Natural history of mild aortic valve disease untreated at the time of rheumatic mitral valve replacement

Natural history of mild aortic valve disease untreated at the time of rheumatic mitral valve... Abstract OBJECTIVES The aim of this study was to examine long-term clinical outcomes and to assess the eventual need for aortic valve replacement (AVR) in patients with mild aortic valve disease (AVD) at the time of mitral valve replacement. METHODS Between 1990 and 2015, 1231 patients undergoing mitral valve replacement were reviewed, stratifying subjects as those with AVD (n = 363) or without AVD (NA; n = 868). Primary end points were progressive AVD (grade ≥ II) and subsequent AVR. Overall mortality and valve-related complications served as secondary end points. Propensity score matching was used for risk adjustment (n = 320 in each group). RESULTS No differences in postoperative complications or clinical outcomes were observed between groups. The 20-year overall survival was similar (before matching: NA 86.1% vs AVD 80.8%, P = 0.128; after matching: 83.5% vs 81.1%, P = 0.425). Of the entire cohort, progressive AVD was observed in 162 patients, and significant AVD (grade ≥ III) was observed in only 60 patients. Subsequent AVR was required in 37 patients due to mitral valve (MV) dysfunction or severe aortic stenosis. The 20-year freedom from significant AVD and subsequent AVR was significantly higher in the NA group than in the AVD group before and after matching (before: NA, 96.5% vs 73.7%, P < 0.001; AVD, 98.5% vs 82.3%, P < 0.001; after: 98.1% vs 73.3%, P < 0.001; 99.3% vs 82.5%, P < 0.001, respectively). CONCLUSIONS Although progressive AVD did not significantly impact long-term survival during the follow-up period, those patients qualifying initially as mild AVD may eventually progress to significant AVD after the first 5 postoperative years. Therefore, aggressive echocardiography should be performed at 5-year lapse after mitral valve replacement to determine the appropriate timing of AVR. Aortic valve disease , Rheumatic heart disease , Mitral valve replacement INTRODUCTION Rheumatic heart disease is one of the most common causes of heart failure and associated mortalities or morbidities in the young populations of developing countries. A significant proportion of patients with rheumatic heart disease show involvement of both mitral and aortic valves [1, 2], approximately one-third displaying some degree of aortic valve regurgitation or stenosis (AR or AS). There is general consensus that in patients undergoing mitral valve replacement (MVR), aortic valve replacement (AVR) is also indicated if AR or AS is severe, symptomatic and associated with left ventricular dysfunction. However, in those with mild-to-moderate aortic valve disease (AVD), the natural history of progressive AVD remains unknown [3–5]. Because combined intervention (MVR and AVR) usually carries higher operative risk, with poorer long-term survival expected (vs MVR only), it is difficult to gauge the need for prophylactic AVR, unless AVD is severe. In a previous study, we demonstrated that coexistent AVD at the time of MVR was not associated with inferior outcomes, given the generally slow progression of mild or moderate AVD; and throughout a lengthy follow-up period, subsequent AVR was rarely needed [5]. Although the prevalence of rheumatic heart disease is still high in our country, the lack of long-term data and the few studies addressing this issue have provided little guidance for establishing an ideal means of managing such patients. The purpose of this study was to examine long-term clinical outcomes in this setting, assessing the need for subsequent AVR if mild-to-moderate AVD coexists at the time of MVR. MATERIALS AND METHODS Study population A retrospective review was conducted by analysing 1852 consecutive patients who underwent MVR at the Severance Cardiovascular Hospital, Yonsei University College of Medicine, between January 1990 and December 2015. Criteria for exclusion were non-rheumatic valve disease (n = 53), congenital heart disease (n = 74), ischaemic or dilated cardiomyopathy (n = 19), infective endocarditis (n = 87), the presence of severe AVD at the time of surgery (n = 26), previous aortic valve surgery (n = 24), double-valve replacement (n = 45) or lack of follow-up data (n = 293). The 1231 patients who qualified for the study were followed up using Doppler echocardiography in our valve clinic. Patients were assigned to one of 2 groups as follows: those with mild-to-moderate AVD (the AVD group, n = 363) or those without AVD (the NA group, n = 868). In each patient, preoperative diagnostics included transthoracic echocardiography, transoesophageal echocardiography and coronary valve computed tomography, during which valve morphology, the presence of left atrial thrombus and haemodynamic parameters were assessed. All subjects were granted written informed consent, and our internal review board approved the study protocol (approval number: 4-2017-0779). Echocardiographic evaluation Standard echocardiographic studies were performed prior to surgical procedures, during the early postoperative period (≤2 weeks), at 1 year and thereafter once every 2-year postoperative mark. In patients with normal left ventricular systolic function, the mean pressure gradient (calculated via the modified Bernoulli equation using continuous-wave Doppler recordings) [6] denoted the severity of AS (mild <25 mm Hg, moderate 25–40 mm Hg and severe >40 mm Hg) [7]. In those with left ventricular systolic dysfunction, the severity of AS corresponded with aortic valve area (mild >1.5 cm2, moderate 1.0–1.5 cm2 and severe <1.0 cm2). AR was graded by colour Doppler, applying a standard index (i.e. regurgitation volume) recommended by the American Society of Echocardiography [8, 9] (Grade I/mild <30 ml, Grade II/moderate 30–44 ml, Grade III/moderate-to-severe 45–59 ml and Grade IV/severe >60 ml). The ratio of maximal AR jet width to left ventricular outflow tract diameter and vena contracta was measured in long-axis views. Clinical outcomes and follow-up monitoring Primary end points of this study were rate of progressive or significant AVD and the need for subsequent AVR, with secondary end points of overall survival and valve-related complications. Clinical and echocardiographic data were obtained from archived hospital records, follow-up monitoring was achieved through patient visits (88.1%) or telephone interviews (11.9%) and searching the ‘cause of death’ statistics was provided by the Statistics Korea. Follow-up was closed on 30 June 2017. Clinical outcomes assessed all-cause mortality, progressive AVD, subsequent AVR and valve-related complications. All-cause mortality was defined as death from any cause after MVR. Cardiac death was defined as deaths from cardiac causes, such as valve-related, sudden unexplained or non-valve-related deaths (from heart failure, acute myocardial infarction or documented arrhythmias) [10]. Progressive AVD was defined as Grade II or more for AR, or as moderate or more for AS [8, 11]. Significant AVD was defined as Grades III–IV for AR, or as moderate-to-severe or more for AS. Valve thrombosis, embolism and bleeding (formerly anticoagulant haemorrhage) constituted valve-related events, as specified in the American Association for Thoracic Surgery Guidelines for reporting morbidity and mortality after cardiac valve interventions [10]. The mean clinical follow-up duration was 12.8 ± 7.3 years (range 0.2–27.4 years), completing follow-up echocardiography data collection in 99.4% (1223 of 1231) during a follow-up period of 11.2 ± 7.3 years (range 0.1–26.9 years). Statistical analysis All data are expressed as mean ± standard deviation or frequency and percentage. Between-group statistical comparisons were achieved using independent samples t-test for continuous variables. All categorical variables were compared between the groups using the χ2 test when the number of cells with expected frequency was 5 or more and using the Fisher’s exact test when the number of cells with expected frequency was less than 5 in any group. Overall survival from the time of surgery, freedom from progressive AVD and subsequent AVR curves were estimated using the Kaplan–Meier method, performing comparisons using the log-rank test. Propensity scores, which were calculated from baseline variables of age, female, body surface area, Society Thoracic Surgeons (STS) risk score, smoking, atrial fibrillation, hypertension, diabetes mellitus, chronic kidney disease, cerebrovascular accident, chronic obstructive pulmonary disease, coronary or peripheral artery disease, previous open mitral commissurotomy or percutaneous mitral valvuloplasty, type of mitral disease (regurgitation, stenosis or mixed lesions), tricuspid regurgitation (TR, Grade ≥ III), left ventricular ejection fraction and end systolic/diastolic dimension, left atrial diameter, prosthesis type and combined procedures, were used to match patients in 2 groups and were estimated by logistic regression. Patient-to-patient matching was performed using the nearest neighbour matching without replacement, with default caliper of 0.2. The Cox proportional hazard regression model was engaged to determine independent risk factors for time-related events (significant AVD and subsequent AVR) after adjusting for multiple baseline covariates. All confounders with P-values <0.2 were included as candidate covariate in the backwards stepwise selection algorithm. The proportional hazards assumption was confirmed by examination of the Grambsch and Therneau test (time-dependent coefficient). Statistical computations relied on standard software, IBM SPSS version 23.0 (IBM Corp., Armonk, NY, USA), setting significance at P <0.05. RESULTS Patient characteristics and operative data Patient demographics and echocardiographic data are listed in Table 1. In the unmatched population, the mean patient age was 51.7 ± 12.5 years, and the majority were female (868 of 1231, 70.5%). There were significant preoperative differences between groups in terms of age, history of diabetes mellitus, predominance of mitral stenosis, and left ventricular ejection fraction. With respect to mitral valve pathology, stenosis predominated in 741 patients (60.2%) and regurgitation in 365 patients (29.7%), whereas 125 patients (10.2%) displayed both. After propensity score matching, characteristics of both groups were comparable (n = 320 in each group). AR predominated in 265 patients (82.8%), AS in 25 patients (7.8%) and mixed in 30 patients (9.4%). Table 1: Patient characteristics and echocardiography data Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Age (years) 52.8 ± 13.2 51.2 ± 12.1 0.046 51.6 ± 12.8 52.0 ± 11.8 0.690 Female 257 (70.8) 611 (70.4) 0.886 221 (69.1) 220 (68.8) >0.999 BSA (m2) 1.56 ± 0.15 1.56 ± 0.16 0.575 1.57 ± 0.15 1.57 ± 0.16 0.752 STS score 2.12 ± 1.48 1.94 ± 1.54 0.062 2.01 ± 1.35 1.96 ± 1.35 0.622 Atrial fibrillation 335 (92.3) 798 (91.9) 0.836 293 (91.6) 285 (89.1) 0.350 Current smoker 41 (11.3) 92 (10.6) 0.720 36 (11.3) 36 (11.3) >0.999 Hypertension 29 (8.0) 79 (9.1) 0.529 27 (8.4) 24 (7.5) 0.766 Diabetes mellitus 32 (8.8) 47 (5.4) 0.026 21 (6.6) 16 (5.0) 0.511 Chronic kidney disease 2 (0.6) 7 (0.8) >0.999 2 (0.6) 2 (0.6) >0.999 Cerebrovascular accidents 38 (10.5) 96 (11.1) 0.761 37 (11.6) 33 (10.3) 0.704 COPD 11 (3.0) 25 (2.9) 0.887 9 (2.8) 13 (4.1) 0.481 Coronary artery disease 15 (4.1) 28 (3.2) 0.430 12 (3.8) 15 (4.7) 0.701 Peripheral artery disease 8 (2.2) 22 (2.5) 0.732 8 (2.5) 9 (2.8) >0.999 Previous OMC 17 (4.7) 35 (4.0) 0.605 15 (4.7) 14 (4.4) >0.999 Previous PMV 60 (16.5) 127 (14.6) 0.398 51 (15.9) 53 (16.6) 0.911 Predominant mitral valve disease 0.002 0.745  Mitral stenosis 245 (67.5) 496 (57.1) 209 (65.3) 208 (65.0)  Mitral regurgitation 84 (23.1) 281 (32.4) 80 (25.0) 75 (23.4)  Mixed 34 (9.4) 91 (10.5) 31 (9.7) 37 (11.6) Predominant aortic valve disease <0.001 <0.001  Aortic stenosis 32 (8.8) 0 25 (7.8) 0  Aortic regurgitation 294 (81.0) 0 265 (82.8) 0  Mixeda 37 (10.2) 0 30 (9.4) 0 Tricuspid regurgitation (grade ≥ III) 93 (25.6) 158 (18.2) 0.003 72 (22.5) 61 (19.1) 0.310 LVEF (%) 59.8 ± 9.8 61.7 ± 9.1 0.001 60.2 ± 9.7 60.3 ± 9.2 0.902 LVESD (mm) 36.9 ± 7.0 36.2 ± 7.4 0.117 36.9 ± 7.0 36.9 ± 7.8 0.918 LVEDD (mm) 52.7 ± 8.0 53.3 ± 19.6 0.576 52.9 ± 8.0 52.8 ± 9.7 0.910 Left atrial diameter (mm) 60.5 ± 11.4 59.3 ± 11.8 0.095 60.3 ± 11.6 60.6 ± 11.6 0.761 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Age (years) 52.8 ± 13.2 51.2 ± 12.1 0.046 51.6 ± 12.8 52.0 ± 11.8 0.690 Female 257 (70.8) 611 (70.4) 0.886 221 (69.1) 220 (68.8) >0.999 BSA (m2) 1.56 ± 0.15 1.56 ± 0.16 0.575 1.57 ± 0.15 1.57 ± 0.16 0.752 STS score 2.12 ± 1.48 1.94 ± 1.54 0.062 2.01 ± 1.35 1.96 ± 1.35 0.622 Atrial fibrillation 335 (92.3) 798 (91.9) 0.836 293 (91.6) 285 (89.1) 0.350 Current smoker 41 (11.3) 92 (10.6) 0.720 36 (11.3) 36 (11.3) >0.999 Hypertension 29 (8.0) 79 (9.1) 0.529 27 (8.4) 24 (7.5) 0.766 Diabetes mellitus 32 (8.8) 47 (5.4) 0.026 21 (6.6) 16 (5.0) 0.511 Chronic kidney disease 2 (0.6) 7 (0.8) >0.999 2 (0.6) 2 (0.6) >0.999 Cerebrovascular accidents 38 (10.5) 96 (11.1) 0.761 37 (11.6) 33 (10.3) 0.704 COPD 11 (3.0) 25 (2.9) 0.887 9 (2.8) 13 (4.1) 0.481 Coronary artery disease 15 (4.1) 28 (3.2) 0.430 12 (3.8) 15 (4.7) 0.701 Peripheral artery disease 8 (2.2) 22 (2.5) 0.732 8 (2.5) 9 (2.8) >0.999 Previous OMC 17 (4.7) 35 (4.0) 0.605 15 (4.7) 14 (4.4) >0.999 Previous PMV 60 (16.5) 127 (14.6) 0.398 51 (15.9) 53 (16.6) 0.911 Predominant mitral valve disease 0.002 0.745  Mitral stenosis 245 (67.5) 496 (57.1) 209 (65.3) 208 (65.0)  Mitral regurgitation 84 (23.1) 281 (32.4) 80 (25.0) 75 (23.4)  Mixed 34 (9.4) 91 (10.5) 31 (9.7) 37 (11.6) Predominant aortic valve disease <0.001 <0.001  Aortic stenosis 32 (8.8) 0 25 (7.8) 0  Aortic regurgitation 294 (81.0) 0 265 (82.8) 0  Mixeda 37 (10.2) 0 30 (9.4) 0 Tricuspid regurgitation (grade ≥ III) 93 (25.6) 158 (18.2) 0.003 72 (22.5) 61 (19.1) 0.310 LVEF (%) 59.8 ± 9.8 61.7 ± 9.1 0.001 60.2 ± 9.7 60.3 ± 9.2 0.902 LVESD (mm) 36.9 ± 7.0 36.2 ± 7.4 0.117 36.9 ± 7.0 36.9 ± 7.8 0.918 LVEDD (mm) 52.7 ± 8.0 53.3 ± 19.6 0.576 52.9 ± 8.0 52.8 ± 9.7 0.910 Left atrial diameter (mm) 60.5 ± 11.4 59.3 ± 11.8 0.095 60.3 ± 11.6 60.6 ± 11.6 0.761 Values are presented as mean ± SD or n (%). a Mixed lesion means that AS (severity of mild or moderate) was mixed with AR (Grade I or II) at the time of preoperative echocardiography evaluation. AR: aortic valve regurgitation; AS: aortic valve stenosis; AVD: aortic valve disease; BSA: body surface area; COPD: chronic obstructive pulmonary disease; LVEDD: left ventricular end diastolic dimension; LVEF: left ventricular ejection fraction; LVESD: left ventricular end systolic dimension; OMC: open mitral commissurotomy; PMV: percutaneous mitral valvuloplasty; SD: standard deviation; STS: Society Thoracic Surgeons. Table 1: Patient characteristics and echocardiography data Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Age (years) 52.8 ± 13.2 51.2 ± 12.1 0.046 51.6 ± 12.8 52.0 ± 11.8 0.690 Female 257 (70.8) 611 (70.4) 0.886 221 (69.1) 220 (68.8) >0.999 BSA (m2) 1.56 ± 0.15 1.56 ± 0.16 0.575 1.57 ± 0.15 1.57 ± 0.16 0.752 STS score 2.12 ± 1.48 1.94 ± 1.54 0.062 2.01 ± 1.35 1.96 ± 1.35 0.622 Atrial fibrillation 335 (92.3) 798 (91.9) 0.836 293 (91.6) 285 (89.1) 0.350 Current smoker 41 (11.3) 92 (10.6) 0.720 36 (11.3) 36 (11.3) >0.999 Hypertension 29 (8.0) 79 (9.1) 0.529 27 (8.4) 24 (7.5) 0.766 Diabetes mellitus 32 (8.8) 47 (5.4) 0.026 21 (6.6) 16 (5.0) 0.511 Chronic kidney disease 2 (0.6) 7 (0.8) >0.999 2 (0.6) 2 (0.6) >0.999 Cerebrovascular accidents 38 (10.5) 96 (11.1) 0.761 37 (11.6) 33 (10.3) 0.704 COPD 11 (3.0) 25 (2.9) 0.887 9 (2.8) 13 (4.1) 0.481 Coronary artery disease 15 (4.1) 28 (3.2) 0.430 12 (3.8) 15 (4.7) 0.701 Peripheral artery disease 8 (2.2) 22 (2.5) 0.732 8 (2.5) 9 (2.8) >0.999 Previous OMC 17 (4.7) 35 (4.0) 0.605 15 (4.7) 14 (4.4) >0.999 Previous PMV 60 (16.5) 127 (14.6) 0.398 51 (15.9) 53 (16.6) 0.911 Predominant mitral valve disease 0.002 0.745  Mitral stenosis 245 (67.5) 496 (57.1) 209 (65.3) 208 (65.0)  Mitral regurgitation 84 (23.1) 281 (32.4) 80 (25.0) 75 (23.4)  Mixed 34 (9.4) 91 (10.5) 31 (9.7) 37 (11.6) Predominant aortic valve disease <0.001 <0.001  Aortic stenosis 32 (8.8) 0 25 (7.8) 0  Aortic regurgitation 294 (81.0) 0 265 (82.8) 0  Mixeda 37 (10.2) 0 30 (9.4) 0 Tricuspid regurgitation (grade ≥ III) 93 (25.6) 158 (18.2) 0.003 72 (22.5) 61 (19.1) 0.310 LVEF (%) 59.8 ± 9.8 61.7 ± 9.1 0.001 60.2 ± 9.7 60.3 ± 9.2 0.902 LVESD (mm) 36.9 ± 7.0 36.2 ± 7.4 0.117 36.9 ± 7.0 36.9 ± 7.8 0.918 LVEDD (mm) 52.7 ± 8.0 53.3 ± 19.6 0.576 52.9 ± 8.0 52.8 ± 9.7 0.910 Left atrial diameter (mm) 60.5 ± 11.4 59.3 ± 11.8 0.095 60.3 ± 11.6 60.6 ± 11.6 0.761 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Age (years) 52.8 ± 13.2 51.2 ± 12.1 0.046 51.6 ± 12.8 52.0 ± 11.8 0.690 Female 257 (70.8) 611 (70.4) 0.886 221 (69.1) 220 (68.8) >0.999 BSA (m2) 1.56 ± 0.15 1.56 ± 0.16 0.575 1.57 ± 0.15 1.57 ± 0.16 0.752 STS score 2.12 ± 1.48 1.94 ± 1.54 0.062 2.01 ± 1.35 1.96 ± 1.35 0.622 Atrial fibrillation 335 (92.3) 798 (91.9) 0.836 293 (91.6) 285 (89.1) 0.350 Current smoker 41 (11.3) 92 (10.6) 0.720 36 (11.3) 36 (11.3) >0.999 Hypertension 29 (8.0) 79 (9.1) 0.529 27 (8.4) 24 (7.5) 0.766 Diabetes mellitus 32 (8.8) 47 (5.4) 0.026 21 (6.6) 16 (5.0) 0.511 Chronic kidney disease 2 (0.6) 7 (0.8) >0.999 2 (0.6) 2 (0.6) >0.999 Cerebrovascular accidents 38 (10.5) 96 (11.1) 0.761 37 (11.6) 33 (10.3) 0.704 COPD 11 (3.0) 25 (2.9) 0.887 9 (2.8) 13 (4.1) 0.481 Coronary artery disease 15 (4.1) 28 (3.2) 0.430 12 (3.8) 15 (4.7) 0.701 Peripheral artery disease 8 (2.2) 22 (2.5) 0.732 8 (2.5) 9 (2.8) >0.999 Previous OMC 17 (4.7) 35 (4.0) 0.605 15 (4.7) 14 (4.4) >0.999 Previous PMV 60 (16.5) 127 (14.6) 0.398 51 (15.9) 53 (16.6) 0.911 Predominant mitral valve disease 0.002 0.745  Mitral stenosis 245 (67.5) 496 (57.1) 209 (65.3) 208 (65.0)  Mitral regurgitation 84 (23.1) 281 (32.4) 80 (25.0) 75 (23.4)  Mixed 34 (9.4) 91 (10.5) 31 (9.7) 37 (11.6) Predominant aortic valve disease <0.001 <0.001  Aortic stenosis 32 (8.8) 0 25 (7.8) 0  Aortic regurgitation 294 (81.0) 0 265 (82.8) 0  Mixeda 37 (10.2) 0 30 (9.4) 0 Tricuspid regurgitation (grade ≥ III) 93 (25.6) 158 (18.2) 0.003 72 (22.5) 61 (19.1) 0.310 LVEF (%) 59.8 ± 9.8 61.7 ± 9.1 0.001 60.2 ± 9.7 60.3 ± 9.2 0.902 LVESD (mm) 36.9 ± 7.0 36.2 ± 7.4 0.117 36.9 ± 7.0 36.9 ± 7.8 0.918 LVEDD (mm) 52.7 ± 8.0 53.3 ± 19.6 0.576 52.9 ± 8.0 52.8 ± 9.7 0.910 Left atrial diameter (mm) 60.5 ± 11.4 59.3 ± 11.8 0.095 60.3 ± 11.6 60.6 ± 11.6 0.761 Values are presented as mean ± SD or n (%). a Mixed lesion means that AS (severity of mild or moderate) was mixed with AR (Grade I or II) at the time of preoperative echocardiography evaluation. AR: aortic valve regurgitation; AS: aortic valve stenosis; AVD: aortic valve disease; BSA: body surface area; COPD: chronic obstructive pulmonary disease; LVEDD: left ventricular end diastolic dimension; LVEF: left ventricular ejection fraction; LVESD: left ventricular end systolic dimension; OMC: open mitral commissurotomy; PMV: percutaneous mitral valvuloplasty; SD: standard deviation; STS: Society Thoracic Surgeons. As seen in Table 2, before propensity score matching, concomitant procedures were performed in 719 patients (58.4%), including maze operation (16.8%), tricuspid valve surgery (TVS, 42.3%) and left atrial thrombectomy (13.3%). More patients underwent TVS in the AVD group than in the NA group (P = 0.028). TVS was performed in 280 (44.4%) patients in the matched population. Comparison of concomitant TVS and non-TVS showed that the incidence of significant TR (Grade ≥ III) was significantly different in the unmatched population (14.0% vs 8.6%, P = 0.003) but not in the propensity-matched population (7.4% vs 8.6%, P = 0.617) (Supplementary Material, Tables S1 and S2). Table 2: Perioperative data Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Mechanical prosthesis 290 (79.9) 770 (88.7) <0.001 273 (85.3) 272 (85.0) >0.999 Valve size (mm) 0.544 0.668  25 28 (7.7) 70 (8.1) 20 (6.3) 27 (8.4)  27 139 (38.3) 284 (32.7) 118 (36.9) 104 (32.5)  29 144 (39.7) 376 (43.3) 133 (41.6) 135 (42.2)  31 46 (12.7) 120 (13.8) 44 (13.8) 47 (14.7)  33 6 (1.7) 18 (2.1) 5 (1.6) 7 (2.2) Concomitant procedures  Maze operation 66 (18.2) 141 (16.2) 0.407 57 (17.8) 67 (20.9) 0.391  Tricuspid annuloplasty 171 (47.1) 350 (40.3) 0.028 141 (44.1) 143 (44.7) 0.936  LA thrombectomy 55 (15.2) 109 (12.6) 0.222 49 (15.3) 38 (11.9) 0.205 Operative time (min) 237.3 ± 62.7 245.7 ± 66.8 0.041 237.6 ± 64.1 246.9 ± 67.8 0.075 CPB time (min) 110.8 ± 36.3 111.4 ± 36.7 0.785 110.1 ± 37.0 114.1 ± 37.3 0.172 ACC time (min) 78.3 ± 28.5 78.9 ± 29.0 0.742 77.5 ± 28.8 81.7 ± 30.3 0.070 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Mechanical prosthesis 290 (79.9) 770 (88.7) <0.001 273 (85.3) 272 (85.0) >0.999 Valve size (mm) 0.544 0.668  25 28 (7.7) 70 (8.1) 20 (6.3) 27 (8.4)  27 139 (38.3) 284 (32.7) 118 (36.9) 104 (32.5)  29 144 (39.7) 376 (43.3) 133 (41.6) 135 (42.2)  31 46 (12.7) 120 (13.8) 44 (13.8) 47 (14.7)  33 6 (1.7) 18 (2.1) 5 (1.6) 7 (2.2) Concomitant procedures  Maze operation 66 (18.2) 141 (16.2) 0.407 57 (17.8) 67 (20.9) 0.391  Tricuspid annuloplasty 171 (47.1) 350 (40.3) 0.028 141 (44.1) 143 (44.7) 0.936  LA thrombectomy 55 (15.2) 109 (12.6) 0.222 49 (15.3) 38 (11.9) 0.205 Operative time (min) 237.3 ± 62.7 245.7 ± 66.8 0.041 237.6 ± 64.1 246.9 ± 67.8 0.075 CPB time (min) 110.8 ± 36.3 111.4 ± 36.7 0.785 110.1 ± 37.0 114.1 ± 37.3 0.172 ACC time (min) 78.3 ± 28.5 78.9 ± 29.0 0.742 77.5 ± 28.8 81.7 ± 30.3 0.070 Values are presented as mean ± SD or n (%). ACC: aortic cross-clamp; AVD: aortic valve disease; CPB: cardiopulmonary bypass; LA: left atrium; SD: standard deviation. Table 2: Perioperative data Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Mechanical prosthesis 290 (79.9) 770 (88.7) <0.001 273 (85.3) 272 (85.0) >0.999 Valve size (mm) 0.544 0.668  25 28 (7.7) 70 (8.1) 20 (6.3) 27 (8.4)  27 139 (38.3) 284 (32.7) 118 (36.9) 104 (32.5)  29 144 (39.7) 376 (43.3) 133 (41.6) 135 (42.2)  31 46 (12.7) 120 (13.8) 44 (13.8) 47 (14.7)  33 6 (1.7) 18 (2.1) 5 (1.6) 7 (2.2) Concomitant procedures  Maze operation 66 (18.2) 141 (16.2) 0.407 57 (17.8) 67 (20.9) 0.391  Tricuspid annuloplasty 171 (47.1) 350 (40.3) 0.028 141 (44.1) 143 (44.7) 0.936  LA thrombectomy 55 (15.2) 109 (12.6) 0.222 49 (15.3) 38 (11.9) 0.205 Operative time (min) 237.3 ± 62.7 245.7 ± 66.8 0.041 237.6 ± 64.1 246.9 ± 67.8 0.075 CPB time (min) 110.8 ± 36.3 111.4 ± 36.7 0.785 110.1 ± 37.0 114.1 ± 37.3 0.172 ACC time (min) 78.3 ± 28.5 78.9 ± 29.0 0.742 77.5 ± 28.8 81.7 ± 30.3 0.070 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Mechanical prosthesis 290 (79.9) 770 (88.7) <0.001 273 (85.3) 272 (85.0) >0.999 Valve size (mm) 0.544 0.668  25 28 (7.7) 70 (8.1) 20 (6.3) 27 (8.4)  27 139 (38.3) 284 (32.7) 118 (36.9) 104 (32.5)  29 144 (39.7) 376 (43.3) 133 (41.6) 135 (42.2)  31 46 (12.7) 120 (13.8) 44 (13.8) 47 (14.7)  33 6 (1.7) 18 (2.1) 5 (1.6) 7 (2.2) Concomitant procedures  Maze operation 66 (18.2) 141 (16.2) 0.407 57 (17.8) 67 (20.9) 0.391  Tricuspid annuloplasty 171 (47.1) 350 (40.3) 0.028 141 (44.1) 143 (44.7) 0.936  LA thrombectomy 55 (15.2) 109 (12.6) 0.222 49 (15.3) 38 (11.9) 0.205 Operative time (min) 237.3 ± 62.7 245.7 ± 66.8 0.041 237.6 ± 64.1 246.9 ± 67.8 0.075 CPB time (min) 110.8 ± 36.3 111.4 ± 36.7 0.785 110.1 ± 37.0 114.1 ± 37.3 0.172 ACC time (min) 78.3 ± 28.5 78.9 ± 29.0 0.742 77.5 ± 28.8 81.7 ± 30.3 0.070 Values are presented as mean ± SD or n (%). ACC: aortic cross-clamp; AVD: aortic valve disease; CPB: cardiopulmonary bypass; LA: left atrium; SD: standard deviation. No statistically significant differences were found in postoperative complications between groups in both the unmatched and matched populations (Table 3). All-cause mortality occurred in 114 patients (9.3%), including 27 cardiac-related deaths due to progressive heart failure, infective endocarditis or sudden death. The overall survival rates at 20 years were 86.1 ± 1.7% in the NA group and 80.8 ± 3.5% in the AVD group (P = 0.128, Fig. 1A). Similar results were observed for the matched population (NA 83.5 ± 3.3% vs AVD 81.1 ± 3.7%, respectively); these rates were not significantly different (P = 0.425, Fig. 1B). Table 3: Clinical outcomes Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Reoperation for bleeding 18 (5.0) 30 (3.5) 0.214 17 (5.3) 14 (4.4) 0.581 Cerebrovascular accidents  Stroke 20 (5.5) 64 (7.4) 0.237 17 (5.3) 24 (7.5) 0.258  TIA 2 (0.6) 5 (0.6) >0.999 2 (0.6) 3 (0.9) >0.999  Cerebral haemorrhage 23 (6.3) 43 (5.0) 0.326 21 (6.6) 18 (5.6) 0.620 Anticoagulation related haemorrhage 23 (6.3) 66 (7.6) 0.434 21 (6.6) 23 (7.2) 0.755 Pacemaker insertion 18 (5.0) 37 (4.3) 0.590 16 (5.0) 13 (4.1) 0.569 Progressive AVD 110 (30.7) 52 (6.0) <0.001 101 (31.6) 13 (4.1) <0.001  Aortic regurgitation 68 (19.0) 30 (3.5) 62 (19.4) 7 (2.2)  Aortic stenosis 26 (7.3) 13 (1.5) 26 (8.1) 2 (0.6)  Mixed 16 (4.5) 9 (1.0) 13 (4.1) 4 (1.3) Significant AVD 43 (12.0) 17 (2.0) <0.001 40 (12.5) 4 (1.3) <0.001 Late TR (Grade ≥III) 53 (14.8) 125 (14.5) 0.873 47 (14.7) 40 (12.5) 0.419 Reoperation 48 (13.2) 74 (8.5) 0.012 41 (12.8) 24 (7.5) 0.026  MVR 8 (2.2) 17 (2.0) 6 (1.9) 7 (2.2)  MVR + TAP/TVR 8 (2.2) 28 (3.2) 7 (2.2) 10 (3.1)  AVR 5 (1.4) 0 (0) 4 (1.3) 0 (0)  AVR + TAP 7 (1.9) 2 (0.2) 6 (1.9) 1 (0.3)  AVR + MVR 5 (1.4) 3 (0.3) 5 (1.6) 0 (0)  AVR + MVR + TAP/TVR 11 (3.0) 4 (0.5) 10 (3.1) 1 (0.3)  TAP/TVR 4 (1.1) 19 (2.2) 3 (0.9) 4 (1.3)  Others 0 (0) 1 (0.1) 0 (0) 1 (0.3) All-cause mortality 38 (10.5) 76 (8.8) 0.345 31 (9.7) 26 (8.1) 0.488  Cardiac death 11 (3.1) 16 (1.9) 0.189 10 (3.2) 5 (1.6) 0.191 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Reoperation for bleeding 18 (5.0) 30 (3.5) 0.214 17 (5.3) 14 (4.4) 0.581 Cerebrovascular accidents  Stroke 20 (5.5) 64 (7.4) 0.237 17 (5.3) 24 (7.5) 0.258  TIA 2 (0.6) 5 (0.6) >0.999 2 (0.6) 3 (0.9) >0.999  Cerebral haemorrhage 23 (6.3) 43 (5.0) 0.326 21 (6.6) 18 (5.6) 0.620 Anticoagulation related haemorrhage 23 (6.3) 66 (7.6) 0.434 21 (6.6) 23 (7.2) 0.755 Pacemaker insertion 18 (5.0) 37 (4.3) 0.590 16 (5.0) 13 (4.1) 0.569 Progressive AVD 110 (30.7) 52 (6.0) <0.001 101 (31.6) 13 (4.1) <0.001  Aortic regurgitation 68 (19.0) 30 (3.5) 62 (19.4) 7 (2.2)  Aortic stenosis 26 (7.3) 13 (1.5) 26 (8.1) 2 (0.6)  Mixed 16 (4.5) 9 (1.0) 13 (4.1) 4 (1.3) Significant AVD 43 (12.0) 17 (2.0) <0.001 40 (12.5) 4 (1.3) <0.001 Late TR (Grade ≥III) 53 (14.8) 125 (14.5) 0.873 47 (14.7) 40 (12.5) 0.419 Reoperation 48 (13.2) 74 (8.5) 0.012 41 (12.8) 24 (7.5) 0.026  MVR 8 (2.2) 17 (2.0) 6 (1.9) 7 (2.2)  MVR + TAP/TVR 8 (2.2) 28 (3.2) 7 (2.2) 10 (3.1)  AVR 5 (1.4) 0 (0) 4 (1.3) 0 (0)  AVR + TAP 7 (1.9) 2 (0.2) 6 (1.9) 1 (0.3)  AVR + MVR 5 (1.4) 3 (0.3) 5 (1.6) 0 (0)  AVR + MVR + TAP/TVR 11 (3.0) 4 (0.5) 10 (3.1) 1 (0.3)  TAP/TVR 4 (1.1) 19 (2.2) 3 (0.9) 4 (1.3)  Others 0 (0) 1 (0.1) 0 (0) 1 (0.3) All-cause mortality 38 (10.5) 76 (8.8) 0.345 31 (9.7) 26 (8.1) 0.488  Cardiac death 11 (3.1) 16 (1.9) 0.189 10 (3.2) 5 (1.6) 0.191 Values are presented as n (%). AVD: aortic valve disease; AVR: aortic valve replacement; MVR: mitral valve replacement; TAP: tricuspid annuloplasty; TIA: transient ischaemic attack; TR: tricuspid regurgitation; TVR: tricuspid valve replacement. Table 3: Clinical outcomes Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Reoperation for bleeding 18 (5.0) 30 (3.5) 0.214 17 (5.3) 14 (4.4) 0.581 Cerebrovascular accidents  Stroke 20 (5.5) 64 (7.4) 0.237 17 (5.3) 24 (7.5) 0.258  TIA 2 (0.6) 5 (0.6) >0.999 2 (0.6) 3 (0.9) >0.999  Cerebral haemorrhage 23 (6.3) 43 (5.0) 0.326 21 (6.6) 18 (5.6) 0.620 Anticoagulation related haemorrhage 23 (6.3) 66 (7.6) 0.434 21 (6.6) 23 (7.2) 0.755 Pacemaker insertion 18 (5.0) 37 (4.3) 0.590 16 (5.0) 13 (4.1) 0.569 Progressive AVD 110 (30.7) 52 (6.0) <0.001 101 (31.6) 13 (4.1) <0.001  Aortic regurgitation 68 (19.0) 30 (3.5) 62 (19.4) 7 (2.2)  Aortic stenosis 26 (7.3) 13 (1.5) 26 (8.1) 2 (0.6)  Mixed 16 (4.5) 9 (1.0) 13 (4.1) 4 (1.3) Significant AVD 43 (12.0) 17 (2.0) <0.001 40 (12.5) 4 (1.3) <0.001 Late TR (Grade ≥III) 53 (14.8) 125 (14.5) 0.873 47 (14.7) 40 (12.5) 0.419 Reoperation 48 (13.2) 74 (8.5) 0.012 41 (12.8) 24 (7.5) 0.026  MVR 8 (2.2) 17 (2.0) 6 (1.9) 7 (2.2)  MVR + TAP/TVR 8 (2.2) 28 (3.2) 7 (2.2) 10 (3.1)  AVR 5 (1.4) 0 (0) 4 (1.3) 0 (0)  AVR + TAP 7 (1.9) 2 (0.2) 6 (1.9) 1 (0.3)  AVR + MVR 5 (1.4) 3 (0.3) 5 (1.6) 0 (0)  AVR + MVR + TAP/TVR 11 (3.0) 4 (0.5) 10 (3.1) 1 (0.3)  TAP/TVR 4 (1.1) 19 (2.2) 3 (0.9) 4 (1.3)  Others 0 (0) 1 (0.1) 0 (0) 1 (0.3) All-cause mortality 38 (10.5) 76 (8.8) 0.345 31 (9.7) 26 (8.1) 0.488  Cardiac death 11 (3.1) 16 (1.9) 0.189 10 (3.2) 5 (1.6) 0.191 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Reoperation for bleeding 18 (5.0) 30 (3.5) 0.214 17 (5.3) 14 (4.4) 0.581 Cerebrovascular accidents  Stroke 20 (5.5) 64 (7.4) 0.237 17 (5.3) 24 (7.5) 0.258  TIA 2 (0.6) 5 (0.6) >0.999 2 (0.6) 3 (0.9) >0.999  Cerebral haemorrhage 23 (6.3) 43 (5.0) 0.326 21 (6.6) 18 (5.6) 0.620 Anticoagulation related haemorrhage 23 (6.3) 66 (7.6) 0.434 21 (6.6) 23 (7.2) 0.755 Pacemaker insertion 18 (5.0) 37 (4.3) 0.590 16 (5.0) 13 (4.1) 0.569 Progressive AVD 110 (30.7) 52 (6.0) <0.001 101 (31.6) 13 (4.1) <0.001  Aortic regurgitation 68 (19.0) 30 (3.5) 62 (19.4) 7 (2.2)  Aortic stenosis 26 (7.3) 13 (1.5) 26 (8.1) 2 (0.6)  Mixed 16 (4.5) 9 (1.0) 13 (4.1) 4 (1.3) Significant AVD 43 (12.0) 17 (2.0) <0.001 40 (12.5) 4 (1.3) <0.001 Late TR (Grade ≥III) 53 (14.8) 125 (14.5) 0.873 47 (14.7) 40 (12.5) 0.419 Reoperation 48 (13.2) 74 (8.5) 0.012 41 (12.8) 24 (7.5) 0.026  MVR 8 (2.2) 17 (2.0) 6 (1.9) 7 (2.2)  MVR + TAP/TVR 8 (2.2) 28 (3.2) 7 (2.2) 10 (3.1)  AVR 5 (1.4) 0 (0) 4 (1.3) 0 (0)  AVR + TAP 7 (1.9) 2 (0.2) 6 (1.9) 1 (0.3)  AVR + MVR 5 (1.4) 3 (0.3) 5 (1.6) 0 (0)  AVR + MVR + TAP/TVR 11 (3.0) 4 (0.5) 10 (3.1) 1 (0.3)  TAP/TVR 4 (1.1) 19 (2.2) 3 (0.9) 4 (1.3)  Others 0 (0) 1 (0.1) 0 (0) 1 (0.3) All-cause mortality 38 (10.5) 76 (8.8) 0.345 31 (9.7) 26 (8.1) 0.488  Cardiac death 11 (3.1) 16 (1.9) 0.189 10 (3.2) 5 (1.6) 0.191 Values are presented as n (%). AVD: aortic valve disease; AVR: aortic valve replacement; MVR: mitral valve replacement; TAP: tricuspid annuloplasty; TIA: transient ischaemic attack; TR: tricuspid regurgitation; TVR: tricuspid valve replacement. Figure 1: View largeDownload slide Overall cumulative survival rates for the NA (blue line) and AVD (red line) groups (A) in the unmatched population and (B) in the propensity-matched population. AVD: aortic valve disease; NA: no AVD. Figure 1: View largeDownload slide Overall cumulative survival rates for the NA (blue line) and AVD (red line) groups (A) in the unmatched population and (B) in the propensity-matched population. AVD: aortic valve disease; NA: no AVD. Progression of aortic valve disease During the follow-up period, progressive AVD developed in 162 patients, 60 of whom showed significant AVD (Table 3). In the NA group, 3.5% of patients (30 of 865) showed progression to pure AR (Grade II, n = 24; Grade III, n = 5; Grade IV, n = 1) and 1.5% (13 of 865) progressed to pure AS (moderate, n = 6; moderate-to-severe, n = 2; severe, n = 5). Significant AVD was evident in 17 patients (AR, n = 6; AS, n = 7; mixed, n = 4). In the AVD group, 19.0% of patients (68 of 358) showed progression to pure AR (Grade II, n = 52; Grade III, n = 12; Grade IV, n = 4) and 7.3% of patients (26 of 358) progressed to pure AS (moderate, n = 11; moderate-to-severe, n = 5; severe, n = 10). Significant AVD was evident in 43 patients (AR, n = 16; AS, n = 15; mixed, n = 12). Of the matched patients, progressive AVD was found in 114 patients (AR, n = 69; AS, n = 28; mixed n = 17), and significant AVD was evident in only 44 patients (AR, n = 16, AS, n = 16, mixed, n = 12). Curves generated for freedom from progressive AVD are presented in Fig. 2A. The 20-year rates of freedom from significant AVD were 96.5 ± 1.1% in the NA group and 73.7 ± 4.4 in the AVD group (P < 0.001, Fig. 2B). A total of 122 patients required cardiac reoperations during the follow-up period. Reoperation was performed in 8.6% of patients (74 of 865) without AVD, in 12.7% of patients (41 of 323) with mild AVD and in 20.0% of patients (7 of 35) with moderate AVD. The most common indications for reoperation were mitral valve dysfunction, AVD progression or severe TR (Supplementary Material, Table S3). Subsequent AVR was performed in 37 patients. Predominant AS prompted reoperation in 7 of these 28 patients, whereas predominant AR was the impetus in the remaining 21 cases. Rates of freedom from subsequent AVR at 20 years was 98.5 ± 0.6% in the NA group, compared with 82.3 ± 3.6% in the AVD group [hazard ratio (HR) = 9.301; 95% confidence interval (CI): 4.386–19.724; P < 0.001] (Fig. 2C). In the propensity-matched population, the 20-year freedom from progressive AVD, significant AVD and subsequent AVR rates were significantly different between 2 groups (Fig. 3). Furthermore, 4.1% (13 of 320) of patients with AVD and 5.3% (17 of 320) of patients without AVD underwent MV reoperation due to paravalvular leakage (n = 7 vs 7), pannus formation (n = 3 vs 2), infective endocarditis (n = 3 vs 2) and valve thrombosis (n = 0 vs 6). Figure 2: View largeDownload slide (A) Rates of freedom from progressive AVD, (B) freedom from significant AVD and (C) freedom from reoperation for AVR plotted for the NA (blue line) and AVD (red line) groups in the unmatched population. AVD: aortic valve disease; AVR: aortic valve replacement; NA: no AVD. Figure 2: View largeDownload slide (A) Rates of freedom from progressive AVD, (B) freedom from significant AVD and (C) freedom from reoperation for AVR plotted for the NA (blue line) and AVD (red line) groups in the unmatched population. AVD: aortic valve disease; AVR: aortic valve replacement; NA: no AVD. Figure 3: View largeDownload slide (A) Rates of freedom from progressive AVD, (B) freedom from significant AVD and (C) freedom from reoperation for AVR plotted for the NA (blue line) and AVD (red line) groups in the propensity-matched population. AVD: aortic valve disease; AVR: aortic valve replacement; NA: no AVD. Figure 3: View largeDownload slide (A) Rates of freedom from progressive AVD, (B) freedom from significant AVD and (C) freedom from reoperation for AVR plotted for the NA (blue line) and AVD (red line) groups in the propensity-matched population. AVD: aortic valve disease; AVR: aortic valve replacement; NA: no AVD. Also, the AVD group showed significantly lower freedom from tricuspid valve (TV) reoperation compared to the non-AVD group (log-rank P = 0.046) in the unmatched population. However, freedom from significant TR (log-rank P = 0.275) and freedom from TV reoperation (log-rank P = 0.108) were not significantly different between the propensity-matched population (Supplementary Material, Fig. S1). In contrast, the TVS group in the unmatched population showed significantly lower overall survival, freedom from TV reoperation and freedom from significant TR compared to the non-TVS group (Supplementary Material, Fig. S2). Predictors of significant aortic valve disease and subsequent aortic valve replacement As determined by the Cox regression multivariable analysis, independent risk factors for significant AVD were age per year, hypertension, peripheral artery disease and AS (HR = 21.542, 95% CI: 9.743–47.631; P < 0.001). Independent predictors of subsequent AVR were AR (HR = 7.251, 95% CI 3.317–15.848; P < 0.001), AS (HR = 35.638, 95% CI 12.500–101.604; P < 0.001) and TR (Grade ≥ III) (HR = 2.171, 95% CI 1.075–4.383; P = 0.031) (Table 4). Table 4: Multivariable Cox proportional hazard regression analysis for significant AVD and subsequent AVR Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Significant AVD  Age (years) 1.065 (1.037–1.093) <0.001 1.060 (1.032–1.089) <0.001  STS score 1.295 (1.126–1.489) <0.001 1.032 (0.764–1.396) 0.836  Hypertension 4.908 (2.070–11.635) <0.001 6.807 (2.660–17.416) <0.001  Diabetes mellitus 2.291 (0.702–7.475) 0.170 0.873 (0.259–2.948) 0.827  COPD 2.506 (0.782–8.037) 0.122 3.294 (0.979–11.086) 0.054  Peripheral artery disease 3.341 (0.802–13.920) 0.098 5.226 (1.209–22.937) 0.027  LVESD (mm) 0.965 (0.935–0.997) 0.030 0.970 (0.935–1.008) 0.118  LVEDD (mm) 0.982 (0.958–1.007) 0.156 1.005 (0.992–1.017) 0.483  Previous AVD   No AVD (reference)   Aortic regurgitation 5.678 (3.147–10.243) <0.001 7.296 (3.905–13.631) <0.001   Aortic stenosis 28.751 (13.138–62.915) <0.001 21.542 (9.743–47.631) <0.001  Bioprosthetic valve 2.222 (0.879–5.619) 0.092 0.885 (0.290–2.700) 0.830 Subsequent AVR  Previous AVD   No AVD (reference)   Aortic regurgitation 7.382 (3.377–16.134) <0.001 7.251 (3.317–15.848) <0.001   Aortic stenosis 42.446 (15.104–119.285) <0.001 35.638 (12.500–101.604) <0.001  TR (grade ≥III) 2.236 (1.122–4.457) 0.022 2.171 (1.075–4.383) 0.031  Tricuspid valve surgery 1.654 (0.853–3.208) 0.136 0.805 (0.300–2.158) 0.666  Bioprosthetic valve 4.010 (1.396–11.516) 0.010 2.797 (0.930–8.417) 0.067 Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Significant AVD  Age (years) 1.065 (1.037–1.093) <0.001 1.060 (1.032–1.089) <0.001  STS score 1.295 (1.126–1.489) <0.001 1.032 (0.764–1.396) 0.836  Hypertension 4.908 (2.070–11.635) <0.001 6.807 (2.660–17.416) <0.001  Diabetes mellitus 2.291 (0.702–7.475) 0.170 0.873 (0.259–2.948) 0.827  COPD 2.506 (0.782–8.037) 0.122 3.294 (0.979–11.086) 0.054  Peripheral artery disease 3.341 (0.802–13.920) 0.098 5.226 (1.209–22.937) 0.027  LVESD (mm) 0.965 (0.935–0.997) 0.030 0.970 (0.935–1.008) 0.118  LVEDD (mm) 0.982 (0.958–1.007) 0.156 1.005 (0.992–1.017) 0.483  Previous AVD   No AVD (reference)   Aortic regurgitation 5.678 (3.147–10.243) <0.001 7.296 (3.905–13.631) <0.001   Aortic stenosis 28.751 (13.138–62.915) <0.001 21.542 (9.743–47.631) <0.001  Bioprosthetic valve 2.222 (0.879–5.619) 0.092 0.885 (0.290–2.700) 0.830 Subsequent AVR  Previous AVD   No AVD (reference)   Aortic regurgitation 7.382 (3.377–16.134) <0.001 7.251 (3.317–15.848) <0.001   Aortic stenosis 42.446 (15.104–119.285) <0.001 35.638 (12.500–101.604) <0.001  TR (grade ≥III) 2.236 (1.122–4.457) 0.022 2.171 (1.075–4.383) 0.031  Tricuspid valve surgery 1.654 (0.853–3.208) 0.136 0.805 (0.300–2.158) 0.666  Bioprosthetic valve 4.010 (1.396–11.516) 0.010 2.797 (0.930–8.417) 0.067 AVD: aortic valve disease; AVR: aortic valve replacement; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HR: hazards ratio; LVEDD: left ventricular end diastolic dimension; LVESD: left ventricular end systolic dimension; STS: Society Thoracic Surgeons; TR: tricuspid regurgitation. Table 4: Multivariable Cox proportional hazard regression analysis for significant AVD and subsequent AVR Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Significant AVD  Age (years) 1.065 (1.037–1.093) <0.001 1.060 (1.032–1.089) <0.001  STS score 1.295 (1.126–1.489) <0.001 1.032 (0.764–1.396) 0.836  Hypertension 4.908 (2.070–11.635) <0.001 6.807 (2.660–17.416) <0.001  Diabetes mellitus 2.291 (0.702–7.475) 0.170 0.873 (0.259–2.948) 0.827  COPD 2.506 (0.782–8.037) 0.122 3.294 (0.979–11.086) 0.054  Peripheral artery disease 3.341 (0.802–13.920) 0.098 5.226 (1.209–22.937) 0.027  LVESD (mm) 0.965 (0.935–0.997) 0.030 0.970 (0.935–1.008) 0.118  LVEDD (mm) 0.982 (0.958–1.007) 0.156 1.005 (0.992–1.017) 0.483  Previous AVD   No AVD (reference)   Aortic regurgitation 5.678 (3.147–10.243) <0.001 7.296 (3.905–13.631) <0.001   Aortic stenosis 28.751 (13.138–62.915) <0.001 21.542 (9.743–47.631) <0.001  Bioprosthetic valve 2.222 (0.879–5.619) 0.092 0.885 (0.290–2.700) 0.830 Subsequent AVR  Previous AVD   No AVD (reference)   Aortic regurgitation 7.382 (3.377–16.134) <0.001 7.251 (3.317–15.848) <0.001   Aortic stenosis 42.446 (15.104–119.285) <0.001 35.638 (12.500–101.604) <0.001  TR (grade ≥III) 2.236 (1.122–4.457) 0.022 2.171 (1.075–4.383) 0.031  Tricuspid valve surgery 1.654 (0.853–3.208) 0.136 0.805 (0.300–2.158) 0.666  Bioprosthetic valve 4.010 (1.396–11.516) 0.010 2.797 (0.930–8.417) 0.067 Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Significant AVD  Age (years) 1.065 (1.037–1.093) <0.001 1.060 (1.032–1.089) <0.001  STS score 1.295 (1.126–1.489) <0.001 1.032 (0.764–1.396) 0.836  Hypertension 4.908 (2.070–11.635) <0.001 6.807 (2.660–17.416) <0.001  Diabetes mellitus 2.291 (0.702–7.475) 0.170 0.873 (0.259–2.948) 0.827  COPD 2.506 (0.782–8.037) 0.122 3.294 (0.979–11.086) 0.054  Peripheral artery disease 3.341 (0.802–13.920) 0.098 5.226 (1.209–22.937) 0.027  LVESD (mm) 0.965 (0.935–0.997) 0.030 0.970 (0.935–1.008) 0.118  LVEDD (mm) 0.982 (0.958–1.007) 0.156 1.005 (0.992–1.017) 0.483  Previous AVD   No AVD (reference)   Aortic regurgitation 5.678 (3.147–10.243) <0.001 7.296 (3.905–13.631) <0.001   Aortic stenosis 28.751 (13.138–62.915) <0.001 21.542 (9.743–47.631) <0.001  Bioprosthetic valve 2.222 (0.879–5.619) 0.092 0.885 (0.290–2.700) 0.830 Subsequent AVR  Previous AVD   No AVD (reference)   Aortic regurgitation 7.382 (3.377–16.134) <0.001 7.251 (3.317–15.848) <0.001   Aortic stenosis 42.446 (15.104–119.285) <0.001 35.638 (12.500–101.604) <0.001  TR (grade ≥III) 2.236 (1.122–4.457) 0.022 2.171 (1.075–4.383) 0.031  Tricuspid valve surgery 1.654 (0.853–3.208) 0.136 0.805 (0.300–2.158) 0.666  Bioprosthetic valve 4.010 (1.396–11.516) 0.010 2.797 (0.930–8.417) 0.067 AVD: aortic valve disease; AVR: aortic valve replacement; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HR: hazards ratio; LVEDD: left ventricular end diastolic dimension; LVESD: left ventricular end systolic dimension; STS: Society Thoracic Surgeons; TR: tricuspid regurgitation. DISCUSSION In the present study, we examined long-term clinical outcomes and echocardiographic results after surgery for rheumatic MVD, comparing patients with and without associated AVD. According to our findings, patients with mild or moderate rheumatic AVD at the time of MVR progressed more often and more rapidly than those without AVD and more frequently required subsequent AVR after a long follow-up period. Furthermore, the clinical outcomes measured, including survival and valve-related complications, did not differ long-term between groups in both the unmatched and propensity-matched populations. Finally, the nature of aortic valvular pathology proved to be an independent predictor of progression to significant AVD in the aftermath of rheumatic MVR. Rheumatic heart disease is rare in advanced nations such as the USA but remains an important cause of AS or AR in developing countries [7, 12, 13]. A sizeable proportion of patients with rheumatic heart disease have multivalvular involvement, primarily joint involvement of mitral and aortic valves (up to one-third of patients) [1, 12, 14]. Unfortunately, the natural evolution of mild-to-moderate rheumatic AVD remains poorly understood, creating a surgical dilemma. In patients with mild or moderate AVD who require MVR, there is controversy regarding the need for concomitant AVR. Combined procedure (AVR and MVR) generally carries higher procedural risk and leads to poorer long-term survival, compared with isolated replacement of either valve [5, 15]. To date, few published reports have chronicled the fate of untreated AVD after MVR for rheumatic mitral valve disease [3–5]. Vaturi et al. [3] have determined that mild AVD at the time of MVR rarely progresses to moderate or severe AVD, even after a lengthy follow-up period. Only 2% of their patients with mild AVD showed sufficient progression to warrant AVR after a 13-year mean follow-up duration. Ha et al. [5] have also concluded that mild-to-moderate AVD can go untreated at the time of MVR, with negligible risk of subsequent AVR. However, before and after propensity score matching, a significant percentage of our patients who initially displayed mild or moderate AVD progressed to significant AVD (before: 12.0% in the AVD group vs 2.0% in the NA group, P < 0.001; after: 12.5% vs 1.3%, P < 0.001, respectively). In addition, freedom from significant AVD at 20 years was significantly higher in the NA group than in the AVD group (before: 96.5% vs 73.7%, P < 0.001; after; 98.1% vs 73.3%, P < 0.001, respectively). Although the basis for above results is unclear, the haemodynamic effects of AVD may well be masked in the presence of severe mitral stenosis resulting from smaller stroke volume [16, 17], so that measured gradients falsely reflect the severity of AVD. Also, the pressure gradient across aortic valve may be elevated postoperatively owing to increased left ventricular preload after MVR, and enhanced blood flow through a previously diseased AV may increase AR considerably after MVR. Unlike degenerative or congenital disorders, rheumatic heart disease is marked by a slowly progressive process [18–20]. Pathologically, inflammation may develop as a result of damage to the valvular endothelium due to the chronic inflammation resulting from rheumatic heart disease. Rheumatic AS is characterized by fusion of the valve commissures because of an inflammatory response. The valve is vulnerable to valvular injury, often eventually resulting in valve fibrosis and calcification. As the aortic valve becomes progressively calcified, the leaflets become less mobile and the aortic valve orifice becomes increasingly stenotic [13, 21]. Valvular stenosis then ensues, which is associated with varying degrees of regurgitation, arrhythmias, atrial dilatation and ventricular dysfunction [13]. Valvular calcification seemingly is the most reliable predictor of outcome in mild-to-moderate AS [21, 22]. Furthermore, rheumatic AS is almost always seen in conjunction with rheumatic mitral stenosis, as the mitral valve is more frequently affected by rheumatic heart disease than the aortic valve. Although the progression of AS is expectedly slow, it may be remarkably rapid paced in certain individuals [23, 24]. It has been suggested that mild AS imparts a greater degree of AVD than mild AR. Indeed, Choudhary et al. [4] have documented a very slow progression of AVD and little need for reintervention in patients with mild AR, whereas mild AS was found to progress more rapidly and occur more frequently. Using a multivariate Cox regression model, we identified AR (HR = 7.296) and AS (HR = 21.542) as independent predictors of significant AVD in our patient population. On average, significant AVD materialized over a significantly shorter period time in patients with AS, as opposed to those with AR only (9.7 ± 4.7 vs 16.01 ± 6.2 years, respectively; P = 0.003). These results are aligned with previous efforts showing progression of native AVD in patients with AS, indicating that the turbulent flow from stenotic valves may contribute to leaflet damage (i.e. advanced commissural fusion and valvular deformity), inflicting further haemodynamic stress and potentially accelerating disease progression [4, 21, 25]. In the majority of patients with AR, the course of disease is chronic and slowly progressive [26], associated with rising LV volume overload and attempted adaptation (chamber dilation and eccentric hypertrophy). LV ejection fraction and diastolic dimension are components of afterload stress that reflect systolic dysfunction and are important in predicting outcomes of progressive AR [27, 28]. A patient with mild or moderate AR but normal LV dimensions is generally free of any clinical ramifications, showing only slight deformity of 1 or more leaflets [29]. Accordingly, our analysis demonstrates that mild AR present at the time of MVR rarely advances to moderate or severe AVD and that subsequent AVR is rarely needed in patients followed at length. As noted in the guidelines for managing patients with valvular heart disease, AVR is considered reasonable in patients with moderate AS and at aortic velocities of 3.0–3.9 m/s or mean pressure gradients of 20–39 mmHg, given other indications for cardiac surgery. AVR is also reasonable in patients with moderate AR who are scheduled for surgery of ascending aorta, coronary artery bypass grafts or mitral valve surgery (Class IIa recommendation) [7, 30]. Although few patients required reoperation for AVRs during the follow-up period, 11 of 31 patients who met the criteria for AVR did not undergo surgical treatment, and only 1 surgery was performed expressly for AR progression. The primary indications for cardiac reoperation were extraneous (severe TR, mitral prosthetic valve dysfunction, infective endocarditis or severe AS). In our previous study, progression of AVD notably was marginal until 10 years postoperatively [5], with no difference between groups. However, in the present study, groups diverged significantly after the 5th year of follow-up. The progression of AVD became prominent after postoperative 5 years, and it rapidly increased at postoperative 10 years in both the unmatched and matched populations. These findings may affect treatment decisions, depending on patients’ circumstances. In our institution, members of the heart valve team discuss the timing of surgery together and make the final decision. Severity of the patient’s symptoms is also considered to be the most important factor of surgical indication. Limitations This study has several acknowledged limitations, the first being its non-randomized and retrospective nature. Selection bias may thus be implicated, although all patients had rheumatic heart disease. Similarly, the relatively small number of patients with AVD was insufficient to ensure statistically robust inferences. After propensity score matching, early complications and long-term outcomes were also similar compared to the unmatched population. Furthermore, as the number of patients with TV surgery was relatively small, we considered that unidentified confounding bias may have influenced the results. Therefore, another propensity score matching to balance confounders (especially, TR grade and TV surgery) between groups is required. To avoid statistical errors, the results based on matched or unmatched data need to be interpreted with caution. It is also worth noting that we lacked a comparator group of patients with mild AVD in whom prophylactic AVR or repair was undertaken; and the timing of AVD progression was approximate, presumed to be the date of discovery by echocardiography. Finally, this homogenous study population was drawn from a single institution, perhaps limiting the generalizability of findings. Although progression of AVD did not significantly impact long-term survival during a lengthy period of follow-up, a significant number of patients with mild AVD at the time of MVR gradually progressed to substantial AVD after the first 5 postoperative years. Moreover, after postoperative 10 years, those patients more rapidly progressed to significant AVD. In particular, considering the occurrence of patient–prosthesis mismatch or pannus formation when the prosthetic aortic valve was inserted at the time of MVR, it would be important to determine the timing of AVR through watchful echocardiographic monitoring. Therefore, we suggest that aggressive echocardiography should be performed at 5 years after MVR surgery in order to confirm AVD progression and determine the appropriate timing of AVR. SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. Conflict of interest: none declared. REFERENCES 1 Bland EF , Jones D. Rheumatic fever and rheumatic heart disease; a twenty year report on 1000 patients followed since childhood . Circulation 1951 ; 4 : 836 – 43 . Google Scholar CrossRef Search ADS PubMed 2 Roberts WC , Virmani R. Aschoff bodies at necropsy in valvular heart disease. Evidence from an analysis of 543 patients over 14 years of age that rheumatic heart disease, at least anatomically, is a disease of the mitral valve . Circulation 1978 ; 57 : 803 – 7 . Google Scholar CrossRef Search ADS PubMed 3 Vaturi M , Porter A , Adler Y , Shapira Y , Sahar G , Vidne B et al. The natural history of aortic valve disease after mitral valve surgery . J Am Coll Cardiol 1999 ; 33 : 2003 – 8 . Google Scholar CrossRef Search ADS PubMed 4 Choudhary SK , Talwar S , Juneja R , Kumar AS. Fate of mild aortic valve disease after mitral valve intervention . J Thorac Cardiovasc Surg 2001 ; 122 : 583 – 6 . Google Scholar CrossRef Search ADS PubMed 5 Ha J-W , Choi S-H , Chang B-C , Nam CM , Jang Y , Chung N et al. Is prophylactic aortic valve replacement indicated during mitral valve surgery for mild to moderate aortic valve disease? Ann Thorac Surg 2002 ; 74 : 1115 – 19 . Google Scholar CrossRef Search ADS PubMed 6 Taylor R. Evolution of the continuity equation in the Doppler echocardiographic assessment of the severity of valvular aortic stenosis . J Am Soc Echocardiogr 1990 ; 3 : 326 – 30 . Google Scholar CrossRef Search ADS PubMed 7 Nishimura RA , Otto CM , Bonow RO , Carabello BA , Erwin JP 3rd , Guyton RA et al. 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 . Circulation 2014 ; 129 : 2440 – 92 . Google Scholar CrossRef Search ADS PubMed 8 Zoghbi WA , Enriquez SM , Foster E , Grayburn PA , Kraft CD , Levine RA et al. 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Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

Natural history of mild aortic valve disease untreated at the time of rheumatic mitral valve replacement

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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1569-9285
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Abstract

Abstract OBJECTIVES The aim of this study was to examine long-term clinical outcomes and to assess the eventual need for aortic valve replacement (AVR) in patients with mild aortic valve disease (AVD) at the time of mitral valve replacement. METHODS Between 1990 and 2015, 1231 patients undergoing mitral valve replacement were reviewed, stratifying subjects as those with AVD (n = 363) or without AVD (NA; n = 868). Primary end points were progressive AVD (grade ≥ II) and subsequent AVR. Overall mortality and valve-related complications served as secondary end points. Propensity score matching was used for risk adjustment (n = 320 in each group). RESULTS No differences in postoperative complications or clinical outcomes were observed between groups. The 20-year overall survival was similar (before matching: NA 86.1% vs AVD 80.8%, P = 0.128; after matching: 83.5% vs 81.1%, P = 0.425). Of the entire cohort, progressive AVD was observed in 162 patients, and significant AVD (grade ≥ III) was observed in only 60 patients. Subsequent AVR was required in 37 patients due to mitral valve (MV) dysfunction or severe aortic stenosis. The 20-year freedom from significant AVD and subsequent AVR was significantly higher in the NA group than in the AVD group before and after matching (before: NA, 96.5% vs 73.7%, P < 0.001; AVD, 98.5% vs 82.3%, P < 0.001; after: 98.1% vs 73.3%, P < 0.001; 99.3% vs 82.5%, P < 0.001, respectively). CONCLUSIONS Although progressive AVD did not significantly impact long-term survival during the follow-up period, those patients qualifying initially as mild AVD may eventually progress to significant AVD after the first 5 postoperative years. Therefore, aggressive echocardiography should be performed at 5-year lapse after mitral valve replacement to determine the appropriate timing of AVR. Aortic valve disease , Rheumatic heart disease , Mitral valve replacement INTRODUCTION Rheumatic heart disease is one of the most common causes of heart failure and associated mortalities or morbidities in the young populations of developing countries. A significant proportion of patients with rheumatic heart disease show involvement of both mitral and aortic valves [1, 2], approximately one-third displaying some degree of aortic valve regurgitation or stenosis (AR or AS). There is general consensus that in patients undergoing mitral valve replacement (MVR), aortic valve replacement (AVR) is also indicated if AR or AS is severe, symptomatic and associated with left ventricular dysfunction. However, in those with mild-to-moderate aortic valve disease (AVD), the natural history of progressive AVD remains unknown [3–5]. Because combined intervention (MVR and AVR) usually carries higher operative risk, with poorer long-term survival expected (vs MVR only), it is difficult to gauge the need for prophylactic AVR, unless AVD is severe. In a previous study, we demonstrated that coexistent AVD at the time of MVR was not associated with inferior outcomes, given the generally slow progression of mild or moderate AVD; and throughout a lengthy follow-up period, subsequent AVR was rarely needed [5]. Although the prevalence of rheumatic heart disease is still high in our country, the lack of long-term data and the few studies addressing this issue have provided little guidance for establishing an ideal means of managing such patients. The purpose of this study was to examine long-term clinical outcomes in this setting, assessing the need for subsequent AVR if mild-to-moderate AVD coexists at the time of MVR. MATERIALS AND METHODS Study population A retrospective review was conducted by analysing 1852 consecutive patients who underwent MVR at the Severance Cardiovascular Hospital, Yonsei University College of Medicine, between January 1990 and December 2015. Criteria for exclusion were non-rheumatic valve disease (n = 53), congenital heart disease (n = 74), ischaemic or dilated cardiomyopathy (n = 19), infective endocarditis (n = 87), the presence of severe AVD at the time of surgery (n = 26), previous aortic valve surgery (n = 24), double-valve replacement (n = 45) or lack of follow-up data (n = 293). The 1231 patients who qualified for the study were followed up using Doppler echocardiography in our valve clinic. Patients were assigned to one of 2 groups as follows: those with mild-to-moderate AVD (the AVD group, n = 363) or those without AVD (the NA group, n = 868). In each patient, preoperative diagnostics included transthoracic echocardiography, transoesophageal echocardiography and coronary valve computed tomography, during which valve morphology, the presence of left atrial thrombus and haemodynamic parameters were assessed. All subjects were granted written informed consent, and our internal review board approved the study protocol (approval number: 4-2017-0779). Echocardiographic evaluation Standard echocardiographic studies were performed prior to surgical procedures, during the early postoperative period (≤2 weeks), at 1 year and thereafter once every 2-year postoperative mark. In patients with normal left ventricular systolic function, the mean pressure gradient (calculated via the modified Bernoulli equation using continuous-wave Doppler recordings) [6] denoted the severity of AS (mild <25 mm Hg, moderate 25–40 mm Hg and severe >40 mm Hg) [7]. In those with left ventricular systolic dysfunction, the severity of AS corresponded with aortic valve area (mild >1.5 cm2, moderate 1.0–1.5 cm2 and severe <1.0 cm2). AR was graded by colour Doppler, applying a standard index (i.e. regurgitation volume) recommended by the American Society of Echocardiography [8, 9] (Grade I/mild <30 ml, Grade II/moderate 30–44 ml, Grade III/moderate-to-severe 45–59 ml and Grade IV/severe >60 ml). The ratio of maximal AR jet width to left ventricular outflow tract diameter and vena contracta was measured in long-axis views. Clinical outcomes and follow-up monitoring Primary end points of this study were rate of progressive or significant AVD and the need for subsequent AVR, with secondary end points of overall survival and valve-related complications. Clinical and echocardiographic data were obtained from archived hospital records, follow-up monitoring was achieved through patient visits (88.1%) or telephone interviews (11.9%) and searching the ‘cause of death’ statistics was provided by the Statistics Korea. Follow-up was closed on 30 June 2017. Clinical outcomes assessed all-cause mortality, progressive AVD, subsequent AVR and valve-related complications. All-cause mortality was defined as death from any cause after MVR. Cardiac death was defined as deaths from cardiac causes, such as valve-related, sudden unexplained or non-valve-related deaths (from heart failure, acute myocardial infarction or documented arrhythmias) [10]. Progressive AVD was defined as Grade II or more for AR, or as moderate or more for AS [8, 11]. Significant AVD was defined as Grades III–IV for AR, or as moderate-to-severe or more for AS. Valve thrombosis, embolism and bleeding (formerly anticoagulant haemorrhage) constituted valve-related events, as specified in the American Association for Thoracic Surgery Guidelines for reporting morbidity and mortality after cardiac valve interventions [10]. The mean clinical follow-up duration was 12.8 ± 7.3 years (range 0.2–27.4 years), completing follow-up echocardiography data collection in 99.4% (1223 of 1231) during a follow-up period of 11.2 ± 7.3 years (range 0.1–26.9 years). Statistical analysis All data are expressed as mean ± standard deviation or frequency and percentage. Between-group statistical comparisons were achieved using independent samples t-test for continuous variables. All categorical variables were compared between the groups using the χ2 test when the number of cells with expected frequency was 5 or more and using the Fisher’s exact test when the number of cells with expected frequency was less than 5 in any group. Overall survival from the time of surgery, freedom from progressive AVD and subsequent AVR curves were estimated using the Kaplan–Meier method, performing comparisons using the log-rank test. Propensity scores, which were calculated from baseline variables of age, female, body surface area, Society Thoracic Surgeons (STS) risk score, smoking, atrial fibrillation, hypertension, diabetes mellitus, chronic kidney disease, cerebrovascular accident, chronic obstructive pulmonary disease, coronary or peripheral artery disease, previous open mitral commissurotomy or percutaneous mitral valvuloplasty, type of mitral disease (regurgitation, stenosis or mixed lesions), tricuspid regurgitation (TR, Grade ≥ III), left ventricular ejection fraction and end systolic/diastolic dimension, left atrial diameter, prosthesis type and combined procedures, were used to match patients in 2 groups and were estimated by logistic regression. Patient-to-patient matching was performed using the nearest neighbour matching without replacement, with default caliper of 0.2. The Cox proportional hazard regression model was engaged to determine independent risk factors for time-related events (significant AVD and subsequent AVR) after adjusting for multiple baseline covariates. All confounders with P-values <0.2 were included as candidate covariate in the backwards stepwise selection algorithm. The proportional hazards assumption was confirmed by examination of the Grambsch and Therneau test (time-dependent coefficient). Statistical computations relied on standard software, IBM SPSS version 23.0 (IBM Corp., Armonk, NY, USA), setting significance at P <0.05. RESULTS Patient characteristics and operative data Patient demographics and echocardiographic data are listed in Table 1. In the unmatched population, the mean patient age was 51.7 ± 12.5 years, and the majority were female (868 of 1231, 70.5%). There were significant preoperative differences between groups in terms of age, history of diabetes mellitus, predominance of mitral stenosis, and left ventricular ejection fraction. With respect to mitral valve pathology, stenosis predominated in 741 patients (60.2%) and regurgitation in 365 patients (29.7%), whereas 125 patients (10.2%) displayed both. After propensity score matching, characteristics of both groups were comparable (n = 320 in each group). AR predominated in 265 patients (82.8%), AS in 25 patients (7.8%) and mixed in 30 patients (9.4%). Table 1: Patient characteristics and echocardiography data Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Age (years) 52.8 ± 13.2 51.2 ± 12.1 0.046 51.6 ± 12.8 52.0 ± 11.8 0.690 Female 257 (70.8) 611 (70.4) 0.886 221 (69.1) 220 (68.8) >0.999 BSA (m2) 1.56 ± 0.15 1.56 ± 0.16 0.575 1.57 ± 0.15 1.57 ± 0.16 0.752 STS score 2.12 ± 1.48 1.94 ± 1.54 0.062 2.01 ± 1.35 1.96 ± 1.35 0.622 Atrial fibrillation 335 (92.3) 798 (91.9) 0.836 293 (91.6) 285 (89.1) 0.350 Current smoker 41 (11.3) 92 (10.6) 0.720 36 (11.3) 36 (11.3) >0.999 Hypertension 29 (8.0) 79 (9.1) 0.529 27 (8.4) 24 (7.5) 0.766 Diabetes mellitus 32 (8.8) 47 (5.4) 0.026 21 (6.6) 16 (5.0) 0.511 Chronic kidney disease 2 (0.6) 7 (0.8) >0.999 2 (0.6) 2 (0.6) >0.999 Cerebrovascular accidents 38 (10.5) 96 (11.1) 0.761 37 (11.6) 33 (10.3) 0.704 COPD 11 (3.0) 25 (2.9) 0.887 9 (2.8) 13 (4.1) 0.481 Coronary artery disease 15 (4.1) 28 (3.2) 0.430 12 (3.8) 15 (4.7) 0.701 Peripheral artery disease 8 (2.2) 22 (2.5) 0.732 8 (2.5) 9 (2.8) >0.999 Previous OMC 17 (4.7) 35 (4.0) 0.605 15 (4.7) 14 (4.4) >0.999 Previous PMV 60 (16.5) 127 (14.6) 0.398 51 (15.9) 53 (16.6) 0.911 Predominant mitral valve disease 0.002 0.745  Mitral stenosis 245 (67.5) 496 (57.1) 209 (65.3) 208 (65.0)  Mitral regurgitation 84 (23.1) 281 (32.4) 80 (25.0) 75 (23.4)  Mixed 34 (9.4) 91 (10.5) 31 (9.7) 37 (11.6) Predominant aortic valve disease <0.001 <0.001  Aortic stenosis 32 (8.8) 0 25 (7.8) 0  Aortic regurgitation 294 (81.0) 0 265 (82.8) 0  Mixeda 37 (10.2) 0 30 (9.4) 0 Tricuspid regurgitation (grade ≥ III) 93 (25.6) 158 (18.2) 0.003 72 (22.5) 61 (19.1) 0.310 LVEF (%) 59.8 ± 9.8 61.7 ± 9.1 0.001 60.2 ± 9.7 60.3 ± 9.2 0.902 LVESD (mm) 36.9 ± 7.0 36.2 ± 7.4 0.117 36.9 ± 7.0 36.9 ± 7.8 0.918 LVEDD (mm) 52.7 ± 8.0 53.3 ± 19.6 0.576 52.9 ± 8.0 52.8 ± 9.7 0.910 Left atrial diameter (mm) 60.5 ± 11.4 59.3 ± 11.8 0.095 60.3 ± 11.6 60.6 ± 11.6 0.761 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Age (years) 52.8 ± 13.2 51.2 ± 12.1 0.046 51.6 ± 12.8 52.0 ± 11.8 0.690 Female 257 (70.8) 611 (70.4) 0.886 221 (69.1) 220 (68.8) >0.999 BSA (m2) 1.56 ± 0.15 1.56 ± 0.16 0.575 1.57 ± 0.15 1.57 ± 0.16 0.752 STS score 2.12 ± 1.48 1.94 ± 1.54 0.062 2.01 ± 1.35 1.96 ± 1.35 0.622 Atrial fibrillation 335 (92.3) 798 (91.9) 0.836 293 (91.6) 285 (89.1) 0.350 Current smoker 41 (11.3) 92 (10.6) 0.720 36 (11.3) 36 (11.3) >0.999 Hypertension 29 (8.0) 79 (9.1) 0.529 27 (8.4) 24 (7.5) 0.766 Diabetes mellitus 32 (8.8) 47 (5.4) 0.026 21 (6.6) 16 (5.0) 0.511 Chronic kidney disease 2 (0.6) 7 (0.8) >0.999 2 (0.6) 2 (0.6) >0.999 Cerebrovascular accidents 38 (10.5) 96 (11.1) 0.761 37 (11.6) 33 (10.3) 0.704 COPD 11 (3.0) 25 (2.9) 0.887 9 (2.8) 13 (4.1) 0.481 Coronary artery disease 15 (4.1) 28 (3.2) 0.430 12 (3.8) 15 (4.7) 0.701 Peripheral artery disease 8 (2.2) 22 (2.5) 0.732 8 (2.5) 9 (2.8) >0.999 Previous OMC 17 (4.7) 35 (4.0) 0.605 15 (4.7) 14 (4.4) >0.999 Previous PMV 60 (16.5) 127 (14.6) 0.398 51 (15.9) 53 (16.6) 0.911 Predominant mitral valve disease 0.002 0.745  Mitral stenosis 245 (67.5) 496 (57.1) 209 (65.3) 208 (65.0)  Mitral regurgitation 84 (23.1) 281 (32.4) 80 (25.0) 75 (23.4)  Mixed 34 (9.4) 91 (10.5) 31 (9.7) 37 (11.6) Predominant aortic valve disease <0.001 <0.001  Aortic stenosis 32 (8.8) 0 25 (7.8) 0  Aortic regurgitation 294 (81.0) 0 265 (82.8) 0  Mixeda 37 (10.2) 0 30 (9.4) 0 Tricuspid regurgitation (grade ≥ III) 93 (25.6) 158 (18.2) 0.003 72 (22.5) 61 (19.1) 0.310 LVEF (%) 59.8 ± 9.8 61.7 ± 9.1 0.001 60.2 ± 9.7 60.3 ± 9.2 0.902 LVESD (mm) 36.9 ± 7.0 36.2 ± 7.4 0.117 36.9 ± 7.0 36.9 ± 7.8 0.918 LVEDD (mm) 52.7 ± 8.0 53.3 ± 19.6 0.576 52.9 ± 8.0 52.8 ± 9.7 0.910 Left atrial diameter (mm) 60.5 ± 11.4 59.3 ± 11.8 0.095 60.3 ± 11.6 60.6 ± 11.6 0.761 Values are presented as mean ± SD or n (%). a Mixed lesion means that AS (severity of mild or moderate) was mixed with AR (Grade I or II) at the time of preoperative echocardiography evaluation. AR: aortic valve regurgitation; AS: aortic valve stenosis; AVD: aortic valve disease; BSA: body surface area; COPD: chronic obstructive pulmonary disease; LVEDD: left ventricular end diastolic dimension; LVEF: left ventricular ejection fraction; LVESD: left ventricular end systolic dimension; OMC: open mitral commissurotomy; PMV: percutaneous mitral valvuloplasty; SD: standard deviation; STS: Society Thoracic Surgeons. Table 1: Patient characteristics and echocardiography data Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Age (years) 52.8 ± 13.2 51.2 ± 12.1 0.046 51.6 ± 12.8 52.0 ± 11.8 0.690 Female 257 (70.8) 611 (70.4) 0.886 221 (69.1) 220 (68.8) >0.999 BSA (m2) 1.56 ± 0.15 1.56 ± 0.16 0.575 1.57 ± 0.15 1.57 ± 0.16 0.752 STS score 2.12 ± 1.48 1.94 ± 1.54 0.062 2.01 ± 1.35 1.96 ± 1.35 0.622 Atrial fibrillation 335 (92.3) 798 (91.9) 0.836 293 (91.6) 285 (89.1) 0.350 Current smoker 41 (11.3) 92 (10.6) 0.720 36 (11.3) 36 (11.3) >0.999 Hypertension 29 (8.0) 79 (9.1) 0.529 27 (8.4) 24 (7.5) 0.766 Diabetes mellitus 32 (8.8) 47 (5.4) 0.026 21 (6.6) 16 (5.0) 0.511 Chronic kidney disease 2 (0.6) 7 (0.8) >0.999 2 (0.6) 2 (0.6) >0.999 Cerebrovascular accidents 38 (10.5) 96 (11.1) 0.761 37 (11.6) 33 (10.3) 0.704 COPD 11 (3.0) 25 (2.9) 0.887 9 (2.8) 13 (4.1) 0.481 Coronary artery disease 15 (4.1) 28 (3.2) 0.430 12 (3.8) 15 (4.7) 0.701 Peripheral artery disease 8 (2.2) 22 (2.5) 0.732 8 (2.5) 9 (2.8) >0.999 Previous OMC 17 (4.7) 35 (4.0) 0.605 15 (4.7) 14 (4.4) >0.999 Previous PMV 60 (16.5) 127 (14.6) 0.398 51 (15.9) 53 (16.6) 0.911 Predominant mitral valve disease 0.002 0.745  Mitral stenosis 245 (67.5) 496 (57.1) 209 (65.3) 208 (65.0)  Mitral regurgitation 84 (23.1) 281 (32.4) 80 (25.0) 75 (23.4)  Mixed 34 (9.4) 91 (10.5) 31 (9.7) 37 (11.6) Predominant aortic valve disease <0.001 <0.001  Aortic stenosis 32 (8.8) 0 25 (7.8) 0  Aortic regurgitation 294 (81.0) 0 265 (82.8) 0  Mixeda 37 (10.2) 0 30 (9.4) 0 Tricuspid regurgitation (grade ≥ III) 93 (25.6) 158 (18.2) 0.003 72 (22.5) 61 (19.1) 0.310 LVEF (%) 59.8 ± 9.8 61.7 ± 9.1 0.001 60.2 ± 9.7 60.3 ± 9.2 0.902 LVESD (mm) 36.9 ± 7.0 36.2 ± 7.4 0.117 36.9 ± 7.0 36.9 ± 7.8 0.918 LVEDD (mm) 52.7 ± 8.0 53.3 ± 19.6 0.576 52.9 ± 8.0 52.8 ± 9.7 0.910 Left atrial diameter (mm) 60.5 ± 11.4 59.3 ± 11.8 0.095 60.3 ± 11.6 60.6 ± 11.6 0.761 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Age (years) 52.8 ± 13.2 51.2 ± 12.1 0.046 51.6 ± 12.8 52.0 ± 11.8 0.690 Female 257 (70.8) 611 (70.4) 0.886 221 (69.1) 220 (68.8) >0.999 BSA (m2) 1.56 ± 0.15 1.56 ± 0.16 0.575 1.57 ± 0.15 1.57 ± 0.16 0.752 STS score 2.12 ± 1.48 1.94 ± 1.54 0.062 2.01 ± 1.35 1.96 ± 1.35 0.622 Atrial fibrillation 335 (92.3) 798 (91.9) 0.836 293 (91.6) 285 (89.1) 0.350 Current smoker 41 (11.3) 92 (10.6) 0.720 36 (11.3) 36 (11.3) >0.999 Hypertension 29 (8.0) 79 (9.1) 0.529 27 (8.4) 24 (7.5) 0.766 Diabetes mellitus 32 (8.8) 47 (5.4) 0.026 21 (6.6) 16 (5.0) 0.511 Chronic kidney disease 2 (0.6) 7 (0.8) >0.999 2 (0.6) 2 (0.6) >0.999 Cerebrovascular accidents 38 (10.5) 96 (11.1) 0.761 37 (11.6) 33 (10.3) 0.704 COPD 11 (3.0) 25 (2.9) 0.887 9 (2.8) 13 (4.1) 0.481 Coronary artery disease 15 (4.1) 28 (3.2) 0.430 12 (3.8) 15 (4.7) 0.701 Peripheral artery disease 8 (2.2) 22 (2.5) 0.732 8 (2.5) 9 (2.8) >0.999 Previous OMC 17 (4.7) 35 (4.0) 0.605 15 (4.7) 14 (4.4) >0.999 Previous PMV 60 (16.5) 127 (14.6) 0.398 51 (15.9) 53 (16.6) 0.911 Predominant mitral valve disease 0.002 0.745  Mitral stenosis 245 (67.5) 496 (57.1) 209 (65.3) 208 (65.0)  Mitral regurgitation 84 (23.1) 281 (32.4) 80 (25.0) 75 (23.4)  Mixed 34 (9.4) 91 (10.5) 31 (9.7) 37 (11.6) Predominant aortic valve disease <0.001 <0.001  Aortic stenosis 32 (8.8) 0 25 (7.8) 0  Aortic regurgitation 294 (81.0) 0 265 (82.8) 0  Mixeda 37 (10.2) 0 30 (9.4) 0 Tricuspid regurgitation (grade ≥ III) 93 (25.6) 158 (18.2) 0.003 72 (22.5) 61 (19.1) 0.310 LVEF (%) 59.8 ± 9.8 61.7 ± 9.1 0.001 60.2 ± 9.7 60.3 ± 9.2 0.902 LVESD (mm) 36.9 ± 7.0 36.2 ± 7.4 0.117 36.9 ± 7.0 36.9 ± 7.8 0.918 LVEDD (mm) 52.7 ± 8.0 53.3 ± 19.6 0.576 52.9 ± 8.0 52.8 ± 9.7 0.910 Left atrial diameter (mm) 60.5 ± 11.4 59.3 ± 11.8 0.095 60.3 ± 11.6 60.6 ± 11.6 0.761 Values are presented as mean ± SD or n (%). a Mixed lesion means that AS (severity of mild or moderate) was mixed with AR (Grade I or II) at the time of preoperative echocardiography evaluation. AR: aortic valve regurgitation; AS: aortic valve stenosis; AVD: aortic valve disease; BSA: body surface area; COPD: chronic obstructive pulmonary disease; LVEDD: left ventricular end diastolic dimension; LVEF: left ventricular ejection fraction; LVESD: left ventricular end systolic dimension; OMC: open mitral commissurotomy; PMV: percutaneous mitral valvuloplasty; SD: standard deviation; STS: Society Thoracic Surgeons. As seen in Table 2, before propensity score matching, concomitant procedures were performed in 719 patients (58.4%), including maze operation (16.8%), tricuspid valve surgery (TVS, 42.3%) and left atrial thrombectomy (13.3%). More patients underwent TVS in the AVD group than in the NA group (P = 0.028). TVS was performed in 280 (44.4%) patients in the matched population. Comparison of concomitant TVS and non-TVS showed that the incidence of significant TR (Grade ≥ III) was significantly different in the unmatched population (14.0% vs 8.6%, P = 0.003) but not in the propensity-matched population (7.4% vs 8.6%, P = 0.617) (Supplementary Material, Tables S1 and S2). Table 2: Perioperative data Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Mechanical prosthesis 290 (79.9) 770 (88.7) <0.001 273 (85.3) 272 (85.0) >0.999 Valve size (mm) 0.544 0.668  25 28 (7.7) 70 (8.1) 20 (6.3) 27 (8.4)  27 139 (38.3) 284 (32.7) 118 (36.9) 104 (32.5)  29 144 (39.7) 376 (43.3) 133 (41.6) 135 (42.2)  31 46 (12.7) 120 (13.8) 44 (13.8) 47 (14.7)  33 6 (1.7) 18 (2.1) 5 (1.6) 7 (2.2) Concomitant procedures  Maze operation 66 (18.2) 141 (16.2) 0.407 57 (17.8) 67 (20.9) 0.391  Tricuspid annuloplasty 171 (47.1) 350 (40.3) 0.028 141 (44.1) 143 (44.7) 0.936  LA thrombectomy 55 (15.2) 109 (12.6) 0.222 49 (15.3) 38 (11.9) 0.205 Operative time (min) 237.3 ± 62.7 245.7 ± 66.8 0.041 237.6 ± 64.1 246.9 ± 67.8 0.075 CPB time (min) 110.8 ± 36.3 111.4 ± 36.7 0.785 110.1 ± 37.0 114.1 ± 37.3 0.172 ACC time (min) 78.3 ± 28.5 78.9 ± 29.0 0.742 77.5 ± 28.8 81.7 ± 30.3 0.070 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Mechanical prosthesis 290 (79.9) 770 (88.7) <0.001 273 (85.3) 272 (85.0) >0.999 Valve size (mm) 0.544 0.668  25 28 (7.7) 70 (8.1) 20 (6.3) 27 (8.4)  27 139 (38.3) 284 (32.7) 118 (36.9) 104 (32.5)  29 144 (39.7) 376 (43.3) 133 (41.6) 135 (42.2)  31 46 (12.7) 120 (13.8) 44 (13.8) 47 (14.7)  33 6 (1.7) 18 (2.1) 5 (1.6) 7 (2.2) Concomitant procedures  Maze operation 66 (18.2) 141 (16.2) 0.407 57 (17.8) 67 (20.9) 0.391  Tricuspid annuloplasty 171 (47.1) 350 (40.3) 0.028 141 (44.1) 143 (44.7) 0.936  LA thrombectomy 55 (15.2) 109 (12.6) 0.222 49 (15.3) 38 (11.9) 0.205 Operative time (min) 237.3 ± 62.7 245.7 ± 66.8 0.041 237.6 ± 64.1 246.9 ± 67.8 0.075 CPB time (min) 110.8 ± 36.3 111.4 ± 36.7 0.785 110.1 ± 37.0 114.1 ± 37.3 0.172 ACC time (min) 78.3 ± 28.5 78.9 ± 29.0 0.742 77.5 ± 28.8 81.7 ± 30.3 0.070 Values are presented as mean ± SD or n (%). ACC: aortic cross-clamp; AVD: aortic valve disease; CPB: cardiopulmonary bypass; LA: left atrium; SD: standard deviation. Table 2: Perioperative data Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Mechanical prosthesis 290 (79.9) 770 (88.7) <0.001 273 (85.3) 272 (85.0) >0.999 Valve size (mm) 0.544 0.668  25 28 (7.7) 70 (8.1) 20 (6.3) 27 (8.4)  27 139 (38.3) 284 (32.7) 118 (36.9) 104 (32.5)  29 144 (39.7) 376 (43.3) 133 (41.6) 135 (42.2)  31 46 (12.7) 120 (13.8) 44 (13.8) 47 (14.7)  33 6 (1.7) 18 (2.1) 5 (1.6) 7 (2.2) Concomitant procedures  Maze operation 66 (18.2) 141 (16.2) 0.407 57 (17.8) 67 (20.9) 0.391  Tricuspid annuloplasty 171 (47.1) 350 (40.3) 0.028 141 (44.1) 143 (44.7) 0.936  LA thrombectomy 55 (15.2) 109 (12.6) 0.222 49 (15.3) 38 (11.9) 0.205 Operative time (min) 237.3 ± 62.7 245.7 ± 66.8 0.041 237.6 ± 64.1 246.9 ± 67.8 0.075 CPB time (min) 110.8 ± 36.3 111.4 ± 36.7 0.785 110.1 ± 37.0 114.1 ± 37.3 0.172 ACC time (min) 78.3 ± 28.5 78.9 ± 29.0 0.742 77.5 ± 28.8 81.7 ± 30.3 0.070 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Mechanical prosthesis 290 (79.9) 770 (88.7) <0.001 273 (85.3) 272 (85.0) >0.999 Valve size (mm) 0.544 0.668  25 28 (7.7) 70 (8.1) 20 (6.3) 27 (8.4)  27 139 (38.3) 284 (32.7) 118 (36.9) 104 (32.5)  29 144 (39.7) 376 (43.3) 133 (41.6) 135 (42.2)  31 46 (12.7) 120 (13.8) 44 (13.8) 47 (14.7)  33 6 (1.7) 18 (2.1) 5 (1.6) 7 (2.2) Concomitant procedures  Maze operation 66 (18.2) 141 (16.2) 0.407 57 (17.8) 67 (20.9) 0.391  Tricuspid annuloplasty 171 (47.1) 350 (40.3) 0.028 141 (44.1) 143 (44.7) 0.936  LA thrombectomy 55 (15.2) 109 (12.6) 0.222 49 (15.3) 38 (11.9) 0.205 Operative time (min) 237.3 ± 62.7 245.7 ± 66.8 0.041 237.6 ± 64.1 246.9 ± 67.8 0.075 CPB time (min) 110.8 ± 36.3 111.4 ± 36.7 0.785 110.1 ± 37.0 114.1 ± 37.3 0.172 ACC time (min) 78.3 ± 28.5 78.9 ± 29.0 0.742 77.5 ± 28.8 81.7 ± 30.3 0.070 Values are presented as mean ± SD or n (%). ACC: aortic cross-clamp; AVD: aortic valve disease; CPB: cardiopulmonary bypass; LA: left atrium; SD: standard deviation. No statistically significant differences were found in postoperative complications between groups in both the unmatched and matched populations (Table 3). All-cause mortality occurred in 114 patients (9.3%), including 27 cardiac-related deaths due to progressive heart failure, infective endocarditis or sudden death. The overall survival rates at 20 years were 86.1 ± 1.7% in the NA group and 80.8 ± 3.5% in the AVD group (P = 0.128, Fig. 1A). Similar results were observed for the matched population (NA 83.5 ± 3.3% vs AVD 81.1 ± 3.7%, respectively); these rates were not significantly different (P = 0.425, Fig. 1B). Table 3: Clinical outcomes Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Reoperation for bleeding 18 (5.0) 30 (3.5) 0.214 17 (5.3) 14 (4.4) 0.581 Cerebrovascular accidents  Stroke 20 (5.5) 64 (7.4) 0.237 17 (5.3) 24 (7.5) 0.258  TIA 2 (0.6) 5 (0.6) >0.999 2 (0.6) 3 (0.9) >0.999  Cerebral haemorrhage 23 (6.3) 43 (5.0) 0.326 21 (6.6) 18 (5.6) 0.620 Anticoagulation related haemorrhage 23 (6.3) 66 (7.6) 0.434 21 (6.6) 23 (7.2) 0.755 Pacemaker insertion 18 (5.0) 37 (4.3) 0.590 16 (5.0) 13 (4.1) 0.569 Progressive AVD 110 (30.7) 52 (6.0) <0.001 101 (31.6) 13 (4.1) <0.001  Aortic regurgitation 68 (19.0) 30 (3.5) 62 (19.4) 7 (2.2)  Aortic stenosis 26 (7.3) 13 (1.5) 26 (8.1) 2 (0.6)  Mixed 16 (4.5) 9 (1.0) 13 (4.1) 4 (1.3) Significant AVD 43 (12.0) 17 (2.0) <0.001 40 (12.5) 4 (1.3) <0.001 Late TR (Grade ≥III) 53 (14.8) 125 (14.5) 0.873 47 (14.7) 40 (12.5) 0.419 Reoperation 48 (13.2) 74 (8.5) 0.012 41 (12.8) 24 (7.5) 0.026  MVR 8 (2.2) 17 (2.0) 6 (1.9) 7 (2.2)  MVR + TAP/TVR 8 (2.2) 28 (3.2) 7 (2.2) 10 (3.1)  AVR 5 (1.4) 0 (0) 4 (1.3) 0 (0)  AVR + TAP 7 (1.9) 2 (0.2) 6 (1.9) 1 (0.3)  AVR + MVR 5 (1.4) 3 (0.3) 5 (1.6) 0 (0)  AVR + MVR + TAP/TVR 11 (3.0) 4 (0.5) 10 (3.1) 1 (0.3)  TAP/TVR 4 (1.1) 19 (2.2) 3 (0.9) 4 (1.3)  Others 0 (0) 1 (0.1) 0 (0) 1 (0.3) All-cause mortality 38 (10.5) 76 (8.8) 0.345 31 (9.7) 26 (8.1) 0.488  Cardiac death 11 (3.1) 16 (1.9) 0.189 10 (3.2) 5 (1.6) 0.191 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Reoperation for bleeding 18 (5.0) 30 (3.5) 0.214 17 (5.3) 14 (4.4) 0.581 Cerebrovascular accidents  Stroke 20 (5.5) 64 (7.4) 0.237 17 (5.3) 24 (7.5) 0.258  TIA 2 (0.6) 5 (0.6) >0.999 2 (0.6) 3 (0.9) >0.999  Cerebral haemorrhage 23 (6.3) 43 (5.0) 0.326 21 (6.6) 18 (5.6) 0.620 Anticoagulation related haemorrhage 23 (6.3) 66 (7.6) 0.434 21 (6.6) 23 (7.2) 0.755 Pacemaker insertion 18 (5.0) 37 (4.3) 0.590 16 (5.0) 13 (4.1) 0.569 Progressive AVD 110 (30.7) 52 (6.0) <0.001 101 (31.6) 13 (4.1) <0.001  Aortic regurgitation 68 (19.0) 30 (3.5) 62 (19.4) 7 (2.2)  Aortic stenosis 26 (7.3) 13 (1.5) 26 (8.1) 2 (0.6)  Mixed 16 (4.5) 9 (1.0) 13 (4.1) 4 (1.3) Significant AVD 43 (12.0) 17 (2.0) <0.001 40 (12.5) 4 (1.3) <0.001 Late TR (Grade ≥III) 53 (14.8) 125 (14.5) 0.873 47 (14.7) 40 (12.5) 0.419 Reoperation 48 (13.2) 74 (8.5) 0.012 41 (12.8) 24 (7.5) 0.026  MVR 8 (2.2) 17 (2.0) 6 (1.9) 7 (2.2)  MVR + TAP/TVR 8 (2.2) 28 (3.2) 7 (2.2) 10 (3.1)  AVR 5 (1.4) 0 (0) 4 (1.3) 0 (0)  AVR + TAP 7 (1.9) 2 (0.2) 6 (1.9) 1 (0.3)  AVR + MVR 5 (1.4) 3 (0.3) 5 (1.6) 0 (0)  AVR + MVR + TAP/TVR 11 (3.0) 4 (0.5) 10 (3.1) 1 (0.3)  TAP/TVR 4 (1.1) 19 (2.2) 3 (0.9) 4 (1.3)  Others 0 (0) 1 (0.1) 0 (0) 1 (0.3) All-cause mortality 38 (10.5) 76 (8.8) 0.345 31 (9.7) 26 (8.1) 0.488  Cardiac death 11 (3.1) 16 (1.9) 0.189 10 (3.2) 5 (1.6) 0.191 Values are presented as n (%). AVD: aortic valve disease; AVR: aortic valve replacement; MVR: mitral valve replacement; TAP: tricuspid annuloplasty; TIA: transient ischaemic attack; TR: tricuspid regurgitation; TVR: tricuspid valve replacement. Table 3: Clinical outcomes Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Reoperation for bleeding 18 (5.0) 30 (3.5) 0.214 17 (5.3) 14 (4.4) 0.581 Cerebrovascular accidents  Stroke 20 (5.5) 64 (7.4) 0.237 17 (5.3) 24 (7.5) 0.258  TIA 2 (0.6) 5 (0.6) >0.999 2 (0.6) 3 (0.9) >0.999  Cerebral haemorrhage 23 (6.3) 43 (5.0) 0.326 21 (6.6) 18 (5.6) 0.620 Anticoagulation related haemorrhage 23 (6.3) 66 (7.6) 0.434 21 (6.6) 23 (7.2) 0.755 Pacemaker insertion 18 (5.0) 37 (4.3) 0.590 16 (5.0) 13 (4.1) 0.569 Progressive AVD 110 (30.7) 52 (6.0) <0.001 101 (31.6) 13 (4.1) <0.001  Aortic regurgitation 68 (19.0) 30 (3.5) 62 (19.4) 7 (2.2)  Aortic stenosis 26 (7.3) 13 (1.5) 26 (8.1) 2 (0.6)  Mixed 16 (4.5) 9 (1.0) 13 (4.1) 4 (1.3) Significant AVD 43 (12.0) 17 (2.0) <0.001 40 (12.5) 4 (1.3) <0.001 Late TR (Grade ≥III) 53 (14.8) 125 (14.5) 0.873 47 (14.7) 40 (12.5) 0.419 Reoperation 48 (13.2) 74 (8.5) 0.012 41 (12.8) 24 (7.5) 0.026  MVR 8 (2.2) 17 (2.0) 6 (1.9) 7 (2.2)  MVR + TAP/TVR 8 (2.2) 28 (3.2) 7 (2.2) 10 (3.1)  AVR 5 (1.4) 0 (0) 4 (1.3) 0 (0)  AVR + TAP 7 (1.9) 2 (0.2) 6 (1.9) 1 (0.3)  AVR + MVR 5 (1.4) 3 (0.3) 5 (1.6) 0 (0)  AVR + MVR + TAP/TVR 11 (3.0) 4 (0.5) 10 (3.1) 1 (0.3)  TAP/TVR 4 (1.1) 19 (2.2) 3 (0.9) 4 (1.3)  Others 0 (0) 1 (0.1) 0 (0) 1 (0.3) All-cause mortality 38 (10.5) 76 (8.8) 0.345 31 (9.7) 26 (8.1) 0.488  Cardiac death 11 (3.1) 16 (1.9) 0.189 10 (3.2) 5 (1.6) 0.191 Variables Unmatched population Matched population AVD (n = 363) No AVD (n = 868) P-value AVD (n = 320) No AVD (n = 320) P-value Reoperation for bleeding 18 (5.0) 30 (3.5) 0.214 17 (5.3) 14 (4.4) 0.581 Cerebrovascular accidents  Stroke 20 (5.5) 64 (7.4) 0.237 17 (5.3) 24 (7.5) 0.258  TIA 2 (0.6) 5 (0.6) >0.999 2 (0.6) 3 (0.9) >0.999  Cerebral haemorrhage 23 (6.3) 43 (5.0) 0.326 21 (6.6) 18 (5.6) 0.620 Anticoagulation related haemorrhage 23 (6.3) 66 (7.6) 0.434 21 (6.6) 23 (7.2) 0.755 Pacemaker insertion 18 (5.0) 37 (4.3) 0.590 16 (5.0) 13 (4.1) 0.569 Progressive AVD 110 (30.7) 52 (6.0) <0.001 101 (31.6) 13 (4.1) <0.001  Aortic regurgitation 68 (19.0) 30 (3.5) 62 (19.4) 7 (2.2)  Aortic stenosis 26 (7.3) 13 (1.5) 26 (8.1) 2 (0.6)  Mixed 16 (4.5) 9 (1.0) 13 (4.1) 4 (1.3) Significant AVD 43 (12.0) 17 (2.0) <0.001 40 (12.5) 4 (1.3) <0.001 Late TR (Grade ≥III) 53 (14.8) 125 (14.5) 0.873 47 (14.7) 40 (12.5) 0.419 Reoperation 48 (13.2) 74 (8.5) 0.012 41 (12.8) 24 (7.5) 0.026  MVR 8 (2.2) 17 (2.0) 6 (1.9) 7 (2.2)  MVR + TAP/TVR 8 (2.2) 28 (3.2) 7 (2.2) 10 (3.1)  AVR 5 (1.4) 0 (0) 4 (1.3) 0 (0)  AVR + TAP 7 (1.9) 2 (0.2) 6 (1.9) 1 (0.3)  AVR + MVR 5 (1.4) 3 (0.3) 5 (1.6) 0 (0)  AVR + MVR + TAP/TVR 11 (3.0) 4 (0.5) 10 (3.1) 1 (0.3)  TAP/TVR 4 (1.1) 19 (2.2) 3 (0.9) 4 (1.3)  Others 0 (0) 1 (0.1) 0 (0) 1 (0.3) All-cause mortality 38 (10.5) 76 (8.8) 0.345 31 (9.7) 26 (8.1) 0.488  Cardiac death 11 (3.1) 16 (1.9) 0.189 10 (3.2) 5 (1.6) 0.191 Values are presented as n (%). AVD: aortic valve disease; AVR: aortic valve replacement; MVR: mitral valve replacement; TAP: tricuspid annuloplasty; TIA: transient ischaemic attack; TR: tricuspid regurgitation; TVR: tricuspid valve replacement. Figure 1: View largeDownload slide Overall cumulative survival rates for the NA (blue line) and AVD (red line) groups (A) in the unmatched population and (B) in the propensity-matched population. AVD: aortic valve disease; NA: no AVD. Figure 1: View largeDownload slide Overall cumulative survival rates for the NA (blue line) and AVD (red line) groups (A) in the unmatched population and (B) in the propensity-matched population. AVD: aortic valve disease; NA: no AVD. Progression of aortic valve disease During the follow-up period, progressive AVD developed in 162 patients, 60 of whom showed significant AVD (Table 3). In the NA group, 3.5% of patients (30 of 865) showed progression to pure AR (Grade II, n = 24; Grade III, n = 5; Grade IV, n = 1) and 1.5% (13 of 865) progressed to pure AS (moderate, n = 6; moderate-to-severe, n = 2; severe, n = 5). Significant AVD was evident in 17 patients (AR, n = 6; AS, n = 7; mixed, n = 4). In the AVD group, 19.0% of patients (68 of 358) showed progression to pure AR (Grade II, n = 52; Grade III, n = 12; Grade IV, n = 4) and 7.3% of patients (26 of 358) progressed to pure AS (moderate, n = 11; moderate-to-severe, n = 5; severe, n = 10). Significant AVD was evident in 43 patients (AR, n = 16; AS, n = 15; mixed, n = 12). Of the matched patients, progressive AVD was found in 114 patients (AR, n = 69; AS, n = 28; mixed n = 17), and significant AVD was evident in only 44 patients (AR, n = 16, AS, n = 16, mixed, n = 12). Curves generated for freedom from progressive AVD are presented in Fig. 2A. The 20-year rates of freedom from significant AVD were 96.5 ± 1.1% in the NA group and 73.7 ± 4.4 in the AVD group (P < 0.001, Fig. 2B). A total of 122 patients required cardiac reoperations during the follow-up period. Reoperation was performed in 8.6% of patients (74 of 865) without AVD, in 12.7% of patients (41 of 323) with mild AVD and in 20.0% of patients (7 of 35) with moderate AVD. The most common indications for reoperation were mitral valve dysfunction, AVD progression or severe TR (Supplementary Material, Table S3). Subsequent AVR was performed in 37 patients. Predominant AS prompted reoperation in 7 of these 28 patients, whereas predominant AR was the impetus in the remaining 21 cases. Rates of freedom from subsequent AVR at 20 years was 98.5 ± 0.6% in the NA group, compared with 82.3 ± 3.6% in the AVD group [hazard ratio (HR) = 9.301; 95% confidence interval (CI): 4.386–19.724; P < 0.001] (Fig. 2C). In the propensity-matched population, the 20-year freedom from progressive AVD, significant AVD and subsequent AVR rates were significantly different between 2 groups (Fig. 3). Furthermore, 4.1% (13 of 320) of patients with AVD and 5.3% (17 of 320) of patients without AVD underwent MV reoperation due to paravalvular leakage (n = 7 vs 7), pannus formation (n = 3 vs 2), infective endocarditis (n = 3 vs 2) and valve thrombosis (n = 0 vs 6). Figure 2: View largeDownload slide (A) Rates of freedom from progressive AVD, (B) freedom from significant AVD and (C) freedom from reoperation for AVR plotted for the NA (blue line) and AVD (red line) groups in the unmatched population. AVD: aortic valve disease; AVR: aortic valve replacement; NA: no AVD. Figure 2: View largeDownload slide (A) Rates of freedom from progressive AVD, (B) freedom from significant AVD and (C) freedom from reoperation for AVR plotted for the NA (blue line) and AVD (red line) groups in the unmatched population. AVD: aortic valve disease; AVR: aortic valve replacement; NA: no AVD. Figure 3: View largeDownload slide (A) Rates of freedom from progressive AVD, (B) freedom from significant AVD and (C) freedom from reoperation for AVR plotted for the NA (blue line) and AVD (red line) groups in the propensity-matched population. AVD: aortic valve disease; AVR: aortic valve replacement; NA: no AVD. Figure 3: View largeDownload slide (A) Rates of freedom from progressive AVD, (B) freedom from significant AVD and (C) freedom from reoperation for AVR plotted for the NA (blue line) and AVD (red line) groups in the propensity-matched population. AVD: aortic valve disease; AVR: aortic valve replacement; NA: no AVD. Also, the AVD group showed significantly lower freedom from tricuspid valve (TV) reoperation compared to the non-AVD group (log-rank P = 0.046) in the unmatched population. However, freedom from significant TR (log-rank P = 0.275) and freedom from TV reoperation (log-rank P = 0.108) were not significantly different between the propensity-matched population (Supplementary Material, Fig. S1). In contrast, the TVS group in the unmatched population showed significantly lower overall survival, freedom from TV reoperation and freedom from significant TR compared to the non-TVS group (Supplementary Material, Fig. S2). Predictors of significant aortic valve disease and subsequent aortic valve replacement As determined by the Cox regression multivariable analysis, independent risk factors for significant AVD were age per year, hypertension, peripheral artery disease and AS (HR = 21.542, 95% CI: 9.743–47.631; P < 0.001). Independent predictors of subsequent AVR were AR (HR = 7.251, 95% CI 3.317–15.848; P < 0.001), AS (HR = 35.638, 95% CI 12.500–101.604; P < 0.001) and TR (Grade ≥ III) (HR = 2.171, 95% CI 1.075–4.383; P = 0.031) (Table 4). Table 4: Multivariable Cox proportional hazard regression analysis for significant AVD and subsequent AVR Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Significant AVD  Age (years) 1.065 (1.037–1.093) <0.001 1.060 (1.032–1.089) <0.001  STS score 1.295 (1.126–1.489) <0.001 1.032 (0.764–1.396) 0.836  Hypertension 4.908 (2.070–11.635) <0.001 6.807 (2.660–17.416) <0.001  Diabetes mellitus 2.291 (0.702–7.475) 0.170 0.873 (0.259–2.948) 0.827  COPD 2.506 (0.782–8.037) 0.122 3.294 (0.979–11.086) 0.054  Peripheral artery disease 3.341 (0.802–13.920) 0.098 5.226 (1.209–22.937) 0.027  LVESD (mm) 0.965 (0.935–0.997) 0.030 0.970 (0.935–1.008) 0.118  LVEDD (mm) 0.982 (0.958–1.007) 0.156 1.005 (0.992–1.017) 0.483  Previous AVD   No AVD (reference)   Aortic regurgitation 5.678 (3.147–10.243) <0.001 7.296 (3.905–13.631) <0.001   Aortic stenosis 28.751 (13.138–62.915) <0.001 21.542 (9.743–47.631) <0.001  Bioprosthetic valve 2.222 (0.879–5.619) 0.092 0.885 (0.290–2.700) 0.830 Subsequent AVR  Previous AVD   No AVD (reference)   Aortic regurgitation 7.382 (3.377–16.134) <0.001 7.251 (3.317–15.848) <0.001   Aortic stenosis 42.446 (15.104–119.285) <0.001 35.638 (12.500–101.604) <0.001  TR (grade ≥III) 2.236 (1.122–4.457) 0.022 2.171 (1.075–4.383) 0.031  Tricuspid valve surgery 1.654 (0.853–3.208) 0.136 0.805 (0.300–2.158) 0.666  Bioprosthetic valve 4.010 (1.396–11.516) 0.010 2.797 (0.930–8.417) 0.067 Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Significant AVD  Age (years) 1.065 (1.037–1.093) <0.001 1.060 (1.032–1.089) <0.001  STS score 1.295 (1.126–1.489) <0.001 1.032 (0.764–1.396) 0.836  Hypertension 4.908 (2.070–11.635) <0.001 6.807 (2.660–17.416) <0.001  Diabetes mellitus 2.291 (0.702–7.475) 0.170 0.873 (0.259–2.948) 0.827  COPD 2.506 (0.782–8.037) 0.122 3.294 (0.979–11.086) 0.054  Peripheral artery disease 3.341 (0.802–13.920) 0.098 5.226 (1.209–22.937) 0.027  LVESD (mm) 0.965 (0.935–0.997) 0.030 0.970 (0.935–1.008) 0.118  LVEDD (mm) 0.982 (0.958–1.007) 0.156 1.005 (0.992–1.017) 0.483  Previous AVD   No AVD (reference)   Aortic regurgitation 5.678 (3.147–10.243) <0.001 7.296 (3.905–13.631) <0.001   Aortic stenosis 28.751 (13.138–62.915) <0.001 21.542 (9.743–47.631) <0.001  Bioprosthetic valve 2.222 (0.879–5.619) 0.092 0.885 (0.290–2.700) 0.830 Subsequent AVR  Previous AVD   No AVD (reference)   Aortic regurgitation 7.382 (3.377–16.134) <0.001 7.251 (3.317–15.848) <0.001   Aortic stenosis 42.446 (15.104–119.285) <0.001 35.638 (12.500–101.604) <0.001  TR (grade ≥III) 2.236 (1.122–4.457) 0.022 2.171 (1.075–4.383) 0.031  Tricuspid valve surgery 1.654 (0.853–3.208) 0.136 0.805 (0.300–2.158) 0.666  Bioprosthetic valve 4.010 (1.396–11.516) 0.010 2.797 (0.930–8.417) 0.067 AVD: aortic valve disease; AVR: aortic valve replacement; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HR: hazards ratio; LVEDD: left ventricular end diastolic dimension; LVESD: left ventricular end systolic dimension; STS: Society Thoracic Surgeons; TR: tricuspid regurgitation. Table 4: Multivariable Cox proportional hazard regression analysis for significant AVD and subsequent AVR Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Significant AVD  Age (years) 1.065 (1.037–1.093) <0.001 1.060 (1.032–1.089) <0.001  STS score 1.295 (1.126–1.489) <0.001 1.032 (0.764–1.396) 0.836  Hypertension 4.908 (2.070–11.635) <0.001 6.807 (2.660–17.416) <0.001  Diabetes mellitus 2.291 (0.702–7.475) 0.170 0.873 (0.259–2.948) 0.827  COPD 2.506 (0.782–8.037) 0.122 3.294 (0.979–11.086) 0.054  Peripheral artery disease 3.341 (0.802–13.920) 0.098 5.226 (1.209–22.937) 0.027  LVESD (mm) 0.965 (0.935–0.997) 0.030 0.970 (0.935–1.008) 0.118  LVEDD (mm) 0.982 (0.958–1.007) 0.156 1.005 (0.992–1.017) 0.483  Previous AVD   No AVD (reference)   Aortic regurgitation 5.678 (3.147–10.243) <0.001 7.296 (3.905–13.631) <0.001   Aortic stenosis 28.751 (13.138–62.915) <0.001 21.542 (9.743–47.631) <0.001  Bioprosthetic valve 2.222 (0.879–5.619) 0.092 0.885 (0.290–2.700) 0.830 Subsequent AVR  Previous AVD   No AVD (reference)   Aortic regurgitation 7.382 (3.377–16.134) <0.001 7.251 (3.317–15.848) <0.001   Aortic stenosis 42.446 (15.104–119.285) <0.001 35.638 (12.500–101.604) <0.001  TR (grade ≥III) 2.236 (1.122–4.457) 0.022 2.171 (1.075–4.383) 0.031  Tricuspid valve surgery 1.654 (0.853–3.208) 0.136 0.805 (0.300–2.158) 0.666  Bioprosthetic valve 4.010 (1.396–11.516) 0.010 2.797 (0.930–8.417) 0.067 Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Significant AVD  Age (years) 1.065 (1.037–1.093) <0.001 1.060 (1.032–1.089) <0.001  STS score 1.295 (1.126–1.489) <0.001 1.032 (0.764–1.396) 0.836  Hypertension 4.908 (2.070–11.635) <0.001 6.807 (2.660–17.416) <0.001  Diabetes mellitus 2.291 (0.702–7.475) 0.170 0.873 (0.259–2.948) 0.827  COPD 2.506 (0.782–8.037) 0.122 3.294 (0.979–11.086) 0.054  Peripheral artery disease 3.341 (0.802–13.920) 0.098 5.226 (1.209–22.937) 0.027  LVESD (mm) 0.965 (0.935–0.997) 0.030 0.970 (0.935–1.008) 0.118  LVEDD (mm) 0.982 (0.958–1.007) 0.156 1.005 (0.992–1.017) 0.483  Previous AVD   No AVD (reference)   Aortic regurgitation 5.678 (3.147–10.243) <0.001 7.296 (3.905–13.631) <0.001   Aortic stenosis 28.751 (13.138–62.915) <0.001 21.542 (9.743–47.631) <0.001  Bioprosthetic valve 2.222 (0.879–5.619) 0.092 0.885 (0.290–2.700) 0.830 Subsequent AVR  Previous AVD   No AVD (reference)   Aortic regurgitation 7.382 (3.377–16.134) <0.001 7.251 (3.317–15.848) <0.001   Aortic stenosis 42.446 (15.104–119.285) <0.001 35.638 (12.500–101.604) <0.001  TR (grade ≥III) 2.236 (1.122–4.457) 0.022 2.171 (1.075–4.383) 0.031  Tricuspid valve surgery 1.654 (0.853–3.208) 0.136 0.805 (0.300–2.158) 0.666  Bioprosthetic valve 4.010 (1.396–11.516) 0.010 2.797 (0.930–8.417) 0.067 AVD: aortic valve disease; AVR: aortic valve replacement; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HR: hazards ratio; LVEDD: left ventricular end diastolic dimension; LVESD: left ventricular end systolic dimension; STS: Society Thoracic Surgeons; TR: tricuspid regurgitation. DISCUSSION In the present study, we examined long-term clinical outcomes and echocardiographic results after surgery for rheumatic MVD, comparing patients with and without associated AVD. According to our findings, patients with mild or moderate rheumatic AVD at the time of MVR progressed more often and more rapidly than those without AVD and more frequently required subsequent AVR after a long follow-up period. Furthermore, the clinical outcomes measured, including survival and valve-related complications, did not differ long-term between groups in both the unmatched and propensity-matched populations. Finally, the nature of aortic valvular pathology proved to be an independent predictor of progression to significant AVD in the aftermath of rheumatic MVR. Rheumatic heart disease is rare in advanced nations such as the USA but remains an important cause of AS or AR in developing countries [7, 12, 13]. A sizeable proportion of patients with rheumatic heart disease have multivalvular involvement, primarily joint involvement of mitral and aortic valves (up to one-third of patients) [1, 12, 14]. Unfortunately, the natural evolution of mild-to-moderate rheumatic AVD remains poorly understood, creating a surgical dilemma. In patients with mild or moderate AVD who require MVR, there is controversy regarding the need for concomitant AVR. Combined procedure (AVR and MVR) generally carries higher procedural risk and leads to poorer long-term survival, compared with isolated replacement of either valve [5, 15]. To date, few published reports have chronicled the fate of untreated AVD after MVR for rheumatic mitral valve disease [3–5]. Vaturi et al. [3] have determined that mild AVD at the time of MVR rarely progresses to moderate or severe AVD, even after a lengthy follow-up period. Only 2% of their patients with mild AVD showed sufficient progression to warrant AVR after a 13-year mean follow-up duration. Ha et al. [5] have also concluded that mild-to-moderate AVD can go untreated at the time of MVR, with negligible risk of subsequent AVR. However, before and after propensity score matching, a significant percentage of our patients who initially displayed mild or moderate AVD progressed to significant AVD (before: 12.0% in the AVD group vs 2.0% in the NA group, P < 0.001; after: 12.5% vs 1.3%, P < 0.001, respectively). In addition, freedom from significant AVD at 20 years was significantly higher in the NA group than in the AVD group (before: 96.5% vs 73.7%, P < 0.001; after; 98.1% vs 73.3%, P < 0.001, respectively). Although the basis for above results is unclear, the haemodynamic effects of AVD may well be masked in the presence of severe mitral stenosis resulting from smaller stroke volume [16, 17], so that measured gradients falsely reflect the severity of AVD. Also, the pressure gradient across aortic valve may be elevated postoperatively owing to increased left ventricular preload after MVR, and enhanced blood flow through a previously diseased AV may increase AR considerably after MVR. Unlike degenerative or congenital disorders, rheumatic heart disease is marked by a slowly progressive process [18–20]. Pathologically, inflammation may develop as a result of damage to the valvular endothelium due to the chronic inflammation resulting from rheumatic heart disease. Rheumatic AS is characterized by fusion of the valve commissures because of an inflammatory response. The valve is vulnerable to valvular injury, often eventually resulting in valve fibrosis and calcification. As the aortic valve becomes progressively calcified, the leaflets become less mobile and the aortic valve orifice becomes increasingly stenotic [13, 21]. Valvular stenosis then ensues, which is associated with varying degrees of regurgitation, arrhythmias, atrial dilatation and ventricular dysfunction [13]. Valvular calcification seemingly is the most reliable predictor of outcome in mild-to-moderate AS [21, 22]. Furthermore, rheumatic AS is almost always seen in conjunction with rheumatic mitral stenosis, as the mitral valve is more frequently affected by rheumatic heart disease than the aortic valve. Although the progression of AS is expectedly slow, it may be remarkably rapid paced in certain individuals [23, 24]. It has been suggested that mild AS imparts a greater degree of AVD than mild AR. Indeed, Choudhary et al. [4] have documented a very slow progression of AVD and little need for reintervention in patients with mild AR, whereas mild AS was found to progress more rapidly and occur more frequently. Using a multivariate Cox regression model, we identified AR (HR = 7.296) and AS (HR = 21.542) as independent predictors of significant AVD in our patient population. On average, significant AVD materialized over a significantly shorter period time in patients with AS, as opposed to those with AR only (9.7 ± 4.7 vs 16.01 ± 6.2 years, respectively; P = 0.003). These results are aligned with previous efforts showing progression of native AVD in patients with AS, indicating that the turbulent flow from stenotic valves may contribute to leaflet damage (i.e. advanced commissural fusion and valvular deformity), inflicting further haemodynamic stress and potentially accelerating disease progression [4, 21, 25]. In the majority of patients with AR, the course of disease is chronic and slowly progressive [26], associated with rising LV volume overload and attempted adaptation (chamber dilation and eccentric hypertrophy). LV ejection fraction and diastolic dimension are components of afterload stress that reflect systolic dysfunction and are important in predicting outcomes of progressive AR [27, 28]. A patient with mild or moderate AR but normal LV dimensions is generally free of any clinical ramifications, showing only slight deformity of 1 or more leaflets [29]. Accordingly, our analysis demonstrates that mild AR present at the time of MVR rarely advances to moderate or severe AVD and that subsequent AVR is rarely needed in patients followed at length. As noted in the guidelines for managing patients with valvular heart disease, AVR is considered reasonable in patients with moderate AS and at aortic velocities of 3.0–3.9 m/s or mean pressure gradients of 20–39 mmHg, given other indications for cardiac surgery. AVR is also reasonable in patients with moderate AR who are scheduled for surgery of ascending aorta, coronary artery bypass grafts or mitral valve surgery (Class IIa recommendation) [7, 30]. Although few patients required reoperation for AVRs during the follow-up period, 11 of 31 patients who met the criteria for AVR did not undergo surgical treatment, and only 1 surgery was performed expressly for AR progression. The primary indications for cardiac reoperation were extraneous (severe TR, mitral prosthetic valve dysfunction, infective endocarditis or severe AS). In our previous study, progression of AVD notably was marginal until 10 years postoperatively [5], with no difference between groups. However, in the present study, groups diverged significantly after the 5th year of follow-up. The progression of AVD became prominent after postoperative 5 years, and it rapidly increased at postoperative 10 years in both the unmatched and matched populations. These findings may affect treatment decisions, depending on patients’ circumstances. In our institution, members of the heart valve team discuss the timing of surgery together and make the final decision. Severity of the patient’s symptoms is also considered to be the most important factor of surgical indication. Limitations This study has several acknowledged limitations, the first being its non-randomized and retrospective nature. Selection bias may thus be implicated, although all patients had rheumatic heart disease. Similarly, the relatively small number of patients with AVD was insufficient to ensure statistically robust inferences. After propensity score matching, early complications and long-term outcomes were also similar compared to the unmatched population. Furthermore, as the number of patients with TV surgery was relatively small, we considered that unidentified confounding bias may have influenced the results. Therefore, another propensity score matching to balance confounders (especially, TR grade and TV surgery) between groups is required. To avoid statistical errors, the results based on matched or unmatched data need to be interpreted with caution. It is also worth noting that we lacked a comparator group of patients with mild AVD in whom prophylactic AVR or repair was undertaken; and the timing of AVD progression was approximate, presumed to be the date of discovery by echocardiography. Finally, this homogenous study population was drawn from a single institution, perhaps limiting the generalizability of findings. Although progression of AVD did not significantly impact long-term survival during a lengthy period of follow-up, a significant number of patients with mild AVD at the time of MVR gradually progressed to substantial AVD after the first 5 postoperative years. Moreover, after postoperative 10 years, those patients more rapidly progressed to significant AVD. In particular, considering the occurrence of patient–prosthesis mismatch or pannus formation when the prosthetic aortic valve was inserted at the time of MVR, it would be important to determine the timing of AVR through watchful echocardiographic monitoring. Therefore, we suggest that aggressive echocardiography should be performed at 5 years after MVR surgery in order to confirm AVD progression and determine the appropriate timing of AVR. SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. Conflict of interest: none declared. REFERENCES 1 Bland EF , Jones D. 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Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Jun 4, 2018

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