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Higher plasma cell-free DNA tracks with worse PAH survival

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A brilliant application of an emerging biomarker

I was very excited to hear Dr. Brusca’s report on using cell-free (cf) DNA to track the severity of pulmonary artery hypertension and survival of these patients. I’m now using cfDNA frequently to monitor heart transplant patients, and the information it provides has been very valuable. But cfDNA may be even better suited to assessing patients with pulmonary artery hypertension (PAH) because it’s a vascular disease, and increases in cfDNA appears to reflect damage to the vascular endothelium. It’s a brilliant application of this technology. Brain natriuretic peptide and troponin are markers of right heart damage, but cfDNA appears to be able to track the progression of the vascular component of PAH. It appears to be the first disease-specific biomarker we have for PAH. It’s time to start routinely measuring levels of cfDNA in trials so we can gather more data on the clinical correlates of changing levels of this biomarker.

Dr. Raymond L. Benza, professor of medicine, Temple University College of Medicine and program director for advanced heart failure at the Allegheny Health Network in Pittsburgh Mitchel L. Zoler/MDedge News

Dr. Raymond L. Benza

Raymond L. Benza, MD , professor of medicine at Temple University, Philadelphia, and program director for advanced heart failure at the Allegheny Health Network in Pittsburgh, made these comments in an interview. He has been a consultant to Actelion, Gilead, and United Therapeutics, and has received research funding from Bayer.



– Cell-free (cf) DNA looked like an informative biomarker for both the severity of pulmonary artery hypertension and the survival prognosis for patients with this disease, based on results from two preliminary studies involving a total of 173 people.

Dr. Samuel B. Brusca, National Institutes of Health Clinical Center, Bethesda, Md. Mitchel L. Zoler/MDedge News

Dr. Samuel B. Brusca

“Plasma levels of cell-free DNA are elevated in patients with pulmonary artery hypertension, compared with healthy controls, and may predict disease severity and mortality,” Samuel B. Brusca, MD, said at the at the annual meeting of the American College of Cardiology.

A growing biomedical literature has documented a role for cfDNA in tracking the course of cancer, septic shock, and transplanted organs (Transplantation. 2019 Feb;103[2]:273-83) (Cell-Free DNA: Applications in Different Diseases, in “Cell-free DNA as Diagnostic Markers.” [New York: Humana Press, 2018, pp. 3-12]). Based on this background Dr. Brusca and his associates decided to examine whether plasma levels of cfDNA linked with pulmonary artery hypertension (PAH) severity and survival.

Their first study included seven patients with mild PAH (defined as patients with a tricuspid annular plane systolic excursion [TAPSE] of more than 18 mm and a maximum oxygen uptake [VO2] of at least 75% of predicted), eight with severe PAH (a TAPSE of 18 mm or less and a VO2 of less than 75%), and seven healthy adult controls. Measurement of plasma cfDNA showed an average level of 19.4 ng/mL among the healthy controls (prior reports had indicated that 10-20 ng/mL were normal levels), 22.0 ng/mL among patients with mild PAH, and 36.2 ng/mL in those with severe PAH. The level among the severe PAH patients was significantly higher than the level in controls by two different statistical tests, said Dr. Brusca, a critical care medicine physician at the National Institutes of Health Clinical Center in Bethesda, Md.

The second analysis by Dr. Brusca and his associates included 151 PAH patients followed by physicians at the Clinical Center for an average of 40 months. Their analysis tracked survival of these patients relative to their baseline levels of cfDNA and divided into tertiles. Patients in the lowest tertile had a starting cfDNA level of up to 39 ng/mL, those in the middle tertile had levels of 39.1-64.0 ng/mL, and those in the top tertile had levels of at least 64.1 ng/mL. A Kaplan-Meier analysis showed statistically significant differences in survival rates between each of the tertiles. Patients in the lowest tertile had a 5-year actuarial survival rate of about 65%, those in the middle tertile had a survival rate of about 48%, and those in the tertile with the highest level of cfDNA had a survival rate of about 28%.

Additional studies of cfDNA are needed in larger numbers of PAH patients, and cfDNA levels should be compared with levels of other, more established biomarkers, such as inflammatory cytokines, Dr. Brusca said in an interview.

Dr. Brusca had no disclosures. The study received no commercial funding.

SOURCE: Brusca SB et al. J Am Coll Cardiol. 2019 March 12;73(9 Suppl 1):1897.

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