Multimodal Analytical Tools to Enhance Mechanistic Understanding of Aortic Valve Calcification

Perez, Katelyn A.; Deppe, Daniel W.; Filas, Aidan; Singh, Sasha A.; Aikawa, Elena

doi:10.1016/j.ajpath.2023.06.017

Cited by 2 publications

(1 citation statement)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is because standard microscopy techniques for pathological screening include stains that dissolve ACP and/or transform ACP to HAP in tissue sections, while x-ray diffraction cannot resolve the short-range ordering of ACP. Since 1975, several comprehensive reviews 12 , 13 , 15 , 25 refer to four basic research studies 26 – 29 that have identified ACP as the primary agent of aortic valve and arterial calcification by combining electron diffraction, standard microscopy and microprobe analyses with optical microscopy on unstained histological cryosections. Now, a half century later, rigorous examination specifically targeting the role of ACP in cardiovascular calcification remains to be completed 12 , 14 , 25 , 29 .…”

Section: Introductionmentioning

confidence: 99%

Osteopontin stabilization and collagen containment slows amorphous calcium phosphate transformation during human aortic valve leaflet calcification

Sivaguru,

Mori,

Fouke

et al. 2024

Sci Rep

View full text Add to dashboard Cite

Calcification of aortic valve leaflets is a growing mortality threat for the 18 million human lives claimed globally each year by heart disease. Extensive research has focused on the cellular and molecular pathophysiology associated with calcification, yet the detailed composition, structure, distribution and etiological history of mineral deposition remains unknown. Here transdisciplinary geology, biology and medicine (GeoBioMed) approaches prove that leaflet calcification is driven by amorphous calcium phosphate (ACP), ACP at the threshold of transformation toward hydroxyapatite (HAP) and cholesterol biomineralization. A paragenetic sequence of events is observed that includes: (1) original formation of unaltered leaflet tissues: (2) individual and coalescing 100’s nm- to 1 μm-scale ACP spherules and cholesterol crystals biomineralizing collagen fibers and smooth muscle cell myofilaments; (3) osteopontin coatings that stabilize ACP and collagen containment of nodules preventing exposure to the solution chemistry and water content of pumping blood, which combine to slow transformation to HAP; (4) mm-scale nodule growth via ACP spherule coalescence, diagenetic incorporation of altered collagen and aggregation with other ACP nodules; and (5) leaflet diastole and systole flexure causing nodules to twist, fold their encasing collagen fibers and increase stiffness. These in vivo mechanisms combine to slow leaflet calcification and establish previously unexplored hypotheses for testing novel drug therapies and clinical interventions as viable alternatives to current reliance on surgical/percutaneous valve implants.

show abstract