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Nalini M. Rajamannan, MD
Northwestern University Feinberg School of Medicine
Calcific aortic stenosis is the most common indication for surgical valve replacement in the United States (www.sts.org). For years this disease has been described as a passive phenomena during which serum calcium attaches to the valve surface and binds to the leaflet to form nodules. However, emerging epidemiologic data and experimental data provide evidence that this disease process is not a passive phenomena but an active cellular biologic process that develops within the valve leaflet and causes a regulated bone formation to develop.
Vascular atherosclerosis which was once thought to be a "degenerative process" is now an active biological process which can be targeted with medical therapy. A similar phenomena has occurred with our understanding of aortic valve disease with the growing number of clinical and experimental studies over the past decade. The growing evidence for the etiology of degenerative calcific aortic valve disease points towards a response to injury mechanism similar to what has been described for vascular atherosclerosis. A growing number of databases confirm vascular atherosclerotic risk factors for calcific aortic stenosis, including elevated low-density lipoproteins, hypertension, male gender and smoking (1). The atherosclerotic hypothesis associated with valvular heart disease has also been implicated in patients with homozygous familial hypercholesterolemia (FH) (2, 3). Despite the increasing prevalence of this condition and the growing epidemiological evidence demonstrating the clinical risk factors, very little is known regarding the cellular mechanisms of calcific aortic stenosis. Furthermore, there are no established medial treatments indicated for calcific aortic stenosis. If cholesterol is a causative risk factor, then medications may have a pivotal role in the management of aortic valve disease. The understanding of medical therapy in aortic valve disease may slow the progression of stenosis and will decrease the number of aortic valve replacements in the future.
For years, "degenerative aortic valve disease was hypothesized to be a passive accumulation of calcium binding to the aortic surface of the valve leaflet. The histology of aortic stenosis has been well described in a number of studies evaluating human calcified aortic valves from surgical valve replacement or autopsy. Ex vivo analysis of human calcified aortic valves have redefined the paradigm that aortic valve disease is not just a passive phenomena but an active cellular process ranging from early atherosclerosis to calcification associated with an increase in bone matrix expression (4, 5). Studies evaluating heavily calcified aortic valves describe mature lamellar bone formation (6) and expression of specific bone markers important in the development of osteoblast bone formation (7). These studies which define the presence of actual bone within the valve provide further evidence that the development of stenosis occurs secondary to an active biological process. Histologic studies in the early valvular sclerotic lesions demonstrated chronic inflammatory cell infiltrates (macrophages and T lymphocytes), and lipids (apolipoprotein apoB, apo(a), apoE) and a-actinexpressing cells in lesion and in adjacent fibrosa and thickening of fibrosa with collagen and elastin (8). These studies provide critical information regarding the pathogenesis of this disease. HMG CoA Reductase inhibitors (statins) have emerged as a potential therapy for treating aortic valve calcification. Recent experimental studies have shown that aortic valves from 2 month experimental hypercholesterolemia study develop aortic valve atherosclerosis and that treatment with atorvastatin demonstrates improvement in the valve lesion (9). Histologic analysis of the effects of cholesterol on the aortic valve is characterized by foam cell formation, aortic valve myofibroblast cell proliferation and bone matrix protein expression. Further analysis at the gene level indicates that specific osteoblast bone markers are expressed in the aortic valve from these samples (9). Finally, this study demonstrates that statins may decrease the atherosclerotic cellular effects, inhibit osteoblast gene markers, and finally inhibit calcification. Statins also have potent LDL lowering and non-LDL lowering effects via inhibition of the rate limiting step in cholesterol synthesis and improvement in the cellular pathways to modify the atherosclerotic process. Currently, there are a growing number of retrospective studies demonstrating that medical therapy is a potential approach for treating aortic valve disease. The magnitude of the effect of therapy is similar to previous studies with all showing an approximately 50% annual reduction in measurable disease progression, whether quantified by Doppler echocardiographic jet velocity or valve area, or by electron beam tomographic valve calcium scores (10-14). A recent small double blind trial, SALTIRE (15) demonstrated that high dose Atorvastatin did not demonstrate a slowing of progression of aortic stenosis in this patient population. SALTIRE initiated Atorvastatin in patients who had advanced aortic stenosis as defined by aortic valve area 1.03 at baseline prior to treatment and elevated calcification scores by electron beam CT scan. This level of disease may have played a role in the outcome in the study and that earlier initiation of therapy with less severe aortic valve areas may play a role in the therapy of these patients. Currently, there are two ongoing prospective trial in Europe for the use of cholesterol lowering medications and to test for slowing of the progression of aortic valve stenosis: SEAS (Simvastatin and Eztimide)(16) and RAAVE (Rousavatin)(17). Results of these studies will be helpful in our further understanding of potential therapies for this disease.
References:
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