Description:
Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorderthat ultimately causes gradual narrowing of the left ventricular outflow orifice withensuing devastating hemodynamic effects on the heart. Calcific mineral accumulationis the hallmark pathology defining this process; however, fibrotic extracellular matrix(ECM) remodeling that leads to extensive deposition of fibrous connective tissueand distortion of the valvular microarchitecture similarly has major biomechanical andfunctional consequences for heart valve function. Significant advances have been madeto unravel the complex mechanisms that govern these active, cell-mediated processes,yet the interplay between fibrosis and calcification and the individual contribution toprogressive extracellular matrix stiffening require further clarification. Specifically, wediscuss (1) the valvular biomechanics and layered ECM composition, (2) patternsin the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3)imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5)molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverseremodeling. This review explores our current understanding of the cellular and moleculardrivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD.