The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications

Abstract

Despite the elucidation of the pathways behind the development of aortic stenosis (AS), there remains no effective medical treatment to slow or reverse its progress. Instead, the gold standard of care in severe or symptomatic AS is replacement of the aortic valve. Oxidative stress is implicated, both directly as well as indirectly, in lipid infiltration, inflammation and fibro-calcification, all of which are key processes underlying the pathophysiology of degenerative AS. This culminates in the breakdown of the extracellular matrix, differentiation of the valvular interstitial cells into an osteogenic phenotype, and finally, calcium deposition as well as thickening of the aortic valve. Oxidative stress is thus a promising and potential therapeutic target for the treatment of AS. Several studies focusing on the mitigation of oxidative stress in the context of AS have shown some success in animal and in vitro models, however similar benefits have yet to be seen in clinical trials. Statin therapy, once thought to be the key to the treatment of AS, has yielded disappointing results, however newer lipid lowering therapies may hold some promise. Other potential therapies, such as manipulation of microRNAs, blockade of the renin-angiotensin-aldosterone system and the use of dipeptidylpeptidase-4 inhibitors will also be reviewed.

Keywords: Severe aortic stenosis; oxidative stress; reactive oxidative species.

Figure 1

Oxidative Stress and Lipid Infiltration

Figure 2

Lipid Deposition and Inflammation

Figure 3

Central illustration. Pathophysiology and mechanistic pathways of oxidative stress in calcific aortic stenosis.