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Department of Cardiovascular Medicine, Chonnam National University Hospital, Gwangju, Republic of KoreaDepartment of Translational Research Center on Aging, Chonnam National University Hospital, Gwangju, Republic of Korea
Department of Cardiovascular Medicine, Chonnam National University Hospital, Gwangju, Republic of KoreaDepartment of Translational Research Center on Aging, Chonnam National University Hospital, Gwangju, Republic of Korea
Department of Cardiovascular Medicine, Chonnam National University Hospital, Gwangju, Republic of KoreaDepartment of Translational Research Center on Aging, Chonnam National University Hospital, Gwangju, Republic of Korea
Department of Cardiovascular Medicine, Chonnam National University Hospital, Gwangju, Republic of KoreaDepartment of Translational Research Center on Aging, Chonnam National University Hospital, Gwangju, Republic of Korea
Department of Cardiovascular Medicine, Chonnam National University Hospital, Gwangju, Republic of KoreaDepartment of Translational Research Center on Aging, Chonnam National University Hospital, Gwangju, Republic of Korea
Atrial remodeling associated with atrial fibrillation (AF) is known to be a risk factor for significant tricuspid regurgitation (TR), but the predictor of reversible TR in patients with severe functional TR and AF has been poorly studied. The aim of this study was to investigate the predictors of reversible TR in patients with severe functional TR and AF.
Methods
Among 232 patients with severe TR, a total of 71 patients with severe functional TR and AF were enrolled and divided into 2 groups: reversible TR group (n = 16, 70.1 ± 15.5 years, 7 males) vs. non-reversible TR group (n = 55, 72.3 ± 11.8 years, 20 males). Improvement of TR to moderate or lesser degree on follow-up (FU) echocardiography was considered as reversible TR in the present study.
Results
During 38.9 ± 26.7 months of FU period, reversible TR was observed in 16 patients (22.5%). The presence of left ventricular (LV) systolic dysfunction was significantly prevalent (43.8% vs. 20.0%, p = 0.03) and the improvement in LV ejection fraction (EF) more than 10% on FU echocardiography was more significantly frequent (62.5% vs. 23.3%, p = 0.003) in the reversible TR group than in the non-reversible TR group. However, the other echocardiographic parameters, including right ventricular function were not different between the groups. In multivariate analysis using Cox proportional hazard model, the improvement of LVEF more than 10% was the only independent predictor of reversible TR (HR = 7.39, 95%CI 1.80–30.28, p = 0.005). Nine patients died only in patients with non-reversible TR (12.7%), but the reversibility of TR was not associated with mortality.
Conclusions
The improvement of LV systolic function was the only independent predictor of reversible TR. Appropriate medical therapy including management for heart failure should be considered before performing surgery in patients with severe functional TR and AF, especially in patients with LV dysfunction.
Tricuspid valve (TV) has been regarded as a “forgotten valve” for decades, because tricuspid regurgitation (TR) is usually asymptomatic, not easily detected on physical examination, often secondary to left-sided heart disease, and controllable by diuretics [
]. However, significant TR is an independent predictor of long-term mortality and increasing severity of TR is associated with poor prognosis regardless of etiology, left ventricular ejection fraction (LVEF), or pulmonary artery pressure [
Significant TR may develop in the absence of structural abnormalities of the TV and its apparatus, so called functional or secondary TR. TV annular dilatation and/or tricuspid leaflet tethering in association with right ventricular (RV) pressure or volume overload are proposed as pathophysiologic mechanisms of functional TR [
American College of Cardiology/American Heart Association Task Force on Practice Guidelines 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).
]. Functional TR is not uncommon in patients with left-sided heart disease or pulmonary hypertension. The incidence of late significant functional TR is reported in up to 40% of the patients who underwent left-sided valve surgery [
]. Atrial fibrillation (AF) is a common arrhythmia in the elderly or patients with structural heart disease. AF usually results in the enlargement of both atria and/or annular dilatation of atrioventricular valves, and these types of atrial remodeling associated with AF are also known to be a risk factor for developing significant functional TR [
Severe functional TR is associated with poor long-term prognosis, and thus surgery is generally indicated in patients with severe primary or functional TR undergoing left-sided valve surgery in the current guidelines on the management of valvular heart disease [
American College of Cardiology/American Heart Association Task Force on Practice Guidelines 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).
]. Nonetheless, there has been no consensus or established guideline for the timing or indications of surgery for functional TR associated with AF. Because functional TR in association with left-sided valve diseases or various cardiomyopathies may diminish or disappear as the improvement in RV function or underlying causes [
], it would be mandatory to know the natural history or reversibility of severe functional TR associated with AF to avoid the risk of unnecessary valve surgery. However, there has been a lack of data on the natural history or predictors of reversibility of functional TR associated with AF. Therefore, the aim of the present study was to investigate the predictors of reversible TR in patients with severe TR and AF.
Materials and methods
Patient population
Between 2005 and 2012, a total of 232 patients (67.4 ± 14.1 years, 80 males) who were first diagnosed as having severe TR on echocardiography were identified. Among these, 156 patients were excluded and the reasons for exclusion were as follows: no follow-up (FU) echocardiography or inappropriate echocardiographic images for analysis (n = 82), prior valve surgery (n = 64), intracardiac device implantation (n = 14), congenital heart disease (n = 9), intrinsic disease of tricuspid valve apparatus such as prolapse or chordae rupture (n = 1), acute or chronic cor pulmonale (n = 3), thyrotoxicosis (n = 1), and rhythms other than AF (n = 44). A total of 71 patients with AF with FU echocardiography were finally enrolled and divided into 2 groups: reversible TR group (n = 16, 7 males, 70.1 ± 15.5 years) vs. non-reversible TR group (n = 55, 20 males, 72.3 ± 11.8 years) (Fig. 1). Improvement in TR to moderate or lesser degree on FU echocardiography was considered as reversible TR in the present study. Improvement in LVEF in the present study was defined as more than 10% increase of EF compared to previous examination. No patient spontaneously converted to sinus rhythm during the follow-up period.
Fig. 1Study flow and clinical outcomes of the studied patients. TR, tricuspid regurgitation; FU, follow-up; AF, atrial fibrillation.
Echocardiographic examinations were performed at initial presentation and during FU period. Images were taken while patients were in the left lateral decubitus position. Conventional echocardiographic studies including Doppler studies were performed according to the recommendations of the American Society of Echocardiography (ASE) [
Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
]. Left ventricular end-systolic and end-diastolic dimensions, interventricular septal and posterior wall thicknesses, and left atrial anteroposterior diameter were determined from two-dimensional images. Ejection fraction was calculated using the conventional Teicholz's and biplane Simpson's method. Doppler echocardiograms were recorded on a strip chart recorder with a sweep speed of 100 mm/s. Early transmitral velocity (E wave) was measured by pulsed-wave Doppler from the apical four-chamber view, with the sample volume located at the tip of the mitral leaflets. Early diastolic (e′), late diastolic (a′), and systolic (s′) velocities at the septal mitral annulus were obtained in this view by tissue Doppler imaging. The E wave deceleration time (DT) was measured as the time between the peak early diastolic velocity and the point at which the steepest deceleration slope was extrapolated to the zero line.
A severe TR was defined as a TR with a distal jet area ≥10 cm2, vena contracta width greater than 0.7 cm, and systolic flow reversal in hepatic veins according to the current guideline of ASE [
American Society of Echocardiography Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography.
]. Right atrial pressure was estimated as 5 mmHg if the inferior vena cava (IVC) was not dilated (<1.7 cm) and there was a 50% decrease in the diameter during inspiration, 10 mmHg if the IVC was dilated with normal inspiratory collapse, and 15 mmHg if the IVC was dilated and did not collapse with inspiration (IVC plethora) [
Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.
]. RV dilation was defined as an RV mid-cavity dimension larger than that of the left ventricle from the apical 4-chamber view, and RV dysfunction was defined as either one of the following: RV fractional area change (FAC) ≤35%; tricuspid annular plane systolic excursion (TAPSE) <1.6 cm; tissue Doppler wave velocities at the TV annulus level <10 cm/s [
Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
J Am Soc Echocardiogr.2010; 23 (quiz 86-8): 685-713
The primary endpoint was the reversibility of severe TR, and the secondary endpoint was cardiac mortality during clinical FU.
Statistical analysis
Continuous variables with normal distributions are presented as mean ± standard deviation and were compared using Student's t-test or Mann–Whitney U test when group distributions were skewed. Categorical variables were compared using the Chi-square test or Fisher's exact test, where appropriate. A regression analysis using Cox proportional hazard model was performed to identify independent predictors of reversibility, and 1-year mortality and adverse events in patients with severe TR. The variables with p < 0.1 on univariate Cox analysis and clinically relevant ones were tested in the model. All statistical tests were 2-tailed and p-values <0.05 were considered significant. All analyses were performed using the Statistical Package for Social Sciences, version 18.0 (SPSS-PC, Chicago, IL, USA).
Results
Baseline clinical characteristics
Baseline clinical characteristics are summarized in Table 1. The prevalence of LV systolic dysfunction was higher and the LVEF was significantly lower in the reversible group than in the non-reversible group. Other baseline characteristics were not different between the groups.
Table 1Comparison of baseline clinical characteristics between reversible and non-reversible severe tricuspid regurgitation.
Echocardiographic findings are summarized in Table 2. LV end-diastolic dimension (LVEDD) was not different between the two groups, while LV end-systolic dimension (LVESD) was significantly larger in the reversible group than in the non-reversible group. Baseline LVEF and s’ velocity of mitral septal annulus were significantly lower in the reversible group than in the non-reversible group. Both LVEDD and LVESD decreased on FU echocardiography. Mitral E velocity significantly decreased in follow-up echocardiography of the reversible group (120.8 ± 41.7 cm/s vs. 103.0 ± 50.3 cm/s, p = 0.034). Parameters for RV function were not different between the groups. Of note, the reversible TR group showed trend toward decreased TV annular size and leaflet tethering distance in FU echocardiography compared to index echocardiography (TV annular size: 4.6 ± 0.6 cm vs. 3.8 ± 0.8 cm, p = 0.07; TV leaflet tethering diameter: 1.2 ± 0.4 cm vs. 0.6 ± 0.1 cm, p = 0.055), while the non-reversible group did not.
Table 2Comparison of echocardiographic findings between reversible and non-reversible severe tricuspid regurgitation.
Prescribed medications are summarized in Table 3. Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and spironolactone were more frequently used in the reversible group than in the non-reversible group. Other prescribed medications were not different between the groups.
Table 3Comparison of medical treatment between reversible and non-reversible severe tricuspid regurgitation.
N (%)
Reversible (n = 16)
Non-reversible (n = 55)
p
Digoxin
6 (37.5)
23 (41.7)
0.763
Beta blocker
7 (43.8)
19 (35.0)
0.519
ACEI or ARB
12 (75.0)
26 (46.7)
0.044
Calcium channel blocker
4 (25.0)
7 (13.3)
0.265
Amiodarone
2 (12.5)
3 (5.0)
0.282
Thiazide
3 (18.8)
7 (11.7)
0.431
Loop diuretics
13 (81.3)
40 (73.3)
0.747
Spironolactone
13 (81.3)
29 (53.3)
0.043
Aspirin
4 (25.0)
15 (26.7)
1.000
Warfarin
11 (68.8)
24 (43.3)
0.071
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
Reversible TR was observed in 16 out of 71 severe functional TR and AF (22.5%). The presence of LV systolic dysfunction and the improvement in LVEF more than 10% on FU echocardiography was a significant predictor of reversible TR in univariate analysis. In multivariate analysis using Cox proportional hazard model, the improvement in LVEF more than 10% was the only independent predictor of reversible TR (HR = 7.39, 95%CI 1.80–30.28, p = 0.005) (Fig. 2).
Fig. 2Independent predictors for reversibility in patients with severe tricuspid regurgitation and atrial fibrillation (forest plot). LVEF, left ventricular ejection fraction.
Thirty-one patients (40.9%) showed clinical stabilization despite non-improvement of severe TR continued medical therapy, whereas 19 patients (26.8%) underwent surgical correction of TR because of the non-improvement or aggravation of heart failure (Fig. 1).
Nine patients died during clinical FU, but the reversibility of TR did not show statistically significant association with cardiac mortality (9 deaths in the non-reversible group vs. 0 deaths in the reversible group, p = 0.083). Five patients died before TR surgery, and 4 patients died after TR surgery (Fig. 1).
Predictors of mortality in patients with severe functional TR and AF
On survival analysis using Cox regression model, hypertension (HR = 19.6, 95%CI 1.70–225.43, p = 0.017) and renal insufficiency (HR = 25.4, 95%CI 1.15–558.29, p = 0.040) were independent predictors of mortality in patients with severe functional TR and AF (Fig. 3). TR reversibility was not a predictor of cardiac mortality in a univariate analysis and also in a multivariate analysis.
Fig. 3Independent predictors for mortality in patients with severe tricuspid regurgitation and atrial fibrillation (forest plot). TR, tricuspid regurgitation; LVEF, left ventricular ejection fraction; RAAS, renin–angiotensin–aldosterone system.
The present study aimed to investigate the incidence or predictors of reversible TR in patients with severe functional TR and AF and demonstrated several clinically important findings. Firstly, the improvement in TR without performing surgical correction is not uncommon in patients with severe functional TR and AF (22.5%). Secondly, the presence of LV systolic dysfunction and the improvement in LV systolic function are significant predictors of TR reversibility in patients with severe functional TR and AF. Therefore, a trial of optimal medical therapy should be considered in patients with severe functional TR and AF before performing cardiac surgery, especially in patients with LV systolic dysfunction.
Etiology of severe TR
It has been reported that right atrium (RA) usually enlarges more easily than left atrium (LA) in the setting of AF because of less fibrous skeleton in tricuspid annulus than mitral valve [
]. Thus tricuspid annular dilatation could contribute to development of TR and cause further dilation of RA. It was reported that AF was one of the most important determinants of TR late after surgery [
]. Mitral valve surgery and AF were predictors of development of severe isolated TR. Although AF has been identified as a predictor of severe TR after mitral valve surgery [
]. This means structural modification will not always obliterate TR. In the present study, we could not compare surgical versus medical treatment of TR. TV surgery was defined as one of the adverse outcomes. Interestingly, LV dysfunction apparently acted as a surrogate marker of reversible TR. Actually, the reversible group had lower LVEF and more patients with LV dysfunction. In addition, medical treatment with renin–angiotensin–aldosterone system blockade and spironolactone were predictors of reversibility of severe TR in univariate analysis. This is thought to be because TR can be improved in the clinical setting of restored LV function. In addition, Fukuda et al. demonstrated that reduced LVEF was independently associated with the tethering of the tricuspid leaflets, not with annular dilatation [
]. This could be a mechanism of association between LVEF and TR. In the present study, however, both tethering of the tricuspid leaflets (p = 0.085) and annular dilatation (p = 0.086) showed trends toward increased value in FU echocardiography of the reversible TR group.
Right ventricular systolic pressure (RVSP) was not significantly different between the two groups at index and FU echocardiography. Moreover, tricuspid peak velocity at FU was lower in the non-reversible group (2.8 ± 0.3 m/s vs. 2.0 ± 1.1 m/s, p < 0.0001). Actually, however, inferior vena cava (IVC) plethora decreased more during follow-up in the reversible group than in the non-reversible group. This suggested that RV pressure at index echocardiography was not so high because of decompression effect by severe TR. However, TR severity affected IVC size and respiratory variability, which eventually led to higher RVSP at follow-up in the non-reversible group.
In general, valvular regurgitation is aggravated by tachyarrhythmia. Treatment for tachycardia also has an important role in reversal of ventricular dysfunction [
]. In the present study, however, multivariate analysis revealed that controlled heart rate was not one of the independent predictors of TR reversibility. Reduction of TR seems to be obtained indirectly by improvement of LV function rather than treatment of tachycardia per se.
Predictors of mortality in patients with severe TR and AF
To the best of our knowledge, no one has demonstrated a mortality difference between reversible and non-reversible TR to date. There was no difference in mortality in the present study, but the results might be changed in a larger study. It has been reported that TR is associated with worse clinical outcomes in various conditions. TR after mitral valve surgery was associated with decreased exercise tolerance and poor quality of life [
]. Lee et al. reported that patients with RV dysfunction showed a lower survival rate. Their study also showed preoperative renal failure was the only determinant of mortality by the Cox proportional hazards model [
]. In the present study, RV dysfunction was not one of the independent predictors of mortality while renal insufficiency turned out to be one of the predictors. The mechanism of RV dysfunction in severe TR could be different between patients with mitral regurgitation surgery and AF. Since the presence of prosthetic MV inevitably leads to the development of pulmonary venous hypertension, ensuing RVSP elevation and TR development follow. Therefore, RV dysfunction after MV surgery may imply deterioration of prosthetic valve function and subsequent higher mortality. But, TR in AF is usually induced by annular dilatation. Hence, RV dysfunction may have relatively less association with clinical outcomes.
Surgery timing and right ventricular function
The American College of Cardiology/American Heart Association guideline does not consider severe TR without RV dysfunction as an indication for operation [
American College of Cardiology/American Heart Association Task Force on Practice Guidelines 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).
] recently studied 74 patients who eventually underwent tricuspid annuloplasty during left-sided heart valve surgery and reported that enlarged RV midcavity diameter and TV tethering area were independently associated with future heart failure and cardiac mortality in those patients. Kim et al. [
Right ventricular reverse remodeling, but not subjective clinical amelioration, predicts long-term outcome after surgery for isolated severe tricuspid regurgitation.
] reported that RV reverse remodeling, defined as 20% reduction in RV end-systolic volume, was a strong predictor of future outcomes after TR surgery in patients with severe TR. So far, RV dimension and function appear to be determinants of surgery in severe TR. In the present study, RV function parameters improved in both groups, but there were no differences between the groups. However, echocardiography at rest alone sometimes does not provide sufficient evidence to draw a solid conclusion. In this situation, simple exercise echocardiography using a Master's two-step test for detection of pulmonary hypertension could have been used [
Firstly, the present study was carried out in a single center using retrospective analysis with all the pertinent limitations. Second, thyroid function could affect the reversibility of TR, although it was not significantly considered in the present study. However, only one patient with hyperthyroidism was identified in this study population. Third, follow-up period of each patient was varied so that event rate could be affected by that. Finally, a small number of study subjects were a limitation of the present study, because it may affect statistical results. Also reversible TR might be an independent predictor of long-term mortality if there were a sufficient number of patients in the reversible TR group.
Conclusions
Reversible TR was not uncommon in patients with severe functional TR and AF. The improvement in LV systolic function was the only independent predictor of reversible TR. Appropriate medical therapy including the management for heart failure should be considered before performing surgery in patients with severe TR and AF, especially in patients with LV dysfunction. Conventional risk factors including hypertension and renal dysfunction should be still considered in terms of predicting long-term mortality. Nevertheless, TR reversibility showed a trend toward lower long-term mortality suggesting future possibility as an independent predictor in a larger population.
Funding
This research was supported by a Grant (CRI 13904-21) of Chonnam National University Hospital Biomedical Research Institute.
Conflict of interest
The authors declare that there is no conflict of interest.
References
Dreyfus G.D.
Corbi P.J.
Chan K.M.
Bahrami T.
Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).
Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.
Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
J Am Soc Echocardiogr.2010; 23 (quiz 86-8): 685-713
Right ventricular reverse remodeling, but not subjective clinical amelioration, predicts long-term outcome after surgery for isolated severe tricuspid regurgitation.
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