The progression of calcific aortic valve disease through injury, cell dysfunction, and disruptive biologic and physical force feedback loops.
Calcific aortic valve disease (CAVD) is the most common form of heart valve disease in Western society and results in the second most common cardiovascular surgery performed. Despite its prevalence, high morbidity, and high mortality, the pathogenesis of CAVD still eludes our understanding. This review article brings together experimental in vivo and in vitro as well as human in vivo research in cell and molecular pathobiology to construct an overarching hypothesis regarding the development and progression of CAVD. We focus on injury, cell dysfunction, and disruptive biologic and physical forces, and how they function in positive feedback loops that result in the eventual calcification of the valve. We propose that injury, inflammation, matrix remodeling, and physical forces are all processes that influence each other and alter the normal physiologic functions of a key player in the pathogenesis of CAVD: the valve interstitial cell. We propose that the different phenotypes of the valve interstitial cell play essential roles in the pathogenesis of CAVD. We describe important physiologic processes which become dysfunctional including proliferation, migration, secretion of growth factors, chemokines and cytokines, and matrix remodeling. We also describe the emergence of chondrogenesis and osteogenesis in the fibrotic valve that lead to the severe clinical conditions of CAVD. CAVD appears to have a complex pathogenesis which fortunately can be studied in vitro and in vivo to identify ways to detect, treat, and prevent CAVD.
Laboratory Medicine Program, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 1L5.
Chen
C
Li
Songyi
S
Xu
Avrum I
AI
Gotlieb
D000818:Animals; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D001024:Aortic Valve Stenosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D001696:Biomechanical Phenomena; D002114:Calcinosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D002465:Cell Movement; D049109:Cell Proliferation; D020219:Chondrogenesis; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005246:Feedback; D006439:Hemodynamics; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D009389:Neovascularization, Pathologic; D010012:Osteogenesis; D010641:Phenotype; D012720:Severity of Illness Index; D013314:Stress, Mechanical
D018836:Inflammation Mediators