Atrial functional tricuspid regurgitation: a novel and underappreciated clinical entity

Contact address: Denisa Muraru M.D., Ph.D., FESC, FACC, FASE IRCCS, Istituto Auxologico Italiano, Department of Cardiac, Neurologic and Metabolic Sciences, San Luca Hospital Piazzale Brescia, 20, 20149, Milan, Italy e-mail: denisa.muraru@unimib.it 1 Istituto Auxologico Italiano, IRCCS, Department of Cardiac, Neurological and Metabolic Sciences, San Luca Hospital, Milan, Italy 2 Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy 3 University of Medicine and Pharmacy of Craiova, Romania 4 University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania 5 Istituto Auxologico Italiano, IRCCS, CardioREC, Corbeanca, Romania Functional or secondary tricuspid regurgitation (FTR) is a progressive disease with a signifi cant negative impact on patient morbidity and mortality. In FTR, the retrograde fl ow from the right ventricle (RV) to the right atrium (RA) during ventricular systole typically occurs in the presence of structurally normal leafl ets of the tricuspid valve (TV). The mechanisms of FTR are either the dilation of TV annulus, the tethering of TV leafl ets, or a combination of both1. For years, the general belief has been that FTR is the hallmark of the disease of the RV, rather than the disease of the TV itself. According to current ESC/ EACTS guidelines2, FTR develops as a result of the geometric changes of TV apparatus due to the dysfunction of the RV following pressure and/or volume overload. Nevertheless, there are often patients with signifi cant FTR that may present with TV annulus dilation, despite a normal RV, and a dilated RA3. Recently, atrial Abstract: Functional or secondary tricuspid regurgitation (FTR) is a progressive disease with a signifi cant negative impact on patient morbidity and mortality. Recently, atrial fi brillation (AF) has been recognized as a cause of FTR (with/without coexisting functional mitral regurgitation) by promoting right atrial (RA) remodeling and secondary tricuspid valve (TV) annulus dilation, even in the absence of right ventricular (RV) dilation or dysfunction. This distinct form of FTR has been called “atriogenic” or “atrial”. Recent evidence suggests that the RA is an important player in FTR pathophysiology not only for patients with AF, but also for those in sinus rhythm. Preliminary reports on atrial FTR show that cardioversion with documented maintenance of sinus rhythm promotes TV annulus and RA reverse remodeling and may signifi cantly reduce FTR severity at follow-up. Large-scale studies on the prognostic benefi ts of rhythm vs rate-control strategy in atrial FTR patients are needed to substantiate specifi c guidelines indications for this subset of patients.

Functional or secondary tricuspid regurgitation (FTR) is a progressive disease with a signifi cant negative impact on patient morbidity and mortality. In FTR, the retrograde fl ow from the right ventricle (RV) to the right atrium (RA) during ventricular systole typically occurs in the presence of structurally normal leafl ets of the tricuspid valve (TV). The mechanisms of FTR are either the dilation of TV annulus, the tethering of TV leafl ets, or a combination of both 1 .
For years, the general belief has been that FTR is the hallmark of the disease of the RV, rather than the disease of the TV itself. According to current ESC/ EACTS guidelines 2 , FTR develops as a result of the geometric changes of TV apparatus due to the dysfunction of the RV following pressure and/or volume overload. Nevertheless, there are often patients with signifi cant FTR that may present with TV annulus dilation, despite a normal RV, and a dilated RA 3 . Recently, atrial fi brillation (AF) has been recognized as a cause of FTR (with/without coexisting functional mitral regurgitation) by promoting RA remodeling and secondary TV annulus dilation, even in the absence of RV dilation or dysfunction (type I of the Carpentier classifi cation) 4 . This distinct form of FTR has been called "atriogenic" or "atrial", and thanks to the use of three-dimensional echocardiography (3DE), its peculiar pathophysiologic mechanisms have now been described [5][6][7][8] .
However, both the 2017 ESC/EACTS Guidelines on the management of valvular heart disease 2 and the recent 2020 ESC Guidelines on the diagnosis and management of AF 9 do not even mention this distinct form of FTR that may typically affect patients with persistent AF. Current literature addressing atrial regurgitation of the TV or mitral valve (MV) has been calling it "neglected", "an underappreciated cause", "new entity", "newly described disorder" 7,10-12 . Only recently, in the newly published 2020 ACC/AHA Guidelines for the management of patients with valvular heart disease, has the atrial mechanism of FTR been given a distinct role 13 . Yet, as there is almost no evidence available on how to manage these patients, there are more open questions than answers. Atrial FTR may require different clinical management and the various interventional treatment options may have different outcomes than in the classical ventricular FTR due to RV dilatation and dysfunction (type IIIb of the Carpentier classifi cation) 14,15 . Since AF is the most common sustained arrhythmia (affecting ~33 million people worldwide) with an increasing prevalence due to the ageing of the population 16 , clinicians and echocardiographers will likely encounter patients affected by atrial FTR. Therefore, we aimed to familiarize the reader with this "new" disease by providing an overview of the pathophysiology, and the key distinguishing features of atrial FTR that may help the clinicians and imaging specialists to differentiate it from the classical ventricular form of FTR.

ANATOMY AND PATHOPHYSIOLOGY
The TV apparatus consists of several componentsvalve leafl ets, annulus, chordae tendineae, papillary muscles, and RV and RA walls. Compared to the MV complex, TV has greater anatomical variability, a more apically insertion of the septal leafl et, and chordal attachments directly inserted to the interventricular septum 17 . The normal TV annulus is an elliptical, saddle-shaped, and dynamic structure. In comparison to the mitral annulus, the TV annulus is larger (normal TV diameter in apical four-chamber view 19 ± 2 mm/ m 2 , and 3D area 7.6 ± 1.7 cm 2 /m 2 ), and more dynamic (systolic fractional shortening of 25% and area change of 30-40%) 18,19 . The TV annulus is mostly a fatty structure, and its signifi cantly smaller fi brotic component with respect to the MV annulus could explain why the TV annulus dilates more easily along with the right heart chamber enlargement and is the main mechanism responsible for the development of atrial FTR 20,21 . TV papillary muscles send chordae to ipsilateral leafl et(s) and become more separated and apically displaced in the context of RV dysfunction, leading to TV leafl et tethering 1 .
The classical (ventricular) form of FTR may occur in various cardiac conditions (left-sided valvular, myocardial, or pulmonary diseases) and includes three main mechanisms: 1) TV annulus dilatation due to RV remodeling; 2) changes in the geometry and dynamics of the annulus, becoming rounder, fl atter and less contractile; 3) leafl et tethering as a consequence of the spatial displacement of the components of the TV apparatus resulting in loss of coaptation and secondary FTR 5,22 . Among these mechanisms, TV leafl et tethering is the primary pathophysiological mechanism of ventricular FTR. It occurs with changes in RV geometry and function due to volume and/or pressure overload, such as an increase in RV volume, RV global or regional systolic dysfunction or shape abnormalities (increased sphericity, abnormal regional curvature, etc.) 3,23 . Annular dilatation is an important contributor to the development of ventricular FTR, leading to edge-to-edge leafl et coaptation 20 .
The importance of the RA has been ignored, despite the close anatomic relationship of the RA vestibule with the TV annulus. The RA vestibule is a smooth muscular rim that anchors the pectinate muscles and surrounds the TV orifi ce, with its thin musculature fibers inserting into the leafl et hinges 3 . In contrast with the MV annulus, which is disconnected from the left atrial myocardium between both fi brous trigones at the base of the anterior leafl et, the TV annulus has a single right fi brous trigone keeping it in closer contact with RA myocardium over a larger part of its circumference. The muscular fi bers of the RA vestibule are responsible for the "sphincteric-like" contraction of TA 24 , and might explain the TV annular dysfunction in AF patients with RA remodeling and atrial FTR.
The proposed model of atriogenic regurgitationtypically with long-standing persistent AF -implies a signifi cantly remodeled RA that promotes a mar-Denisa Muraru et al.

Atrial functional tricuspid regurgitation
ked and progressive dilatation of TV annulus in the presence of no or minimal dilation of the RV 4,25 . TV annulus is considerably enlarged in AF patients, even with less than severe FTR, and independently of the presence of cardiac structural abnormalities, supporting that TA dilation is the direct consequence of AF itself, rather than the result of FTR 26 . Compared with ventricular FTR patients and for similar FTR severity, patients with atrial FTR had increased dimensions and posterior displacement of the TV annulus, larger RA, and smaller RV 6 . Moreover, in patients with so-called "idiopathic FTR" (most of them being actually atrial FTR due to AF), Topilsky 27 observed that the RV assumes a triangular shape with dilation occurring at the basal level, resulting in a large TV annular area without leafl et tethering (Figure 1). In contrast, in patients with pulmonary hypertension and ventricular FTR, the RV becomes elliptical due to dilation occurring at the mid-ventricular level, resulting in signifi cant valvular tethering with no or mild TV annular dilatation ( Figure 2). Thus, the tethering of TV leafl ets is commonly seen in patients with a ventricular form of FTR (with/without signifi cant annular dilation) due to pressure/volume RV overload, while in atrial FTR due to AF the tethering is characteristically absent because the RV is normal. Once the pathophysiological cascade is initiated (either by ventricular or atrial factors), a vicious cycle ensues, with progressive FTR and further dilatation of the TA due to either RA or RV volume overload, resulting in further FTR and ultimately a combination of both atrial and ventricular FTR 4,28,29 . Therefore, in advanced stages with massive or torrential FTR, marked remodeling of TV apparatus, and secondary RA and RV dysfunction due to longstanding volume overload, it may be more challenging to distinguish the primary cause of FTR 6,16 . However, the prognosis of massive/torrential FTR is severe 30,31 and there is likely little clinical benefi t in clarifying the pathophysiological sequence at this advanced stage of the disease. Figure  3 presents the main imaging features that may help in differentiating the atrial FTR from the ventricular FTR.
Recent evidence suggests that the RA is important not only in AF patients but also in sinus rhythm. Indeed, RA could be a major player in the development of FTR and a key determinant of TV annular dilation 32 , irrespective of its cause 3 . We demonstrated that in all FTR groups (including atrial form due to AF and ventricular form due to both RV pressure and volume overload), as well as in healthy subjects, the TA area was more closely related to RA volume than to RV end-diastolic volume measured by 3DE 3 .

ECHOCARDIOGRAPHIC ASSESSMENT
Transthoracic 2D-Doppler echocardiography is the primary imaging modality in the evaluation of FTR patients. By assessing TV morphology and annulus size, right-heart chambers' size and hemodynamics, echocardiography generally provides the data needed to be integrated for evaluating the mechanisms and the severity of TR and to orient the subsequent clinical management 22 . If unclear or confl icting results from transthoracic echocardiography, transesophageal echocardiography, cardiac magnetic resonance and cardiac computed tomography can be used for a comprehensive imaging assessment of the patient with FTR 33 .

TWO-DIMENSIONAL AND DOPPLER ECHOCARDIOGRAPHY
The state-of-the-art echocardiographic evaluation of TR should follow several steps: 1) attesting the presence of pathological FTR; 2) evaluating the morphological characteristics of the TV; 3) assessing the key features of FTR (annulus dilation, leafl et coaptation, etc.); 4) discriminating between a ventricular and an atrial form of FTR; 5) quantifying the severity of FTR  35,36 . A small and brief color fl ow jet is considered to be specifi c for mild regurgitation. However, grading of FTR severity based on this sole parameter is not recommended 17,34,36 . The semi-quantitative parameters comprise regurgitant jet's color fl ow area, PISA radius, vena contracta width, hepatic vein fl ow, and tricuspid infl ow patterns 35 . Quantitative parameters are PISA-derived EROA and regurgitant volume. Although the majority of Doppler methods used in grading left-sided valvular heart disease are applicable and its hemodynamic impact on right-heart chambers 15 .
In clinical routine practice, TR assessment is performed by 2D and Doppler echocardiography as recommended by guidelines 17,34 . When quantifying TR severity, different parameters (qualitative, semi-quantitative, or quantitative) should be evaluated ( Figure  4). Structural parameters include TV morphology, IVC diameter, and RV and RA size 35 . In some cases, 2D speckle-tracking echocardiography can detect the initial RV subclinical dysfunction. In advanced stages, RV dilatation is present, mainly due to chronic volume overload 22 . Qualitative parameters consist of in- ating atrial FTR from ventricular FTR [38][39][40] . 3DE allows the simultaneous visualization of all three valve leafl ets to reliably exclude any structural abnormalities and the quantitative automated analysis of all components of the TV apparatus accounting for their complex three-dimensional shape.
An important benefi t of 3DE is increased accuracy in sizing the TV annulus.
Currently, the indication for TV annulus repair in the context of left-sided valvular disease surgery is based on a cut-off value of >40mm or >21mm/ m 2 measured from the apical four-chamber view by 2DE, assuming that the annulus is symmetrical, fl at, and circular 22 . Due to the complex, three-dimensional confi guration, with variable spatial orientation, of the tricuspid annulus, 3DE should be the fi rst-line modality in imaging the patient with FTR. Another key parameter to evaluate is the tethering of TV leafl ets. The coaptation of TV normally occurs at the leafl ets' body, at the annulus level, or just below it. With tethering of the valves, the coaptation takes place on the leafl ets' free edges with consequent FTR (Figure 5). The measurements of the tethering distance and tenting area by 2DE assume a symmetrical tethering pattern and that the longest distance to the coaptation point of the three leafl ets occurs exactly in the 4-chamber view plane (i.e. displaying two out of three leafl ets), which is unlikely in patients with FTR. Tenting volume measured by 3DE is a more precise parameter in grading FTR severity, as it does not depend on any plane posi-when evaluating FTR, it is important to remember that, in most cases, TR jet has lower pressure and velocity (strictly correlated to jet momentum) compared to MR. This has a direct impact on volumetric and jet analysis 35 . In addition, the current criteria for FTR severity grading are seldom used in clinical practice due to paucity of validation studies and lack of prognostic data. Recently, newly validated prognostic cut-offs for grading FTR have been proposed by our group 37 . By using patients' outcome data as reference, we found that the threshold values to defi ne severe TR were >6 mm, >0.30 cm 2 , >30 mL, and >45% for vena contracta average, EROA, regurgitant volume and regurgitant fraction, respectively. Notably, these cut-off values are signifi cantly smaller than those recommended by current guidelines.
Even though FTR severity grading remains a challenging task, there have been formulated several specifi c severity indices (severe valve lesions such as fl ail leafl et, large, holosystolic fl ow convergence zone, and systolic fl ow reversal in the hepatic veins) 35,36 .

THREE-DIMENSIONAL ECHOCARDIOGRAPHY
When quantifying the right-chambers' sizes by 2D echocardiography (2DE), signifi cant underestimation may occur due to foreshortening or geometrical assumptions. The 3D-derived methods allow a more accurate and reliable measure of both the RV and the RA, which is one of the key prerequisites in differenti- reports show that cardioversion in atrial FTR with documented maintenance of sinus rhythm promotes TV annulus and RA reverse remodeling and may signifi cantly reduce the severity of FTR at follow-up 26,44,45 .
However, current recommendations are largely based on expert opinion and large-scale studies on the prognostic benefi ts of rhythm vs rate-control strategy in atrial FTR patients are needed to substantiate specifi c guideline indications for this subset of patients.

CONCLUSIONS
Functional tricuspid regurgitation is a common fi nding in several cardiac conditions, either isolated or in association with left-heart valvular diseases. Emerging evidence suggests a novel pathophysiological model of atrial functional tricuspid regurgitation in patients with long-standing AF. Three-dimensional echocardiography has revolutionized the noninvasive imaging of the tricuspid valve apparatus, conferring new insights and better understanding of the pathophysiology of functional tricuspid regurgitation. Awareness about the atrial tricuspid functional regurgitation is key to identify tion and accounts for the tethering of all three leafl ets, as well as for the enlargement of the annulus area.
Finally, novel quantitative parameters by the 3D color Doppler method have been proposed in the evaluation of FTR severity. 3D vena contracta area, EROA by 3D PISA, and regurgitant volume can be obtained, but their routine use is not recommended due to their limited clinical and prognostic validation 22,41 .

CLINICAL IMPLICATIONS AND UNMET NEEDS
The key message for cardiologists and echocardiographers is that atrial TR should nowadays be recognized as one of the potential complications of AF and one of the contributing factors for heart failure symptoms. Up to 25% of patients with non-valvular AF develop signifi cant atrial FTR, with 33% of lone AF cases occurring in young patients 42,43 . The awareness regarding atrial FTR and the known adverse prognostic implications of isolated severe FTR may intuitively justify a more aggressive rhythm control in patients with persistent AF that present an associated FTR. Preliminary