In individuals with pulmonary arterial hypertension (PAH), insulin-like growth factor binding protein 4 (IGFBP4) is a potential new circulating biomarker that is linked to disease severity and patient survival, according to findings from a cohort analysis published in Pulmonary Circulation.

With the emergence of symptoms associated with PAH frequently presenting later on in the disease course, detection of PAH in its early stages continues to be challenging. Although circulating N-terminal pro-brain natriuretic peptide is generally used clinically, use of this marker is fraught with several issues. Thus, an urgent need exists for a more specific, precise, causally related biomarker that could improve the noninvasive diagnosis and monitoring of PAH.

The researchers of the current study sought to determine the association between IGFBP4 and PAH severity, along with survival, in the following study cohorts:

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  • Johns Hopkins pulmonary hypertension (JHPH) cohort: n=127
  • National biological sample and data repository for pulmonary arterial hypertension, or PAH Biobank (PAHB) cohort: n=2579
  • Vanderbilt longitudinal (VLPH) cohort: n=127
  • Control cohort: n=90

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All serum concentrations of IGFBP4 were measured with the use of a commercially available enzyme-linked immunosorbent assay.

The JHPH cohort was considered the test cohort. This cohort comprised adults aged 18 years or older with a PAH diagnosis based on right heart catheterization. The median patient follow-up in JHPH was 4.2 years.

The PAHB cohort, which was funded by the National Heart, Lung, and Blood Institute (NHLBI), included biological samples, clinical data, and genetic data from 38 US centers. For most enrollees, hemodynamic evaluation was via right heart catheterization at diagnosis. Participants were aged 18 years or older; the median follow-up was 40.1 months. This was designated the validation cohort.

The VLPH cohort, which was also funded by the NHLBI, included biologic samples, along with clinical, genetic, and invasive hemodynamic data, among the participants. These individuals were followed longitudinally for 60 months.

Serum from the healthy control volunteers was obtained at the Johns Hopkins Pulmonary Center and Vanderbilt University Medical Center.

Median ages in the JHPH, PAHB, and VLPH cohorts were similar (62, 52, and 55 years, respectively). The sex in these 3 cohorts was primarily female (85%, 79%, and 81%, respectively). PAH subtypes were mainly idiopathic PAH (36%, 43%, and 49%, respectively) and associated PAH (64%, 48%, and 51%, respectively).

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In all cohorts evaluated, serum IGFBP4 concentrations were significantly increased in participants with PAH compared with controls (P <.0001). IGFBP4 levels were highest in those with connective tissue-associated PAH and idiopathic PAH subtypes (876 and 784 ng/mL, respectively).

Following adjustments for sex and age, IGFBP4 was significantly associated with worse PAH severity, based on 6-minute walk distance, New York Heart Association functional class, higher right atrial pressures, and REVEAL 2.0 class.

In the VLPH cohort, IGFBP4 was prospectively significantly associated with shorter based on 6-minute walk distance, worse New York Heart Association functional class, and decreased survival. In the overall PAHB cohort, IGFBP4 was shown to be an independent predictor of survival.

“This study established that higher circulating IGFBP4 levels were significantly associated with . . . disease progression in PAH,” the researchers noted. “Dysregulation of the IGF metabolism/growth axis may play a  role in PAH cardio-pulmonary pathobiology,” they concluded.


Torres G, Yang J, Griffiths M, et al. Insulin-like growth factor binding protein-4: a novel indicator of pulmonary arterial hypertension severity and survival. Pulm Circ. Published online May 3, 2023. doi:10.1002/pul2.12235