Protection of the remote myocardium after myocardial infarction by inhibition of mitochondrial complex I.

• Applicant: Dr. Katherine Sattler
• Subject Area: Cardiology, Angiology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566002945

Myocardial infarction (Ml) occurs if the blood flow through a coronary artery is (sub)totally blocked. The cardiac muscle perfused by this artery is damaged both by the interruption of blood flow and by its therapeutic restoration (ischemia-reperfusion injury). The remodeling of the injured myocardium causes a decline of myocardial function, resulting in a disease termed ischemic heart failure or ischemic cardiomyopathy. Apart from the muscle section perfused by the blocked vessel, other parts of the heart are supplied with blood by intact blood flow (“remote myocardium”). However, these sections also undergo remodeling after myocardial infarction, thereby taking part in the development of ischemic heart failure. One cause of remodeling is the production of reactive oxygen species by complex I of the respiratory chain in mitochondria. Previously, several substances targeting this mitochondrial dysfunction were successfully tested in animal models (i.e. cyclosporine A, elamipretide (MTP-131)) but failed to improve heart failure in humans. The reagent anethol-trithione, OP211 3, was successfully tested in vivo in shep and rats during a short time follow up of 5 days resp. 3 hours. The aim of this project is to test the reagent for its efficacy of reducing long-term ischemic heart failure after myocardial infarction. The first part of the project will study the effect of OP2113 on the development of ischemic cardiomyopathy during long term-follow up in a mouse model of myocardial infarction. Myocardial infarction will be induced by ligation and re-opening of a coronary artery. OP2113 will be administered during reperfusion. Sham groups with and without OP2113 will serve as control groups. Functional and structural changes of the heart muscle will be quantified by cardiac magnet resonance imaging after 7 days and after 6 weeks. Clinical outcome and plasma levels of parameters indicating myocardial damage and heart failure will be used to assess myocardial function in vivo. The second part of the project will examine the effects of OP2113 on molecular levels. Cardiac samples from the animal model will be studied for gene expression by single-cell sequencing. By the same method, the immune response of different cardiac cells will be analyzed. The effect on cellular metabolism will be examined by measuring different parameters of mitochondrial function. During the third phase of the project, the effect of OP2113 will be tested on human cells to assess the possibility of application in humans. We will use human cardiac organoids to analyze the expression of genes and of the immune response by single-cell sequencing. Cardiac organoids, being multicellular aggregates are an equivalent of a cultured heart muscle (“heart in a dish”) and are best suited for drug screening on a multicellular level. Similarly, effects of OP2113 on mitochondrial function, cellular contractility and signaling pathways will be studied in cardiac organoids.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Ibrahim Akin