Calcification of blood vessels and structures in the heart is a widespread issue in later life. Cells in the cardiovascular system become altered by the changing signal environment and molecular damage of aging, and adopt behaviors normally associated with the osteoblast cells responsible for building bone. These errant cells deposit calcium into the extracellular matrix structure, stiffening the normally elastic blood vessel and heart tissues and ultimately degrading their function. Prominent contributing factors are thought to include the chronic inflammation of aging and presence of senescent cells in cardiovascular tissues.
There is presently little that can be done about calcification. The progression can be slowed somewhat by good lifestyle choices, as is the case for cardiovascular disease in general, but only EDTA chelation therapy has shown any effectiveness in reducing established calcification - and this isn't a great therapy in the grand scheme of things, only offering modest gains. New approaches are needed. In today's open access paper, researchers dive into the biochemistry of calcification, in search of points of intervention that might more aggressively prevent it from occurring.
There is mounting unmet need to discover new clinical therapies for the prevention and treatment of calcification in the human circulatory system. This process of cardiovascular calcification is a significant factor in the more than 18 million lives claimed globally each year by heart disease. Stenosis of vasculature associated with blood flow restriction and heart valve calcification is a common health disorder in people of all ages, genders, and ethnic backgrounds, is associated with other comorbidities, and is the most prevalent form of heart disease in patients 65 and older. Yet beyond invasive valve implants, there are no viable alternative drug therapies or clinical treatment options available.
The evolutionary success of invertebrate and vertebrate organisms through geological time has relied on their ability to harness the precipitation of thermodynamically unstable amorphous calcium phosphate (ACP) before it spontaneously transforms into crystalline hydroxyapatite (HAP). While ACP calcification is fundamental to an organism's ability to precipitate essential hard parts such as bone and teeth, the capacity of ACP to morphologically shape-shift and atomically rearrange also results in various soft tissue pathologies.
Previous research on aortic valve calcification has primarily focused on cellular and molecular pathophysiology processes, including extracellular matrix biochemistry and biomechanics, but has not specifically targeted the etiological processes recorded by the calcification deposits themselves. 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 refer to four basic research studies 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.
Here, we use transdisciplinary geology, biology, and medicine 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.
View the full article at FightAging
