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Development of calcific aortic valve disease: Do we know enough for new clinical trials?
- Source :
-
Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2019 Jul; Vol. 132, pp. 189-209. Date of Electronic Publication: 2019 May 25. - Publication Year :
- 2019
-
Abstract
- Calcific aortic valve disease (CAVD), previously thought to represent a passive degeneration of the valvular extracellular matrix (VECM), is now regarded as an intricate multistage disorder with sequential yet intertangled and interacting underlying processes. Endothelial dysfunction and injury, initiated by disturbed blood flow and metabolic disorders, lead to the deposition of low-density lipoprotein cholesterol in the VECM further provoking macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines. Such changes in the valvular homeostasis induce differentiation of normally quiescent valvular interstitial cells (VICs) into synthetically active myofibroblasts producing excessive quantities of the VECM and proteins responsible for its remodeling. As a result of constantly ongoing degradation and re-deposition, VECM becomes disorganised and rigid, additionally potentiating myofibroblastic differentiation of VICs and worsening adaptation of the valve to the blood flow. Moreover, disrupted and excessively vascularised VECM is susceptible to the dystrophic calcification caused by calcium and phosphate precipitating on damaged collagen fibers and concurrently accompanied by osteogenic differentiation of VICs. Being combined, passive calcification and biomineralisation synergistically induce ossification of the aortic valve ultimately resulting in its mechanical incompetence requiring surgical replacement. Unfortunately, multiple attempts have failed to find an efficient conservative treatment of CAVD; however, therapeutic regimens and clinical settings have also been far from the optimal. In this review, we focused on interactions and transitions between aforementioned mechanisms demarcating ascending stages of CAVD, suggesting a predisposing condition (bicuspid aortic valve) and drug combination (lipid-lowering drugs combined with angiotensin II antagonists and cytokine inhibitors) for the further testing in both preclinical and clinical trials.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Aortic Valve physiopathology
Aortic Valve Stenosis complications
Calcinosis complications
Heart Valve Diseases etiology
Humans
Aortic Valve pathology
Aortic Valve Stenosis physiopathology
Calcinosis physiopathology
Clinical Trials as Topic
Heart Valve Diseases pathology
Heart Valve Diseases therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1095-8584
- Volume :
- 132
- Database :
- MEDLINE
- Journal :
- Journal of molecular and cellular cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 31136747
- Full Text :
- https://doi.org/10.1016/j.yjmcc.2019.05.016