Circulating long noncoding RNA PDE4DIPP6: A novel biomarker for improving the clinical management of acute coronary syndrome

Aim: Long noncoding RNAs (lncRNAs) have emerged as promising diagnostic biomarkers owing to their dynamic regulation in response to pathological conditions and their detection in clinically relevant samples. Here, we explored the utility of the cardiac expressed and plasma detectable lncRNA PDE4DIPP6 as a biomarker for acute coronary syndrome (ACS). The final goal was to improve the diagnostic efficacy of state-of-the-art tests, particularly the high-sensitivity cardiac troponin assay (hs-cTnT). Methods: The study enrolled individuals presenting with suspected ACS at the emergency department (ED). LncRNA quantification was performed in plasma samples using RT-qPCR. Discriminatory performance was evaluated by calculating the Area Under the Curve (AUC). Reclassification metrics, including the Integrated Discrimination Improvement (IDI) and Net Reclassification Improvement (NRI) indexes, were employed to assess enhancements in diagnostic accuracy. Results: The sample comprised 252 patients, 50.8% were diagnosed with ACS and 13.9% with Non-ST Segment Elevation Myocardial Infarction (NSTEMI). Elevated levels of PDE4DIPP6 were observed in ACS patients compared to non-ACS subjects. There was no significant correlation between lncRNA and hs-cTnT levels (rho=0.071), and no association between PDE4DIPP6 levels and potential confounding factors was observed. The inclusion of PDE4DIPP6 on top of troponin T significantly enhanced the discrimination and classification of ACS patients reflected in an improved AUC of 0.734, an IDI of 0.066 and NRI of 0.471. Similarly, elevated levels of the lncRNA were observed in NSTEMI patients compared to ACS patients without NSTEMI. Consistent with previous findings, the addition of PDE4DIPP6 to hs-cTnT improved the discrimination and classification of patients, evident in an increased AUC from 0.859 to 0.944, IDI of 0.237, and NRI of 0.658. Conclusion: PDE4DIPP6 offers additional diagnostic insights beyond hs-cTnT, suggesting its potential to improve the clinical management of patients with ACS. ### Competing Interest Statement TT and CB filed and licensed patents in the field of noncoding RNA therapeutics and diagnostics. TT is founder and shareholder of Cardior Pharmaceuticals GmbH. MB reports grants from Deutsche Stiftung für Herzforschung, during the conduct of the study; grants and non-financial support from AstraZeneca, non-financial support from Brahms Thermo Fisher, outside the submitted work. ### Clinical Trial NCT02116153 ### Funding Statement DdGC has received financial support from Instituto de Salud Carlos III (Miguel Servet 2020: CP20/00041), co-funded by the European Social Fund (ESF) Investing in your future. MCGH held predoctoral fellowship Ayudas al Personal Investigador en Formación from IRBLleida/Diputación de Lleida. CIBERES is an initiative of the Instituto de Salud Carlos III. TT and CB acknowledge funding from the German Research Foundation (DFG, SFB Transregio TRR267). MB has received financial support from the German Heart Foundation/German Foundation of Heart Research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The research received approval from the ethics committee of the University of Heidelberg and adhered to the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from each participating patient. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data is included in the manuscript