Emerging cardiac CT biomarkers: a systematic review of diagnostic and prognostic utility in cardiovascular disease

Background: Cardiac computed tomography (CT) has evolved from an anatomic test to a platform that quantifies functional, inflammatory, and tissue-characterization biomarkers. We synthesized evidence on the diagnostic and prognostic value of CT-based biomarkers. Methods: Systematic review of 29 human studies (2015–2025) appraising low-attenuation plaque (LAP), perivascular fat attenuation index (FAI/PCAT), total/non-calcified plaque burden, epicardial adipose tissue, CT-derived fractional flow reserve (FFR-CT), and CT myocardial perfusion. Study quality was assessed with risk of bias (RoB) 2.0, Newcastle-Ottawa Scale (NOS), and AMSTAR 2. Results: CT biomarkers extended risk assessment beyond stenosis severity. LAP burden > 4% predicted myocardial infarction (MI) [hazard ratio (HR) 4.65; 95% CI 2.06–10.5] and per-doubling LAP predicted MI (HR 1.60; 95% CI 1.10–2.34). Perivascular FAI/PCAT showed independent prognostic value: high FAI was associated with ~2-fold higher cardiac mortality (derivation HR 2.15, validation HR 2.06), and RCA PCAT ≥ −70.5 Hounsfield unit (HU) predicted MI (HR 2.45) with additive risk when combined with high-risk plaque (HRP) features (reported up to ~6-fold vs. reference). FFR-CT achieved up to 81% diagnostic accuracy (sensitivity ~86%, specificity ~79%) vs. invasive FFR, improving specificity over CTA alone. Emerging metrics (e.g., total plaque volume, CT perfusion) demonstrated incremental discrimination in selected cohorts, though standardization remains variable. Discussion: CT-based biomarkers provide measurable diagnostic and prognostic information on coronary anatomy, function, inflammation, and tissue health. Priorities include standardized acquisition/analysis, multicenter validation, and integration into decision pathways to optimize individualized risk stratification and therapy.