The relationship between pulmonary hypertension and graft vascular resistance and rejection in liver transplant patients

Abstract

Purpose

Pulmonary hypertension (PH) is associated with systemic hemodynamic changes that may influence graft perfusion following liver transplantation (LT). In this study, we aimed to evaluate whether pre-transplant PH risk, as estimated by transthoracic echocardiography (TTE), is associated with early post-transplant hepatic artery Doppler parameters, including resistive index (RI) and peak systolic velocity (PSV). We also sought to assess whether echocardiography-derived PH risk is associated with biopsy-proven graft rejection.

Methods

In this retrospective cohort study, 283 patients who underwent LT were included. Patients were stratified based on TTE-derived systolic pulmonary artery pressure (sPAP). Hepatic artery RI and PSV were measured using Doppler ultrasound (US) at predefined postoperative time points. Longitudinal changes were analyzed using generalized estimating equation models, and graft rejection was assessed based on biopsy findings during follow-up.

Results

RI values differed across PH risk groups, particularly in the early postoperative period. Longitudinal analysis showed a significant effect of time and a significant interaction between PH risk and time, while the overall effect of PH risk approached significance after adjustment for covariates. PSV values also varied over time; however, no independent association between PH risk and PSV was observed after adjustment for age and sex. Subgroup analysis indicated that both RI and PSV values were significantly higher in adult compared to pediatric patients. No statistically significant association was found between PH risk and biopsy-proven graft rejection.

Conclusion

Pre-transplant TTE-derived PH risk may influence postoperative hepatic artery Doppler parameters, particularly RI in the early postoperative period. However, its association with graft rejection remains unclear and should be interpreted with caution. Further prospective studies with larger patient cohorts are needed to clarify these relationships better.

Introduction

Liver transplantation (LT) is the gold-standard treatment for patients with end-stage liver disease (ESLD), fulminant hepatitis, some metabolic diseases, and early-stage liver malignancy [1]. Post-transplant outcomes are influenced by a range of systemic factors, including cardiovascular function [2].

Pulmonary hypertension (PH) is a systemic condition associated with increased morbidity and mortality [3]. The PH is hemodynamically defined as a mean pulmonary artery pressure (mPAP) greater than 20 mmHg and a pulmonary vascular resistance greater than 2 Wood Units [4–8]. However, because right heart catheterization is an invasive procedure and has low accessibility, its routine use for pulmonary pressure assessment in the preoperative period and postoperatively is limited. Therefore, the American Association for the Study of Liver Diseases recommends transthoracic echocardiography (TTE) as part of the preoperative evaluation of LT candidates [9]. The systolic pulmonary artery pressure (sPAP) is commonly used as a surrogate marker of pulmonary pressures and correlates reasonably well with mPAP, allowing a noninvasive estimation of PH risk [9, 10].

Resistive index (RI) may increase in the presence of vasoconstriction. In LT patients, the RI value is typically expected to be between 0.5 and 0.7 under normal conditions. A higher RI, up to 0.8, may be accepted within the first 72 h after LT due to postoperative factors such as vasospasm and reperfusion edema [8, 11]. Increased RI values may reflect elevated vascular resistance due to various underlying mechanisms, including graft-related pathology or systemic hemodynamic changes, and should not be interpreted as a direct indicator of graft rejection. Similarly, hepatic artery peak systolic velocity (PSV) may vary depending on the underlying mechanism. At the same time, increased resistance due to inflammatory or structural changes may be associated with higher PSV values, whereas more pronounced resistance or reduced perfusion may result in lower flow velocities. The normal range of PSV of the hepatic artery, another parameter evaluated by Doppler ultrasound (US), is accepted as 84 ± 40 cm/s in uncomplicated cases and 46 ± 27 cm/s in patients with hepatic artery stenosis [9–12]. Doppler US plays an essential role in the postoperative evaluation of patients undergoing LT. Preoperative TTE-based assessment of PH risk may therefore be helpful when interpreting postoperative Doppler findings.

Pre-transplant PH risk, as estimated by TTE [13], may influence postoperative Doppler US parameters and their interpretation in patients undergoing LT. Previous studies have explored the relationship between PH and post-transplant outcomes, including graft dysfunction and mortality. However, data on the relationship between pre-transplant PH risk and postoperative hepatic artery Doppler parameters are limited. This highlights an important gap in the literature. Therefore, the primary aim of this study was to evaluate the relationship between pre-transplant PH risk, as estimated by TTE, and early post-transplant hepatic artery Doppler parameters (RI and PSV). We also examined whether TTE-derived PH risk is associated with biopsy-proven graft rejection.

Methods

This retrospective cohort study was approved by the Ethics Committee of Başkent University (No. KA25/101-441276, 10 March 2025) and conducted in accordance with the Declaration of Helsinki. Informed consent was waived because the data were anonymized. Two hundred and ninety participants who underwent LT between July 2018 and April 2023 were enrolled in the study. Five were excluded from the study because TTE reports were missing from the archive, and two were excluded due to incomplete Doppler US data. Consequently, 283 patients were included in the study, and the flow chart of participants is summarized in Fig. 1.

Fig. 1.

Flow chart of the study population

Furthermore, patients with hepatic artery thrombosis, portal vein thrombosis, biliary complications, and severe graft dysfunction were excluded from the study. Patients were grouped according to the etiology of their liver failure. These exclusions were applied to minimize confounding by major technical and vascular complications that could independently affect hepatic artery Doppler parameters and obscure the evaluation of systemic hemodynamic influences. For these patients, the Pediatric End-Stage Liver Disease (PELD) score was extracted from medical records for patients under 12 years of age, while the Model for End-Stage Liver Disease (MELD) score was applied for patients 12 years of age and older (Table 2). The patients were divided into groups based on sPAP values derived from their TTE findings.

Table 2.

Distribution of liver disease etiology across PH risk groups

Etiology of liver failure (%)	All Patients (n = 283)	Normal (n = 237)	Mild PH (n = 19)	Moderate/Severe PH (n = 27)
Infection (HBV, HCV, etc.)	54 (19.08%)	39 (16.45%)	5 (26.32%)	10 (37.04%)
Storage diseases (Wilson disease, glycogen storage disease, etc.)	37 (13.07%)	29 (12.23%)	4 (21.05%)	4 (14.81%)
Cryptogenic	32 (11.31%)	28 (11.81%)	3 (15.79%)	1 (3.70%)
Enzyme deficiency	51 (18.02%)	45 (18.99%)	4 (21.05%)	2 (7.41%)
Biliary pathologies	82 (28.98%)	76 (32.07%)	3 (15.79%)	3 (11.11%)
Alcoholic cirrhosis	5 (1.77%)	4 (1.69%)	0 (0.0%)	1 (3.70%)
Budd-Chiari syndrome	4 (1.41%)	3 (1.27%)	0 (0.0%)	1 (3.70%)
Other rare causes	18 (6.36%)	13 (5.49%)	0 (0.0%)	5 (18.52%)

Additionally, tricuspid regurgitation velocity (TRV) and Tricuspid annular systolic plane excursion (TAPSE)/sPAP < 0.55 mm/mmHg) values were determined from TTE findings (Table 2). RI and PSV were determined from Doppler US findings in these patients on postoperative days 3, 1 week, 1 month, 3 months, and 6 months. At our institution, LT patients are routinely followed postoperatively using this protocol. In addition, rejection was determined by the results of true-cut biopsy during the first 5 years after LT. Rejection was evaluated as a secondary outcome, and the analysis was intended to assess overall associations rather than a direct temporal relationship with early postoperative Doppler measurements. The relationship between pre-transplant portopulmonary hypertension risk, as estimated by TTE, and postoperative Doppler US parameters and biopsy findings was evaluated. Portopulmonary hypertension was not confirmed invasively; instead, PH risk was estimated based on preoperative TTE-derived sPAP values.

The TTE parameters used to determine PH risk include a resting mPAP greater than 20 mmHg. The literature indicates that sPAP strongly predicts mPAP in adults and is calculated using the formula: mPAP = 0.61 × sPAP + 2 mmHg. The threshold of mPAP = 20 mmHg in defining PH equals 38 mmHg for sPAP with the above formula. Considering the sPAP values, patients were grouped as normal (< sPAP 38 mmHg), mild (sPAP 38–50 mmHg), moderate (sPAP 50–70 mmHg), and severe (sPAP > 70 mmHg) [9].

Since mPAP > 45 mmHg is contraindicated for LT, no patients in our archive search had a preoperative sPAP value that could be calculated to exceed 45 mmHg. There was only one patient with a sPAP of 70 mmHg and a calculated mPAP of 44.7 according to the formula, and he was included in the severe group.

In our routine clinical practice, US-guided true-cut biopsy is performed by two expert interventional radiologists when allograft rejection is suspected. A single expert pathologist in LT evaluates biopsy specimens. Pathology reports of patients who subsequently developed rejection revealed acute cell-mediated rejection in all patients.

The primary outcome of this study was the association between pre-transplant PH risk, as estimated by TTE, and postoperative hepatic artery Doppler parameters (RI and PSV). Biopsy-proven graft rejection was evaluated as a secondary outcome.

Statistical analysis

Statistical analyses were performed using SPSS version 27 (IBM Corp., Armonk, NY, USA). Descriptive statistics were expressed as mean ± standard deviation for continuous variables and as frequency (percentage) for categorical variables.

Longitudinal changes in hepatic artery RI and PSV were evaluated using generalized estimating equations (GEEs), accounting for repeated measurements within the same patient across postoperative follow-up time points. The models included the PH risk group, postoperative time point, and their interaction. Age group (pediatric vs. adult) and sex were also included as covariates.

Due to the limited number of patients in the severe PH risk group (n = 1), the moderate and severe PH risk groups were combined for statistical analyses.

Subgroup analysis was performed by stratifying patients into pediatric (< 18 years) and adult (≥ 18 years) groups to evaluate differences in Doppler parameters.

Associations between categorical variables were assessed using contingency table analyses with either Fisher’s exact test or the chi-square test, as appropriate. Statistical significance was defined as p < 0.05.

Results

Participants and demographics

A total of 283 patients who underwent LT were included in the study. Baseline demographic and clinical characteristics are summarized in Tables 1 and 2.

Table 1.

Study group characteristics

Variable	All Patients (n = 283)
Age (years), mean ± SD	41.36 ± 12.48
Male sex, n (%)	188 (66.4%)
Female sex, n (%)	95 (33.6%)
Pediatric (< 18 years), n (%)	185 (65.4%)
Adult (≥ 18 years), n (%)	97 (34.3%)
PH risk groups, n (%)
– Normal	237 (83.8%)
– Mild	19 (6.7%)
– Moderate/Severe	27 (9.5%)
Rejection, n (%)	80 (28.3%)
No rejection, n (%)	203 (71.7%)

Patients were classified into PH risk groups based on preoperative TTE-derived sPAP values as normal (n = 237), mild PH risk (n = 19), and moderate/severe PH risk (n = 27). Due to the limited number of patients in the severe PH risk group (n = 1), the moderate and severe PH risk groups were combined for analysis.

Biopsy-proven rejection occurred in 80 patients (28.3%), while 203 patients (71.7%) had no evidence of rejection during follow-up. The distribution of rejection across PH risk groups is presented in Table 3.

Table 3.

Distribution of rejection according to PH risk groups

PH Risk Group	No Rejection	Rejection	Total
Normal	174 (73.4%)	63 (26.6%)	237
Mild	12 (63.2%)	7 (36.8%)	19
Moderate/Severe	17 (63.0%)	10 (37.0%)	27
Total	203 (71.7%)	80 (28.3%)	283

Primary outcome: association between PH risk and doppler parameters

Resistive Index (RI)

Hepatic artery RI values differed across PH risk groups, particularly in the early postoperative period. On postoperative day 3 (POD3), mean RI values were 0.668 ± 0.093 in the normal group, 0.703 ± 0.077 in the mild PH risk group, and 0.724 ± 0.076 in the moderate/severe PH risk group.

Longitudinal analysis showed a significant effect of time (p = 0.003) and a significant interaction between PH risk group and time (p = 0.020). After adjustment for age group and sex, the overall effect of PH risk on RI did not reach statistical significance but showed a trend toward significance.

Detailed Doppler US findings across all time points are summarized in Table 4 and illustrated in Fig. 2.

Table 4.

Hepatic artery Doppler parameters according to PH risk groups

Time Point	Normal	Mild	Moderate/Severe
Resistive Index (RI), mean ± SD
POD 3	0.668 ± 0.093	0.703 ± 0.077	0.724 ± 0.076
Day 7	0.67 ± 0.04	0.70 ± 0.05	0.69 ± 0.06
Month 1	0.63 ± 0.06	0.66 ± 0.08	0.67 ± 0.05
Month 3	0.65 ± 0.06	0.68 ± 0.08	0.68 ± 0.05
Month 6	0.65 ± 0.05	0.67 ± 0.06	0.69 ± 0.05
Peak Systolic Velocity (PSV), mean ± SD
POD 3	90.5 ± 38.0	101.9 ± 22.6	96.9 ± 34.6
Day 7	94.5 ± 26.5	108.1 ± 48.7	106.4 ± 28.3
Month 1	107.3 ± 37.2	114.4 ± 33.9	117.3 ± 43.5
Month 3	92.3 ± 33.8	111.5 ± 68.7	112.7 ± 59.8
Month 6	93.6 ± 34.1	103.0 ± 36.3	106.0 ± 39.4

Note: Statistical comparisons were performed using longitudinal GEE models; p values for overall effects (time, PH risk group, and interaction) are reported in the “Results” section

Fig. 2.

Longitudinal changes in hepatic artery resistive index (RI) across pulmonary hypertension (PH) risk groups

Peak Systolic Velocity (PSV)

Hepatic artery PSV values were higher in PH risk groups in descriptive analyses. However, longitudinal analysis showed that PSV varied over time (p = 0.047), with no independent association between PH risk and PSV after adjustment for age group and sex.

In contrast, age group was significantly associated with PSV values (p < 0.001), suggesting that patient-related factors may play a greater role in PSV variability than PH risk alone. These longitudinal changes in PSV are illustrated in Fig. 3.

Fig. 3.

Longitudinal changes in hepatic artery peak systolic velocity (PSV) across pulmonary hypertension (PH) risk groups

Subgroup analysis: Pediatric vs. Adult

Subgroup analysis showed significant differences between pediatric and adult patients. Adult recipients had significantly higher RI values on POD3 compared to pediatric patients (0.703 ± 0.087 vs. 0.662 ± 0.092, p = 0.0007). Similarly, PSV values were significantly higher in adult patients (p < 0.001).

These findings are summarized in Table 5 and illustrated in Fig. 4.

Table 5.

Subgroup analysis: Pediatric vs. Adult patients

Parameter	Pediatric (< 18)	Adult (≥ 18)	p-value
POD3 RI	0.662 ± 0.092	0.703 ± 0.087	0.0007
POD3 PSV	58.86 ± 30.12	78.59 ± 34.72	< 0.001

Fig. 4.

Comparison of postoperative day 3 hepatic artery resistive index (RI) between pediatric and adult patients

Secondary outcome: association between PH risk and graft rejection

The biopsy-proven rejection rate was 26.6% in the normal PH risk group, 36.8% in the mild PH risk group, and 37.0% in the moderate/severe PH risk group.

However, no statistically significant association was found between PH risk and rejection.

Summary of findings

PH risk was associated with higher hepatic artery RI values, particularly in the early postoperative period, although this relationship appeared to be influenced by time and patient characteristics. PSV values varied over time but were primarily associated with age rather than PH risk. No significant association was observed between PH risk and biopsy-proven graft rejection.

Discussion

In this study, we evaluated the association between pre-transplant PH risk, as estimated by TTE, and postoperative hepatic artery Doppler parameters in LT recipients. Our findings showed that hepatic artery RI values were higher in patients with increased PH risk, particularly in the early postoperative period. However, this association appeared to be influenced by time and patient characteristics and did not remain statistically significant after adjustment.

In contrast, although PSV values varied over time, no independent association between PH risk and PSV was observed after adjustment for age and sex. Subgroup analysis showed that adult recipients had significantly higher RI values compared to pediatric patients. This suggests that age-related differences in vascular compliance and systemic hemodynamics may influence Doppler parameters and should be considered when interpreting these results.

To our knowledge, data on the relationship between pre-transplant TTE-derived PH risk and postoperative hepatic artery Doppler findings, particularly RI and PSV, remain limited.

The observed increase in RI may be related to systemic hemodynamic changes associated with PH. Previous studies have suggested that pulmonary vascular remodeling and an imbalance between vasodilatory and vasoconstrictive mediators, favoring vasoconstriction, may contribute to increased vascular resistance in PH [14]. In this context, the higher RI values observed in patients with increased PH risk may reflect these systemic vascular changes rather than a direct graft-specific process. However, given the observational design of our study, a causal relationship cannot be established.

An important clinical implication of these findings relates to the interpretation of elevated hepatic artery RI values. In routine post-transplant follow-up, increased RI is often considered a potential indicator of graft dysfunction or rejection, prompting further diagnostic evaluation or adjustments in immunosuppressive therapy. Our results suggest that, in patients with pre-transplant PH risk, elevated RI values may instead reflect systemic hemodynamic influences rather than graft-specific pathology. Therefore, RI findings should be interpreted with caution in this population to avoid unnecessary interventions and potential overtreatment.

PSV values varied across postoperative time points; however, no independent association between PH risk and PSV was observed after adjustment for age and sex. This finding indicates that PSV may be more strongly influenced by patient-related factors, such as age and systemic hemodynamic conditions, rather than PH risk alone. Given the absence of systematic post-transplant cardiac evaluation, these findings should be interpreted with caution. Available data on the relationship between pre-transplant TTE-derived PH risk and postoperative hepatic artery PSV are limited, and further studies are needed to define this association better.

In our study, although higher RI values were observed in patients with increased PH risk, no significant association was found between PH risk and biopsy-proven graft rejection. These findings suggest that elevated RI values should not be interpreted as a direct indicator of rejection in this patient population. Similarly, sPAP values derived from pre-transplant TTE were not associated with graft rejection, suggesting that PH-related hemodynamic alterations may not directly translate into increased rejection risk.

In clinical practice, Doppler US abnormalities are often evaluated in the context of potential graft-related complications, including rejection, hepatic venous congestion, or parenchymal pathologies [15]. Our findings indicate that increased RI values in patients with pre-transplant PH risk may reflect systemic hemodynamic influences rather than graft-specific pathology. Therefore, PH-related vascular changes should be considered when interpreting elevated RI values. It should also be noted that multiple perioperative and systemic factors, including fluid status, vasopressor use, reperfusion-related changes, graft quality, and technical aspects of LT, may influence hepatic artery Doppler parameters. These factors were not systematically controlled in the present study and may have contributed to variability in RI and PSV measurements.

Previous studies have explored the relationship between PH and post-transplant outcomes. In a large retrospective cohort study including 63,142 LT recipients, Jose et al. reported an increased risk of graft failure in patients with portopulmonary hypertension [16]. However, they did not find a significant association between pre-transplant hemodynamic parameters, such as mPAP and pulmonary vascular resistance, and mortality.

Similarly, our findings indicate that TTE-derived PH risk may not be directly associated with graft rejection. These results underscore the complexity of the relationship between pulmonary hemodynamics and post-transplant outcomes and suggest that multiple factors beyond PH risk may contribute to graft prognosis. A study by Yılmaz et al. reported that elevated preoperative pulmonary pressure was associated with increased mortality in LT recipients [2]. However, no significant association was found between pulmonary pressure and allograft rejection. Consistent with these findings, our study also did not show a significant association between TTE-derived PH risk and biopsy-proven graft rejection. These results indicate that while pulmonary hemodynamic alterations may influence overall LT outcomes, their direct relationship with graft rejection remains uncertain. Further studies with larger cohorts are needed to clarify this association better.

This study has several limitations. First, its retrospective design may introduce selection and information bias, as TTE and Doppler US data were obtained from institutional records, and different clinicians performed follow-up evaluations. In addition, Doppler measurements were performed by a single radiologist, which may limit external validity and reproducibility. The PH in this study was defined based on TTE-derived sPAP values, and this approach should be interpreted with caution, as it does not replace invasive hemodynamic assessment.

Second, patients with major vascular and technical complications were excluded to allow a more focused evaluation of systemic hemodynamic influences on Doppler parameters. However, this may have resulted in a relatively selected cohort, limiting the generalizability of the findings.

Third, there is a temporal mismatch between early postoperative Doppler measurements and biopsy-proven rejection assessed over long-term follow-up. As a result, these findings do not establish a causal relationship between early RI and PSV values and graft rejection and should be interpreted as exploratory.

Additionally, the absence of systematic post-transplant cardiac evaluation represents an important limitation, as right heart function may influence hepatic arterial Doppler parameters, particularly PSV.

Finally, the rejection analysis may be underpowered due to the relatively low number of rejection events and the imbalance between groups. Accordingly, the absence of a statistically significant association between Doppler parameters and rejection should be interpreted with caution.

The PH risk, as estimated by pre-transplant TTE, may influence postoperative hepatic artery Doppler parameters, particularly RI in the early postoperative period. However, no significant association was found between PH risk and biopsy-proven graft rejection.

These results indicate that preoperative TTE assessment may provide useful context when interpreting postoperative Doppler US findings, although its role in predicting graft outcomes appears limited. Further prospective studies with larger cohorts and more comprehensive cardiac evaluation are needed to better define the relationship between pulmonary hemodynamics and LT outcomes.

Conclusion

Pre-transplant TTE-derived PH risk may influence postoperative hepatic artery Doppler parameters, particularly the RI in the early postoperative period. However, its association with graft rejection remains unclear and should be interpreted with caution, given the study’s limitations.

These findings suggest that preoperative TTE assessment can aid in interpreting postoperative Doppler US findings and underscore the need for prospective studies with larger patient groups and more comprehensive cardiac evaluation to define its clinical significance better.

Authors’ contributions

Burak Yagdiran: Conceptualization, Data curation, Methodology, Software, Writing – review & editing, Writing – original draft, Supervision, Funding acquisition. Batuhan Kirisci: Writing – review & editing, Visualization, Software, Formal analysis, Validation, Methodology, Data curation. Nedim Cekmen: Validation, Software, Supervision, Writing – review & editing, Writing – original draft. Ahmed Uslu: Visualization, Software, Formal analysis, Data curation. Mehmet Haberal: Supervision, Writing – review & editing, Writing – original draft.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

The datasets generated or analyzed during the study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This retrospective cohort study was approved by the ethics committee of the Baskent University Medical and Health Sciences Research Board (Date: 10/03/2025, No: KA25/101-441276) and conducted in accordance with the principles outlined in the Declaration of Helsinki. Written informed consent was waived due to the retrospective nature of this study.

Consent for publication

This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. All the authors have approved the manuscript and agree with its submission to your esteemed journal.

Competing interests

The authors declare no competing interests.