A Rock and a Hard Place

Article, see p 1935 Nonrheumatic aortic stenosis has assumed center stage in contemporary cardiology because of the aging of the population and the prodigious advances in percutaneous approaches to its treatment. Many refer to this disease dismissively as “degenerative”. That term implies an inevitable, ineluctably progressive, and inherent process that defies slowing or regressing. Use of the term degenerative cloaks our ignorance regarding mechanisms, much as do the designations idiopathic cardiomyopathy or essential hypertension. Yet, in step with the remarkable advances in addressing the mechanical aspects of aortic stenosis, researchers continue to stride toward better mechanistic understanding of the pathophysiology of this condition. Rather than “degenerative” aortic stenosis, we advocate use of the terms fibrocalcific or sclerocalcific aortic valve disease: nomenclature that captures the hardening of the valve tissue and its mineralization. We now recognize a number of active biological mechanisms that pave the pathway to alterations in the structure and function of the aortic valve (Figure 1).Figure 1. Multifactorial mechanisms contribute to fibrocalcific aortic valve disease. DPP-4 indicates dipeptidyl peptidase-4; and Lp(a), lipoprotein(a).A healthy aortic valve maintains its physiological functions by means of highly organized tissue architecture. The aortic valve leaflets contain 3 distinct extracellular matrix layers: a collagen-rich fibrosa, an elastin-rich ventricularis, and a spongiosa, a middle layer rich in glycosaminoglycans (Figure 2A). This trilaminar structure determines the biomechanical properties of the valve leaflets. Disease progression involves simultaneous thickening and stiffening of the valve leaflets attributable to fibrosis and the formation of calcific nodules that originate on the base of the fibrosa/aortic aspect of the leaflet (Figure 2B).Figure 2. Structure of a normal and diseased aortic valve. A , A healthy aortic valve leaflet contains valvular endothelial cells (VECs) and quiescent fibroblast-like valvular interstitial cells (VICs), and 3 distinct extracellular matrix layers: a collagen-rich fibrosa, a glycosaminoglycan-enriched …