Immunosuppression and vascular remodeling after liver transplantation: Mechanisms, surrogate markers, and modifiable pathways

Abstract

Liver transplantation (LT) has achieved excellent short-term outcomes; however, long-term survival remains limited by cardiovascular disease, now a leading cause of late mortality in transplant recipients. Immunosuppressive therapy is a major contributor to this risk through both direct vascular toxicity and indirect metabolic effects. This review examines the clinical impact of immunosuppression-associated vascular remodeling and strategies to reduce cardiovascular complications after LT. Calcineurin inhibitors remain central to post-transplant immunosuppression but are strongly associated with hypertension, endothelial dysfunction, nephrotoxicity, and progressive vascular injury. Corticosteroids further increase cardiovascular risk by promoting insulin resistance, dyslipidemia, weight gain, and blood pressure elevation, supporting widespread adoption of steroid-sparing protocols. Mammalian target of rapamycin inhibitors may limit vascular smooth muscle proliferation and intimal hyperplasia and are frequently used to facilitate calcineurin inhibitor minimization, though careful patient selection is required due to metabolic and thrombotic concerns. Antimetabolites are generally vascularly well tolerated and play a key role in combination regimens. Subclinical vascular injury can be detected using noninvasive measures such as pulse wave velocity, carotid intima-media thickness, and flow-mediated dilation, enabling earlier identification of patients at increased cardiovascular risk. Host factors including metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, diabetes mellitus, and pre-existing cardiovascular disease further modify outcomes and should guide individualized immunosuppressive planning. Prospective studies incorporating vascular endpoints are needed to refine immunosuppressive strategies and improve long-term outcomes after LT.

Key Words: Liver transplantation; Immunosuppression; Vascular remodeling; Endothelial dysfunction; Cardiovascular disease; Calcineurin inhibitors; Metabolic complications; Arterial stiffness; Graft survival

Core Tip: Long-term survival after liver transplantation is increasingly limited by cardiovascular disease driven by immunosuppression-associated vascular remodeling. This review highlights how commonly used immunosuppressive agents, particularly calcineurin inhibitors and corticosteroids, promote endothelial dysfunction, arterial stiffening, and metabolic injury, while alternative strategies such as mammalian target of rapamycin inhibitor-based regimens and antimetabolites may reduce vascular harm. We emphasize noninvasive vascular markers and individualized immunosuppression as emerging tools to balance graft protection with long-term cardiovascular health in liver transplant recipients.

INTRODUCTION

Liver transplantation (LT) is a life-saving therapy that has undergone tremendous advancements over recent decades. It remains the only definitive treatment for end-stage liver disease, acute fulminant hepatic failure, hepatocellular carcinoma, hilar cholangiocarcinoma, and selected metabolic disorders[1]. Surgical innovation, perioperative management, and immunosuppression have greatly improved short-term graft and patient survival[1]. However, the field continues to face challenges related to donor organ shortage and limitations in long-term outcomes, with the development of allograft vasculopathy and general vascular remodeling emerging as a major barrier to extended graft survival[1]. Vascular remodeling involves structural and functional changes in blood vessels in response to chronic stimuli like immunosuppression[2-6]. Structural alterations include intimal thickening driven by extracellular matrix (ECM) reorganization. Functional remodeling is characterized by increased arterial stiffness due to decreased vascular compliance, as well as endothelial dysfunction because of reduced nitric oxide (NO) bioavailability and increased levels of oxidative stress. This review explores the effects of immunosuppression on vascular remodeling following LT and its association with the downstream effects of cardiovascular events and metabolic comorbidities.

The liver acts as a critical immunologic barrier between the gastrointestinal tract and systemic circulation. Portal venous inflow contains nutrients, environmental antigens, and gut microflora, which are continuously surveyed by hepatic immune cells[2]. T-cell-mediated rejection is the most frequent rejection subtype and typically occurs within the first six weeks to three months post-transplant, mainly due to insufficient immunosuppression[2]. Other rejection forms include hyperacute antibody-mediated rejection, acute antibody-mediated rejection, and chronic rejection. Hyperacute rejection, caused by ABO-incompatibility, now rarely occurs due to improved crossmatch techniques and requires immediate re-transplantation and immunosuppression. Chronic rejection may develop following prolonged under-immunosuppression or recurrent acute rejection and is irreversible. Biopsies may be required to determine subtype and severity. Without adequate immunosuppression, these processes can lead to irreversible graft injury and graft loss[2].

Immunosuppression is therefore essential to graft and patient survival, yet its long-term vascular consequences are increasingly recognized. Immunosuppressants are associated with endothelial injury and allograft vasculopathy, which may increase cardiovascular disease-related mortality in LT recipients[3]. Endothelial damage, driven by immunosuppressive drug exposure, rejection episodes, hypertension, and diabetes mellitus, results in endothelial activation, intimal hyperplasia, increased vascular resistance, adhesiveness, and thrombogenicity[3]. These mechanisms underlie endothelial dysfunction and atherogenesis and contribute to elevated cardiovascular disease risk following transplantation[3].

This review focuses on vascular remodeling associated with immunosuppression and examines how commonly used immunosuppressive agents alter vascular biology and influence long-term cardiovascular outcomes in post-transplant patients.

POST-LIVER TRANSPLANT CARDIOVASCULAR RISK LANDSCAPE

Long-term graft and patient survival after LT have plateaued, despite continued improvement in short-term outcomes. Figure 1 illustrates the life-course trajectory of cardiovascular risk following liver transplantation and highlights the cumulative impact of metabolic and immunosuppressive factors over time. The 10-year post-transplant survival rate remains approximately 60%-65%, with cardiovascular disease now the leading cause of long-term mortality in this population[4]. Chronic kidney disease (CKD), frequently driven by calcineurin inhibitor (CNI) nephrotoxicity, further increases cardiovascular event risk through its adverse effects on renal and vascular function, thus amplifying vascular remodeling[4]. Although cardiovascular diseases are common causes of death in the general population, their incidence is significantly higher in LT recipients. This elevation reflects immunosuppression-associated vascular injury in combination with lifestyle and metabolic risk factors. In the United States, an estimated 12%-16% of deaths occurring within the first year post-transplantation are attributed to cardiovascular disease[5].

Figure 1 Life-course framework of cardiovascular risk after liver transplantation. CV: Cardiovascular.

Several conditions contribute to this heightened cardiovascular event risk, including diabetes, obesity, hyperlipidemia, hypertension, and CKD. Hypertension occurs in 30%-50% of LT recipients and increases to nearly 70% five years after transplant[5]. Patients with end-stage liver disease often exhibit high cardiac output, low systemic vascular resistance, and low mean arterial pressure before transplant[5]. Following transplantation, systemic vascular resistance rises, resulting in increased arterial pressure. This shift is multifactorial and is worsened by preexisting cardiovascular risk factors and the vasoconstrictive effects of immunosuppressive medications. Additional early post-transplant hemodynamic changes, including abrupt increases in vascular resistance, can lead to pulmonary edema, heart failure, and postoperative atrial fibrillation[5].

Whether this screening impacts long-term cardiovascular outcomes remains unclear; however, post-transplant identification and management of these risk factors are critical. Early lifestyle intervention, strict blood pressure and lipid control, diabetes management, and immunosuppressant titration are central to improving long-term graft and patient survival and quality of life after LT[5].

IMMUNOSUPPRESSIVE AGENTS: PROFILES AND VASCULAR EFFECTS

The success of LT depends on careful selection and combination of immunosuppressive agents to prevent rejection. Figure 2 summarizes how immunosuppressive injury pathways translate into measurable noninvasive vascular phenotypes used to assess vascular remodeling in LT recipients. Therapeutic classes include CNIs, corticosteroids, mammalian target of rapamycin (mTOR) inhibitor (mTORi), antimetabolites (mycophenolate and azathioprine), and emerging biologics such as mesenchymal stem cell (MSC) therapy. These agents target different steps within the immune pathway and vary in their vascular effects, making an understanding of their mechanisms essential for individualizing therapy and optimizing graft and vascular outcomes.

Figure 2 Linking immunosuppressive injury pathways to noninvasive vascular phenotypes. NO: Nitric oxide; eNOS: Endothelial nitric oxide synthase; PWV: Pulse wave velocity; AIx: Augmentation index; cIMT: Carotid intima-media thickness; FMD: Flow-mediated dilation; CT calcium: Coronary artery calcium score; CNI: Calcineurin inhibitor; CKD: Chronic kidney disease.

CNIs: Mechanisms and vascular remodeling

CNIs are first-line agents that suppress T-cell activation via inhibition of calcineurin, preventing nuclear factor of activated T cells activation and interleukin (IL)-2 production[3]. However, these benefits occur alongside vascular consequences. CNIs induce endothelial and smooth muscle dysfunction[6], in part by upregulating nicotinamide adenine dinucleotide phosphate oxidase through nuclear factor kappa B and nicotinamide adenine dinucleotide phosphate oxidase 2 activation, generating superoxide and peroxynitrite and impairing NO signaling[7]. Through toll-like receptor 4 signaling, CNIs upregulate cytokines and adhesion molecules, intensifying leukocyte adhesion and vascular inflammation[8].

CNIs also stimulate vascular smooth muscle proliferation and vessel wall thickening[9]. Paradoxically, although calcineurin normally supports factor of activated T cells-regulated growth responses, CNIs promote alternative inflammatory pathways, upregulating monocyte chemoattractant protein-1 and enhancing angiotensin II responsiveness, leading to pathological remodeling[10].

Clinical evidence

Clinical data demonstrate CNI-associated vascular remodeling. Observational studies show associations between CNI exposure and hypertension in LT recipients, driven by increased vascular tone and endothelin activity[11]. In a cohort of 149 LT patients, cyclosporine therapy was associated with higher blood pressure, while tacrolimus resulted in fewer vascular complications - although both CNIs were linked to long-term vascular injury[12]. These findings support a consistent association between CNIs, endothelial dysfunction, and vascular remodeling over time.

Corticosteroids and vascular/metabolic effects

Corticosteroids exert broad immunosuppressive and anti-inflammatory effects by altering gene transcription and suppressing cytokines such as IL-2, IL-6, and tumor necrosis factor-α[13]. Vascularly, steroids enhance angiotensin II receptor signaling and α1-adrenergic activity, increasing vascular responsiveness to vasoconstrictors[14]. They promote sodium and water retention, expanding extracellular volume and raising blood pressure[15], and downregulate endothelial NO synthase (eNOS), reducing NO-mediated vasodilation[16]. Metabolically, corticosteroids disrupt carbohydrate, lipid, and protein homeostasis, contributing to insulin resistance, hyperglycemia, dyslipidemia, and obesity[17], which compound cardiovascular risk through additive mechanisms.

Evidence in transplant populations

Clinical studies support detrimental steroid-related vascular effects. A randomized dose-response trial demonstrated impaired insulin-mediated metabolic actions even at low steroid doses[17]. In renal transplant patients, steroid-free regimens showed improved fibrinolytic capacity[18], and another retrospective analysis associated low-dose steroid therapy with higher cardiovascular mortality[19]. Together, these findings support steroid-minimizing protocols in transplant care.

mTORi: Signaling and vascular characteristics

mTORi downregulate the mTOR kinase pathway, arresting T-cell proliferation at G1 and suppressing angiogenic signaling[20]. By inhibiting mTOR complex 1/2 and reducing hypoxia-inducible factor 1α translation, they limit vascular endothelial growth factor production and endothelial proliferation, reducing angiogenesis and smooth muscle growth[21].

Comparative vascular phenotype

Relative to CNIs, mTORi demonstrate less endothelial dysfunction and reduced vasoconstrictive signaling, and may limit vascular smooth muscle proliferation and transplant vasculopathy[22]. However, adverse effects include impaired wound healing, hyperlipidemia, and, in some cases, proteinuria or thrombotic microangiopathy - especially when combined with CNIs[23]. Agent selection therefore requires case-specific vascular and metabolic consideration.

Antimetabolites: Vascularly neutral profiles

Mycophenolate and azathioprine inhibit de novo purine synthesis, suppressing T-cell and B-cell proliferation[24,25]. Compared to CNIs and mTORi, antimetabolites have the most favorable vascular profile[26] and are rarely associated with hypertension, dyslipidemia, or endothelial dysfunction.

Mycophenolate may even reduce endothelial activation, cytokine production, and angiogenesis[27], while azathioprine is considered vascularly neutral. Overall, this class is regarded as the most benign with respect to vascular remodeling[26].

Biologic therapies: Emerging strategies and future directions

MSC-based therapy and MSC-derived extracellular vesicles are promising biologic approaches aimed at reducing toxicity and improving tolerance[28]. Early clinical evidence demonstrates excellent MSC infusion tolerability with no observed vascular remodeling or fibrosis up to five years post-transplant[29]. A randomized trial also showed pre-transplant MSC infusion improved immunoregulatory cell profiles without increasing vascular complications or rejection[30]. While other biologics such as tumor necrosis factor-α or complement inhibitors remain investigational, MSC platforms currently show the strongest vascular safety potential[31].

MECHANISTIC PATHWAYS LINKING IMMUNOSUPPRESSION TO VASCULAR REMODELING

Immunosuppression in LT is closely linked to ongoing vascular remodeling. Beyond suppressing immune activation, these agents influence endothelial function, angiogenic balance, and vascular tone, demonstrating that graft outcomes are not purely immunologic, but also vascular processes. Figure 3 compares the vascular and metabolic profiles of major immunosuppressive drug classes and their differential effects on endothelial and vascular biology.

Figure 3 Comparative vascular and metabolic profiles of major immunosuppressive classes. mTOR: Mammalian target of rapamycin; VEGF: Vascular endothelial growth factor.

Endothelial dysfunction and NO loss

Endothelial dysfunction in immunosuppressed patients largely reflects reduced NO bioavailability. Mechanisms include increased oxidative stress, impaired NO synthesis, limited substrate availability, and upregulation of vasoconstrictors[32-34]. CNIs such as cyclosporine A, along with corticosteroids, decrease eNOS expression[32]. Tacrolimus accelerates NO breakdown and induces eNOS uncoupling, shifting NO synthase activity toward superoxide generation[33]. Elevated levels of asymmetric dimethylarginine (ADMA), an endogenous eNOS inhibitor, exacerbate the decline in NO bioavailability[35]. Collectively, these mechanisms promote vasculopathy in transplant recipients receiving immunosuppression.

Endogenous vasoconstrictors also contribute to remodeling. Expression and signaling of endothelin-1 (ET-1) and endothelin-A receptors on vascular smooth muscle are enhanced by CNIs such as cyclosporine A and tacrolimus[32]. ET-1-mediated vasoconstriction, oxidative stress, and inflammatory signaling amplify endothelial dysfunction and hypertension, overshadowing compensatory vasodilatory mediators such as prostacyclin (prostaglandin I2)[36]. Dysregulated ET-1 signaling therefore accelerates vascular remodeling under immunosuppression.

Reactive oxygen species and oxidative injury

Reactive oxygen species play a central role in the vascular effects of immunosuppression. Increased reactive oxygen species generation disrupts oxidant-antioxidant balance and induces endothelial oxidative injury[37]. Oxidative stress degrades NO and contributes to eNOS uncoupling, compounding vascular dysfunction. Persistent oxidative stress can exhaust glutathione reserves, impair mitochondrial function, and influence immune cell metabolism, increasing susceptibility to vascular injury and infection[38]. Antioxidant strategies have therefore been proposed to restore redox balance in immunosuppressed patients[39].

Smooth muscle proliferation and fibrotic remodeling

CNIs promote vascular smooth muscle cell proliferation, vessel wall thickening, and maladaptive remodeling[9]. Although calcineurin normally regulates vascular smooth muscle proliferation and migration, CNI therapy paradoxically worsens these processes by activating alternative pro-inflammatory pathways. Tacrolimus and cyclosporine have been shown to activate transforming growth factor-β signaling, driving vessel wall thickening[40]. These effects reinforce the contribution of CNIs to long-term vascular remodeling.

Furthermore, immunosuppressive classes have various effects on ECM turnover and fibrosis. CNIs do not effectively limit ECM deposition and may activate fibrogenic pathways, increasing collagen accumulation and vascular thickening[41]. CNIs also stimulate transforming growth factor-β signaling, a major driver of ECM remodeling[42]. By contrast, mTORi suppress fibroblast proliferation and myofibroblast differentiation while enhancing collagenase activity[43]. Mycophenolate exerts antifibrotic activity by reducing type I collagen production and enhancing matrix metalloproteinase-1-mediated collagen degradation[44]. Corticosteroids also decrease ECM synthesis by reducing hyaluronan production and fibroblast proliferation. Overall, most non-CNI immunosuppressants are associated with reduced ECM accumulation relative to CNIs.

Metabolic pathways and vascular consequences

Immunosuppressive agents are strongly associated with metabolic syndrome development in LT recipients, contributing to vascular injury[45]. CNIs are linked to new-onset diabetes due to impaired insulin secretion and increased insulin resistance[46], and are major contributors to nephrotoxicity and CKD in this setting[47]. Corticosteroids exacerbate obesity and diabetes risk, while mTORi induce dyslipidemia and glucose dysregulation, although they are generally less diabetogenic than CNIs. Individualized immunosuppressive regimens and early dose modification remain essential to minimize long-term cardiovascular injury[48].

SURROGATE MARKERS AND NONINVASIVE MEASURES IN LT COHORTS

Early vascular remodeling following LT can be detected well before overt cardiovascular events. Subtle structural and functional arterial changes are measurable through non-invasive markers, now widely used in transplant cardiology to assess the cumulative impact of immunosuppression, inflammation, and post-LT physiologic changes on arterial stiffness, endothelial responsiveness, and subclinical atherosclerosis. These markers form an important framework for early diagnosis and risk intervention, as cardiovascular disease remains a major contributor to long-term morbidity and mortality in LT recipients. Figure 4 illustrates the relative mechanistic burden of vascular injury across major immunosuppressive drug classes.

Figure 4 Comparative mechanistic burden across drug classes. NO: Nitric oxide; CNI: Calcineurin inhibitor; mTORi: Mammalian target of rapamycin inhibitor; CV: Cardiovascular; mTOR: Mammalian target of rapamycin.

Pulse wave velocity (PWV) remains the gold-standard index of arterial stiffness and a strong predictor of cardiovascular events. PWV increases with aging, systolic pressure, and cumulative immunosuppressive exposure[49]. In LT patients, PWV reflects accelerated vascular aging, particularly in the setting of CNI-associated and steroid-associated hypertension and endothelial injury. The augmentation index (AIx), a related stiffness marker, quantifies wave reflections and microvascular resistance and is useful in states of heightened peripheral vasoconstriction or inflammation[50]. Together, PWV and AIx provide complementary assessment of large-artery rigidity and central hemodynamic stress.

Additional noninvasive measures are emerging to assess vascular biology beyond standard ultrasound and stiffness indices. Peripheral arterial tonometry and the cardio-ankle vascular index provide insight into autonomic tone and microvascular health[51]. Circulating biomarkers - including endothelial microparticles, ADMA, soluble vascular cell adhesion molecule-1, and E-selectin - offer biochemical evidence of endothelial disruption[52]. Advanced imaging approaches, such as computed tomography-based calcium scoring, magnetic resonance imaging vessel-wall mapping, and positron emission tomography vascular inflammation imaging, may further refine risk stratification. Collectively, these surrogate vascular markers support noninvasive, personalized monitoring strategies to quantify the vascular sequelae of immunosuppression in LT cohorts.

HOST/RECIPIENT MODIFIERS AND INTERACTION EFFECTS

Vascular remodeling after LT reflects the combined effects of immunosuppression and pre-existing host factors influencing susceptibility to vascular injury. Patient comorbidities, metabolic status, genetic risk, and environmental exposures interact with endothelial dysfunction, oxidative stress, inflammation, and arterial stiffening, creating heterogeneous cardiovascular trajectories among LT recipients.

Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are increasingly recognized contributors to vascular decline in LT patients. Recurrent or de novo metabolic dysfunction-associated steatotic liver disease develops from weight gain, insulin resistance, corticosteroid exposure, and lifestyle changes, generating a lipotoxic and inflammatory milieu that damages endothelium and accelerates arterial stiffness[53]. CKD, highly prevalent due to CNI nephrotoxicity, increases vascular calcification and oxidative stress; reduced estimated glomerular filtration rate correlates with higher PWV and carotid intima-media thickness in LT populations[54,55].

Chronic viral hepatitis (hepatitis B virus/hepatitis C virus) adds complexity through systemic inflammation and endothelial dysfunction[56]. Although antiviral therapy improves vascular biology, residual metabolic risk and ongoing immunosuppression limit full recovery. Traditional cardiovascular factors - obesity, diabetes, hypertension, and dyslipidemia - further contribute to arterial stiffening and atherosclerosis, and immunosuppressive agents (CNIs, mTORi, corticosteroids) may amplify these risks by altering glucose and lipid metabolism[5].

Genetic, demographic, and environmental modifiers also influence vascular remodeling after LT. Older age and male sex correlate with increased stiffness and reduced endothelial resilience. Genetic variation affecting NO synthesis, oxidative responses, and drug metabolism may alter individual vascular vulnerability to immunosuppressive exposure[49,57]. Environmental factors - diet, smoking, inactivity, socioeconomic status - and donor characteristics such as graft age, vascular integrity, and ischemia-reperfusion injury may further shape early vascular outcomes. Together, these modifiers act as amplifiers of immunosuppression-related vascular injury, emphasizing the need for personalized immunosuppressive strategies, targeted risk reduction, and long-term cardiovascular surveillance in LT care.

CNI MINIMIZATION/WITHDRAWAL APPROACHES

Higher trough levels of CNIs contribute to vascular and renal toxicity, with endothelial dysfunction and hypertension as key amplifiers of the vascular remodeling process[58]. CNI minimization or withdrawal strategies aim to limit nephrotoxicity and vascular injury, although complete withdrawal succeeds only in a minority of carefully selected recipients, with up to approximately 20% achieving long-term tolerance without rejection[59]. CNI minimization, commonly via early introduction of mycophenolate mofetil (MMF) or mTORi, can preserve vascular function, though the risk of acute or chronic rejection persists[60]. A major randomized multicenter trial showed reduced tacrolimus + MMF significantly lowered rejection rates (28% vs 46%, P = 0.024) and reduced renal dysfunction compared with standard tacrolimus alone, though with higher rates of leukopenia, thrombocytopenia, and diarrhea in the combination group[61]. mTOR-based regimens may attenuate intimal proliferation and produce renal benefit, particularly when conversion occurs early, though long-term gains depend on patient selection and timing[62]. Steroid-sparing regimens are widely used due to adverse metabolic and vascular effects associated with corticosteroids; most centers withdraw steroids within 3-6 months post-LT, except in autoimmune hepatitis. Data consistently show no increase in rejection or graft loss with steroid minimization, and a meta-analysis demonstrated comparable survival and lower hypertension risk with steroid-free therapy[63]. Contemporary post-LT immunosuppression therefore emphasizes CNI minimization and steroid-sparing strategies, supported by adjunctive MMF and/or mTORi to reduce renal and vascular toxicity while maintaining graft protection. True operational tolerance (complete immunosuppression withdrawal) remains rare and limited to a small minority of long-term survivors. Major evidence gaps remain, as few studies assess vascular endpoints directly; most report outcomes based on renal function or rejection, leaving uncertainty regarding which regimen best preserves vascular structure in LT.

SURVEILLANCE AND RISK MITIGATION FRAMEWORK

Surveillance after LT should be structured around three complementary objectives: Early identification of graft vascular complications, longitudinal assessment of systemic vascular remodeling, and mitigation of cardiometabolic amplifiers that interact with immunosuppression to accelerate endothelial dysfunction and arterial stiffening[49,64-66].

Graft-focused vascular surveillance

In the early post-transplant period, surveillance prioritizes detection of macrovascular complications, including hepatic artery thrombosis or stenosis, portal vein thrombosis, and hepatic venous outflow obstruction, which remain leading causes of early graft dysfunction and ischemic biliary injury[67-69]. Doppler ultrasonography is the primary noninvasive modality for evaluating graft inflow and outflow when clinical or biochemical abnormalities arise, with cross-sectional imaging reserved for equivocal or high-risk cases[67]. Invasive testing, including biopsy, should be selectively employed when graft dysfunction cannot be explained by vascular or biochemical evaluation[65-71].

Systemic vascular remodeling and subclinical injury

Beyond graft-specific complications, LT recipients experience accelerated systemic vascular remodeling driven by cumulative immunosuppressive exposure, hypertension, kidney dysfunction, and post-transplant metabolic injury[49,57]. Noninvasive surrogate markers allow early detection of subclinical vascular injury before overt cardiovascular events. Measures of arterial stiffness (PWV and AIx), structural atherosclerosis (carotid intima-media thickness), and endothelial function (flow-mediated dilation or peripheral arterial tonometry) have demonstrated prognostic value in LT cohorts and identify risk underestimated by traditional cardiovascular scoring systems[49,50,57]. Circulating markers of endothelial injury (e.g., ADMA, soluble adhesion molecules, endothelial microparticles) remain investigational but may complement imaging-based assessment in research or specialized settings[52].

Integrated cardiometabolic risk mitigation

Cardiometabolic risk factor control is central to limiting vascular remodeling and late cardiovascular mortality after LT. Hypertension, diabetes, dyslipidemia, obesity, and CKD are highly prevalent and strongly modified by immunosuppressive choice and intensity[5,58]. Risk mitigation strategies emphasize CNI minimization, steroid-sparing or early withdrawal, and use of adjunctive agents such as MMF or mTORi when appropriate to reduce nephrovascular and metabolic toxicity[60-63]. Pharmacologic management of blood pressure, lipids, and glycemia should account for drug-drug interactions and renal function, while lifestyle intervention remains foundational but insufficient as monotherapy in most recipients[72-75]. A major limitation in current practice is the lack of standardized vascular endpoints and surveillance protocols in LT. Most studies prioritize graft survival and rejection rather than vascular structure or function, underscoring the need for prospective trials incorporating harmonized Doppler criteria, arterial stiffness metrics, and endothelial function measures as clinically meaningful outcomes[49,76].

INDIVIDUALIZATION OF IMMUNOSUPPRESSION WITH VASCULAR SAFETY IN MIND

Individualizing immunosuppressive therapy after LT is essential to balance rejection prevention with minimizing vascular injury and its amplifiers, such as nephrotoxicity and metabolic complications. This need is driven by the diverse toxicity profiles of available immunosuppressive agents. Accordingly, immunosuppression strategies have shifted away from uniform treatment protocols toward individualized models that preserve graft function while attempting to reduce chronic vascular remodeling.

Drug class selection remains central to this process. CNIs, particularly tacrolimus, continue to serve as the cornerstone of most LT immunosuppressive protocols despite their association with nephrotoxicity, hypertension, and chronic vascular dysfunction. To mitigate these effects, mTORi (e.g., everolimus) and antimetabolites (e.g., MMF) are increasingly used to support CNI minimization, with the goal of improving long-term vascular outcomes. Corticosteroids are generally tapered over 3-6 months to limit diabetes, dyslipidemia, and weight gain, although prolonged use is often necessary for autoimmune hepatitis. Induction agents, such as basiliximab or alemtuzumab, may be used selectively to delay CNI initiation, lower early nephrovascular stress, or address high immunologic risk[60,77-79].

Personalized pharmacokinetic approaches are emerging, including algorithm-based tacrolimus dosing platforms and parabolic personalized dosing models that utilize clinical and pharmacogenomic data to optimize trough attainment, reduce nephrovascular toxicity, and minimize rejection events[80]. Future practice will likely rely more heavily on individualized tacrolimus mapping, metabolomic guidance, and adaptive dosing based on physiologic stress or vascular injury patterns.

Practical considerations and challenges

The individualized approach remains complex. Post-LT immunosuppression typically involves combinations of CNIs, mTORi, antimetabolites, and steroids, with dynamic adjustments based on complications, rejection episodes, and cardiovascular evolution[48,60]. Decision-making is complicated by the lack of robust noninvasive biomarkers capable of reliably predicting rejection or tolerance. Thus, clinical practice still relies heavily on biopsy-based evaluation and donor-specific antibody profiling[2,79,81]. True immunologic tolerance remains rare (< 5% of long-term survivors), limiting CNI or steroid withdrawal strategies[82].

Predicting which patients may achieve minimization success is difficult: Histology, donor-specific antibodies, trough levels, and graft function offer partial insight but no definitive predictive model. Individualized trough monitoring is critical, particularly since tacrolimus levels > 7-8 ng/mL early post-transplant are associated with vascular toxicity; troughs of approximately 4-7 ng/mL may provide safer vascular outcomes without increasing rejection[80,82-85].

Institutional variation further influences feasibility. Some centers have extensive experience with mTOR-based or steroid-free regimens, whereas others lack the infrastructure or expertise to support complex combination therapy, advanced trough monitoring, or tolerance selection[86]. There are also key gaps in long-term data regarding the vascular safety of newer biologics, maintenance mTOR monotherapy, and late-stage CNI withdrawal[2].

Knowledge gaps, future directions, and research priorities

Significant gaps remain regarding vascular endpoints in LT. Most trials prioritize graft survival and rejection outcomes, while vascular remodeling, endothelial dysfunction, hepatic artery thrombosis, intimal hyperplasia, and microvascular biology are rarely primary endpoints. Prospective multicenter studies are needed to quantify vascular complication incidence, timing, and progression using standardized ultrasound and biomarker criteria[76].

Direct head-to-head comparisons between tacrolimus-centered, mTOR-centered, and MMF-centered regimens are lacking, particularly with respect to arterial thickness, stiffness, thrombosis, and microvascular remodeling endpoints. While CNI minimization appears beneficial, its vascular implications are not fully defined. Emerging data suggest mTOR-based regimens may increase thrombotic risk in certain individuals, reinforcing the need for vascular phenotyping, thrombosis risk scoring, and possibly thrombophilia screening before conversion[87].

Adjunctive vascular-directed therapies remain under study. Observational evidence supports aspirin prophylaxis for hepatic artery thrombosis prevention, while routine anticoagulation remains controversial due to bleeding risk. Endovascular rescue therapies are effective for established stenosis or thrombosis, but prevention strategies remain poorly defined. Standardization of vascular imaging protocols - including Doppler waveform interpretation, carotid intima-media thickness monitoring, and flow-mediated dilation acquisition - is needed to reduce center-to-center variability and support vascular-specific clinical trials.

Collectively, individualization of post-transplant immunosuppression remains a dynamic and evolving strategy focused on graft protection, vascular safety, and long-term survival. Current advances in risk stratification, combination therapy, biomarker development, and modeling platforms suggest a future toward precision immunosuppression, but robust vascular endpoint data and long-term validation are urgently needed to guide practice change.

CONCLUSION

Long-term survival after LT is increasingly limited by cardiovascular disease, driven in part by immunosuppression-associated vascular remodeling. Although immunosuppressive therapy is essential for graft protection, CNIs and corticosteroids promote endothelial dysfunction, arterial stiffening, and metabolic injury that cumulatively increase cardiovascular risk. Accordingly, contemporary post-LT management should prioritize CNI minimization when feasible, early steroid withdrawal, and aggressive control of modifiable cardiometabolic risk factors, supported by adjunctive antimetabolites or selective use of mTORi in appropriately selected patients.

Noninvasive vascular markers offer practical tools to detect subclinical vascular injury and may guide individualized immunosuppression strategies before overt cardiovascular events occur. Future research should clarify the vascular effects of specific immunosuppressive drugs and biologics and their impact on long-term cardiovascular outcomes. Transplant programs should also adopt structured cardiovascular screening protocols pre-transplant and post-transplant to identify high-risk patients earlier and support individualized immunosuppressive planning. Ultimately, optimizing immunosuppression to preserve graft survival while protecting vascular health will require integrated efforts in clinical research, biomarker discovery, and multidisciplinary care pathways. Such an approach is essential to improving long-term cardiovascular and overall outcomes in LT recipients.