Remote cardiac remodeling following an ischemic heart injury – Role of activated myofibroblasts in the development of heart failure

• Applicant: Dr. Timo Zadegh Nazari-Shafti, since 4/2024
• Subject Area: Cardiac and Vascular Surgery ; Biochemistry
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 510857108

Globally, more than 60 million people suffer from heart failure. A key factor in the progression from acute to chronic heart failure is cardiac fibrosis. It is characterized by a remodeling process of the heart in which activated myofibroblasts proliferate excessively and secrete large amounts of extracellular matrix proteins, for example, in response to ischemic heart injury. This mechanism serves to maintain the structural integrity of the damaged heart, but prolonged and uncontrolled cardiac fibrosis can lead to decreased ventricular filling and contraction, ultimately contributing to the development of heart failure.The hypothesis for this project is that in response to ischemic heart injury, pro-fibrotic signaling pathways are activated not only in the infarct zone, but also in distant heart tissue (remote cardiac remodeling), which contribute to the development of heart failure. The aim is, therefore, to better understand cardiac remodeling processes following ischemic heart injury in non-ischemic heart regions. The specific sub-goals are: (i) correlation between local ischemic heart damage and the presence of cardiac fibrosis in the infarct area (left ventricle) and in a distant non-ischemic heart region (right atrial appendage), (ii) analysis of known molecular mechanisms of cardiac fibrosis in both ischemic and non-ischemic areas of the heart, and (iii) identification of mediators of remote cardiac remodeling.It is planned to analyze tissue samples from the left ventricle and the right atrial appendage of the heart from the following groups: (i) patients with acute or subacute myocardial infarction with an indication for surgical revascularization, (ii) patients with chronic ischemic heart failure with an indication for surgical revascularization, and (iii) control patients with no evidence of coronary heart disease or heart valve defects with an indication for the replacement of the aorta ascendens. In addition to assessing the collagen deposition by trichrome staining, tissue sections will also be stained immunohistologically for proliferation markers as well as markers of pro-fibrotic signaling pathways and activated myofibroblasts and then analyzed by immunofluorescence microscopy. To gain insights into the mechanisms of remote cardiac remodeling and to identify associated mediators, microRNA analysis and single-nucleus RNA sequencing will be carried out. This project will provide important insights into the pathological cardiac remodeling processes following an ischemic heart injury, especially in non-ischemic regions, by analyzing human tissue samples. In the future, it is planned to test the data obtained in this exploratory study on a larger patient cohort and to further work on the mechanisms of remote cardiac remodeling in cell and mouse models in order to optimize existing measures for the clinical treatment of heart failure.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Sebastian Neuber, until 4/2024