Metabolites Can Help Identify PAH Linked to Systemic Sclerosis: Study

9 molecules in metabolism can tell scleroderma-PAH from IPAH

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

Share this article:

Share article via email
systemic sclerosis pulmonary arterial hypertension | Pulmonary Hypertension News | illustration of blood in test tubes and syringe

A new study has found that there are nine metabolites — molecules that take part in metabolism — in the blood that can tell pulmonary arterial hypertension (PAH) linked to systemic sclerosis from idiopathic PAH, the label given when the disease is due to an unknown cause.

Researchers also observed that some of these metabolites were associated with worse disease in patients with PAH tied to systemic sclerosis.

These findings “offer a more comprehensive metabolic guide to much needed diagnostic, prognostic, and therapeutic strategies of precision medicine” in patients with systemic sclerosis-PAH (or SSc-PAH), the researchers wrote.

“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 team wrote.

The study, “Metabolomic profiles differentiate scleroderma-PAH from idiopathic PAH and correspond with worsened functional capacity,” was published in the journal Chest.

Recommended Reading
pulmonary hypertension types | Pulmonary Hypertension News | causes of death | illustration of woman with megaphone

Leading Causes of Death Differ by PH Type, Study Shows

Investigating systemic sclerosis in PAH

PAH occurs when there is high blood pressure in the blood vessels, called the pulmonary arteries, that supply the lungs. Sometimes, the reason why blood pressure rises is unknown. When this happens, it is called idiopathic PAH.

In other cases, the cause is well-known.

Systemic sclerosis, also known as scleroderma, results in hardened, thickened skin and problems with blood vessels and internal organs. When the pulmonary arteries are affected, PAH may occur.

Patients with PAH linked to systemic sclerosis have a worse prognosis than those with idiopathic PAH — meaning they will have worse symptoms over time. They also respond less well to treatment.

While the exact reason behind these differences is unclear, changes in metabolism — the collection of chemical reactions that take place in cells — may play a role.

Now, a team of researchers in the U.S. and China investigated whether any circulating metabolite, or metabolites, could help doctors distinguish PAH linked to systemic sclerosis from idiopathic PAH. The researchers focused on lipid (fat) molecules that are involved in many processes related to blood vessels and inflammation.

According to the scientists, finding such a “metabolic signature” could help in “guiding the development and tailoring of more effective management strategies.”

Their study included 310 patients — 267 of them women — with systemic sclerosis and PAH. The mean age of these patients was 64.1.

Another 864 patients with idiopathic PAH also were involved in the study. Among them were 663 women.

Overall, the idiopathic PAH patients were a mean of 12.2 years younger than those with systemic sclerosis and PAH, which was a statistically significant difference. Notably, however, the mean pulmonary arterial pressure of the iPAH patients was significantly higher — 50.8 vs. 43.3 millimeters of mercury.

Recommended Reading
case study, PAH, systemic sclerosis

PAH Caused by Undiagnosed Systemic Sclerosis in Case Study

Nine key metabolites identified

The researchers sampled the participants’ plasma, which is the clear, liquid part of blood, and compared the levels of more than 700 metabolites between the samples. To do this, they used liquid chromatography, which allows separation of a mixture of molecules, and mass spectrometry, which identifies molecules based on their mass (weight) and charge.

After taking some factors into account, such as age, use of medication, and walking distance on a six-minute walking distance (6MWD) test, the team found significant differences in nine metabolites. Seven were present at higher levels in the plasma of patients with PAH linked to systemic sclerosis than they were in individuals with idiopathic PAH; the other two were at lower levels.

These nine metabolites included lipid molecules involved in fatty acid oxidation, the metabolism of eicosanoids (derivatives of polyunsaturated fatty acids), and sex hormones. Used together, they were 85.5% accurate in telling PAH linked to systemic sclerosis from idiopathic PAH.

The findings continued to hold true when the researchers compared two other groups of patients: one group of 91 patients (82 women) with PAH linked to systemic sclerosis, and one group of 213 patients (133 women) with idiopathic PAH.

To ensure these nine metabolites were specific to PAH occurring in people with systemic sclerosis, the researchers watched for changes in their levels in yet two other groups of patients. In one group there were 100 patients (87 women) with systemic sclerosis but no PAH, and in the other group there were 44 patients (38 women) with both systemic sclerosis and PAH.

The levels of five of the nine metabolites were higher in the systemic sclerosis with PAH group than in patients who did not have PAH. This means that these metabolites are linked to PAH “and not simply [due] to the presence of scleroderma itself,” the researchers wrote.

Most of the metabolites were linked to at least one marker of disease severity in systemic sclerosis with PAH. For example, higher levels of nervonic acid and 17-beta-estradiol were linked to a shorter distance in the 6MWD test.

“These data provide important metabolic insights into the molecular heterogeneity underlying differences between subgroups of PAH,” the researchers concluded.

The findings also “offer viable directions for further investigation of mechanisms underlying the worse prognosis and response to therapy seen in patients with [PAH linked to systemic sclerosis],” they wrote.