Understanding the role of cell-cell interactions in cardiac arrhythmogenesis

• Applicant: Dr. Praveen Vasudevan
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499104113

Cardiac arrhythmias are one of the leading causes of death worldwide and have been shown to occur during the course of inflammation-associated conditions such as myocardial infarction and myocarditis. Effective treatment options for prevention and treatment of arrhythmic events are limited owing to the lack of a clear understanding of the cellular and pathophysiological mechanisms involved. Current concepts assume a significant contribution of the immune cells to electrical instability. A critical subset of this immune response is represented by macrophages, which have been shown to facilitate electrical conduction in the heart through their coupling with cardiomyocytes. Cardiac macrophage subpopulations are largely defined by their differential expression of MHC class II and CC chemokine receptor 2 (CCR2) and our recent work provides evidence that cardiomyocyte transplantation following myocardial infarction alters the cardiac CCR2 macrophage response, which in turn could potentially explain the arrhythmias observed from other studies following transplantation. In order to better understand how these cardiac macrophage subpopulations alter the electrophysiology of cardiomyocytes and contribute to arrhythmias, we intend to investigate cell-cell interactions between cardiac macrophages and cardiomyocytes from the healthy and ischemic heart and characterize the resulting changes at the molecular and electrophysiological level. Further, to understand the influence of these interactions on cell-cell conduction and drug response conformant with internationally accepted Comprehensive In Vitro Proarrhythmia Assay guidelines, we will utilize embryonic stem cell-derived and alternatively neonatal cardiomyocytes that - unlike adult cardiomyocytes - can be cultivated in vitro as monolayers for facilitating these measurements. We will use state-of-the-art methods like RNA sequencing at the single cell level, whole cell patch clamp, single-molecule localization microscopy and micro-electrode array to analyze these interactions and their effects. We expect our approach to enable a deeper understanding of the mechanism of cardiac arrhythmogenesis as well as the development of better strategies to prevent, diagnose and treat cardiac arrhythmias.

• DFG Programme: Research Grants