Alpha-cardiac Actin Serum Expression Levels Detect Acute Cellular Rejection in Heart Transplant Patients

Background. Given the central role of sarcomeric dysfunction in cardiomyocyte biology and sarcomere alterations described in endomyocardial biopsies of transplant patients with rejection, we hypothesized that the serum expression levels of genes encoding sarcomeric proteins were altered in acute cellular rejection (ACR). The aim of this study is to identify altered sarcomere-related molecules in serum and to evaluate their diagnostic accuracy for detecting rejection episodes. Methods. Serum samples from transplant recipients undergoing routine endomyocardial biopsies were included in an RNA sequencing analysis (n = 40). Protein concentrations of alpha-cardiac actin were determined using a specific enzyme-linked immunoassay (n = 80). Results. We identified 17 sarcomeric genes differentially expressed in patients with clinically relevant rejection (grade >= 2R ACR). A receiver operating characteristic curve was done to assess their accuracy for ACR detection and found that 6 relevant actins, myosins, and other sarcomere-related genes showed great diagnostic capacity with an area under the curve (AUC) > 0.800. Specifically, the gene encoding alpha-cardiac actin (ACTC1) showed the best results (AUC = 1.000, P < 0.0001). We determine ACTC1 protein levels in a larger patient cohort, corroborating its overexpression and obtaining a significant diagnostic capacity for clinically relevant rejection (AUC = 0.702, P < 0.05). Conclusions. Sarcomeric altera-tions are reflected in peripheral blood of patients with allograft rejection. Because of their precision to detect ACR, we pro -pose sarcomere ACTC1 serum expression levels as potential candidate for to be included in the development of molecular panel testing for noninvasive ACR detection. (Transplantation 2023;107: 466-474).

Automated summary

In this study, we found differential expression of 17 sarcomeric genes associated with acute cellular rejection (ACR) using RNA sequencing analysis of serum samples from transplant recipients. Among them, the gene encoding alpha-cardiac actin (ACTC1) showed the most significant results with high diagnostic capacity. We further confirmed the overexpression of ACTC1 protein and its significant diagnostic potential for clinically relevant rejection. Therefore, we suggest incorporating ACTC1 serum expression levels into the development of a molecular panel test for noninvasive ACR detection.