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 [44]. 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) [45]. 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 [48], 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 mm/m${}^2$) or more in diameter, leaflet tethering, transvalvular leads, RV dysfunction, pulmonary hypertension and atrial fibrillation [49], and finally jeopardize late survival and functional outcomes [50, 51]. It is important to underline that patients with severe TR after mitral valve surgery undergoing isolated TV surgery usually have high perioperative mortality (10%) and poor late survival [52, 53, 54, 55], so that TV repair at index procedure may limit disease progression and eventually provide long-term clinical benefit [11].

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 [11].

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 $>$2 was more common in patients with moderate/severe TR, suggesting that significant TR limits mid-term benefits of TEER in patients affected by secondary MR. Of note, moderate/severe TR independently predicted death and re-hospitalization for heart failure at 1 year [12]. In a recent analysis [13], patients with at least moderate TR presented worse clinical and echocardiographic characteristics than those with no or mild TR, and had higher rate of the composite of death or hospitalization for heart failure at 2 years when treated with medical therapy alone, while this was not the case following TEER with MitraClip.

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].

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 [17]. 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 [63]. 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 [18]. 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${}^2$ increase in effective regurgitant orifice area (EROA) and per 1 mL increase in regurgitant volume, respectively. Severe functional TR (defined as EROA $>$40 mm${}^2$) yields an increased risk of mortality and cardiac events of 80% and 120%, respectively [32].

Even more striking, thresholds for moderate TR as per current guidelines, that is $\ge$20 mm${}^2$ of EROA, $>$5 mm of vena contracta and $>$20 mL of regurgitant volume, are actually associated with increased mortality [63]. Moderate to severe functional TR increased the risk of heart failure and overall mortality also in patients with at least mild secondary MR. In particular, patients with no, mild, moderate and severe functional TR had a survival free of all-cause mortality at 6 years of 69%, 67%, 51% and 40%, respectively [16].

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].

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 [23].

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 40% [21].

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 [20].

Atrial TR is defined as such when holosystolic and functional, with no likely pulmonary hypertension, no overt cause and no previous valve surgery [27]. 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 [2]. Nonetheless, the reported 10-year survival rate of patients with an effective regurgitant orifice $\ge$40 mm${}^2$ is 38%, and severe TR predicts higher mortality when graded both qualitatively and quantitatively, regardless of RV size or function, pulmonary pressures or relevant comorbidities [27, 36]. The surgical benefit in patients with significant atrial TR was also investigated, and a trend towards benefit in survival rate was observed when comparing patients undergoing TV surgery and patients managed medically [67].

Despite the evidence that quantitative grading of TR is a strong independent predictor of clinical outcomes, even superior to qualitative assessment [22], only one single study reported results according to such grading in a recent meta-analysis of 70 studies [27]. Given the possible underestimation of severity of disease with biplanar measurement of vena contracta [71], focus moved upon the utility of proximal isovelocity hemispheric surface area (PISA) for risk stratification [22]. 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 $>$20 mm${}^2$ and regurgitant volume $>$20 mL [18]. An additional issue is the extended grading scheme of TR [74] that was recently proposed, which addresses the unmet need of classifying patients currently undergoing percutaneous treatment in clinical trials, who often suffer from a degree of TR greater than merely severe, be it for the long symptoms tolerance or for the missed acknowledgment of the disease. In this context, many studies investigated the role of using additional cutoffs for vena contracta width and EROA, and consistently showed worse prognosis in patients classified as having either massive or torrential TR [72, 73, 74, 75].

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 $\le$0.5%/mmHg, predicted all-cause mortality in patients with severe secondary MR enrolled in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial [81]. Right ventricular systolic pressure is also often measured non-invasively by estimation via TR velocity, but some limitations need to be ascertained, especially when encountering patients with higher degrees of severity of TR. Indeed, discordance of pulmonary hypertension estimation via invasive and non-invasive measurement was a marker of more advanced valvular and ventricular disease, and should be taken into account when predicting procedural success and long-term outcomes [82]. It is thus important to keep in mind that invasive measurements yielding often underestimated hemodynamic information, including the type and eventual reversibility of pulmonary hypertension, might shed light onto the optimal TR population to be treated.

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 [53], 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 [88], 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 [85]. 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 [6]. 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.