According to the Global Burden of Disease (GBD) study, ischemic heart disease (IHD) remained the leading cause of mortality and morbidity globally, accounting for 9,440,000 deaths and 185,000,000 disability-adjusted life years in 2021 (Vaduganathan et al., 2022). Acute myocardial infarction (AMI) is often deemed the most severe manifestation of IHD due to its rapid and irreversible damage to cardiomyocytes (Mechanic OJ and Grossman, 2024). Within the past decades, progressive treatment of cardiovascular risk factors and improvement in healthcare system facilitated a slow but gradual reduction of mortality rate (Nowbar et al., 2019). However, along with this slow decline of AMI mortality, non-fatal events occurred post-survival of AMI (i.e., heart failure, stroke, and bleeding) have incidentally increased (Shah et al., 2021), further deteriorating patients’ quality of life and intensifying the indirect economic burden on society (Weintraub et al., 2011). Therefore, early and accurate diagnosis of AMI is crucial for subsequent revascularization therapy, bringing substantial benefits for both individuals and the society.

Long noncoding RNAs (lncRNAs) have been demonstrated to participate multifarious cardiomyocyte activities, including genomic imprinting, epigenetic regulation, cell proliferation, development, aging, and apoptosis (Wang and Sun, 2020). During the occurrence of AMI, functional impairment of cardiomyocytes may cause the release of heart-specific lncRNAs. In this regard, lncRNAs exhibited promising potential in assisting the diagnosis and therapeutic targets of AMI. HLA complex group 15 (HCG15), one of the differentially expressed lncRNA, was proved to be encapsulated in exosomes released by cardiomyocytes during hypoxia and involved in cardiomyocyte apoptosis, inflammatory response, and proliferation inhibition through the activation of the NF-κB/p65 and p38 pathways (Lin et al., 2021). Another lncRNA named myeloid RNA regulator of Bim-induced death (Morrbid) was initially identified as a leukocyte-specific lncRNA and plays a key role in controlling leukocyte lifespan (Kotzin et al., 2016). Recently, Morrbid was also identified to be overexpressed in the cardiomyocytes with hypoxia or oxidative stress, potentially protecting the heart from AMI via antiapoptosis through its target gene serpine1 (Yu et al., 2023). However, the analysis of the correlation between those lncRNAs and AMI remained in the laboratory settings. Clinical evidence supporting the diagnostic and prognostic value of HCG15 and Morrbid in AMI is currently lacking.

This study aimed at evaluating the potential diagnostic and prognostic value of HCG15 and Morrbid in AMI management to introduce potential novel biomarkers for application in clinical practice.

Figure 2A exhibited a non-linear association between the hazard ratio of MACCE within 12 months and the relative expression level of HCG15 among AMI patients. The relative expression level of HCG15 associated with a hazard ratio of more than 1.00 for MACCE within 12 months was 3.6. Figure 2B similarly showed a non-linear association between the hazard ratio of MACCE within 12 months and the relative expression level of Morrbid. The threshold of the relative expression level of Morrbid associated with a hazard ratio of 1.00 of MACCE within 12 months was 4.0.

Timely and accurate diagnosis of AMI is of great importance to maximize the benefits of treatment and further prognosis. To date, the rapid rule-in and rule-out of suspected AMI cases without apparent abnormalities in the ECG presentation in clinical practice relies on the elevated level of high-sensitivity cardiac troponin (hs-cTn) within 0 h/1 h algorithm above the upper limit of 99th among health population (Byrne et al., 2023). However, the diagnostic value of hs-cTn is confounded by general background (e.g., age, renal dysfunction, time from chest pain onset, and sex) (Byrne et al., 2023), other myocardial injury conditions (e.g., myocarditis, chronic heart failure, and cardiomyopathy) (Park et al., 2017; Ammirati et al., 2020), and extra-cardiac disease (e.g., diabetes mellitus, hypertension, and stroke) (Agewall et al., 2011), thereby challenging differential diagnosis of AMI in some particular patient status. An optimal biomarker should possess high specificity and sensitivity for disease diagnosis, providing timely and cost-effective results that hold significance. Furthermore, it should offer additional value beyond existing markers or clinical characteristics, and potentially even have the ability to predict prognosis (Chan and Ng, 2010). However, ideal biomarkers are still warrant in clinical practice.

Recently, mounting evidence has uncovered the potential predictive value of lncRNAs in AMI diagnosis (Zhu et al., 2023; Xie et al., 2022), given their widespread involvement in roles of normal cardiomyocyte activities (Wang and Sun, 2020). In this study, we assessed the potential diagnostic utility of HCG15 and Morrbid in cases of AMI due to their potential higher cardiac specificity and may be less disturbed by individual profiles, initial suggested in animal and cellular models (Lin et al., 2021; Yu et al., 2023). We also examined their predictive value for MACCE within 12 months following the diagnosis of AMI. Ultimately, this study revealed the potential supplementary diagnosis and predictive value of HCG15 and Morrbid in AMI management with real-world data, which might provide novel insight in AMI.

HCG15 was suggested to be the potential novel biomarker associated with AMI (Lin et al., 2021), and this hypothesis was further verified by our results. Cardiomyocyte apoptosis and inflammatory reaction are involved in the process of AMI with the activation of multiple signaling pathways. For instance, the mitogen-activated protein kinase (MAPK) signaling pathway and its subunit p38 induce cardiomyocyte apoptosis, dysfunction, and fibrosis (Ding et al., 2018). Moreover, the activation of NF-κB and its subunit signaling pathway can regulate the expression of inflammatory cytokines, which are involved in the development of AMI (Stokes and Winn, 2014). A previous study confirmed that HCG15 was higher among AMI patients compared with health individuals and participated in apoptosis, inflammatory reaction, and proliferation inhibition of cardiomyocytes by activating the p38 and NF-κB/p65 pathways (Lin et al., 2021). In addition, for the first time to our knowledge, we indicated the prognostic value of HCG15 in predicting the MACCE within 12 months. This may be explained by the involvement of HCG in cardiomyocyte apoptosis, indirectly reflecting the extent of myocardial fibrosis, which is associated with malignant arrhythmias and chronic heart failure. However, this theory requires further verification in future studies.

Morrbid was initially identified as a leukocyte-specific lncRNA that existed in both mice and humans to regulate leukocyte lifespan with its anti-apoptotic effect (Kotzin et al., 2016). After that, its association with left ventricular hypertrophy and AMI was further discovered (Yu et al., 2023; Zhang et al., 2015). Cardiac Morrbid levels increase during the pathophysiological process of AMI, such as hypoxia stress and oxidative stress, exerting an anti-apoptotic effect on cardiomyocytes to protect against infarct enlargement and cardiac dysfunction (Yu et al., 2023). However, our findings revealed that a higher risk of MACCE within 12 months was predicted by a higher level of Morrbid just after presentation to the hospital. Indeed, leucocytes play a central role in the inflammatory response of cardiomyocytes in AMI (Naruko et al., 2002; Sasmita et al., 2022), and increased Morrbid expression in leukocytes may prolong and intensify the inflammatory response, contributing to more severe cardiac injury and adverse clinical outcomes. Similarly, this hypothesis warrants further validation in future studies.

Several limitations should be addressed in this study. First, selective bias inevitably existed in this study due to some AMI patients refusing to participate. Therefore, multicenter studies with large sample sizes are warranted to validate our pioneering results. Second, informative or recall bias also occurred in this study because of the history taking of medical and medication history. Future studies should incorporate additional objective evidence, such as the comorbidity with diabetes being defined by the elevated level of fasting blood glucose or glycated hemoglobin. Third, the potential involvement of these two lncRNAs in other pathological processes needs to be more adequately considered. Hence, it is crucial to interpret the results of this study with caution. Last, although this study revealed the association between two lncRNAs and the value of diagnosis and prognosis in AMI, the underlying mechanisms of that remain to be elucidated.

In this study, we investigated the predictive value of HCG15 and Morrbid in AMI diagnosis, revealing that both of them were potential biomarkers for AMI diagnosis. In addition, we identified, for the first time, their predictive capability for MACCE within 12 months after AMI diagnosis. Conclusively, HCG15 and Morrbid emerge as novel and promising biomarkers associated with AMI, warranting further research focusing on them.