Abstract
Background: Heart transplantation (HT) remains the definitive therapy for end-stage heart failure, yet rejection and cardiac allograft vasculopathy (CAV) continue to limit long-term outcomes. Beyond donor-specific HLA antibodies, non-HLA antibodies, particularly anti-angiotensin II type 1 receptor antibodies (AT1R-Abs), have been implicated in allograft injury, but published findings are heterogeneous. Aim: The aim of this study is to systematically evaluate the evidence linking AT1R gene expression and anti-AT1R antibodies with key post-heart transplant outcomes. Methods: We conducted a systematic review in accordance with PRISMA guidelines. Scopus, PubMed, Web of Science, and the Cochrane Library were searched (December 2025) for cohort and case–control studies evaluating AT1R gene expression and/or AT1R-Ab status in HT recipients and their association with post-transplant outcomes. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the NIH Quality Assessment Tool. Results: Twelve studies encompassing 951 recipients met the inclusion criteria. Five studies evaluated AT1R mRNA expression, reporting variable patterns: several observed reduced AT1R/AT2R transcription after transplantation without clear clinical correlation, whereas others associated higher donor or recipient AT1R expression with transplant coronary artery disease and recurrent rejection. AT1R-Ab prevalence varied widely and appeared to increase after mechanical circulatory support, with substantial seroconversion reported during LVAD support in initially antibody-negative patients. Associations between AT1R-Ab and acute cellular rejection and antibody-mediated rejection were inconsistent across studies, and survival findings were inconclusive; however, some reports linked elevated AT1R-Abs to poorer long-term freedom from adverse events. Evidence regarding CAV was mixed, with signals of increased vasculopathy risk in some cohorts but not others. Conclusions: Current evidence suggests a potential role for AT1R expression and AT1R-Abs in cardiac allograft dysfunction, including rejection phenotypes and vasculopathy. Larger prospective studies with harmonized testing strategies are needed to define clinically meaningful AT1R-Ab cutoffs and clarify their utility in risk stratification and targeted therapeutic trials.