Tricuspid Remodeling: Sex-Dependent Mechanobiological Mechanisms and Pharmacological Treatment

Tricuspid regurgitation (TR) affects an estimated 1.6 million Americans and is associated with substantial morbidity and mortality. Although traditionally considered a secondary consequence of right heart dysfunction, increasing evidence demonstrates that the tricuspid valve itself actively remodels during disease. This maladaptive remodeling, characterized by leaflet thickening, stiffening, and extracellular matrix reorganization, contributes to progressive valve dysfunction. Importantly, both clinical and experimental studies demonstrate that disease progression and valve remodeling differ across sexes. The biological mechanisms responsible for these sex-dependent differences, however, remain poorly understood. Tricuspid valve interstitial cells (tVICs) are the primary regulators of valve remodeling and respond to pathological environments by activating profibrotic signaling pathways, including Transforming Growth Factor-β (TGF-β). In contrast, Interferon (IFN) signaling has been implicated as an inhibitory pathway of profibrotic activation. Together, these opposing signaling pathways represent promising therapeutic targets for reducing tVIC activation and maladaptive valve remodeling; however, their interaction across sexes is unclear. Given the limited pharmacological options currently available for TR, defining the therapeutic potential of these pathways across sexes could identify new strategies to limit disease progression. The objective of this fellowship is to determine how biological sex influences tVIC profibrotic activation and pharmacological response, and whether these mechanisms translate to sex-dependent valve remodeling in vivo. In Aim 1, male- and female-derived human tVICs will be subjected to pathological environments to define how biological sex regulates profibrotic activation and therapeutic responsiveness in vitro. In Aim 2, these findings will be translated to a rat model of functional TR to determine how biological sex influences valve remodeling, biomechanics, transcriptomic remodeling, and treatment response in vivo. The proposed study will establish mechanistic links between biological sex, profibrotic signaling, and therapeutic effectiveness in the context of TR. By identifying mechanisms that underlie sex-dependent disease progression and therapeutic response, this work will provide a foundation for the development of precision, sex-informed therapies for patients with functional TR.