Aortic valve sclerosis: new help from echocardiography in the assessment of cardiovascular risk

Aortic valve sclerosis is defined by echocardiography as focal areas of increased echogenecity on aortic cusps not inducing stenosis. A maximal aortic velocity value ≥ 2 m/s or ≥ 2.5 m/s is used to differentiate stenosis from sclerosis [1]. The normal aortic valve leaflets consist of a single layer of endothelial cells that envelopes the spongiosa on the aortic side, and the ventricularis on the ventricular side, whereas the central collagenous layer is the fibrosa characterized by a dense collagen [1,2]. Aortic sclerosis probably starts with an endothelial disruption on the aortic side yielding to thickening of the subendothelium and adjacent fibrosa due to accumulation of lipids and inflammatory cells. These aggregates colocalize with areas of microscopic calcification, and some macrophages produce osteopontin, a protein involved in the calcification process. Angiotensin-converting enzyme with local production of angiotensin II has been also identified in human sclerotic aortic valves [1–4]. This stage can be visualized by echocardiography as an irregular leaflet thickening without commissural fusion and stenosis. The prevalence of aortic sclerosis increases with age. In this issue of the journal, Agno et al. [5] report that the prevalence of aortic sclerosis among a population of 1624 patients with hypertension was 5% in patients aged between 45 and 55 years, increasing up to 35% in patients aged 75–85 years. Similarly, the Cardiovascular Health Study (CHS) showed that, among 5621 subjects aged 65 years or older, a prevalence of aortic sclerosis of 29% [6]. When patients with electrocardiographic evidence of left-ventricular hypertrophy (LVH) are considered, the prevalence of aortic sclerosis increases to 40%, as demonstrated by the LIFE study [7]. The attention to this condition has been increased by the observation that aortic sclerosis is not a benign incidental finding on echocardiography, but a marker for increased risk for cardiovascular events, even when baseline cardiovascular factors are taken into account [1]. The CHS demonstrated that, in adult patients older than 65 years, who were followed-up for 5 years, aortic sclerosis is associated with a 40% increase in the risk of myocardial infarction and, in patients without known coronary artery disease at study entry, with a 50% increase in the risk of cardiovascular death [6]. This adverse clinical outcome was also observed in the LIFE study, in which hypertensive patients with such a condition had almost twice the risk for serious cardiovascular events [7]. This adverse outcome is not likely to be related to the reduction of valve area, in that the estimated rate of progression to symptomatic aortic stenosis in adults with a jet velocity below 3.0 m/s is 8% per year or less [8]. Mechanisms other than valve disease per se have to be advanced to understand the factors influencing the prognosis in patients with aortic sclerosis. Epidemiological studies performed during the last decade have demonstrated that the aortic sclerotic process, normally termed ‘degenerative’, shares risk factors and inflammatory similarities with atherosclerosis. Presently, we know that aortic sclerosis is associated with older age, hypertension, elevated low-density lipoprotein cholesterol levels, diabetes, carotid and proximal aortic atherosclerosis and endothelial dysfunction; the association with an inflammatory status has been confirmed in aortic specimens, whereas the association with systemic inflammatory markers remains controversial [1–3,9–13]. By studying only patients with hypertension, Agno et al. [5] showed that aortic sclerosis is independently associated with concentric LVH, worse diastolic function and mitral annular calcification. The assessment of LV mass and geometry, and their changes during treatment, is useful in stratifying cardiovascular risk, and hypertensive patients with concentric hypertrophy have the greatest likelihood of experiencing a cardiovascular event [14,15]. Therefore, the greater prevalence of aortic sclerosis in uncomplicated patients with increased LV mass, which is a well-known and established sign of ‘preclinical disease’, is of particular interest. Agno et al. [5] have confirmed an association previously observed in patients with electrocardiographic LVH participating in the LIFE study [7], and in the elderly normotensive and hypertensive population of the CHS [6], and have further expanded upon these results, evaluating LV geometry. The association with higher LV mass and relative wall thickness, independent of other risk factors, might, at least in part, explain why patients with aortic sclerosis may be at a greater risk of cardiovascular complications. The mechanism of the association remains to be elucidated, although haemodynamic load (peak aortic velocity and gradient) does not appear to play a significant role, and genetic polymorphisms, mainly of the renin–angiotensin–aldosterone system, need to be more accurately evaluated. However, it remains to be demonstrated that normalization of aortic valve sclerosis may be associated with a more favourable outcome and, until this is the case, aortic sclerosis should be considered as a marker, rather than a cause or a consequence, of cardiac hypertrophy and related cardiovascular risk. The association between aortic sclerosis and indices of diastolic dysfunction (increased isovolumic relaxation time and left atrial enlargement) and mitral annular calcification is of interest. In particular, left atrial enlargement is a marker of diastolic dysfunction in the general population and, when used together with Doppler echocardiography, can identify elderly patients with worse diastolic dysfunction who are at an increased risk of developing atrial fibrillation [16,17]. The presence and the severity of mitral annular calcification has been found to be a predictor of morbidity and mortality as demonstrated by the CHS and Framingham Heart Study [18,19]. Left atrial enlargement and mitral annular calcification shares with aortic sclerosis risk factors such as hypertension, coronary artery disease and diabetes mellitus, and the power of an index of cardiovascular risk. The data of Agno et al. [5] suggest that mechanisms capable of inducing changes in myocardial properties, resulting in increased filling pressures, and changes in the structure of mitral annulus, are strictly related to changes in the aortic valve that probably represent a more generalized sclerotic process of the vascular tree [10]. Although the primum movens of the disease process is probably the same, the mechanism activated locally in each structure is different and remains difficult to clarify. The finding that degenerative aortic valve is not a static process, but an active specifically regulated process, suggests that it is potentially modifiable. Retrospective and non-randomized clinical studies have suggested that treatment with statins may be associated with a lower aortic valve calcification progression, as evaluated by electron beam computed tomography, or with a lower progression of aortic stenosis [20–23]. In the LIFE study, the use of statins was similar in patients with and without aortic valve abnormalities, and no significant differences on changes in aortic valve sclerosis and stenosis prevalence were observed between patients randomized to atenolol or losartan-based treatment [24], suggesting that changes in LV mass (and in geometry) during treatment do not parallel improvement or progression of aortic valve sclerosis. Surprisingly, the prevalence of diabetic patients was greater in those patients showing a normalization of aortic valve abnormalities, and the effect of oral antidiabetic agents (or anti-inflammatory drugs) on aortic sclerosis cannot be ruled out. Other prospective studies evaluating the effect of several classes of drugs on aortic valve abnormalities, possibly in younger patients and with a long period of follow-up, are needed to assess the clinical significance of aortic valve sclerosis in hypertensive patients. In conclusion, although the associations and mechanisms of aortic sclerosis remain to be elucidated further, it is now time to bring together the data so far obtained and then create a score in which clinical and echocardiographic alterations, such as aortic sclerosis, contribute to the assessment of the ‘global’ cardiovascular risk. This will have probably the potential for identifying those patients who require more aggressive therapy and/or a closer follow-up.