MicroRNA signatures in dilated cardiomyopathy: diagnostic performance and prognostic value from the European BestAgeing study
C Reich, E Kayvanpour, F Sedaghat-Hamedani, A Amr, J Haas, K Frese, H Katus, N Frey, B MederAbstract
Background
Dilated cardiomyopathy (DCM) and Non-dilated left ventricular cardiomyopathy (NDLVC) diagnosis relies on imaging and clinical criteria, yet molecular biomarkers could enhance diagnostic accuracy and risk stratification. We evaluated the diagnostic and prognostic potential of circulating microRNA (miRNA) signatures in a European multicenter cohort.
Methods
Genome-wide miRNA profiles were assessed in 201 DCM patients and 848 matched controls from the prospective European BestAgeing study across 7 European centers. Using AI-assisted literature mining, we identified 56 DCM-associated miRNAs. We developed two machine learning models: aPRIORI (literature-derived) and DISCOVERY (data-driven). We evaluated diagnostic accuracy, incremental value over NT-proBNP, and associations with 5-year all-cause mortality.
Results
Fifty-six miRNAs previously linked to DCM were systematically validated within the aPRIORI framework. The aPRIORI model achieved an AUC of 0.848 (95% CI: 0.791-0.905) with 95.6% sensitivity and 30.9% specificity for DCM diagnosis. The DISCOVERY model showed comparable performance (AUC 0.845). Key discriminatory miRNAs included miR-150-5p, miR-30a-5p, and miR-126-3p, with miR-150-5p showing the strongest individual performance (AUC 0.66). When combined with NT-proBNP in patients below the median NT-proBNP threshold (<790 pg/mL), the miRNA signature significantly improved diagnostic performance (combined AUC 0.948 vs NT-proBNP alone 0.837, ΔAUC +0.111, p<0.001), particularly valuable in patients with intermediate NT-proBNP levels (125-450 pg/mL). Prognostically, patients with high miRNA-predicted disease probability showed significantly worse 5-year survival compared to low-risk patients (33.3% vs 10.7% mortality, p=0.022) and more severe phenotype with significantly lower LVEF (25.4±11.4% vs 33.5±14.2%, p=0.027). High-risk patients also demonstrated trends toward elevated NT-proBNP levels, indicating more advanced heart failure. Notably, miR-150-5p was significantly downregulated in DCM patients (adjusted p<0.001, log₂FC=-0.382), consistent with its known protective role against cardiac apoptosis and fibrosis through targeting of pro-apoptotic SPRR1A and pro-fibrotic HOXA4.
Discussion
Our study confirms circulating miRNAs as clinically relevant biomarkers in DCM diagnosis and prognosis. The substantial improvement in diagnostic performance when combined with NT-proBNP, coupled with significant survival stratification, supports the potential clinical utility of miRNA profiling into multimarker approaches for DCM assessment, pending further external validation studies.Key findings.For image description, please refer to the figure legend and surrounding text.