The Complex Interplay of Inflammation, Metabolism, Epigenetics, and Sex in Calcific Disease of the Aortic Valve

Abstract

Calcification of the aortic valve is one of the most rapidly increasing pathologies in the aging population worldwide. Traditionally associated to cardiovascular risk conditions, this pathology is still relatively unaddressed on a molecular/cellular standpoint and there are no available treatments to retard its progression unless valve substitution. In this review, we will describe some of the most involved inflammatory players, the metabolic changes that may be responsible of epigenetic modifications and the gender-related differences in the onset of the disease. A better understanding of these aspects and their integration into a unique pathophysiology context is relevant to improve current therapies and patients management.

Global burden of calcific aortic valve disease and attributable risk factors from 1990 to 2019

“…Once an estimate told that the hazard of AS increases by 75% for each decade increase in age ( 20 ). As life expectancy remains increasing, inevitably, the burden of AS is anticipated to surge ( 21 ). Globally, male individuals were more likely to suffer from CAVD than female individuals with higher prevalence cases, death cases, DALYs, and corresponding age-standardized rates ( 6 ).…”

“…Moreover, female individuals tended to present more fibrotic remodeling and less calcification than male individuals ( 22 ). Meanwhile, female individuals showed a more advanced age of onset of the disease ( 21 ). Studies focused on sex-specific features implied that the progression, pathophysiology, and hemodynamic severity of aortic valve calcification varied in males and females ( 23 – 25 ).…”

“…Meanwhile, it may cause faster and more abrupt closing of the aortic valve leading to the increase of tensile stress in early diastole ( 31 , 33 ). All these mechanical stresses may damage endothelial cells of valve leaflets resulting in inflammatory activation and the infiltration of lipids ( 1 , 17 , 21 , 31 ). Furthermore, a study consisting of 737 elder patients manifested that after adjustment for atherosclerosis-related risk factors, only ambulatory mean diastolic blood pressure (DBP) displayed a significant association with advanced AVC independently, which suggests that DBP may play a more important role in the early stage of CAVD than SBP ( 19 ).…”

“…Although the exact mechanism and pathophysiology of CAVD are still not clear, the existing research demonstrates that it is a series of the chronic progression of endothelium damage, lipid infiltration and oxidation, chronic inflammation, and finally fibrosis and biomineralization ( 1 , 6 , 17 , 21 , 35 , 36 ). In this study, we found some relevant exposure factors related to the burden of CAVD, which may provide some ideas and orientations for prevention.…”

VLA4-Enhanced Allogeneic Endothelial Progenitor Cell-Based Therapy Preserves the Aortic Valve Function in a Mouse Model of Dyslipidemia and Diabetes

“…The development of new therapies for AVS has been impeded by a limited understanding of the complex mechanisms driving CAVD initiation and progression towards clinically relevant interventions. One of the first events triggering CAVD is the damage of the endothelium on both sides of the valve leaflets, resulting from local alterations of blood shear stress [ 6 ]. It has recently been shown that the valvular endothelial cells (VECs) and valvular interstitial cells (VICs) cultured in a gelatin methacrylate 3D construct and exposed to high glucose conditions presented increased expressions of various cytokines, cell adhesion molecules and matrix metalloproteinases, with a rapid and strong response in VECs, while in VICs the chronic inflammation developed and persisted longer [ 7 ].…”