Aortic Stenosis sexual dimorphism as a biological variable to decode the molecular mechanisms of aortic valve stenosis: The future toward sex-based precision therapies
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Abstract
Aortic valve stenosis (AVS) exhibits significant sexual dimorphism, influencing its pathophysiology, clinical presentation, and outcomes. Despite growing recognition of sex as a biological variable in cardiovascular diseases, the molecular mechanisms underlying AVS remain inadequately explored through a sex-specific lens. This paper investigates the role of sexual dimorphism in AVS by analyzing a large cohort of congenital heart disease (CHD) cases in Saudi Arabia, utilizing a comprehensive dataset of over 3 million variables. Our findings confirm a strong male predominance in AVS cases, with a male-to-female ratio of 3:1 (p=0.003), suggesting intrinsic biological differences in disease development. This paper highlights key genetic, epigenetic, and hormonal factors contributing to these disparities, including X-chromosome inactivation escape genes, Y-chromosome-linked risk factors, and sex-specific variations in valvular interstitial cell behavior. Furthermore, transcriptomic analyses reveal distinct male and female responses to fibrotic and calcific remodeling, potentially guiding future sex-based precision therapies. These insights emphasize the need to incorporate sex-specific considerations into AVS diagnosis, treatment, and therapeutic development, promoting a shift toward personalized medicine in congenital and acquired cardiovascular diseases.
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References
2. Simard L, Côté N, Dagenais F, et al. Sex-related discordance between aortic valve calcification and hemodynamic severity of aortic stenosis: is valvular fibrosis the explanation? Circ Res. 2017;120:681-691. doi:10.1161/CIRCRESAHA.116.309306
3. Voisine M, Hervault M, Shen M, et al. Age, sex, and valve phenotype differences in fibro-calcific remodeling of calcified aortic valve. J Am Heart Assoc. 2020;9:e015610. doi:10.1161/JAHA.119.015610
4. Sritharen Y, Enriquez-Sarano M, Schaff HV, Casaclang-Verzosa G, Miller JD. Pathophysiology of aortic valve stenosis: is it both fibrocalcific and sex specific? Physiology (Bethesda). 2017;32:182-196. doi:10.1152/physiol.00025.2016
5. Fuchs C, Mascherbauer J, Rosenhek R, et al. Gender differences in clinical presentation and surgical outcome of aortic stenosis. Heart. 2010;96:539-545. doi:10.1136/hrt.2009.186650
6. Ji H, Zheng W, Wu X, et al. Sex chromosome effects unmasked in angiotensin II-induced hypertension. Hypertension. 2010;55:1275-1282. doi:10.1161/hypertensionaha.109.144949
7. Pessôa BS, Slump DE, Ibrahimi K, et al. Angiotensin II type 2 receptor- and acetylcholine-mediated relaxation: essential contribution of female sex hormones and chromosomes. Hypertension. 2015;66:396-402. doi:10.1161/HYPERTENSIONAHA.115.05303
8. Hinton RB Jr, Lincoln J, Deutsch GH, et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ Res. 2006;98:1431-1438.
9. Lincoln J, Garg V. Etiology of valvular heart disease-genetic and developmental origins. Circ J. 2014;78(8):1801-1807. doi:10.1253/circj.cj-14-0510
10. McCoy CM, Nicholas DQ, Masters KS. Sex-related differences in gene expression by porcine aortic valvular interstitial cells. PLoS One. 2012;7:e39980. doi:10.1371/journal.pone.0039980
11. Masjedi S, Lei Y, Patel J, Ferdous Z. Sex-related differences in matrix remodeling and early osteogenic markers in aortic valvular interstitial cells. Heart Vessels. 2017;32:217-228. doi:10.1007/s00380-016-0909-8
12. Shah K, McCormack CE, Bradbury NA. Do you know the sex of your cells? Am J Physiol Cell Physiol. 2014;306:C3-18. doi:10.1152/ajpcell.00281.2013
13. Porras AM, McCoy CM, Masters KS. Calcific aortic valve disease: a battle of the sexes. Circ Res. 2017;120:604-606. doi:10.1161/CIRCRESAHA.117.310440
14. Tukiainen T, Villani AC, Yen A, et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017;550(7675):244-248. doi:10.1038/nature24265
15. Wainer Katsir K, Linial M. Human genes escaping X-inactivation revealed by single-cell expression data. BMC Genomics. 2019;20:201. doi:10.1186/s12864-019-5507-6
16. Charchar FJ, Bloomer LD, Barnes TA, et al. Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome. Lancet. 2012;379:915-922. doi:10.1016/S0140-6736(11)61453-0
17. Maan AA, Eales J, Akbarov A, et al. The Y chromosome: a blueprint for men’s health? Eur J Hum Genet. 2017;25:1181-1188. doi:10.1038/ejhg.2017.128
18. Witt E, Lorenz M, Völker U, et al. Sex-specific differences in the intracellular proteome of human endothelial cells from dizygotic twins. J Proteomics. 2019;201:48-56. doi:10.1016/j.jprot.2019.03.016
19. Addis R, Campesi I, Fois M, et al. Human umbilical endothelial cells (HUVECs) have a sex: characterisation of the phenotype of male and female cells. Biol Sex Differ. 2014;5:18. doi:10.1186/s13293-014-0018-2
20. Hartman RJG, Kapteijn DMC, Haitjema S, et al. Intrinsic transcriptomic sex differences in human endothelial cells at birth and in adults are associated with coronary artery disease targets. Sci Rep. 2020;10:12367. doi:10.1038/s41598-020-69451-8
21. Lorenz M, Blaschke B, Benn A, et al. Sex-specific metabolic and functional differences in human umbilical vein endothelial cells from twin pairs. Atherosclerosis. 2019;291:99-106. doi:10.1016/j.atherosclerosis.2019.10.007
22. Trexler CL, Odell AT, Jeong MY, Dowell RD, Leinwand LA. Transcriptome and functional profile of cardiac myocytes is influenced by biological sex. Circ Cardiovasc Genet. 2017;10:e001770. doi:10.1161/CIRCGENETICS.117.001770
23. Lindholm ME, Huss M, Solnestam BW, et al. The human skeletal muscle transcriptome: sex differences, alternative splicing, and tissue homogeneity assessed with RNA sequencing. FASEB J. 2014;28:4571-4581. doi:10.1096/fj.14-255000
24. Ronen D, Benvenisty N. Sex-dependent gene expression in human pluripotent stem cells. Cell Rep. 2014;8:923-932. doi:10.1016/j.celrep.2014.07.013
25. Aguado BA, Walker CJ, Grim JC, et al. Genes that escape X chromosome inactivation modulate sex differences in valve myofibroblasts. Circulation. 2022;145(7):513-530. doi:10.1161/CIRCULATIONAHA.121.054108
26. Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2009;48:143-157. doi:10.2165/00003088-200948030-00001
27. Franconi F, Brunelleschi S, Steardo L, Cuomo V. Gender differences in drug responses. Pharmacol Res. 2007;55:81-95. doi:10.1016/j.phrs.2006.11.001
28. Penaloza C, Estevez B, Orlanski S, et al. Sex of the cell dictates its response: differential gene expression and sensitivity to cell death inducing stress in male and female cells. FASEB J. 2009;23:1869-1879. doi:10.1096/fj.08-119388
29. James BD, Guerin P, Allen JB. Let’s talk about sex: biological sex is underreported in biomaterial studies. Adv Healthc Mater. 2021;10:e2001034. doi:10.1002/adhm.202001034
30. Forte E. How sex matters to aortic valves. Nat Cardiovasc Res. 2022;1:107. doi:10.1038/s44161-022-00024-w
31. Alabdulgader A. Intelligent insights for noninvasive aortic valve stenosis therapeutics. Med Res Arch. 2024;12(8). Web. 5 Nov. 2024.