New protein marker may improve diagnosis, prognosis in iPAH
Blood NOTCH3 levels ID condition with over 90% accuracy in study
A part of NOTCH3, a protein involved in disease-related alterations in blood vessels, may be a biomarker of idiopathic pulmonary arterial hypertension (iPAH), a rare type of pulmonary hypertension (PH) that’s hard to diagnose, a recent study suggests.
The researchers found that blood levels of the extracellular, or outside-the-cell, part of this protein — which they dubbed NOTCH3-ECD — were increased in people with iPAH and associated with more severe disease and lower three-year survival rates. Further, taking into account the NOTCH3-ECD levels made existing risk stratification models, which take into account various clinical, laboratory, and imaging parameters, better at estimating PAH prognosis, the scientists noted.
The results suggest that NOTCH3-ECD could be used to improve both the diagnosis and prognosis of iPAH among patients.
In fact, according to the team, an accuracy rate of more than 95% — with similar accuracy in men and women — was found for individuals with protein levels above a certain cutoff.
“Widespread clinical adoption of NOTCH3-ECD testing has the future potential to transform the iPAH diagnosis and management landscape, enabling possibly earlier treatment and improved outcomes,” the researchers wrote.
The study, “The NOTCH3 extracellular domain is a serum biomarker for pulmonary arterial hypertension,” was published in the journal Nature Medicine.
PAH is characterized by narrowing of the pulmonary arteries, which are the blood vessels that transport blood through the lungs. It is driven by vascular remodeling, or the excessive growth of vascular smooth muscle cells that line blood vessels. This restricts blood flow through the lungs, causing high blood pressure, or hypertension, and making the right side of the heart work harder to pump blood across the lungs.
The protein receptor NOTCH3 is present in vascular smooth muscle cells. Because individuals with iPAH have high levels of the protein, it is thought to play a role in the disease’s development.
Upon binding to a specific molecule at the cell membrane, NOTCH3 splits. While several studies have focused on the part of the protein that sits inside the cell, “little is known about the fate of NOTCH3-ECD after … cleavage,” or that splitting, the scientists wrote.
Does NOTCH-ECD work as a biomarker? Study says yes.
Here, researchers investigated whether NOTCH3-ECD could be used as an iPAH biomarker. Their work involved 341 iPAH patients and 376 healthy individuals from three U.S. regions: San Diego, Phoenix, and Boston. The patients’ mean age was 52.7, and most (78%) were women.
The mean blood levels of NOTCH3-ECD were significantly greater among individuals with iPAH than in those without the disease — 19.9 versus 1.9 nanograms (ng)/mL. High protein levels were significantly associated with higher pulmonary arterial pressure and right atrial pressure, or the right heart’s filling pressure. They were also significantly linked to pulmonary vascular resistance, a measure of how hard it is for the heart to pump blood.
Higher blood NOTCH3-ECD levels were also associated with worse exercise capacity, assessed by the distance walked in six minutes, and higher blood levels of NT-proBNP, a marker of heart damage.
Additionally, increased NOTCH3-ECD levels were linked with higher disease severity, measured by the New York Heart Association classification system.
The blood levels of NOTCH3-ECD effectively differentiated individuals with iPAH from healthy controls, the researchers noted. In fact, levels higher than a 13 ng/mL cutoff meant an accuracy of 96%, with accuracy similar regardless of the patients’ sex.
In this study, the diagnostic value of NOTCH3-ECD was more robust than that of blood NT-proBNP, another often-used measure, according to the researchers.
NOTCH3-ECD levels were specifically elevated in people with iPAH, but not in those with other types of PH, including heritable PAH, which is caused by gene mutations.
iPAH diagnosis 95% accurate in analysis of newly diagnosed patients
During a three-year follow-up, 102 patients died, and 10 received a lung or heart and lung transplant. Those with NOTCH3-ECD levels higher than 13 ng/mL were 3.3 times more likely to die, and 3.7 times more likely to die or undergo a lung transplant.
After adjusting for patients’ age, sex, and iPAH prognostic factors, the risk of three-year mortality increased by 18% for each 3 ng/mL of NOTCH3-ECD above the cutoff.
The [blood] NOTCH3-ECD biomarker test represents an advance toward overcoming barriers in effectively screening, monitoring and risk-stratifying individuals with [iPAH].
In a separate analysis of 100 newly diagnosed patients who had not been treated for iPAH, the levels of NOTCH3-ECD enabled disease diagnosis with 95% accuracy at the same 13 ng/mL cutoff value.
During approximately six years of follow-up, NOTCH3-ECD was also significantly associated with disease progression and with measures of disease severity.
According to the researchers, “the [blood] NOTCH3-ECD biomarker test represents an advance toward overcoming barriers in effectively screening, monitoring and risk-stratifying individuals with [iPAH].”
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