Carotid Plaque Calcification Associates with Cardiac Morbidity, Mortality and Systemic Atherosclerotic Disease in a Sex-Specific Manner

Background Carotid plaque calcification is commonly interpreted as a marker of atherosclerotic burden, but its prognostic meaning may depend on calcification morphology. Whether histologically defined calcification subtypes in carotid plaques identify systemic cardiovascular disease and long-term cardiac risk remains unclear. Methods We studied 479 patients, including 154 women, undergoing carotid endarterectomy in the Helsinki Carotid Endarterectomy Study 2 with 10-year follow-up. Hematoxylin-eosin-stained plaque sections were digitized, and artificial intelligence-based image analysis was used to quantify sheet, nodular, and total calcification as proportions of plaque tissue area. The primary endpoint was cardiac death; secondary endpoints were major coronary events and major adverse limb events (MALE). Associations between calcification tertiles and outcomes were assessed using Fine-Gray regression models adjusted for conventional cardiovascular risk factors, with prespecified sex-stratified analyses. Results Total calcification was associated with baseline coronary artery disease and chronic heart failure but did not predict cardiac mortality. In contrast, nodular calcification was independently associated with cardiac death. Compared with the lowest tertile, the middle and highest tertiles of nodular calcification were associated with increased cardiac mortality in the whole cohort (subdistribution hazard ratio [sHR], 2.87 [95% CI, 1.39-5.91] and 2.55 [95% CI, 1.24-5.27], respectively). Nodular calcification was also associated with baseline peripheral artery disease. High sheet calcification was associated with cardiac death in men (sHR, 2.3 [95% CI, 1.0-5.1]) but not in women. Exploratory sex-stratified analyses suggested that high total calcification was associated with major coronary events and MALE in women, but not in men. Conclusions Carotid plaque calcification morphology, rather than total calcification burden alone, is associated with long-term cardiac mortality after carotid endarterectomy. Nodular calcification emerged as the strongest prognostic phenotype, while exploratory sex-stratified findings suggest that total calcification may reflect coronary and peripheral event risk in women.