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The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications
Kailun Phua1, Nicholas Ws Chew1, William Kf Kong1
1Department of Cardiology, National University Heart Centre, National University Hospital, Singapore, Singapore.
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.
Insights
Oxidative stress drives aortic stenosis (AS) progression, but effective medical treatments are lacking. Targeting oxidative stress shows promise for AS, though clinical trials are pending.
Area of Science:
- Cardiovascular Medicine
- Pathophysiology
- Biochemistry
Background:
- Aortic stenosis (AS) is a progressive cardiovascular disease with no current medical treatments to halt or reverse its course.
- Current management for severe or symptomatic AS relies on aortic valve replacement.
- Oxidative stress is a key factor in AS pathogenesis, contributing to lipid infiltration, inflammation, and calcification.
Purpose of the Study:
- To review the role of oxidative stress in the pathophysiology of degenerative aortic stenosis.
- To explore potential therapeutic strategies targeting oxidative stress for AS treatment.
- To evaluate the clinical efficacy of emerging therapies beyond statins.
Main Methods:
- Review of existing literature on oxidative stress and aortic stenosis.
- Analysis of preclinical (animal and in vitro) studies on oxidative stress mitigation in AS.
- Examination of clinical trial data for various AS therapeutic interventions.
Main Results:
- Oxidative stress contributes to extracellular matrix breakdown, valvular interstitial cell differentiation, and calcium deposition in AS.
- Preclinical studies show promise for oxidative stress-targeted therapies, but clinical translation remains limited.
- Statin therapy has shown disappointing results in AS treatment, while newer lipid-lowering agents warrant further investigation.
Conclusions:
- Oxidative stress represents a significant therapeutic target for aortic stenosis.
- Further clinical research is needed to validate the efficacy of targeting oxidative stress and other novel pathways in AS management.
- Exploring microRNA manipulation, renin-angiotensin-aldosterone system blockade, and dipeptidylpeptidase-4 inhibitors may offer future treatment avenues for AS.
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