Identification of plasma tRNA-derived small RNA i-tRF-15:31-Lys-CTT-1 as a biomarker for diagnosis and prognosis of pulmonary arterial hypertension.

Introduction: tRNA-derived small RNAs (tsRNAs) are emerging as noninvasive biomarkers of cellular damage. However, their role in pulmonary arterial hypertension (PAH) remains unclear. Methods: Plasma i-tRF-15:31-Lys-CTT-1 levels were quantified in a discovery cohort (n = 141 PAH patients; n = 50 controls) and a verification cohort (n = 254 PAH patients; n = 70 controls). Diagnostic performance was assessed using receiver operating characteristic analysis, and survival outcomes were evaluated with Kaplan-Meier curves and multivariable Cox regression models. Results: In discovery cohort, the median age was 41 years (IQR 27-54), with 65.9 % female and a median REVEAL 2.0 score of 7 (IQR 6-8). In verification cohort, the median age was 36 years (IQR 31-52), with 63.4 % female and a median REVEAL 2.0 score of 6 (IQR 4-7). i-tRF-15:31-Lys-CTT-1 showed the greatest fold change among tsRNAs in idiopathic PAH (P < 0.0001). Levels of i-tRF-15:31-Lys-CTT-1 were significantly lower in the high-risk REVEAL group (P < 0.0001). The area under the curve (AUC) of i-tRF-15:31-Lys-CTT-1 for idiopathic PAH diagnosis was 0.90 in discovery cohort and 0.81 in verification cohort. Kaplan-Meier analysis revealed that lower i-tRF-15:31-Lys-CTT-1 levels correlated with poorer prognosis (P < 0.0001). After adjusting for age, sex, and BMI, patients in the highest quartile had a significantly lower incidence of clinical events compared to those in the lowest quartile (HR = 0.08; 95 % CI 0.032-0.18; P < 0.001). Incorporating i-tRF-15:31-Lys-CTT-1 into the REVEAL 2.0 model improved predictive accuracy (AUC from 0.67 to 0.75, P < 0.0001). Conclusions: i-tRF-15:31-Lys-CTT-1 levels are decreased in PAH, correlate with disease severity, and are promising to improve clinical diagnosis and risk stratification.