B18-07 Linoleic Acid and Alpha-Linolenic Acid Metabolism Is Associated With Right Ventricle Function in Endomyocardial Tissue and Peripheral Blood in Pulmonary Hypertension

Rationale We previously identified that linoleic acid (LA) and alpha-linolenic acid (ALA) pathways are enriched in surveilled scleroderma patients two years prior to pulmonary hypertension (PH) diagnosis. LA (18:2) and ALA (18:3) are essential polyunsaturated fatty acid (FA) precursors to omega-6 and omega-3, respectively, and have roles in cellular structure, signaling and proliferation. LA is depleted in autopsied right ventricles (RVs) from humans with end-stage PH. Due to the early enrichment of LA/ALA pathways in PH, we hypothesized that increased LA/ALA metabolism observed in PH may reflect adaptive RV remodeling in response to increasing afterload. Methods We performed right heart catheterization (RHC), pressure-volume (PV) loop analysis, endomyocardial biopsy (EMB), and blood sample collection on 22 patients with known or suspected PH at a single center. Serum samples were sent for liquid chromatography-mass spectrometry (LC-MS)-based high-resolution lipidomics using the Metabolon® Complex Lipid Panel (CLP). RV EMB tissue underwent single-nucleus RNA-sequencing (snRNA-seq) using the iCell8 platform. After standard pre-processing and quality control of lipidomic and transcriptomic data, biologically-based LA-/ALA-related ratios were constructed from blood lipid measurements. Gene sets reflecting LA/ALA metabolism were identified in the Human Molecular Signatures Database (MSigDB). LA-/ALA-related blood-based lipid ratios and tissue-based gene sets were associated with RHC and PV loop measurements using correlation analyses and cell type-specific gene set variation analyses (GSVA), respectively. Results Circulating LA-/ALA-containing lipids did not correlate with RHC-based hemodynamic measurements but were associated with indices of RV function on PV loops. The ratio of ALA with headgroup lysophosphyatidylethanolamine (LPE) to downstream EPA (LPE-ALA:EPA) was associated with RV contractility (Ees) (Figure 1A). LPE-ALA:DHA was associated with RV contractility (Ees) and ability to augment contractility with exercise (ΔEes) (Figure 1A). Cellular populations in the PH RV were identified (Figure 1B). In tissue-based analyses, gene sets related to ALA metabolism were associated with RV contractility (Ees) in RV pericytes/smooth muscle cells (Figure 1C). LA metabolic gene sets were associated with RV-PA coupling (i.e., the RV’s ability to effectively contract in response to afterload; Ees/Ea) in the RV endothelium (Figure 1C). Conclusion Circulating ratios of LA-/ALA-containing lipids are associated with RV function in PH patients. In alignment with circulating lipidomic signatures, ALA metabolic gene sets in RV tissue are associated with RV contractility. LA-/ALA-containing lipid composites may hold potential as circulating blood-based biomarkers localizable to the RV. Expression of LA-/ALA-related metabolic programs in the RV may contribute to an adaptive phenotype of preserved RV contractility in PH. This abstract is funded by: NIH