Master switches in cardiac ischaemia: the Collaborative Research Center (CRC) 1116 of the German Research Foundation

In Western Europe and the USA, the mortality from acute myocardial infarction has decreased continuously over the last decades as a consequence of reperfusion therapy, adjunctive antithrombotic therapy, and improved logistics. However, with an aging population, this overall trend does not continue, but—in contrast—mortality increases tremendously in the elderly population with ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI). In addition, severe sequelae such as heart failure and arrhythmias develop in survivors of myocardial infarction and are increasing despite the current standard treatment. The medical need to attenuate the increased morbidity of STEMI and NSTEMI survivors requires novel therapeutic approaches beyond that by rapid reperfusion which are then based on an improved understanding of the underlying mechanisms and relevant confounders of acute myocardial infarction and its consequences. Increasing evidence supports the view of myocardial infarction as a systemic disease with multiple layers of inter-organ communication between the heart and the immune system, glucose and fat metabolism, and other organs such as brain, bone marrow, liver, pancreas, spleen, and kidney. These systemic interactions are also involved in the impact of comorbidities and co-medications on the acute and chronic outcome of myocardial infarction. The fundamental aim of the Collaborative Research Center (CRC) 1116 ‘Master switches in cardiac ischaemia’ is to identify new targets, i.e. molecules, pathways, and mechanisms that are critical for the acute and subacute response to myocardial ischaemia, which we define as ‘master switches ’. We aim to discover master switches of relevant adaptive and maladaptive responses which are relevant for cardiac function and outcome from infarction. Our focus is on local responses and systemic interactions of infarcting myocardium, particularly on metabolic comorbidities (obesity, insulin resistance, type 2 diabetes mellitus) and anaemia and on systemic interferences from the immune system and peripheral ischaemia/reperfusion. The CRC 1116 has been approved and founded by the German Research Foundation in 2014 and seen two successful 4-year funding periods since; it is up for a final 4-year renewal this year. The CRC 1116 is organized in two chapters (Figure 1). In chapter A, the local cardiomyocyte stiffness in remote myocardium and its modification by type 2 diabetes,1 the protective function of mitochondrial TERT2 and other mitochondrial molecules, the protective role of platelets, of the growth factor IGF-13 and of the extracellular matrix molecule hyaluronic acid4 in the repair processes post-myocardial infarction are studied in mouse models of reperfused and non-reperfused myocardial infarction. In chapter B, inflammatory processes in myocardial injury and repair and systemic signalling molecules involved in the metabolic syndrome5,6 are studied in mouse models. Special emphasis is on confounding comorbidities of myocardial infarction and their impact on outcome from infarction, notably anaemia and the role of erythrocyte nitric oxide7 and type 2 diabetes with its metabolic consequences.8 The systemic interaction between peripheral ischaemia/reperfusion and the infarcting myocardium and the signal transduction of remote ischaemic conditioning are studied in a translational model of reperfused myocardial infarction in pigs9 and in patients undergoing coronary bypass surgery.2 Schematic diagram of the structure of the CRC (local vs. systemic effectors with impact of myocardial ischaemia/reperfusion and its consequences) and its main topics. The individual research projects are supported by platforms of advanced and comprehensive magnetic resonance imaging,10 omics technology (in collaboration with the ISAS institute Dortmund), and single cell RNA sequencing. Of particular importance is the recruitment of a large cohort of patients with acute myocardial infarction who are extensively phenotyped for the metabolic features of a metabolic syndrome and diabetes. The CRC has seven individual projects studying local effectors in myocardial ischaemia (chapter A) and eight projects aiming to characterize systemic interferences in STEMI and NSTEMI (chapter B) which are led by 23 principal investigators, among whom a third are female investigators. In the upcoming funding period, we plan to have seven junior investigators who will have then grown into the position of principal investigator. Within the CRC 1116, an Integrated Research Training Group is aiming to provide a coordinated environment to foster scientific education and long-term development of medical scientists (PhDs from natural sciences) and clinician scientists (MDs) to pursue their career in the field of cardiovascular biomedicine. Two highly visible international symposia ‘Inflammation and Regeneration of the Injured Heart’ (December 2017) and ‘Myocardial infarction—Pathomechanisms and Novel Therapeutic Options’ (September 2021) have been organized with an esteemed international faculty. P.L. Bollyky/Stanford, N. Frangogiannis/New York, B. Ibanez/Madrid, and M. Mayr/London serve on the international advisory board. In the upcoming funding period, we aim to achieve as much translation as possible for the ongoing projects, notably to develop the identified protective signals (mitochondrial TERT, IGF-1, sphingosine-1-phosphate) into therapeutic targets, to further develop and validate comprehensive multi-marker MRI imaging technologies, to characterize specific features of the metabolic syndrome and its interaction with infarcting myocardium, to further analyze the signal transduction of ischaemic conditioning and obstacles to it, and finally to identify subtypes of diabetes and anaemia and use them for prognostication in patients. The authors are funded by the CRC 1116 of the German Research Foundation. Conflict of interest: none declared.