Abstract 20164: Profiling of Circulating MicroRNAs After Heart Transplantation and During Acute Cellular and Antibody-Mediated Rejection
Introduction: Heart transplantation (HTx) is the definitive treatment for advanced heart failure. Despite universal immunosuppressive therapy, the threat of allograft rejection is persistent. Rejection is generally diagnosed by histology of graft myocardium obtained by biopsy which is invasive and prone to sampling error. Study of novel biomarkers such as circulating microRNAs (miRs) may allow noninvasive diagnosis of rejection.
Methods: We studied serum levels of miRs associated with immune cell function (miR-155, 125b, 142-3p, 144, 223-3p, 27a and 101), myocardial damage (miR-1) and immunosuppression (let-7a). Blood was obtained from HTx recipients >2 months post-HTx. Rejection was defined by histology of cardiac biopsy specimens and graded according to ISHLT guidelines. MiRs were analyzed with RT-PCR and normalized to 5S rRNA.
Results: We analyzed samples from 12 healthy volunteers (44±6 yrs), 12 HTx recipients without evidence of rejection (54±11 yrs), 11 patients with acute cellular rejection (ACR; 48±12 yrs), and 6 patients with antibody-mediated rejection (AMR; defined by C4D+ immunohistochemistry; 48±13 yrs). The ACR group included 7 patients with ISHLT 1R/1B rejection and 4 with 2R/3A. 6 of 11 ACR and 5 of 6 AMR patients had evidence of donor-specific antibodies. Let-7a levels were significantly lower among the HTx group vs. controls (0.09±0.13 vs. 1.00±1.53 RU; p=0.02) and increased only among the ACR group (0.44±0.64, p=0.03) vs. the HTx group. MiR-223-3p was lower among HTx (0.31±0.38), ACR (0.33±0.37) and AMR (0.38±0.37) vs. control (1.00±0.87, p<0.01). MiR-101 levels were increased among ACR (1.83±1.61, p<0.01) and AMR groups (1.66±1.24, p<0.01) vs. HTx (0.41±0.51). There were trends towards higher miR-142-3p among ACR (p=0.06) and AMR (p=0.09) vs. the HTx group. Combination of let-7a and miR-101 and 144 identified patients with acute rejection compared to stable HTx patients (ROC AUC 0.82).
Conclusion: Circulating miRNAs related to immune function may aid in diagnosis of cardiac allograft rejection. Our data show that miR-101 and 223-3p and let-7a have diagnostic potential for identifying patients with ACR and AMR. Our ongoing studies will analyze roles for miRs as ancillary markers of graft rejection following HTx.
Author Disclosures: R. Givens: None. D. Templeton: None. R. Ji: None. P. Kennel: None. D. Mancini: None. Y. Naka: None. H. Takayama: None. I. George: None. P.C. Schulze: None.
- © 2014 by American Heart Association, Inc.