Pulmonary Arterial Hypertension Studies Need to Consider Sex-Based Differences

Female doctor checks heartbeat of a senior man
In studies of pulmonary arterial hypertension, to what extent does sex/gender affect baseline values for measures such as 6MWD, hemodynamics, and functional class?

In pulmonary arterial hypertension (PAH), sex-based differences exist in common disease measures, including 6-minute walk distance (6MWD), functional class, and hemodynamics, according to study findings published in Annals of the American Thoracic Society.

Sex-based differences in measures of PAH have received little attention. Researchers therefore conducted a secondary analysis of participant-level data from randomized clinical trials (RCTs) to evaluate whether sex or gender, as reported on case report forms, is associated with baseline values of 6MWD, hemodynamics, and functional class in RCT participants with PAH. Researchers also examined whether any existing sex/gender-based associations were modified by participants’ age and body mass index (BMI).

Data from 6633 participants from 18 RCTs of investigational therapies for PAH, conducted from 1998 and 2014, were included in the study. Overall, 5197 of the patients were female (mean age, 49.1 years; mean BMI, 27.0 kg/m2) and 1436 were male (mean age, 49.7 years; mean BMI, 26.4 kg/m2). Although the most common etiology of PAH was idiopathic, female participants were less likely than male participants to be diagnosed with idiopathic PAH and more likely to have connective tissue disease PAH.

Shorter 6MWD at baseline was reported among female participants. Furthermore, f or every 1-kg/m2 increase in BMI among female participants, 6MWD decreased significantly by 2.3 meters (95% CI, 1.6-3.0; P <.0001). In contrast, 6MWD did not exhibit significant change according to BMI in male participants (decrease, 0.31 meters; 95% CI, –0.30 to 0.92; P =.32).

Additionally, compared with male participants, female participants had lower right atrial pressure (RAP) and mean pulmonary artery pressure (PAP), as well as a higher cardiac index at baseline (P <.03 for all). Age significantly altered the sex by RAP and mean PAP relationships. For each 10-year increase in age, there was a statistically significant decrease in RAP in male participants (0.5 mm Hg; 95% CI, 0.3-0.7; P <.001), but not among female participants (0.13 mm Hg; 95% CI, –0.03 to 0.28; P =.10).

A significant decrease in pulmonary vascular resistance (PVR) was reported with increasing age regardless of sex (P <.001). For every 1-kg/m2 increasein BMI, a 3% decrease in PVR was observed in male participants (P <.001), compared with a 2% decrease in PVR in female participants (P <.001).

Several limitations of the current study are notable. The conclusions extend only to participants with PAH who would have been eligible for enrollment in these RCTs. Thus, inferences could not be made about those patients who would have been excluded (ie, individuals with 6MWDs above or below threshold values, World Health Organization functional class IV patients), with scant data available on screen failures.

The researchers concluded that “Sex, age, and body size should be considered in the evaluation and interpretation of surrogates and therapeutic efficacy in PAH.”


Ventetuolo CE, Moutchia J, Baird GL, et al. Baseline sex differences in pulmonary arterial hypertension randomized clinical trials. Ann Am Thorac Soc. Published online
September 2, 2022. doi:10.1513/AnnalsATS.202203-207OC