TY - JOUR
T1 - Spatial Metabolomics Identifies LPC(18:0) and LPA(18:1) in Advanced Atheroma With Translation to Plasma for Cardiovascular Risk Estimation
AU - Cao, Jianhua
AU - Martin-Lorenzo, Marta
AU - van Kuijk, Kim
AU - Wieland, Elias
AU - Gijbels, Marion J
AU - Claes, Britt S R
AU - Heredero, Angeles
AU - Aldamiz-Echevarria, Gonzalo
AU - Heeren, Ron M A
AU - Goossens, Pieter
AU - Sluimer, Judith
AU - Balluff, Benjamin
AU - Alvarez-Llamas, Gloria
PY - 2024/3
Y1 - 2024/3
N2 - BACKGROUND: The metabolic alterations occurring within the arterial architecture during atherosclerosis development remain poorly understood, let alone those particular to each arterial tunica. We aimed to identify, in a spatially resolved manner, the specific metabolic changes in plaque, media, adventitia, and cardiac tissue between control and atherosclerotic murine aortas. Second, we assessed their translatability to human tissue and plasma for cardiovascular risk estimation. METHODS: In this observational study, mass spectrometry (MS) imaging was applied to identify region-specific metabolic differences between atherosclerotic (n=11) and control (n=11) aortas from low-density lipoprotein receptor-deficient mice, via histology-guided virtual microdissection. Early and advanced plaques were compared within the same atherosclerotic animals. Progression metabolites were further analyzed by MS imaging in 9 human atherosclerotic carotids and by targeted MS in human plasma from subjects with elective coronary artery bypass grafting (cardiovascular risk group, n=27) and a control group (n=27). RESULTS: MS imaging identified 362 local metabolic alterations in atherosclerotic mice (log2 fold-change, =1.5; =0.05). The lipid composition of cardiac tissue is altered during atherosclerosis development and presents a generalized accumulation of glycerophospholipids, except for lysolipids. Lysolipids (among other glycerophospholipids) were found at elevated levels in all 3 arterial layers of atherosclerotic aortas. Lysophosphatidylcholine(18:0; =0.024) and lysophosphatidic acid(18:1; =0.025) were found to be significantly elevated in advanced plaques as compared with mouse-matched early plaques. Higher levels of both lipid species were also observed in fibrosis-rich areas of advanced- versus early-stage human samples. They were found to be significantly reduced in human plasma from subjects with elective coronary artery bypass graft ( <0.001 and =0.031, respectively), with lysophosphatidylcholine(18:0) showing significant association with cardiovascular risk (odds ratio, 0.479 [95% CI, 0.225-0.883]; =0.032) and diagnostic potential (AUC, 0.778 [95% CI, 0.638-0.917]). CONCLUSIONS: An altered phospholipid metabolism occurs in atherosclerosis, affecting both the aorta and the adjacent heart tissue. Plaque-progression lipids lysophosphatidylcholine(18:0) and lysophosphatidic acid(18:1), as identified by MS imaging on tissue, reflect cardiovascular risk in human plasma.
AB - BACKGROUND: The metabolic alterations occurring within the arterial architecture during atherosclerosis development remain poorly understood, let alone those particular to each arterial tunica. We aimed to identify, in a spatially resolved manner, the specific metabolic changes in plaque, media, adventitia, and cardiac tissue between control and atherosclerotic murine aortas. Second, we assessed their translatability to human tissue and plasma for cardiovascular risk estimation. METHODS: In this observational study, mass spectrometry (MS) imaging was applied to identify region-specific metabolic differences between atherosclerotic (n=11) and control (n=11) aortas from low-density lipoprotein receptor-deficient mice, via histology-guided virtual microdissection. Early and advanced plaques were compared within the same atherosclerotic animals. Progression metabolites were further analyzed by MS imaging in 9 human atherosclerotic carotids and by targeted MS in human plasma from subjects with elective coronary artery bypass grafting (cardiovascular risk group, n=27) and a control group (n=27). RESULTS: MS imaging identified 362 local metabolic alterations in atherosclerotic mice (log2 fold-change, =1.5; =0.05). The lipid composition of cardiac tissue is altered during atherosclerosis development and presents a generalized accumulation of glycerophospholipids, except for lysolipids. Lysolipids (among other glycerophospholipids) were found at elevated levels in all 3 arterial layers of atherosclerotic aortas. Lysophosphatidylcholine(18:0; =0.024) and lysophosphatidic acid(18:1; =0.025) were found to be significantly elevated in advanced plaques as compared with mouse-matched early plaques. Higher levels of both lipid species were also observed in fibrosis-rich areas of advanced- versus early-stage human samples. They were found to be significantly reduced in human plasma from subjects with elective coronary artery bypass graft ( <0.001 and =0.031, respectively), with lysophosphatidylcholine(18:0) showing significant association with cardiovascular risk (odds ratio, 0.479 [95% CI, 0.225-0.883]; =0.032) and diagnostic potential (AUC, 0.778 [95% CI, 0.638-0.917]). CONCLUSIONS: An altered phospholipid metabolism occurs in atherosclerosis, affecting both the aorta and the adjacent heart tissue. Plaque-progression lipids lysophosphatidylcholine(18:0) and lysophosphatidic acid(18:1), as identified by MS imaging on tissue, reflect cardiovascular risk in human plasma.
KW - aorta, thoracic
KW - atherosclerosis
KW - heart disease risk factors
KW - lipids
KW - plaque progression
U2 - 10.1161/ATVBAHA.123.320278
DO - 10.1161/ATVBAHA.123.320278
M3 - Article
SN - 1079-5642
VL - 44
SP - 741
EP - 754
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 3
ER -