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Review
. 2024 Jun 11;6(9):1125-1137.
doi: 10.1016/j.cjco.2024.06.002. eCollection 2024 Sep.

Molecular Features of Calcific Aortic Stenosis in Female and Male Patients

Emma Le Nezet  1 , Chloé Marqueze-Pouey  1 , Isabelle Guisle  1 , Marie-Annick Clavel  1
Affiliations
Review

Molecular Features of Calcific Aortic Stenosis in Female and Male Patients

Emma Le Nezet et al. CJC Open. .

Abstract
in English, French

Over the past 15 years, sex-related differences in aortic valve (AV) stenosis (AS) have been highlighted, affecting various aspects of AS, such as the pathophysiology, AV lesions, left ventricle remodelling, and outcomes. Female patients were found to present a more profibrotic pattern of leaflet remodelling and/or thickening, whereas male patients have a preponderance of calcification within stenosed leaflets. The understanding of these sex differences is still limited, owing to the underrepresentation of female patients in many basic and clinical research studies and trials. A better understanding of sex differences in the pathophysiology of AS may highlight new therapeutic targets that potentially could be sex-specific. This review aims to summarize sex-related differences in AS, as discovered from basic research experiments, covering aspects of the disease ranging from leaflet composition to signalling pathways, sex hormones, genetics and/or transcriptomics, and potential sex-adapted medical treatments.

Au cours des 15 dernières années, des différences liées au sexe dans la sténose (SA) de la valve aortique (VA) ont été mises en évidence, affectant divers aspects de la SA, tels que la pathophysiologie, les lésions de la VA, le remodelage du ventricule gauche et les pronostics associés. Il a été constaté que les patientes présentaient un patron plus profibrotique du remodelage des feuillets ou de leur épaississement, tandis que les patients de sexe masculin voyaient une prépondérance de la calcification au sein des feuillets sténosés. La compréhension de ces différences entre les sexes est encore limitée, en raison de la sous-représentation des femmes dans de nombreuses études et essais de recherche fondamentale et clinique. Une meilleure compréhension des différences entre les sexes dans la physiopathologie de la SA pourrait mettre en évidence de nouvelles cibles thérapeutiques qui pourraient être spécifiques au sexe. Cette revue vise à résumer les différences liées au sexe dans la SA, telles qu'elles ont été découvertes par des expériences de recherche fondamentale, couvrant des aspects de la maladie allant de la composition du feuillet aux voies de signalisation, aux hormones sexuelles, à la génétique ou à la transcriptomique, ainsi qu'aux traitements médicaux potentiels adaptés en fonction du sexe.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Sex-related differences observed in aortic stenosis (AS). VECs, valvular endothelial cells; VICs, valvular interstitial cells. Figure created with BioRender.com.
Figure 2
Figure 2
Pathophysiology of aortic stenosis (AS) and possible impact of sex hormones and sex differences. An endothelial lesion induces the infiltration of lipids, quickly followed by their oxidation, and inflammatory cells in the fibrosa. The renin-angiotensin-aldosterone system (RAAS) regulates valvular inflammation and seems to be anti-inflammatory in female patients through the effect of estrogen, and proinflammatory in male patients via testosterone. The transforming growth factor-β (TGF-β) pathway, upregulated in female patients, may promote the endothelial-mesenchymal transition (EndoMT) observed in AS. Valvular interstitial cells (VICs) are activated by several factors, including oxidized lipids. Their osteogenic transition seems to be inhibited by estrogen and promoted by testosterone, resulting in more calcification in stenotic aortic valves in male patients than in female patients. Moreover, the Ak strain transforming (Akt) pathway inhibits calcification in female patients, whereas the nuclear factor kappa beta (NFκB) pathway favours it through the receptor activator of nuclear factor κ B, receptor activator of nuclear factor kappa-B ligand, osteoprotegerin (RANK/RANKL/OPG) pathway in male patients. At the same time, chymase, produced by mast cells, and angiotensin-converting enzyme (ACE) induce fibrosis through the RAAS. Deposition of fibrosis is favoured by TGF-β1/β2 and wingless-related integration site (Wnt), a pathway upregulated by estrogen and potentially by testosterone. Vascular endothelial growth factor (VEGF) is an angiogenic factor secreted by male and female VICs in AS. In female patients, basic fibroblast growth factor (bFGF) also seems to promote angiogenesis. Gla, Matrix Gla protein ; ox, oxidized; PL, phospholipids; ROS, reactive oxygen species; VEC, valvular endothelial cells; VEGF, vascular endothelial growth factor; oVIC, osteoblastic VICs ; qVIC, quiescent VICs. Figure created with BioRender.com.
Figure 3
Figure 3
Sex differences in pathways involved in aortic stenosis (AS), and possible impact of sex hormones. Pathways leading to calcification and fibrosis may be modulated by sex hormones. In female patients, fibrosis markers may be increased through the renin-angiotensin-aldosterone system (RAAS), whereas in male patients, calcification markers may be upregulated. Estrogens may play a protective role in the calcification of the aortic valve by inhibiting the receptor activator of nuclear factor κ B (RANK) pathway. The Notch pathway may favour calcification processes and may be regulated by sex hormones, but no evidence has been found regarding its sex-specific regulation in AS. Several pieces of evidence show that transforming growth factor-β (TGF-β) may favour fibrosis in female patients. The wingless-related integration site (Wnt/β)-catenin pathway may favour a pro-osteogenic response in AS, but the involvement of sex hormones in its regulation needs to be clarified. ACE, angiotensin-converting enzyme; AT1R, angiotensin II type I receptor; BMP-2, bone morphogenic protein 2; IL-6, interleukine-6; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor kappa-B ligand; RUNX2, runt-related transcription factor 2; TNF-α, tumour necrosis factor alpha. Figure created with BioRender.com.
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