The levels of certain metabolites — molecules that take part in metabolism — circulating in the blood may help differentiate pulmonary arterial hypertension (PAH) due to scleroderma (SSc-PAH) from idiopathic PAH, a new study shows.
The “metabolic signature” correlated with worse disease severity in PAH tied to SSc.
“Taken together, these findings provide molecular insights into the heterogeneity that is consistently seen across PAH subgroups — and offer viable directions for further investigation of mechanisms underlying the worse prognosis and response to therapy seen in patients with SSc-PAH,” the scientists wrote.
The study “Metabolomic Profiles Differentiate Scleroderma-PAH from Idiopathic PAH and Correspond with Worsened Functional Capacity” was published in CHEST.
PAH is marked by the narrowing of small blood vessels, called pulmonary arteries, that transport blood through the lungs. It can be associated with a connective tissue disease, such as scleroderma. People with SSc-PAH have worse prognosis and response to therapies than those with other forms of PAH.
Heightened inflammation, self-directed immune attacks, and differences in blood vessel damage have been proposed as possible causes for this variation. Metabolic impairment has been suggested as an explanation. Which metabolites may underlie differences between SSc-PAH and other types of PAH remain unknown, however.
Unveiling these mechanisms, “could accelerate the development of more effective approaches to managing and treating this especially challenging PAH subtype [SSc-PAH],” the scientists wrote.
Researchers in the US and China used a technique called liquid chromatography-high resolution mass spectrometry (LC-MS) to profile the metabolites in samples of plasma, the clear, liquid part of blood.
They first analyzed 310 patients with SSc and PAH (mean age 64; 86.1% women) and 864 idiopathic PAH (IPAH) patients (age 51.9; 76.7% women) who made up a discovery group.
The LC-MS analysis revealed, after adjusting for age, sex and body mass index (BMI, a measure of body fat), that the circulating levels of nine metabolites were able to differentiate between SSc-PAH and IPAH. These were linked with fatty acid oxidation, metabolism of eicosanoids (derivatives of polyunsaturated fatty acids), and sex hormones.
The metabolites remained significantly able to distinguish SSc-PAH from IPAH after adjusting for patients’ exercise capacity on the 6-minute walking distance test (6MWD).
The researchers then confirmed the metabolites’ diagnostic potential in a second group, called the validation group, which included 91 SSc-PAH patients (mean age 63.7; 90.1% women) and 213 IPAH patients (age 53.2; 77.9% women).
This “metabolic signature” was able to differentiate SSc-PAH from IPAH with an 85.5% accuracy.
To understand if this group of metabolites was specific to SSc, the team next compared the levels of these nine metabolites in 44 SSC-PAH patients (38 women) to 100 SSc patients without PAH (87 women).
The researchers found that levels of five metabolites were significantly elevated in SSc-PAH versus SSc participants without PAH.
These findings suggest that the altered metabolites “are specific to the condition of SSc-PAH and not the presence of SSc alone,” the researchers wrote.
The research team also analyzed if these five metabolites were related to functional capacity and PAH severity in 58 patients (including 18 with SSc-PAH).
Functional capacity was assessed with the 6MWD and disease severity with the World Health Organization functional classification (WHO-FC, the higher the classification, the worse the patient’s condition). Right atrial pressure — the blood pressure in the upper right chamber of the heart — and cardiac index (how much blood is pumped by the heart in one minute taking into account body size) were also assessed.
All five metabolites were linked to at least one marker of PAH severity when combining the SSc-PAH and IPAH groups, and three were associated with at least one marker of disease severity in SSc-PAH. Elevated levels of two metabolites (17-beta-estradiol and nervonic acid) were linked with poorer exercise capacity, as measured by the 6MWD, in the SSc-PAH group, in particular.
These findings suggest that “SSc-PAH is characterized by significant metabolomic alterations that associate with markers of disease severity which may explain accelerated disease course and contribute to poor response to therapy compared to IPAH,” the researchers wrote, noting their “observations now offer a more comprehensive metabolic guide to much needed diagnostic, prognostic, and therapeutic strategies of precision medicine in SSc-PAH patients.”