Abstract
Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in 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 reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD.
Highlights
Aortic valve stenosis (AS) is a devastating disorder characterized by progressive narrowing of the aortic valve (AV) orifice and has a high prevalence [1] exceeding 2% in a population ≥75 years of age [2]
Even early-stage AV sclerosis associates with increased cardiovascular morbidity and mortality [9, 10], and recent clinical studies have suggested that intervention prior to late-stage stenosis may improve overall cardiovascular outcomes [11,12,13]
endothelial-to-mesenchymal transdifferentiation (EndMT) leading to a myofibroblastic phenotype appears to precede differentiation of valvular endothelial cells (VECs) to an osteoblastic phenotype [42], suggesting that VECs may actively contribute to sclerosis and calcification of the valve in addition to their protective role as a barrier against the invasion of pathological mediators into the valvular interstitium
Summary
Aortic valve stenosis (AS) is a devastating disorder characterized by progressive narrowing of the aortic valve (AV) orifice and has a high prevalence [1] exceeding 2% in a population ≥75 years of age [2]. While tissue fibrosis plays a major role in the initiation phase of calcific aortic valve disease (CAVD), the differential contribution of fibrosis and calcification to latestage AS is less clear. This conundrum is exemplified by the larger relative contribution of fibrosis to the same hemodynamically defined degree of AS in women compared with men [18, 19]. Uncovering mechanisms promoting AV fibrosis has the potential to lead to the development of therapeutic interventions targeting the early stage of CAVD and may address the need for sex-specific treatment paths
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