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Autograft and pulmonary allograft performance in the second post-operative decade after the Ross procedure: insights from the Rotterdam Prospective Cohort Study

M. Mostafa Mokhles, Dimitris Rizopoulos, Eleni R. Andrinopoulou, Jos A. Bekkers, Jolien W. Roos-Hesselink, Emmanuel Lesaffre, Ad J.J.C. Bogers, Johanna J.M. Takkenberg
DOI: http://dx.doi.org/10.1093/eurheartj/ehs173 2213-2224 First published online: 22 June 2012

Abstract

Aims The objective of the present study was to report our ongoing prospective cohort of autograft recipients with up to 21 years of follow-up.

Methods and results All consecutive patients (n = 161), operated between 1988 and 2010, were analysed. Mixed-effects models were used to assess changes in echocardiographic measurements (n = 1023) over time in both the autograft and the pulmonary allograft. The mean patient age was 20.9 years (range 0.05–52.7)—66.5% were male. Early mortality was 2.5% (n = 4), and eight additional patients died during a mean follow-up of 11.6 ± 5.7 years (range 0–21.5). Patient survival was 90% [95% confidence interval (CI), 78–95] up to 18 years. During the follow-up, 57 patients required a re-intervention related to the Ross operation. Freedom from autograft reoperation and allograft re-intervention was 51% (95% CI 38–63) and 82% (95% CI 71–89) after 18 years, respectively. No major changes were observed over time in autograft gradient, and allograft gradient and regurgitation. An initial increase of sinotubular junction and aortic anulus diameter was observed in the first 5 years after surgery. The only factor associated with an increased autograft reoperation rate was pre-operative pure aortic regurgitation (AR) (hazard ratio 1.88; 95% CI 1.04–3.39; P= 0.037).

Conclusion We observed good late survival in patients undergoing autograft procedure without reinforcement techniques. However, over half of the autografts failed prior to the end of the second decade. The reoperation rate and the results of echocardiographic measurements over time underline the importance of careful monitoring especially in the second decade after the initial autograft operation and in particular in patients with pre-operative AR.

  • Autograft
  • Surgery
  • Survival
  • Aortic valve
  • Pulmonary valve
  • Allograft
  • Valvular echocardiographic data

Introduction

The Ross procedure (or pulmonary autograft procedure), first introduced by Donald Ross in 1967, has become a widely accepted option for aortic valve replacement in a selected group of patients.13

Although the operative mortality and long-term survival have been satisfactory, a major drawback of this procedure is the progressive dilatation of the autograft root, often combined with autograft valve insufficiency, necessitating reoperation.48

Data on patient survival, durability of the autograft and the pulmonary allograft, and the incidence of potential risk factors for valve dysfunction and reoperation after the Ross procedure are scarce beyond the first decade.9,10 In this regard, we report the results of the longest and most complete ongoing prospective cohort of autograft recipients, with a follow-up now reaching up to an unprecedented 21 years.

Methods

Patient population

Between September 1988 and November 2010, 161 consecutive patients underwent the autograft procedure in our institution. The patients included in this study are also part of the German-Ross registry.11 Approval from the Institutional Review Board was obtained for this prospective follow-up study; all patients gave their written informed consent.

Operative techniques

Timing of surgery was determined in a regular heart team meeting between (congenital) cardiologists and cardiac surgeons during which all cases were discussed. The decision whether to operate or not was based on contemporary clinical practice. Most procedures (72%) were performed by two surgeons. The remainder of the procedures was performed by another four surgeons. The surgical procedures were performed using standard cardiopulmonary bypass with moderate hypothermia, myocardial protection with crystalloid cardioplegia (St Thomas Hospital solution), and topical cooling. Additional deep hypothermia with total circulatory arrest was employed for surgery on the aortic arch.

In 155 patients, the root replacement technique was employed, and the pulmonary autograft was inserted at the level of the anulus, with care taken to reduce the subannular muscular rim of the autograft to 3 to 4 mm. The proximal suture line of the autograft was constructed, with interrupted sutures in 19% (n = 30) of the procedures and running sutures in the remainder. In 159 of the 161 patients, no root reinforcement measures were taken. In two patients, an autologous pericardial strip supported the proximal suture line.

Three patients required concomitant coronary artery bypass grafting due to a procedural complication. The details of these patients have been previously reported.6

Allograft properties

In all patients, the right ventricular outflow tract (RVOT) was reconstructed using an allograft. The Rotterdam Heart Valve Bank provided most of the allografts (n = 131), which were allocated by Bio Implant Services, Leiden, The Netherlands. The remaining allografts were shipped from Hospital Clinic I, Barcelona, Spain (n = 16), Deutsches Herzzentrum, Berlin, Germany (n = 7), the Karolinska Homograft Bank, Stockholm, Sweden (n = 4), and the National Heart Hospital, London, UK (n = 3). In 98%, a pulmonary allograft was used and 99% of the allografts were cryopreserved. Patient's body surface area was used as a guideline to determine the allograft diameter. No attempt was made to achieve ABO blood type or HLA type matching. Previous publication from our centre showed that blood group compatibility and assignment of quality codes do not have an impact on allograft durability.12

Data collection

Hospital mortality and morbidity were registered and the causes of death were documented. Hospital mortality was defined as death of the patient within hospital or within 30 days after surgery. All patients were followed-up prospectively, contacted annually, and interviewed over telephone. Patients >16 years underwent standardized echocardiography biannually.13 In case of suspected complications, the attending physician was contacted for verification. The total follow-up was 1875 patient-years and was 98.1% complete. Three patients moved abroad and were lost to follow-up (data from these patients were included in the analyses until the moment when they moved abroad). Valve-related events were defined according to the guidelines for reporting morbidity and mortality after cardiac valvular operations.14 Sudden, unexplained, unexpected deaths (SUUD) without further clinical data or autopsy were classified as valve-related deaths according to these guidelines.14 Failure of the autograft or pulmonary allograft was determined at the time of reoperation or death. Patient survival started at the time of Ross operation and ended at the time of death or at the last follow-up. Survival of the autograft or pulmonary allograft started at the time of operation and ended when a reoperation or re-intervention was done, when the patient died, or at the last follow-up. Echocardiographic measurements were systematically and prospectively obtained for all patients until the time of death or autograft explant. The echocardiographic follow-up was 94% complete. The database was frozen on 31 December 2010.

Statistical analyses

Analyses of clinical data

Patient data were entered into a computerized relational database (Microsoft Access 2000). The statistical software SPSS for Windows version 10 (SPSS, Inc., Chicago, IL, USA) was used for data analysis. Patient survival was estimated using the Kaplan–Meier method.15 The log-rank test was used to assess the effect of potential risk factors on patient survival, freedom from valve-related reoperation, and freedom from valve-related events. To investigate independent risk factors for mortality and morbidity caused by allograft failure, the Cox proportional hazard model was used. Risk factors were selected with a backward stepwise method (required significance of P > 0.10 for elimination from the model and P < 0.05 for retention in the model). Given the relatively small number of deaths, no multivariable analysis was performed for mortality in our patient population. Kaplan–Meier survival estimates were compared with the survival of the general population matched for age, sex, year of surgery, and years of follow-up, using the Dutch population life table.16

Analyses of serial echocardiographic data

Although the statistical analysis of serial echocardiographic data is often performed by means of the Kaplan–Meier method, the echocardiographic data in the present study were analysed with mixed-effects models instead. Mixed-effects modelling allows for more accurate analyses of dependent data such as hierarchical data, observations taken on related individuals (e.g. siblings), or measurements collected over time on the same individuals (e.g. echocardiographic measurements).17,18 This approach of longitudinal data analyses is also proposed by the 2008 guidelines for reporting mortality and morbidity after cardiac valvular interventions.14

Mixed-effects models were used to assess changes in echocardiographic measurements over time while accounting for the correlation between repeated follow-up measurements in each patient. For the continuous outcomes, linear mixed models were used, whereas for the ordinal outcomes, mixed-effects continuation ratio models were employed. To allow for more flexibility in the specification of the patient-specific longitudinal trajectories, we utilized natural cubic splines with three internal knots placed at the corresponding percentiles of the follow-up times. Residual plots were used to validate the model's assumption, and when appropriate transformations of the outcome variables were performed. Missing echocardiogram measurements were assumed to be missing at random.19,20 In both the univariable and multivariable analyses, F-tests were used to assess which variables/prognostic factors were most associated with the echocardiographic measurements.

All analyses were performed with the R statistical software (version 2.13.2, 2011. R Development Core Team 2011, R Foundation for Statistical Computing, Vienna, Austria).

All statistical tests with a P-value of 0.05 or lower were considered significant.

Results

Patient and operation characteristics

The mean age of the patients was 20.9 ± 13.7 years (range 0.05–52.7). Patient characteristics are shown in Table 1. Twelve patients underwent previous AVR: six subcoronary allografts, three biological prostheses, and three mechanical prostheses were used. Perioperative data are shown in Table 2.

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Table 1

Pre-operative characteristics of 161 patients

Baseline characteristicsAll patients (N = 161), n (%)<18 years (N = 75), n (%)18–30 years (N = 43), n (%)>30 years (N = 43), n (%)
Median age [± SD; range (years)]20.9 ± 13.7 (0.05–52.7)8.6 ± 5.9 (0.05–17.8)24.7 ± 3.3 (18.33–24.69)38.5 ± 6.1 (30.0–52.7)
Gender
 Males107 (66.5)54 (72.0)26 (60.5)27 (62.8)
 Females54 (33.5)21 (28.0)17 (39.5)16 (37.2)
Prior cardiac surgery
 Prior AVR12 (7.5)0 (0.0)6 (14.0)6 (14.0)
Aetiology
 Endocarditis8 (4.9)3 (4.0)1 (2.3)4 (9.4)
 Congenital (including bicuspid)123 (76.4)70 (93.3)30 (69.8)23 (53.5)
 Other (mainly prosthetic valve)18 (11.2)2 (2.7)10 (23.3)6 (14.0)
 Degenerative/rheumatic11 (6.8)0 (0.0)1 (2.3)10 (23.3)
 Aneurysm/dissection1 (0.6)0 (0.0)1 (2.3)0 (0.0)
Diagnosis
AR46 (28.6)13 (17.3)15 (34.9)18 (41.9)
 AS47 (29.2)19 (25.3)14 (32.6)14 (32.6)
 AR + AS68 (42.2)43 (57.3)14 (32.6)11 (25.6)
Systolic LVF
 Good (EF > 50%)135 (83.8)63 (84.0)36 (83.7)35 (81.4)
 Impaired (EF 40–50%)17 (10.6)9 (12.0)3 (7.0)5 (11.6)
 Moderate/bad (EF < 40%)9 (5.5)2 (2.6)4 (9.3)3 (7.0)
Sinus rhythm161 (100)75 (100)43 (100)43 (100)
Creatinine (µmol/L)61.7 ± 24.4 (12–157)41.4 ± 15.9 (12–89)75.6 ± 19.5 (49–157)78.6 ± 15.4 (42–121)
NYHA class
 I68 (42.2)42 (56.0)15 (34.9)11 (25.6)
 II60 (37.3)20 (26.7)18 (41.9)22 (51.2)
 III25 (15.5)7 (9.3)9 (20.9)9 (20.9)
 IV8 (4.9)6 (8.0)1 (2.3)1 (2.3)
Type of operation
 Emergency2 (1.2)1 (1.3)1 (2.3)0 (0.0)
 Urgent25 (15.5)18 (24.0)2 (4.7)5 (11.6)
 Elective134 (83.2)56 (74.7)40 (93.0)38 (88.4)
  • AS, aortic stenosis; AR, aortic regurgitation; AVR, aortic valve replacement; EF, ejection fraction; LVF, left ventricular function.

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Table 2

Perioperative characteristics of 161 patients

All patients (N = 161), n (%)<18 years (N = 75), n (%)18–30 years, n (%)>30 years, n (%)
Aortic valve
 Bicuspid99 (61.5)49 (65.3)27 (62.8)23 (53.5)
 Tricuspid51 (31.7)26 (34.7)10 (23.3)15 (34.9)
 Prosthesis11 (6.8)0 (0.0)6 (13.9)5 (11.6)
Surgical technique
 Autograft root replacement155 (96.3)75 (100)43 (100)37 (86.0)
 Inlay autograft6 (3.7)0 (0.0)0 (0.0)6 (14.0)
Concomitant procedures
 CABG3 (1.9)0 (0.0)1 (2.3)2 (4.7)
 LVOT enlargement16 (9.9)10 (13.3)4 (9.3)2 (4.7)
 Mitral valve surgery2 (1.2)1 (1.3)0 (0.0)1 (1.3)
 Othera20 (12.4)12 (16.0)4 (9.3)4 (9.3)
CPB time (min)200 ± 68 (114–685)175 ± 54 (118–465)214 ± 55 (114–366)227 ± 84 (142–685)
Cross-clamp time (min)141 ± 32 (90–240)125 ± 28 (90–240)151 ± 33 (90–238)156 ± 27 (117–225)
Circulatory arrest (min)30 ± 29 (11–64) (n = 3)15 (n = 1)64 (n = 1)11 (n = 1)
Complications
 Bleeding/tamponade21 (13.0)2 (2.7)10 (23.3)9 (20.9)
 Pacemaker2 (1.2)1 (1.3)0 (0.0)1 (2.3)
 Perioperative MI1 (0.6)01 (2.3)0 (0.0)
Early mortality4 (2.5)1 (1.3)2 (4.7)1 (2.3)
  • CABG, coronary artery bypass graft; CPB, cardiopulmonary bypass; LVOT, left ventricular outflow tract; MI, myocardial infarction.

  • aIncludes patients requiring tailoring of the ascending aorta or subvalvular membrane resection.

Hospital mortality and late survival

Hospital mortality was 2.5% (four patients) (Table 2). Two patients, both female, died perioperatively. One 26-year-old male patient died due to massive pulmonary emboli shortly after the operation. Furthermore, one 24-year-old female patient with Turner syndrome and extreme LV hypertrophy died due to mediastinitis and sepsis 13 days after surgery.

The mean follow-up duration was 11.6 ± 5.7 years (range 0–21.5 years; median 12.7 years; interquartile range 8.6–15.3 years). During the follow-up, eight more patients died. Three were valve-related. One patient died suddenly 13.9 years after autograft operation at the age of 50 years. The other patient with SUUD died 10.7 years after autograft operation at the age of 39 years. The third patient with valve-related death was a 12-year-old girl with severe juvenile rheumatic disease and severe aortic regurgitation (AR) and mitral valve incompetence resulting in progressive heart failure. She died 6 months after operation. Furthermore, there were five non-valve-related deaths, of which four were cardiac deaths. Causes of the non-valve-related deaths included (1) septic shock (Candida albicans) in one infant 51 days after autograft operation; (2) heart failure resulting in cardiogenic shock in another infant 1.7 years after autograft operation; (3) gastroenteritis (Staphylococcus aureus) resulting in septic shock and multiorgan failure 14.6 years after autograft operation; (4) heart failure due to restrictive cardiomyopathy 16.3 years after autograft operation, and (5) an acute myocardial infarction in an adult patient 4.7 years after autograft operation and 2 months after autograft reoperation for structural valve deterioration with the implantation of a mechanical prosthesis.

Overall, survival was 89% [95% confidence interval (CI) 78–95] up to 18 years of follow-up (Figure 1A).

Figure 1

Kaplan–Meier plot of (A) patient survival after the autograft procedure (the asterisk represents instantaneous hazard of death); (B) survival comparison of autograft patients with that of general population; (C) freedom from autograft reoperation; (D) freedom from allograft reoperation; (E) freedom from autograft or allograft reoperation; (F) freedom from any valve-related event.

The instantaneous hazard of mortality was highest in the immediate post-operative period. This hazard then declined in the first 6 years after surgery, but started to slightly increase again after this period (Figure 1A).

At the most recent follow-up, 81 (54%) of our patients were in NYHA functional class I, 38 (26%) were in NYHA functional class II, 16 (11%) were in NYHA functional class III, and 5 (3%) were in NYHA functional class IV. NYHA functional class was unknown in 9 (6%) patients at the most recent follow-up.

Table 3 displays the risk factors associated with long-term mortality after autograft procedure that were identified in univariate analyses.

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Table 3

Potential predictors of mortality, autograft reoperation, and allograft reoperation

PredictorSurvival, HR (95% CI)P-valueAutograft reoperation, HR (95% CI)P-valueAllograft reoperation, HR (95% CI)P-value
Gender1.78 (0.44–7.17)0.240.63 (0.32–1.22)0.160.87 (0.33–2.30)0.77
Age0.99 (0.94–1.05)0.991.02 (0.99–1.04)0.200.98 (0.95–1.02)0.29
NYHA
 IReferenceReferenceReference
 II2.39 (0.22–26.44)0.291.17 (0.60–2.29)0.670.59 (0.18–1.96)0.38
 III or IV10.58 (1.23–90.67)0.021.88 (0.90–3.95)0.111.55 (0.51–4.76)0.45
Hypertension11.07 (1.23–99.42)0.031.08 (0.15–7.85)0.95NANA
Previous AV surgery0.02 (0.00–11.37)0.240.53 (0.27–1.06)0.480.60 (0.20–1.83)0.49
Creatinine1.01 (0.97–1.04)0.841.01 (0.99–1.03)0.130.99 (0.97–1.01)0.29
LV function1.03 (0.39–2.75)0.871.34 (0.92–1.94)0.131.04 (0.55–1.97)0.91
Timing
 ElectiveReferenceReferenceReference
 Urgent3.13 (0.74–13.25)0.990.89 (0.37–2.11)0.991.97 (0.65–6.01)0.99
Inclusion techniqueNANA0.45 (0.06–3.24)0.42
Cross-clamp time1.01 (0.99–1.03)0.891.00 (0.99–1.01)0.831.00 (0.98–1.02)0.99
Perfusion time1.01 (0.99–1.02)0.171.00 (0.99–1.01)0.791.00 (0.99–1.01)0.73
Bicuspid AV0.33 (0.08–1.38)0.270.97 (0.52–1.78)0.88
Aorta ascendens aneurysmNANA1.58 (0.67–3.75)0.301.15 (0.27–5.03)0.85
Aortic regurgitation7.40 (1.49–36.85)0.031.88 (1.04–3.39)0.03
Adult age (>18 years)1.05 (0.25–4.47)0.861.63 (0.84–3.17)0.150.75 (0.30–1.89)0.55
  • Results were obtained from univariate analyses.

  • AV, aortic valve; CI, confidence interval; HR, hazard ratio; LV, left ventricle; NA, not assessable; NYHA, New York Heart Association Class.

Long-term mortality rates of our patient population are relatively low and comparable with that of the general population in the first decade. However, the survival rate of Ross patients shows, in our experience, a decline in the second post-operative decade compared with the general population (Figure 1B).

Survival rate in different age categories

Patient survival in the age category 2 weeks to 18 years was 94% (95% CI 87–99) at both 10 years as well as up to 18 years of follow-up. Univariate analyses indicated that previous aortic valve surgery (P-value 0.030) and pre-operative aortic anulus aneurysm (P-value 0.048) were associated with impaired survival during the follow-up in this patient group.

Patient survival in the age category 18 to 30 years was 98% (95% CI 84–99) after 10 years of follow-up and 95% (95% CI 80–98) up to 18 years of follow-up. Hypertension (P-value 0.011), previous aortic valve surgery (P-value 0.030), bicuspid aortic valve (P-value 0.007), and pre-operative aortic anulus aneurysm (P-value 0.043) were correlated with impaired survival in this patient group.

Patient survival in the age category ≥30 years was 100% after 10 years of follow-up and 76% (95% CI 24–95) up to 18 years of follow-up. The use of inclusion technique (P-value 0.038) and pre-operative aortic anulus aneurysm (P-value 0.043) were associated with impaired survival in this group of patients.

Reoperation

Fifty-seven patients required a re-intervention related to the Ross operation. Of these, 33 patients required isolated pulmonary autograft replacement, 9 patients required simultaneous replacement of both the pulmonary autograft and allograft, 5 patients required isolated pulmonary allograft replacement, 2 patients with neo-aortic root dilatation required re-implantation of the autograft after replacement of the aortic root with Vascutec prostheses, 1 patient underwent autograft repair according to Yacoub's method,21 and 1 patient underwent reoperation after a recurrent episode of rheumatic fever involving the autograft. Furthermore, two patients underwent a reoperation without valve replacement (one patient underwent enlargement of the pulmonary outflow tract due to supravalvular pulmonary stenosis and the other patient required reoperation for constrictive pericarditis). In addition, two patients underwent balloon valvuloplasty of the RVOT to relieve supravalvular pulmonary stenosis.

Percutaneous pulmonary allograft replacement with the Melody valve was required in two patients.

Progressive dilatation of the neo-aortic root was the main cause for autograft reoperation (n = 40). Causes for pulmonary allograft re-intervention were mainly structural failure, calcification, or degeneration of the valve. In our study group, four patients required a second re-intervention on the pulmonary allograft during the follow-up.

All reoperations on the autograft were performed through a median sternotomy, with cardiopulmonary bypass and moderate hypothermia. We mostly used central canulation in the ascending aorta and right atrium or caval veins. To anticipate possible perforation of the heart or aorta when reopening the chest, we instituted cardiopulmonary bypass with canulation of the femoral vessels and deep cooling in four patients before performing the sternotomy. Crystalloid cardioplegia and topical cooling were used for myocardial protection. Total circulatory arrest with deep hypothermia was needed in 11 patients, with ascending aorta or arch reconstruction. In patients without aortic root dilatation, the valve leaflets were excised, followed by mechanical valve implantation. The neo-aortic root was in most cases dilated without any signs of root or valve calcification. After opening the autograft root, the autograft valve leaflets were inspected, and most of them were excised and the coronary buttons mobilized. Excess autograft wall tissue was removed, leaving parts of the autograft at the annular level in situ. Standard valved conduit implantation was performed. When appropriate, the valve leaflets were spared, using the aortic valve re-implantation technique.

Freedom from reoperation for autograft failure was 84% (95% CI 77–92) and 51% (95% CI 38–62) after 10 and 18 years, respectively (Figure 1C). Freedom from re-intervention for allograft failure was 90% (95% CI 83–94) and 81% (95% CI 71–88) after 10 and 18 years, respectively (Figure 1D). Freedom from re-intervention for autograft or allograft failure was 80% (95% CI 72–86) and 41% (95% CI 28–53) after 10 and 18 years, respectively (Figure 1E).

Risk factors that were associated with autograft reoperation in the univariate analyses are shown in Table 3. There was no re-operative mortality.

Reoperation rate in different age categories

In young patients up to 18 years of age at the time of the Ross procedure, freedom from reoperation for autograft failure was 84% (95% CI 71–92) and 62% (95% CI 39–79) after 10 and 18 years of follow, respectively. In the univariate analyses, pre-operative AR (P-value 0.041), higher creatinine (P-value 0.031), and higher age (P-value 0.009) were associated with autograft failure in these young patients. However, none of these factors remained significant in the multivariate analyses. Freedom from re-intervention for allograft failure was 86% (95% CI 71–94) and 81% (95% CI 64–91) after 10 and 18 years of follow-up, respectively. No potential risk factors could be identified for allograft failure in this specific patient group. Freedom from re-intervention for autograft or allograft failure was 77% (95% CI 62–87) and 49% (95% CI 25–68) after 10 and 18 years, respectively.

In young adult patients between 18 and 30 years of age, freedom from reoperation for autograft failure was 80% (95% CI 64–90) and 37% (95% CI 19–56) after 10 and 18 years of follow-up, respectively. Pre-operative aortic sinus aneurysm (P-value 0.025) was the only risk factor found to be associated with autograft failure. Freedom from re-intervention for allograft failure was 87% (95% CI 72–94) and 81% (95% CI 64–91) after 10 and 18 years of follow-up, respectively. No risk factors were found for allograft failure. Freedom from re-intervention for autograft or allograft failure was 73% (95% CI 56–84) and 32% (95% CI 15–50) after 10 and 18 years, respectively.

In patients of ≥30 years, freedom from reoperation for autograft failure was 90% (95% CI 76–96) and 58% (95% CI 19–56) after 10 and 18 years of follow-up, respectively. Freedom from re-intervention for allograft failure was 98% (95% CI 84–99) and 76% (95% CI 40–92) after 10 and 18 years of follow-up, respectively. No risk factors were found for autograft or allograft failure. Freedom from re-intervention for autograft or allograft failure was 90% (95% CI 76–96) and 45% (95% CI 22–66) after 10 and 18 years, respectively.

Other valve-related events

Two patients developed endocarditis of the autograft during the follow-up (0.11%/patient-year). In one patient, the endocarditis was complicated by stroke. Furthermore, one patient developed endocarditis of the allograft (0.05%/patient-year) which was treated with antibiotics. One patient developed pulmonary emboli (0.05%/patient-year). Bleeding events, valve thrombosis, or non-structural failure was not observed.

Freedom from any valve-related event was 79% (95% CI 71–85) and 40% (95% CI 27–52) after 10 and 18 years, respectively (Figure 1F).

Functional performance of the autograft and allograft over time

During the study period, 1023 echocardiograms were reviewed for 161 subjects. Figure 2 shows time-related changes in autograft gradient (Figure 2A), allograft gradient (Figure 2B), autograft regurgitation (Figure 2C) and allograft regurgitation (Figure 2D). Figure 3 shows time-related changes in aortic anulus diameter (Figure 3A) and sinotubular junction (STJ) (Figure 3B).

Figure 2

Mixed-effects models of echocardiogram variables after the autograft procedure: (A) transaortic gradients; (B) transpulmonary gradient; (C) marginal probability of aortic insufficiency grades; (D) marginal probability of pulmonary insufficiency grades.

Figure 3

Mixed-effects models of (A) aortic anulus diameter increase over time and (B) sinotubular junction diameter increase over time.

Risk factors associated with changes in echocardiographic measurements during the follow-up are shown in Table 4. Female gender was found to be consistently associated with better echocardiographic outcomes. Pre-operative AR was found to be consistently associated with worse echocardiographic outcomes.

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Table 4

Risk factors associated with changes in echocardiographic measurements during follow-up

Echocardiographic measurementRisk factorsUnivariable analyses estimate (±SE)P-valueMultivariable analyses estimate (±SE)P-value
Aortic gradientFemale gender0.39 (0.14)0.0070.40 (0.14)0.005
Older age0.01 (0.01)0.0140.01 (0.01)0.009
ARImpaired LVF−0.70 (0.24)0.003aa
Aortic anulusFemale gender−4.54 (0.81)<0.001−3.77 (0.79)<0.001
Pre-operative creatinine0.06 (0.02)0.0150.04 (0.02)0.02
Pre-operative AR2.24 (0.90)0.011.83 (0.83)0.028
STJFemale gender−5.31 (1.02)<0.001aa
Allograft gradientFemale gender−0.63 (0.29)0.029aa
Allograft regurgitationHypertension2.21 (1.02)0.0300.02 (0.01)0.02
Older age0.03 (0.01)0.008aa
  • AR, aortic regurgitation; LVF, left ventricular function; SE, standard error; STJ, sinotubular junction.

  • aNo longer significant in the multivariable model.

Discussion

The present study is the first to show that long-term patient survival after the Ross procedure is relatively good in contemporary practice, even at the end of the second post-operative decade. Compared with the original pioneer series by Donald Ross (1967–84), which reported an early mortality of 13% and a 20-year survival of only 61% in hospital survivors, our results illustrate the tremendous innovations that have taken place in cardiac surgery over the past decades. The present study also shows that, with increasing follow-up time, in particular the autograft has a limited durability. In addition, mixed-effects model analyses of echocardiographic measurements do not show major changes in transaortic gradients during the follow-up period. The results of mixed-effects models do, however, show that freedom from autograft regurgitation grades 3–4 was only 66% after 18 years of follow-up. Regarding neo-aortic dimensions, the mixed-effects model shows an initial increase in the STJ diameter in the first five post-operative years, which was then followed by a constant phase. Furthermore, an initial slight increase in aortic anulus diameter was observed in the first 10 post-operative years.

Survival after the Ross procedure

Although initially there was concern about the outcome of the Ross procedure, several short and mid-term studies have proven that the procedure can be performed with low operative risk and survival rates comparable with the general population.6,22,23

It remains unclear whether this excellent survival is a consequence of autograft attributes (living valve with superior haemodynamics and low valve-related event occurrence rates)20 or the careful selection of patients for the Ross procedure.24

The present study adds to current knowledge that although long-term mortality rates are relatively low and comparable with that of the general population in the first decade, as reported by several other authors,6,11,23 the survival rate of Ross patients in our experience shows a decline in the second post-operative decade compared with the general population. Of the four observed deaths in the second post-operative decade, two were valve-related (SUUD). Although the numbers are small, this observation suggests that valve-related mortality hazard may increase in the second post-operative decade after the Ross procedure.

Autograft performance

The longevity of the autograft within our patient population is a point of concern. At the end of the second decade, over half of the patients were re-operated for autograft failure.

The main cause for reoperation after the Ross operation is dilatation of the neo-aortic root. Owing to this dilatation, coaptation of the cusps is lost and AR occurs. The exact cause of autograft root dilatation is unknown. It is speculated that several factors may contribute to dilatation of the aortic root. Younger patient age,22 congenital aortic valve disease,25 rheumatic valve disease,26 and pre-operative AR27 and dilatation22 are the most commonly reported patient-related determinants of durability of the autograft valve. It should also be noted that the outcome of the Ross procedure varies considerably between different centres23 and surgical techniques employed and by individual variation of the application of the root replacement technique.28 Furthermore, due to significantly increased mechanical stress, post-operative hypertension may potentially have a negative effect on autograft durability.29,30

The presence of pre-operative AR was an independent risk factor of autograft failure during the follow-up. Furthermore, the longitudinal analyses of echocardiographic data indicated that the presence of pre-operative AR was significantly associated with the increased aortic anulus diameter during the follow-up. Pre-operative AR was not associated with the STJ diameter during the follow-up at all. This suggests that pre-operative AR might specially be a risk factor for the dilatation of the aortic anulus after the Ross procedure.

The association between pre-operative AR and autograft failure is in agreement with other recent publications on this subject.10,27,31,32 Two studies hypothesize that annular dilatation associated with AR may be a factor, and one suggests a role for altered geometry and tissue characteristics of the subvalvular left ventricular outflow tract resulting from chronic AR.27,32

Allograft performance

In contrast to the performance of autografts, allografts performed adequately within our patient population, with freedom from reoperation for allograft failure of 81% after 18 years of follow-up. Although there are no studies at the moment with such a long-term follow-up as the present study, the freedom from allograft failure that we have observed after 10 years of follow-up in our patient population was comparable with that of the other series.4,33 The main reason for allograft reoperation in the present study was degeneration with calcification of the allograft. Pulmonary allograft stenosis is indeed another important issue that has to be taken into account when considering the Ross procedure. The stenosis appears to represent an early post-operative inflammatory reaction to the pulmonary allograft that leads to extrinsic compression and/or shrinkage and is characterized by intimal hyperplasia at the distal anastomosis and an inflammatory-mediated external compression by fibrous tissue.34

Clinical implications

The observed high reoperation rate after the Ross procedure has tempered our initial enthusiasm for the procedure: in our early experience, we applied the Ross procedure generously in children and young adults, performing up to 18 Ross procedures per year, whereas in more recent years this number has gone down to 1 or 2 per year, mainly in young children.

In most of our patients (n = 159, 99%), no reinforcement procedures were taken. It has been shown that in patients undergoing the Ross procedure, autograft reinforcement procedures are associated with lower AR development rates and reduced reoperation rates for autograft failure.35 This is of particular importance since autograft reoperation rate in the present study was mainly driven by root dilatation. Furthermore, it should be noted that surgical techniques employed can considerably influence the outcome after the Ross procedure. A recent publication from the German–Dutch Ross registry showed that freedom from autograft or allograft reoperation was 92% at 10 years and 87% at 15 years in young and middle-aged patients operated with the subcoronary technique.36 These reported results are better than those observed in our study population where mainly (96%) the root replacement technique was used. The widely varying durability results obtained with different surgical techniques applied in the Ross procedure illustrates the technical complexity of the procedure and the requirement of a particular surgical expertise with this procedure.

The Ross procedure represents only a fraction of all aortic valve replacement in contemporary practice.37 Obviously, surgical expertise required to perform a Ross procedure is a limiting factor, although one may hypothesize that by avoiding this technically challenging procedure with potentially increased early risks, we are withholding young adult patients from a potentially better solution in the long run.37 Several other options exist in replacement of the diseased aortic valve in young adult patients: mechanical prostheses, biological prostheses, or homografts.

Although mechanical valves provide excellent durability and low re-operative hazard,38,39 the choice for the mechanical valve implies lifelong anticoagulation and is associated with an increased risk for thrombo-embolic and bleeding events.40,41 The use of anticoagulation may also complicate pregnancy because of the foetal and maternal complications of taking warfarin,42,43 and may require lifestyle adjustments in this relatively young and active patient group. Also, the haemodynamic performance of mechanical valves is less favourable compared with autograft valves.44 Furthermore, prosthetic valve endocarditis occurs in up to 6% of mechanical valve recipients and is associated with considerable mortality.38 However, it still remains unclear whether the excellent survival observed in Ross patients is a consequence of autograft attributes (living valve with superior haemodynamics and low valve-related event occurrence) or the careful selection of patients for the Ross procedure. A recent publication from our group showed that in comparable patients, there is no late survival difference in the first post-operative decade between the Ross procedure and mechanical aortic valve implantation with optimal anticoagulation self-management.24

Bioprostheses are frequently used as an aortic valve substitute and have a low thrombogenicity and absent need for lifelong anti-thrombotic therapy. Recently published studies reporting the results of Hancock II bioprosthesis have shown a freedom from reoperation of only 30–50% after 20 years of follow-up.45,46

Homograft valves have, similar to the autograft procedure, the advantage of a low risk for thrombo-embolism and absent need of lifelong anticoagulation. However, the results of a recently published prospective randomized trial between the Ross procedure and the aortic homograft, both implanted as full roots, showed that the performance of allografts was inferior to that of autografts.23 Furthermore, the performance of the homograft valves have also been shown to be inferior compared with xenografts with more modern tissue processing including anticalcification processes.47

In light of the limitations of contemporary prosthetic valve options, the optimal prosthesis choice for young adults remains controversial. Therefore, an individualized approach is needed in the selection of the optimal prosthetic valve. This approach should combine the evidence on outcome with different therapeutic strategies with the preferences of the informed patient since the inherent limitations of each prosthetic valve can be valued differently by individual patients.

Strengths and limitations

The present study is the longest and most complete prospective cohort study allowing for new insights into patient outcome and autograft and pulmonary allograft function well into the second post-operative decade. In addition of reporting hard clinical endpoints, the number of available echocardiograms and the powerful longitudinal data analysis techniques enabled us to be the first to provide insight into autograft and allograft valve function over time until the end of second decade. The long-term evidence of patient outcome and valve performance is helpful in the selection of most optimal prosthetic aortic valve since it provides an unprecedented time horizon regarding the Ross procedure.

The present study has several limitations. The survival of patients is reported at 18 years of follow-up and future studies are required to confirm the results of the present study. An additional limitation is the absence of a control group in the present study. Furthermore, the results of present study only apply to the unsupported root replacement technique, which is both a strength and a limitation of the data. Finally, the generalizability of our study results requires further investigation.

Conclusions

The present study shows that, in patients who undergo autograft procedure without any reinforcement techniques, the autograft procedure indeed meets the prospect with respect to relatively good long-term survival. However, the observation that over half of the autografts failed prior to the end of the second decade is a point of concern. The reoperation rate and echocardiographic function over time underline the importance of careful monitoring, especially in the second decade after the initial autograft operation and particularly in patients with pre-operative AR.

Funding

M.M.M. is funded by a Mosaic grant of the Netherlands Organisation for Scientific Research (NWO 017.006.058).

Conflict of interest: none declared.

References

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