annular plane systolic excursion (TAPSE) and
the overall survival in patients with severe TR undergoing TTVI systolic pulmonary artery pressure showed only a slight influence
seems to be higher than that of patients on medical therapy, though on procedural and clinical outcome.68,69 These findings suggest
prospective randomized data are still lacking64 ; (ii) untreated severe that TAPSE alone is not sufficient to assess RV function, and all the
concomitant TR does not predictably improve after left-sided other common parameters commonly used to assess RV function
valve surgery; and (iii) once severe RV dilatation/dysfunction has (S′ velocity by tissue Doppler imaging, RV free-wall longitudinal
established, the operative mortality is high and surgery should be strain, RV fractional area change, and 3D RV ejection fraction)
avoided.65 are extremely load-dependent and not accurate in the setting of
Currently, most patients undergoing TTVI are in the advanced severe TR.
disease stage,66 because timing and decision-making strategies In general, several parameters should be considered in the
are following current guidelines that are based on consensus decision-making process of TR patient management. Patients with

© 2021 European Society of Cardiology

10 G. Russo et al.

moderate-to-severe TR, normal RV function, no tethering and mild the TV74,75 : patient selection has a critical role for post-procedural

...............................................................................................
remodelling might be considered possible candidates for percu- outcomes and delayed interventions might reduce the probability
taneous options as these interventions may impact significantly of prognostic improvement. In this regard, whether the concept of
on the natural history of TV with low procedural risk. Similarly, proportionate and disproportionate mitral regurgitation may apply
patients in the early phases of severe TR are good candidates also to the TV is too early to say. However, the TV apparatus
for both surgical or percutaneous intervention if at low or high and the right chambers are at least as complex as the MV and
risk, respectively. Treatment options for patients with torrential the left chambers, therefore a comprehensive evaluation including
TR should be assessed case by case: although benefits have been right chamber assessment is fundamental to describe TR pathology
reported in those with successful procedure, procedural failure and to predict possible treatments benefit.76 On top of that, a
and mortality are higher than in severe TR,70 and these valves multiparametric approach involving also RHC may help to better
are usually more amenable to replacement than repair. In such identify good candidates for TR treatment.77
cases, any possible functional or symptom benefit should be care- Another point coming from the MV is the importance of insti-
fully weighed against mortality71 (Figure 2). Recently the prognostic tutional experience.78,79 Current available data suggest that oper-
value of increased cardiac output, as related with advanced conges- ators’ experience might impact procedural results also in TEER,
tive hepatopathy, a substantial decrease in peripheral vascular tone, although a precise learning curve has not been established yet.27
and a lack of response of central venous pressures to TR reduc- In this perspective, the role of comprehensive heart valve clinics,
tion, has been shown.72 Malnutrition, as an expression of systemic involving specialized and dedicated interventionist and imagers, will
congestion, has also prognostic significance and may be, at least represent the place for advanced valve treatments.
partially, reversed by effective transcutaneous treatment.73

Open issues
The lesson learnt from the mitral Despite the significant growth of the TTVI field and the early
valve promising results, some hurdles to overcome still remain. Such
The MV and TV share some similarities and differences (Figure 4). challenges involve both theoretical and technical aspects.
The broader experience and the larger data collected for the MV
are useful to understand TV opportunities, limitations and possible
The need for a Tricuspid Valve Academic
future directions.
The edge-to-edge technology is the most used for transcatheter Research Consortium
MV repair. Beside the anatomical characteristics of MV and TV with The institution of a Mitral Valve Academic Research Consor-
the consequent interventional implications, the recent MITRA-FR tium defining principles and endpoints for MV interventions rep-
and COAPT trials suggested some useful hints applicable also to resented a crucial step to standardize and interpret MV studies.

Figure 4 Similarities and differences between right chambers/tricuspid valve and left chambers/mitral valve. AV, atrioventricular, CS, coronary
sinus; Cx, circumflex coronary artery; EROA, effective regurgitant orifice area; IVC, inferior vena cava; LA, left atrium; LAA, left atrial appendage;
LVOTO, left ventricular outflow tract obstruction; MV, mitral valve; PM, papillary muscle; PV, pulmonary valve; RA, right atrium; RAA, right
atrial appendage; RCA, right coronary artery; RVOTO, right ventricular outflow tract obstruction; SVC, superior vena cava; TV, tricuspid valve.

© 2021 European Society of Cardiology

Tricuspid regurgitation and transcatheter therapies 11

Although some efforts have already been done to create a uni- Replacement challenges

........................................................................................................................................................................
form intraprocedural nomenclature and imaging assessment,80 the Transcatheter TV implantation shares some challenges with tran-
process towards a similar standardization for TV is just starting. scatheter TV repair and some others with typical transcatheter
Indeed, the analysis of the first studies reporting early experi- MV interventions. First, the indication for repair or replacement
ence with the different devices raises the issue of how to report has not been defined yet. Moreover, the best candidate charac-
TTVI outcomes. To date, procedural success has been defined as teristics for replacement should take into account not only who
a successful implantation of the clip and a post-procedural TR of will benefit the most but also who will tolerate abrupt TR res-
grade 2+ or less. However, given the possible discordance between olution. Afterload mismatch is a common issue for MV and has
echocardiographic and clinical improvement, it is evident that the recently been described in a computational model also for TV.87
definitions for procedural success for the aortic and mitral valves Second, access site represents an issue due to the thin RV wall
cannot be applied also to the TV. Moreover, a reduction from for transapical access and to the 45∘ angle from the IVC for the
torrential to severe TR may still be beneficial for the patient by transfemoral access. Indeed, in the early compassionate use with
reducing anasarca and gut and kidney congestion and improving the GATE device, only the transatrial (83%) and transjugular (17%)
the efficacy of medical therapy in patients with right heart failure. accesses were used.49 This should be considered in addition to the
These observations suggest the need for developing standard def- fact that the larger TV annular size requires larger devices and,
initions to evaluate and report outcomes in the field of TR and TV consequently, larger delivery system sizes. Consequently, whether
interventions. there will be space for transfemoral access is still to be defined.
Third, the right chamber low pressure and slow flow suggest the
need for anticoagulation, although the best drug regimen and dura-
Anatomical challenges
tion remain to be established for transcatheter MVinterventions.88
Important anatomical similarities and differences with MV are This point is closely linked to long-term durability, which should be
detailed in Figure 4. The most relevant anatomical structures sur- investigated in future studies. In general, transcatheter TV replace-
rounding the TV include the conduction system, the aortic valve, ment is going to expand the TTVI toolbox playing a complementary
the coronary sinus and the right coronary artery. These structures role with TV repair devices.89
should be considered for both pre-procedural planning (especially
for annuloplasty devices) and for possible intraprocedural compli-
cations. The variability of leaflet distribution can be a challenge for
TEER. Moreover, the tricuspid annulus is the largest among the
Conclusions
heart valves, and this should be considered when developing a spe- Functional TR is a common condition and is associated with poor
cific device for the TV. In addition, TV leaflets and chordae are more clinical outcome. Surgical limitations together with the develop-
fragile than those of the MV and the annulus is not a well-defined ment of transcatheter therapies have moved the attention to per-
structure.81 The thin right ventricle and the angulation from venous cutaneous approaches for TR correction. Currently, four devices
access might further complicate transcatheter interventions. In this are CE marked (Cardioband, Pascal, TriClip, TricValve) and many
regard, left femoral vein has been proposed as a first-choice access others have demonstrated to be feasible. However, multiple open
site for both mitral and tricuspid transcatheter interventions to issues remain from patient selection to the best timing of inter-
better manoeuvre delivery and to gain height from the annular vention and the definition of successful repair. Current evidence
planes.82–84 from TTVI experience is pushing forward the TV field but larger
Finally, the possible presence of a prominent Eustachian valve or randomized studies are needed to define the clinical and procedu-
a Chiari network can also interfere with positioning of the delivery ral endpoints and outcomes of TTVI in order to draw more solid
system. Altogether these challenges suggest that TV interventions conclusions. In future perspective, the percutaneous era of the TV
are much more than a MV intervention on the right side, requiring has just begun and, pulled by the aortic and mitral field, is going to
dedicated devices and experienced operators. rapidly grow and to side surgery for the treatment of TR. In this
exciting time, a question remains unanswered: “do we know the
right time to apply our solutions”?
Imaging challenges Conflict of interest: G.R. received fellowship training grant from
Transoesophageal echocardiography is the mainstay for intrapro- EAPCI, sponsored by Edwards Lifesciences. M.T. reports consul-
cedural guidance of TTVI. In some cases, TEE window can be tancy fees from Abbott Vascular, Edwards Lifesciences, 4Tech,
inadequate due to the distance between the TV and the probe, Boston Scientific, CoreMedic, Mitraltech, and SwissVortex, outside
the variable TV anatomy, possible RA/RV dilatation and finally the the submitted work. M. Gavazzoni is a consultant for Biotronik.
presence of other prosthetic devices (valves, rings, pacing leads). D.M. has received research support and speaker fees from and con-
Consequently, adequate TEE imaging represents one of the first sults for GE Healthcare; and has received research support from
steps in the patient selection process and might affect procedural TomTec Imaging Systems L.P.B. has received research support from
success. However, multiple alternative TEE views can be used by an GE Healthcare, Siemens, and TomTec Imaging Systems; and is a
expert team of operators and imagers.85 In this regard, next gener- member of the GE Healthcare Speakers Bureau. F.M. is a consul-
ation multiplanar intracardiac imaging might represent an additional tant for Abbott Vascular, Medtronic, Edwards Lifesciences, Peri-
tool for intraprocedural imaging guidance.86 fect, Xeltis, Transseptal Solutions, Magenta and Cardiovalve; has

© 2021 European Society of Cardiology

12 G. Russo et al.

received grant support from Abbott Vascular, Medtronic, Edwards 19. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al.;

........................................................................................................................................................................
ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and
Lifesciences, Biotronik, and Boston Scientific, NVT, Terumo; has
treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–726.
received royalties from Edwards Lifesciences and 4Tech, and is 20. Connolly HM, Schaff HV, Abel MD, Rubin J, Askew JW, Li Z, et al. Early and
co-founder/shareholder of Transseptal Solutions, 4Tech, Cardio- late outcomes of surgical treatment in carcinoid heart disease. J Am Coll Cardiol.
2015;66:2189–96.
valve, Magenta, Perifect; Coregard and SwissVortex. All other
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authors have nothing to disclose. invasive isolated tricuspid valve surgery. J Heart Valve Dis. 2010;19:189–92.
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