The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation · 2025
Metabolomic signature of right ventricular-pulmonary arterial coupling differentiates hemodynamic response to imatinib therapy in pulmonary arterial hypertension.
СтатьяКлиническое исследование II фазыНазвание и аннотация: Перевод пока не подготовлен
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Harbaum Lars, Klose Hans, Lund Jonas, Sinn Martin, Lund Gunnar K, Francke Paul, Sinning Christoph R, Tello Khodr, Rothman Alexander M K, Wilkins Martin R
Аннотация
BACKGROUND: Right ventricular (RV) dysfunction is the leading cause of mortality in pulmonary arterial hypertension (PAH). Although RV metabolic remodeling in chronic pressure overload is recognized, 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 hemodynamic 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, 9 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 optimize the benefit-harm ratio.
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 hemodynamic 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, 9 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 optimize the benefit-harm ratio.