Project Details
Projekt
Defining the benefit of physical exercise on T-cell mediated inflammation upon myocardial infarction
Applicant
Marcel Michla, Ph.D.
Subject Area
Cardiology, Angiology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 554988920
Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Primarily, the destabilization of atherosclerotic plaques leading to the occlusion of coronary arteries and myocardial infarction (MI) accounts for most deaths. Current MI treatment mainly focuses on recanalization and restoring blood flow to the occluded coronary artery. However, while necessary to preserve myocardial tissue, this reperfusion drives additional myocardial damage in the form of cardiac ischemia-reperfusion injury (CIRI). Cardiovascular inflammation plays a key role in CIRI and its long-term consequences. However, despite MI being a common clinical event, there is limited understanding on the immune mechanisms that underpin CIRI, and whether these can be modulated therapeutically. As such, there is a critical unmet need to better understand and treat the inflammatory drivers of CIRI. In this application, we hypothesise that exercise-mediated immunomodulation significantly protects against MI by modulating the adaptive immune response. Using the voluntary wheel running (VWR) model in murine CIRI mimics enhanced physical exercise, evaluating exercise’s preconditioning effects on the immune response and tissue repair post CIRI. Given exercise-based cardiac rehabilitation is also prescribed post-MI, despite limited mechanistic understanding, we will further define the therapeutic efficacy of such rehabilitation. Importantly, we will compare the protective impact of early versus late intervention to inform the clinical application of exercise therapies, with their significant variation in time-to-treatment across different countries and health providers. To improve our fundamental mechanistic understanding of CIRI, we will use single-cell RNA sequencing (scRNA-seq) and multi-color spectral flow cytometry (CYTEK). Furthermore, echocardiography and histology will be used to investigate cardiac function in exercised versus sedentary mice. In parallel to our murine exercise studies, we will also explore this exercise-immune axis in humans by defining the immune profile of patients with MI undergoing exercise-based rehabilitation versus those receiving standard care. In line with our pre-clinical work, this clinical study will include an early and late start of exercise after MI. We will assess blood-derived PBMCs from these patients using scRNA-Seq and multi-color flow cytometry. Our combined pre-clinical and clinical studies will conclusively determine if exercise-mediated interventions modulate the immune system. We anticipate that our results will provide a long sought-after mechanistic basis testing if dampening inflammation will ultimately result in exercise-mediated cardio-protection. Our findings will further identify underlying putative pathways for future therapeutic targeting and provide key data on the impact of early versus late intervention providing novel mechanistic insights and ultimately delivering a better outcome for patients with MI.
DFG Programme
WBP Fellowship
International Connection
Australia
