The prevalence of AT1R antibodies in OHT recipients ranges from 40 to 60% and may be associated with increased risk of AMR, cellular-mediated rejection (CMR), and CAV [1,8]. vascular easy muscle proliferation, cellular migration, fibrosis, and inflammation. Consequently, anti-AT1R antibodies can cause endothelial cell activation and have proinflammatory and profibrotic effects that have been implicated in reports of AMR in cardiac and other transplant Ginkgolide B recipients [1]. Known risk factors for the formation of anti-AT1R antibodies include blood transfusions, pregnancy, and a history of mechanical circulatory support commonly used TNFSF13 as a bridge to heart transplantation [2]. We statement a case of a heart transplant recipient presenting with anti-AT1R antibody-induced AMR, highlighting the need for pre-transplant screening for non-HLA antibodies in select patients to identify those at risk of AMR despite the absence of DSAs. 2. Case Presentation A highly sensitized (cPRA 90%) 56-year-old female patient received an orthotopic heart transplant (OHT) due to her history of end-stage congestive heart failure and cardiomyopathy. The pre-transplant HLA antibody screening showed a borderline presence of class I DSA (Physique 1). The pre-transplant serum was strongly positive for anti-AT1R (titer 1:6400) and five other autoantibodies (>50% above the respective cutoffs) (Physique 1A,B). Open in a separate window Physique 1 Non-HLA (AT1R and autoantibodies) monitoring during AMR diagnosis. (A) Following the biopsy-proven AMR diagnosis, the patient underwent five initial sessions of therapeutic plasmapheresis (TPE), followed by an additional five sessions of TPE. On day 502, the anti-AT1R level temporarily fell by 61% from 47.8 to 18.7 U/mL. The patient was discharged. However, the anti-AT1R level started to increase again and, at the time of writing, were at a high level (>40 U/mL). (B) After the AMR diagnosis, the levels of the five non-HLA antibodies remained above the threshold. (Abbreviations: EIF2A, eukaryotic translation initiation factor 2A; PRKCZ, protein kinase C zeta type; PTPRN, receptor-type tyrosine-protein phosphatase-like N; Ginkgolide B PRKCH, protein kinase C eta type; and GDNF, glial cell line-derived neurotrophic factor. Notably, there was concern for early AMR based on a biopsy within one month of her transplant, which Ginkgolide B showed diffuse C4d staining (>50%) and a strong positivity. This was concurrent with the emergence of a de novo class I DSA that responded well to a course of oral corticosteroids. The patient was asymptomatic without clinical evidence of allograft dysfunction based on an assessment via cardiac catheterization and echocardiogram. Subsequent HLA antibody screening a month later indicated a reduction in DSAs below the threshold. On day 255 post transplantation, the recipient underwent a routine biopsy that, once again, suggested AMR, with diffuse C4d staining (ISHLT 2013 pAMR 2 [H1, I1]) (Physique 2). The patient was again asymptomatic without clinical evidence of allograft dysfunction but treated with five sessions of plasmapheresis and IVIG, in addition to increasing the dose of corticosteroids (Table 1). Subsequent assessments for DSAs remained negative. However, the patient experienced a persistently high level of AT1R antibodies (>40 U/mL) and autoantibodies against EIF2A (eukaryotic translation initiation factor 2A), PRKCZ (protein kinase C zeta type), PTPRN (receptor-type tyrosine- protein phosphatase-like N), PRKCH (protein kinase C eta type), and GDNF (glial cell line-derived neurotrophic factor). Program biopsy on day 481 post transplantation once again found evidence of AMR with positive C4d and C1q immunofluorescence in the presence of high-level anti-AT1R and autoantibodies with no class I and class II DSAs. Cardiac catheterization at this time revealed normal hemodynamics but a presence of cardiac allograft vasculopathy (CAV), as evidenced by 30% stenosis of the proximal left anterior descending artery and 30% stenosis of the first diagonal branch. Based on the absence of.