A collagen-based laboratory model to mimic sex-specific features of calcific aortic valve disease

Calcific aortic valve disease (CAVD) shows in the deposition of calcium phosphates in the collagen-rich layer of the valve leaflets. This stiffens the leaflets and eventually leads to heart failure. Recent research suggests that CAVD follows sex-specific pathways: at the same severity of the disease, women tend to have fewer and less crystalline calcifications, and the phases of their calcifications are decidedly different than those of men; namely, dicalcium phosphate dihydrate (DCPD) - one of the mineral phases in CAVD - occurs almost exclusively in females. Furthermore, the morphologies of heart valve calcifications might be sex-specific, but the sex dependence of the morphologies has not been systematically investigated. Herein, we first show that male CAVD patients have more compact and less fibrous calcifications than females, establishing sex-dependent morphological features of heart valve calcification. We then build a model that recapitulates the sex differences of the calcifications in CAVD, which is based on a collagen gel that we calcify in simulated body fluid with varying fetuin A concentrations. With increasing fetuin A concentration, the calcifications become less crystalline and more fibrous, and more DCPD deposits in the collagen matrix, resembling the physicochemical characteristics of the calcifications in female valves. Lower fetuin A concentrations give rise to a model that replicates male-specific mineral characteristics. The models could be used to develop sex-specific detection and treatment methods for CAVD. STATEMENT OF SIGNIFICANCE: Although calcific aortic valve disease (CAVD) affects ∼10 million people globally, researchers have only discovered recently that the disease follows sex-specific pathways, and many of its sex-specific features remain unknown. To further our understanding of sex differences in CAVD and to develop better detection and treatment methods, there is an urgent need to establish models for CAVD that account for its sex-specific manifestations. In this study, we first show that CAVD calcifications in men and women take on different morphologies. Second, we present a model that can replicate physicochemical calcification characteristics of male or female valves, including morphology, and that can help to develop sex-specific detection and treatment methods for CAVD.