Abstract

Background: This study aims to evaluate the long-term outcomes of patients undergoing right ventricle-to-pulmonary artery reconstruction with valved homografts.

Methods: A total of 106 patients (49 males, 57 females; median age: 5 years; range, 2 to 49 years) who underwent right ventricle-to-pulmonary artery reconstruction between January 2002 and January 2024 were retrospectively analyzed. The study utilized cryopreserved homografts and surgical procedures were conducted under moderate hypothermic conditions using cardiopulmonary bypass. Homograft failure was defined as the need for reintervention or replacement. The primary outcome measures were overall survival, freedom from conduit replacement rate, and freedom from any required reinterventions rate.

Results: The median follow-up was 7 years. The overall survival rate was 92.5%, with early mortality primarily due to low cardiac output. Freedom from reintervention rates were 90.8%, 84.8%, and 76.3% at three, five, and 10 years, respectively. Thirteen patients required conduit replacement, with pulmonary homografts showing improved durability. Risk factors for homograft failure included pulmonary valve regurgitation treatment, lower patient weight, younger age, and female sex.

Conclusion: This study highlights the excellent survival and durability of valved homografts in cardiac reconstruction, with implications for patient management and surgical decision-making in complex congenital heart disease procedures.

Valved conduits connecting the subpulmonic ventricle and pulmonary circulation have been utilized for over five decades in biventricular repair of complex congenital anomalies characterized by right ventricular outflow tract (RVOT) hypoplasia or atresia.[1] The incorporation of homografts for RVOT reconstruction between the 1960s and 1970s has facilitated significant progress in numerous congenital heart disease procedures, leading to enhanced patient survival rates.[2] H owever, t he d egeneration of the homograft and the resulting stenosis remain substantial complications of this surgical approach.[3]

Homografts have been extensively utilized in right ventricle-to-pulmonary artery (RV-PA) reconstruction procedures due to their advantageous properties, such as ease of surgical implantation and high compatibility with the patient's native cardiovascular tissue. These favorable characteristics have made homografts a preferred choice for this type of cardiac reconstructive procedure. However, researches have shown that homografts often undergo rapid degeneration following the surgical intervention, necessitating the initial use of non-homograft biological conduits and subsequently synthetic grafts.[4],[5] T he a vailability, p erformance, and cost of these alternative conduit options are important factors which influence the surgical utilization plan. While the range of available conduit solutions has expanded over time, an optimal conduit choice has not yet been achieved yet.

In the present study, we aimed to evaluate long-term outcomes of patients who underwent RV-PA reconstruction with a valved homograft and to examine the incidence and risk factors associated with major complications, the need for reintervention, and conduit replacement.

Methods

This single-center, retrospective study was conducted at Ege University Faculty of Medicine, Department of Cardiovascular Surgery between January 2002 and January 2024. Medical data of the patients who underwent biventricular repair with RV-PA reconstruction using aortic or pulmonary homografts were reviewed. The study population consisted of patients who received this surgical treatment at our institution and those who were followed at external healthcare facilities. For patients who were followed externally, the research team obtained data from the national database or through direct communication with patients and/or their attending physicians. Individuals with incomplete follow-up data or who received duplicate homograft implantations were excluded from the analysis to prevent data redundancy. Finally, a total of 106 patients (49 males, 57 females; median age: 5 years; range, 2 to 49 years) who met the inclusion criteria were recruited. Written informed consent was obtained from the patients and parents and/or legal guardians of the patients. The study protocol was approved by the Ege University Medical Research Ethics Committee (date: 11.07.2024, no: 24-7T/39). The study was conducted in accordance with the principles of the Declaration of Helsinki.

This study utilized cryopreserved homografts, 57 of which were obtained from our institutional homograft b ank p rior t o 2 011. E stablished a s the first homograft bank of Türkiye, it provided homografts for clinical use until its closure in 2011. Recently, homografts are sourced from external suppliers, as our homograft bank is no longer operational. During the homograft size selection process, a moderately large size (conduit Z-score from 0 to + 2) was usually preferred to accommodate the patient's anatomical dimensions and ensure a proper fit. Furthermore, the dimensions of all implanted homografts were meticulously evaluated intraoperatively using a Hegar dilator to verify the appropriate size and ensure a secure and precise placement.

All surgical procedures were conducted under moderate hypothermic conditions, utilizing cross-clamping and cardiopulmonary bypass techniques. Diastolic arrest was induced through the administration of a blood cardioplegia solution. The selection of homografts was not randomized, but instead based on the specific pathological characteristics of each patient and the availability of the grafts. For patients with evidence of pulmonary hypertension or suboptimal PA development, aortic homografts were the preferred choice due to their more robust muscular layer, which can better withstand the higher pressures in the pulmonary system. In contrast, for all other patients, pulmonary homografts were the preferred graft type due to their superior tissue compatibility with the RV-PV. Early mortality was defined as any death occurring either prior to hospital discharge or within 30 days of the surgical procedure.

An interdisciplinary team of pediatric cardiology and cardiovascular surgery experts defined homograft failure as requiring either reintervention or replacement. This assessment comprehensively evaluated the status and function of the implanted homograft using transthoracic echocardiography and, when necessary, cardiac catheterization data.

The primary outcome measures were overall survival (OS) from the time of the surgical procedure through the end of the study period on December 31st, 2023, as well as the duration of freedom from conduit replacement (FCR) and freedom from any required reinterventions (FFR). The FCR was defined as the time between initial conduit implantation and the requirement of surgical or transcatheter conduit replacement, while the FFR was defined as freedom from either operative conduit replacement or transcatheter conduit intervention.

Statistical analysis

Statistical analysis was performed using the Jamovi for MAC version 2.5.2 software (Jamovi Research, Vienna, Austria). Continuous variables were expressed in mean ± standard deviation (SD) or median (min-max), while categorical variables were expressed in number and frequency. The distribution of continuous variables was assessed using the Shapiro-Wilk test. All variables were found to be non-normally distributed, and non-parametric methods were used accordingly. Survival outcomes, including OS, FCR, and FFR, were analyzed using the Kaplan-Meier method, with comparisons between conduit types performed using the log-rank test. The Cox proportional hazards model was used to evaluate potential risk factors for homograft failure, with hazard ratios (HRs), p-values, and 95% confidence intervals (CIs) reported for each variable. A p value of <0.05 was considered statistically significant.

Results

The most common diagnosis was pulmonary stenosis (30.2% n=32), followed by tetralogy of Fallot (TOF) (18%, n=19). The median follow-up was 7 years (range: 2 days to 16.6 years). Pulmonary homografts were preferred in the majority of patients (79.2%) owing to superior tissue compatibility. Aortic homografts were used in 22 (20.8%) patients due to either the unavailability of suitably sized pulmonary homografts or the expectation of elevated PA pressures. The demographic and clinical characteristics of the patients and type of used homograft conduit are summarized in Table 1.

Table 1: Demographic data of patients

The OS rate was 92.5%. In the early postoperative period, four patients succumbed to death, with two having double-outlet RV and two diagnosed with TOF. Three of these patients weighed less than 10 kg, and two were under one year of age. All of these patients died due to low cardiac output. Additionally, late mortality was observed in four patients, with three passing away from pneumonia during the novel coronavirus disease 2019 (COVID-19) pandemic. The final late mortality occurred due to non-cardiac causes secondary to trauma. The five-year, 10-year, and 15-year survival rates were 95.1%, 89.7%, and 84.7%, respectively.

During the follow-up period, 21 patients required reintervention. Of these, 13 patients underwent conduit replacement, and 14 patients underwent percutaneous interventions. Notably, six of the 14 patients who initially underwent percutaneous intervention later required conduit replacement (Table 1). The rates of FFR were 90.8%, 84.8%, and 76.3% at three, five, and 10 years, respectively. The Kaplan-Meier curve depicting the FFR is presented in Figure 1.

Figure 1: Kaplan-Meier curves showing freedom from reintervention.

Of the 13 patients who required conduit replacement, five underwent conduit reimplantation using bovine jugular vein grafts. Three patients received percutaneous transcatheter valve implantation, while five underwent surgical biological valve implantation along with PA patch plasty. The rates of FCR at three, five, and 10 years were 97.7%, 94.1%, and 81%, respectively. No patients with homograft implantation developed endocarditis, except for one who underwent transcatheter valve replacement for conduit failure and subsequently developed endocarditis two months later, requiring pulmonary valve replacement and pulmonary arterioplasty.

The analysis of various factors, including operative details, patient conditions, and diagnostic findings, revealed that the need for reintervention was statistically more common in patients who received homograft implantation for the treatment of pulmonary valve regurgitation (p=0.02). Although Cox regression analysis did not identify statistically significant predictors of homograft failure, certain trends were observed, with failure occurring more frequently in female patients, in those weighing less than 23 kg, in those younger than seven years of age, and in those who received an aortic homograft (Table 2). The 10-year FCT rate was 79.3% for aortic homografts, compared to a higher rate of 84.9% for pulmonary homografts. The log-rank test confirmed a statistically significant difference, indicating that pulmonary homografts may exhibit superior long-term durability in this patient population (p=0.042). The Kaplan-Meier curves depicting the FCR for aortic and pulmonary homografts are presented in Figure 2.

Table 2: Cox regression analysis for predictors of homograft failure

Figure 2: Kaplan-Meier curves showing freedom from conduit replacement for aortic and pulmonary homografts

Discussion

In our center, the long-term evaluation of individuals who underwent RV-PA reconstruction using valved homografts revealed outcomes and complications associated with this surgical approach. Valved homografts have been utilized for RV-PA reconstruction in numerous congenital and acquired cardiac procedures due to their long-term durability, resistance to infections, lack of anticoagulant requirement, and excellent tissue compatibility.

The patient population in our study was similar to those in previous reports, with the largest cohort consisting of individuals diagnosed with TOF and pulmonary stenosis/atresia. However, unlike many prior studies, which included heterogeneous conduit types such as Contegra® ( Medtronic I nc., M N, USA), bovine jugular vein grafts, and handmade synthetic conduits, our study focused exclusively on homograft conduits. This allows for a detailed evaluation of homograft performance over time and its comparison with other options in the literature.[6, 7] In our center, we have utilized xenografts such as Contegra® and BioIntegral® (BioIntegral Surgical Inc., Ontario, Canada); however, we have preferred homografts as our first choice whenever available and anatomically appropriate.

The existing literature indicates that patients who undergo RV-PA reconstruction using homografts have demonstrated 10-year survival rates ranging from 87 to 96%. The most common causes of early mortality reported in the literature include low c ardiac o utput, h emorrhage, a nd s troke. Early mortality rates are reported to range from 2.5 to 4.2% across different studies with variations depending on patient age, underlying pathology, and surgical complexity. Low cardiac output is consistently identified as a predominant factor mortality in younger patients, particularly neonates and infants, while hemorrhage and stroke are more frequently observed in older pediatric patients or those underwent complex repairs.[1, 6, 8] Consistent with these findings, the present study observed a 10-year survival rate of 89.7% and an early mortality rate of 3.7%, with the primary cause being low cardiac output following the repair of complex congenital cardiac defects.

The degeneration of homografts, often requiring reintervention or replacement, is a significant concern in this patient population. Several studies have shown that only 20 to 30% of aortic or pulmonary homografts remain durable beyond 20 years. However, FCR has been reported in 80% of patients at 10 years and 70% at 20 years.[5, 9] Our study found that 19.8% of patients required intervention during follow-up, with 12.2% needing conduit replacement. However, the rates of FCR were relatively high at three, five, and 10 years, being 97.7%, 94.1%, and 81%, respectively, suggesting good early durability of homograft conduits.

In the current study, we identified several risk factors associated with homograft failure. Patients who received homograft implants for the treatment of pulmonary valve regurgitation exhibited a statistically higher frequency of reintervention. Additionally, lower patient weight, younger age, and female sex were recognized as potential risk factors for

increased homograft failure rates. While the existing literature has reported similar risk factors, other factors such as the duration of homograft storage, donor age, and blood group compatibility between the donor and recipient have also been identified as potential contributors to graft dysfunction.[10-12] Although the type of homograft implanted is not considered a risk factor for graft failure, studies have demonstrated that pulmonary homografts exhibit higher survival rates in RV-PA reconstruction compared to aortic homografts.[1, 6, 12] Consistent with these findings, the present study observed a higher survival rate for pulmonary homografts compared to aortic homografts. Therefore, when pulmonary hypertension was not present and a suitable homograft was available, a pulmonary homograft was preferred.

Despite the unique advantages and broad applicability of homografts, their availability remains the most significant limitation to their widespread use. Homograft procurement and storage necessitates specialized centers and expertise, which can make it challenging to access homografts of the desired size on demand.[13] Furthermore, the specialized transport conditions required for homografts pose logistical difficulties for healthcare facilities without their own homograft banks. As a result, alternative biologically valved conduits, including non-homograft biological options and handmade synthetic conduits, have been increasingly utilized. These non-homograft biological conduits have demonstrated durability comparable to homografts, with the added benefit of more readily available sizes to suit patient-specific needs, in contrast to the limited accessibility of homografts.[14]

Handmade synthetic conduits have been extensively utilized, particularly during the COVID-19 pandemic when supply chain challenges were encountered. The ability to fabricate these conduits to the patient's specific size requirements eliminates the issue of size mismatch. While the short- and medium-term durability of these synthetic conduits appears satisfactory, their long-term performance as an alternative to homografts remains underexplored in the existing literature.[15]

While non-homograft conduits have demonstrated satisfactory short- and mid-term outcomes, the available evidence suggests that homografts exhibit superior resistance to infection.[6] Our extensive experience with homografts has not revealed any cases of endocarditis.

Nonetheless, this study is limited by its retrospective design, which is inherently prone to selection bias and incomplete data collection. As a single-center study, the findings may not be also generalizable to other institutions with differing surgical practices or patient populations. Additionally, while the study focuses exclusively on homografts, comparisons with other conduit types, such as synthetic or xenografts, were not included. Finally, the long study period introduces potential variability in surgical techniques and patient management over time. Another potential limitation to our study is the sample size, which may have reduced the statistical power of the Cox regression analysis, potentially masking significant associations. Future multi-center, large-scale, prospective studies may provide more definitive conclusions regarding risk factors for homograft failure.

Nevertheless, one of the strengths of this study is the completeness of the dataset. No missing data were present in the variables included in the analysis, minimizing the risk of bias related to data loss or imputation methods.

In conclusion, autologous tissue remains the gold standard for right ventricular outflow tract reconstruction owing to its excellent biocompatibility, lack of immunogenicity, and ability to grow with the patient. However, its use is limited by challenges such as donor-site morbidity, the complexity of harvesting and preparation, and its feasibility in small pediatric patients. In clinical practice, autologous pericardial patches or valves may be used in select cases, particularly in older children or adults, but their application is often constrained in neonates and infants due to size and technical considerations. Despite these limitations, the exploration of autologous tissue remains a valuable avenue for future advancements in right ventricular outflow tract reconstruction. Synthetic vascular grafts have exhibited promising potential; nonetheless, they continue to confront challenges such as thrombogenicity, intimal hyperplasia, susceptibility to infection, and lack of growth capacity. Based on our study results, long-term follow-up of right ventricle-to-pulmonary artery reconstruction using homografts can yield promising results, demonstrating excellent survival rates and acceptable reintervention rates. While certain patient characteristics, including age, weight, and underlying diagnosis, may be potential risk factors for homograft failure, the overall durability of these conduits remains noteworthy.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Idea/concept, writing the article, references and fundings: O.N.T., M.A.; Design: O.N.T., Y.A.; Control/supervision, critical review: Y.A., E.D.; Data collection and/or processing: M.A.; Analysis and/or interpretation, literature review, materials: O.N.T.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

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