Distinct Lipid Metabolic Profiles Unveil Pathophysiological Differences Between Postcapillary and Combined Pre- and Postcapillary Pulmonary Hypertension

Highlight

1. Combined pre- and postcapillary pulmonary hypertension (Cpc-PH) exhibits a distinct plasma metabolomic profile characterized by elevated polyunsaturated fatty acids and fatty acyl esters of hydroxy fatty acids compared to isolated postcapillary PH.
2. The metabolomic signature of Cpc-PH closely resembles pulmonary arterial hypertension (PAH), suggesting shared molecular pathways.
3. Specific bioactive lipids such as adrenic acid and fatty acyl esters of hydroxy fatty acids correlate with increased mortality in Cpc-PH.
4. Preclinical validation in animal models supports the translational potential of lipid metabolism pathways as therapeutic targets.

Background

Pulmonary hypertension (PH) is a complex clinical syndrome classified into several groups based on etiology. Group 2 PH, secondary to left heart disease, is the most prevalent and comprises two subtypes: isolated postcapillary PH and combined pre- and postcapillary PH (Cpc-PH). These subtypes differ significantly in hemodynamic profiles, clinical outcomes, and likely pathophysiology, with Cpc-PH associated with worse prognosis and treatment challenges.

Identifying molecular mechanisms underlying these subphenotypes remains an unmet need to improve diagnostic accuracy, prognostication, and personalized therapies. Lipid mediators, including polyunsaturated fatty acids and their oxidized derivatives (oxylipins), regulate vascular tone, inflammation, and remodeling, pivotal processes in pulmonary vascular disease. However, the differential role of lipid metabolism in distinct Group 2 PH subtypes has been sparsely characterized.

Study Design and Methods

This cross-sectional study investigated plasma bioactive lipid profiles in a well-characterized cohort of 128 patients with Group 2 PH subtypes—isolated postcapillary PH (n=21) and Cpc-PH (n=69)—alongside 38 patients with idiopathic PAH for comparison. Bioactive lipids were quantified using high-resolution liquid chromatography-mass spectrometry, profiling 844 metabolites encompassing polyunsaturated fatty acids, fatty acyl esters of hydroxy fatty acids, and oxylipins.

Additionally, plasma samples from well-established preclinical models of severe PH, notably the Su5416/hypoxia (Su/Hx) rat model, were analyzed to validate human findings and explore mechanistic pathways. The authors applied stringent statistical correction for multiple testing, with false discovery rate (q)<0.05 as significance criterion. Associations between metabolites and mortality were examined to appraise clinical relevance.

Key Findings

Metabolomic Differences Between PH Subtypes
Among 844 profiled metabolites, 158 significantly differed between Cpc-PH and isolated postcapillary PH. Notably, 28 bioactive lipid species were elevated in Cpc-PH, predominantly those derived from polyunsaturated fatty acids and fatty acyl esters of hydroxy fatty acids (FAHFAs). These included increased levels of adrenic acid, linoleic acid, docosatrienoic acid, and palmitoleic acid. In contrast, pro-resolving and vasodilatory oxylipins were reduced in Cpc-PH compared to isolated postcapillary PH.

Similarity of Cpc-PH Lipid Profile to PAH
When comparing with PAH patients, 24 of the 28 elevated metabolites in Cpc-PH were not significantly different, indicating a PAH-like bioactive lipid signature. This finding suggests shared pathobiological mechanisms involving lipid metabolic dysregulation between Cpc-PH and PAH, two clinically distinct but overlapping pulmonary vascular diseases.

Prognostic Implications
Metabolites such as adrenic acid, linoleic acid, docosatrienoic acid, palmitoleic acid, and FAHFAs were independently associated with increased mortality risk in patients with Cpc-PH. This highlights the potential utility of lipid metabolites as prognostic biomarkers to identify higher-risk patients who might benefit from targeted interventions.

Preclinical Validation
Using the Su/Hx rat model that recapitulates key features of PAH, the study demonstrated consistent elevation of a subset of metabolites elevated in human Cpc-PH plasma. This validation reinforces the biological relevance of altered fatty acid and oxylipin metabolism and offers a platform for mechanistic studies and therapeutic exploration.

Expert Commentary

This investigation provides compelling evidence that lipid metabolic signatures can discriminate between isolated postcapillary and combined pre- and postcapillary pulmonary hypertension, marking a significant advance in biomarker discovery and molecular classification of Group 2 PH subtypes.

The shared lipidomic profile of Cpc-PH and PAH challenges traditional hemodynamic-centric subclassification and supports the concept of overlapping pathogenic pathways driven by disturbances in bioactive lipid mediators. Specifically, elevated polyunsaturated fatty acids and FAHFAs may fuel vascular remodeling and inflammation, while reduced pro-resolvin oxylipins may impair resolution of pulmonary vascular injury.

These findings suggest a paradigm shift toward integrating metabolic profiling into PH classification systems and highlight novel targets for pharmacologic intervention. However, the cross-sectional design precludes causal inference, and longitudinal studies are needed to assess lipid metabolite dynamics and treatment response.

Moreover, the relatively small sample size of postcapillary PH subgroup warrants cautious generalization, and validation in external cohorts is essential. Future research should explore the mechanistic roles of implicated lipid pathways, including their interactions with inflammation, endothelial dysfunction, and right ventricular adaptation.

Conclusion

This study delineates a distinct, PAH-like fatty acid and oxylipin metabolomic signature in patients with combined pre- and postcapillary pulmonary hypertension, distinguishing it from isolated postcapillary PH. These bioactive lipid alterations correlate with adverse outcomes and are corroborated in animal models, providing critical insights into disease heterogeneity.

Incorporating lipid metabolism profiling into PH diagnostics may improve phenotyping accuracy and prognostication, ultimately facilitating precision medicine approaches. Furthermore, the identified lipid pathways offer promising therapeutic targets to modulate pulmonary vascular remodeling and improve clinical outcomes in Group 2 PH.

Funding and ClinicalTrials.gov

The study was supported by institutional and governmental research grants. Details on clinical trial registration were not specified.

References

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