AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Prognostic Significance, Reproducibility, and Therapeutic Modification of Non-Calcified Plaque Volume by CCTA: Evidence from SCOT-HEART, ICONIC, CONFIRM, and PARADIGM
By Ansari S, Budoff MJ
Background: Coronary artery disease remains the leading cause of cardiovascular mortality worldwide. A critical proportion of acute coronary events arise from rupture of non-calcified, lipid-rich plaques undetected by conventional coronary artery calcium (CAC) scoring. Coronary computed tomographic angiography (CCTA) enables direct visualization and volumetric quantification of non-calcified plaque volume (NCPV), capturing a biologically active component of atherosclerosis that calcium scoring cant assess. This review synthesizes evidence on the prognostic significance, measurement reproducibility, and pharmacological modifiability of NCPV assessed by CCTA. Methods: A systematic review of published literature through March 2025 was conducted using PubMed. Search terms included non-calcified plaque volume, coronary CT angiography, atherosclerosis, and lipid-lowering therapy. Evidence was synthesized from multicenter trials and registries including SCOT-HEART, ICONIC, CONFIRM, and PARADIGM, and AI-based quantification studies including INVICTUS and DECODE. Results: NCPV is independently associated with major adverse cardiovascular events (MACE) beyond CAC score, cardiovascular risk scores, and stenosis severity. Low-attenuation plaque (LAP) burden is among the strongest predictors of myocardial infarction across conventional risk markers (HR 1.60 per doubling, SCOT-HEART). Nonobstructive high-risk plaques constitute the majority of culprit lesion precursors and confer risk comparable to obstructive lesions without high-risk features (ICONIC). In the CONFIRM registry, higher NCPV was independently associated with all-cause mortality in asymptomatic individuals after multivariable adjustment. Sex-related differences in plaque composition are clinically meaningful, with women demonstrating lower fibrous and fibrofatty plaque volumes than men despite similar cardiovascular risk profiles. Artificial intelligence-based quantitative CT platforms have substantially improved reproducibility, achieving interobserver variability below 3%, enabling serial pharmacodynamic monitoring. NCPV regression of –16.4 mm ³ /year has been demonstrated with intensive lipid-lowering therapy, with further regression observed with icosapentaenoic acid (EVAPORATE) and PCSK9 inhibition (GLAGOV). Regulatory interest is increasing, highlighted by submission of a Biomarker Qualification Program Letter of Intent to the FDA evaluating NCPV as a potential biomarker for clinical trial enrichment. Conclusions: NCPV by CCTA is a reproducible, prognostically significant, and pharmacologically modifiable biomarker that captures atherosclerotic risk beyond conventional metrics. Integration of AI-based NCPV quantification may enhance cardiovascular risk stratification and support future clinical trial design. Graphical Abstract: