Prognostic Implications of Significant Isolated Tricuspid Regurgitation in Patients With Atrial Fibrillation Without Left-Sided Heart Disease or Pulmonary Hypertension

The prognostic impact of isolated tricuspid regurgitation (TR) in patients with atrial fibrillation (AF) has not been investigated. The purpose of this study was to investigate the prognostic implications of significant isolated TR in AF patients without left-sided heart disease, pulmonary hypertension, or primary structural abnormalities of the tricuspid valve.A total of 63 AF patients with moderate and severe TR were matched for age and gender to 116 AF patients without significant TR. Patients were followed for the occurrence of all-cause mortality, hospitalization for heart failure and stroke. Patients with significant isolated TR (mean age 71 ± 8 years, 57% men) more often had paroxysmal AF as compared with patients without TR (mean age 71 ± 7 years, 60% men) (60% vs 43%, p = 0.028). In addition, right atrial size and tricuspid annular diameter were significantly larger in patients with significant isolated TR compared with their counterparts. During follow-up (median 62 [34 to 95] months), 53 events for the combined endpoint occurred. One- and 5-year event-free survival rates for patients with significant isolated TR were 76% and 56%, compared with 92% and 85% for patients without significant TR, respectively (Log rank Chi-Square p <0.001). The presence of significant isolated TR was independently associated with the combined endpoint (hazard ratio, 2.853; 95% confidence interval, 1.458 to 5.584; p = 0.002). In conclusion, in the absence of left-sided heart disease and pulmonary hypertension, significant isolated TR is independently associated with worse event-free survival in patients with AF. The prognostic impact of isolated tricuspid regurgitation (TR) in patients with atrial fibrillation (AF) has not been investigated. The purpose of this study was to investigate the prognostic implications of significant isolated TR in AF patients without left-sided heart disease, pulmonary hypertension, or primary structural abnormalities of the tricuspid valve. A total of 63 AF patients with moderate and severe TR were matched for age and gender to 116 AF patients without significant TR. Patients were followed for the occurrence of all-cause mortality, hospitalization for heart failure and stroke. Patients with significant isolated TR (mean age 71 ± 8 years, 57% men) more often had paroxysmal AF as compared with patients without TR (mean age 71 ± 7 years, 60% men) (60% vs 43%, p = 0.028). In addition, right atrial size and tricuspid annular diameter were significantly larger in patients with significant isolated TR compared with their counterparts. During follow-up (median 62 [34 to 95] months), 53 events for the combined endpoint occurred. One- and 5-year event-free survival rates for patients with significant isolated TR were 76% and 56%, compared with 92% and 85% for patients without significant TR, respectively (Log rank Chi-Square p <0.001). The presence of significant isolated TR was independently associated with the combined endpoint (hazard ratio, 2.853; 95% confidence interval, 1.458 to 5.584; p = 0.002). In conclusion, in the absence of left-sided heart disease and pulmonary hypertension, significant isolated TR is independently associated with worse event-free survival in patients with AF. Isolated tricuspid regurgitation (TR) is an increasingly recognized subtype of TR, which is defined by the absence of concomitant left-sided heart disease or pulmonary hypertension and which is frequently associated with the presence of atrial fibrillation (AF).1Prihadi 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 (89) Google Scholar Isolated TR accounts for 6% to 10% of all patients with significant (moderate and severe) TR.2Topilsky 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 (264) Google Scholar,3Fender EA Zack CJ Nishimura RA Isolated tricuspid regurgitation: outcomes and therapeutic interventions.Heart. 2018; 104: 798-806Crossref PubMed Scopus (126) Google Scholar However, due to lack of outcome studies, the management of isolated TR is not clearly addressed in current guidelines.4Nishimura RA Otto CM Bonow RO Carabello BA Erwin 3rd, JP Guyton RA O'Gara PT Ruiz CE Skubas NJ Sorajja P Sundt 3rd, TM Thomas JD 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014; 63: 2438-2488Crossref PubMed Scopus (1400) Google Scholar,5Baumgartner H Falk V Bax JJ De Bonis M Hamm C Holm PJ Iung B Lancellotti P Lansac E Rodriguez Munoz D Rosenhek R Sjogren J Tornos Mas P Vahanian A Walther T Wendler O Windecker S Zamorano JL 2017 ESC/EACTS Guidelines for the management of valvular heart disease.Eur Heart J. 2017; 38: 2739-2791Crossref PubMed Scopus (2) Google Scholar Similar to atrial functional mitral regurgitation,6Deferm S Bertrand PB Verbrugge FH Verhaert D Rega F Thomas JD Vandervoort PM Atrial functional mitral regurgitation: JACC review topic of the week.J Am Coll Cardiol. 2019; 73: 2465-2476Crossref PubMed Scopus (150) Google Scholar a significant proportion of patients with isolated TR have AF.7Mutlak D Lessick J Reisner SA Aronson D Dabbah S Agmon Y Echocardiography-based spectrum of severe tricuspid regurgitation: the frequency of apparently idiopathic tricuspid regurgitation.J Am Soc Echocardiogr. 2007; 20: 405-408Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar The prognostic implications of isolated significant TR in patients with AF have not been extensively studied. The aim of this study was therefore to assess the prognostic influence of isolated significant TR in patients with AF in the absence of left-sided heart disease, pulmonary hypertension or primary structural abnormalities of the tricuspid valve. Of 1,604 patients with a diagnosis of significant (moderate or severe) TR in the departmental echocardiographic database at the Leiden University Medical Center (LUMC) between June 1995 and September 2016, patients with AF and isolated TR were selected. To identify those patients, a query was performed based on a history of AF. As per current guidelines,8Kirchhof P Benussi S Kotecha D Ahlsson A Atar D Casadei B Castella M Diener HC Heidbuchel H Hendriks J Hindricks G Manolis AS Oldgren J Popescu BA Schotten U Van Putte B Vardas P 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.Eur Heart J. 2016; 37: 2893-2962Crossref PubMed Scopus (5134) Google Scholar AF was diagnosed either on 12-lead ECG or during 24-hour Holter ECG monitoring. Subsequently, patients with any of the following conditions which could lead to primary or secondary TR were excluded – structural abnormalities of the tricuspid valve leaflets, significant (moderate or severe) aortic and/or mitral valve disease, previous cardiac surgery, congenital heart disease, left ventricular (LV) ejection fraction <50%, systolic pulmonary artery pressure >40 mm Hg, pacemaker or implantable cardioverter defibrillator leads and new onset AF (defined as AF that has not been diagnosed before, irrespective of the duration).8Kirchhof P Benussi S Kotecha D Ahlsson A Atar D Casadei B Castella M Diener HC Heidbuchel H Hendriks J Hindricks G Manolis AS Oldgren J Popescu BA Schotten U Van Putte B Vardas P 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.Eur Heart J. 2016; 37: 2893-2962Crossref PubMed Scopus (5134) Google Scholar Patients with isolated significant TR were matched for age and gender in a 1:2 ratio by computer-generated frequency matching to patients who underwent echocardiographic evaluation for AF between June 1995 and September 2016, who did not show significant TR and in whom the same exclusion criteria as the significant TR group were applied. Baseline data included demographic and clinical characteristics at the time of echocardiographic evaluation. Clinical data comprised cardiovascular risk factors, medication use, thyroid hormone levels, creatinine levels, New York Heart Association (NYHA) functional class and type of AF (paroxysmal AF vs persistent/permanent AF).8Kirchhof P Benussi S Kotecha D Ahlsson A Atar D Casadei B Castella M Diener HC Heidbuchel H Hendriks J Hindricks G Manolis AS Oldgren J Popescu BA Schotten U Van Putte B Vardas P 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.Eur Heart J. 2016; 37: 2893-2962Crossref PubMed Scopus (5134) Google Scholar Coronary artery disease was defined as previous myocardial infarction or diagnosis of significant stenosis of an epicardial coronary artery (>70%) by invasive coronary angiography. Data were analyzed retrospectively from the departmental Cardiology Information System (EPD-Vision; Leiden University Medical Center, Leiden, the Netherlands). The institutional review board of the Leiden University Medical Center authorized the study design and waived the need for patient written informed consent for retrospective analysis of anonymously handled data. Transthoracic echocardiography was performed systematically according to institutional clinical protocols utilizing commercially available ultrasound systems (Vivid 7, E9 and E95 systems; GE-Vingmed, Horton, Norway). All images were digitally stored for offline analysis (EchoPAC version 113.0.3 and 202; GE-Vingmed, Horten, Norway). Parasternal, apical, and subcostal views were used to acquire M-mode and 2D images and color, continuous and pulsed wave Doppler data according to the current recommendations.5Baumgartner H Falk V Bax JJ De Bonis M Hamm C Holm PJ Iung B Lancellotti P Lansac E Rodriguez Munoz D Rosenhek R Sjogren J Tornos Mas P Vahanian A Walther T Wendler O Windecker S Zamorano JL 2017 ESC/EACTS Guidelines for the management of valvular heart disease.Eur Heart J. 2017; 38: 2739-2791Crossref PubMed Scopus (2) Google Scholar,9Rudski LG Lai WW Afilalo J Hua L Handschumacher MD Chandrasekaran K Solomon SD Louie EK Schiller NB 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: 685-713Abstract Full Text Full Text PDF PubMed Scopus (4841) Google Scholar, 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 from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.J Am Soc Echocardiogr. 2017; 30: 303-371Abstract Full Text Full Text PDF PubMed Scopus (1602) Google Scholar, 11Lancellotti P Tribouilloy C Hagendorff A Popescu BA Edvardsen T Pierard LA Badano L Zamorano JL Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging. 2013; 14: 611-644Crossref PubMed Scopus (1085) Google Scholar TR severity was classified using a multiparametric approach based on qualitative, semiquantitative, and quantitative assessment.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 from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.J Am Soc Echocardiogr. 2017; 30: 303-371Abstract Full Text Full Text PDF PubMed Scopus (1602) Google Scholar Patients were divided into 2 groups according to TR grade: nonsignificant (none to mild) TR versus significant (moderate to severe) TR. LV and left atrial volumes were measured on the apical 2- and 4-chamber views by the Simpson's biplane method. LV ejection fraction was calculated and expressed as percentage.12Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Flachskampf FA Foster E Goldstein SA Kuznetsova T Lancellotti P Muraru D Picard MH Rietzschel ER Rudski L Spencer KT Tsang W Voigt JU Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging. 2015; 16: 233-270Crossref PubMed Scopus (4276) Google Scholar The peak velocity of the transmitral early diastolic flow (E) and late diastolic flow (A) in patients with sinus rhythm were measured and the E/A ratio calculated. The tricuspid annular diameter, right atrial (RA) dimensions, right ventricular (RV) dimensions and RV areas were measured on a focused RV apical view.12Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Flachskampf FA Foster E Goldstein SA Kuznetsova T Lancellotti P Muraru D Picard MH Rietzschel ER Rudski L Spencer KT Tsang W Voigt JU Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging. 2015; 16: 233-270Crossref PubMed Scopus (4276) Google Scholar All left and right ventricular and atrial size measurements were indexed for body surface area.12Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Flachskampf FA Foster E Goldstein SA Kuznetsova T Lancellotti P Muraru D Picard MH Rietzschel ER Rudski L Spencer KT Tsang W Voigt JU Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging. 2015; 16: 233-270Crossref PubMed Scopus (4276) Google Scholar To assess RV systolic function, tricuspid annular plane systolic excursion was measured on M-mode recordings of the lateral tricuspid annulus in a focused RV apical view. In addition, fractional area change (%) was derived from the RV end-systolic and end-diastolic areas traced on a focused RV apical view.12Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Flachskampf FA Foster E Goldstein SA Kuznetsova T Lancellotti P Muraru D Picard MH Rietzschel ER Rudski L Spencer KT Tsang W Voigt JU Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging. 2015; 16: 233-270Crossref PubMed Scopus (4276) Google Scholar The systolic pulmonary artery pressure was estimated based on the TR jet velocity, adding 3, 8 or 15 mm Hg based on the inferior vena cava collapsibility.9Rudski LG Lai WW Afilalo J Hua L Handschumacher MD Chandrasekaran K Solomon SD Louie EK Schiller NB 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: 685-713Abstract Full Text Full Text PDF PubMed Scopus (4841) Google Scholar All-cause mortality data were ascertained from the Departmental Cardiology Information system, which is updated based on municipal civil registry data. All-cause mortality data were complete for all patients. Last follow-up date corresponded to the date of death or last recorded visit. The primary endpoint for this study was a composite of all-cause mortality, hospitalization for heart failure and stroke. Secondary end points were catheter ablation for AF and tricuspid valve surgery. Continuous variables are expressed as mean ± SD, or median (interquartile range) in case of Gaussian or non-Gaussian distributions, respectively. Categorical variables are presented as numbers and percentages. Differences between groups were evaluated by the unpaired t-test for normally distributed continuous variables, by the Mann-Whitney U test for continuous variables with skewed distribution and by the Chi-Square test for categorical variables. Event rates of the composite endpoint (all-cause mortality, hospital admission for heart failure and stroke) were estimated by the Kaplan-Meier method and compared between groups by the Log-rank test. Multivariable Cox proportional hazards regression analysis was performed to determine the clinical and echocardiographic factors that were independently associated with prognosis. The variables included in the multivariable analysis were selected based on the sample size and number of events at follow-up. Variables with a p-value <0.05 in univariable Cox regression analysis and considered of clinical significance were entered into the multivariable model. Odds ratios and 95% confidence intervals were calculated. All p-values were 2-sided and values <0.05 were considered of statistical significance. All statistical analyses were performed using SPSS for Windows, version 23 (SPSS Inc, Armonk, NY:IBM Corp). Of the 1,604 patients with significant TR evaluated within the study period, a total of 79 (4.9%)patients were classified as having isolated TR and AF. Sixty-three of these patients could be matched for age and gender by computer-generated frequency matching with 116 AF patients without significant TR, resulting in a total study population of 179 patients (mean age 71 ± 7 years, 59% male). The baseline clinical characteristics of the overall population and for patients with versus without isolated significant TR are summarized in Table 1. Per design of the study, no significant differences in age and gender were observed between the 2 groups. The prevalence of hypertension in the overall population was high (84%) and 49% of the patients had hypercholesterolemia. Patients with isolated significant TR were more likely to be on rhythm control, as these patients had more often paroxysmal AF compared with patients without TR (60% vs 43%, p = 0.028). In addition, patients with isolated significant TR less frequently had coronary artery disease, but more often had NYHA functional class >2 heart failure symptoms. In terms of cardiovascular risk factors and medication use, no differences were observed between patients with and without significant TR. Hemoglobin levels were significantly lower and renal function was worse in patients with significant TR compared with patients without significant TR.Table 1Clinical characteristics of the total population with atrial fibrillation and according to tricuspid regurgitation severityVariableOverallTricuspid regurgitationp Value(n = 179)None/mild (n = 116)Moderate/severe (n = 63) Age (years)71 ± 771 ± 771 ± 80.940 Men106 (59%)70 (60%)36 (57%)0.677 Body surface area (m2)1.96 ± 0.231.98 ± 0.221.92 ± 0.250.081 Paroxysmal atrial fibrillation88 (49%)50 (43%)38 (60%)0.028 Coronary artery disease51 (29%)40 (35%)11 (18%)0.022 Obstructive pulmonary disease21 (12%)14 (12%)7 (12%)1.000 NYHA class >225 (14%)7 (6%)18 (31%)<0.001 Hypertension143 (84%)96 (83%)47 (86%)0.656 Hypercholesterolemia83 (49%)60 (52%)23 (42%)0.226 Diabetes mellitus25 (15%)17 (15%)8 (14%)0.949 (Ex-)smoker38 (22%)28 (24%)10 (18%)0.352Medications Anticoagulants129 (76%)87 (75%)42 (78%)0.693 Beta-blockers114 (67%)81 (70%)33 (61%)0.260 ACE-inhibitors90 (53%)58 (50%)32 (59%)0.260 Aldosterone antagonists12 (7%)6 (5%)6 (11%)0.159 Calcium channel antagonists36 (21%)24 (21%)12 (22%)0.820 Statins78 (46%)53 (46%)25 (46%)0.941 Diuretics59 (34%)37 (32%)22 (37%)0.525Laboratory values Hemoglobin (mmol/L)8.8 (8.0-9.5)9.0 (8.4-9.2)8.3 (6.1-9.2)<0.001 Total cholesterol (mmol/L)4.7 (4.1-5.8)4.7 (4.2-5.7)4.9 (3.6-6.4)0.720 Total cholesterol (mg/dL)85 (74-105)85 (76-103)88 (65-115)0.720 TSH (mU/L)1.8 (1.2-3.0)1.8 (1.2-3.1)1.8 (1.4-3.0)0.931 T4 (pmol/L)17 (15-19)16 (15-19)17 (15-21)0.610 Creatinine (µmol/L)85 (73-102)81 (73-96)95 (73-114)0.030Values are mean ±SD, median (IQR) or n (%). p-value by unpaired t test or Mann-Whitney U test for Gaussian and non-Gaussian distributed continuous variables, respectively. p-value by Chi-Square for categorical variables. ACE = angiotensin-converting enzyme; IQR = interquartile range; NYHA = New York Heart Association; SD = standard deviation; TSH = thyroid-stimulating hormone; TR = tricuspid regurgitation. Open table in a new tab Values are mean ±SD, median (IQR) or n (%). p-value by unpaired t test or Mann-Whitney U test for Gaussian and non-Gaussian distributed continuous variables, respectively. p-value by Chi-Square for categorical variables. ACE = angiotensin-converting enzyme; IQR = interquartile range; NYHA = New York Heart Association; SD = standard deviation; TSH = thyroid-stimulating hormone; TR = tricuspid regurgitation. Table 2 shows the echocardiographic characteristics of the overall population with AF and the comparison between the 2 groups with vs without isolated significant TR. As per inclusion/exclusion criteria of the current study, LV ejection fraction was normal and subsequently did not differ significantly between groups (none/mild TR: 58% [55 to 64] vs moderate/severe TR: 57% [54 to 62], p = 0.335). RA maximum dimensions were significantly larger in patients with isolated significant TR compared with patients without significant TR. As expected, the tricuspid annular diameter was more dilated in patients with isolated significant TR. Interestingly, RV basal and midventricular dimensions were significantly larger in patients with TR, while no significant differences in RV areas and fractional area change were observed between groups. However, RV function measured with tricuspid annular plane systolic excursion was significantly less in patients with significant TR.Table 2Echocardiographic characteristics of the total population with atrial fibrillation and according to tricuspid regurgitation severityVariableOverallTricuspid regurgitationp Value(n = 179)None/mild (n = 116)Moderate/severe (n = 63)Heart rate (bpm)72 (61-85)69 (59-82)75 (65-90)0.020LV end-diastolic volume (ml/m2)48 ± 1448 ± 1348 ± 160.967LV end-systolic volume (ml/m2)20 ± 720 ± 620 ± 80.597LVEF (%)58 (54-63)58 (55-64)57 (54-62)0.335E/A ratio1.1 (0.8-1.5)1.0 (0.8-1.3)1.5 (1.0-2.6)<0.001LA maximum volume (ml/m2)42 (30-56)41 (31-50)48 (29-60)0.145Tricuspid annular diameter (mm)38 ± 835 ± 543 ± 9<0.001RV basal dimension (mm/m2)23 ± 422 ± 324 ± 4<0.001RV mid dimension (mm/m2)18 ± 317 ± 319 ± 4<0.001RV longitudinal dimension (mm/m2)38 ± 538 ± 537 ± 60.065RV end-diastolic area (cm2/m2)12 (10-14)12 (10-14)12 (10-14)0.642RV end-systolic area (cm2/m2)7 (6-8)7 (6-8)7 (6-9)0.608RV fractional area change (%)39 ± 1238 ± 1139 ± 130.535TAPSE (mm)20 ± 621 ± 617 ± 5<0.001Systolic pulmonary artery pressure (mmHg)30 (25-35)32 (27-36)27 (24-33)0.001RA maximum area (cm2/m2)11 (9-15)10 (9-11)16 (13-19)<0.001RA long-axis dimension (mm/m2)29 (26-33)27 (25-31)34 (30-38)<0.001RA short-axis dimension (mm/m2)23 (21-27)22 (19-24)28 (25-32)<0.001Values are mean ±SD, median (IQR) or n (%). p-value by unpaired t test or Mann-Whitney U test for non-Gaussian and Gaussian distributed continuous variables, respectively. p-value by Chi-Square test for categorical variables. AF = atrial fibrillation; E/A = ratio of mitral inflow peak early diastolic flow-velocity to atrial contraction peak-velocity; IQR = interquartile range; LA = left atrium; LV = left ventricular; RA = right atrial; RV = right ventricular; SD = standard deviation; TAPSE = tricuspid annular plane systolic excursion; TR = tricuspid regurgitation. Open table in a new tab Values are mean ±SD, median (IQR) or n (%). p-value by unpaired t test or Mann-Whitney U test for non-Gaussian and Gaussian distributed continuous variables, respectively. p-value by Chi-Square test for categorical variables. AF = atrial fibrillation; E/A = ratio of mitral inflow peak early diastolic flow-velocity to atrial contraction peak-velocity; IQR = interquartile range; LA = left atrium; LV = left ventricular; RA = right atrial; RV = right ventricular; SD = standard deviation; TAPSE = tricuspid annular plane systolic excursion; TR = tricuspid regurgitation. During a median follow-up of 62 (34 to 95) months, 53 adverse events for the combined endpoint occurred. Of the overall population, 19 (11%) patients were hospitalized for heart failure, 16 (10%) had a stroke and 37 (21%) patients died. All-cause mortality and the amount of hospitalizations for heart failure during follow-up were significantly higher in patients with isolated significant TR compared with patients without significant TR. During follow-up, 47 patients (27%) underwent catheter ablation and 6 patients with isolated significant TR received tricuspid valve annuloplasty (Table 3). In the overall population, the cumulative event-free survival for the combined endpoint at 1 year and 5 years was 87% and 75%, respectively. Figure 1 shows the Kaplan-Meier curves for event-free survival of the combined endpoint according to the presence or absence of isolated significant TR. At long-term follow-up, the clinical outcome was significantly worse in patients with TR (Log rank Chi-Square: 18.694; p <0.001). One- and 5-year event-free survival rates for patients with isolated significant TR were 76% and 56%, compared with 92% and 85% in patients without significant TR, respectively.Table 3Follow-up variables for the overall population with atrial fibrillation and according to tricuspid regurgitation severityVariableOverallTricuspid regurgitationp Value(n = 179)None/mild (n = 116)Moderate/severe (n = 63)All-cause mortality37 (21%)14 (12%)23 (37%)<0.001Stroke16 (10%)7 (7%)9 (15%)0.085Hospital admission for heart failure19 (11%)5 (4%)8 (13%)0.039Catheter ablation47 (27%)30 (26%)17 (28%)0.774TR surgery6 (3%)0 (0%)6 (10%)0.001TR = tricuspid regurgitation. Open table in a new tab TR = tricuspid regurgitation. In the multivariable Cox proportional hazard model adjusted for age, gender, NYHA functional class >2, renal function and RV function, the presence of isolated significant TR was independently associated with the combined endpoint of all-cause mortality, hospitalization for heart failure and stroke (Table 4). In addition, older age, NYHA functional class >2 and worse renal function were significantly associated with the combined endpoint.Table 4Univariable and multivariable Cox proportional hazard models for freedom of adverse events (death, hospital admission for heart failure, stroke) for patients with atrial fibrillationVariableUnivariate analysisMultivariate analysisHazard ratio (95% CI)p ValueHazard ratio (95% CI)p ValueAge1.053 (1.012-1.095)0.0121.061 (1.012-1.113)0.015Male gender0.959 (0.552-1.663)0.8810.676 (0.352-1.297)0.239BSA (m2)0.563 (0.160-1.990)0.373Paroxysmal atrial fibrillation1.431 (0.823-2.486)0.204Coronary artery disease1.142 (0.646-2.020)0.647NYHA class >23.069 (1.685-5.589)<0.0012.179 (1.089-4.357)0.028Hemoglobin0.698 (0.575-0.847)<0.001Creatinine1.007 (1.004-1.009)<0.0011.006 (1.003-1.010)<0.001Heart rate1.009 (0.996-1.022)0.181LVEF1.003 (0.958-1.050)0.902E/A ratio1.275 (0.937-1.735)0.122TAPSE0.940 (0.898-0.985)0.0101.023 (0.968-1.081)0.427Systolic pulmonary artery pressure0.975 (0.936-1.015)0.213RA maximum area, indexed1.048 (0.994-1.104)0.080Tricuspid annulus diameter1.049 (1.015-1.081)0.004Significant TR3.130 (1.810-5.415)<0.0012.853 (1.458-5.584)0.002BSA = body surface area; CI = confidence interval; E/A = ratio of mitral inflow peak early diastolic flow-velocity to atrial contraction peak-velocity; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; RA = right atrial; RV = right ventricular; TAPSE = tricuspid annular plane systolic excursion; TR = tricuspid regurgitation. Open table in a new tab BSA = body surface area; CI = confidence interval; E/A = ratio of mitral inflow peak early diastolic flow-velocity to atrial contraction peak-velocity; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; RA = right atrial; RV = right ventricular; TAPSE = tricuspid annular plane systolic excursion; TR = tricuspid regurgitation. TR is a heterogeneous disease with diverse characteristics due to various underlying mechanisms. Isolated TR is a morphologic type of TR characterized by the absence of primary tricuspid valve abnormality, left-sided heart disease and pulmonary hypertension.1Prihadi 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 (89) Google Scholar Compared to left-sided heart disease-related TR, isolated TR is associated with older age, female sex and a high prevalence of AF.7Mutlak D Lessick J Reisner SA Aronson D Dabbah S Agmon Y Echocardiography-based spectrum of severe tricuspid regurgitation: the frequency of apparently idiopathic tricuspid regurgitation.J Am Soc Echocardiogr. 2007; 20: 405-408Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar,13Topilsky Y Khanna A Le Tourneau T Park S Michelena H Suri R Mahoney DW Enriquez-Sarano M Clin