Is Cell-Free DNA the Solution to Pulmonary Arterial Hypertension Risk Assessment?

Samuel Brusca, MD

Investigators from the National Institutes of Health (NIH) identified a novel blood test to assess the severity of disease activity in patients with pulmonary arterial hypertension (PAH), a rare lung disease.

Because of the lack of biomarkers for this condition, clinicians rely on regular subjective functional assessments and invasive hemodynamic measurements for risk assessment. With further research, cfDNA concentration could serve as a noninvasive biomarker of underlying disease activity in patients with the disease, investigators stated.

"Therefore, novel, noninvasive biomarkers of PAH disease progression remain an unmet need, particularly if such biomarkers are plausibly related to and can inform on the extent of PAH pathogenesis," investigators wrote.

Patients living with the condition have narrowed, blocked or destroyed blood vessels in the lungs, which reduces blood flow and causes high blood pressure throughout the organ. Symptoms can develop over time and become life-threatening. This research supports the utilization of the PAH-specific blood test so earlier intervention can allow for less potential disease progression.

Additionally, cfDNA measurements have the potential to add prognostic value to pulmonary arterial hypertension risk scores already being used. The ability to realiably categorize cfDNA according to tissue origin "may provide a unique, noninvasive window into pulmonary arterial hypertension pathogenesis."

Cell-Free DNA: Noninvasive Marker of Cellular Injury

Samuel Brusca, MD, Pulmonary Arterial Hypertension Section of the Critical Care Medicine Department, National Institutes of Health Clinical Center, and investigators assessed the measurements of plasma cell-free DNA (cfDNA) in patients with PAH and controls.

Patient data was collected from Allegheny General Hospital (cohort A; n=48) and Tufts Medical Center (cohort B; n=161). Healthy controls (n=48) were identified during voluntary blood donation at the NIH Clinical Center.

Patients were divided into risk groups based on their Registry to Evaluate Early and Long-Term PAH Disease Managment (REVEAL) scores: low (≤6), medium (7–8), and high (≥9). Then, total cfDNA concentration levels were compared among controls and each risk group by 1-way analysis of variance.

Predicting PAH Severity by cfDNA Concentration

Both cohorts showed that cfDNA concentrations differed among patients with PAH of varying REVEAL risk and controls. Concentrations were also greater in high-risk patients when compared with low-risk patients.

"In 2 independent pulmonary arterial hypertension patient cohorts, cfDNA concentrations increased with severity of disease and predicted transplant-free survival in the larger of the 2 cohorts," investigators wrote.

In cohort B, lung transplant or death occurred in 14 patients in the lowest cfDNA tertile (n=54), 23 in the middle tertile (n=53), and 35 in the highest tertile (n=54).

"Methylation patterns revealed increased cfDNA originating from biologically plausible sites including erythrocyte progenitor and myeloid lineage inflammatory cells, vascular endothelium, and cardiac myocytes," they reported.

Results revealed that patients in the PAH high-risk category had greater cfDNA concentrations derived from erythrocyte progenitor cells, cardiac myocytes, and vascular endothelium when compared to the PAH low-risk category.

"Circulating cfDNA is elevated in patients with PAH, correlates with disease severity, and predicts worse survival," the team concluded. "Results from cfDNA methylation analyses in patients with PAH are consistent with prevailing paradigms of disease pathogenesis."

The study, "Plasma Cell-Free DNA Predicts Survival and Maps Specific Sources of Injury in Pulmonary Arterial Hypertension" was published in Circulation.