Levels of circulating cell-free DNA are higher in patients with pulmonary arterial hypertension (PAH), a new study published in Circulation found. These levels also correlate with the severity of disease and can predict survival.

The significance of cell-free DNA, a marker of cellular injury, was not yet known in PAH. 

Here, a team of researchers led by Sean Agbor-Enoh, MD, PhD, and Michael A. Solomon, MD, MBA, from the National Heart, Lung, and Blood Institute and the National Institutes of Health Clinical Center, respectively, in Bethesda, Maryland, measured plasma levels of cell-free DNA in patients with PAH and healthy controls. 

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The patients were divided into 3 groups based on their Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) scores. According to this system, patients with a score of 6 or less were grouped as low risk, those with a score of 7 to 8 were classified as medium risk, and those with a score of 9 or more were considered high risk. 

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The researchers calculated that the concentration of cell-free DNA differed among PAH patients with varying REVEAL scores and healthy controls. Moreover, the cell-free DNA concentration was higher in high-risk patients than in low-risk patients.

The researchers also found that death or lung transplant occurred in 26% of patients with the lowest cell-free DNA concentration tertiles, 43% of patients with mid-level tertiles, and 65% of patients with the highest tertiles. 

Cell-free DNA levels stratified as tertiles and REVEAL risk groups could predict transplant-free survival. Adding cell-free DNA levels to REVEAL scores improved discrimination. 

Researchers also conducted cell-specific cell-free DNA methylation analyses for some patients. These analyses showed there was more cell-free DNA originating from erythrocyte progenitors, neutrophils, monocytes, adipocytes, natural killer cells, vascular endothelium, and cardiac myocytes in patients with PAH than in controls. 

Moreover, cell-free DNA concentrations derived from erythrocyte progenitors, cardiac myocytes, and vascular endothelium were higher in PAH patients who had a high REVEAL score than in those with a low REVEAL score.

These results “are consistent with prevailing paradigms of disease pathogenesis,” the researchers said.


Brusca SB, Elinoff JM, Zou Y, et al. Plasma cell-free DNA predicts survival and maps specific sources of injury in pulmonary arterial hypertension. Circulation. Published online August 25, 2022. doi:10.1161/CIRCULATIONAHA.121.056719