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Probing the earliest calcifications on artery walls Although a few investigators have used croprobe beam stable, highly energetic, The researchers expected the miproton microprobes to look for calcifiand narrow enough to move across an crocalcifications to be hydroxyapatite, cations in artery walls, they have paid entire cross section of a coronary artery Ca10(PO4)6(OH)2, which forms chunks little attention to the earliest stages of wall in 0.5 µm steps. They created refer- in more advanced lesions and is also atherosclerosis. However, in research ence samples by embedding potassium found in bones and teeth. But none of published in AC (2008, 80, 55–61), sci- dihydrogen phosphate in polyethylene the hot spots scanned had the correct entists at Maastricht University and the glycol and cutting sections that were Ca:P mass ratio (2.157). “We found a Eindhoven University of whole array of ratios [1.62 Technology (both in The to 2.79], so we had to con(a) (b) Netherlands) report that clude that there is not one even coronary artery walls type of crystal but maybe with minimal thickening a whole array of calcium are riddled with calcified phosphate deposits that are hot spots. Those specks most likely amorphous,” are clustered in the intima, van der Vusse says. He is the thin inner layer that puzzled by the fact that surrounds an artery’s luthe ratio varied from one men. “Are these innocent hot spot to the next in the (c) bystanders, or do they play same sample. an important role in the In ongoing studies, the sequence of events that group hopes to determine eventually leads to overt why calcium precipitates in atherosclerosis?” Ger van the artery wall. They are der Vusse asks. therefore making knockout As the first step in an (a) An overview (2.5 × 2.5 mm) of a coronary artery shows the distribution and knockin mice, focusextensive study, the reof hydrogen (gray) and calcium (blue). Detailed scans show (b) microcalciing on genes for bonesearchers acquired autopsy fications and (c) the distribution of calcium in a single microcalcification. forming enzymes. They samples from six patients also want to determine the who did not die from heart disease. as thick as the biological samples. They consequences of early calcium deposiOne patient had normal coronary arteralso wrote computer programs to hantion. “It is possible that those microies, whereas the others had the earlidle the vast amount of data generated calcifications—which can be considest signs of atherosclerosis: fat-gorged by each scan. ered to be foreign bodies in the artery macrophages, called foam cells, and After showing that the microprobe wall—participate in the progression of drops of lipid. None of the patients could detect calcifications just 1 μm in atherosclerosis by provoking inflammahad progressed to the point of having diameter, the researchers found only tion and other detrimental processes,” obvious atherosclerotic lesions. The a few calcified specks in the coronary van der Vusse says. Maastricht group, led by van der Vusse, arteries of the patient with no early If this hypothesis turns out to be freeze-dried and sectioned the artersigns of atherosclerosis. Moreover, the correct, it could lead to novel ways ies, then stained some sections and sent Ca:P mass ratio (0.14) was in line with of thinking about atherogenesis and adjacent ones to the microprobe lab at published values for normal artery launch a search for new treatments. Eindhoven. walls. But the sections from the other However, a way would also have to be When protons from a microprobe five patients had numerous calcificadeveloped to identify people with mireach a sample, they can eject innertions, ranging from 1 to 10 µm in dicrocalcifications in their artery walls. shell electrons from their orbits. When ameter, in the intima of their coronary “The drawback of the proton microthe electrons fall back into place, X-rays artery walls. “Our conclusion is that probe is that it can only be used to can be emitted. From measurements of calcium deposition is a very early event study postmortem material,” van der the energy and intensity of those X-rays, in the atherosclerotic process,” van Vusse says. “But maybe in the future the elements that are emitting them can der Vusse says. Staining did not reveal there will be noninvasive techniques for be identified and quantified. any microcalcifications. (Its resolution monitoring coronary artery calcification The Eindhoven group, led by Peter may be 10–100× less than that of the at a micrometer scale.” a Mutsaers, spent months making the mi- microprobe.) —Linda Sage 12
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