Project Details
Projekt
P5: Impact of Interstitial Remodelling on the Rate Dependence of Cardiac Conduction
Subject Area
Cardiology, Angiology
Anatomy and Physiology
Cell Biology
Anatomy and Physiology
Cell Biology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564978926
Cardiac systolic dysfunction, for example in response to pressure-overload, involves progressive electrical and structural remodeling, that are correlated with the risk of severe ventricular arrhythmias and sudden cardiac death. Understanding how the progression of interstitial remodeling is linked to changes in conduction and their frequency-dependence holds the potential to improve risk stratification and to better inform treatment timepoints and options. Using cutting-edge imaging approaches, we aim to (i) systematically characterize diffuse interstitial remodeling, (ii) identify the extent and organization of fibrosis that start to give rise to conduction changes, and (iii) determine the level at which they become arrhythmogenic. To do so, mice will undergo transverse aortic constriction (TAC) to lead to pressure overload-induced remodeling. After 7, 28, or 56 days, hearts will be isolated and subjected to systematic electrophysiological characterization using a panoramic optical mapping setup. Hearts will then be fixed, optically cleared, immuno-stained, and 3D-imaged using an advanced lightsheet imaging approach. Structural and electrophysiological data from the same heart will be directly mapped to each other using machine-learning-based tools, enabling insights into the microstructural basis of macroscopic changes in electrical function. The developed tools will allow the systematic investigation of relationships between electrophysiological function and microscopic structure across many diseases, not just pressure-overload induced remodeling. Once we have characterized how interstitial remodeling affects conduction, we will assess the roles of cardiomyocyte and fibroblast electrophysiology and their coupling to determine the magnitude and frequency-dependence of effects. Genetic mouse models expressing a light-activated non-selective cation channel channelrhodopsin 2 (ChR2) in either cardiomyocytes or fibroblasts will be used in combination with optical stimulation to acutely modulate electrophysiology. Furthermore, a genetic mouse model with knockout of connexin channels (Cx43) in fibroblasts will be used to reduce coupling between cardiomyocytes and fibroblasts. With these models, we will dissect whether cardiomyocytes, fibroblasts, or both underlie the frequency-dependence of conduction in fibrotic myocardium. In this project, using cutting-edge imaging approaches, we will obtain clear mechanistic insight into the determinants of conduction, providing potentially new targets (in cardiomyocytes, non-myocytes, or the extracellular matrix) for preserving electrical function during interstitial remodeling.
DFG Programme
Research Units
