Atrial arrhythmias and Ca2+ waves in HF: simulation and experimental studies

Project: Research project

Project Details

Description

Abstract
Heart failure (HF) and atrial fibrillation (AF) affect more than 5 million patients in the US and cause substantial morbidity and mortality. There is increasing evidence of a close relationship between HF and AF, and several studies have shown that a large fraction of patients with HF go on to develop AF. However, despite years of effort, the mechanism linking HF and AF is not well understood. A well-established feature of HF is the remodeling of subcellular structures which disrupts the finely tuned Ca signaling between ion channels in the cardiac cell. Furthermore, this disruption promotes the formation of subcellular Ca waves which are believed to drive triggered arrhythmias in the heart. The goal of this study is to explore the precise link between subcellular remodeling and arrhythmias using a multi-scale computational model of Ca at the subcellular, whole cell, and tissue scale. This model will be based directly on state-of-the-art laser scanning confocal imaging of the intact dog atrium in experimentally-induced HF. Our approach to this problem is to first develop a detailed model of subcellular Ca signaling, which will shed light on how structural rearrangement disrupts the coupling fidelity between L-type Ca channels (LCC) and RyR channels. By analyzing the population dynamics of thousands of signaling units in an atrial cell we will determine the mechanisms for wave formation, and how they disrupt Ca cycling at the whole cell level. These computational studies will be directly based on our imaging data of subcellular Ca within single cells and groups of cells in the intact atrium. Our aim is to fit detailed wave properties such as the number of nucleation sites and wave propagation velocity, and also to record the nature of Ca dysregulation due to subcellular Ca waves. Finally, based on our findings, we will proceed to develop a phenomenological model of voltage and Ca of HF cells, which can be used to simulate two and three dimensional cardiac tissue. We will then explore how Ca dysregulation in HF can contribute to the formation of AF through formation of both ectopic focal excitations and a heterogeneous electrophysiological substrate capable of inducing and maintaining reentry. Our combined experimental and simulation approach will provide critical new insights into the mechanistic relationship between HF and AF.
StatusFinished
Effective start/end date9/1/145/31/20

Funding

  • National Heart, Lung, and Blood Institute (5R01HL119095-03)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.