Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

Abstract

Calcific aortic valve disease (CAVD) is a common acquired valvulopathy, which carries a high burden of mortality. Chronic inflammation has been postulated as the predominant pathophysiological process underlying CAVD. So far, no effective medical therapies exist to halt the progression of CAVD. This review aims to outline the known pathways of inflammation and calcification in CAVD, focussing on the critical roles of mechanical stress and mechanosensing in the perpetuation of valvular inflammation. Following initiation of valvular inflammation, dysregulation of proinflammatory and osteoregulatory signalling pathways stimulates endothelial-mesenchymal transition of valvular endothelial cells (VECs) and differentiation of valvular interstitial cells (VICs) into active myofibroblastic and osteoblastic phenotypes, which in turn mediate valvular extracellular matrix remodelling and calcification. Mechanosensitive signalling pathways convert mechanical forces experienced by valve leaflets and circulating cells into biochemical signals and may provide the positive feedback loop that promotes acceleration of disease progression in the advanced stages of CAVD. Mechanosensing is implicated in multiple aspects of CAVD pathophysiology. The mechanosensitive RhoA/ROCK and YAP/TAZ systems are implicated in aortic valve leaflet mineralisation in response to increased substrate stiffness. Exposure of aortic valve leaflets, endothelial cells and platelets to high shear stress results in increased expression of mediators of VIC differentiation. Upregulation of the Piezo1 mechanoreceptor has been demonstrated to promote inflammation in CAVD, which normalises following transcatheter valve replacement. Genetic variants and inhibition of Notch signalling accentuate VIC responses to altered mechanical stresses. The study of mechanosensing pathways has revealed promising insights into the mechanisms that perpetuate inflammation and calcification in CAVD. Mechanotransduction of altered mechanical stresses may provide the sought-after coupling link that drives a vicious cycle of chronic inflammation in CAVD. Mechanosensing pathways may yield promising targets for therapeutic interventions and prognostic biomarkers with the potential to improve the management of CAVD.

Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling

“…Upon stress or tissue damage, VIC change their quiescent fibroblastoidal phenotype toward an activated myofibroblastoidal phenotype with higher contractility, which is indicated by an increased expression of ACTA2 ( 19 – 21 ). The term “VIC activation” used in this work thus refers to this phenomenon, and does not necessarily involve concomitant enhanced matrix remodeling as commonly described for pathological changes in CAVD (recently reviewed in ( 22 ).…”

Cellular Senescence, Aging and Non-Aging Processes in Calcified Aortic Valve Stenosis: From Bench-Side to Bedside

“…Valvular endothelium disruption may occur as a result of several aging and nonaging factors, usually as a multifactorial and complex process. Age-related (replicative) and stress-induced cellular senescence processes are discussed above, and further proinflammatory and profibrotic processes are involved in the initiation phase [ 8 , 9 , 10 , 11 , 12 , 13 ]. Even under physiological circumstances, the mechanical stress pattern caused by the blood flow over the years might initiate aortic valve sclerosis, affecting mainly the aortic side of the valve, usually beginning at the base of the leaflet [ 47 ].…”

“…On the aortic side of the normal valve, within the sinuses of Valsalva, valvular endothelial cells are exposed to “sclerosis prone” oscillatory low shear stress in systole and turbulent flow vortices in diastole. Meanwhile, cells on the ventricular side of the normal aortic valve experience “less sclerosis prone” linear high-shear stress of systolic forward laminar flow [ 9 , 48 ]. The laminar flow on the ventricular side becomes turbulent in the case of AS.…”

“…A comprehensive understanding of the initiation and progression pathways of aortic valve calcification is critical. Nonetheless, a significant proportion of elderly people have no significant AS, indicating that both aging and nonaging pathways are involved in the pathomechanism of the disease [ 8 , 9 , 10 , 11 , 12 , 13 ]. Previously, AS was thought to be a passive, degenerative process involving age-related, replicative cellular senescence [ 11 ].…”

“…Previously, AS was thought to be a passive, degenerative process involving age-related, replicative cellular senescence [ 11 ]. Now it is understood to be a complex process with active elements, including endothelial injury, chronic inflammation, fibrosis, lipid deposition, matrix remodeling and calcium deposition [ 8 , 9 , 10 , 11 , 12 , 13 ]. Current routine clinical diagnostic tools can identify only the later stages of the disease when calcification is already present [ 7 ].…”