Development of calcific aortic valve disease: Do we know enough for new clinical trials?
Kostyunin Alexander E,Yuzhalin Arseniy E,Ovcharenko Evgeniy A,Kutikhin Anton G
Journal of molecular and cellular cardiology
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.
Macrophages Promote Aortic Valve Cell Calcification and Alter STAT3 Splicing.
Raddatz Michael A,Huffstater Tessa,Bersi Matthew R,Reinfeld Bradley I,Madden Matthew Z,Booton Sabrina E,Rathmell W Kimryn,Rathmell Jeffrey C,Lindman Brian R,Madhur Meena S,Merryman W David
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:Macrophages have been described in calcific aortic valve disease, but it is unclear if they promote or counteract calcification. We aimed to determine how macrophages are involved in calcification using the model of calcific aortic valve disease. Approach and Results: Macrophages in wild-type and murine aortic valves were characterized by flow cytometry. Macrophages in aortic valves had increased expression of MHCII (major histocompatibility complex II). We then used bone marrow transplants to test if differences in macrophages drive disease. mice had increased valve thickness, macrophage infiltration, and proinflammatory macrophage maturation regardless of transplanted bone marrow genotype. In vitro approaches confirm that aortic valve cells promote macrophage invasion as quantified by migration index and proinflammatory phenotypes as quantified by Ly6C and CCR2 positivity independent of macrophage genotype. Finally, we found that macrophage interaction with aortic valve cells promotes osteogenic, but not dystrophic, calcification and decreases abundance of the STAT3β isoform. CONCLUSIONS:This study reveals that aortic valve disease involves increased macrophage recruitment and maturation driven by altered aortic valve cell secretion, and that increased macrophage recruitment promotes osteogenic calcification and alters STAT3 splicing. Further investigation of STAT3 and macrophage-driven inflammation as therapeutic targets in calcific aortic valve disease is warranted.