In-situ lipid alterations of aortic atherosclerosis in LDLR-deficient mice using mass spectrometry imaging

Background and Aims : We aim to characterize the in-situ lipid alterations associated with atherosclerosis in mice aortic roots.Methods: Lipidomic non-targeted analysis by mass spectrometry imaging was performed of aortic roots obtained from low-density lipoprotein receptor deficient (ldlr-/-) mice fed with high fat diet (n=11), in comparison to a control group fed with normal diet (n=11) during 8 weeks. Additionally, targeted mass-spectrometry was performed in human plasma samples of patients at CV-risk (n=27) and controls (n=27) to investigate a potential translation of the tissue-based lipid alterations to a biological fluid with diagnostic potential.Results: We found 362 m/z values significantly altered between control and atherosclerosis mice (p-value≤0.05; log2-fold-change≥1.5). In cardiomyocytes, a decreased trend in lysolipids and heptanoylcarnitine and an imbalance in phospholipids were found. In the aortic region, an accumulation of glycerophospholipids was observed in all three arterial layers. N-stearoyl-glutamine, lysoPI(20:3) and SM(d18:0/15:0) were increased in the intima in agreement with a potential role for SMs and lysolipids in the progression of atherosclerosis. In human plasma, Trimethylamine N-oxide and carnitine were found at higher levels and heptanoylcarnitine at reduced levels in subjects with CV-risk. The combination of these three molecules into a panel showed a promising performance as diagnostic markers (area-under-the-curve=0.916; CI: 0.842-0.990).Conclusions: This study indicates an altered phospholipid metabolism occurring in atherosclerosis, which affects both, the aorta as well as the adjacent cardiomyocyte area. Some of the in-tissue lipidic changes identified are reflected in human plasma and show diagnostic potential. Background and Aims : We aim to characterize the in-situ lipid alterations associated with atherosclerosis in mice aortic roots. Methods: Lipidomic non-targeted analysis by mass spectrometry imaging was performed of aortic roots obtained from low-density lipoprotein receptor deficient (ldlr-/-) mice fed with high fat diet (n=11), in comparison to a control group fed with normal diet (n=11) during 8 weeks. Additionally, targeted mass-spectrometry was performed in human plasma samples of patients at CV-risk (n=27) and controls (n=27) to investigate a potential translation of the tissue-based lipid alterations to a biological fluid with diagnostic potential. Results: We found 362 m/z values significantly altered between control and atherosclerosis mice (p-value≤0.05; log2-fold-change≥1.5). In cardiomyocytes, a decreased trend in lysolipids and heptanoylcarnitine and an imbalance in phospholipids were found. In the aortic region, an accumulation of glycerophospholipids was observed in all three arterial layers. N-stearoyl-glutamine, lysoPI(20:3) and SM(d18:0/15:0) were increased in the intima in agreement with a potential role for SMs and lysolipids in the progression of atherosclerosis. In human plasma, Trimethylamine N-oxide and carnitine were found at higher levels and heptanoylcarnitine at reduced levels in subjects with CV-risk. The combination of these three molecules into a panel showed a promising performance as diagnostic markers (area-under-the-curve=0.916; CI: 0.842-0.990). Conclusions: This study indicates an altered phospholipid metabolism occurring in atherosclerosis, which affects both, the aorta as well as the adjacent cardiomyocyte area. Some of the in-tissue lipidic changes identified are reflected in human plasma and show diagnostic potential.