Tools for predicting COVID-19 outcomes enable personalized healthcare, potentially easing the disease burden. This collaborative study by 15 institutions across Europe aimed to develop a machine learning model for predicting the risk of in-hospital mortality post-SARS-CoV-2 infection. Blood samples and clinical data from 1286 COVID-19 patients collected from 2020 to 2023 across four cohorts in Europe and Canada were analyzed, with 2906 long non-coding RNAs profiled using targeted sequencing. From a discovery cohort combining three European cohorts and 804 patients, age and the long non-coding RNA LEF1-AS1 were identified as predictive features, yielding an AUC of 0.83 (95% CI 0.82–0.84) and a balanced accuracy of 0.78 (95% CI 0.77–0.79) with a feedforward neural network classifier. Validation in an independent Canadian cohort of 482 patients showed consistent performance. Cox regression analysis indicated that higher levels of LEF1-AS1 correlated with reduced mortality risk (age-adjusted hazard ratio 0.54, 95% CI 0.40–0.74). Quantitative PCR validated LEF1-AS1’s adaptability to be measured in hospital settings. Here, we demonstrate a promising predictive model for enhancing COVID-19 patient management.

Background and purpose: MicroRNA (miRNA) therapy is a promising approach to induce cardioprotection. We have previously identified cardiac microRNA‐125b* (microRNA‐125b‐2‐3p; miR‐125b*) as a potential cardioprotective miRNA, termed ProtectomiR. We aimed to characterize the pharmacokinetics and pharmacodynamics, and the effect of miR‐125b* mimic on infarct size using an in vivo mouse model.Experimental approach: To characterize the pharmacokinetics properties of miR‐125b* mimic, a single injection of 10‐μg miR‐125b* mimic or its scramble miRNA control, or vehicle i.v. was given to C57BL/6 mice. MiR‐125b* expression was measured from plasma, heart, kidney and liver samples. Effect of miR‐125b* on area at risk and infarct size was assessed after 45‐min coronary occlusion, followed by 24‐h reperfusion; 10‐μg miR‐125b* mimic or 10‐μg non‐targeting miRNA mimic control or vehicle were administered via the right jugular vein at 10th mins of coronary occlusion. To assess molecular mechanism involved in cardioprotection, expression of mRNA targets of miR‐125b* were measured from ventricular myocardium at 1, 2, 4, 8 or 24 h post‐treatment using quantitative real time polymerase chain reaction.Key results: MiR‐125b* expression was markedly increased in plasma and myocardium 1 h, and in the liver 2h after treatment. Infarct size was significantly reduced after miR‐125b* mimic treatment when compared to the vehicle. The expression of Ccna2, Eef2k and Cacnb2 target mRNAs was significantly reduced 8 h after injection of miR‐125b* mimic.Conclusion and implications: This is the first demonstration of pharmacokinetic and molecular pharmacodynamic properties as well as the cardioprotective effect of miR‐125b* mimic in vivo.LINKED ARTICLES: This article is part of a themed issue Non‐coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc

Cardiac hypertrophy resulting from sympathetic nervous system activation triggers the development of heart failure. The transcription factor Y-box binding protein 1 (YB-1) can interact with transcription factors involved in cardiac hypertrophy and may thereby interfere with the hypertrophy growth process. Therefore, the question arises as to whether YB-1 influences cardiomyocyte hypertrophy and might thereby influence the development of heart failure. YB-1 expression is downregulated in human heart biopsies of patients with ischemic cardiomyopathy (n = 8), leading to heart failure. To study the impact of reduced YB-1 in cardiac cells, we performed small interfering RNA (siRNA) experiments in H9C2 cells as well as in adult cardiomyocytes (CMs) of rats. The specificity of YB-1 siRNA was analyzed by a miRNA-like off-target prediction assay identifying potential genes. Testing three high-scoring genes by transfecting cardiac cells with YB-1 siRNA did not result in downregulation of these genes in contrast to YB-1, whose downregulation increased hypertrophic growth. Hypertrophic growth was mediated by PI3K under PE stimulation, as well by downregulation with YB-1 siRNA. On the other hand, overexpression of YB-1 in CMs, caused by infection with an adenovirus encoding YB-1 (AdYB-1), prevented hypertrophic growth under α-adrenergic stimulation with phenylephrine (PE), but not under stimulation with growth differentiation factor 15 (GDF15; n = 10–16). An adenovirus encoding the green fluorescent protein (AdGFP) served as the control. YB-1 overexpression enhanced the mRNA expression of the Gq inhibitor regulator of G-protein signaling 2 (RGS2) under PE stimulation (n = 6), potentially explaining its inhibitory effect on PE-induced hypertrophic growth. This study shows that YB-1 protects cardiomyocytes against PE-induced hypertrophic growth. Like in human end-stage heart failure, YB-1 downregulation may cause the heart to lose its protection against hypertrophic stimuli and progress to heart failure. Therefore, the transcription factor YB-1 is a pivotal signaling molecule, providing perspectives for therapeutic approaches.