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.

Keywords: 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.