Valvular interstitial cells as a novel therapeutic target for preventing calcific aortic valve disease

Calcific aortic valve disease (CAVD) is a common heart valve disease among elderly individuals, and despite its prevalence, the causal mechanisms behind CAVD development remain poorly understood. The current standard treatment for symptomatic aortic stenosis is surgical or transcatheter aortic valve replacement (AVR). Nevertheless, surgical interventions come with disadvantages such as lifelong anticoagulation therapy in patients with mechanical valves and high rates of reoperation due to valve degeneration in adults or somatic growth in pediatric patients. To date, no pharmacological therapy has been established to prevent aortic valve calcification. The increased life expectancy combined with AVR has led to a significant rise in healthcare costs. Annual Medicare payments for patients with aortic stenosis in the US increased from 2.9 billion in 2010 to 4.6 billion in 2019, a difference of more than 1.7 billion dollars. Hence there is a demand for new drugs to prevent the development of valvular calcification. Ongoing clinical trials are currently exploring new potential treatments, targeting molecular pathways associated with calcification in aortic stenosis. It is known that dysregulation of the valvular interstitial cells (VICs) that populate the valve matrix is a key driver of the pathology. VICs undergo apoptosis or osteoblastic differentiation, and by producing bone-related proteins, including, osteocalcin, osteopontin, and alkaline phosphatase, they ultimately influence calcium deposition and contribute to the calcification process. This review aims to outline the established inflammatory and calcific pathways involved in CAVD, with a particular focus on the role of valvular interstitial cells.