Sex-Specific Differences in Etiology and Prognosis in Patients With Significant Tricuspid Regurgitation

Abstract

The aim of this study was to assess differences in etiology, comorbidities, echocardiographic parameters, and prognosis between men and women with significant tricuspid regurgitation (TR). Clinical and echocardiographic characteristics of 1569 patients (age 71 [62 to 78] years) at first diagnosis of significant TR were compared between men and women. Patients with congenital heart disease or previous tricuspid valve surgery were excluded. TR etiologies were defined as primary, left valvular disease related, left ventricular (LV) dysfunction related, pulmonary hypertension related, or isolated. The primary endpoint was all-cause mortality. Sex-specific differences in outcomes were compared in the total population and after propensity score matching. There were 798 (51%) women and 771 (49%) men in the study population. Women were diagnosed with significant TR at an older age compared with men (72 [62 to 79] years vs. 70 [61 to 77] years; p = 0.003). The TR etiology in women was more often left valvular disease related and isolated whereas men more often had LV dysfunction related TR. In the total population women had better 10-year survival compared with men (49% vs. 39%; p=0.001). After propensity score matching, the influence of sex on survival was neutralized (p = 0.228) but the TR etiologies remained significantly associated with all-cause mortality. Patients with left valvular disease or LV dysfunction related TR had lower survival compared with patients with primary TR (p = 0.004 and p = 0.019, respectively). In conclusion, long-term survival of patients with significant TR was similar between men and women after propensity score matching, while the etiology of TR remained significantly associated with all-cause mortality. The aim of this study was to assess differences in etiology, comorbidities, echocardiographic parameters, and prognosis between men and women with significant tricuspid regurgitation (TR). Clinical and echocardiographic characteristics of 1569 patients (age 71 [62 to 78] years) at first diagnosis of significant TR were compared between men and women. Patients with congenital heart disease or previous tricuspid valve surgery were excluded. TR etiologies were defined as primary, left valvular disease related, left ventricular (LV) dysfunction related, pulmonary hypertension related, or isolated. The primary endpoint was all-cause mortality. Sex-specific differences in outcomes were compared in the total population and after propensity score matching. There were 798 (51%) women and 771 (49%) men in the study population. Women were diagnosed with significant TR at an older age compared with men (72 [62 to 79] years vs. 70 [61 to 77] years; p = 0.003). The TR etiology in women was more often left valvular disease related and isolated whereas men more often had LV dysfunction related TR. In the total population women had better 10-year survival compared with men (49% vs. 39%; p=0.001). After propensity score matching, the influence of sex on survival was neutralized (p = 0.228) but the TR etiologies remained significantly associated with all-cause mortality. Patients with left valvular disease or LV dysfunction related TR had lower survival compared with patients with primary TR (p = 0.004 and p = 0.019, respectively). In conclusion, long-term survival of patients with significant TR was similar between men and women after propensity score matching, while the etiology of TR remained significantly associated with all-cause mortality. The prevalence of tricuspid regurgitation (TR) increases with age and is higher in women than in men in the general population.1Topilsky Y Maltais S Medina Inojosa J Oguz D Michelena H Maalouf J Mahoney DW Enriquez-Sarano M. Burden of tricuspid regurgitation in patients diagnosed in the community setting.JACC Cardiovasc Imaging. 2019; 12: 433-442Crossref PubMed Scopus (124) Google Scholar, 2Singh JP Evans JC Levy D Larson MG Freed LA Fuller DL Lehman B Benjamin EJ. Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study).Am J Cardiol. 1999; 83: 897-902Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar, 3Andell P Li X Martinsson A Andersson C Stagmo M Zoller B Sundquist K Smith JG. Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study.Heart. 2017; 103: 1696-1703Crossref PubMed Scopus (94) Google Scholar Multiple studies have demonstrated the impact of significant (moderate and severe) TR on prognosis, but differences between men and women remain unclear.4Wang N Fulcher J Abeysuriya N McGrady M Wilcox I Celermajer D Lal S. Tricuspid regurgitation is associated with increased mortality independent of pulmonary pressures and right heart failure: a systematic review and meta-analysis.Eur Heart J. 2019; 40: 476-484Crossref PubMed Scopus (56) Google Scholar,5Benfari G Antoine C Miller WL Thapa P Topilsky Y Rossi A Michelena HI Pislaru S Enriquez-Sarano M. Excess mortality associated with functional tricuspid regurgitation complicating heart failure with reduced ejection fraction.Circulation. 2019; 140: 196-206Crossref PubMed Scopus (66) Google Scholar TR is a heterogeneous disease with different characteristics, treatment and prognosis depending on the etiology.6Prihadi EA Delgado V Leon MB Enriquez-Sarano M Topilsky Y Bax JJ. Morphologic types of tricuspid regurgitation: characteristics and prognostic implications.J Am Coll Cardiol Img. 2019; 12: 491-499Crossref Scopus (38) Google Scholar The prevalence of the cardiac diseases that may cause TR, such as ischemic heart disease, left valvular disease or atrial fibrillation, vary between men and women.7Westerman S Wenger NK. Women and heart disease, the underrecognized burden: sex differences, biases, and unmet clinical and research challenges.Clin Sci (Lond). 2016; 130: 551-563Crossref PubMed Scopus (43) Google Scholar Recent studies have demonstrated differences in the distribution of the various TR etiologies between sexes.1Topilsky Y Maltais S Medina Inojosa J Oguz D Michelena H Maalouf J Mahoney DW Enriquez-Sarano M. Burden of tricuspid regurgitation in patients diagnosed in the community setting.JACC Cardiovasc Imaging. 2019; 12: 433-442Crossref PubMed Scopus (124) Google Scholar,8Bohbot Y Chadha G Delabre J Landemaine T Beyls C Tribouilloy C. Characteristics and prognosis of patients with significant tricuspid regurgitation.Arch Cardiovasc Dis. 2019; 112: 604-614Crossref PubMed Scopus (6) Google Scholar,9Santoro C Marco Del Castillo A González-Gómez A Monteagudo JM Hinojar R Lorente A Abellás M Vieitez JM Garcia Martìn A Casas Rojo E Ruíz S Barrios V Luis Moya J Jimenez-Nacher JJ Zamorano Gomez JL Fernández-Golfín C Mid-term outcome of severe tricuspid regurgitation: are there any differences according to mechanism and severity?.Eur Heart J Cardiovasc Imaging. 2019; 20: 1035-1042Crossref PubMed Scopus (23) Google Scholar Consequently, differences between men and women in clinical and echocardiographic characteristics may be expected. It is important to clarify these sex-specific differences in presentation of TR and their prognostic implications to improve risk stratification and treatment. However, differences between men and women in characteristics, etiology and prognosis in the natural history of TR have not been extensively studied. Therefore, the aim of our study was (1) to describe sex-specific differences in clinical characteristics, echocardiographic parameters and etiology in patients with significant TR and (2) to assess the association between sex and prognosis in the overall population and a propensity score matched population of patients with significant TR. The data that support the findings of this study are available on reasonable request to the corresponding author. Patients diagnosed with significant (moderate and severe) TR at the Leiden University Medical Center (Leiden, the Netherlands) between June 1995 and September 2016 were identified by performing a query in the departmental echocardiographic database. TR was evaluated in all patients by transthoracic echocardiography using a multiparametric approach as recommended by the current guidelines.10Zoghbi WA Adams D Bonow RO Enriquez-Sarano M Foster E Grayburn PA Hahn RT Han Y Hung J Lang RM Little SH Shah DJ Shernan S Thavendiranathan P Thomas JD Weissman NJ. Recommendations for noninvasive evaluation of native valvular regurgitation: a report the of in with the for Am 2017; Full Text Full Text PDF PubMed Scopus Google Scholar Patients with previous surgery of the tricuspid valve and patients with congenital heart disease were excluded. and clinical data were and the departmental Leiden University Medical The review of the Leiden University Medical Center this and of data and the for was at the of first diagnosis of significant TR by transthoracic Clinical and echocardiographic characteristics and TR etiology were compared between men and women. Clinical data risk and and was by the of in and of of the outcomes clinical PubMed Scopus Google Scholar echocardiography was with patients at available and with or were to that were for with available and and data were on and according to the current WA Adams D Bonow RO Enriquez-Sarano M Foster E Grayburn PA Hahn RT Han Y Hung J Lang RM Little SH Shah DJ Shernan S Thavendiranathan P Thomas JD Weissman NJ. Recommendations for noninvasive evaluation of native valvular regurgitation: a report the of in with the for Am 2017; Full Text Full Text PDF PubMed Scopus Google P Tribouilloy C A T LA Zamorano Recommendations for the echocardiographic of native valvular regurgitation: an the of Heart J Cardiovasc Imaging. PubMed Scopus Google Scholar, H V Bax JJ M C B P E D R J P A T S Zamorano JL for the of valvular heart Heart J. 2017; PubMed Scopus (2) Google Scholar, J K for the echocardiographic of the right heart in a report the of by the of a of the of and the of Am Full Text Full Text PDF PubMed Scopus Google Scholar ventricular (LV) ejection was by the LV that were on the and RM V J A Foster E T P D Recommendations for cardiac by echocardiography in an the of and the of Heart J Cardiovasc Imaging. PubMed Scopus Google Scholar atrial was on the and and for RM V J A Foster E T P D Recommendations for cardiac by echocardiography in an the of and the of Heart J Cardiovasc Imaging. PubMed Scopus Google Scholar (moderate or severe) aortic was defined by an aortic valve was by the H Hung J J T S P M Miller Recommendations on the echocardiographic of aortic valve a the of and the of Am 2017; Full Text Full Text PDF PubMed Scopus Google Scholar regurgitation and TR were by an approach on and parameters evaluated on and data according to the current WA Adams D Bonow RO Enriquez-Sarano M Foster E Grayburn PA Hahn RT Han Y Hung J Lang RM Little SH Shah DJ Shernan S Thavendiranathan P Thomas JD Weissman NJ. Recommendations for noninvasive evaluation of native valvular regurgitation: a report the of in with the for Am 2017; Full Text Full Text PDF PubMed Scopus Google Scholar The tricuspid right atrial and right ventricular were on a and for was by tricuspid as on of the tricuspid RM V J A Foster E T P D Recommendations for cardiac by echocardiography in an the of and the of Heart J Cardiovasc Imaging. PubMed Scopus Google Scholar pulmonary was by the the tricuspid with of or on the and of the J K for the echocardiographic of the right heart in a report the of by the of a of the of and the of Am Full Text Full Text PDF PubMed Scopus Google Scholar parameters of TR were as recommended by current guidelines.10Zoghbi WA Adams D Bonow RO Enriquez-Sarano M Foster E Grayburn PA Hahn RT Han Y Hung J Lang RM Little SH Shah DJ Shernan S Thavendiranathan P Thomas JD Weissman NJ. Recommendations for noninvasive evaluation of native valvular regurgitation: a report the of in with the for Am 2017; Full Text Full Text PDF PubMed Scopus Google Scholar of TR was defined by a on the by Topilsky and Y Maltais S Medina Inojosa J Oguz D Michelena H Maalouf J Mahoney DW Enriquez-Sarano M. Burden of tricuspid regurgitation in patients diagnosed in the community setting.JACC Cardiovasc Imaging. 2019; 12: 433-442Crossref PubMed Scopus (124) Google Scholar primary TR was defined in of of the tricuspid patients with or severe valvular disease at such as or with previous valvular surgery were as left valvular disease related TR. The was as LV dysfunction related TR, in patients with a LV ejection The defined TR associated with pulmonary hypertension in of and the patients were as isolated TR. The primary outcome of was all-cause mortality while on data were by the departmental is to the for heart tricuspid valve any valvular and the of atrial was in the total population and in a of propensity score matched of men and women to for the of clinical and echocardiographic differences on with distribution are as and with distribution as A of the data was compared with a to the to are as and differences between men and women were by the the and the as for in the of differences in prognosis, a matched for outcome was using propensity to propensity score are in women were a propensity score using a of and matched to The and 10-year survival in the total population and in the propensity score matched population were with the for tricuspid valve between men and women in the primary endpoint were using the differences in the were compared using the was to the association of TR etiologies with all-cause mortality in the propensity score matched population. and were were and were were with for A total of 1569 patients with significant TR age 71 years were in the There were 798 (51%) women and 771 (49%) clinical characteristics of the total population and according to sex are in In women were older at diagnosis of significant TR compared with men (72 years [62 to 79] vs. 70 years [61 to p = 0.003). were more to have and a more often had disease compared with women vs. p and more often had a or in vs. p significant differences between the were in the of atrial characteristics of the total population of patients with and severe tricuspid regurgitation and the differences between men and ejection aortic tricuspid are or by or for and by for = = = = = LA = left LV = left = = right = right = = = pulmonary = tricuspid in a are or by or for and by for = = = = = LA = left LV = left = = right = right = = = pulmonary = tricuspid echocardiographic characteristics of the total population and according to sex are in LV ejection and were reduced in the overall population. In LV and were better in women compared with men (p for for LV and were in men than in women (p for Women more often had significant aortic vs. p = but differences were in the of regurgitation vs. p = the distribution of the total population according to the etiologies of TR. valvular disease related TR was the etiology = in of the patients had significant had significant aortic and had previous heart valve In this patients had LV dysfunction ejection with women had more left valvular disease related TR and isolated TR vs. and vs. whereas LV dysfunction related TR was more in men vs. In patients with or the tricuspid the TR etiologies were to the overall population a of years to with for tricuspid valve patients The and 10-year survival were and In the evaluation of outcome according to the demonstrated a significantly better survival treatment for women compared with men p = and 10-year survival according to were as and for women and and for between men and women for the of are in patients tricuspid valve surgery with significant differences between men and women. In women more valvular surgery in general compared with men vs. p = higher all-cause mortality men were more often for heart failure compared with women vs. p = differences were demonstrated in the of atrial and for score of matched men and women with significant TR. clinical and echocardiographic characteristics of the matched population were between men and women The distribution of TR etiologies after is in valvular disease related TR was in women = while more men had LV dysfunction related TR = women with isolated TR remained in the matched compared with men with isolated TR. the primary and in the propensity score matched of patients with significant TR. The a of the survival for women after p = In there were differences in heart failure in women vs. in p = In the between men and women in the of any valvular surgery more vs. p = these were isolated aortic valve The valve atrial remained between men and women after propensity score matching. of the matched that the TR etiologies were significantly associated with all-cause mortality for tricuspid valve surgery after (p = valvular disease related TR and LV dysfunction related TR were associated with an increased risk of all-cause mortality compared with primary TR to p = 0.004 and to p = 0.019, respectively). The between sex and TR etiology was not significant (p = for all-cause mortality for tricuspid valve surgery in the propensity score matched population of patients with significant tricuspid etiologies were defined by TR = of the tricuspid valvular disease related TR = or severe valvular disease at or previous valvular LV dysfunction related TR = LV ejection hypertension related TR = pulmonary = LV = left = TR = tricuspid regurgitation in a TR etiologies were defined by TR = of the tricuspid valvular disease related TR = or severe valvular disease at or previous valvular LV dysfunction related TR = LV ejection hypertension related TR = pulmonary = LV = left = TR = tricuspid regurgitation In a of patients with and severe TR, women had more left valvular disease related TR and isolated TR, whereas men had more LV dysfunction related TR. Women had better prognosis in of all-cause mortality and for heart failure compared with However, after the patients for clinical and echocardiographic characteristics, sex-specific differences in survival while TR etiology remained significantly associated with all-cause mortality. The distribution of men and women diagnosed with significant TR in the current study was findings are in with the higher prevalence and of TR women in previous nationwide and Y Maltais S Medina Inojosa J Oguz D Michelena H Maalouf J Mahoney DW Enriquez-Sarano M. Burden of tricuspid regurgitation in patients diagnosed in the community setting.JACC Cardiovasc Imaging. 2019; 12: 433-442Crossref PubMed Scopus (124) Google Scholar, 2Singh JP Evans JC Levy D Larson MG Freed LA Fuller DL Lehman B Benjamin EJ. Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study).Am J Cardiol. 1999; 83: 897-902Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar, 3Andell P Li X Martinsson A Andersson C Stagmo M Zoller B Sundquist K Smith JG. Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study.Heart. 2017; 103: 1696-1703Crossref PubMed Scopus (94) Google Scholar differences be by the population to a in the to the of a Swedish nationwide hospital-based women with significant TR at an older age than P Li X Martinsson A Andersson C Stagmo M Zoller B Sundquist K Smith JG. Epidemiology of valvular heart disease in a Swedish nationwide hospital-based register study.Heart. 2017; 103: 1696-1703Crossref PubMed Scopus (94) Google Scholar The for the sex-specific in prevalence of TR remain to be sex differences in clinical presentation and etiology of TR have not been extensively studied. the of our the studies on sex differences in patients with TR were studies of patients isolated tricuspid valve P C E differences in isolated tricuspid valve Am Coll Cardiol. 2017; Google B S J M M M J differences in patients tricuspid valve Cardiovasc Google Scholar isolated tricuspid valve surgery is in patients significant valve disease and is often the characteristics of these patients not the overall population of patients with TR and are to to our study H V Bax JJ M C B P E D R J P A T S Zamorano JL for the of valvular heart Heart J. 2017; PubMed Scopus (2) Google Scholar However, the sex differences in the study the of these men were more to have risk and disease while women more often left valvular P C E differences in isolated tricuspid valve Am Coll Cardiol. 2017; Google B S J M M M J differences in patients tricuspid valve Cardiovasc Google Scholar studies to have compared echocardiographic characteristics between men and women with TR. In of etiology, more women in the current study had TR associated with left valvular disease and isolated TR, while men more often had TR associated with LV A similar sex distribution was demonstrated by Topilsky Y Maltais S Medina Inojosa J Oguz D Michelena H Maalouf J Mahoney DW Enriquez-Sarano M. Burden of tricuspid regurgitation in patients diagnosed in the community setting.JACC Cardiovasc Imaging. 2019; 12: 433-442Crossref PubMed Scopus (124) Google of patients with left valvular disease related TR and of patients with isolated TR were while of patients with LV dysfunction related TR were of the In to the pulmonary hypertension related TR for of the total population with Y Maltais S Medina Inojosa J Oguz D Michelena H Maalouf J Mahoney DW Enriquez-Sarano M. Burden of tricuspid regurgitation in patients diagnosed in the community setting.JACC Cardiovasc Imaging. 2019; 12: 433-442Crossref PubMed Scopus (124) Google Scholar The studies by Y Chadha G Delabre J Landemaine T Beyls C Tribouilloy C. Characteristics and prognosis of patients with significant tricuspid regurgitation.Arch Cardiovasc Dis. 2019; 112: 604-614Crossref PubMed Scopus (6) Google Scholar and C Marco Del Castillo A González-Gómez A Monteagudo JM Hinojar R Lorente A Abellás M Vieitez JM Garcia Martìn A Casas Rojo E Ruíz S Barrios V Luis Moya J Jimenez-Nacher JJ Zamorano Gomez JL Fernández-Golfín C Mid-term outcome of severe tricuspid regurgitation: are there any differences according to mechanism and severity?.Eur Heart J Cardiovasc Imaging. 2019; 20: 1035-1042Crossref PubMed Scopus (23) Google Scholar more women in the isolated TR compared with the these studies are not to the study to different of the etiologies of TR. C Marco Del Castillo A González-Gómez A Monteagudo JM Hinojar R Lorente A Abellás M Vieitez JM Garcia Martìn A Casas Rojo E Ruíz S Barrios V Luis Moya J Jimenez-Nacher JJ Zamorano Gomez JL Fernández-Golfín C Mid-term outcome of severe tricuspid regurgitation: are there any differences according to mechanism and severity?.Eur Heart J Cardiovasc Imaging. 2019; 20: 1035-1042Crossref PubMed Scopus (23) Google Scholar women in patients with TR in the of left valvular may be by the of a different population of patients with severe TR of were women or to the of TR etiologies was on of a studies the independent prognostic impact of significant TR to report the independent influence of sex on N Fulcher J Abeysuriya N McGrady M Wilcox I Celermajer D Lal S. Tricuspid regurgitation is associated with increased mortality independent of pulmonary pressures and right heart failure: a systematic review and meta-analysis.Eur Heart J. 2019; 40: 476-484Crossref PubMed Scopus (56) Google Scholar,5Benfari G Antoine C Miller WL Thapa P Topilsky Y Rossi A Michelena HI Pislaru S Enriquez-Sarano M. Excess mortality associated with functional tricuspid regurgitation complicating heart failure with reduced ejection fraction.Circulation. 2019; 140: 196-206Crossref PubMed Scopus (66) Google Scholar Y Chadha G Delabre J Landemaine T Beyls C Tribouilloy C. Characteristics and prognosis of patients with significant tricuspid regurgitation.Arch Cardiovasc Dis. 2019; 112: 604-614Crossref PubMed Scopus (6) Google Scholar a significant association of the sex with all-cause mortality in patients with and severe TR. men with TR had a significantly higher risk for mortality compared with women in a of heart failure patients the D P J I J Bax J Leon M Enriquez-Sarano M. of tricuspid regurgitation on survival in patients with heart failure: a J Heart PubMed Scopus Google Scholar findings the of the current study that women had a better prognosis compared with men in the overall population of patients with significant TR. However, after propensity score for clinical and echocardiographic parameters, sex was associated with prognosis in patients with TR. In left valvular heart disease related TR and LV dysfunction related TR were associated with lower survival compared with primary TR. that the survival in women is by clinical presentation and while the in TR etiologies is a prognostic for risk stratification in men and women with significant TR in clinical findings and the of the to TR etiologies as by Topilsky Y Maltais S Medina Inojosa J Oguz D Michelena H Maalouf J Mahoney DW Enriquez-Sarano M. Burden of tricuspid regurgitation in patients diagnosed in the community setting.JACC Cardiovasc Imaging. 2019; 12: 433-442Crossref PubMed Scopus (124) Google Scholar, demonstrated survival in patients with left valvular disease related TR and LV dysfunction related TR in patients with significant TR in a The current study prognosis in patients with significant TR while on in our the for tricuspid valve surgery was as as tricuspid valve surgery may significantly improve prognosis in men and M Smith Grayburn PA A JM M of isolated tricuspid valve surgery have in the 2019; Full Text Full Text PDF PubMed Scopus Google Scholar P C E differences in isolated tricuspid valve Am Coll Cardiol. 2017; Google Scholar differences in after isolated tricuspid valve surgery between of propensity score matched men and women. B S J M M M J differences in patients tricuspid valve Cardiovasc Google Scholar demonstrated sex-specific differences in long-term survival after isolated tricuspid valve surgery in a population of patients with severe TR or in a of a study the of tricuspid valve in propensity matched TR M G P H A P D E S P R N C M J E JM R C S A A V M G T G G A R J J H H Topilsky Y Delgado V A M S M M Leon MB Hahn RT Bax JJ Enriquez-Sarano M treatment of patients severe tricuspid Am Coll Cardiol. 2019; PubMed Scopus Google Scholar demonstrated a significant of mortality and heart failure after in men TR etiologies were not in this It be to in TR etiology between men and women was the cause of the differences in the of tricuspid valve with the of studies are to assess the prognostic of and tricuspid valve for men and women and to the of in the of TR. The of this study are to a propensity score was the current study is not a and not be in the propensity score have the However, the to while sex differences of and different of etiologies of TR have been Y Chadha G Delabre J Landemaine T Beyls C Tribouilloy C. Characteristics and prognosis of patients with significant tricuspid regurgitation.Arch Cardiovasc Dis. 2019; 112: 604-614Crossref PubMed Scopus (6) Google Scholar,9Santoro C Marco Del Castillo A González-Gómez A Monteagudo JM Hinojar R Lorente A Abellás M Vieitez JM Garcia Martìn A Casas Rojo E Ruíz S Barrios V Luis Moya J Jimenez-Nacher JJ Zamorano Gomez JL Fernández-Golfín C Mid-term outcome of severe tricuspid regurgitation: are there any differences according to mechanism and severity?.Eur Heart J Cardiovasc Imaging. 2019; 20: 1035-1042Crossref PubMed Scopus (23) Google Scholar to the of Topilsky Y Maltais S Medina Inojosa J Oguz D Michelena H Maalouf J Mahoney DW Enriquez-Sarano M. Burden of tricuspid regurgitation in patients diagnosed in the community setting.JACC Cardiovasc Imaging. 2019; 12: 433-442Crossref PubMed Scopus (124) Google Scholar was the defined approach and prognostic was in a population. However, is important to to this the of TR etiologies the the of may or the of patients in a patients with congenital heart disease as a different population. review review review review review J. review review the of the of research and Delgado and and J Bax The have to with

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