Mechanisms for Amyloid Fibrils to Accelerate Calcification of Heart Valves

Amyloids are formed from a few varieties of protein that can misfold or otherwise become altered in ways that encourage other molecules of the same protein to also misfold or become altered in the same way. They spread and gather to form solid aggregates, disruptive to normal cell tissue function. Forms of amyloid relevant to the heart and vasculature include amyloid-β, transthyretin, and medin. Researchers here note that amyloid fibrils may act to encourage and accelerate unwanted calcification of tissue. They focus on the heart, but one might argue for the same processes to operate throughout the cardiovascular system.

Calcific aortic valve disease (CAVD) is the major heart valve disease that afflicts nearly 10 million patients globally with an annual mortality exceeding 100,000, and the numbers continue to rise. In CAVD, microcrystals of hydroxyapatite (a calcium phosphate mineral) deposit onto the heart valve leaflets and impair cardiac function. The disease has a dismal prognosis with most untreated patients dying two years after diagnosis. Currently, the only available treatment is surgical aortic valve replacement, which is not appropriate for all patients. While previous studies of the histology samples from explanted calcified aortic valves have found amyloid deposits in or near calcified areas, the causal relationship between amyloid deposition and calcification is unclear.

Researchers have now proposed a molecular mechanism that links amyloid deposition in the aortic valve with degenerative calcification. They also theorize that other risk factors for CAVD, such as high blood levels of lipoprotein, can contribute to calcification both directly and indirectly through the mechanisms that involve amyloid accumulation.

Harnessing the "resolution revolution" in cryogenic electron microscopy, groups of researchers around the world were able to determine hundreds of structures of patient-derived protein aggregates called amyloid fibrils. Such fibrils are associated with major human diseases including Alzheimer's and Parkinson's diseases, diabetes, and heart diseases such as atherosclerosis and calcific aortic valve disease. "We noticed that the unique geometry of amyloid fibrils, with their periodic arrays of acidic residues on the surface, provides a perfect match for the precursors of calcium phosphate crystals that deposit in the heart valve and impair its normal function."


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