Biological and Clinical Implications of Sex Differences in Right Heart Failure Associated With Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder in which right heart failure remains the leading cause of morbidity and mortality. Although PAH occurs more frequently in women, female patients consistently demonstrate superior right ventricular (RV) function, more favorable RV-pulmonary arterial coupling, and improved survival compared with men-a phenomenon commonly referred to as the sex paradox in PAH. These observations highlight the central role of biological sex in shaping RV adaptation to chronic pressure overload and underscore RV dysfunction as an independent determinant of clinical outcomes in PAH. In this brief review, we synthesize emerging clinical, translational, and experimental evidence delineating sex-specific differences in RV adaptation and maladaptation in PAH. We focus on key biological processes that exhibit pronounced sexual dimorphism, including immune and inflammatory signaling, angiogenesis and microvascular remodeling, metabolic reprogramming and mitochondrial function, and fibrotic remodeling of the pressure-overloaded RV. Accumulating data indicate that estrogen signaling confers RV protection through coordinated effects on myocardial contractility, metabolic efficiency, angiogenic capacity, and immune regulation, whereas androgens and male-predominant pathways are associated with maladaptive hypertrophy, fibrosis, and earlier RV-pulmonary artery uncoupling. Importantly, these sex-linked mechanisms help explain why reductions in pulmonary vascular resistance alone are often insufficient to prevent right heart failure and why current PAH therapies exert limited direct effects on the RV. We further discuss the clinical implications of sex differences in PAH, including their relevance for risk stratification, therapeutic response, and trial design, and highlight emerging RV-directed therapeutic strategies targeting sex hormone signaling, immune pathways, metabolism, angiogenesis, and fibrosis. We discuss how hormonal states across the lifespan (eg, pregnancy, menopause, exogenous hormone exposure, and gender-affirming care) shape clinical outcomes in PAH. Finally, we identify key knowledge gaps and future directions needed to advance sex-informed, RV-centric precision medicine approaches for PAH.