J Heart Lung Transplant. 2025 Dec 5:S1053-2498(25)02413-1. doi: 10.1016/j.healun.2025.11.024. Online ahead of print.
ABSTRACT
BACKGROUND: Right ventricular (RV) dysfunction is the leading cause of mortality in pulmonary arterial hypertension (PAH). Although RV metabolic remodelling in chronic pressure overload is recognised, the circulating metabolic signatures of RV-pulmonary arterial (PA) coupling and their clinical relevance remain poorly defined.
METHODS: We first integrated pressure-volume-derived RV/PA metrics with untargeted plasma metabolomics in 33 PAH patients, using both network-based and single-metabolite analyses. Findings were replicated in 14 patients using echocardiographic surrogates. In 16 participants from the phase 2 PIPAH trial of imatinib, we examined longitudinal metabolite changes in relation to haemodynamic responses obtained from implanted devices.
RESULTS: The end-systolic to arterial elastance ratio (Ees/Ea), a load-independent measure of RV contractility and RV-PA coupling, emerged as a central node in the metabolic network, while metrics related to afterload and RV stiffness were more peripherally located. In individual metabolite analyses, nine metabolites were significantly associated with Ees/Ea and its echocardiographic surrogate, independent of potential confounders, including kidney and liver function. Pathway enrichment analysis confirmed a predominance of fatty acid metabolism, particularly acylcarnitines. In the PIPAH study cohort, individual-level analyses showed that reductions in acylcarnitine levels at 4 and 24 weeks of imatinib therapy discriminated patients with improved cardiac output (area under the curves 0.89 and 0.84).
CONCLUSIONS: We identify a distinct circulating metabolomic signature, enriched in fatty acid metabolites, associated with RV-PA coupling in PAH. These metabolites may inform on the risk and trajectory of RV maladaptation during treatment and guide therapeutic decisions to optimise the benefit-harm ratio.
PMID:41354112 | DOI:10.1016/j.healun.2025.11.024