Computational Approaches to Understanding the Role of Fibroblast-Myocyte Interactions in Cardiac Arrhythmogenesis
Tashalee R Brown1, Trine Krogh-Madsen2, David J Christini3
1Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medical College, New York, NY 10065, USA ; Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA.
Insights
Cardiac fibroblasts influence heart function and disease by altering electrical and mechanical properties. This study reviews computational models of fibroblast-myocyte interactions and explores the role of gap junctions in heart arrhythmias.
Area of Science:
- Cardiovascular Biology
- Computational Biology
- Cardiac Electrophysiology
Background:
- The adult heart contains cardiomyocytes and nonmyocytes, primarily cardiac fibroblasts.
- Increased fibroblast density (fibrosis) is linked to cardiac diseases like myocardial infarction and dilated cardiomyopathy.
- Fibroblasts contribute to cardiac electrical and mechanical dysfunction through mechanisms like extracellular matrix production and direct electrical coupling.
Purpose of the Study:
- To summarize computational studies on fibroblast-myocyte interactions in normal and diseased hearts.
- To investigate the role of voltage-dependent gap junctions in fibroblast-myocyte interactions.
- To elucidate mechanisms underlying fibroblast-mediated cardiac dysfunction and arrhythmogenesis.
Main Methods:
- Review of existing computational modeling studies on fibroblast-myocyte interactions.
- In vitro experiments to investigate fibroblast-myocyte coupling.
- Analysis of the impact of fibroblast-myocyte interactions on cardiomyocyte action potential, conduction velocity, and excitability.
Main Results:
- Fibroblast-derived collagenous septa can slow conduction and create arrhythmogenic substrates.
- Emerging evidence suggests direct electrical interactions via gap junctions contribute to fibroblast-mediated arrhythmogenesis.
- Computational models and in vitro studies are crucial for understanding these complex interactions.
Conclusions:
- Fibroblast-myocyte interactions significantly impact cardiac function and disease, particularly in arrhythmogenesis.
- Voltage-dependent gap junctions represent a key area for further investigation into fibroblast roles in cardiac electrophysiology.
- Understanding these interactions is vital for developing therapeutic strategies for cardiac diseases.
Abstract:
The adult heart is composed of a dense network of cardiomyocytes surrounded by nonmyocytes, the most abundant of which are cardiac fibroblasts. Several cardiac diseases, such as myocardial infarction or dilated cardiomyopathy, are associated with an increased density of fibroblasts, that is, fibrosis. Fibroblasts play a significant role in the development of electrical and mechanical dysfunction of the heart; however the underlying mechanisms are only partially understood. One widely studied mechanism suggests that fibroblasts produce excess extracellular matrix, resulting in collagenous septa. These collagenous septa slow propagation, cause zig-zag conduction paths, and decouple cardiomyocytes resulting in a substrate for arrhythmia. Another emerging mechanism suggests that fibroblasts promote arrhythmogenesis through direct electrical interactions with cardiomyocytes via gap junctions. Due to the challenges of investigating fibroblast-myocyte coupling in native cardiac tissue, computational modeling and in vitro experiments have facilitated the investigation into the mechanisms underlying fibroblast-mediated changes in cardiomyocyte action potential morphology, conduction velocity, spontaneous excitability, and vulnerability to reentry. In this paper, we summarize the major findings of the existing computational studies investigating the implications of fibroblast-myocyte interactions in the normal and diseased heart. We then present investigations from our group into the potential role of voltage-dependent gap junctions in fibroblast-myocyte interactions.
