Abstract

Background: This study aimed to outline the valvular changes following heart transplantation and describe the management options to address these conditions.

Methods: A l iterature s earch u sing E MBASE, M EDLINE, and PubMed databases was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in this study. Clinical studies involving patients who had their first heart transplant and articles that mentioned management for valvular heart disease were included. Treatment options were grouped into four categories: cardiac surgery other than retransplant and valve surgery, valve replacement and repairs, nonsurgical interventions, and conservative management.

Results: Nine hundred and three (6.56%) patients out of 13,757 patients (10,529 males, 3,228 females; mean age: 60.3±10.4 years; range, 20 to 83 years) undergoing heart transplantation were identified with valvular disease affecting one or more valves. The mean interval between the transplant and the diagnosis of valve disease was 11.31±6.95 years. The most common valvular heart disease was tricuspid regurgitation, with 796 (94.09%) occurrences, followed by mitral regurgitation (n=22, 2.6%), aortic regurgitation (n=14, 1.65%), aortic stenosis (n=11, 1.3%), and mitral stenosis (n=3, 0.35%). Additionally, the number of surgical valve replacement and repairs (n=89) was higher than nonsurgical interventions (n=20).

Conclusion: Acquired valvular heart diseases after cardiac transplantation are an infrequent clinical presentation that can cause valvular changes in the recipient. According to the extracted data, there is no sole superior management option, and more research is needed in this area.

Heart transplantation remains the gold standard treatment for end-stage cardiac failure.[1] Recent developments, spanning from new mechanical circulatory support devices to the first porcine-tohuman heart transplantation, show that the field of heart transplantation is evolving rapidly using novel technologies and techniques.[2] These improvements have led to improved survival after cardiac transplants, despite higher risk and more complex patients.[3] The rates of long-term survival differ among populations. Suarez-Pierre et al.[4] found that the 10-year survival in the USA was 53%, whereas it was 61% in the Scandinavian cohort conducted by Dellgren et al.[5] However, improved survival also means an increase in the incidence of long-term complications, such as cardiac allograft vasculopathy (CAV), malignancy, or valvular disease.[6]

Valvular dysfunction can cause heart failure, and in cases refractory to medical treatment, cardiac transplantation is applied as the treatment of choice.[7,8] Valvular cardiomyopathy only makes up 3% of the indications for cardiac transplantation compared to major indications such as nonischemic cardiomyopathy (53%) and ischemic cardiomyopathy (38%).[8] Although cardiac transplantation is expected to treat the underlying valve dysfunction, the changes in the valves following the transplantation may lead to a clinical presentation similar to the pretransplantation period.

A well-documented valve dysfunction following cardiac transplantation is tricuspid regurgitation (TR), the incidence of which varies from 19 to 84% based on its severity.[9] Studies on the pathophysiology of posttransplant TR show that geometric distortion of the tricuspid annulus due to central regurgitant jet and repeated endomyocardial biopsies can result in valvular dysfunction.[9-11] The former cause likely leads to functional TR, which is characterized by central regurgitant jet flow, whereas the latter causes anatomic TR due to scarring and disruption of tricuspid annulus and chordae tendineae anatomical positioning.[9]

Although there are various studies reporting the occurrence of TR after heart transplantation, as mentioned above, there is a lack of systematic evidence about other valvular diseases in this setting.[12,13] Therefore, this scoping review examines valve dysfunction following heart transplantation and delineates the management options in this setting.

Methods

Data sources and search strategies
This scoping review followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols Extension) for Scoping Reviews.[14] The literature search was performed with search terms related to valve disease and heart transplantation in the postoperative period: "cardiac transplant," "heart transplant," "valvular heart disease," "heart valve disease," "aortic valve," "pulmonary valve," "mitral valve," "tricuspid valve," "transplant recipients," and "postoperative period" in meaningful combinations with the use of Boolean operators. The following databases were searched: MEDLINE, PubMed, and EMBASE. The PROSPERO (International Prospective Register of Systematic Reviews) was also checked for any previously published reviews on the same topic. References were cross-checked to ensure a comprehensive literature search, and grey literature was adequately screened.

Eligibility criteria
The search was limited to articles written in the English language published between January 1, 2007, and April 30, 2022. In addition, only clinical studies on patients who had their first heart transplant when they were over the age of 18 and articles that mentioned the management of valvular heart disease after a heart transplant were included. Articles including patients having any kind of intervention before or during heart transplantation and patients under 18 years of age who had received a heart transplant were removed as part of the exclusion criteria.

Data characterisation, summary, and synthesis
Information about the study type, patient characteristics, diagnosis, management, and outcomes were recorded. In each study, the number of transplant patients was noted, as well as the number diagnosed with one or more types of valvular heart disease. Demographic variables included were age, sex, type of valve dysfunction, and interval to diagnosis of valve dysfunction after transplantation. Valvular heart disease was categorized as aortic regurgitation (AR), aortic stenosis (AS), mitral regurgitation (MR), mitral stenosis, pulmonary regurgitation, pulmonary stenosis, TR, tricuspid stenosis, and infective endocarditis. The management options were grouped into four categories: Category A, cardiac surgery excluding retransplant and valve surgery; Category B, valve surgery; Category C, nonsurgical interventions; Category D, conservative management of valve disease.

After the categories were created, the procedures and treatments falling into each category were defined. According to these identifications, Category A was generated for including composite valve procedure, valve-sparing aortic root replacement, and coronary artery bypass graft surgery in one group, whereas Category B covered surgical bioprosthetic or mechanical valve replacements and valve repair surgery. Category C included nonsurgical interventions of percutaneous coronary intervention (PCI), percutaneous tricuspid valve repair, transcatheter aortic valve replacement, and transcatheter mitral valve repair (TMVR). Category D was composed of patients receiving conservative treatment.

Patients were categorized into the mentioned groups according to the management protocol that applied to them. Moreover, overall death rates were reported per study rather than overall mortality rates associated with individual treatment plans since the high number of case reports may skew the overall mortality rates.

Results

Following the database search, exclusion by abstract, and removal of duplicates, 51 articles were identified and deemed eligible for full-text screening. Of these 51 articles, 18 articles were excluded for the following reasons: 10 included interventions on valves before or during heart transplantation, three had no data on intervention, two had no information on valve disease, two articles did not mention relevant patient outcomes in accordance with the inclusion criteria, and finally, one article did not report any information on heart transplantation. The PRISMA flowchart of the study selection process is reported in Figure 1.

Figure 1. The PRISMA flowchart outlining study selection process.

The final number of articles included in the scoping review was 33. Of these, 23 (69.70%) reported a single case and discussed the relevant treatment, nine (27.27%) were retrospective studies, and one (3.03%) paper was a systematic review. The list of articles and their types is displayed in Table 1.

Table 1. Distribution of publications and patient demographics

Patient demographics
A total of 13,757 patients (10,529 males, 3,228 females; mean age: 60.3±10.4 years; range, 20 to 83 years) having heart transplantation were reported in the 33 studies included in this review. Out of the total population, 903 (6.56%) patients had one or more valvular disease. The mean interval from the transplant to the diagnosis of valve disease was 11.31±6.95 years. Patients" clinical characteristics are summarized in Table 1.

Diagnosis
Tricuspid regurgitation was the most common valve dysfunction, diagnosed on 796 occasions. This was followed by MR in 22 occurrences, AR in 14 occurrences, AS in 11 occurrences, and mitral stenosis in three separate occasions. More than one heart valve dysfunction was observed in some patients concurrently. In addition to aortic valve disease, a bicuspid aortic valve was detected in three patients, of whom one had an aortic root dilation.

Pulmonary valve stenosis, pulmonary valve regurgitation, and tricuspid stenosis were not observed in any of the reviewed articles. Additionally, infective endocarditis was identified on 62 occasions, which are ranked in the following order: 27 mitral, 16 tricuspid, 16 aortic, and three pulmonary valve endocarditis. Studies including infective endocarditis also mentioned patients having infection in nonvalvular structures of the heart and pacemakers, but these patients were not included. The distribution of patients with the diagnoses of valve disease, including endocarditis, are summarized in Table 2.

Table 2. Distribution of valvular diseases and treatment categories

Management
As mentioned above, the management options described in the literature have been divided into categories for simplification. Category A, which is non-retransplant nonvalve surgeries, comprised 54 cases. These operations are listed as valve-sparing aortic root replacement, coronary artery bypass graft, pulmonary artery graft replacement, and pacemaker extraction. Category B is surgical valve repair or replacement applied in 89 operations. The distribution of operations was as follows: there were 49 instances of tricuspid valve replacement or repairs, 26 instances of mitral valve replacement and repairs, and 13 instances of aortic valve replacement and repairs. When inspected in detail, it was recognized that 14 of these operations were performed due to the indication of infective endocarditis.

Category C, which is defined as nonsurgical interventions, occurred in 20 patients and is characterized as follows: 11 of the patients underwent transcatheter aortic valve replacement, and the rest of the nine patients were equally divided between TMVR, percutaneous tricuspid valve repair, and PCI. Moreover, the majority of patients (n=801) were in Category D. The detailed classifications are summarized in Table 2.

In addition to the management options, overall death rates are calculated per study. The management plans and overall death rates per study are summarized in Table 3.

Table 3. The management and overall death

Discussion

This review confirms that valvular disease following heart transplantation is a rare condition. As far as the preliminary search has shown, there is no number available for the occurrence of valvular dysfunction following heart transplantation in the literature. However, the results of this review demonstrate that only 6.56% of cardiac transplant patients experienced valvular dysfunction. It is striking that the percentage is low, and when the reasons for this are investigated, it is found that the patients diagnosed with valvular dysfunction after heart transplantation are not recorded in the International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation.[3] Consequently, underreporting of posttransplant valvular disease must be considered. Furthermore, it has been indicated that there was insufficient information about the surgical treatment of late complications after heart transplantation.[15] Normally, a contraindication to harvest a graft is the presence of any echocardiographic valvular changes, and yet, valve procedures can be performed on marginal donors before the transplantation, and this can help expand the donor pool without affecting outcomes.[16,17] Moreover, it is well-known that valvular dysfunction following cardiac transplantation is not as frequent as CAV, a condition that is responsible for long-term graft dysfunction.[3,18]

Tricuspid regurgitation following cardiac transplantation is the most commonly diagnosed valve dysfunction.[6,19] This can be explained with right heart strain and repeated endomyocardial biopsy. According to Kwon and Shemin,[10] loss of coaptation of the valve results in regurgitation of blood in systole and causes right heart pressures to rise. Furthermore, endomyocardial biopsy is a requirement for screening for graft rejection, and trauma can occur to the chordal tissue during this procedure. This damage can lead to regurgitation and, eventually, right-sided heart failure in case of inadequate treatment. Moreover, López-Vilella et al.[12] demonstrated that timing of TR onset is related to the etiology, and Aziz et al.[20] reported that early development of TR was correlated with allograft rejection and high pulmonary resistance.

The treatment for TR following heart transplantation is primarily medical, but surgical intervention may be needed to achieve functional improvement.[21] In case the competence is due to structural damage, it is challenging to repair; thus, valve replacement is recommended. However, the coaptation defects due to annular dilation can be repaired via ring annuloplasty.[22] To prevent the occurrence of TR, regular echocardiographic follow-ups are crucial to detect early signs of regurgitation and initiate treatment when necessary.[12]

Although the incidence of TR varies in the literature, the data is limited on the dysfunction of other valves.[6,9] When valve diseases other than TR are examined, MR diagnoses are the second most common in the review. It is thought that frequent biopsy is behind this disease, similar to TR, and it is stated that graft atherosclerosis may also be a cause.[23] As the left ventricle dilates due to ischemia and fibrosis, it causes chordal arrangement to change and restricts mitral valve closure.[7] Although the MR can persist to a mild degree, there is a risk of developing severe MR, and patients with severe MR present with dyspnea and exercise intolerance.[7] There are various options to treat severe MR, either conservatively via minimally invasive interventions or surgery, but the ultimate decision will be made in accordance with patient factors and the clinical presentation. For instance, if the patient has both MR and TR, mitral valve replacement performed concomitantly with intervention for TR would protect from increased TR postoperatively.[24] In this review, the number of patients attending surgical valve replacement or surgical repair of the mitral valve was 26. However, TMVR has become a solid alternative for the management of MR in high-risk patient populations.[25,26]

Another possible valvular dysfunction in this patient population is AR. In this review, AR is identified on 14 occasions, two of which are concomitant with aortic root enlargement, and one of the cases presented includes infective endocarditis.[27-29] The number of occasions was less than TR because left-sided valves are less affected by degenerative processes.[30]

In addition, AS is identified in 11 patients in this review.[6,15,31-38] Two of the patients underwent cardiac transplantation with a graft that has bicuspid aortic valve.[31,38] Bicuspid aortic valve is the most common congenital valvular abnormality in which only two cusps of the aortic valve are present since the separation of valve cusps does not happen in the fetal period.[7,31] Not only can this condition be defined at any age without any clinical findings but it also has a potential to cause stenosis and regurgitation in the aortic valve.[39] Although the appropriate treatment for transplant patients with bicuspid aortic valve is not clearly identified, this review found two different approaches in two different patients. While the first patient with bicuspid aortic valve received aortic valve replacement, the second patient underwent transcatheter aortic valve implantation (TAVI).[31,38] Additionally, there is limited data on the outcomes of TAVI in patients having bicuspid aortic valve; thus, there is no standard treatment that has been established for this condition and its associated valve dysfunction.[38]

Postcardiac transplant patients are at a higher risk for redo cardiac surgery for a number of reasons, such as receiving immunosuppressive therapy and its complications, along with other comorbidities.[25] Thus, nonsurgical interventional procedures may be considered for these patients as an alternative to repeat surgery. This review found 20 patients undergoing these procedures, and 16 of them had these procedures in the last 10 years.[15,30,31,34-37,40,41] Significant developments in nonsurgical interventions, such as with TAVI and TMVR, provide more useful and safer approaches.[25,33,42] Although there are no studies identifying long-term outcomes for heart transplant patients receiving TAVI compared to surgical aortic valve replacement, this procedure can be an alternative for high-risk patients.[31]

In addition to the valvular dysfunction, five articles evaluated for this review reported infective endocarditis on heart valves.[19,29,43-45] Immunosuppressive treatment following cardiac transplant increases the risk of patients having infections requiring challenging management. Martínez-Sellés et al.[44] conducted a review with 8,305 patients with cardiac transplants, and 18 infective endocarditis cases were detected. They also found that the major pathogens were Staphylococcus sp., Enterococcus sp., and Aspergillus. In addition to these five articles, Jandhyala et al.[46] presented a patient infected with Coxiella burnetti a nd h e h ad undergone a mitral valve replacement with an aortic valvuloplasty. However, it is not possible to indicate which microorganism has more incidence in the selected patient cohort for this review.

Alternatively, a dilated aortic root can be replaced with the David procedure.[47] In the review, there was one case report presenting a valve sparing aortic root replacement, but they also replaced the ascending aorta.[28] In terms of comparing these two operations mentioned in the general population, it was found that valve-sparing root replacement has better long-term outcomes and fewer operative deaths.[48]

Another condition that can be seen with valvular heart disease is CAV. Cardiac allograft vasculopathy is characterized by diffuse intimal proliferation, mostly in the distal portions of the coronary artery. The exact reason for occurrence has not been identified, and yet, it is thought that an immunologic response can cause the vasculopathy.[49] In this review, two patients with MR and one patient with TR had undergone PCI due to significant coronary stenosis.[12,50] Information is limited in terms of the relation between valve dysfunction and CAV. However, a pathologic study of allograft hearts has showed that two out of 64 allografts had end-stage valvular disease.[49] Moreover, patients with cardiac transplantation need to be closely followed to identify CAV and prevent its complications.

The main limitation of this review is the small number of studies reporting patients with valvular disease after heart transplantation. In addition, most of the studies were case reports, which are considered low-level evidence.[51] Furthermore, the articles excluded during the literature search may have included information relevant to this review. This research review was carried out by two authors, which may cause selection bias.

In conclusion, due to the longer survival following heart transplantation, there is a higher likelihood of experiencing more complications. One of these complications is valvular heart disease, which can be seen in this patient group even though it is less frequent. The lack of patients presenting with this condition is a challenge to ensure timely, appropriate, and adequate treatment, which can be grouped as surgical, nonsurgical, or conservative. Consequently, it is not possible to indicate which treatment method is superior according to the extracted data unless more information is obtained from the databases.

Acknowledgements: The corresponding author would like to thank Prof Oscar Traynor and Dr Marie Morris for their vision and teaching during the time at MCh Masters in Surgical Science and Practice (MSSP) programme at Royal College of Surgeons in Ireland.

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: O.Y., N.M.K.; Design, critical review: N.M.K.; Control/supervision, data collection and/ or processing, analysis and/or interpretation, literature review, writing the article, references: O.Y.

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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