The origin and arrhythmogenic potential of fibroblasts in cardiac disease

Abstract

Fibroblasts play a major role in normal cardiac physiology and in the response of the heart to injury and disease. Cardiac electrophysiological research has primarily focused on the mechanisms of remodeling that accompany cardiac disease with an emphasis on myocyte electrophysiology. Recently, there has been increasing interest in the potential role of fibroblasts in cardiac electrophysiology. This review focuses on the arrhythmia mechanisms involving interactions between myocytes and fibroblasts. We also discuss the available evidence supporting the contribution of intracardiac and extracardiac sources to the fibroblast and myofibroblast populations in diseased hearts.

Fig. 1

Functions of cardiac fibroblasts. Fibroblast function is affected by a number of stimuli including chemical mediators, neurotransmitters, mechanical forces, and injury. Fibroblasts respond to stimuli by releasing chemical mediators and altering the synthesis and degradation of extracellular matrix (ECM) proteins, ATP release, connexin expression, migration, proliferation, and adhesion properties

Fig. 2

Cellular sources that contribute to the cardiac fibroblast population following injury. In response to cardiac injury, resident cardiac fibroblasts proliferate and migrate to the site of injury. Fibroblasts in injured sites are also derived from transformed epicardial, endothelial, and bone marrow sources

Fig. 3

Arrhythmogenic mechanisms of fibroblasts myocyte interactions. a Fibrotic regions act as physical or functional barriers to electrical conduction. Electrical wavefronts that encounter such regions break at the proximal side and reconnect on the distal side. b Fibroblast–myocyte electrical coupling allows for slow electrotonic conduction through fibrotic regions. c Partial electrical isolation of myocytes can lead to successful electrical conduction of impulses originating from ectopic foci. d Chemical mediators released from fibroblasts can exert paracrine effects on myocytes leading to slow conduction