Mechanisms of aortic valve calcification

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Endothelial disease

The normal aortic valve leaflet is composed of a single layer of endothelial cells that envelopes a spongiosa layer made up of loosely organized connective tissue on the aortic side and a ventricularis layer that contains elastin on the ventricular side. Similar to atherosclerotic disease in arteries, an early event in valve disease appears to be endothelial injury (Figure 1). The endothelial cell layer of calcified aortic valves appears damaged on electron microscopy (Figure 2), especially at

Atherosclerotic risk factors and aortic valve calcification

Traditional atherosclerotic risk factors, such as total cholesterol, increased low-density lipoprotein cholesterol, increased lipoprotein(a), increased triglycerides, decreased high-density lipoprotein cholesterol, male gender, cigarette smoking, hypertension, and diabetes are reported to increase the incidence of aortic stenosis and likely contribute to endothelial dysfunction and leaflet damage.7, 12, 13, 14, 15, 16, 17, 18 Although age and hypertension are associated with aortic valve

Inflammation

A manifestation of endothelial dysfunction is decreased availability of nitric oxide and prostacyclin, 2 molecules believed to modulate inflammation of vessels.23 Inflammation is a prominent feature of aortic valve calcification and may develop due to endothelial dysfunction fueled by atherosclerotic risk factors.24 T lymphocytes are present in calcified valves,25, 26, 27 even during early disease, and when found with inflammatory cytokines indicate that an injury-repair cycle is operative,

Lipids

Lipid in calcified aortic valves was reported decades ago, but the pathologic mechanistic relation to calcium was unknown. Recent evidence has indicated that lipid in vascular tissue stimulates calcification.37, 38 The mineral component of aortic valves is intimately associated with cholesterol at the ultrastructural level, and cholesterol is believed to play a role in the precipitation of calcium crystals.39 Products of cholesterol oxidation, such as 25-hydroxy cholesterol, found in coronary

Calcifying vascular cells

Recent studies have indicated that cells that reside in the valve may undergo transdifferentiation and participate in the calcific process. Vascular smooth muscle cells are important in fibrous tissue accumulation and calcification of atherosclerotic plaques in arteries. The aortic valve contains cells similar to vascular smooth muscle cells in the interstitial layer, called myofibroblasts, that are primarily believed to be secretory in nature, with protein-staining characteristics similar to

Matrix metalloproteinases

To maintain integrity and pliability, the aortic valve must undergo physiologic remodeling that entails degradation and reorganization of the interstitial tissue or so-called extracellular matrix. Putatively important regulators of aortic valve remodeling are the MMPs and tissue inhibitors of metalloproteinases. MMPs are endopeptidases with common functional domains and a common mechanism of action due to their ability to degrade extracellular matrix components.48, 49 MMPs have been implicated

Bone

Lamellar bone is also found in severely calcified aortic valves and is preceded by ectopic calcification.24 Hematopoietic elements similar to bone marrow have been seen in areas of lamellar bone (Figure 4). Bone growth and fracture healing are not passive but involve an orchestrated expression of extracellular bone proteins (osteoid components) that provide a scaffold for the calcific process.63 Similarly, calcified aortic valves contain extracellular bone matrix protein, such as osteopontin,

Genetic influences

Recent genetic studies of 2 extracellular molecules, matrix γ-carboxylated glutamate protein and osteoprotegerin, in mice have indicated that extracellular matrix calcification may be inhibited directly or indirectly by these proteins.70, 71 Although not proved, downregulation of inhibitors of calcification is a plausible scenario that may contribute to accumulation of calcium in aortic valve cusps. If this is the case, then administration of these molecules may attenuate valve calcification.

Renin-angiotensin system

The renin-angiotensin system controls blood pressure and fluid and electrolyte balances through coordinated effects on blood vessels, kidneys, and the heart, but, if unregulated, it may have proatherothrombotic effects.74, 75, 76, 77, 78 Angiotensin-converting enzyme, angiotensin II, and bradykinin receptor binding were observed in aortic valves from Sprague-Dawley rats.79 Interestingly, high-density angiotensin-converting enzyme binding was anatomically coincident with sites of fibrosis and

Observational studies of therapeutic interventions

There is no currently approved medication by the United States Food and Drug Administration for medical management of aortic valve stenosis. Recent, nonrandomized, clinical studies have indicated that medical therapy may slow progression of aortic valve calcification. Two retrospective studies82, 83 and 1 prospective population-based study84 noted echocardiographically that patients who used statin drugs had a significantly decreased annualized rate of aortic stenotic progression, but the rate

Acknowledgment

I thank Robert Zimmerman, MD, for providing the photomicrograph shown in Figure 4 and Frederick S. Kaplan, MD, for insightful comments.

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    This work was supported in part by grant KO8 HL03974-01 from the National Institutes of Health, Bethesda, Maryland.

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