Abstract
Vascular and cardiac valvular calcification was once considered to be a degenerative and end stage product in aging cardiovascular tissues. Over the past two decades, however, a critical mass of data has shown that cardiovascular calcification can be an active and highly regulated process. While the incidence of calcification in the coronary arteries and cardiac valves is higher in men than in age-matched women, a high index of calcification associates with increased morbidity, and mortality in both sexes. Despite the ubiquitous portending of poor outcomes in both sexes, our understanding of mechanisms of calcification under the dramatically different biological contexts of sex and hormonal milieu remains rudimentary. Understanding how the critical context of these variables inform our understanding of mechanisms of calcification—as well as innovative strategies to target it therapeutically–is essential to advancing the fields of both cardiovascular disease and fundamental mechanisms of aging. This review will explore potential sex and sex-steroid differences in the basic biological pathways associated with vascular and cardiac valvular tissue calcification, and potential strategies of pharmacological therapy to reduce or slow these processes.
Highlights
Ectopic calcification in cardiovascular tissue was once considered to be a passive consequence of cardiovascular disease processes with increasing age
The association-based clinical observations driving this model painted a remarkably appealing picture, with vascular calcification being evident in roughly 25% of patients at age of 50 years, and soaring to over 60% in patients over the age of 75 years [1]
Given clinical observations of disproportionately augmented Transforming Growth Factor-β (TGF-β) signaling and fibrosis in women [15], it is evident that the net impact of sex hormones on the molecular and phenotypic sequelae of TGF-β signaling will be paramount to the advancement of pharmacotherapies targeting valvular stenosis
Summary
Ectopic calcification in cardiovascular tissue was once considered to be a passive consequence of cardiovascular disease processes with increasing age. Given clinical observations of disproportionately augmented TGF-β signaling and fibrosis in women (which is not associated with increases in deposition of dystrophic calcific deposits) [15], it is evident that the net impact of sex hormones on the molecular and phenotypic sequelae of TGF-β signaling will be paramount to the advancement of pharmacotherapies targeting valvular stenosis These estrogenic effects are independent of the Y chromosome, as atherosclerosis, vascular calcification, and bone growth were accelerated in a man with estrogen receptor dysfunction [76]. While beyond the scope of this review [and covered recently in Sritharen et al [14]], emerging data strongly suggest that incoming risk profiles, outcomes for surgical valve replacement, outcomes for transcatheter valve replacement, and comorbid condition frequency following disease diagnosis differ robustly amongst men and women, and can serve as a critical catalyst for driving impactful investigation in the biological mechanisms underlying such observations
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