Sex-dependent Pathophysiology and Therapeutic Considerations in Right Heart Disease

Right ventricular (RV) adaptation to the increased afterload in the setting of pulmonary hypertension (PH) and other cardiac and pulmonary vascular conditions is a major determinant of survival. Although the RV remains understudied and less well understood than the left ventricle, recent advances have been made in understanding the function and biology of the RV in health and in disease, particularly in PH. RV adaptation in PH exhibits significant sexual dimorphisms in pathophysiology, adaptation, and outcomes. Despite a higher incidence of PH, women consistently demonstrate better RV adaptation and survival rates in the setting of increased RV afterload compared with men. Sexual dimorphisms extend to therapy responsiveness, with women benefiting more from certain pulmonary vasodilators and exhibiting superior RV recovery. In this review we discuss the current literature on sexual dimorphisms in RV structure, function, and molecular pathways in health and disease, as well as in RV-specific clinical manifestations, treatments, and outcomes in PH. Sex steroid-mediated effects as well as emerging studies on sex steroid-independent effects are reviewed. In general, sex steroids such as 17β-estradiol and dehydroepiandrosterone exert RV-protective effects. In contrast, testosterone negatively impacts RV structure and function. Emerging evidence highlights the influence of nonhormonal genetic determinants, such as BMPR1A and DMRT2 loci, which are associated with better RV function in women. A better understanding of the interplay between sex hormones, genetic factors, and RV biology is crucial for advancing and developing RV-directed therapies for patients of either sex.