A pre-transplant signature combining circulating METTL8 expression, graft ischemic time, donor age, and mechanical circulatory support predicted primary graft dysfunction onset (AUC 0.989, p<0.001).
Observational (n=66)
Does a pre-transplant epitranscriptomic signature combined with clinical variables predict primary graft dysfunction after heart transplantation in patients with advanced heart failure?
A pre-transplant molecular signature combining circulating METTL8 mRNA expression with clinical variables accurately predicts primary graft dysfunction after heart transplantation.
Effect estimate: AUC 0.989 (95% CI 0.961 - 1.000)
p-value: p=< 0.001
Abstract Background Heart transplant (HT) remains the gold standard treatment for the management of advanced heart failure (AHF), when guideline-directed medical and device therapy no longer improves the patient’s status. Despite excellent post-transplant survival, primary graft dysfunction (PGD) is still the leading cause of 30-day mortality after HT. Given its importance, various models have been developed to predict this event; however, they don’t incorporate molecular biomarkers which would provide a deeper insight into the pathophysiology of PGD and enhance predictive accuracy. In this sense, studies on pre-HT recipient-specific biomarkers are scarce, and elucidating how the recipient’s molecular and epitranscriptomic background contributes to PGD may reveal novel cardiovascular biomarkers. Purpose This study aimed to investigate mRNA expression of epitranscriptomic regulators in plasma samples from AHF patients to identify a recipient-specific molecular signature related to epitranscriptomic mechanisms and clinical variables that predicts PGD onset. Methods This study included 34 plasma samples from patients with AHF, and 32 control samples from non-diseased patients, for plasma mRNA-sequencing (N = 66) (NovaSeq 6000 Sequencing System (Illumina)). One of the patients was excluded from the waiting list and therefore was not transplanted. Consequently, 33 samples were used to identify predictors of PGD before HT (non-PGD = 20, PGD = 13). Results A total of 77 molecules involved in epitranscriptomic regulatory mechanisms were detected by mRNA-seq, of them, 42 showed altered expression in AHF patients (p 0.05), compared to the control group. In addition, METTL8, NOP58 and NSUN3 were significantly altered (p 0.05) in patients who developed PGD, in comparison with the non-PGD group. We found that the combination of circulating METTL8 expression levels, ischemic time of the graft, donor age and the use of mechanical circulatory support as bridge to transplantation (MCS-BTT), showed an excellent diagnostic ability to predict PGD onset (AUC = 0.989, p 0.001, 95% CI 0.961 - 1.000; SS: 92%, SP: 100%, PPV: 100%, NPV: 93%). Conclusions We identify a pre-transplant molecular signature that combines circulating mRNA expression and clinical variables as potential tool to predict PGD onset. These findings provide new insights into the pathophysiology of PGD in cardiac transplantation and may help develop non-invasive diagnostic approaches to reduce post-transplant complications.
Marrero et al. (Fri,) conducted a observational in Advanced heart failure (n=66). Pre-transplant epitranscriptomic signature and clinical variables vs. Non-PGD patients / Non-diseased controls was evaluated on Primary graft dysfunction (PGD) onset (AUC 0.989, 95% CI 0.961 - 1.000, p=< 0.001). A pre-transplant signature combining circulating METTL8 expression, graft ischemic time, donor age, and mechanical circulatory support predicted primary graft dysfunction onset (AUC 0.989, p<0.001).