Dual Contrast-Enhanced Microcomputed Tomography Uncovers Leaflet-Dependent Patterns of Macrocalcification, Fibrous Extracellular Matrix Remodeling, and Adipocyte Degeneration in Calcific Aortic Stenosis.

BACKGROUND

Clinical imaging studies of calcific aortic stenosis have suggested interleaflet pathological differences in patients. In this cross-sectional study, we sought to investigate interleaflet differences in calcification, fibrous extracellular matrix remodeling, and adipocyte degeneration in explanted human aortic valves.

METHODS

Diseased (n=45) and control (n=39) tricuspid aortic valve leaflets obtained from patients with aortic stenosis and normal aortic valves on echocardiography were assessed for calcification, fibrous extracellular matrix remodeling, and adipocyte degeneration using contrast-enhanced microcomputed tomography in conjunction with scanning and transmission electron microscopy, with interleaflet differences analyzed by fractional response regression.

RESULTS

In diseased leaflets, the calcification volume fraction was significantly greater in the noncoronary cusp than the left coronary cusp (LCC; β=0.313 [95% CI, 0.048-0.579], P=0.021) but not than the right coronary cusp (RCC; β=0.196 [95% CI, -0.107 to 0.499], P=0.204), with no difference between the RCC and LCC (β=0.117 [95% CI, -0.150 to 0.385], P=0.390). However, the fibrous extracellular matrix volume fraction was significantly greater in the RCC and LCC than the noncoronary cusp (β=0.502 [95% CI, 0.300-0.704], P<0.001; β=0.388 [95% CI, 0.188-0.589], P<0.001), with the RCC also greater than the LCC (β=0.114 [95% CI, 0.065-0.163], P<0.001). The volume fraction of osmium-labeled inclusions observed on microcomputed tomography-confirmed to be predominantly adipocytes (95.4 [IQR, 72.4-99.0]%) and occasionally membranous fat necrosis (4.6 [IQR, 1.0-27.6]%) on electron microscopy-was significantly less in the noncoronary cusp than the LCC (β=-0.269 [95% CI, -0.441 to -0.096], P=0.002) but not than the RCC (β=-0.185 [95% CI, -0.409 to 0.038], P=0.104), with no difference between the RCC and LCC (β=-0.083 [95% CI, -0.348 to 0.182], P=0.538).

CONCLUSIONS

Valvular calcification diverges from fibrous extracellular matrix remodeling but converges with adipocyte degeneration in terms of preferential impact on the noncoronary cusp versus, in particular, the LCC. Future mechanistic studies to elucidate the intimate relationship between adipocyte degeneration and valvular calcification may provide opportunities for further therapeutic development.