Non-calcified plaque volume assessed by coronary computed tomographic angiography: prognostic significance, reproducibility, and temporal progression.

AIMS: Coronary artery disease remains the leading cause of cardiovascular mortality worldwide, with a substantial proportion of acute coronary events arising from rupture of non-calcified, lipid-rich plaques not detected by conventional coronary artery calcium scoring. Coronary computed tomographic angiography (CCTA) enables direct visualization and volumetric quantification of non-calcified plaque volume (NCPV), capturing a biologically active component of coronary atherosclerosis. No comprehensive synthesis of NCPV's prognostic significance, measurement reproducibility, and pharmacological modifiability has been published. This review addresses that gap. METHODS AND RESULTS: We conducted a narrative review of published literature through March 2025 using PubMed, synthesizing evidence from multicentre trials and registry analyses. Studies including SCOT-HEART, ICONIC, CONFIRM, and PARADIGM demonstrate that NCPV is associated with major adverse cardiovascular events independent of coronary artery calcium score, cardiovascular risk scores, and stenosis severity. Low-attenuation plaque burden represents one of the strongest predictors of myocardial infarction. Non-obstructive high-risk plaques confer risk comparable to obstructive lesions without high-risk features. Sex-related differences in plaque composition are clinically relevant, with women demonstrating lower fibrous and fibrofatty plaque volumes than men. Artificial intelligence-based quantitative CCTA has improved reproducibility, with interobserver variability below 3%. Serial imaging demonstrates that NCPV is modifiable with intensive lipid-lowering therapy. CONCLUSION: NCPV assessed by CCTA represents a reproducible and prognostically relevant measure of coronary atherosclerosis that is responsive to therapy. Recent regulatory interest, including submission of a Biomarker Qualification Program Letter of Intent to the US Food and Drug Administration, highlights its potential role as a biomarker for clinical trial enrichment.