Pulmonary arterial hypertension (PAH) develops in 15% of patients with scleroderma. Screening has improved survival, but current strategies under-diagnose the condition in its earliest, most treatable stage. Given the need for predictive biomarkers, we conducted an untargeted lipidomics study to identify resting and exercise-induced lipid biomarkers of scleroderma-associated PAH.
We studied 109 subjects in 3 groups: healthy controls (n=37), scleroderma patients at low risk for PAH using the DETECT algorithm (n=21), and scleroderma patients at high risk for PAH using the DETECT algorithm (n=51). High-risk patients were further sub-divided based upon right heart catheterization hemodynamics: normal pulmonary arterial pressure (mPAP<21 mmHg, n=10), borderline pressure (mPAP>21 mmHg and<25 mmHg, n=21), and PAH (mPAP ≥25 mmHg, n=20). All high-risk patients had normal left-sided filling pressures. Blood was drawn at rest and at peak exercise. Lipids were extracted using a modified Bligh-Dyer method and processed via liquid chromatography mass spectrometry. ANOVA was performed in the setting of rest and exercise. T-tests were performed to evaluate changes associated with exercise within each sub group.
Subjects in the high-risk scleroderma group had statistically significant elevations in long chain fatty acids (LCFA’s) and very long chain fatty acids (VLCFA’s) at rest, compared to healthy controls and low-risk scleroderma patients (p< 0.00001). Compared to healthy, low-risk scleroderma and high-risk scleroderma with normal mPA pressure groups, statistically significant reductions in LCFA’s were found in the scleroderma-associated PAH and borderline mPAP groups during exercise (p<0.004 and p<0.0008, respectively).
Resting plasma lipidomic profiles are unique in scleroderma patients at high-risk for the presence of PAH. In addition, altered LCFA metabolism during exercise was found in high-risk scleroderma patients with PAH and borderline mPA pressures. These findings support the further investigation of resting and exercise plasma lipidomic profiles as biomarkers of, or potential contributors to, scleroderma-associated PAH.