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Published on: April 28, 2013
Fibrosis Process Activation in Patients with Acute Cardiac Rejection: A Novel Noninvasive Diagnostic Approach
Marta Delgado-Arija1,2, Lorena Pérez-Carrillo1,2, Irene González-Torrent1
1Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain.
Insights
Altered serum mRNAs linked to cardiac fibrosis, including fibroblast activators and TGF-β/WNT pathways, were identified in heart transplant recipients with acute cellular rejection (ACR). Specific markers show high accuracy in detecting moderate to severe rejection.
Area of Science:
- Cardiology
- Immunology
- Molecular Biology
Background:
- Cardiac allograft fibrosis limits long-term graft survival after heart transplantation.
- The fibrotic process during acute cellular rejection (ACR) in cardiac allografts is not well understood.
Purpose of the Study:
- To identify serum messenger RNAs (mRNAs) associated with cardiac fibrosis in ACR patients.
- To assess the diagnostic accuracy of these mRNAs for detecting rejection episodes.
Main Methods:
- Analysis of 40 serum samples from heart transplant recipients undergoing routine endomyocardial biopsies.
- Comparison of serum mRNA profiles between patients with ACR (grades ≥ 1R) and those without rejection.
Main Results:
- Several fibrosis-related mRNAs were altered in ACR patients.
- Significant differences in fibroblast/myofibroblast activators (TNS1, FAP, ACTA2) and TGF-β/WNT signaling pathways (TGFBR1, JAK1, WNT7A, WLS) were observed.
- TNS1 and WLS demonstrated high diagnostic accuracy (AUC > 0.90) for moderate to severe cardiac rejection.
Conclusions:
- Circulating fibroblast activators (FAP, ACTA2) and profibrotic pathways (TGF-β, WNT) are altered in clinically relevant cardiac rejection.
- These findings may enhance surveillance strategies for heart transplant patients.
- Potential for new therapeutic targets to inhibit fibrosis activation in cardiac allografts.
Abstract:
Background/Objectives: Cardiac allograft fibrosis is an important limiting factor for long-term graft survival. However, the fibrotic process operating in patients with acute cellular rejection (ACR) remains unclear. We aimed to identify altered serum mRNAs related to cardiac fibrosis in patients with ACR and to evaluate their diagnostic accuracy in detecting rejection episodes. Methods: We included 40 serum samples from recipients of transplants undergoing routine endomyocardial biopsies. Results: Several altered mRNAs associated with fibrosis were detected in patients with ACR. Specifically, the activators of fibroblasts and myofibroblasts (TNS1, FAP and ACTA2), TGF-β signaling (TGFBR1 and JAK1) and WNT signaling (WNT7A and WLS) pathways were significantly different when we compared grade ≥ 2R ACR and/or grade 1R ACR groups with the nonrejection group. Furthermore, TNS1 and WLS presented an area under the curve value > 0.90 for identifying patients with moderate and severe grades of cardiac rejection. Conclusions: In conclusion, we found alterations in the relative abundance of circulating activators of fibroblasts and myofibroblasts, such as FAP or ACTA2, as well as in major profibrotic pathways, including TGF-β and WNT signaling, especially in clinically relevant cardiac rejection. These findings may contribute to improving the surveillance of patients with cardiac transplant and provide new therapeutic strategies for targeting fibrosis process activation.
