Is degenerative calcification of the native aortic valve similar to calcification of bioprosthetic heart valves?

Abstract

See related articles on pages 965 and 969. R ecent epidemiologic, histologic, and molecular studies suggest that the pathogenesis of degenerative disease of the native aortic valve resembles that of atherosclerosis. The initial aortic valve lesion, valve sclerosis, is related to infiltration and oxidation of lipoproteins similar to that seen in atherosclerosis. Calcification, one of the principal features of degenerative disease of the native aortic valve, is also present in atherosclerotic plaques. Not surprisingly, retrospective studies showed an association between risk factors for coronary artery disease, such as male sex, cigarette smoking, high blood pressure, diabetes, and hyperlipidemia, and progression of aortic valve stenosis. However, a recent prospective, population-based epidemiologic study showed no correlation between coronary artery risk factors and the rate of progression of aortic stenosis. What many studies have shown more consistently is that treatment with 3-hydroxy-3-methyl-glutamyl coenzyme A reductase inhibitors (statins) reduces the rate of progression of aortic valve stenosis. In most studies the slower rate of calcification of the aortic cusps produced by statins did not appear directly related to the reduction of serum cholesterol level but rather caused by its pleiotropic effects. Statins affect a multitude of cellular functions: they increase production of nitric oxide by endothelial cells, reduce inflammatory reactions, decrease secretion of metalloproteins and osteopontin by macrophages, stabilize atherosclerotic plaques, prevent thrombus formation, and have many other less defined effects, such as reducing the risk of dementia. Calcification of the native aortic cusps is a complex and poorly understood process, but it appears to be related to inflammation, infiltration of lipoproteins, and ossification. Statins probably delay calcification of the native aortic cusps by reducing inflammation and decreasing the deposition of lipoproteins and ossification, as they do in coronary arteries. However, the notion that coronary artery risk factors increase the risk of aortic valve stenosis remains controversial. The pathogenesis of calcification of bioprosthetic heart valves is even less well understood than that of the native aortic valve. Clinical experience with bioprosthetic heart valves far exceeds the scientific knowledge of the interactions between the host and the glutaraldehyde-fixed tissue that makes up the cusps of a bioprosthetic valve. Calcification is the principal cause of failure of first-generation bioprosthetic heart valves, and young age is the single most important determinant of calcification. The mechanism of accelerated calcification in young patients remains largely unknown. It might involve an immune-mediated reaction and an increased adsorption of proteins related to bone formation. The clinical observation that prolonged corticosteroid therapy restricts calcification of bioprosthetic valves in young patients corroborates the notion that immune reaction might play a role in calcific degeneration. These findings suggest that the cross-links between glutaraldehyde and certain immunogenic proteins in the xenograft tissue might be incomplete or short lived. Indeed, it has been shown experimentally that valves stored in glutaraldehyde solutions for a prolonged period are less likely to calcify than those implanted soon after fixation. Another interesting finding on calcification of bioprosthetic valves is that removal of lipids with certain solvents, such as alcohol, mitigates calcification in experimental animals. Newer porcine and periFrom the Department of Surgery, University of Toronto, Toronto, Ontario, Canada.