Tricuspid valve (TV) and right ventricle (RV) have emerged in recent years as major structures with important prognostic and therapeutic implications. Once called the forgotten ventricle and valve, the cardiology community came to the realization that in many patients, tricuspid regurgitation (TR) does not always regress after correction of mitral and aortic valve disease, or treatment of left ventricular (LV) dysfunction by medical therapy or revascularization with bypass surgery. Thousands of cardiologists including myself with 2 or more decades of experience and a practice spanning from the era of technical modernization to the current era, remember our mentors as saying “if you repair the left side abnormalities, TR will regress on its own” [1]. However, the experience accumulated in recent years and studies conducted in the field of valvular heart disease and cardiac surgery have demonstrated that this old vision does not hold true anymore. Tricuspid Regurgitation is now recognized as a valvular heart disease with poor prognosis if left untreated.

In this review, we begin with a case vignette that describes a patient with severe TR, its clinical manifestation, then will review pertinent studies relating the relevance of methods of evaluation and mechanism of TR before examining the result of medical, surgical and transcatheter therapy for TR. This review will also expand on recent trials with transcatheter therapy as an alternative to surgery for treatment of TR.

The patient is a 57-year-old woman with past medical history of mitral stenosis for which she received a bioprosthetic mitral valve replacement at the age of 28. Subsequently, she was found with degenerative bioprosthetic mitral valve and underwent a second mitral valve replacement with a mechanical valve at the age of 42. On follow-up visits, she was found with signs of right heart failure including jugular venous distention (JVD), lower extremity edema (LEE) and ascites for which transthoracic echocardiography (TTE) demonstrated severe TR. This was associated with RV dilatation and remodeling with preserved RV function. Patient was started on medical therapy including diuretics and mineralocorticoid receptor antagonists (MRA) Spironolactone. She initially had good response to diuretics with decrease in LEE and ascites. However, she presented with recurrent signs of right heart failure. Patient was referred to the valve team for management.

Valvular heart diseases (VHD) are a significant public health issue, with prevalence increasing with age and high mortality associated with the disease. Tricuspid regurgitation is a growing public health problem, as more than 4% of people $>$75 years old have a clinically relevant TR diagnosed by Doppler echocardiography [2]. Compared with other VHD, TR is more prevalent in women. The reason for the gender difference is not well known but it could be related to higher life expectancy and high prevalence of heart failure with preserved ejection fraction with or without atrial fibrillation (AF) in women [2, 3, 4]. Compared to mitral and aortic valve disease, the outcome of moderate or greater degree of TR is worse than that of mitral or aortic valve disease [5]. The 3-year survival is about 58% and the mortality increases with worsening of the degree of TR [6]. In an analysis of national echocardiography database, it has been shown that the mortality risk was associated with increasing grades of TR. Even mild TR was independently associated with intermediate prognosis when compared with no or trivial TR [6]. It is speculated that the excess mortality in mild TR is likely due to future risk for AF and comorbidities [6]. In patients with heart failure, with reduced and preserved ejection fraction, TR has an impact on survival [7]. Progression of significant TR over time in patients who have undergone left heart surgery without concomitant tricuspid valve surgery has an adverse impact on their outcome and has led to search of therapy for TR [4, 8].

As shown in Fig. 1 (Ref. [9, 10]), tricuspid valve is the largest of all human cardiac valves (surface area 6–8 cm²) and is composed of 3 unequal size leaflets with a small septal leaflet and a larger anterior and posterior leaflet. However, in about 40% of normal subjects there may be additional leaflets or doubled commissures [11]. Tricuspid valve has a saddle shape configuration with the posterior leaflet placed more inferiorly and the anterior leaflet more superiorly. For this reason, the posterior leaflet is called inferior leaflet, and the anterior leaflet is called superior leaflet by pediatric cardiologists [12]. Tricuspid valve is located anteriorly compared to other cardiac valves; a fact that needs to be considered when evaluating TR by transesophageal echocardiography (TEE).

Fig. 1.

Tricuspid valve anatomy with neighboring structures. Schematic (A,B) and autopsy (C) demonstrate the 3 leaflets of tricuspid valve and its anatomic relationship with adjacent structures. Note the vicinity of the right coronary artery and AV node to tricuspid annulus. The proximity to AV node may cause potential complication as heart block during transcatheter intervention. The anterior papillary muscle is the principal papillary muscle and send chordae to both anterior and septal leaflets. A, anterior leaflet; P, posterior (or inferior) leaflet; S, septal leaflet; RCA, right coronary artery; CS, coronary sinus; TV, tricuspid valve; IVC, inferior vena cave; AVN, atrioventricular node; AV, aortic valve; MV, mitral valve; PV, pulmonic valve; RC, right coronary cusp; LC, left coronary cusp; NC, non coronary cusp; LCx, left circumflex artery; AVNa, atrioventricular node artery. The Fig. 1A is from the reference [9], the Fig. 1B is from the reference [10], the Fig. 1C from the link: https://radiologykey.com/17-the-tricuspid-valve-apparatus/. Reprinted with permission from the corresponding author.

Like mitral valve, tricuspid valve is part of tricuspid apparatus including tricuspid valve and annulus, papillary muscles, and right ventricle. There are usually 2 to 3 papillary muscles including 1 prominent anterior papillary muscle attached to the RV free wall and 2 smaller ones called posterior and septal, attached to posterior RV wall and to the septum [13, 14]. Chordae tendinea arise from papillary muscles (and sometimes from the interventricular septum) and supply the edges of tricuspid leaflets. This anatomical configuration explains why TR can occur from RV dilatation and/or chordal elongation and displacement. An important anatomical point to consider is the proximity of atrio-ventricular node and the right coronary artery to tricuspid annulus which may be at risk of injury during transcatheter or surgical valve repair. Another important point to mention is related to the structure of tricuspid annulus which contains more collagen fibers in the area where the septal leaflet is attached to tricuspid annulus compared to anterior and posterior leaflets. This difference explains why the anteroposterior and postero-septal annuli are more susceptible to dilatation under pressure and volume loading [15].

In the absence of pulmonary hypertension or RV failure, mild TR is generally well tolerated [16]. Patients with significant ($\ge$ moderate) TR or pulmonary hypertension present with signs and symptoms of reduced cardiac output and right heart failure including dyspnea, reduced functional capacity, and exercise intolerance [17, 18]. When TR becomes severe, signs and symptoms of hepatic congestion and ascites develop progressively [16, 17, 18, 19]. Patients may present with ascites which may mimic liver disease [20, 21, 22]. It is not uncommon for these patients to be referred to gastroenterologists for evaluation of liver disease (personal observation). On physical exam, patients with severe TR have jugular venous distension (JVD) with prominent c-v wave and deep y wave that can be seen on inspection of jugular venous pulsation ( Supplementary Video 1 shows a real patient with severe TR and JVD). Hepatomegaly may develop and is recognized by a soft pulsatile liver edge usually detectable by palpation. Patient may complain of right upper quadrant pain due to hepatomegaly and tension on liver capsule. Hepato-jugular reflux is another cardinal sign of severe TR. Peripheral edema is one of the prominent and earliest clinical features of RV failure. Bilateral lower extremities edema develops due to low cardiac output and backflow of blood into the systemic venous system. In early stages Antigen carbohydrate 125 and N-terminal pro-B-type natriuretic peptide may help in the detection of systemic congestion [23]. On cardiac auscultation, the murmur of mild TR may be subtle. With significant TR, the systolic murmur may be heard at the right 4th intercostal space or subxiphoid area and it increases with inspiration (Carvallo sign). However, with massive and torrential TR the murmur may become faint due to equalization of pressures in the RV and right atrium (RA). With pulmonary hypertension a loud P2 may be heard at the 2nd left sternal border. When RV failure occurs a right-side S3 gallop may be heard at subxiphoid area [23].

Other clinical manifestations of severe TR are related to complications resulting from back flow of blood into the systemic venous system including hepatic congestion as mentioned above and renal failure (Fig. 2). Hepatic congestion may cause synthetic liver dysfunction with decreased protein synthesis [24]. Abnormalities in liver function include prolonged PT and elevated alkaline phosphatase and total Bilirubin and less often elevated transaminases leading to congestive hepatopathy [21, 23, 24]. Infiltration of intestinal wall with edema may cause protein losing enteropathy and eventually cachexia. The increase in renal central venous pressure and consequently the rise in renal pressure may cause worsening renal function and increase in diuretic requirement which exposes patients to diuretic resistance [25, 26]. We have previously demonstrated the role of moderate or severe TR as a risk factor in development of cardiorenal syndrome in patients with decompensated heart failure [26]. Severe TR may lead in later stages to decrease in cardiac output resulting in cerebral and peripheral hypoperfusion [27, 28]. Moreover, at later stages, ventricular interdependence leads to pulmonary congestion by shifting the interventricular septum toward the left ventricle adversely affecting LV diastolic filling and compliance resulting in increase in LV filling pressures and pulmonary edema [23, 27].

Fig. 2.

Clinical manifestations and consequences of severe TR. These include hepatomegaly and liver dysfunction, ascites, renal failure and cardiorenal syndrome, pulmonary congestion and edema from increased left ventricular filling pressures and reduced cardiac output due to ventricular interdependence, brain hypoperfusion, protein and nutrient malabsorption due to edema of intestinal wall resulting in cachexia.

Atrial arrhythmias, especially atrial flutter and fibrillation are common in patients with moderate or greater TR and lead to left and right atrial dilatation as well as tricuspid annular dilatation which accentuates the degree of TR [29]. Restoration of sinus rhythm by electrical cardioversion or catheter ablation of atrial fibrillation may improve functional TR and promote right heart reverse remodeling [30].

Echocardiography is the cornerstone of imaging modality for assessment of tricuspid valve and should be performed by an experienced operator (trained sonographer or physician) at a dedicated valve center. All the echocardiography modalities including 2- and 3-dimensional echocardiography, color flow Doppler, continuous wave and pulsed wave Doppler play an important role for a comprehensive multi-parametric assessment of tricuspid valve [31]. TTE allows only visualization of 2 leaflets on a single plane in patients with adequate acoustic window due to saddle shape configuration of tricuspid valve and annulus. From parasternal long axis of the right ventricle, one can usually see the anterior and posterior leaflets. From the same view, with mild transducer rotation inferiorly one can visualize the ostium of coronary sinus with the leaflet next to it being the septal leaflet. From parasternal short axis view, at the level of aortic valve, one can see either the anterior leaflet, or anterior and posterior leaflets; with mild angulation toward the left ventricular outflow tract (LVOT), one can see the septal and part of anterior leaflets [32]. From apical 4 chamber view, the septal leaflet can be clearly visualized with the opposing leaflet being either the anterior if a portion of LVOT can be seen, or the posterior leaflet if the ostium of coronary sinus can be seen simultaneously [32] (Fig. 3 and Supplementary Video 2).

Fig. 3.

Multi-parametric assessment of TR by TTE. 2-D view of tricuspid valve from parasternal RV long axis (A) with color flow Doppler of TR jet (B); 2-D view of tricuspid valve from parasternal short axis (C) with color flow Doppler (D); Continuous wave Doppler demonstrates a triangular envelope (E) and systolic flow reversal in hepatic vein by pulsed Doppler (F) all characteristic of severe TR. Ant, anterior leaflet; Sep, septal leaflet; Post, posterior leaflet; CS, coronary sinus; 2D, 2-dimensional; TTE, transthoracic echocardiography.

TEE is essential to image the tricuspid valve when transcatheter therapy is considered. Since the RV and TV are seated more inferiorly close to the diaphragm, 3 imaging planes are employed including mid esophageal, deep esophageal, and trans-gastric view with clockwise rotation of the probe. From trans-gastric view with clockwise rotation, one can visualize simultaneously the 3 leaflets by using orthogonal plane [32] (Fig. 4 and Supplementary Videos 3–6).

Fig. 4.

TEE assessment of TR. 2-D TEE from deep esophageal view (A) with color flow Doppler (B) and from trans- gastric orthogonal plane view (C) with color flow Doppler (D) demonstrate severe to massive TR. Ant, anterior leaflet; Post, posterior leaflet; Sep, septal leaflet; ERO, effective regurgitant orifice area obtained by planimetry of non-coaptation area delimited by color flow Doppler.

Three-dimensional Echocardiography (3-D echo) has been an important addition to imaging tricuspid valve and like for mitral valve, it obviates the need for mental reconstruction and identification of leaflets. However, the quality of 3-D echo images depends significantly on the quality of 2-D echo and since tricuspid valve is an anterior structure 3-D TTE images may sometimes have better quality than 3-D TEE images. In addition, 3-D echo systems have lower resolution than 2-D echo and higher far field attenuation which may cause 3-D imaging more challenging to acquire. At our institution, we acquire 2-D and 3-D TEE images from mid esophagus and deep esophagus position as well as trans-gastric position with clockwise rotation (Figs. 4,5). The trans-gastric view is very important for pre-procedural identification of leaflets morphology and measurement of non-coaptation area. We measure the vena contracta in orthogonal plane at mid esophageal view and effective regurgitant orifice area (EROA) from short axis trans-gastric view. The flow convergence radius is measured after reducing the Nyquist limit to ~28 cm/sec. Having part of adjacent anatomic structures such as coronary sinus and aortic valve in the acquisition field may improve the image orientation and identification of different leaflets (Supplementary Videos 7–11). There is a learning curve in imaging tricuspid valve and determining the degree of TR by 2-D and 3-D TEE. The American Society of Echocardiography (ASE) guidelines recommend orienting the aortic valve on the left of the frame and interatrial septum in the far field at 6 o’clock when looking at the valve from RV or RA view [33].

Fig. 5.

3-D TTE assessment of TR. image of tricuspid valve from RA side (A) and RV side with color Doppler (B) showing effective regurgitant orifice area by 3-D. See also video section. The arrow shows the non-coaptation area. 3D, 3-dimensional; RA, right atrium.

Along with TR, it is also important to evaluate RV size and function. Right ventricle is a complex structure that does not follow a geometric shape which makes RV size measurement a challenging task [34]. The guideline of the ASE recommends obtaining the RV focused apical 4-chamber view due to RV linear dimensions being dependent on probe orientation. At our institution, we evaluate RV function by at least one or a combination of parameters including tricuspid annulus plane systolic excursion (TAPSE), RV fractional area change (FAC), RV systolic velocity by tissue Doppler (RVS’), RV free wall strain (FWS) and 3-dimensional RV function [35, 36] (Table 1, Supplementary Video 12). Other imaging modalities with cardiac magnetic resonance (CMR) which is the gold standard modality for RV function and cardiac computer tomography (CCT) have additive role and provide complementary information on the severity of TR and RV function. Cardiac CT is performed in preparation for transcatheter TV edge-to-edge repair or TV replacement as shown in Fig. 6. A TR regurgitant volume of $>$45 mL and regurgitant fraction of $>$50% by CMR are associated with poor outcome [37]. CCT provides detailed anatomic assessment of the tricuspid annulus as well as surrounding relationship with vascular structures such as inferior and superior vena cava and right coronary artery [38, 39].

Fig. 6.

Cardiac CT assessment of TR. Using tricuspid valve protocol during administration of intravenous contrast in preparation for transcatheter TV replacement. Measurements include TV annulus in systole and diastole, RV height perpendicular to TV plane and RA height. TV, tricuspid valve; CT, computed tomography.

Once the diagnosis and the degree of severity of TR are established, the next step is to evaluate pulmonary artery pressures by right heart catheterization (RHC) and to differentiate pre-from post-capillary phenotypes. The degree of TR may vary significantly depending on preload and it is therefore important to optimize the volume status prior to RHC [40].

TR is classified into primary tricuspid valve disease leading to regurgitation and secondary or functional TR due to alteration in geometry of tricuspid valve apparatus [38, 39]. Primary TR accounts for 5–10% of cases and is caused by primary structural alterations of tricuspid valve apparatus that can be either acquired or congenital. Secondary TR (85–90% of cases) is the most common phenotype encountered in adult patients [23] and is subdivided into atrial and ventricular functional TR because of their different prognostic implications [41, 42] (Fig. 7). Although this classification is important when considering therapy for functional TR, in many instances valvular regurgitation may lead to progressive RV and RA dilatation and geometric changes and results in a mixed phenotype with both RV and RA dilatation. Coexistence of TR with severe mitral regurgitation in 30 to 50% of patients and with severe aortic stenosis in 25% of patients is well established [43]. In addition, coexistence of TR with mitral and aortic regurgitation may adversely affect short- and long-term outcomes [43]. A third category of TR is associated with cardiac implantable electronic devices (CIED) which has been growing in incidence due to increasing indication and use of CEID (see below).

Fig. 7.

Classification and causes of TR. TR is divided into primary valve disease causing TR and secondary or functional TR resulting from mal-coaptation of the tricuspid valve due to RA and/or RV dilatation and remodeling. CIED, cardiac implantable electronic device.

Ebstein’s anomaly which may have a genetic basis (mutation in the MYH7 gene) represents the most frequent congenital abnormality of tricuspid valve in which tricuspid leaflets are tethered to the RV myocardium causing leaflets non coaptation and TR [12, 44]. The mechanism of TR in Ebstein’s anomaly is a defect in the process of delamination of leaflets, so that leaflets remain tethered to RV myocardium to a variable degree [12]. In addition, there is anterior displacement and downward rotation of tricuspid leaflets causing a non-coaptation orifice. The degree of TR and atrialization of RV are variable among patients with Ebstein’s anomaly and determine the severity and age of clinical manifestations [45].

The incidence of tricuspid valve endocarditis correlates with that of intravenous drug abuse which is unfortunately on the rise. Vegetations can cause valvular lesions, perforation, valvular abscess and may extend to chordae causing chordal rupture, all of which may cause impairment in valvular coaptation leading to various degree of TR [46].

Tricuspid valve prolapse due to myxomatous degeneration is rare and usually associated with mitral valve prolapse. Trauma to tricuspid valve can occur after blunt chest trauma such as motor vehicle accident and trauma from kick to the chest in martial sport. Recurrent RV myocardial biopsy in patients after heart transplant can cause flail tricuspid valve leading to severe TR [47]. Rheumatic tricuspid valve disease is usually associated with rheumatic mitral valve disease and may cause either stenosis or regurgitation or both [48]. Carcinoid heart disease is a rare condition that is part of carcinoid syndrome and associated with carcinoid tumors and metastasis to the liver [49]. Carcinoid tumors secrete toxic substances such as serotonin which causes fibrosis and retraction of tricuspid leaflets and lead to characteristic fixed immobile leaflets and severe TR seen by echocardiography. TR in carcinoid valve disease is often associated with acquired pulmonic stenosis as well [50].

The entity of TR associated with CIED has been refined recently and involves impingement or perforation of the valve leaflets by an implantable intracardiac device leading to TR [51]. The degree of TR in patients with implantable intracardiac devices varies from mild to severe and sometimes more. The diagnosis can be made with the use of 3-D echo by demonstrating the intracardiac wire causing impairment in tricuspid’s leaflet opening and closing properly [52].

Secondary TR is the most common cause of TR encountered in clinical practice and is subdivided into atrial and ventricular TR [53]. However, once TR becomes significant enough to cause symptoms, every component of tricuspid apparatus may be involved in the mechanism of TR including dilatation and remodeling of the RA and RV, displacement of papillary muscles and tricuspid annulus dilatation [54] (Fig. 8). The rationale behind dividing secondary TR to atrial and ventricular mechanism is that their prognosis and therapeutic implications differ [55, 56]. Patients with ventricular TR phenotype and either severe pulmonary hypertension or left heart disease have higher mortality than patients with atrial TR [57]. Patients with ventricular secondary TR have 2.7- fold higher risk of experiencing the combined endpoint of death and hospitalization for heart failure than patients with atrial TR phenotype [57]. However, once RV function deteriorates, differences in the outcomes of patients with atrial and ventricular severe TR becomes less pronounced [58].

Fig. 8.

Classification and causes of functional tricuspid regurgitation into atrial and ventricular causes. In atrial TR, the primary mechanism is the dilatation of the RA and tricuspid annulus. Whereas, in ventricular TR, the primary cause of TR is RV dilatation and remodeling which could be a consequence of long-standing left-sided myocardial or valvular disease. In advanced stages a combination of atrial and ventricular TR is often encountered. LV, left ventricular; PAP, pulmonary arterial pressure; pulmonary HT, pulmonary hypertension.

Transthoracic echocardiography remains the first imaging modality to evaluate the degree of TR with multiparametric assessment including color flow Doppler as previously mentioned. It is important to bear in mind that pressures in the right heart are lower and therefore the evaluation of TR by color Doppler only may underestimate the severity of TR. For this reason, a multi-parametric approach including continuous wave Doppler of TR jet and pulsed Doppler of hepatic vein, inferior vena cave(IVC) size and respiratory variation has been proposed to better evaluate the severity of TR and to address the degree of TR beyond severe. Color flow Doppler remains the primary modality for evaluation of the degree of TR. Understanding principles behind color flow jet area is important since it is governed primarily by jet momentum and machine settings. Jet momentum itself depends on flow rate and blood flow velocity. In general, a jet area of $>$10 cm² in the RA and a vena contracta $>$0.7 cm suggest severe TR (Table 2, Ref. [59]).

The new grading system was developed because many patients with secondary TR were presenting in a stage of advanced heart failure having massive or torrential TR [60, 61]. It has also been shown that quantitative assessment of TR, particularly EROA, is the most powerful predictor of outcome and superior to standard qualitative assessment. Peri et al. [62] showed that the best discriminator value for severe TR was an EROA $>$0.35 cm² using Cox hazard analysis and EROA $>$0.30 cm² using receiver operating characteristic (ROC) curves for 1 year mortality similar but slightly lower than guidelines proposed EROA of 0.4 cm². This grading system showed to be useful in terms of reporting the efficacy of transcatheter reduction of the degree of TR and clinical benefits of such devices.

Tricuspid regurgitation is now recognized as a major valvular heart disease with poor prognosis if left untreated. Many patients remain asymptomatic and present with severe or greater degree of TR and many of them have already had left-sided valve surgery or coronary artery bypass grafting. It is in this context that transcatheter therapy has become a major viable alternative to re-do surgery in the management of patients with severe or greater TR. Because of diversity of commercially available devices and techniques, it is important to adopt an approach that is personalized to every patient’s anatomy and mechanism of TR for the expected success of the intervention to be maximal. Patient selection for transcatheter or surgical intervention is very important and should be considered by a multi-disciplinary team including interventionalist, cardiac surgeon, and imaging specialist with expertise in structural echocardiography. It has been shown that major determinants of success in transcatheter edge-to-edge repair (TEER) devices are complexity of leaflets structure, leaflet coaptation gap, the location of TR jet and the degree of annular dilatation and leaflets tethering [93].

The patient in our case vignette received transcatheter Evoque valve replacement with only trace residual TR (Supplementary Videos 13,14). The patient has not been admitted for recurrent heart failure exacerbation since the valve replacement and was in NYHA class II at her last follow-up 6 month after TV replacement.

It is expected that transcatheter interventions for severe TR will expand in the coming years parallel to increasing demand as many patients may be at high risk for open-heart surgery. As biotechnology industry generates more efficient devices, there will be an increasing need of high level of training in structural interventionalists and echocardiographers for these procedures to be performed in a safe and efficient manner.

FSE: review of literature, writing the manuscript, creation of Figs. 2,3,4,5,6,7,8,9, obtained copyright permission for Figs. 1,2,3,4,5,6,7,8,9,10, obtained consent for publication of images from patient, creation of tables, importing images and videos from echocardiography lab. KL: contributed to manuscript review and helped in manuscript writing and helped in review of references and selection of figures and videos. Both authors contributed to editorial changes in the manuscript. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

In this article we use videos from one patient like when one submits a case report. The identity of the patient and personal information such as name, medical record number, date of study are not visible.

This research received no external funding.

The authors declare no conflict of interest.