Towards medical therapy of calcific aortic stenosis—lessons from molecular biologyThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. Calcific aortic stenosis, with a prevalence of 3–9%, is the most frequent heart valve disease and the main reason for valve replacement in patients over 60 years of age.1 Histopathologically, sclerosis of the aortic valve is defined as fibrous thickening and calcification of the valve cusps.2 For many years, these changes were thought to be caused by passive calcium precipitation within the valve. However, there is increasing evidence that the development and progression of calcific aortic stenosis may be triggered by underlying genetic and acquired risk factors.3 Early valvular lesions have much in common with the early lesion of atherosclerosis, putting forward the hypothesis that calcific aortic stenosis may be an atherosclerotic disease.4 However, the distinct pattern of tissue calcification and fibrosis found during the progression of calcific aortic stenosis suggests an at least partially different pathomechanism. The accumulation of macrophages and lymphocytes observed in stenotic valves indicates that calcific aortic stenosis might be based on a chronic inflammatory process.4–6 Recent studies have further corroborated this concept, demonstrating that by release of pro-inflammatory cytokines, leukocytes can induce an inflammatory activation of myofibroblasts which, in turn, develop an osteoblast-like, calcifying phenotype.5–7 Thus, as this is an actively regulated inflammatory process, hopes are high that the cause of calcific aortic stenosis might be modifiable by medical therapy.3 While many studies have addressed the pathogenesis of tissue calcification as a prominent feature of calcific aortic stenosis, less research has been conducted on the molecular mechanisms of the matrix remodelling observed in this disorder. Indeed, extensive fibrous thickening occurs during the progression of calcific aortic stenosis, which is due to an increased proliferation of local myofibroblasts and synthesis of matrix proteins.5,6 The expression and activation of matrix metalloproteinases, proteolytic enzymes mediating virtually all physiological and pathological processes of tissue remodelling, additionally promote the profound conversion of the valvular tissue.5,6 Recent data also suggest that angiotensin-converting enzyme (ACE) may mediate the fibrous thickening of the valve, possibly by accumulation of the profibrotic and proinflammatory peptide angiotensin II.8 However, ACE inhibition did not slow the progression of calcific aortic stenosis in a clinical study,9 and the precise mechanisms of valvular matrix remodelling and fibrosis still remain poorly understood. In their study, Helske et al. extensively addressed the effects of bradykinin, its receptors, and the bradykinin-degrading enzyme neutral endopeptidase (NEP) on aortic valve myofibroblasts.10 Bradykinin can exert antifibrotic effects on fibroblasts, and is cleaved by various proteolytic enzymes found in stenotic valves including NEP and ACE. The current results reveal that NEP is upregulated in stenotic aortic valves, possibly contributing to the disturbed balance of profibrotic and antifibrotic factors. The upregulation of NEP is mediated by the pro-inflammatory cytokine tumour necrosis factor-α, which previously has been shown to induce the molecular mechanisms of both tissue calcification and matrix remodelling, in calcific aortic stenosis.6,7 Thus, the observed disturbances in the bradykinin system are likely to be secondary to inflammation as an underlying pathological process. The current cell culture experiments show that the inhibition of NEP decreased the expression of the profibrotic cytokine transforming growth factor-β, suggesting an influence on the progression of valvular fibrosis. These effects could be additive to those of ACE inhibitors since ACE inhibition does not sufficiently suppress NEP activity. In summary, Helske et al. describe a new piece in the puzzle of the pathogenesis of calcific aortic stenosis. The data underline the importance of inflammation as a central mechanism of the disease, and point to a potential medical therapy. Targeted drug therapy to prevent the progression of calcific aortic valve disease should ideally be based on the risk factors and the molecular pathogenesis of the disease. For calcific aortic stenosis, most evidence exists on 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e. statins) which may influence both risk factors and inflammatory pathways by lowering lipid levels and exerting anti-inflammatory properties, respectively.3 Two smaller, prospective clinical studies have yielded heterogenous conclusions, while at least two larger, prospective trials are currently under way.3 The study by Helske et al. shows us that research on the molecular mechanisms of calcific aortic stenosis may lead to the identification of drugs other than statins that have the potential to retard the progression of calcific aortic stenosis.10 However, the high hopes placed on NEP inhibitors for treatment of hypertension and heart failure have been dampened by an increased frequency of severe angioedema in previous studies, making it unlikey that these substances will be given clearance for patients with calcific aortic stenosis in the near future.11 Despite this fact, further basic research on this drug class should be performed, given the potential effects of enhanced bradykinin levels on both valve and myocardium. Whether the bradykinin system has an effect on the mechanisms of tissue calcification should also be elucidated. The increasing number of publications on the pathological mechanisms of calcific aortic stenosis indicates that the concept of medical therapy for slowing down disease progression remains an exciting topic. The results of the studies on statin therapy are eagerly awaited, and research on other drugs is likely to follow. In the meantime, we should continue to treat our patients with calcific aortic stenosis according to the current international guidelines. Conflict of interest: none declared.