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Dr. Raphael Rosenhek ,
Retrospective studies suggest that statins (but not ACE-Inhibitors) reduce the progression of aortic stenosis, thereby creating new hope in the improvement of the clinical outcome of these patients through medical therapy. However these findings need confirmation in prospective trials.
The incidence of calcific aortic stenosis in developed countries is steadily increasing due to an aging population. Aortic stenosis is the most frequent valvular heart disease and accounts for a significant number of open-heart surgical procedures, thus posing an increasing challenge for health care. Recent insights into the disease mechanism have brought on the concept of medically slowing disease progression.
Histopathological studies have revealed that calcific aortic stenosis (which is the most common etiology of aortic stenosis) is an active disease process sharing a number of similarities with atherosclerosis. In both diseases, lipid infiltration, inflammation, neo-angiogenesis, calcification and ossification are observed. Furthermore, the angiotensin converting enzyme is present in stenotic but not in normal aortic valves.
Additionnaly, there are indications that aortic sclerosis is associated with endothelial dysfunction. As aortic sclerosis can be viewed as a precursor of aortic stenosis, it is therefore very likely that endothelial dysfunction is present in patients with aortic stenosis (1).
These observations have led to the concept that therapies that are of benefit in patients with atherosclerotic disease might also be in patients with aortic stenosis. Statins and ACE-Inhibitors have been identified as the two most promising candidates. Both statins and ACE-Inhibitors have been shown to reduce the progression of atherosclerotic disease and to significantly improve the clinical outcome among patients with coronary artery disease.
In fact, retrospective studies determining the degree of valvular calcification by electron-beam computer tomography have shown a lesser degree of aortic valve calcium accumulation both among patients receiving statins(2) and patients receiving ACE-inhibitors(3). Nevertheless in a retrospective echocardiographic study, ACE-Inhibitor therapy did not seem to significantly slow hemodynamic progression of aortic stenosis with progression rates of 0.29 ± 0.44 m/s/yr and of 0.35 ± 0.44 m/s/yr in patients with and without ACEI treatment, respectively (p=0.29)(4).
In contrast, four retrospective echocardiographic studies have observed a significantly slower rate of aortic stenosis progression among statin-treated patients(4-7). These studies include between 156 and 211 patients who were followed between 21 and 44 months. Rates of hemodynamic progression of aortic stenosis (expressed as an increase in peak gradient, peak aortic jet velocity or reduction of the valve area) in the different trials for patients receiving or not receiving statin therapy, respectively were: Aronow et al.(5) (3.4±1.0 mmHg/yr vs. 6.3±1.4 mmHg/yr, p<0.0001), Novaro et al.(7) (-0.06±0.16cm2/yr vs. –0.09±0.17cm2/yr, p<0.03); Bellamy et al.(4) (-0.04±0.15cm2/yr vs. –0.09±0.17cm2/yr, p<0.04) and Rosenhek et al.(3) (0.10±0.41m/s/yr vs. 0.39±0.42m/s/yr, p<0.0001). Controversy remains with regard to the cholesterol dependency of this effect. A slower rate of hemodynamic progression among statin treated patients was related to lower cholesterol levels in two of these studies(5,6), whereas no such association was observed in the other two studies(3,4), suggesting that the effect might be due to pleiotropic or anti-inflammatory properties of statins rather than their cholesterol-lowering action.
Although encouraging, these studies are all limited by their retrospective design, and results of prospective randomised trials are required before a medical therapy aimed at slowing disease progression in aortic stenosis can be generally recommended. The retrospective results for statin-therapy appear to be promising and their effects are currently studied in prospective trials. We will have to await the results of these trials - and should they confirm the findings of the retrospective studies, it will indeed be important to assess whether the effects are dose dependent. The current studies were not designed to address this question As aortic stenosis and even aortic sclerosis are associated with an increased cardiovascular risk, it will also be of interest to assess the effects of statins on the cardiovascular event-rate independently from hemodynamic progression. Further insights into the pathophysiological mechanisms might lead to development of new effective drugs to prevent or slow down the progression of aortic stenosis.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Poggianti E, Venneri L, Chubuchny V, Jambrik Z, Baroncini LA, Picano E. Aortic valve sclerosis is associated with systemic endothelial dysfunction. J Am Coll Cardiol. 2003 Jan 1;41(1):136-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12570956
2. Shavelle DM, Takasu J, Budoff MJ, Mao S, Zhao XQ, O'Brien KD. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 2002;359:1125-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11943265
3. Caulfield MT, Budoff MJ, Takasu J, et al. Angiotensin Converting Enzyme Inhibitor Use Is Associated with a Decreased Rate of Aortic Valve Calcium Accumulation. (abstr.). Circulation 2002;106(suppl II):II-640. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12390952
4. Rosenhek R, Rader F, Loho N, et al. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004;110:1291-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15337704
5. Bellamy MF, Pellikka PA, Klarich KW, Tajik AJ, Enriquez-Sarano M. Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community. J Am Coll Cardiol 2002;40:1723-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12446053
6. Aronow WS, Ahn C, Kronzon I, Goldman ME. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am J Cardiol 2001;88:693-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11564402
7. Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis. Circulation 2001;104:2205-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11684632
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