Severe tricuspid regurgitation (TR) is a common heart valve disease, affecting ≈1.6 million people in the United States and, if not treated, it results in progressive right ventricular (RV) dilation and failure, with an associated increase in morbidity and mortality.1 The prevalence of significant TR increases with age, nearing 1.5% and 5.6% in men and women > 70 years of age, respectively.2

Despite the increase in mortality associated with significant TR, management has classically been conservative.3 However, recent studies have shown chronic RV overload to be associated with irreversible RV dysfunction and poor prognosis. Thus, tricuspid valve repair at the time of left-sided valve surgery has recently gained acceptance.4,5 However, the optimal timing for surgery in isolated TR remains controversial and surgery is commonly undertaken at a late stage.3,4

Mortality in severe TR surgical series is high, ranging from 15% to 20% during hospitalization to 17% to 24% during the first year of follow-up.6 This high mortality rate has been attributed to delay in surgery since patients may develop anemia, RV dysfunction, cirrhosis, and/or renal failure.7 In a recent longitudinal echocardiographic study by Axtell et al.7 in a cohort of 3276 patients with severe TR, surgery was not associated with improved long-term survival compared with medical management alone after accounting for immortal time bias. Those authors hypothesized that a delay of up to 8 years from diagnosis to surgery could account for the absence of differences and recommended that the optimal timing for surgery be defined. If not, forthcoming randomized controlled trials with novel percutaneous techniques8,9 to address severe TR may fail to yield differences in mortality.

Data available to define the appropriate timing for surgery to improve survival in patients with severe TR are lacking. Thus, the present study aimed to define the main predictors of outcomes in a prospective cohort of patients with severe functional TR referred for surgery. The findings could be useful to plan the intervention (percutaneous or surgical) in this population to reduce outcomes at follow-up.

This was an observational, single-center, prospective, nonrandomized study. The study was conducted in a public tertiary referral hospital with 1146 beds and more than 750 open-heart procedures per year. From April 2014 to December 2017, we included all consecutive patients with severe functional TR with an indication for surgery on the tricuspid valve (left-sided valve disease surgery could be associated if required). The indication for TR surgery was based on the current ESC guidelines for valvular heart disease management.10,11 Follow-up of patients with severe TR was based on annual 2-dimensional color Doppler echocardiography. Patients were referred to surgery when they had signs and symptoms of right heart failure refractory to optimal medical treatment as long as they did not present a RV ejection fraction < 30% or < 45% but associated with the presence of pulmonary arterial pressure ≥ 60mmHg (according to our study protocol).3 We excluded patients with a pacemaker, contraindication for cardiovascular magnetic resonance (CMR), congenital tricuspid valve disease, significant left-sided valvular heart disease (with an indication of surgical treatment per se), or severe pulmonary stenosis or regurgitation.

Patients included in the study were evaluated by anamnesis, complete physical examination, blood test, 2-dimensional color Doppler echocardiography, CMR, left cardiac catheterization to assess coronary artery disease and right cardiac catheterization to evaluate pulmonary pressure. Patients were followed up at the outpatient department and New York Heart Association (NYHA) functional class, hospitalization for heart failure and cardiovascular mortality were recorded. No functional tests were performed. The primary endpoint was the combination of hospitalization for heart failure and cardiovascular mortality at follow-up. The second endpoint was cardiovascular mortality alone. Cardiovascular operative mortality was included when it occurred within 30 days after surgery in or out of the hospital, and after 30 days during the same hospitalization subsequent to the intervention.12 Follow-up was started at the time of surgery.

Before discharge, a follow-up echocardiogram was performed in all patients who survived the first 24hours after surgery to determine the presence and the main predictors of residual TR.

Over a 32-month period, 47 consecutive patients were enrolled in the study. However, 4 patients were excluded: 2 for severe claustrophobia and 2 for having a non-CMR conditional pacemaker. Thus, a final population of 43 patients was included in the analysis. Before surgery, all patients were under optimal medical treatment: beta-blockers in 11 patients (25.6%), digoxin in 26 (60.4%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 34 (79%), mineralocorticoid receptor antagonist in 34 (79%) and diuretics in 43 (100%). Demographic characteristics are shown in table 1. Twenty-nine patients (67.4%) were women, mean age: 66.9 ± 9.6 years, 37 (86.1%) were in atrial fibrillation, and 97.6% were symptomatic (NYHA ≥ II). Nineteen patients (44.2%) had had prior surgery (57.9% mitral valve, 10.5% aortic valve, 10.5% mitral+aortic valves, 5.3% tricuspid valve, 5.3% mitral + tricuspid valve, 5.3% coronary artery bypass grafting, 5.3% others). TR was severe in 6 patients (13.9%) and massive in 37 (86%). None of the patients had torrential TR. Although the main indication for surgery was TR, 26 patients (60.5%) also required mitral valve repair (moderate secondary to endoleak), 4 (9.3%) aortic bioprosthesis for moderate aortic stenosis and 1 (2.3%) required tricuspid valve repair, mitral valve repair and aortic valve replacement (severe TR with moderate mitral regurgitation and moderate aortic stenosis). Tricuspid annuloplasty with a semirigid ring was performed in all patients. None of them received a valve prosthesis (bioprosthesis or a mechanical valve) since the study included only patients treated for secondary TR. Late gadolinium enhancement was not present in any of the patients.

All patients were followed up for a median of 38 months [interquartile range, 14-63 months].

Predictors of the primary endpoint

Twelve patients (27.9%) required hospitalization for heart failure or had a cardiovascular death. Median time from surgery to the event was 2.5 [0.3-15.3] months.

Compared with event-free patients, those with the primary outcome had a higher incidence of hypertension (P = .02), diabetes (P = .005), anemia (lower hemoglobin and hematocrit concentrations, P = .02 in both cases), higher indexed RV end-diastolic volume ([iRVEDV] 132.9mL/my vs 90.5mL/my, P = .001), higher indexed right ventricle end-systolic volume ([iRVESV] 67.6mL/my vs 44.2mL/my, P = .002), and higher systolic pulmonary arterial pressure estimated by echocardiography (64.1mmHg vs 49.7mmHg, P = .004) and right cardiac catheterization (P = .01) (table 1). The incidence of the primary event did not differ between patients who underwent isolated tricuspid surgery and those who associated a combined surgical approach (P = .61).

After adjustment for hypertension, diabetes, body mass index, hemoglobin, aspartate aminotransferase, iRVEDV, iRVESV, and systolic pulmonary arterial pressure variables, on multivariate Cox regression analysis, only iRVEDV was the main predictor of the primary outcome with a hazard ratio (HR) of 1.1 (95% confidence interval [95%CI], 1.01-1.13); P = .024 (table 2). The proportional hazards assumption was confirmed by Schoenfeld residual analysis (P = .90). The ability of iRVEDV to predict the primary endpoint was also confirmed by the C-statistic = 0.91 (95%CI, 0.74-0.95). Kaplan-Meier survival curves for the primary endpoint by iRVEDV tertiles are represented in figure 1A. In particular, the incidence of the primary outcome in patients with an iRVEDV > 104mL/m2 was 66% higher than in those with a lower threshold (10 patients vs 2, respectively; log-rank 16.375, P < .001).

Table 2.

Predictors of the primary endpoint (cardiovascular mortality and hospitalization for heart failure)

Risk factors	Adjusted HR	95%CI	P
Hypertension	2.10	0.27-16.18	.481
Diabetes	0.71	0.07-7.35	.773
Body mass index	0.75	0.55-1.01	.057
Hemoglobin	0.66	0.33-1.32	.242
AST	1.00	0.95-1.05	.990
iRVEDV	1.10	1.01-1.13	.024
iRVESV	1.03	0.92-1.03	.364
sPAP (echocardiography)	1.03	0.96-1.11	.395

95%CI, 95% confidence interval; AST, aspartate aminotransferase; HR, hazard ratio; iRVEDV, indexed right ventricular end-diastolic volume; iRVESV, indexed right ventricular end-systolic volume; sPAP, systolic pulmonary artery pressure.

Figure 1.

Kaplan-Meier survival curves for the primary endpoint (A) and secondary endpoint (B) by iRVEDV (indexed right ventricular end-diastolic volume tertiles during follow-up. iRVEDV, indexed right ventricular end-diastolic volume.

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Variables associated with postsurgical tricuspid regurgitation recurrence

All patients (except 3 with early death) underwent a follow-up echocardiogram predischarge and TR recurrence was present in 32 patients: 19 (47.5%) mild, 8 (20.0%) moderate and 5 (12.5%) severe. Predictors of significant TR (degrees of regurgitation II or III/IV assessed by quantitative Doppler measures) recurrence are shown in table 2 of the supplementary data. There was a rise in renin levels (P = .033), increased iRVEDV (P = .025) and an increase in RV function: RV ejection fraction (P = .009), RV free wall global longitudinal strain (P = .002), RV circumferential strain (P = .009) and RV radial strain (P = .025) were the main variables associated with significant TR recurrence, thereby suggesting that the better the RV function, the higher the velocity through the tricuspid valve, resulting in a higher Doppler signal of recurrent TR. However, on multivariate logistic regression analysis, only iRVEDV was associated with TR recurrence (OR, 1.06; 95%CI, 1.01-1.13; P = .044) (table 4). The area under the receiver operator characteristics curve (AUC) of the logistic model to predict TR recurrence was 0.939 (P < .01) (figure 2). Paradoxically, tricuspid annulus diameter presurgery was not associated with TR recurrence.

Table 4.

Multivariate analysis for significant tricuspid regurgitation recurrence

Risk factors	OR	95%CI	P
Diabetes	0.93	0.03-33.49	.970
Global longitudinal strain	0.89	0.59-1.35	.589
iRVEDV	1.06	1.01-1.13	.044
RVEF	1.12	0.88-1.42	.367
Isolated tricuspid regurgitation	0.01	0.00-1.69	.077

95%CI, 95% confidence interval; iRVEDV, indexed right ventricular end-diastolic volume; OR, odds ratio; RVEF, right ventricular ejection fraction.

Figure 2.

Area under the ROC curve for the recurrence of tricuspid regurgitation after surgery. ROC, receiver operator characteristics.

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Interestingly, the presence of recurrent significant TR (moderate or severe) was not associated with either the primary endpoint (HR, 2.26; 95%CI, 0.65-7.83; P = .197) or cardiovascular mortality (HR, 2.87; 95%CI, 0.48-17.21; P = .249).

TR has long been considered a forgotten entity owing to the belief that left-sided valve treatment prevented the development of significant TR.3 However, follow-up studies found this conservative approach to be associated with a high incidence of significant residual TR in 25% of patients.16,17 Thus, current ESC/EACTS11 and AHA/ACC18 guidelines for the management of valvular heart diseases recommend surgery in patients with mild or moderate secondary TR with a dilated annulus (≥ 40mm or > 21mm/m2 by 2-dimensional echocardiography) undergoing left-sided valve surgery (IIa and IIb class indication, respectively).

Significant TR is associated with increased morbidity and mortality.2,16 High functional class, RV dilation and dysfunction, pulmonary hypertension, renal failure, and severe liver dysfunction have been considered the main risk factors. The problem in patients with TR is that they can remain asymptomatic for a long time and, when symptoms appear, could be at an irreversible stage in which RV dysfunction persists despite treatment.6,7 A recent study by Axtell et al.7 in 3276 patients with isolated TR showed that surgical treatment performed up to 8 years after diagnosis was not associated with improved long-term survival compared with medical management alone and after adjustment for immortal time bias. Therefore, it is important to establish the precise moment when the surgical indication should be established to avoid progression to an irreversible stage. In addition, the new percutaneous approach for significant TR before irreversible RV dysfunction is established would reduce the mortality rate associated with surgical treatment. The need to recognize the ‘optimal timing’ for percutaneous treatment of the TR is vital to avoid unnecessary procedures.19,20 Our study is the first prospective work in patients with severe TR to evaluate the prognostic role of clinical, blood, echocardiographic, CMR and hemodynamic variables as predictors of major cardiac events (such as cardiovascular mortality and/or admission for heart failure). The main finding of our study was that RVEDVi assessed by CMR constituted the best predictor of cardiovascular outcomes during follow-up. Thus, RVEDVi > 104mL/m2 was associated with a 23.3% primary endpoint rate and an 11.6% cardiovascular mortality rate, with this value being independent of the degree of pulmonary hypertension or RV dysfunction severity. Kim et al.21 found that a RV end-systolic area < 20cm2 predicted event-free survival. Similarly, our results showed that a surgical intervention before significant RV dilation is present ( > 104mL/m2) could have reduced the primary endpoint incidence from 23.3% to 4.6% and overall mortality from 11.6% to 4.6%. In addition, our study is in line with a recent retrospective echocardiographic study by Dietz et al.22 who observed that the presence of RV dilation (defined as a tricuspid annulus ≥ 40mm) associated with ventricular dysfunction (defined as a TAPSE < 17mm) constituted the main predictors of global mortality in patients with severe TR. However, in that study, only 21% of the patients had a severe TR and only 8% underwent surgery. Similarly to our study, Kim et al.23 reported that, in 31 patients undergoing tricuspid valve surgery (especially tricuspid valve replacement in 81% of cases), an indexed end-diastolic volume of the RV < 164mL/m2 was the best predictor of recovery of RV function during follow-up. However, although patients in that study had a similar degree of RV dysfunction compared with that in our study (49.7 ± 8.3% vs 49.3 ± 8.2%), the threshold of iRVEDV obtained was clearly different (164mL/m2 vs 104mL/m2, respectively). Several reasons could explain these differences: the study by Kim et al. aimed to determine only RV function recovery without prognostic implications, the population was younger (56.6 ± 9.1 vs 66.9 ± 9.6 years, respectively), the proportion of male sex was lower (13% vs 33%, respectively), most patients underwent tricuspid valve replacement (81% vs 0%, respectively), systolic pulmonary arterial pressure value was not included and, finally, 6 patients who died at follow-up were excluded.23

Surgery is the treatment of choice for severe TR when medical treatment fails. However, it carries a high mortality rate (17%-24%)24 secondary to a late indication when patients have multiple comorbidities and is associated with irreversible RV remodeling. However, RV remodeling is not only influenced by TR severity, other factors such as pressure overload, cell death or myocardial fibrosis are also involved in the pathophysiology of the RV.22 Furthermore, similarto what occurs in the presence of severe mitral regurgitation, RV ejection fraction is not the best method for calculating the ventricular function in severe TR.25 Thus, in line with our results, the combination of RV dilatation/dysfunction associated with significant TR seems to be needed for right heart failure to occur,26,27 which is associated with tachyarrhythmias, ascites, liver dysfunction, lower cardiac output, and worse cardiovascular outcomes.26 The European11 and American18 guidelines for the management of heart valve diseases recommend surgery with indications IIa and IIb (respectively) in patients with severe TR when they are symptomatic or when they show progressive RV dilation/dysfunction, in the absence of severe left ventricular/RV dysfunction or significant pulmonary hypertension. However, the specific cutoff point at which surgery should be indicated has not been established, and the indication is thus made arbitrarily according to different centers. The overall cardiovascular mortality rate in our study was 16.3%. Moreover, the cardiovascular operative mortality rate was 9.3% similar to that reported by Verdonk et al.28 (5-13%) and lower than that reported by Rodríguez-Capitán et al.29 (18.5%). Unexpectedly, the combination of left valve surgery (required in 60.5% of patients with no severe left valve disease) was not associated with an increase in mortality. This could be explained by the fact that the indication for surgery in our population was based on the presence of TR severity and not on severe left valve disease. Furthermore, since all patients received optimal medical treatment at discharge (table 1) according to current clinical practice guidelines, inadequate treatment could not explain long-term mortality.

Similar to previous studies, in our series, most patients (97.6%) were symptomatic with a functional class (NYHA) ≥ II; however, compared with patients with no clinical outcomes, NYHA functional class was not statistically significant (P = .51) to predict outcomes, as published elsewhere.30,31 Moreover, various risk factors have been evaluated to stratify the risk of cardiovascular events in patients with significant TR. The presence of liver enzyme alterations, cirrhosis, or high bilirubin levels has been associated with increased mortality in tricuspid valve surgery.6,32 In addition, the presence of anemia has been associated with poor clinical outcomes.21 Several mechanisms have been associated with anemia in patients with significant TR such as low renal perfusion, malabsorption, nutritional deficiencies, hemodilution, and hypersplenism (secondary to systemic venous congestion).21 In our study, neither hemoglobin nor liver enzymes had prognostic implications. This could be explained by the fact that we evaluated a surgical population and therefore patients were not in the end-stage of the disease. The role of pulmonary arterial hypertension in patients undergoing TV surgery is controversial since some studies have shown that patients with pulmonary arterial hypertension do not recover RV function, while other studies have reported opposite findings.3,18 Our study demonstrated that pulmonary arterial hypertension is associated with a higher rate of cardiovascular events during follow-up with an HR of 1.05 (P = .004); however, its role in the prediction of outcomes is subject to the degree of RV dilation (P = .395, in the adjusted model).

In patients with isolated severe TR referred for surgical tricuspid valve repair, an end-diastolic RV volume > 104mL/m2 was associated with the need for hospitalization for RV heart failure and a high cardiovascular mortality rate during follow-up. These findings suggest that surgical valvular repair or percutaneous procedures should be performed before this threshold is reached in order to optimize results and improve patients’ quality of life.

This work was partially funded by a Clinical Research Project Grant in Cardiology from the Spanish Society of Cardiology and Spanish Heart Foundation. There are no relationships with industry.

I. Ferreira-González is Editor-in-Chief of Rev Esp Cardiol. The journal's editorial procedure to ensure impartial handling of the manuscript has been followed. The remaining authors confirm they have no disclosures regarding this manuscript.