The tricuspid valve and the pathologies linked to it have remained in the background until recently, when the evidence on the diagnosis and treatment of tricuspid regurgitation (TR) was updated. Traditionally, mitral valve disease was considered the primary valvulopathy, rendering the tricuspid valve relatively insignificant in therapeutic decision-making, with its repair being an addition to the main surgery. Subsequently, it has become known that severe TR is an entity associated with high morbidity and mortality and that diagnostic delay has major consequences. Available treatments have traditionally been scarce and limited to diuretics and subsequent surgery. However, isolated TR surgery presented a high perioperative mortality rate, and given the limited evidence on its long-term effectiveness, the risk-benefit balance has been considered, at the very least, questionable. This was due to the fact that many interventions were carried out in advanced stages of valvulopathy, often as reoperations following previous left valve surgeries. In this context, the growing interest in TR treatment has been accompanied by the development of edge-to-edge transcatheter repair techniques as a potential alternative to tricuspid valve surgery, which has also been suggested for earlier and more frequent treatment of TR.
The comprehensive review conducted by Hahn et al. provides a complete breakdown of TR as follows:
Epidemiology: It is undeniable that the prevalence of this disease increases with age, particularly in women. Female sex is an independent predictor of severity and progression in TR assessment scales. Other predictive factors include atrial fibrillation, elevated pulmonary artery systolic pressure, and left atrial dilation. The importance of these factors is such that they have been routinely included in studies conducted in recent years; specifically, two studies indicated that after adjusting mortality results by age and sex, a 2-fold and 3.2-fold increase in risk was observed, respectively.
Valvular Anatomy: The tricuspid valve has been described as the largest heart valve of the four. Anatomically, it typically has three leaflets of different sizes. However, it is now known that the number of leaflets in the healthy general population is variable. These leaflets are supported by chordae tendineae anchored to the larger anterior papillary muscle and one or several smaller posterior papillary muscles. According to anatomical variants, each papillary muscle more frequently supplies chordae tendineae to one leaflet or another, achieving an adequate seal along the coaptation zone. As for the tricuspid annulus, it is a fibrous structure composed of collagen, with a three-dimensional shape and dynamic behavior. It is estimated, based on model results, that adaptability to closure is such that only 40% of annular dilations would lead to significant valve regurgitation compared to the mitral valve. Knowledge of the anatomical relationships of the tricuspid valve, particularly with respect to the right coronary artery and the atrioventricular node, is of special interest, as some surgical and percutaneous annular correction devices may involve these structures with the consequences that this entails.
Clinical Presentation:
The most frequently reported symptoms include dyspnea, lower limb edema, and abdominal enlargement due to ascites. These symptoms progress in more advanced stages, culminating in multi-organ failure, including renal, hepatic, and coagulation issues, as well as signs of low cardiac output. Specifically, heart failure-induced liver dysfunction (or cardiohepatic syndrome) is an independent predictor of increased mortality or hospitalization for heart failure (HF) in patients with tricuspid regurgitation after one year of transcatheter therapy.
Diagnosis:
The assessment of structural heart disease begins with a transthoracic echocardiogram. The traditional three-grade severity classification has transitioned to a multiparametric assessment, leading to an extended classification of five grades: mild [+1], moderate [+2], severe [+3], massive [+4], and torrential [+5]. Color Doppler study is not recommended for assessing TR due to its frequent association with underestimation of the condition. Given the extensive limitations of transthoracic echocardiography, transesophageal echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography have been incorporated into the diagnosis of TR. Another test of special interest in TR is invasive diagnosis through right heart catheterization, particularly for associated comorbidities such as pulmonary hypertension (PH), with a Class I recommendation.
Medical or Conservative Treatment:
Various classes of diuretics, particularly loop diuretics and mineralocorticoid receptor antagonists, constitute the pharmacological arsenal available for the treatment of TR, with a Class IIa recommendation. Initially, the response to this treatment is usually adequate, but neurohormonal activation and perpetuation of systemic response (tissue edema, increased distribution volume, distal nephron hypertrophy) often lead to frequent diuretic resistance. For this reason, medical treatment ends up being insufficient in the advanced stages of the disease. Additionally, it is essential to establish targeted treatment in cases of secondary regurgitation (left ventricular dysfunction, atrial fibrillation, or concurrent mitral regurgitation).
Invasive Treatment: The Future of the Disease:
Surgery:
Large series attribute in-hospital mortality rates of 10-20% to isolated tricuspid valve replacement for tricuspid regurgitation. As previously mentioned, the historical intervention of these patients in advanced stages of valvulopathy has significantly contributed to these results. The procedure of choice is repair, often through isolated annuloplasty, preferably over valve replacement. In cases involving leaflet tenting, tissue deficiency, or extreme annular dilation (>44 mm), additional techniques for anterior leaflet extension with a pericardial patch may be necessary. Surgical treatment for severe TR is recommended at a Class I level when a left-heart intervention is planned, and at a Class IIa level when TR is moderate or, regardless of grade, when annular dilation exceeds 40 mm or 21 mm/m². In cases of isolated surgery on the tricuspid valve in patients with symptomatic severe TR or those where medical treatment has failed, the recommendation class remains at IIa. This is feasible as long as the patient does not have additional PH, in which case each case should be assessed individually. Finally, Class IIb is limited to those who present with asymptomatic primary TR with associated right ventricular dilation and/or dysfunction. As mentioned in previous blog entries, these recommendations may not be sufficiently updated and may require future review.
Percutaneous Intervention:
In recent years, the development of transcatheter devices has been accelerated. Although options are currently extensive, edge-to-edge repair or clip devices represent the fastest-growing treatment in developed countries. Currently available tricuspid valve-specific devices on the market include the TriClip® and Pascal®. Transcatheter valves available for mitral valvulopathy are also beginning to be used. In this context, the TriValve registry has emerged as a multinational study aimed at more accurately describing the characteristics of patients undergoing these treatments. Baseline characteristics identified in the TriValve registry have been shown to be reproducible and consistent across different series. Furthermore, short- and long-term outcome predictors are influenced by the type of patient, as the sample of individuals undergoing these treatments is highly heterogeneous. Similar to valve repair surgery, isolated transcatheter annuloplasty is more useful in patients with annular dilation without significant tenting. Patients eligible for edge-to-edge therapy have more extensively studied criteria, enabling more specific selection and higher device success rates. Clips can reduce TR to moderate or less in 80-85% of patients and to mild or lower in 30-50%, with the statistical conclusions to be further analyzed later. Given the constant research in this field, it has been suggested that orthotopic transcatheter valves may become the most effective device for reducing TR severity in the near future. A milestone of the past year was the publication of the TRILUMINATE study, a pivotal study involving patients with severe TR, comparing two groups of patients: those who underwent surgical treatment and those who received medical treatment. Three study objectives were established: all-cause mortality or tricuspid valve surgery, HF hospitalization, and quality-of-life improvement in standardized questionnaires. After one year of follow-up, no significant differences were observed in the secondary endpoints between both groups; however, these differences were found in the quality-of-life measure according to the KCCQ questionnaire (12.3±1.8 points in the transcatheter therapy group versus 0.6±1.8 points in the control group). We will further analyze the dichotomy of these results in the following section.
COMMENTARY:
This article systematically reviews TR, addressing the latest therapeutic options incorporated into routine clinical practice. The first takeaway from this review is the importance of early identification of patients with TR to initiate the indicated treatment as soon as possible for each specific situation. To support appropriate clinical practice, the article includes illustrative summary figures of the different types of TR and specific treatment options that facilitate decision-making. The significance of this can be readily understood when we consider tricuspid valvulopathy as having the highest all-cause mortality rate compared to other valvular diseases, according to comparative studies. The new five-grade severity classification, along with the emphasis on atrial, annular, or ventricular origins of TR, has transformed the understanding of tricuspid regurgitation in recent years, shedding light on some of the major questions surrounding this valvulopathy.
The TriValve registry was established to promote an adequate understanding of the disease in patients undergoing transcatheter interventions. It should be noted that the sample presented discordant data: individuals who were not of very advanced age, who showed no signs of advanced right-sided HF with low prevalence of ascites, and who had lower proBNP levels compared to those usually observed in clinical practice or in classic surgical series; versus more congruent data: a predominance of female patients, prior cardiac surgery involving left-heart structures, high rates of previous hospitalization in the last six months, or a prior diagnosis of atrial fibrillation. While the consistency of baseline characteristics has been assured in subsequent studies, at this time, it would be prudent to interpret these data with caution and continue with an individualized approach.
Delving into the different types of TR, in the case of primary TR, it is important to note that the incidence of endocarditis associated with this valve is rising in the United States in parallel with increasing antibiotic resistance, the growing number of implanted devices with leads, and, to a lesser extent, parenteral drug use. Updated literature is available to guide decision-making on the optimal timing for lead explantation in these cases to minimize comorbidity in a severe and complex disease (Nappi F., et al.; J Am Heart Assoc 2020). Another entity to emphasize, despite its low prevalence (20%), is TR post-cardiac transplantation, as it is often associated with allograft vasculopathy and damage caused by endomyocardial biopsies.
In secondary TR, although it is thoroughly categorized in supplementary material tables within the main text, it is worth noting that distinguishing between atrial and ventricular forms has implications for prognosis and treatment, given that mortality and complication rates are clearly higher in the ventricular etiology of TR.
Finally, device-related TR represents a group that has gained its own significance due to the increasing frequency of these interventions. Moderate-to-severe regurgitation is observed in up to 27% of patients following device implantation, a notably high figure considering the associated pacemaker rates (25-29%), excluding other devices.
One emphasized point is the importance of recognizing that the presence of morphological factors associated with certain clinical entities may indicate an increased risk of TR progression:
For patients with PH, predictors to consider include right ventricular dilation, increased sphericity, annular dilation, and increased tenting area of the valve leaflets.
In patients with AF, increased annular diameter, right ventricular remodeling, valve tenting, and increased left atrial volume are additional factors.
Other factors of rapid progression inherent to any patient with TR include previous pacemaker or defibrillator implantation, moderate regurgitation, or association with another valvulopathy requiring surgical intervention. Annular dilation of the tricuspid valve is mentioned again, underscoring the importance of its measurement in assessing right-heart pathology.
Age and female sex have also been proposed as independent risk factors in various published studies.
Regarding medical treatment, it is a developing field where proper assessment of TR type and degree, the presence of PH, left ventricular function, and AF diagnosis are crucial. This is important because directed treatment for secondary TR should be implemented early to modify the disease’s natural course; however, these cases represent a minority, and there is no recent solid evidence supporting a significant change in clinical practice.
To conclude, within interventional management, I would like to focus on edge-to-edge or clip therapies, which are novel devices that have facilitated advancements in TR treatment and are currently supported by recently reviewed literature suggesting a potential shift in the treatment of choice for TR. Specifically, the pivotal TRILUMINATE study, presented at the recent ACC/AHA congress, has yielded promising results regarding TR treatment and progression. This study was analyzed in previous blog entries. The sample indeed presents considerable biases that favor positive results in the primary composite outcome; conversely, no statistically significant differences were observed in the remaining objectives.
Furthermore, discrepancies are noted in participant profiles:
The sample selection was based on TR severity (most cases being severe, massive, or torrential), functional class (usually II), and lower hospitalization rates (in essence, more stable patients despite the severity). Additionally, the impact of the COVID-19 pandemic should not be overlooked.
The surgical risk selection of the sample was performed subjectively by the research team rather than blindly. Notably, there was a lack of data on the etiology of TR or predominant pathophysiological mechanisms, which is striking, as several previous studies have shown that the primary etiology of TR determines its prognosis and that the pathophysiological mechanism also directly affects outcomes after a specific percutaneous repair technique.
It is interesting to note that to achieve the proposed sample size of 350 patients, up to 795 patients were excluded due to screening failure, confirming that a significant percentage of patients with significant TR, presumably with a higher severity profile, were not represented in this study.
In conclusion, TR is a pathology that is currently gaining ground in clinical practice and invasive treatment fields due to the implications of its severity. Percutaneous repair is solidifying as a viable option in routine clinical practice and is strengthened by recent studies. Further analyses will be needed to ascertain the true differences between surgical and percutaneous techniques and the results of new devices that are continually being developed.
REFERENCE:
Hahn RT. Tricuspid Regurgitation. N Engl J Med. 2023 May 18;388(20):1876-1891. doi: 10.1056/NEJMra2216709.
