Sex Differences in Survival Among Patients With Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) presents a unique paradox in which women are significantly more likely to develop PAH, yet men with PAH experience worse survival outcomes. This phenomenon has been termed the “sex paradox” and has been the subject of extensive research. Theories for worse male survival include differences in hemodynamics, immune responses, right ventricular (RV) function, and therapy responses.
A recent study published in Journal of Heart and Lung Transplant aimed to investigate the “sex paradox” by analyzing data sourced from the Pulmonary Hypertension Association Registry (PHAR), including 1891 adult patients with PAH. Of these patients, 75% were female. Baseline evaluations revealed that women presented with more severe disease, as indicated by higher functional class, lower 6-minute walk distances, and worse health-related quality of life (HRQOL) scores. Despite presenting with more severe disease, women had a 48% lower risk of mortality than men after multivariate adjustments (HR 0.52; 95% CI, 0.36-0.74; P < 0.001).
Investigators proposed biological and hormonal differences may partially explain the paradox. They noted that RV function is a key determinant of survival in PAH, and men are hypothesized to have maladaptive RV responses to the increased afterload caused by PAH. Testosterone has been linked to adverse RV remodeling and fibrosis, while estrogen may provide protective effects on RV function.
Additionally, researchers explored collider-stratification bias as a potential explanation, a statistical phenomenon that may artificially create an associate between sex and survival by stratifying the analysis based on the presence of PAH. Men may require higher-risk causal pathways to develop PAH, which are independently associated with worse outcomes. Researchers also found that men in the cohort had a higher prevalence of risk behaviors, such as smoking and methamphetamine use. Although these factors were controlled for in the analysis, residual effects may still contribute to poorer survival. Men were also more likely to have PAH associated with high-risk conditions, such as portopulmonary PAH, while women were more likely to have connective tissue disease-associated PAH.
Further research is needed; however, this study underscores the importance of considering both biologic and epidemiologic factors when interpreting survival differences in PAH.
“While sex may be an immutable factor, a better understanding of the causal structure underlying the ‘sex paradox’ in PAH provides foundations for future research and informs investigations of hormonal-based therapies for PAH,” researchers concluded. “In the future, registries should emphasize collecting more detailed data on PAH risk factors and avoid the over-simplification of classification of PAH etiologies.”
Reference
DesJardin JT, Kime N, Kolaitis NA, et al. Investigating the ”sex paradox” in pulmonary arterial hypertension: results from the Pulmonary Hypertension Association Registry (PHAR). J Heart Lung Transplant. 2024;43(6):901-910. doi:10.1016/j.healun.2024.02.004
