Theodoropoulou Theoni, Mourouzis Iordanis, Katsaouni Athanasia, Pantos Constantinos, Tsioufis Konstantinos, Toutouzas Konstantinos
Unit for Structural Heart Diseases and Valvulopathies, First Department of Cardiology, Athens School of Medicine, Hippokration Hospital, Athens, Greece.
Department of Pharmacology, National and Kapodistrian University of Athens, Athens, Greece.
Eur J Pharmacol. 2025 Sep 15;1003:177985. doi: 10.1016/j.ejphar.2025.177985. Epub 2025 Jul 22.
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.
钙化性主动脉瓣疾病（CAVD）是老年人中常见的心脏瓣膜疾病，尽管其发病率很高，但CAVD发展背后的致病机制仍知之甚少。有症状的主动脉瓣狭窄的当前标准治疗方法是外科手术或经导管主动脉瓣置换术（AVR）。然而，外科手术干预存在一些缺点，例如机械瓣膜患者需要终身抗凝治疗，以及由于成人瓣膜退变或儿科患者身体生长导致的高再次手术率。迄今为止，尚未确立预防主动脉瓣钙化的药物治疗方法。预期寿命的延长与AVR相结合导致了医疗保健成本的显著上升。美国医疗保险每年为主动脉瓣狭窄患者支付的费用从2010年的29亿美元增加到2019年的46亿美元，相差超过17亿美元。因此，需要新的药物来预防瓣膜钙化的发展。正在进行的临床试验目前正在探索新的潜在治疗方法，针对与主动脉瓣狭窄钙化相关的分子途径。已知构成瓣膜基质的瓣膜间质细胞（VICs）失调是病理学的关键驱动因素。VICs经历凋亡或成骨细胞分化，并通过产生包括骨钙素、骨桥蛋白和碱性磷酸酶在内的骨相关蛋白，最终影响钙沉积并促进钙化过程。本综述旨在概述CAVD中已确立的炎症和钙化途径，特别关注瓣膜间质细胞的作用。
