Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, Kemerovo 650002, Russian Federation.
Research Institute for Complex Issues of Cardiovascular Diseases, 6 Sosnovy Boulevard, Kemerovo 650002, Russian Federation.
J Mol Cell Cardiol. 2019 Jul;132:189-209. doi: 10.1016/j.yjmcc.2019.05.016. Epub 2019 May 25.
Calcific aortic valve disease (CAVD), previously thought to represent a passive degeneration of the valvular extracellular matrix (VECM), is now regarded as an intricate multistage disorder with sequential yet intertangled and interacting underlying processes. Endothelial dysfunction and injury, initiated by disturbed blood flow and metabolic disorders, lead to the deposition of low-density lipoprotein cholesterol in the VECM further provoking macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines. Such changes in the valvular homeostasis induce differentiation of normally quiescent valvular interstitial cells (VICs) into synthetically active myofibroblasts producing excessive quantities of the VECM and proteins responsible for its remodeling. As a result of constantly ongoing degradation and re-deposition, VECM becomes disorganised and rigid, additionally potentiating myofibroblastic differentiation of VICs and worsening adaptation of the valve to the blood flow. Moreover, disrupted and excessively vascularised VECM is susceptible to the dystrophic calcification caused by calcium and phosphate precipitating on damaged collagen fibers and concurrently accompanied by osteogenic differentiation of VICs. Being combined, passive calcification and biomineralisation synergistically induce ossification of the aortic valve ultimately resulting in its mechanical incompetence requiring surgical replacement. Unfortunately, multiple attempts have failed to find an efficient conservative treatment of CAVD; however, therapeutic regimens and clinical settings have also been far from the optimal. In this review, we focused on interactions and transitions between aforementioned mechanisms demarcating ascending stages of CAVD, suggesting a predisposing condition (bicuspid aortic valve) and drug combination (lipid-lowering drugs combined with angiotensin II antagonists and cytokine inhibitors) for the further testing in both preclinical and clinical trials.
钙化性主动脉瓣疾病（CAVD）以前被认为是瓣膜细胞外基质（VECM）的被动退化，现在被认为是一种复杂的多阶段疾病，具有连续但相互交织和相互作用的潜在过程。内皮功能障碍和损伤，由血流紊乱和代谢紊乱引起，导致低密度脂蛋白胆固醇在 VECM 中的沉积，进一步引发巨噬细胞浸润、氧化应激和促炎细胞因子的释放。瓣膜内稳态的这种变化诱导通常静止的瓣膜间质细胞（VICs）分化为合成活跃的肌成纤维细胞，产生过量的 VECM 和负责其重塑的蛋白质。由于持续不断的降解和再沉积，VECM 变得无序和僵硬，进一步促进 VICs 的肌成纤维细胞分化，并使瓣膜更难适应血流。此外，破坏和过度血管化的 VECM 容易受到钙和磷酸盐在受损胶原纤维上沉淀引起的营养不良钙化的影响，同时伴随着 VICs 的成骨分化。被动钙化和生物矿化相结合，协同诱导主动脉瓣的骨化，最终导致其机械功能不全，需要手术置换。不幸的是，尽管进行了多次尝试，但仍未能找到有效的 CAVD 保守治疗方法；然而，治疗方案和临床环境也远非最佳。在这篇综述中，我们重点关注了上述机制之间的相互作用和转变，这些机制标志着 CAVD 的上升阶段，并提出了一种易感条件（二叶式主动脉瓣）和药物联合（降脂药物联合血管紧张素 II 拮抗剂和细胞因子抑制剂），以便在临床前和临床试验中进一步测试。
