This article has been updated to correct that Johns Hopkins patients were not participants in the study.
NEW YORK — A recently published study suggests that an experimental blood test could provide a noninvasive measurement of disease severity in patients with pulmonary arterial hypertension (PAH), a rare progressive cardiopulmonary condition.
The results of the National Institutes of Health-led study indicate that patients with more severe disease tend to have higher levels of cell-free DNA (cfDNA) originating from the same types of tissues known to be affected by the disease, suggesting a sort of map of cellular or tissue injury patterns that could enable the noninvasive monitoring of specific disease pathogenesis pathways and disease progression, the study's authors wrote.
Furthermore, cfDNA monitoring may allow for earlier recognition of pulmonary vascular remodeling and earlier therapy initiation, before the development of right ventricular dysfunction, the researchers said.
In the study, published Aug. 25 in the journal Circulation, the researchers compared cfDNA measurements among 209 adults diagnosed with PAH and 48 healthy volunteers who acted as controls, and found that higher cfDNA corresponded with more severe disease.
After analyzing 11 tissue and cell types with quantifiable cfDNA concentrations detected in most of the participating PAH patients, the authors found seven cell types were significantly elevated in PAH patients in comparison with controls. Three could be used to differentiate patients by PAH risk: erythrocyte progenitor, cardiac myocyte, and vascular endothelium cells.
Michael Solomon, a study author and codirector of the NIH Clinical Center's Pulmonary Arterial Hypertension Section, said the researchers used methylation analysis to show the elevated cfDNA concentrations in PAH patients had resulted from damage to cell types that are known to be affected by the disease.
About 1,000 people develop PAH in a typical year, two-thirds of them women, the NIH said. Most cases occur among people with no known family history of the disease.
It is characterized by progressive narrowing and blockage of the small pulmonary arteries that carry blood to the lungs, resulting in high blood pressure in those arteries, strain on the right side of the heart, and eventual death from heart failure.
PAH can be tough to identify, Solomon said. People with the disease often live with symptoms that are associated with more common conditions such as asthma, chronic obstructive pulmonary disease, or heart failure, and their illness can linger years before a correct diagnosis.
Right heart catheterization to measure pressure in the lung vessels and heart is the gold standard for PAH diagnosis and monitoring, and echocardiography can be a useful alternative. Solomon said a blood draw is easier for doctors and patients and a fitting cfDNA pattern could help doctors reach a diagnosis sooner.
Coauthor Sean Agbor-Enoh, chief of the Laboratory of Applied Precision Omics in the National Heart, Lung, and Blood Institute, said multiple companies make diagnostic platforms capable of performing the blood test. But the NIH researchers need to further validate their findings and translate the cfDNA measurements into results meaningful to clinicians.
Solomon noted that if the results are validated through large-scale trials, commercialization also would require demonstrating that the test benefits patients and could provide a return on investment.
Paul Hassoun, the director of the pulmonary hypertension program at Johns Hopkins University, said patients with PAH tend to survive less than three years without treatment and most have an advanced stage of the disease when they seek medical care. If the cfDNA assay is validated in a much larger cohort, it could become part of a panel for understanding the severity of a PAH patient's illness and whether their predicted survival would be measured in months or years.
Hassoun, who was not involved in the study, said the cfDNA assay described in the study results may be helpful in diagnosing the disease in populations at elevated risk, such as patients with scleroderma or other connective tissue diseases. But the most severe form of the disease has an unknown cause, and he doubts the test would help doctors diagnose cases earlier among a broader population unless further testing shows it can distinguish PAH from other lung diseases or other types of pulmonary hypertension.
Solomon said in response that he and Agbor-Enoh are planning studies to help address questions about distinguishing PAH from other diseases, and he would like to next study cfDNA levels and their sources across pulmonary hypertension groups.
Hassoun also noted that a figure from the NIH study also shows that cfDNA levels in the blood of some controls overlapped with levels found in high-risk PAH patients. The NIH researchers wrote in reply that many tests have such overlap, with varying degrees of sensitivity and specificity among tests.
Startups and research groups have announced this year developments toward expanding the use of cell-free DNA or RNA for other conditions including predicting pregnancy complications, identifying tumor subtypes, and detecting stem cell transplant complications as well as in developing equipment to enhance cfDNA collection.