The role of statins in aortic stenosis, even when serum cholesterol is not very elevated

Aortic valve stenosis (AS) is the most frequently encountered valve disease in the developed world, affecting about 3-5% of the population above 75 years with at least moderate AS. 
Because populations there are aging, this represents a considerable health problem as well as a socio-economical burden, and the only current therapy for this progressive condition in symptomatic patients is still surgery. Without surgery, symptomatic AS patients face a poor prognosis.

I – AS is closely associated with atheroslerotic diseases

Over recent years, the understanding of and potential therapeutic options for AS have changed dramatically. Calcific aortic stenosis has – in all stages of the disease spectrum - been recognised as an active inflammatory process, closely associated with atherosclerotic diseases. This has been demonstrated through :

• A number of epidemiologic studies demonstrating similar risk factors for AS as for atherosclerotic diseases in general, among them hypercholesterolemia, hypertension, diabetes mellitus, male sex and age1, 2.
• Several histopathological studies have demonstrated changes compatible with chronic inflammation, with lipoprotein deposition and with activation of the renin-angiotensin system.
• There are close similarities between the coronary artery plaque and the “early lesion” of AS3. The calcification process also includes osteoblast-like activity and bone formation in end-stage AS.
• Results of in vitro and animal studies indicate that this might be a potentially modifiable process4. The association of lipid abnormalities such as high lipoprotein (a) levels and the presence of the apolipoprotein E4 allele with aortic stenosis, as well as the presence of several inflammatory markers both in plasma and in surgically excised valves, suggest that the stenotic process is driven by many of the same factors as those that are behind atherosclerosis3, 5, 6.
• The aortic valves of animals fed with a cholesterol-rich diet exhibit many characteristics in common with the early stages of aortic stenosis4.
• Recently Weiss et al demonstrated that hypercholesterolemic mice in old age develop aortic stenosis6.

II –Implications for treatment and prevention

Statins have been demonstrated to influence several components in the inflammatory process:

- latest by Dr. Osman et al, who demonstrated the influence of atorvastatin on human valve interstitial cells involved in valve calcification.

This finding opens up the potential of retarding the process through interventional strategies7. A number of studies have focused on various risk factors for progression, demonstrating that a rapid rate of stenosis progression, severe valve calcification and aortic valve jet velocity > 3 m/s are the best predictors of outcome8-10.

III – Risk

Calcific aortic valve disease represents an elevated cardiovascular risk, which goes beyond the hemodynamic obstruction itself.

From the Cardiovascular Health Study as well as in works by Dr.Rosenhek et al it has been demonstrated that even the early stages of aortic valve remodelling, commonly referred to as aortic sclerosis, is not just a benign disease, but bears considerable CVD risk – 50% increase in the risk of cardiovascular death11, 12. Even mild to moderate AS bears a 1.8 times higher mortality than an age- and gender-matched control population according to Rosenhek at al9.

The mechanism of this increased cardiovascular risk remains unclear, but it has been demonstrated that aortic valve disease is associated with endothelial dysfunction13. This represents a considerable cardiovascular burden, knowing that 25% of adults over 65 years have some degree of aortic sclerosis, and that 16% of these progress to hemodynamically significant AS over 7 years.

Likewise, it has been demonstrated that aortic valve sclerosis even without obstruction is significantly associated with coronary artery disease and as such might serve as a “window” to detect coronary atherosclerotic disease.

IV -  Prevention

There has been a considerable focus over the latter years to find means of medical therapy to slow AS progression and/or rate of aortic valve replacement.

Lipid lowering therapy by statins has received most attention, after demonstrating a reduced progression rate in several retrospective studies. The first prospective study with statins, the SALTIRE study14 however demonstrated no effect, though this might imply that treatment should start in the early stages, or the duration was too short to observe any effect.

For coronary heart disease, “lower has proven better” in the overall trial cohorts, with improved prognosis by lowering cholesterol even when cholesterol is not very elevated. Non-lipid or pleiotropic effects of statins on cardiovascular risk have been postulated, possibly through improvement of endothelial dysfunction. A possible anti-inflammatory effect of statins have also been forwarded. The same may apply also to aortic valve stenosis13, 15.

Recently it was demonstrated that endothelial dysfunction in calcified aortic stenosis persists beyond aortic valve replacement16. This might imply that medical therapy, and statin therapy in particular, might be beneficial in aortic valve disease at all stages of the disease, to slow progression, and to reduce cardiovascular risk, morbidity and mortality, possibly even after AVR. This remains to be demonstrated in larger, long-term prospective trials. To date the ASTRONOMER and SEAS trials are ongoing and hopefully will provide answer in the near future.

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.