Academic Editor: Alexander Lauten
Tricuspid regurgitation (TR) has a considerable prevalence in the overall population, that further increases in selected categories of patients. Three morphologic types of TR prevail, namely primary, secondary and atrial TR, mostly, but not always, occurring in different subsets of patients. Recent evidences demonstrate a negative impact of TR on outcomes, irrespective of etiology and even when less than severe in grading. Unfortunately, current surgical standards are void of strong prospective evidence of positive impact on clinical outcomes. While on one hand recent advances in diagnosis and risk stratification of patients with TR are shedding light onto the population that may benefit from intervention and its appropriate timing, on the other hand the arrival on stage of percutaneous treatment options is widening even more the therapeutic options for such population. In this review we will address and discuss the available evidence on the prognostic impact of TR in different clinical contexts encountered in practice.
Progressive accrual of insights into the prevalence, pathophysiology, natural history and clinical relevance of tricuspid regurgitation (TR) has been witnessed in recent years [1, 2, 3, 4], and treatment of TR gradually shifted from a conservative to a more interventional therapeutic and preventive approach. Advances in echocardiographic techniques have been accomplices for such radical changes in management. Three different types of TR can be distinguished, that is primary, secondary and atrial TR (Fig. 1). While primary TR is due to an abnormality of the tricuspid valve (TV) apparatus, TR may be caused by dilation of TV annulus, right ventricular (RV) remodeling and leaflet tethering secondary to left heart disease and pulmonary hypertension (secondary TR), or caused by atrial fibrillation (AF) and right atrium (RA) remodeling (atrial TR) [4, 5, 6]. Secondary TR is the most common manifestation of TV disease, and has traditionally been considered a benign disease manageable with diuretic therapy and by addressing left heart disease. On the other hand, growing evidence has shown deleterious outcomes of untreated TR irrespective of left or right ventricular function and pulmonary hypertension in the surgical, percutaneous, and heart failure populations studied [7, 8]. In light of this evidence and the mortality risk associated with surgical intervention in candidate patients at high risk, novel transcatheter devices have been developed to address this unmet clinical need. This review will address the available evidence concerning the prognostic impact of TR in the different contexts with a particular focus on secondary TR (Table 1, Ref. [2, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23]).
Classification of types of tricuspid regurgitation and related mechanisms. The three main types of TR are associated with different mechanisms of disease, which may overlap. CIED, cardiovascular implantable electronic device; LV, left ventricle; RA, right atrium; RV, right ventricle.
|Year, author||N||Population||Follow-up (years)||Main results|
|Mitral valve disease||2003, Henein et al. ||42||MVR for rheumatic disease||5||50% vs. 100% survival in patients with severe vs. mild TR|
|2004, Ruel et al. ||708||MVR||5||Increased risk of mortality with persistent TR (HR 2.17)|
|2009, Di Mauro et al. ||165||Mitral valve surgery for secondary MR||5||Increased risk of mortality with moderate or more vs. mild or less TR (HR 3.1)|
|2014, Ohno et al. ||146||TEER for secondary MR||1||Moderate/severe TR predicted death and re-hospitalization for heart failure (HR 2.67)|
|2020, Hahn et al. ||599||Medical therapy alone or medical therapy and TEER for secondary MR||2||Increased risk of death and hospitalization for heart failure if moderate or more TR treated with medical therapy alone (HR 1.74)|
|2020, Essayagh et al. ||5083||Primary MR||10||Increased adjusted risk of mortality with moderate (HR 1.40) and severe TR (HR 2.10)|
|LV dysfunction||2002, Koelling et al. ||1,421||Left ventricular ejection fraction 35% or less||1||Increased adjusted risk of poor outcome with severe TR (HR 1.55)|
|2012, Agricola et al. ||373||Heart failure, left ventricular ejection fraction
||3||Moderate to severe functional TR independently predicted heart failure (HR 1.4) and mortality (HR 1.6)|
|2013, Neuhold et al. ||576||Congestive systolic heart failure||6||Increased risk of death/heart transplantation/left ventricular-assist device implantation in patients with TR (HR 2.07)|
|2019, Benfari et al. ||11,507||Heart failure stage B–C, left ventricular ejection fraction
||4||Increased adjusted risk of mortality with mild (HR 1.09), moderate (HR 1.21) and severe TR (HR 1.57) vs. trivial TR|
|2019, Bartko et al. ||382||Heart failure and reduced ejection fraction||5||0.9% and 1.3% increased risk of mortality per 1 mm|
|Aortic valve disease||2021, Tomii et al. ||2,008||TAVI||1||Excess risk of mortality with severe (90%) and massive TR (117%) after TAVI|
|Other settings||2004, Messika-Zeitoun et al. ||60||TR due to flail leaflets||10||Excess risk of mortality (39%) with severe TR when compared to matched United States population|
|2014, Hoke et al. ||239||CIED-related TR||5||Increased risk of mortality and heart failure-related events with significant TR (HR 1.69)|
|2014, Topilsky et al. ||353||Atrial TR||6||Increased risk of mortality with qualitatively and quantitatively measured severe TR (HR 1.78 and 2.67, respectively)|
|2019, Topilsky et al. ||417||Moderate or more TR of various etiologies (8.1% atrial TR)||Up to 15||Increased risk of mortality with atrial TR (HR 1.68)|
|2020, Chorin et al. ||33,305||TR of various etiologies||3||Increased risk of mortality with moderate (1.15) and severe TR (1.43) vs. no or minimal TR|
|EROA, effective regurgitant orifice area; HR, hazard ratio; MR, mitral regurgitation; MVR, mitral valve replacement TEER, transcatheter edge-to-edge repair; TR, tricuspid regurgitation.|
TR is a common echocardiographic finding, reported in up to 70 to 90% of adults  and clinically relevant TR is found in approximately 4% of subjects aged 75 years . Historically, the management of TR by the medical community has been to treat it medically, driven by the belief that it would resolve upon resolution of the underlying cause [7, 24, 25, 26]. Nonetheless, recent evidence from several studies suggests not only that significant TR impacts negatively patient prognosis (Fig. 2) [7, 15, 22], but also that it does so more and more for every increase in grade of severity [23, 27]. This might be well explained by the fact that chronic RV volume overload due to self-perpetuating significant TR may result in progressive RV dilation and remodeling, which in turn might then lead to progressive irreversible RV myocardial damage and symptomatic right heart failure . In advanced stages, low cardiac output might not only be due to the relevant amount of regurgitant flow at expense of forward flow, but also due to the inability to proportionally increase cardiac output to metabolic needs related to increased left heart pressures caused by diastolic ventricular interaction and pericardial restraint [29, 30]. In the end, such natural history suggests a non-marginal role of TR in disease, especially upon the onset of the vicious cycle encompassing RV myocardial damage and remodeling.
The role of tricuspid regurgitation in disease. Incremental impact on survival is witnessed with worsening of the grade of TR. Mechanisms of disease and therapeutic considerations according to severity of TR are also depicted. RHF, right heart failure; RV, right ventricle; TR, tricuspid regurgitation.
Of note, whether TR predicts mortality independently from left-sided valve disease, pulmonary hypertension, RV dysfunction and other comorbidities has only recently been investigated in a more punctual and thorough manner [7, 15, 31]. Not surprisingly, the severity of disease does play a central role:
- Severe TR is associated with increased risk of mortality when compared with patients with no TR in retrospective registries, with reported overall mortality rates at 1-year of up to almost 50% vs. 8%, respectively [7, 23]. Of note, the association of severe TR with increased overall mortality persists when adjusting also for RV function, with more than 40% increase in events as compared with patients with no TR .
- Moderate TR also yields a 15% increase in mortality when compared with no or minimal TR . Patients with moderate or severe primary or secondary TR from a comprehensive, although heterogeneous, large-scale meta-analysis including more than 30,000 patients  had double the risk of overall mortality when compared with no or minimal TR. Such results might allow inference on the generalizability of the dreadful prognostic impact of TR in different settings, irrespective of the underlying etiology [2, 7, 22, 32, 33, 34].
- Mild TR has been linked to increased mortality as well . This might be related to the progressive nature of TR, and the fact that TR progression is paralleled by worse outcomes [35, 36, 37]. Also, the rapidity of significant TR development impacts all-cause mortality [33, 36]. Presence of pacemaker or defibrillator leads, surgical left-sided valvular treatment, elevated pulmonary pressures, increase of RV sphericity, tricuspid annular dilatation and increased TV tenting area predict fast development of significant TR , and could reveal useful for early identification of patients at risk and intervention before onset of irreversible right ventricular dysfunction.
TR is frequently present in patients with primary and secondary mitral valve disease, and may occur also late after mitral valve intervention [15, 38, 39, 40, 41, 42]. For this reason, aggressive correction with tricuspid annuloplasty at the time of mitral valve surgery is actually encouraged.
More than 30% of patients with mitral stenosis have at least moderate TR [43, 44], which is associated with higher New York Heart Association (NYHA) functional class than mild or no TR at long term follow-up . Also, patients with pre-procedural severe TR among those undergoing balloon mitral valvotomy not only present more advanced mitral valve disease, higher pulmonary vascular resistance and smaller increase in mitral valve area after valvotomy, but also they have poorer outcome in terms of overall survival, heart failure episodes and need for repeat intervention or mitral valve replacement (MVR) . The incidence of moderate or severe late TR in rheumatic patients is up to 37% and 68%, respectively. In these cases, TR is often diagnosed years after MVR, ten on average [46, 47]. The pathophysiological basis for such condition is poorly defined , nonetheless significant TR is associated with higher NYHA functional class III or IV, heart failure episodes and all-cause death at 5 years [9, 10].
TR is common among patients undergoing mitral valve surgery for primary mitral
regurgitation (MR) [2, 14]. When severe, TR is often addressed during the index
procedure, but the operative management of mild or moderate TR is widely debated.
If not corrected at the time of left-sided cardiac surgery, TR may progress in a
quarter of patients, especially in presence of annular dilation of 40 mm (or 21
When focusing on patients with secondary MR undergoing mitral valve surgery, the impact of at least moderate functional TR on outcomes is substantial. Indeed, affected patients presented one half the chance to be alive at 5 years when compared with patients with less than moderate TR .
Thus, The prognostic role of tricuspid regurgitation (TR) associated with organic left-sided valvular heart disease is well known.
More recent reports addressed the role of TR in patients undergoing
transcatheter edge-to-edge repair (TEER) treatment of secondary MR. Although TEER
leads to improvement in MR, TR and NYHA functional class irrespective of baseline
TR, NYHA functional class
Finally, although TR after mitral valve surgery has mostly been reported in patients with primary mitral valve disease, it may present also in patients after surgical repair of MR due to dilated ischemic or non-ischemic cardiomyopathy [56, 57, 58].
Secondary TR is often found in conjunction with aortic stenosis, especially when low-flow, low-gradient, and it is associated with increased risk of mortality . The reported incidence of TR in patients candidate to surgical aortic valve replacement or transcatheter aortic valve implantation (TAVI) is of 11% . TR does not improve up to 4 years after intervention in almost half of patients undergoing aortic valve replacement , and post-operative progression is observed in a quarter of patients . In a recent analysis conducted on patients undergoing TAVI, more than 50% of patients experienced TR reduction after the procedure, whereas in little less than 10% of cases TR worsened . Such evidence may lead to speculate that, in order to avoid late TR, a concomitant TV procedure might be considered in selected patients.
The impact of TR in patients undergoing TAVI has also been recently addressed: severe and massive TR post-TAVI is associated with a 2-fold increased risk of 1-year all-cause death, while this is not the case for baseline TR severity .
Notwithstanding the pathophysiological mechanisms described above by which TR can negatively affect patient outcomes, its independent association to poor prognosis in the subset of patients with left ventricle (LV) systolic dysfunction has been subject of debate as well. In this population, functional TR has been consistently associated with more dyspnea, older age, renal dysfunction, lower cardiac output, lower LV ejection fraction, MR, atrial fibrillation, and pulmonary hypertension . Nonetheless, evidence of TR as a prognostic interventional target rather than mere indicator of worse prognosis in patients with heart failure has been accruing .
Early reports revealed a strong impact of TR on clinical outcome , and this is true also when focusing on patients with severe heart failure secondary to idiopathic-dilated cardiomyopathy or to ischemic cardiomyopathy . When compared to trivial TR, different degrees of TR jeopardize outcomes to different levels in patients with secondary TR and heart failure with reduced LV ejection fraction. In particular, 9%, 21% and 57% increase in mortality is described at long-term follow-up for patients with mild, moderate and severe TR, independently of LV systolic dysfunction and pulmonary hypertension .
Of note, the prognostic role of TR might depend upon the degree of heart failure. Indeed, when stratifying patients according to mildly or moderately vs. severely impaired LV function, TR is significantly associated to the risk of death/heart transplantation/LV assist device implantation in the former group, not in the latter . Also, when stratifying patients according to N-terminal-pro-B-type natriuretic peptide concentrations, TR is related with outcome in patients with concentrations below the median, not those with values above it . The impact of TR in advanced heart failure might thus be limited, and might be considered merely a marker of advanced disease, and, as such, not an attractive therapeutic target. On the other hand, treatment of severe TR might have a favorable impact on outcome in patients with less severe HF.
Earlier studies addressing significance of TR in chronic heart failure used
qualitative measures of TR grading, but assessment of secondary TR severity by
quantitative measures might be useful to unravel its natural history .
Quantitative metrics of TR severity were indeed found to be consistently
associated with mortality; namely, an increase in risk of mortality of 0.9% and
1.3% were observed per 1 mm
Even more striking, thresholds for moderate TR as per current guidelines, that
Overall, the evidence supports an important prognostic role for TR in patients with LV systolic dysfunction and calls for a paradigm shift in evaluation and therapeutic approach of patients with LV systolic dysfunction and secondary TR. Interventions aiming at TR treatment should be investigated also in this population, and the definition of the appropriate timing for intervention will be of paramount importance. In this setting, awareness not only of the dynamic nature of TR, but also of the risk of worsening pulmonary hypertension, right ventricular remodeling and mortality associated with non-severe TR progression is key [36, 64].
As already introduced, additional morphologic types of TR can be recognized, including primary and atrial TR , and it is important to recognize that although they often have a separate course of disease, they might coexist in the settings described above as well . As already introduced, the main cause of TR is mitral or aortic valve disease, in more than 50% of TR cases . On the other hand, a primary etiology is present in 7.4% of TR patients, with cardiovascular implantable electronic device (CIED)-related TR being the most common cause (66%), while atrial TR is present in 17% of non-primary cases [1, 65].
Patients with severe primary TR due to any congenital or organic cause, irrespective of LV function, left valvular function or pulmonary pressure, demonstrate a trend towards worse prognosis than those with no or trace TR .
The mechanism behind CIED-related TR, the most common cause of primary TR, is
usually impingement of leaflet, subvalvular apparatus or papillary muscles, but
leaflet perforation, fibrosis, thrombosis and endocarditis may occur as well. In
this subgroup of patients, worse long-term survival and increased risk of heart
failure-related events are reported when patients with significant TR are
compared to those without significant TR, especially when focusing on patients
with baseline LV ejection fraction
TV leaflet flail is often due to trauma, and leads to TR of mostly severe grade. Excess mortality is present in patients with TR due to flail leaflets, and excess tricuspid-related events accrue also in those asymptomatic at presentation. Moreover, severe dilation of right-sided chambers is an independent predictor of poor outcomes in such patients, so that early intervention before irreversible right heart chamber remodeling and dysfunction should be considered .
Atrial TR is defined as such when holosystolic and functional, with no likely
pulmonary hypertension, no overt cause and no previous valve surgery . It is
important to note that outcomes do differ when analyzing TR patients according to
etiology. Indeed, atrial TR, even though associated with excess mortality, was
observed to have less impact on yearly mortality, atrial fibrillation or heart
failure hospitalization rates when compared to secondary or even primary disease
. Nonetheless, the reported 10-year survival rate of patients with an
effective regurgitant orifice
The proposed algorithm in the latest American College of Cardiology/American Heart Association guidelines  supports TV surgery with Class I indication only at the time of left-sided valve surgery. On the other hand, only Class IIa and IIb indications exist for treatment of TR in other clinical settings, and these are based upon evaluation not only of TR severity and etiology, but also of symptoms, severity of pulmonary hypertension and RV size and function. The Class I indication to proceed to surgery for severe symptomatic isolated TR in absence of severe RV dysfunction and Class IIa indication for surgery in severe secondary TR either symptomatic or progressive RV dilation reported in the latest European Society of Cardiology guidelines might stem from the recent evidence of improved outcomes after isolated TV surgery with careful patient selection and current perioperative management .
In addition, the latest European guidelines report transcatheter treatment of symptomatic severe secondary TR in inoperable patients with a Class IIb indication (Table 2) . Thus, upon re-evaluation of correct indication and timing of TR intervention, different factors need to be taken into account.
|Class of recommendation||Level of evidence|
|AHA/ACC 2020 Guidelines|
|Surgery for severe TR at the time of left-sided valve surgery||I||B|
|Surgery for symptoms caused by severe TR not responsive to medical therapy||IIa||B|
|Surgery for asymptomatic severe TR and progressive right ventricular dilatation and dysfunction||IIb||C|
|Surgery for severe TR at the time of left-sided valve surgery||I||B|
|Surgery for progressive TR at the time of left-sided valve surgery with either a dilated annulus (
|Surgery for symptoms caused by severe TR attributable to annular dilation (in the absence of pulmonary hypertension or left-sided dysfunction) not responsive to medical therapy||IIa||B|
|Surgery for persistent symptoms caused by isolated severe TR after previous left-sided valve surgery in absence of severe pulmonary hypertension or right ventricular dysfunction||IIb||B|
|ESC/EACTS 2021 guidelines|
|Surgery for severe TR at the time of left-sided valve surgery||I||C|
|Surgery for severe symptomatic isolated TR without severe right ventricular dysfunction||I||C|
|Surgery for moderate TR at the time of left-sided valve surgery||IIa||C|
|Surgery for asymptomatic or mildly symptomatic isolated severe TR and right ventricular dilatation, if appropriate for surgery||IIa||C|
|Surgery for severe TR at the time of left-sided valve surgery||I||B|
|Surgery for mild or moderate TR with dilated annulus (
|Surgery for severe TR with or without previous left-sided valve surgery with symptoms or progressive right ventricular dilatation, in absence of severe right or left ventricular dysfunction and severe pulmonary vascular disease/hypertension||IIa||B|
|Transcatheter treatment for symptomatic severe TR in inoperable patients at a Heart Valve Centre with expertise in the treatment of tricuspid valve disease||IIb||C|
Despite the evidence that quantitative grading of TR is a strong independent
predictor of clinical outcomes, even superior to qualitative assessment ,
only one single study reported results according to such grading in a recent
meta-analysis of 70 studies . Given the possible underestimation of severity
of disease with biplanar measurement of vena contracta , focus moved upon the
utility of proximal isovelocity hemispheric surface area (PISA) for risk
stratification . Nonetheless, it is important to recognize that PISA might be
underestimating TR severity as well [71, 72, 73], which might explain the
sustained increase in mortality associated with EROA
Quantification of RV size and function [75, 76, 77], of severity of pulmonary
hypertension and of the relationship between RV and pulmonary artery [78, 79]
should be integral to the evaluation of TR. Ventriculo-arterial coupling
represents the ability of the RV to balance its contractility with the afterload
due to the pulmonary arterial vascular bed. Its reference method of assessment is
pressure-volume loop analysis, but several non-invasive surrogated combining
indices of RV function or chamber size with a metric of load have been proposed
[78, 80]. Recently, abnormal ventriculo-arterial coupling, defined as RV free
wall longitudinal strain/RV systolic pressure
The first major implication for intervention is that TR should be treated during index left-sided valve surgery, especially if the latter is of rheumatic origin. Given the wide variation in adoption of concomitant TV and mitral valve surgery [8, 49, 83, 84], evidence not only of the absence of increased risk-adjusted mortality irrespective of the grade of TR, but actually of the lower risk of cardiac-related mortality and improved echocardiographic TR outcomes after concomitant TV repair at the time of left-sided valve surgery is of particular importance [50, 51, 83].
Similarly, prevention of long-term progression of functional TR by adopting a more aggressive strategy involving concomitant TR treatment upon mitral valve surgery should be acknowledged, especially when considering optimal timing for intervention [70, 85].
The second major implication for intervention is that, notwithstanding the potential for positively affecting the natural history of TR, isolated TV surgery has long been paralleled by high risk of mortality. Unfortunately, it has been difficult to generate prospective randomized evidence to demonstrate whether isolated TV surgery for TR has a positive prognostic effect, mainly due to a vicious cycle deriving from high reported mortality (9–10%), in-hospital complications (31%), poor late survival and no significant improvement in functional capacity after TV surgery [9, 10, 47, 48], yielding reluctancy of cardiologists to refer patients to surgery unless extremely symptomatic. Indeed, given the good response of TR to diuretic therapy, referral usually occurred late in the course of the disease concomitantly with onset of RV dysfunction. Earlier referral of TV surgery before RV function compromise might yield better outcomes , and, although not thoroughly investigated yet, recent studies reported promising results [69, 86, 87].
Finally, pre-operative clinical and echocardiographic features affect outcomes more than etiology or mechanism of TR , so that scoring systems to predict mortality after TV surgery might reveal useful to properly select patients to intervene upon and guide clinical decision-making . Taking into consideration the lessons learned in the surgical context [51, 86, 87], the introduction of transcatheter tricuspid valve interventions might offer patients a less invasive and safer procedure . Appropriate patient selection and timing of intervention will be of paramount importance in order to impact positively the history of disease and avoid futility in patients at a too advanced disease stage.
There is a growing body of evidence today that significant TR is not merely a bystander in the different disease processes in which it is involved, but rather is an active player in the pathophysiology and evolution of disease, impacting negatively on outcomes. Moreover, recent advances in diagnostic evaluation and risk stratification will allow us to more appropriately identify the adequate population to treat and the proper timing of intervention. Thus, we believe that the synergistic effect of medical, surgical and, more recently, percutaneous treatment of TR has the potential to positively affect clinical outcomes in this large population of patients, and testing of this concept in properly designed trials is eagerly awaited.
CIED, cardiovascular implantable electronic device; EROA, effective regurgitant orifice area; HR, hazard ratio; LV, left ventricular; MR, mitral regurgitation; MVR, mitral valve replacement; NYHA, New York Heart Association; PISA, proximal isovelocity surface area; RA, right atrium; RV, right ventricle; TAVI, transcatheter aortic valve implantation; TEER, transcatheter edge-to-edge repair; TR, tricuspid regurgitation; TV, tricuspid valve.
PPL and AM contributed to conception of the review. PPL, AM and MC contributed to design of the article. PPL wrote the first draft of the manuscript. MC wrote sections of the manuscript. DR, MP, LM, BP, FL, GS, DP, BR, AC, AL contributed to editorial changes and manuscript revision. PPL, MC, DR, MP, LM, BP, FL, GS, DP, BR, AC, AL and AM read and approved the submitted version.
We would like to express our gratitude to all those who helped us during the writing of this manuscript.
This research received no external funding.
The authors declare no conflict of interest. Azeem Latib and Antonio Mangieri are serving as Guest editors of this journal. We declare that Azeem Latib and Antonio Mangieri had no involvement in the peer review of this article and have no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Alexander Lauten.