, based on data from approximately 1,500 individuals.
The overall prognosis and therapeutic response for patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH) tends to be worse than for patients with other types of PAH, such as idiopathic pulmonary arterial hypertension (IPAH), but the impact of different metabolite profiles among subtypes of disease has not been explored, wrote Mona Alotaibi, MD, of the University of California, San Diego, and colleagues.
“Recently, metabolic dysregulation has been proposed as a key mechanism by which IPAH and SSc-PAH differ and could control such disparities,” they noted. Clarifying the molecular mechanisms of SSc-PAH could inform management and treatment, they added.
In a study published in the journal Chest, the researchers sought to identify a bioactive lipid signature unique to SSc-PAH. They identified 400 patients with SSc-PAH and 1,082 with IPAH. An additional 100 patients with scleroderma but no PH and 44 patients with scleroderma who had PH were included for external validation. The mean ages of the patients with IPAH and SSc-PAH in the discovery and validation cohorts ranged from approximately 51 to 65 years; more than 75% of patients across the groups were women.
The researchers tested more than 700 bioactive lipid metabolites using liquid chromatography/mass spectrometry. They found five metabolites that distinguished SSc-PAH and IPAH that were significantly associated with markers of disease severity: 17-beta estradiol, novel Eic, nervonic acid, fatty acid esters of hydroxy fatty acids, and prostaglandin F2 alpha (PGF 2 alpha).
The biomarkers were increased in SSc-PAH patients compared to patients with SSC alone, which suggests that the biomarkers are related to PAH and not to scleroderma alone, the researchers noted.
In particular, nervonic acid was associated with worse functional capacity, in SSc-PAH patients, as were higher levels of 17-beta estradiol and prostaglandin F2 alpha. Also, 17-beta estradiol was associated with lower cardiac impairment (CI) and stroke volume index (SVI) in SSc-PAH patients, but higher SVI in IPAH patients. PGF 2 alpha was associated with lower CI and SVI and higher pulmonary vascular resistance in SSc-PAH and IPAH combined.
The study findings were limited by several factors including the inability to adjust for all potential confounders between IPAH and SSc-PAH, and the fact that a clear causal relationship could not be determined, the researchers noted. Inadequate statistical power to analyze SSc-PAH data was another limitation, and studies with detailed scleroderma phenotypes are needed to validate the results, they said.
However, the current study provides insight on the metabolic differences in SSc-PAH and the potential impact on disease pathology that may inform diagnosis, prognosis, and treatment strategies for SSc-PAH patients, they concluded.
The study was supported by the National Institutes of Health. Several individual investigators received support from organizations including the American Heart Association and the Chest Foundation, and from companies including Livanova, Equillium, Corvus, Bayer, and Actelion, but the authors had no relevant financial conflicts to disclose.