New study backs use of blood test checks to aid diagnosis of PAH
Levels of oxygen-sensitive proteins may be useful noninvasive tools
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Low blood levels of several oxygen‐sensing molecules are found in people with pulmonary arterial hypertension (PAH), and testing for them may be a useful noninvasive tool for helping make a PAH diagnosis, according to a new study.
Specifically, levels of a protein subunit known as HIF-1alpha showed strong potential in distinguishing people with PAH from healthy individuals, while low HIF-2alpha levels were linked to higher-risk disease, the scientists noted. Several techniques can be used in a laboratory to test HIF protein levels from samples taken from a simple blood test.
HIF stands for hypoxia-inducible factor, a protein inside cells that acts like an emergency oxygen alarm system. When cells don’t get enough oxygen, it activates genes to help the body adapt.
“These markers, particularly [HIF-1alpha and HIF-2alpha], show potential for diagnostic screening and risk stratification, suggesting a systemic exhaustion of oxygen-sensing mechanisms,” the researchers wrote.
The team noted that “clinically, PAH presents with nonspecific symptoms such as [shortness of breath during physical activity], fatigue, … and [chest pain], frequently leading to delayed diagnosis and advanced disease at presentation.” Given this, “risk stratification is central to patient management and prognosis,” the researchers wrote.
Titled “Reduced Circulating HIF-1α, HIF-2α, HIF-3α, and VHL Levels in Patients With Pulmonary Arterial Hypertension,” the study was published in the journal Pulmonary Circulation by a research team in Turkey.
PAH is a form of pulmonary hypertension characterized by a narrowing of the pulmonary arteries, which transport blood in the body, making the right side of the heart work harder to pump blood.
What drives disease progression and determines the variable presentation of PAH remains unknown. But inflammation, damage to endothelial cells that line blood vessels, and abnormal growth of pulmonary artery smooth muscle cells (PASMCs) are all thought to play a role in PAH.
HIF pathway is key to several processes in body
The HIF pathway is central to these processes. HIFs are transcription factors, meaning they regulate the expression, or activity, of genes related to blood vessel formation, cellular growth and division, and survival in low-oxygen conditions.
To learn more, researchers at Necmettin Erbakan University analyzed the blood levels of three oxygen‐sensitive HIF protein subunits — HIF‐1alpha, HIF‐2alpha, and HIF‐3alpha — and their association with PAH severity and clinical measures. The study enrolled 71 PAH patients and 93 age- and sex-matched healthy controls at a single center in the country.
In more than half of the patients, the disease was idiopathic, meaning the cause is unknown. For about one-third, it was associated with congenital heart disease, and in almost 10% with a connective tissue disorder. Most patients were classified as World Health Organization functional classes 1 or 2, meaning they had no limitations or felt uncomfortable and short of breath with ordinary activities.
Clinical data confirmed precapillary PH, meaning high blood pressure that affects the pulmonary arteries before reaching the capillaries (tiny blood vessels) in the lungs, and high pulmonary vascular resistance — a measure of the resistance that must be overcome for blood to flow through the lungs.
Echocardiographic assessments, ultrasounds that create moving images of the heart, demonstrated that PAH patients had an enlarged right ventricle of the heart and impaired systolic function, related to the heart’s ability to contract and pump blood.
Compared with healthy controls, people with PAH had higher blood levels of high-sensitivity cardiac troponin T, a biomarker of heart muscle injury. Meanwhile, HIF‐1alpha, HIF‐2alpha, and HIF‐3alpha subunits were present at significantly lower levels in the PAH patients. The levels of von Hippel‐Lindau, a protein that mediates the degradation of HIF subunits, were also lower in the PAH group.
The diagnostic potential of HIF proteins was assessed with a statistical tool called area under the curve (AUC), with scores ranging from zero to one; the higher the AUC value, the better the ability to discriminate people with a given disease from those without.
Best accuracy for PAH diagnosis seen with HIF-1alpha
HIF‐1alpha showed the highest diagnostic accuracy, with an AUC of 0.891. HIF‐3alpha also showed strong diagnostic performance, with an AUC of 0.755, followed by HIF‐2alpha and VHL.
According to the researchers, it’s been reported that HIF‐1alpha production is significantly reduced in PASMCs isolated from idiopathic PAH patients compared with healthy people. This suggests that its suppression in smooth muscle cells may enhance blood-vessel tightening in the lungs and contribute to PAH development.
Additionally, HIF‐2alpha levels decreased as disease severity increased, as determined by a PAH risk assessment model. Patients classified as low–intermediate risk had significantly higher HIF‐2alpha levels than those in the intermediate-high risk category.
Finally, a subgroup analysis found no significant differences in blood levels of HIF subunits or VHL among the specific PAH causes.
These findings suggest “that the HIF pathway is generally impaired and that this imbalance may play a role in the [mechanisms] of the disease,” the researchers wrote. According to the team, further studies are needed to “better define the disease specificity, diagnostic performance, and clinical utility of these molecules as potential biomarkers in PAH.”
