DOI: 10.1161/atvbaha.125.324430 ISSN: 1079-5642

Linking Lipidomics to Vulnerable Coronary Plaques: A PROSPECT II Substudy

Tania Sharma, Tove Fall, Sergi Sayols-Baixeras, Akiko Maehara, Michael Maeng, Lars Kjøller-Hansen, Thomas Engstrøm, Ori Ben-Yehuda, Mitsuaki Matsumura, Ole Fröbert, Jonas Persson, Rune Wiseth, Alf Inge Larsen, J. Gustav Smith, Gunnar Engström, Johan Ärnlöv, Jan Borén, Ramzi Khamis, Sotirios Tsimikas, Sasha Koul, Rebecca Rylance, Ziad A. Ali, Stefan K. James, Gregg W. Stone, David Erlinge
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BACKGROUND:

Lipidomics, the comprehensive profiling of circulating lipid species, has emerged as a powerful tool to investigate metabolic alterations underlying coronary atherosclerosis. Understanding the mechanisms driving high-risk vulnerable plaque formation and progression to myocardial infarction remains a key therapeutic priority. This study investigates associations between circulating lipid metabolites and imaging-defined features of vulnerable coronary plaque.

METHODS:

Following revascularization, patients with myocardial infarction underwent 3-vessel coronary artery imaging with near-infrared spectroscopy and intravascular ultrasound to assess nonflow-limiting plaques for lipid core burden index and plaque burden. Multivariable models evaluated associations between 424 lipid metabolites in plasma, quantified by mass spectrometry, pan-coronary lipid, pan-coronary plaque burden, and high-risk vulnerable plaque measures (maximum lipid core burden index within any 4-mm segment across the entire lesion ≥324.7 and plaque burden ≥70%) in 877 patients. Findings were validated in the SCAPIS study (Swedish Cardiopulmonary Bioimage Study) using coronary computed tomography angiography–based measures of coronary artery calcium score and segment involvement score.

RESULTS:

We identified 156 significant associations ( P <0.05) between lipid metabolites and coronary plaque characteristics across 39 metabolic pathways. Sphingomyelins were inversely associated with all plaque metrics, and 1-palmitoyl-2-oleoyl-GPE (16:0/18:1), a phosphatidylethanolamine, was positively associated with all plaque metrics. After correcting for multiple testing, 27 lipid species across 7 pathways remained significant (q<0.05). The majority were linked to pan-coronary lipid burden, with the strongest inverse association observed for sphingomyelin d18:1/22:1, d18:2/22:0, and d16:1/24:1. Similar inverse patterns were seen for select dihydrosphingomyelins and fatty acid dicarboxylates. In contrast, 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) remained positively associated with pan-coronary lipid. In the SCAPIS validation cohort, 19 of the 27 significant lipid associations were successfully replicated (q<0.05).

CONCLUSIONS:

This study is the first to demonstrate that sphingomyelins are negatively and 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) positively associated with vulnerable coronary plaque features based on multimodality intracoronary imaging in patients with myocardial infarction. Moreover, these associations were validated in a large cohort using coronary computed tomography angiography–derived measures of plaque burden. These novel results may enable the development of new diagnostic and therapeutic strategies.

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