What are the pathophysiological mechanisms in calcific aortic stenosis?

Human population is aging globally and the prevalence of calcific aortic stenosis is increasing. Aortic stenosis has now become the most common valvular heart disease in adults. Progressive calcification of the aortic valve leads to increasing obstruction. Other than progressive calcification of the valve, other pathophysiological mechanisms have been implicated in calcific aortic stenosis. Oxidative stress, chronic inflammation, deposition of lipoproteins and induction of osteogenic signaling are important mechanisms involved in the progression of calcific aortic stenosis [1]. These may have potential implications in development of new therapeutic targets to prevent initiation and progression of calcific aortic stenosis.

Valvular interstitial cells in the aortic valve leaflets can redifferentiate into osteoblast like phenotype. This can occur due to reduction in nitric oxide signaling and increase in oxidative stress. Redifferentiation of valvular interstitial cells can lead to initiation and progression calcified lesions in aortic stenosis. Endothelial derived nitric oxide is a regulator of Notch1 signaling in aortic valve interstitial cells. That is how endothelial dysfunction triggers calcification of valvular interstitial cells [2]. Nitric oxide synthase in calcified aortic valves shifts from producing protective nitric oxide to synthesising harmful reactive oxygen species like superoxide, leading to markedly elevated levels of superoxide and hydrogen peroxide.

References

1. Desai MY, Braunwald E. The Pathophysiologic Basis and Management of Calcific Aortic Valve Stenosis: JACC State-of-the-Art Review. J Am Coll Cardiol. 2025 Sep 2;86(9):659-672. doi: 10.1016/j.jacc.2025.06.049. PMID: 40866051.
2. Bosse K, Hans CP, Zhao N, Koenig SN, Huang N, Guggilam A, LaHaye S, Tao G, Lucchesi PA, Lincoln J, Lilly B, Garg V. Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease. J Mol Cell Cardiol. 2013 Jul;60:27-35. doi: 10.1016/j.yjmcc.2013.04.001. Epub 2013 Apr 11. Erratum in: J Mol Cell Cardiol. 2018 Aug;121:307. doi: 10.1016/j.yjmcc.2018.04.013. PMID: 23583836; PMCID: PMC4058883.