Outcomes of tricuspid valve regurgitation after heart transplantation; a single center retrospective cohort study

Tricuspid valve regurgitation (TR) of the donor's heart is a common problem that can develop immediately after cardiac transplantation. There is still little data about its impact on clinical outcomes. We aimed to evaluate the short-term and 1-year effects of significant TR after heart transplantation. We retrospectively analyzed 120 patients who underwent elective orthotopic heart transplantation between 2011 and 2022. According to the postoperative TR, the patients were divided into insignificant (n= 106) and significant (n= 14) TR groups. Patients with significant TR were younger [median age: 38 (Q1- Q3: 36- 39) vs. 49 (35- 55) years, p=0.037] and had a higher prevalence of nonischemic cardiomyopathy (85.71% vs. 42.45%, p=0.003) and donor female gender (35.7% vs. 19.8%,p=0.021). The patients with significant TR had a longer ICU stay [19 (14-27) vs. 11 (9-14) days, p=0.001], more frequent acute kidney injury (57.14% vs. 32.08%, p=0.023), and continuous renal replacement therapy (14.3% vs. 5.66%, p=0.031), with higher 30-day mortality (7.14% vs. 1.9%, p=0.046) and 1-year mortality (14.3% vs. 2.8%, p=0.022) compared to patients with insignificant TR. The degree of TR significantly decreased during the follow-up [β: -0.18 (95% CI: -0.25 to -0.10); p<0.001]. All patients with TR were managed medically without surgical interventions. Logistic multivariable regression revealed that nonischemic heart disease (OR: 3.41,95% CI: 1.31-41.2, p=0.024) and female donor (OR:1.56, 95%CI: 1.13-25.3, p=0.013) independently predicted significant postoperative TR. Significant TR was associated with early mortality and morbidities with prolonged hospitalization. The degree of TR significantly decreased during the first year after transplantation.


Background
Tricuspid valve regurgitation (TR) is the most common valvular lesion after orthotopic heart transplantation (OHT), with a reported wide incidence (19%-84%) [1][2][3][4].The wide variability in the incidence of posttransplant TR could be attributed to the different designs and populations of the involved studies and the timing of TR diagnosis.Significant TR was linked to decreased survival post-transplantation [3,5], and several authors recommended prophylactic tricuspid repair; however, no clinical evidence supports this practice [4].The dynamic state of postoperative TR and response to medical therapy make it difficult to approach and predict the outcomes and survival.
Little data have evaluated the effect of post-transplant TR, and the outcomes are affected by the center volume and experience [4].We aimed to report the incidence of TR in our transplantation center and its impact on patient outcomes.The primary outcome was 30-day and 1-year mortality, and the secondary outcomes included ICU length of stay, occurrence of acute kidney injury (AKI), and need for continuous renal replacement therapy (CRRT).

Study design and data collection
The study was a retrospective cohort enrolling patient who underwent orthotopic heart transplantation in a tertiary referral center between October 2011 and January 2022.The study was approved by the ethical committee and given a reference number (2181238).Patients who underwent emergency transplantation or died within the first week after surgery were excluded.Donors with any degree of TR were excluded from this study.

The variables and outcomes
The data were collected from electronic hospital records.
The preoperative variables included age, body mass index, gender, underlying heart disease, laboratory variables (creatinine, bilirubin, hemoglobin, and albumin), and right heart catheterization (RHC) data.From RHC, we reported direct measurements of systolic, diastolic, and mean pulmonary artery pressures (PAP).The transpulmonary gradient (TPG) was calculated as the mean PAP -mean pulmonary capillary wedge pressure (PCWP).Pulmonary vascular resistance (PVR) was calculated as TPG divided by cardiac output [6].

Echocardiographic assessment
The assessment of the degree of TR was performed by echocardiographer cardiologists.According to the guidelines, the degrees of TR were none, mild, moderate, or severe [7].Grading of TR was done using the regurgitation jet area and the width of vena contracta.Assessment of right ventricular function was done using tricuspid annular plane systolic excursion (TAPSE).The enrolled patients were divided into two groups: the significant TR group included moderate or severe TR, and the insignificant TR group included less than moderate degrees of TR.

Statistical analysis
Data were presented as the median (interquartile range) for continuous data and frequency and percent for dichotomous data.

Baseline characteristics
The study cohort included 120 adult patients who received bi-caval orthotopic heart transplantation.The median age was [49 (35-55) vs. 38 (36-39) years, p=0.037], and the nonischemic underlying cardiomyopathy was (42.45% vs. 85.71%,p=0.003) in the insignificant and significant TR groups, respectively.The two groups had no statistically significant differences regarding other preoperative clinical, laboratory, or pulmonary hemodynamics.The studied variables of the donors were comparable in both groups except higher frequency of female gender donor in the significant TR group (Tables 1 and 2).

Tricuspid regurgitation
Among the 14 patients with significant TR, one had severe right ventricular failure (RVF) and died during the hospital admission.Another two patients with RVF did not improve and continued to have significant RVF and died during the first year after transplantation.For the remaining 11 patients, the degree of tricuspid regurgitation significantly decreased during the follow-up [β: -0.18 (95% CI: -0.25 to -0.10); p<0.001].Among the patients with postoperative insignificant TR, 17 patients (16.04%) developed severe TR after three months and then regressed in 13 (12.3%)patients after one year, and only 4 (3.8%)patients continued to have severe TR.All patients with TR were managed medically without surgical interventions.Logistic multivariable regression revealed that nonischemic heart disease (OR: 3.41,95% CI: 1.31-41.2,p=0.024) and female donor (OR:1.56,95%CI: 1.13-25.3,p=0.013) were the independent predictors of significant postoperative TR.Although preoperative age, PVR, and TPG were significantly different between the two groups by univariable analysis, they were insignificant in the logistic regression analysis (Table 3).The data of postoperative RHC and RV functions were summarized in Table 4.

Discussion
The main findings in our cohort were that 11.7% of patients had postoperative significant TR and were younger with more frequent nonischemic cardiomyopathy and more female donors than patients with insignificant TR.Published studies have reported differences regarding the incidence, risk factors, and predictors of posttransplant TR.Bishawi et al. [8] studied 542 patients post-OHT and reported the occurrence of significant TR in 21% of patients without differences in age, BMI,  or operative variables between patients with and without TR.Algarni et al [4] studied 30 patients post heart transplantation and reported occurrence of significant TR in 37% of the patients studied.López-Vilella et al. [3] studied 1009 patients with OHT and reported a 19.8% incidence of significant postoperative TR, and the patients with significant TR were statistically younger without gender differences but with frequent female donors compared to those without significant TR.Recipient female gender was a statistically insignificant variable while donor female gender was significantly more frequent in the significant TR group in our cohort, which was similar to López-Vilella et al. [3], who reported that recipient gender was insignificantly different; however, donor-female gender and donor-recipient sex mismatch were statistically significant predictors of significant TR.Recipient female gender was more frequent (p=0.001) in the significant TR group, and donor male gender was   [9].The pre-OHT cardiomyopathy was significantly different in our cohort, and the patients with significant TR had a higher frequency of nonischemic cardiomyopathy.Moreover, nonischemic cardiomyopathy predicted postoperative TR (OR: 3.41,95% CI: 1.31-41.2,p=0.024).Our finding was consistent with previous reports [3,4,7] and this could be explained by donor-recipient heart size mismatch in patients with dilated cardiomyopathy.In logistic regression model, nonischemic cardiomyopathy was a predictor of postoperative significant TR.Although age, TPG, and PVR were statistically significant between the two groups in the univariable analysis, they were insignificant in the multivariable logistic regression model.TPG and PVR are frequently used as parameters of pulmonary vascular remodeling but cannot differentiate reversible from fixed pulmonary vascular changes [10].
According to our cohort, significant TR was associated with worse outcomes, prolonged ICU stay, and higher mortality than patients with insignificant TR.Our results are similar to those of Bishawi et al. [8], who linked significant TR with prolonged ICU stay, renal dysfunction, and 1-year mortality.López-Vilella et al. [3] reported a significant association between postoperative significant TR and decreased survival.In other reports, significant TR was linked to different worse outcomes and greater mortality [5,[11][12][13][14].Prophylactic tricuspid valve annuloplasty during OHT was recommended and was performed in a few studies to avoid worse outcomes [15][16][17].Marelli and colleagues modified inferior vena cava anastomosis to decrease TR by using a flap from the recipient right atrium (RA) to augment the donor RA wall [15].The modified bicaval technique was associated with a short ICU stay and eliminated significant TR for one year [15].Greenberg and colleagues analyzed 330 patients with OHT; 52.4% had a donor TV repair and found no significant benefit or harm regarding mortality, hemodialysis, or tricuspid valve procedures after OHT [16].
Jeevanandam and colleagues conducted a small randomized controlled trial and compared 30 patients with OHT to 30 patients with OHT with DeVega tricuspid annuloplasty [17].The group with annuloplasty had a shorter reperfusion time, lower mortality, and better right ventricular performance than those without annuloplasty.At the 1-year follow-up, the tricuspid annuloplasty group showed less TR, without a difference in renal function compared to the OHT without annuloplasty group.The study had significant limitations, including underpower and different surgeons; one surgeon performed OHT with tricuspid annuloplasty, and another performed OHT without annuloplasty [17].In our cohort, at the 1-year follow-up, the TR degree decreased without tricuspid valve procedures.Bishawi et al. [8] reported the improvement of TR over time.Similarly, Algarni et al [4] reported improvement of TR with medical therapy after 6 months of transplantation.
In summary, TR is not a benign postoperative finding, as significant TR was associated with early mortality and morbidities with prolonged hospitalization.The degree of TR significantly decreased during the first year after transplantation.

Fig. 1
Fig. 1 of the patients studied to TR

Table 1
Baseline characteristics of patients with and without significant tricuspid regurgitation after heart transplantation BMI Body mass index, sPAP Systolic pulmonary artery pressure, dPAP Diastolic pulmonary artery pressure, mPAP Mean pulmonary artery pressure, TPG Transpulmonary gradient, PCWP Pulmonary capillary wedge pressure, PVR pulmonary vascular resistance, WU Wood unit.Data were presented as median (interquartile range) or numbers and percentages

Table 2
The studied variables of the donors

Table 3
Multivariable logistic regression for postoperative significant TR OR Odds ratio, CI Confidence interval, TPG Transpulmonary gradient, PVR Pulmonary vascular resistance

Table 4
The postoperative RHC and echocardiographic variables RHC Right heart catheterization, RV Right ventricle, sPAP Systolic pulmonary artery pressure, dPAP Diastolic pulmonary artery pressure, mPAP Mean pulmonary artery pressure, TPG Transpulmonary gradient, PVR Pulmonary vascular resistance, WU Wood unit

Table 5
Perioperative data and outcomes in patients with and without significant tricuspid valve regurgitation after heart transplantation CRRT Continuous renal replacement therapy, AKI Acute kidney injury, ICU Intensive care unit, sPAP Systolic pulmonary artery pressure, dPAP Diastolic pulmonary artery pressure, mPAP Mean pulmonary artery pressure, TPG Transpulmonary gradient, PVR Pulmonary vascular resistance, WU Wood unit.