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Study Highlights Need for Validated Blood Biomarkers in PAH


Collecting more than 3 decades’ worth of data, researchers determined that none of the identified blood biomarkers are accurate enough to take the place of current diagnostic approaches, either due to lack of data or lack of specificity.

New findings from a meta-analysis indicate that blood biomarkers expressed in pulmonary arterial hypertension (PAH) are not reliable enough to replace current, invasive diagnostic techniques.

Collecting more than 3 decades’ worth of data, the researchers of this study determined that none of the identified blood biomarkers produce enough accuracy to take the place of current diagnostic approaches, either due to a lack of data or a lack of specificity. Their findings were published in European Respiratory Journal Open Research.

The group noted a need for further validation studies, as well as studies that assess different combination of biomarkers, because the availability of noninvasive biomarkers that facilitate a faster PAH diagnosis and, in turn, initiation of therapy, may improve survival and quality of life.

“Until now, N-terminal prohormone of brain natriuretic protein (NT-proBNP) remains the most useful clinical marker of myocardial strain and is employed for risk stratification of patients in guidelines and clinical practice,” described the researchers. “However, improved understanding of the pathways leading to PAH, which include endothelial dysfunction, immunity, and altered cellular metabolism, may result in the emergence of novel biomarkers that can detect proliferation and occlusive remodeling of the vascular wall with higher specificity.”

The current study validated the use of NT-proBNP as a biomarker with high sensitivity for PAH. However, the researchers flagged that the high sensitivity came with low specificity.

The researchers analyzed 26 biomarkers differentially expressed in PAH and non-PAH controls identified from 149 articles, most of which assessed the utility of a single biomarker. These biomarkers included hematologic biomarkers, metabolic biomarkers, coagulation markers, inflammatory markers, and renal markers. Of these biomarkers, 17 were consistently found to be related to PAH.

In addition to NT-proBNP, red cell distribution width (RDW), low-density lipid cholesterol (LDL-C), D-dimer, interleukin-6 (IL-6), and uric acid (UA) were identified as biomarkers with the biggest observed differences, largest sample size, and low risk of publication bias. Among the biomarkers, the researchers found there were insufficient data for determining the diagnostic accuracy of IL-6, RDW, LDL-C, d-dimer, and UA. All of the single biomarkers lacked specificity.

“Considering the fact that research on single biomarkers has failed to identify a single biomarker with sufficient sensitivity and specificity to foster a noninvasive PAH diagnosis, various approaches may be considered to improve noninvasive diagnostics in the future,” explained the researchers. “The first involves combining biomarkers with a strong relation to PAH pathophysiology, which have insufficient diagnostic accuracy on an individual basis; for example, implementing a panel of circulating biomarkers from several domains, weighed by importance to improve biomarker specificity.”

Other approaches outlined by the researchers included combining biomarkers with noninvasive radiological or hemodynamic measurements and an unbiased compilation of large data sets that measure multiple biomarkers that represent different disease domains in the condition.


Smits A, Botros L, Mol M, et al. A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension. ERJ Open Res. Published online May 30, 2022. doi:10.1183/23120541.00009-2022

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