Dynamic lipidome remodeling in acute myocardial ischemia and reperfusion – from organ to systemic response

M. Fischer (Tübingen)¹, C. Coman (Wien)², J. Yang (Tübingen)³, D. Kopczynski (Wien)⁴, A. Bileck (Wien)⁵, N. Troppmair (Wien)⁵, S. Rubenzucker (Wien)⁵, F. Kollotzek (Tübingen)⁶, G. Lingens (Tübingen)⁷, D. Rath (Tübingen)⁶, M. Droppa (Tübingen)¹, M. Zdanyte (Tübingen)⁶, C. Hornef (Tübingen)⁷, T. Harm (Tübingen)¹, P. Sowa (Tübingen)⁶, M. Sigle (Tübingen)¹, R. Tegtmeyer (Tübingen)⁶, D. Heinzmann (Tübingen)⁶, T. Geisler (Tübingen)⁶, T. Petzold (Berlin)⁸, A. Polzin (Düsseldorf)⁹, G. Köllensperger (Wien)¹⁰, C. Gerner (Wien)¹¹, A. Birkenfeld (Tübingen)¹², M. Gawaz (Tübingen)⁶, R. Lukowski (Tübingen)¹³, P. Münzer (Tübingen)¹, R. Ahrends (Wien)², O. Borst (Tübingen)^6
1Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Angiologie Tübingen, Deutschland; ²Institut für Analytische Chemie Wien, Österreich; ³Institute of Pharmacy Tübingen, Deutschland; ⁴Institute of Analytical Chemistry Wien, Deutschland; ⁵University of Vienna Institute of Analytical Chemistry Wien, Deutschland; ⁶Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Kreislauferkrankungen Tübingen, Deutschland; ⁷Universitätsklinikum Tübingen Kardiovaskuläre Thrombo-Inflammation & Translationale Thrombokardiologie Tübingen, Deutschland; ⁸Deutsches Herzzentrum der Charite (DHZC) Klinik für Kardiologie, Angiologie und Intensivmedizin Berlin, Deutschland; ⁹Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; ¹⁰University of Vienna of Analytical Chemistry Wien, Deutschland; ¹¹University of Vienna, Austria Institute of Analytical Chemistry Wien, Deutschland; ¹²Universitätsklinikum Tübingen Innere Medizin IV - Diabetologie, Endokrinologie und Nephrologie Tübingen, Deutschland; ¹³Universitätsklinikum Tübingen Tübingen, Deutschland

Background: Myocardial ischemia-reperfusion (I/R) injury triggers profound metabolic disturbances. Yet, dynamic lipidomic shifts across cardiac and systemic compartments during ischemic and post-ischemic myocardial remodeling still remain unclear.

Methods: We employed quantitative lipidomics to characterize region-specific alterations in myocardial lipid composition within infarcted and remote myocardial areas at distinct time points following ischemia or I/R in mice after transient occlusion of the left coronary artery. In a translational approach, the findings from experimental myocardial infarction (MI) in mice were compared to lipidome changes in patients with ST-elevation myocardial infarction (STEMI) due to coronary artery occlusion either before or after reperfusion therapy.

Results: The impact of myocardial ischemia on the lipidome was detectable within 30 min, comprising fatty acyl and glycerolipid remodeling. Lipase activities drove the breakdown of triacylglycerols, such as TAG 52:3, resulting in the accumulation of simpler lipids, including fatty acyls (DHA, EPA, AA), monoacylglycerols (MAG 22:6), and diacylglycerols (DAG 18:1_18:2). Within 60-120 min of ischemic progress, the levels of these lipids continued to rise contributing to cytotoxic stress. The sequestration of free fatty acids (FAs) into TAGs partially mitigated this detrimental effect. This lipid remodeling was reversed upon reperfusion.

Notably, lipid classes identified as affected in experimental I/R were also altered in STEMI patients. TGs and ceramide levels increased during reperfusion in both species, while dihydroceramides and FAs exhibited opposing trends. The observed decline in FA levels in humans, alongside an increase in dihydroceramides, suggests a persistent and unresolved oxidative stress following ischemic injury.

Using chemical space models, the experimental results were correlated with the lipidomic profiles of STEMI patients before and after reperfusion therapy, providing translational insights into the metabolic perturbations accompanying myocardial I/R.

Conclusions: Our findings highlight the dynamic nature of lipid remodeling in the heart and communicating organs following myocardial ischemia, providing important new insights into metabolic processes occurring in acute myocardial infarction.