Large-scale quantitative metabolomics and mass spectrometry imaging define the metabolic atlas in human acute type A aortic dissection.

BACKGROUND

Acute type A aortic dissection (ATAAD) is the most frequent acute aortic disease with high mortality. To date, a comprehensive metabolic characterization of the human ATAAD ascending aorta remains elusive.

METHODS

We used large-scale targeted metabolomics on ascending aortas obtained from patients with ATAAD, patients with ascending thoracic aortic aneurysm (ATAA), and healthy donors to quantify the 1,349 metabolites. By integrating with transcriptomics and mass spectrometry imaging (MSI) analysis, we further visualized the spatial distribution of the key ATAAD-altered metabolic network.

FINDINGS: Quantitative profiling revealed distinct hydrophilic metabolite and glycerophospholipid profiles in ascending aortas from patients with ATAAD (n = 20), which remarkably differed from those in patients with ATAA (n = 20) and healthy controls (n = 20). Various metabolites in purine, pyrimidine, and amino acid metabolic pathways were found to be specifically and significantly altered in the ascending aorta of ATAAD. MSI analysis indicated that those differentiated metabolites were mainly enriched in the tunica media and intima. Two key ATAAD-altered metabolites-hypoxanthine and pyroglutamic acid-were selected as proof-of-concept candidates. In a prospective ATAAD cohort (n = 196), circulating levels of both metabolites correlated positively with adverse clinical outcomes. Functional studies confirmed they promote aortic dissection by impairing vascular smooth muscle and endothelial cell functions.

CONCLUSIONS

Our study presents the first large-scale quantitative and spatial metabolic atlas of the human ATAAD ascending aorta, highlighting key metabolic disturbances with potential as risk markers and therapeutic targets for acute aortic diseases.

FUNDING: This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project and the Beijing Natural Science Foundation.