Bridging the Troponin Blind Window via the miAMI Standard: A Systematic Review and Meta-Analysis of the Circulating...

Background and Objectives: Early diagnosis of acute myocardial infarction (AMI) remains challenging due to the "diagnostic blind window" of conventional protein biomarkers and the limited sensitivity of electrocardiograms in non ST-segment elevation myocardial infarction (NSTEMI). Cardiospecific circulating microRNAs, specifically the microRNA-208 (miR-208) family, have emerged as promising candidates to bridge this gap. This systematic review and meta-analysis evaluated the diagnostic accuracy of circulating miR-208 and outlines a proposed conceptual framework to guide its clinical translation. Materials and Methods: PubMed and Embase were systematically searched up to June 24th, 2026, for clinical studies evaluating the diagnostic performance of circulating miR-208a and/or miR-208b against standard reference definitions for AMI. Risk-of-bias assessment using the QUADAS-2 tool was performed independently by two reviewers. Pooled sensitivity and specificity were estimated using bivariate random effects modeling, and sources of heterogeneity were explored via subgroup analyses. Results: Forty-one studies enrolling 6306 participants were included in the qualitative synthesis, of which 14 were eligible for meta-analysis. The pooled sensitivity and specificity of circulating miR-208 for AMI detection were 0.89 (95% CI: 0.81-0.94) and 0.90 (95% CI: 0.83-0.94), respectively. Marked between-study heterogeneity was observed. Subgroup analyses revealed significantly higher diagnostic accuracy in isolated STEMI (sensitivity: 0.95) or NSTEMI (sensitivity: 0.93) cohorts compared to mixed chest pain populations (sensitivity: 0.65; p < 0.0001). Specificity dropped from 0.90 with healthy controls to 0.80 when using non-AMI controls (p = 0.002), indicating spectrum bias. Funnel plots suggested prominent small-study effects. Conclusions: Circulating miR-208 exhibits a powerful biological signal for the early detection of cardiomyocyte injury, but its standalone clinical utility is constrained by methodological heterogeneity and publication bias. Rather than an immediate clinical tool, future prospective translation requires evaluating this biomarker within the standardized miAMI framework-conceptually prioritizing future investigation of the hyper-acute (<2 h) window, absolute quantification to resolve normalization variability, and integration into multi-marker point-of-care panels.