Non-calcific leaflet thickening and calcific burden in aortic stenosis

Background

Aortic stenosis (AS) is characterised by progressive fibrocalcific leaflet thickening. While computed tomography (CT) calcium scoring is an established discriminator of haemodynamic severity and outcomes, the independent haemodynamic and prognostic relevance of non-calcific leaflet thickening remains uncertain.

Purpose

To quantify the contribution of non-calcific leaflet thickening across the haemodynamic spectrum of AS and evaluate its diagnostic and prognostic significance relative to calcific burden.

Methods

In 1,505 patients undergoing contrast-enhanced cardiac CT, the aortic valve was segmented into calcific and non-calcific components using semi-automated software (AutoPlaque; Cedars-Sinai, Los Angeles, USA). Component volumes were indexed to annulus area and compared across concordant severe, concordant non-severe, and discordant AS defined by echocardiography. Associations with haemodynamic severity were assessed using correlation and receiver-operating characteristic analyses. The primary endpoint was a composite of all-cause death or aortic valve replacement evaluated using multivariable Cox regression.

Results

Non-calcific tissue constituted the major structural component of all haemodynamic strata. Indexed non-calcific volume increased modestly across severity strata (221.8, 232.7, 257.9 mm³/m²; p<0.001) and correlated weakly with aortic valve area (r=−0.067) and peak velocity (r=0.147; both p<0.001). Discrimination for concordant severe AS was poor (c-statistic 0.417).

In contrast, calcific volume index increased markedly (41.8, 92.4, 205.1 mm³/m²; p<0.001), correlated strongly with haemodynamic severity (r=0.697; p<0.001), and demonstrated excellent discrimination for severe AS (c-statistic 0.940 in women; 0.921 in men). The fibro-calcific ratio declined across severity strata (5.3 to 1.2 p<0.001), reflecting disproportionate calcium expansion. Women had higher non-calcific volume (253.7 [175.8–359.2] vs 227.3 [161.1–307.4] mm³/m²; p<0.0001), but lower calcific volume than men (92.8 [32.4–188.3] vs 123.4 [59.1–224.9] mm³/m²; p<0.0001), resulting in a higher fibro-calcific ratio (2.8 vs 1.8 p<0.001). A progressive decline with increasing haemodynamic severity was observed in both sexes.

Non-calcific volume failed to improve diagnostic performance beyond calcium volume overall or by sex. Over a median follow-up of 42 months, high calcific volume independently predicted the primary endpoint (HR 2.46 [1.89–3.22]; p<0.001), whereas higher indexed non-calcific volume was independently associated with lower risk (HR 0.63 [0.48–0.82]; p=0.001).

Conclusion

Non-calcific leaflet thickening represents a fundamental structural substrate of AS, particularly in earlier disease and in women. However, its quantification does not enhance identification of severe AS or add diagnostic value beyond calcium. Further research is required to clarify the role of non-calcific thickening in disease progression.