Among 479 patients (154 women) undergoing carotid endarterectomy and followed for a decade, nodular calcification within carotid plaques emerged as the dominant predictor of cardiac death, with middle and highest tertiles carrying subdistribution hazard ratios of 2.87 and 2.55 respectively — independent of conventional cardiovascular risk factors. Sheet calcification predicted cardiac mortality in men but not women, while total calcification burden appeared more predictive of coronary and peripheral arterial events specifically in women. AI-assisted histological image analysis quantified three distinct calcification subtypes: sheet, nodular, and total.
This finding challenges the long-standing clinical assumption that calcification is uniformly protective or merely a passive marker of atherosclerotic burden. Nodular calcification, previously linked to plaque instability and erosion in coronary contexts, may signal a fundamentally more dangerous plaque phenotype in carotid territory as well. The sex-stratified signals are particularly intriguing — if replicated, they would argue for morphology-aware and sex-specific risk stratification protocols after endarterectomy, a population currently lacking robust prognostic tools beyond conventional risk scores.
Limitations are real: this is a single-center surgical cohort, meaning findings may not generalize to patients managed medically or those with subclinical carotid disease. The sex-stratified analyses were exploratory. Crucially, this is a preprint posted on medRxiv and has not yet been peer-reviewed — the effect size estimates and subgroup findings require independent replication before influencing clinical practice. Still, the mechanistic specificity here is notable and positions this as a potentially practice-shaping contribution.
