Currently, for patients with pulmonary arterial hypertension (PAH), there are no prognostic biomarkers that directly measure the disease process. Risk scores such as the REVEAL score, which stratifies patients based on clinical and functional characteristics such as NYHA stage, a 6-minute walk test, and etiology, do not rely heavily on laboratory tests. Specifically, the only biomarker included in REVEAL is serum brain-type natriuretic peptide (BNP). However, BNP reflects right ventricular overload and not the underlying pathophysiology of PAH itself. Recently though, researchers have found that cell-free DNA (cfDNA) may address that gap.1
cfDNA are short bits of DNA, around 165 base pairs, that circulate in the bloodstream and are associated with cell turnover. Thus, cfDNA has become a clinically useful biomarker in tracking transplant rejection, cancer, and fetal aneuploidy: pathologies where cell-proliferation and turnover are occurring.2
In this study, the research team retrospectively analyzed serum samples from two cohorts, one from Allegheny General Hospital, and the other from Tufts Medical Center, for a total of 144 patients known to have PAH. 48 patients who were known to be without PAH and had donated blood to the NIH Clinical Center served as controls. The team examined the relationship between serum cfDNA and clinical outcomes. For cfDNA, they looked at two key features: concentration and the DNA methylation pattern, which is specific to the cell of origin. Clinical outcomes included each patients REVEAL score and transplant free survival.
For both cohorts, the median age was around 60 years old, and the median follow-up time was 2.7 years. The majority of the patients included in the study were female and had low to medium REVEAL risk scores. The most common etiologies for PAH were idiopathic and connective tissue disease. The results showed that cfDNA concentration was correlated with REVEAL score risk strata (analysis of variance P<0.002) and cfDNA concentration predicted transplant-free survival. Further, patients with the highest cfDNA tertile had a higher risk of death or transplant compared to the lowest tertile (HR, 2.5 [95% CI, 1.3-4.9]).
With these results in mind, the question of mechanism arises: what is the biology underlying this relationship? The team found that the increased cfDNA primarily originated from cells such as erythrocyte progenitors, neutrophils, cardiac myocytes, and vascular endothelial cells. These findings suggest that cfDNA may signal adaptive and destructive processes in response to PAH.
From a clinical point of view, this study indicates that cfDNA may be an effective, non-invasive measure that could be used to monitor progression and guide PAH treatment in the future.