Aortic valve sclerosis (AVS) is defined as an abnormal valve morphology in the absence of a hemodynamically significant valve orifice obstruction, and is regarded as a precursor to aortic valve stenosis.1) AVS and aortic valve stenosis, characterized by increased leaflet thickness, stiffening and calcification, are common in the elderly population.2) There is increasing evidence that this condition is regulated by active cellular processes, including complex inflammation-related mechanisms. Several population-based longitudinal studies have found that cardiovascular risk factors such as hypercholesterolemia impact the development of degenerative aortic valve stenosis.3) Wierzbicki and Shetty4) described an ‘early lesion’ resembling the early lesions in atherosclerotic plaques, and proposed classifying calcific aortic stenosis as an atherosclerotic disease.

Therefore, it seems logical to hypothesize that the modification of atherosclerotic risk factors would slow the progression of aortic valve stenosis.5) General experimental support for this hypothesis has been provided by animal model studies; however, statins do not appear to have a specific role in the progression of aortic stenosis.6)7) Due to the limited and inconsistent data available, there remains a question about the therapeutic role of statins in human patients with AVS.8)9)10)

The aim of our study was to evaluate the effects of statins on the progression of AVS, an early stage of aortic valve lesions.

We retrospectively analyzed the echocardiograms of all patients with AVS diagnosed by 2-D and Doppler echocardiography (irregular leaflet thickening, focally increased echogenicity on 2-D echocardiogram and increased peak aortic valve velocity [> 1.5 and < 2 m/s] on Doppler echocardiogram), and subsequently selected patients who had undergone at least two echocardiography examinations at least 6 months apart from August 2010 to August 2015. Initially, 3,695 patients were enrolled. The exclusion criteria included the presence of other significant valvular diseases, left ventricular dysfunction (left ventricular ejection fraction < 40%), congenital heart disease, cardiomyopathy, a permanent pacemaker, uncontrolled tachycardia or bradycardia and a history of cardiac surgery. Of the 3,695 candidate patients, 541 were included in the present study (Figure 1).

Clinical data including the medical history and presence of risk factors were obtained by a complete review of each patient's medical records. The presence of hypercholesterolemia (total cholesterol > 200 mg/dL or use of lipid-lowering therapy), diabetes mellitus (fasting plasma glucose > 126 mg/dL, plasma glucose level [anytime] > 200 mg/dL or use of antidiabetic medication), hypertension (blood pressure ≥ 140/90 mmHg or use of antihypertensive medication) and coronary artery disease (previously documented myocardial infarction or coronary artery stenosis with a lumen diameter > 50% on angiography) were recorded. The progression rate of AVS was expressed as the increase in peak velocity per year (m/s/yr). Inclusion in the statin-treated group required patients to have been prescribed a statin during the study follow-up period.

This study was approved by the Ethical Review Board of our institution.

In this study, statins did not appear to influence the mean progression rate of AVS. Some retrospective studies in humans have suggested that statin therapy might slow the progression of aortic stenosis.12)13)14)15) In addition, a prospective study (Rosuvastatin Affecting Aortic Valve Endothelium [RAAVE]) revealed that the rate of disease progression was significantly slower in hypercholesteremic patients treated with rosuvastatin than in untreated patients with normal cholesterol levels.16) However, three recent prospective randomized studies found neither regression nor reduction in the progression of aortic stenosis in statin-treated patients: SEAS (Simvastatin and Ezetimibe in Aortic Stenosis),17) SALTIRE (Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression)18) and ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin).19) Finally, a meta-analysis that included 10 studies with 3,822 participants (2,214 non-statin-treated and 1,608 statin-treated) did not support the use of statins to improve outcomes or reduce disease progression in patients with non-rheumatic calcific aortic valve stenosis.20)

Several studies have examined the role of statins in the progression of AVS. In 2005, Antonini-Canterin et al.8) reported that the rate of change in peak aortic velocity (Vmax) was significantly lower in statin-treated patients than in non-statin-treated patients (0.04 ± 0.04 vs. 0.08 ± 0.06 m/s/yr, p = 0.007). However, the number of patients with AVS in this study was low (n = 52; 26 statin-treated, 26 controls). An additional study involving a large number of patients with long-term follow-up demonstrated that statins effectively slowed the progression of aortic valve disease in AVS. The progression rate of AVS was 0.04 ± 0.09 m/s/yr in patients receiving statins and 0.07 ± 0.10 m/s/yr in untreated patients (p = 0.01).21) In contrast, in animal models, the cellular response to statin therapy did not result in full regression of the sclerotic process in established AVS.9)

To validate these limited and conflicting findings, we assessed a large human patient population and determined whether statin treatment improved AVS progression. We did not find a link between statin treatment and the rate of disease progression. Given the higher baseline risk for stenosis progression in the statin-treated group (higher prevalence rates of hypertension, diabetes, ischemic heart disease and stroke, and higher CRP levels) and the fact that Vmax did not increase in statin-treated patients with AVS, it is plausible that statins have beneficial effects, since more rapid disease progression could be expected in this group.

In our study, the mean follow-up period was shorter than those in previous studies. For example, in the reports by Antonini-Canterin et al., the mean follow-up durations were 54 ± 34 months in 20058) and 5.6 ± 3.2 years in 2008.21) AVS is a slowly progressing disease. Therefore, the duration of follow-up in our study may have been too short to detect differences in the disease progression rate between the two groups.

The mean progression rate was 0.012 ± 0.340 m/s/yr in the statin-treated group and 0.014 ± 0.245 m/s/yr in the non-statin-treated group. These values were lower than those in previous studies8)21) and consistent with results in patients with aortic stenosis. In a previous study involving Korean patients,22) the progression rate of aortic stenosis was similar to that found in Japanese patients but slower than those reported for the Western population. Ethnic differences have also been reported for aortic valve calcification, which plays an important role in the progression of AVS.23) Therefore, ethnicity and other as-yet unrecognized factors may influence the progression rate of AVS. More research is needed in this area.

Multivariate analysis revealed that the initial peak aortic jet velocity was the only independent predictor of the AVS progression rate. Previously, Palta et al.24) reported that the initial aortic valve area (AVA), smoking status, and serum calcium levels were associated with the progression of aortic stenosis. Also, Bahler et al.25) found that the severity index (based on valve calcification and mobility) was an independent predictor of aortic stenosis progression, as was the initial AVA. However, in our study, no severity index of aortic valvular calcification was used, and the smoking status and serum calcium levels did not appear to be associated with the progression of AVS.

This study had several limitations. First, due to the retrospective study design, we encountered incomplete records of clinical and echocardiographic parameters. Second, we did not grade aortic valve calcification based on echocardiography. Aortic valve calcification has been shown to be associated with more rapid progression of aortic stenosis.26) However, we believe that the quantitation of aortic valve calcification by echocardiography is not reliable, because it relies heavily on the machine settings, image quality and echocardiographer experience. Third, we could not analyze the data according to the type and dose of statin, due to the small sample size. Lastly, the retrospective nature of this study limited the participants to a single center and a single ethnicity. Therefore, our findings should be expanded and further verified in well-controlled prospective studies.

In conclusion, our retrospective study demonstrated that statin treatment had no effect on the progression of AVS. The progression rate of AVS observed herein was slower than that in the Western population. Therefore, well-designed, prospective, large-volume randomized controlled studies including participants from all races are needed to further define the prognosis and specific management of AVS.