Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease with an increasing global burden. Although hemolytic disorders are established causes of PAH, their contribution to the global PAH burden remains unclear. This study aimed to evaluate the association between hemolysis-associated disorders and PAH incidence and to identify the relative contribution of hemolytic disorder subtypes compared with socio-demographic factors.
Using Global Burden of Disease 2021 data, temporal trends in the age-standardized incidence rate (ASIR) of PAH were analyzed using Joinpoint regression. Pearson correlation analysis assessed associations between PAH ASIR and the age-standardized prevalence rates of hemolytic disorder subtypes, hemolysis-related infections, malnutrition, and the Socio-demographic Index (SDI). Random forest regression was used to quantify the contributions of hemolytic disorders to PAH ASIR. Geographic distributions of PAH incidence and hemolytic disorder prevalence were compared, and Bayesian age-period-cohort modeling was used to project their burdens through 2050.
Global PAH ASIR increased from 0.50 to 0.52 per 100,000 from 1990 to 2021. The prevalence of hemoglobinopathies and hemolytic anemias correlated positively with PAH ASIR (R = 0.61, P = 7.70 × 10 -22 ). The random forest model explained 73% of the variance in PAH ASIR (R² = 0.73, P = 0.01), with G6PD trait (percentage increase in mean squared error [%IncMSE]: 18.43), other hemoglobinopathies/hemolytic anemias of unknown etiology (%IncMSE: 18.38), and vitamin A deficiency (%IncMSE: 17.27) identified as the top predictors, surpassing SDI (%IncMSE: 13.25) and sex (%IncMSE: 1.25). Temporal changes in hemolytic disorder prevalence strongly mirrored changes in PAH incidence (R = 0.76, P = 6.34 × 10 -39 ). Exploratory analyses suggested that natural product exposures may contribute to the unexplained hemolytic burden that drives PAH. Projections indicated a continued rise through 2050 in both PAH burden (ASIR increasing from 0.52 in 2022 to 0.57 per 100,000) and hemolytic disease burden (prevalence rising from 27,760.54 to 31,863.72 per 100,000).
This ecological study of 204 countries and territories identified hemolysis-associated disorders as major drivers of the escalating global PAH burden. G6PD trait, other hemoglobinopathies/hemolytic anemias of unknown etiology, and vitamin A deficiency were the predominant contributors to PAH incidence, exceeding the impact of SDI and sex. Furthermore, given the projected continued rise in hemolytic disorder prevalence through 2050, these conditions are expected to persistently exacerbate the global PAH burden. These findings highlight hemolytic disorders as a critical, underrecognized driver of PAH that requires prioritized attention in global health policy.
Full text:
https://www.xiahepublishing.com/2835-6357/FIM-2026-00004
The study was recently published in the Future Integrative Medicine .
Future Integrative Medicine (FIM) is the official scientific journal of the Capital Medical University. It is a prominent new journal that promotes future innovation in medicine.It publishes both basic and clinical research, including but not limited to randomized controlled trials, intervention studies, cohort studies, observational studies, qualitative and mixed method studies, animal studies, and systematic reviews.
Follow us on X: @xiahepublishing
Follow us on LinkedIn: Xia & He Publishing Inc.
Future Integrative Medicine
Hemolysis-associated Disorder and Natural Product Exposures: Underrecognized Drivers of an Escalating Global Pulmonary Arterial Hypertension Burden—An Ecological Study of 204 Countries and Territories
18-Jun-2026