Circulating HMGB1 Not a Reliable Biomarker in Pediatric PAH

Circulating levels of the protein high mobility group box-1 (HMGB1) are not associated with pulmonary arterial hypertension (PAH) in children with congenital heart disease, according to a new report.

The findings differ from those of a similar analysis conducted among adult patients with congenital heart disease. The new report suggests that while HMGB1 might be a meaningful biomarker for adults, the same does not appear to be true in children. The report was published in the Journal of Cardiothoracic and Vascular Anesthesia.

Clinician taking child's blood pressure | image credit: ALEXSTUDIO - stock.adobe.com

Though PAH is a life-threatening condition at any age, it is a particularly grim diagnosis for children, as the 5-year mortality rate for pediatric patients is approximately 30%, noted corresponding author Katherine Taylor, MD, PhD, of the Hospital for Sick Children, and colleagues.¹ PAH in children is often linked with congenital heart disease, but the authors said correcting the underlying heart condition does not always stop the development of PAH.

“Our incomplete understanding of the pathogenesis of this clinical entity has limited our ability to devise transformational therapies,” they wrote.

Making matters worse, it can be more difficult to diagnose PAH in children, due in part to the invasive nature of right heart catheterization.

“Given the relatively poor reliability of non-invasive measurement (transthoracic echocardiography), there is a focus on defining novel noninvasive tests for diagnosis of PAH or to at least risk stratify and minimize the number of patients being sent for invasive pressure measurement,” the investigators wrote.

A reliable circulating biomarker could thus be a valuable tool, Taylor and colleagues noted. So far, circulating N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and baseline uric acid have both have both been identified as being associated with survival in pediatric PAH, but they said neither is a great biomarker for PAH because each can also be elevated in other diseases.

HMGB1 has been suspected as playing a role in the pathogenesis of PAH, and a 2016 study of 106 adults with congenital heart disease found that patients with PAH had higher serum levels of the protein.² That study further found that 6 months of therapy with sildenafil led to a decrease in HMGB1.

Those findings, along with the apparent role of HMGB1 in the pathogenesis of the disease, led Taylor and colleagues to seek to assess the potential of HMGB1 as a biomarker of PAH secondary to congenital heart disease in pediatric patients. The investigators created a prospective cohort of children under the age of 18 years who had congenital heart disease and who were undergoing right heart catheterization (or right and left heart catheterization) as part of their routine clinical care.¹ Plasma samples were analyzed from the patients, and data such as age, pulmonary vascular resistance (PVR), cardiac output, and mean arterial pressure were collected. Patients with infections, cancers, or other conditions associated with HMGB1 release were excluded.

A total of 74 patients agreed to participate, and plasma samples were obtained from 67 of those participants, the authors said. The authors also recruited a control group, from which biomarkers alone were measured.

Participants with PAH had a mean PVR of 10 Wood units/m², the authors found. However, neither HGMB1 nor NT-proBNP levels differed significantly between any of the groups. NT-proBNP was highest in patients with congenital heart disease without PAH (mean of 134.5 pg/mL compared to 114.5 pg/mL in patients with PAH secondary to congenital heart disease; in the control group the mean was 69.2 pg/mL). HMGB1 levels were similar in all 3 groups, they found.

“Our work did not demonstrate the use of HMGB1 as a biomarker in our population,” the investigators said. “This lack of link was seen despite patients with severe disease in our cohort.”

The authors said one limitation of their study is the relatively small sample size, but they noted that the rarity of the disease in children makes it difficult to study. Despite the failure to identify a biomarker in this investigation, they said work should continue to examine possible other biomarkers.

References:

1. Caracci B, Pehora C, Benson L, Steinberg BE, Goldenberg NM, Taylor K. Circulating high mobility group box-1 does not predict pulmonary arterial hypertension in children with congenital heart disease: a prospective cohort study. J Cardiothorac Vasc Anesth. Published online July 11, 2024. doi:10.1053/j.jvca.2024.07.020
2. Huang YY, Su W, Zhu ZW, et al. Elevated serum HMGB1 in pulmonary arterial hypertension secondary to congenital heart disease. Vascul Pharmacol. 2016;85:66-72. doi:10.1016/j.vph.2016.08.009